JPH09221473A - 3-hydroxy-4-aminomethylpyridine derivative and maillard reaction inhibitor containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a 3-hydroxy-4-aminomethylpyridine derivative which has an activity of inhibiting the Maillard reaction and is useful as preventive or therapeutic agent for diabetic complication and diseases caused by aging, further as cosmetics or food products of high safety. SOLUTION: This 3-hydroxy-4-aminomethylpyridine derivative is represented by formula I (R<1> , R<2> and R<3> are each H, an alkyl; A is an alkylene; B is an alkylene or an alkenylene; R is H, hydroxyl; Y is O, S), typically 4- aminomethyl-5-benzyloxymethyl-3-hydroxy-2-methylpyridine. The compound of formula I is prepared by treating a pyridoxine derivative of formula II (B<1> is an alkylene, an alkenylene; R<4> is H, protected hydroxyl) with an oxidizing agent such as manganese dioxide to form a pyridoxal derivative of formula III, allowing the pyridoxal with hydroxylamine to give an oxime derivative of formula IV, catalytically hydrogenating the oxime derivative using a catalyst of platinum oxide in acetic acid followed by hydrolysis.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 3-hydroxy-4-aminomethylpyridine derivative useful as a medicine and a pharmaceutically acceptable salt thereof.

More specifically, the present invention has a general formula which has a Maillard reaction inhibitory activity and is useful as a preventive and therapeutic agent for diseases associated with the Maillard reaction, and in cosmetics and foods.

[0003]

Embedded image

(In the formula, R ¹ , R ² and R ³ may be the same or different and each is a hydrogen atom or a lower alkyl group, A is a lower alkylene group, B is an alkylene group or an alkenylene group. Or R is an alkynylene group, R is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a halogen atom as a substituent, a hydroxyl group, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a cyano group, an acylamide Group, amino group, carbamoyl group, lower alkyl-substituted carbamoyl group or di-lower alkyl-substituted carbamoyl group, optionally aryl group, aryloxy group optionally having halo lower alkyl group as a substituent, cycloalkyl A group or a heterocyclic group, or B is a substituent together with R A hydroxy group or an aryl group which may have a lower alkoxy group, and Y is an oxygen atom or a sulfur atom) and a 3-hydroxy-4-aminomethylpyridine derivative represented by And a Maillard reaction inhibitor containing them as an active ingredient.

[0005]

2. Description of the Related Art In the field of food chemistry, it has been observed that reducing sugars such as glucose react with amino compounds in foods to form brown pigments. On the other hand, in recent years, it has been confirmed that a similar reaction occurs in the living body, and is considered to be strongly involved as one of the onset factors of diseases such as diabetic complications and arteriosclerosis. I'm taking a bath.

The above-mentioned reaction is called the Maillard reaction. The Maillard reaction in the living body is such that reducing sugars such as glucose, fructose and pentose, their phosphoric acid esters or carbonyl compounds such as ascorbic acid liberate proteins in the living body. A Schiff base is non-enzymatically reacted with an amino group to form a Schiff base, which is converted to an Amadori rearrangement product by chemical rearrangement, and subsequent reactions such as oxidation, dehydration, polymerization, and cleavage cause the protein to intermolecular and A late-stage reaction product (AGE: Advan, which is denatured with formation of intramolecular crosslinks, exhibits a brown color, is poorly soluble, and is difficult to be decomposed by protease
ced Glycation End Product
The reaction proceeds by a series of reactions consisting of the later stages up to s).

[0007] AG produced in the process of the Maillard reaction
The production of E and its precursors increases with the concentration of sugar and protein and the reaction time. Therefore, renal diseases such as diabetes, where hyperglycemic conditions persist, ageing for a long period of exposure to sugar, or in vivo proteins in tissues with a long half-life of proteins, and decrease in clearance. It is known that proteins in blood and tissues of patients such as are susceptible to Maillard reaction.

[0008] From these facts, examples of the in-vivo protein which undergoes the Maillard reaction include ocular lens crystallin, serum albumin, collagen and elastin of connective tissues such as skin and blood vessel wall, nerve myelin protein, hemoglobin, and thread of kidney. There are many proteins such as the basement membrane of the sphere,
The Maillard reaction is the onset of diabetic complications such as retinopathy, nephropathy, cardiovascular system disorders, neuropathy and cataracts caused by degeneration, abnormality or functional decline of these proteins, and diseases caused by arteriosclerosis or aging. It is considered to be one of the causes. Therefore, for the prevention and treatment of these diseases, developmental research has been attempted to find new compounds that inhibit the Maillard reaction.

The 3-hydroxy-4-aminomethylpyridine derivative of the present invention has the formula:

[0010]

Embedded image

Although the compound represented by the formula (1) and its dihydrochloride are known, it has not been reported that these compounds inhibit the Maillard reaction (Biochemis).
try, Volume 2, Issue 6, 1414-1419 (19
63); Klim. Geterotsikl. Soe
din. , Volume 7, Issue 3, Pages 365-367 (197
1 year)).

[0012]

SUMMARY OF THE INVENTION An object of the present invention is to provide a highly safe compound having a chemical structure different from that of the conventional compound having a Maillard reaction inhibitory action.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The present inventors have conducted intensive studies to find compounds having a Maillard reaction inhibitory action,
The present inventors have obtained the finding that the 3-hydroxy-4-aminomethylpyridine derivative of the present invention has excellent Maillard reaction inhibitory activity, and completed the present invention.

That is, the present invention has the general formula

[0015]

Embedded image

(In the formula, R ¹ , R ² and R ^{3, which} may be the same or different, each represents a hydrogen atom or a lower alkyl group, A represents a lower alkylene group, B represents an alkylene group or an alkenylene group. Or R is an alkynylene group, R is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a halogen atom as a substituent, a hydroxyl group, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a cyano group, an acylamide Group, amino group, carbamoyl group, lower alkyl-substituted carbamoyl group or di-lower alkyl-substituted carbamoyl group, optionally aryl group, aryloxy group optionally having halo lower alkyl group as a substituent, cycloalkyl A group or a heterocyclic group, or B is a substituent together with R A hydroxy group or an aryl group which may have a lower alkoxy group, and Y is an oxygen atom or a sulfur atom) and a 3-hydroxy-4-aminomethylpyridine derivative represented by And a Maillard reaction inhibitor containing them as an active ingredient.

Here, in the present invention, the lower alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a te group.
An rt-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group or the like is a linear or branched alkyl group having 1 to 6 carbon atoms, and a lower alkoxy group is a methoxy group, Ethoxy group,
Propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, hexyloxy group, etc. 6 refers to a straight-chain or branched alkoxy group. The alkylene group is a methylene group, ethylene group, propylene group, trimethylene group, tetramethylene group, dimethylethylene group, pentamethylene group, hexamethylene group, heptamethylene group, octamethylene group, decamethylene group, dodecamethylene group, hexadeca group. A linear or branched alkylene group having 1 to 20 carbon atoms such as a methylene group, and an alkenylene group is a linear or branched alkylene group having 2 to 20 carbon atoms such as a vinylene group, a propenylene group, a butenylene group, or a pentenylene group. It refers to a branched alkenylene group, and the alkynylene group refers to an alkynylene group having 2 to 20 carbon atoms such as ethynylene group and propynylene group, and the lower alkylene group refers to the above alkylene group having 1 to 6 carbon atoms. The aryl group refers to an aromatic hydrocarbon group such as a phenyl group and a naphthyl group, and the cycloalkyl group is 3 to 8
A membered ring cyclic alkyl group, and an acylamido group means an aminocarbonyl group substituted with an alkylcarbonyl group having a linear or branched lower alkyl group such as an acetyl group, a propionyl group, and a butyryl group. Further, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and the halo lower alkyl group is one of the above halogen atoms such as a trifluoromethyl group and a 2,2,2-trifluoroethyl group. The above-mentioned substituted lower alkyl group means a heterocyclic group, and 6-hydroxy-
2,5,7,8-tetramethyl-3,4-dihydro-2
An alicyclic group or aromatic ring group containing a hetero atom such as H-benzo [1,2-b] pyranyl group in the ring, which may have a substituent such as a hydroxyl group or a lower alkyl group. .

3-in the formula (I) of the present invention
The hydroxy-4-aminomethylpyridine derivative contains a known compound in part, and is described in the literature (for example, JP-A No. SHO 5/1985).
2-128378 gazette; J. Org. Chem. , 5
6, 2940-2946 (1991);
Am. Chem. Soc. 70, 3434 (1948); Helv. Chem. Acta. , 8
1, 1004 (1948); British Patent No. 773354; Am. Chem. So
c. , 66, 2088 (1944); Kli
m. Geterotsikl. Soedin. , Volume 7,
No. 3, pp. 365-367 (1971), etc.) or a method similar thereto, or a combination of other known methods.

For example, the compound represented by the general formula (I) of the present invention can be represented by the general formula

[0020]

[Chemical 6]

(B ¹ in the formula is an alkylene group, an alkenylene group or an alkynylene group, and R ⁴ is a hydrogen atom, a protected hydroxyl group, a lower alkoxy group, a halogen atom as a substituent, a protected hydroxyl group, a lower alkyl group. Having a halo lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a cyano group, an acylamide group, a protected amino group, a carbamoyl group, a lower alkyl-substituted carbamoyl group or a di-lower alkyl-substituted carbamoyl group. Is an aryl group, an aryloxy group optionally having a halo lower alkyl group as a substituent, a cycloalkyl group or a heterocyclic group, or B ¹ is a hydroxyl group protected together with R ⁴ as a substituent, or an aryl group which may have a lower alkoxy group, a, R ¹ R ^2, R ³ and Y are treated with an oxidizing agent, manganese dioxide pyridoxine derivative represented by have) the same meanings as defined above, the general formula

[0022]

Embedded image

(A, B ¹ , R ¹ , R ² , R ³ , R in the formula
⁴ and Y have the same meanings as described above), and a pyridoxal derivative represented by the general formula

[0024]

Embedded image

(A, B ¹ , R ¹ , R ² , R ³ , R in the formula
⁴ and Y have the same meanings as described above), and catalytic reduction of oxime derivative represented by acetic acid, using platinum oxide catalyst or the like, or reduction treatment using zinc dust in acetic acid is carried out. After removing the protective group of, if desired, it can be produced by hydrolysis according to a conventional method.

The compound represented by the general formula (I) of the present invention has the general formula

[0027]

Embedded image

(A, B ¹ , R ¹ , R ² , R ³ , R in the formula
⁴ and Y have the same meanings as described above), after protecting the phenolic hydroxyl group with a suitable protecting group and further treating it with a reagent such as thionyl chloride or methanesulfonic acid halide, Azide using an azidating agent such as sodium azide to give the general formula

[0029]

Embedded image

(In the formula, R ⁵ is a hydroxyl-protecting group,
A, B ¹ , R ¹ , R ² , R ³ , R ⁴ and Y have the same meanings as described above), and further,
After reduction treatment such as reduction with a reducing agent such as lithium aluminum hydride or catalytic reduction using a palladium-carbon catalyst, etc., if necessary, after removing a protective group such as a hydroxyl group,
If desired, it can be produced by hydrolysis according to a conventional method.

Further, the compound represented by the above general formula (I) of the present invention has the general formula

[0032]

Embedded image

A pyridoxamine derivative represented by the formula (A, R ¹ , R ² and R ³ have the same meanings as described above) is prepared by using carboethoxyphthalimide or phthalic anhydride in the presence of a base. Alternatively, the reaction may be carried out in the absence to protect the amino group, the phenolic hydroxyl group is protected with a suitable protecting group, and further treated with a reagent such as thionyl chloride or methanesulfonic acid halide, then the general formula

HY-B ¹ -R ⁴ (VII)

Reaction with an alcohol or thioalcohol derivative represented by the formula (B ¹ , R ⁴ and Y have the same meanings as described above)

[0036]

Embedded image

(In the formula, R ⁵ is a hydroxyl-protecting group,
A, B ¹ , R ¹ , R ² , R ³ , R ⁴ and Y have the same meanings as described above), and after further removing the amino and hydroxyl protecting groups, if desired, It can be produced by hydrolysis according to a conventional method.

The compound represented by the general formula (II) used as a starting material in the above production method has the general formula

[0039]

Embedded image

The pyridoxine derivative represented by the formula (A, R ¹ , R ² , R ³ and Y have the same meanings as described above) or a salt thereof and 2,2-dimethoxypropane in an inert solvent, By reacting in the presence of an acid such as methanesulfonic acid, the general formula

[0041]

Embedded image

After obtaining the pyridoxine derivative represented by the formula (A, R ¹ , R ² , R ³ and Y have the same meanings as described above),

X-B ¹ -R ⁴ (XI)

(Wherein X represents a halogen atom or a sulfonic acid residue, B ¹ and R ⁴ have the same meanings as described above), and, if desired, amidated by a conventional method. Then, it can be produced by treating with an acid such as hydrochloric acid.

Further, the compound represented by the general formula (II) used as a starting material in the above production method is
General formula

[0046]

Embedded image

The pyridoxine derivative represented by the formula (A, R ¹ , R ² and R ³ have the same meanings as described above) or a salt thereof and 2,2-dimethoxypropane are mixed with methanesulfone in an inert solvent. After reacting in the presence of an acid such as an acid,
General formula obtained by treatment with a reagent such as thionyl chloride or methanesulfonic acid halide

[0048]

Embedded image

The pyridoxine derivative represented by the formula (A, R ¹ , R ² , R ³ and X have the same meanings as described above) can be prepared by using the alcohol or thioalcohol derivative represented by the general formula (VII). It can also be produced by reacting with, if desired, amidation by a conventional method, and then treating with an acid such as hydrochloric acid.

The compound represented by the general formula (VI) used as a starting material in the above-mentioned production method may be purchased as a commercially available product, or a method described in the literature (eg, Tetr).
ahedron Letters, 1747-1751
Page (1967); Org. Chem. , 29
Vol., Pp. 574-579 (1964); Me
d. Chem. , Volume 8, pages 112-115 (196
5 years); Med. Chem. , 10 volumes, 345-3
52 (1967)) or a method similar thereto.

The compounds represented by the above general formulas (IX) and (XII) used as starting materials in the above production method may be purchased as a commercial product or may be obtained by a method described in a literature (eg, J. Am. Chem. Soc. ., 80 volumes, 6
244 (1958); Am. Chem. S
oc. , 106, No. 5, 1490 (1984)
Year)) or a method similar thereto.

The compounds represented by the above general formulas (VII) and (XI) used as starting materials in the above production method may be purchased as a commercial product, or may be produced by a method described in the literature or a method similar thereto. it can.

3-in the formula (I) of the present invention
The hydroxy-4-aminomethylpyridine derivative can be converted into a pharmacologically acceptable salt by a conventional method.
Such salts include one or more acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfone. Acid, p-toluenesulfonic acid, propionic acid,
One or more acid addition salt with an organic acid such as citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, sodium salt , One or more salts with inorganic bases such as potassium salts and calcium salts, organic amines such as morpholine and piperidine, and salts with amino acids.

The compounds represented by the above general formula (I) of the present invention also include hydrates and solvates with pharmaceutically acceptable solvents such as ethanol.

3- represented by the above general formula (I) of the present invention
The hydroxy-4-aminomethylpyridine derivative has one or more asymmetric carbon atoms depending on the kind of the substituent, and there are two optical isomers of R configuration and S configuration at each asymmetric carbon. In the above, any optical isomer may be used, and a mixture of those optical isomers may be used.

When an unsaturated bond is present in the substituent B or R among the compounds represented by the general formula (I) of the present invention, the compound having an unsaturated bond has two geometric isomers. Although present, in the present invention, cis (Z)
Either the body compound or the trans (E) compound may be used.

In the compound represented by the above general formula (I) of the present invention, the substituent R ³ is preferably a hydrogen atom.

The compound represented by the above general formula (I) of the present invention is an in vitro compound containing lysozyme and fructose.
In the Maillard reaction inhibitory activity test of ro, it showed an extremely excellent inhibitory activity against dimerization of lysozyme, as compared with aminoguanidine known as a substance having a Maillard reaction inhibitory activity.

As described above, the compound represented by the above general formula (I) and the pharmaceutically acceptable salt thereof of the present invention have excellent Maillard reaction inhibitory activity, and diseases associated with the Maillard reaction. It is a very useful compound as a prophylactic and therapeutic agent for.

The compound represented by the above general formula (I) of the present invention and the pharmacologically acceptable salt thereof have a Maillard reaction inhibitory activity and are effective against diseases associated with the Maillard reaction. It is valid. Such diseases include:
Coronary artery disease, peripheral circulation disorder, cerebrovascular disorder, diabetic neuropathy, nephropathy, arteriosclerosis, arteriosclerosis, cataract, retinopathy, coagulopathy, diabetic complications such as diabetic osteopenia, atheroma Diseases considered to be caused by aging such as arteriosclerosis, glomerulonephritis, senile cataract, osteoarthritis, periarticular stiffness, arteriosclerosis and senile osteoporosis can be mentioned. It is very useful as a preventive and therapeutic agent for. Also, as is well known, the Maillard reaction proceeds in cosmetics and foods containing proteins and amino acids, and protein and amino acids are degraded. Therefore, they are also useful as cosmetics and foods as compounds that inhibit the Maillard reaction.

The compound represented by the above general formula (I) of the present invention can be used, for example, in an acute toxicity test using mice.
4-aminomethyl-3-hydroxy-2-methyl-5-
Neopentyloxymethylpyridine is 1000 mg / k
No deaths were observed after a single dose of g. Thus, the compound of the present invention is a highly safe compound and a very useful compound as a Maillard reaction inhibitor.

3-in the formula (I) of the present invention
When the hydroxy-4-aminomethylpyridine derivative and a pharmacologically acceptable salt thereof are used for actual treatment, a suitable pharmaceutical composition such as tablets, powders, fine granules, granules, capsules, liquids , Orally, as an injection, external preparation, eye drop, suppository and the like. These pharmaceutical compositions can be prepared by a pharmaceutical method performed in a general preparation, by using carriers, excipients, and other additives for pharmaceuticals that are generally used.

Among the above-mentioned pharmaceutical compositions, in tablets, powders, fine granules, granules, capsules, etc., the excipients, disintegrants, binders, lubricants, etc. that are commonly used are used. As the excipient, for example, sugar or sugar alcohol D-mannitol, lactose, sucrose, starch or starch derivative wheat starch, rice starch, corn starch, potato starch, pregelatinized starch, partial α Starch, dextrin, cyclodextrin, pullulan, hydroxypropyl starch, etc., cellulose or cellulose derivative crystalline cellulose, crystalline cellulose / carmellose sodium, methyl cellulose, hydroxypropyl methylcellulose, etc. and other sodium alginate, acacia, agar, macrogol, Aluminum stearate, Aluminum stearic acid, inorganic excipients such as calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, magnesium aluminometasilicate, synthetic aluminum silicate, synthetic hydrotalcite aluminum hydroxide, magnesium hydroxide, calcium phosphate, dried Amminium hydroxide gel, precipitated calcium carbonate, light anhydrous silicic acid and the like can be used, but these are not limited as excipients and can be used as disintegrants or binders.

As the disintegrant, carmellose calcium, carmellose, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, croscarmellose sodium, tragacanth, starch or starch derivatives such as wheat starch, rice starch, corn starch, potato starch , Α-starch, partially α-starch, dextrin, pullulan, hydroxypropyl starch and the like can be used, but these are not limited as disintegrants and can be used as excipients.

Examples of the binder include hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, povidone, starch or starch derivatives such as wheat starch, rice starch, corn starch, potato starch, pregelatinized starch, pregelatinized starch, dextrin and pullulan. , Hydroxypropyl starch and the like can be used.

Examples of lubricants include calcium stearate, magnesium stearate, stearic acid, talc, cetanol, polyoxyl 40 stearate, leucine, lubricy wax, sodium lauryl sulfate, paraffin, polyoxyethylene glycol fatty acid ester and fatty acid ester. Although they can be used, they are not limited to lubricants and can be used as excipients.

The tablets may be coated with a film of lactose, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer or hydroxypropylmethylcellulose phthalate.

Examples of the diluent for the liquid agent include:
Purified water, polyol, sucrose, invert sugar, glucose or the like can be used. In addition to the diluent, a solubilizing agent, a wetting agent, a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent, an antiseptic agent and the like may be added to the liquid agent, if desired.

As the diluent for the injection, for example, distilled water, physiological saline, alcohol, glycerol, polyol, vegetable oil and the like can be used. In addition to the diluent, a buffer, an isotonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, a solubilizing agent and the like may be added to the injection, if desired.

As the ophthalmic solution, in addition to a diluent, if desired, a buffering agent, a tonicity agent, a stabilizer, a preservative, an antioxidant, a thickener, a preservative, a solubilizing agent, etc. may be added. May be.

As the carrier for suppositories, lipids, waxes, semi-solid or liquid polyols, natural oils or hydrogenated oils can be used. Further, in the suppository, in addition to the carrier, a dispersant, a dispersion aid, an absorption promoter and the like may be added.

The dose is appropriately determined depending on the sex, age, weight, degree of symptom and the like of the subject patient, but in the case of oral administration, it is generally 1 to 1000 per adult per day.
mg, parenteral administration: about 0.1
It is administered within the range of 100 mg in a single dose or in divided doses.

When the compound represented by the general formula (I) of the present invention is used as an eye drop, it is 0.05 W / V% to 5%.
It is mixed in the range of W / V% and prepared by a conventional method, and the frequency of administration is appropriately determined depending on the degree of symptom of the patient.

When the compound of the present invention represented by the general formula (I) is used as an external preparation or cosmetic, the content of the compound of the present invention is about 0.05 based on the whole preparation.
It can be produced by blending it in an amount of 10 to 10 parts by weight and preparing it by a conventional method using a general external base or cosmetic base. Further, the compound of the present invention can be prepared for foods by a conventional method, or can be added to foods for use.

The contents of the present invention will be described in more detail with reference to Reference Examples, Examples and Prescription Examples below, but the present invention is not limited to these contents.

[0076]

【Example】

Reference Example 1 5-hydroxymethyl-2,2,8-trimethyl-4H
-1,3-Dioxino [4,5-c] pyridine Pyridoxine hydrochloride 38.0 g of acetone 425 ml solution was added with 2,2-dimethoxypropane 305 ml and p-toluenesulfonic acid 121.6 g and reacted at room temperature for 17 hours. It was The reaction mixture was made weakly basic with sodium hydrogen carbonate and concentrated under reduced pressure to about 1/2 volume. Water was added to the residue, extracted with chloroform, washed with 2N sodium hydroxide and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the obtained oily residue for crystallization, and 5-hydroxymethyl-2,2,8-trimethyl-4H-1,3-dioxino [4,5-c] 30.3 g of pyridine was obtained.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.56 (6H, s), 1.75 (1H, t, J =
5.4 Hz), 2.41 (3H, s), 4.59 (2
H, d, J = 5.4 Hz), 4.94 (2H, s),
7.94 (1H, s)

Reference Example 2 5-benzyloxymethyl-3-hydroxy-4-hydroxymethyl-2-methylpyridine 5-hydroxymethyl-2.2.8-trimethyl-4H
-1,3-Dioxino [4,5-c] pyridine 36.5
7.67 g of sodium hydride (60% oily) was added to a 400 ml solution of tetrahydrofuran in 60 g, and the mixture was stirred at room temperature for 10 minutes, then, a solution of 21.8 ml of benzyl bromide in 50 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 16 hours at 60 ° C. And reacted for 2 hours. The solvent was distilled off under reduced pressure to about 1/3 volume, 200 ml of 2N hydrochloric acid was added, and the mixture was stirred at 80 ° C for 2 hours.
Allowed to react for hours. The reaction solution is 1N sodium hydroxide 20
The mixture was made basic with 0 ml and sodium hydrogen carbonate, and the precipitate was collected by filtration. The precipitate was dissolved in chloroform, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 5-benzyloxymethyl-3-hydroxy-4-hydroxymethyl-2-methylpyridine (38.0 g).

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.48 (3H, s), 4.45 (2H, s),
4.47 (2H, s), 5.04 (2H, s), 7.2
0-7.40 (5H, m), 7.89 (1H, s)

Reference Example 3 5-Benzyloxymethyl-3-hydroxy-2-methyl-4-pyridinecarbaldehyde 5-Benzyloxymethyl-3-hydroxy-4-hydroxymethyl-2-methylpyridine 10.3 g of methylene chloride After adding 34.8 g of manganese dioxide to the 110 ml solution and heating under reflux for 30 minutes, 7.0 g of manganese dioxide was further added and reacted at 50 ° C. for 30 minutes. The reaction liquid was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 8.77 g of 5-benzyloxymethyl-3-hydroxy-2-methyl-4-pyridinecarbaldehyde.

Yellow oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.54 (3H, s), 4.58 (2H, s),
4.75 (2H, s), 7.25-7.40 (5H,
m), 8.04 (1H, s), 10.41 (1H,
s), 11.46 (1H, s)

Reference Example 4 5-Benzyloxymethyl-3-hydroxy-2-methyl-4-pyridinecarbaldehyde Oxime 5-Benzyloxymethyl-3-hydroxy-2-methyl-4-pyridinecarbaldehyde 8.8 g of methanol Sodium acetate 8.4 in a 270 ml solution of water (2: 1)
0 g and 5.70 g of hydroxylamine hydrochloride were added and reacted. After stirring for 1 hour, the precipitate was collected by filtration, washed with a methanol-water (2: 1) solution and diethyl ether, and washed with 5
8.60 g of -benzyloxymethyl-3-hydroxy-2-methyl-4-pyridinecarbaldehyde oxime was obtained.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.40 (3H, s), 4.52 (2H, s),
4.64 (2H, s), 7.25-7.40 (5H,
m), 7.98 (1H, s), 8.53 (1H, s),
10.69 (1H, s), 12.20 (1H, s)

Example 1 4-Aminomethyl-5-benzyloxymethyl-3-hydroxy-2-methylpyridine 5-benzyloxymethyl-3-hydroxy-2-methyl-4-pyridinecarbaldehyde oxime 31.0 g
Of acetic acid in 400 ml of zinc powder under stirring with ice cooling.
0.0 g was added and reacted for 2 hours. The reaction mixture was filtered through Celite, 300 ml of water was added, the mixture was neutralized with sodium hydrogen carbonate, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 23.0 g of 4-aminomethyl-5-benzyloxymethyl-3-hydroxy-2-methylpyridine.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.46 (3H, s), 4.23 (2H, s),
4.45 (2H, s), 4.46 (2H, s), 7.2
0-7.40 (5H, m), 7.85 (1H, s)

Example 2 4-aminomethyl-5-benzyloxymethyl-3-hydroxy-2-methylpyridine dihydrochloride 4-aminomethyl-5-benzyloxymethyl-3-hydroxy-2-methylpyridine 23. A hydrogen chloride-methanol solution was added to a solution of 0 g of methanol in 200 ml, and the precipitate was collected by filtration to obtain 23.9 g of 4-aminomethyl-5-benzyloxymethyl-3-hydroxy-2-methylpyridine dihydrochloride. .

White crystal ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.68 (3H, s), 4.19 (2H, br)
s), 4.62 (2H, s), 4.84 (2H, s),
7.30-7.40 (5H, m), 8.26 (1H,
s), 8.50 (3H, br)

Example 3 4-Aminomethyl-3-hydroxy-2-methyl-5-
(4-Methylbenzyloxymethyl) pyridine Using 4-methylbenzyl bromide, Reference Example 2 to Reference Example 4
And 4-aminomethyl-3- according to the method of Example 1.
Hydroxy-2-methyl-5- (4-methylbenzyloxymethyl) pyridine was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.26 (3H, s), 2.29 (3H, s),
4.02 (2H, s), 4.40 (2H, s), 4.4
1 (2H, s), 7.15 (2H, d, J = 8.0H
z), 7.20 (2H, d, J = 8.0 Hz), 7.7
2 (1H, s)

Example 4 4-Aminomethyl-5- (4-chlorobenzyloxymethyl) -3-hydroxy-2-methylpyridine Using 4-chlorobenzyl chloride, Reference Examples 2 to 4 were used.
And 4-aminomethyl-5- according to the method of Example 1.
(4-Chlorobenzyloxymethyl) -3-hydroxy-2-methylpyridine was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.27 (3H, s), 4.03 (2H, s),
4.43 (2H, s), 4.46 (2H, s), 7.3
4 (2H, d, J = 8.5Hz), 7.40 (2H,
d, J = 8.5 Hz), 7.74 (1H, s)

Example 5 4-Aminomethyl-3-hydroxy-5- (4-methoxybenzyloxymethyl) -2-methylpyridine Using 4-methoxybenzyl chloride, Reference Examples 2 to 4
And 4-aminomethyl-3- according to the method of Example 1.
Hydroxy-5- (4-methoxybenzyloxymethyl) -2-methylpyridine was synthesized.

Light yellow solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.27 (3H, s), 3.74 (3H, s),
4.01 (2H, s), 4.39 (4H, s), 6.9
0 (2H, d, J = 8.7 Hz), 7.24 (2H,
d, J = 8.7 Hz), 7.73 (1H, s)

Example 6 4-Aminomethyl-3-hydroxy-5- (4-methoxybenzyloxymethyl) -2-methylpyridine dihydrochloride According to the method of Example 2, 4-aminomethyl-3- Hydroxy-5- (4-methoxybenzyloxymethyl)-
2-Methylpyridine to 4-aminomethyl-3-hydroxy-5- (4-methoxybenzyloxymethyl) -2
-Methylpyridine dihydrochloride was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.64 (3H, br s), 3.75 (3H,
s), 4.15 (2H, brs), 4.53 (2H,
s), 4.76 (2H, br s), 6.92 (2H,
d, J = 8.6 Hz), 7.31 (2H, d, J = 8.
6 Hz), 8.22 (1 H, s), 8.30-8.50
(3H, br s)

Reference Example 5 Methyl 4-bromomethylbenzoate 1.06 g of 1,3-dicyclohexylcarbodiimide and a catalytic amount of 4-dimethyl were added to a solution of 1.0 g of 4-bromomethylbenzoic acid in 30 ml of acetonitrile-methanol (1: 1) at room temperature. Aminopyridine was added, and the mixture was stirred as it was for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, ethyl acetate was added, the precipitate generated under ice cooling was filtered off, and the filtrate was concentrated under reduced pressure. This was purified by silica gel column chromatography and methyl 4-bromomethylbenzoate 45
5 mg were obtained.

White solid ¹ H-NMR (CDCl ₃ , 270 MHz) δ pp
m: 3.92 (3H, s), 4.50 (2H, s),
7.46 (2H, d, J = 8.3Hz), 8.02 (2
H, d, J = 8.3 Hz)

Example 7 4-Aminomethyl-3-hydroxy-5- (4-methoxycarbonylbenzyloxymethyl) -2-methylpyridine Methyl 4-bromomethylbenzoate was used to prepare Reference Examples 2 to 4 and Examples. 4-Aminomethyl-3-hydroxy-5- (4-methoxycarbonylbenzyloxymethyl) -2-methylpyridine was synthesized according to the method of 1.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.70 (3H, br s), 3.91 (3H,
s), 4.36 (2H, s), 4.75-4.85 (4
H, m), 7.52 (2H, d, J = 8 Hz), 8.0
4 (2H, d, J = 8Hz), 8.20-8.35 (1
H, br)

Example 8 4-Aminomethyl-3-hydroxy-5- (4-methoxycarbonylbenzyloxymethyl) -2-methylpyridine dihydrochloride According to the method of Example 2, 4-aminomethyl-3- Hydroxy-5- (4-methoxycarbonylbenzyloxymethyl) -2-methylpyridine to 4-aminomethyl-3
-Hydroxy-5- (4-methoxycarbonylbenzyloxymethyl) -2-methylpyridine dihydrochloride was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.50-2.60 (3H, br), 3.85
(3H, s), 4.05-4.15 (2H, br),
4.67 (2H, s), 4.65-4.75 (2H, b
r), 7.51 (2H, d, J = 8.4 Hz), 7.9
6 (2H, d, J = 8.4 Hz), 8.05-8.20
(4H, m)

Example 9 4-Aminomethyl-5- (4-carboxybenzyloxymethyl) -3-hydroxy-2-methylpyridine hydrochloride 4-aminomethyl-3-hydroxy-5- (4-methoxycarbonylbenzyl) (Oxymethyl) -2-methylpyridine (92 mg) was dissolved in 2N hydrochloric acid (3 ml), and the solution was added at 100 ° C for 2
The mixture was heated and stirred for an hour. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was dried in the presence of nitric oxide. Methanol-diethyl ether was added to the obtained amorphous substance, and the precipitate was collected by filtration,
Wash with diethyl ether, dry under reduced pressure, and 4-aminomethyl-5- (4-carboxybenzyloxymethyl).
-3-Hydroxy-2-methylpyridine / hydrochloride 85m
g was obtained.

White solid ¹ H-NMR (DMSO-d ₆ , 270 MHz) δ p
pm: 2.56 (3H, br s), 4.1-4.2
(2H, m), 4.67 (2H, s), 4.72-4.
78 (2H, br), 7.48 (2H, d, J = 8.3)
Hz), 7.94 (2H, d, J = 8.3 Hz), 8.
1-8.3 (4H, m)

Reference Example 6 5- (4-methoxycarbonylbenzyloxymethyl)
-2,2,8-Trimethyl-4H-1,3-dioxino [4,5-c] pyridine 5-hydroxymethyl-2,2,8-trimethyl-4H
-1,3-Dioxyno [4,5-c] pyridine 198m
45 mg of sodium hydride (60% oily) was added to a solution of 2 g of dimethylsulfoxide at room temperature, and the mixture was stirred for 10 minutes. Then, a solution of 260 mg of methyl 4-bromomethylbenzoate in 1 ml of dimethylsulfoxide was added dropwise, and the mixture was stirred at room temperature.
Stirred for hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 5- (4-methoxycarbonylbenzyloxymethyl) -2,2,8-trimethyl-4H-1,3-dioxino [4,5-c] pyridine 1.
47 mg was obtained.

Light yellow oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.55 (6H, s), 2.41 (3H, s),
3.92 (3H, s), 4.46 (2H, s), 4.5
5 (2H, s), 4.88 (2H, s), 7.38 (2
H, d, J = 8.4 Hz), 7.95 (1H, s),
8.02 (2H, d, J = 8.4Hz)

Reference Example 7 5- (4-carbamoylbenzyloxymethyl) -2,
2,8-trimethyl-4H-1,3-dioxino [4,
5-c] pyridine 5- (4-methoxycarbonylbenzyloxymethyl)
-2,2,8-Trimethyl-4H-1,3-dioxino [4,5-c] pyridine 200 mg to a solution of 1,4-dioxane in 4 ml, ammonium chloride 16 mg and 28% aqueous ammonia 6 ml were added, and the temperature was 130 ° C in a sealed tube. Stirred overnight.
After completion of the reaction, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 130 mg of 5- (4-carbamoylbenzyloxymethyl) -2,2,8-trimethyl-4H-1,3-dioxino [4,5-c] pyridine. .

Yellow solid ¹ H-NMR (CDCl ₃ , 270 MHz) δ pp
m: 1.50 (6H, s), 2.42 (3H, s),
4.45 (2H, s), 4.57 (2H, s), 4.9
0 (2H, s), 7.42 (2H, d, J = 8.4H
z), 7.80 (2H, d, J = 8.4 Hz), 7.9
6 (1H, s)

Example 10 4-Aminomethyl-5- (4-carbamoylbenzyloxymethyl) -3-hydroxy-2-methylpyridine 5- (4-carbamoylbenzyloxymethyl) -2,
2,8-trimethyl-4H-1,3-dioxino [4,
5-c] pyridine was deacetalized by stirring at 60 ° C. in formic acid-water overnight, and 4-aminomethyl-5- (4-carbamoylbenzyl) was prepared according to the methods of Reference Examples 2 to 4 and Example 1. Oxymethyl) -3-hydroxy-2-methylpyridine was synthesized.

Yellow solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.24 (3H, s), 4.04 (2H, s),
4.45 (2H, s), 4.51 (2H, s), 7.3
1 (1H, br), 7.38 (2H, d, J = 8.1H
z), 7.75 (1H, br), 7.86 (2H, d,
J = 8.1 Hz), 7.92 (1H, br), 8.25
(1H, s)

Example 11 4-Aminomethyl-3-hydroxy-5- (3-methoxybenzyloxymethyl) -2-methylpyridine Using 3-methoxybenzyl chloride, Reference Examples 2 to 4
And 4-aminomethyl-3- according to the method of Example 1.
Hydroxy-5- (3-methoxybenzyloxymethyl) -2-methylpyridine was synthesized.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.46 (3H, s), 3.80 (3H, s),
4.25 (2H, s), 4.44 (2H, s), 4.4
5 (2H, s), 6.80-6.95 (3H, m),
7.26 (1H, t, J = 7.7Hz), 7.86 (1
H, s)

Example 12 4-Aminomethyl-3-hydroxy-5- (3-methoxybenzyloxymethyl) -2-methylpyridine dihydrochloride According to the method of Example 2, 4-aminomethyl-3- Hydroxy-5- (3-methoxybenzyloxymethyl)-
2-Methylpyridine to 4-aminomethyl-3-hydroxy-5- (3-methoxybenzyloxymethyl) -2
-Methylpyridine dihydrochloride was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.65 (3H, s), 3.76 (3H, s),
4.18 (2H, br s), 4.58 (2H, s),
4.81 (2H, s), 6.80-7.00 (3H,
m), 7.28 (1H, t, J = 8.0 Hz), 8.2
4 (1H, s), 8.43 (3H, br s)

Reference Example 8 3-Methoxymethoxybenzyl alcohol In an argon atmosphere, 1.93 g of sodium hydride (60% oily) was added to a solution of 3-hydroxybenzyl alcohol (5 g) in N, N-dimethylformamide (50 ml) and stirred at room temperature for 30 minutes. After cooling, the mixture was cooled to -40 ° C, and a solution of 3.89 g of chloromethyl methyl ether in 8 ml of N, N-dimethylformamide was added dropwise. After reacting at -40 ° C for 20 minutes, water was added, the mixture was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, 3-
5.91 g of methoxymethoxybenzyl alcohol was obtained.

Light yellow oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.64 (1H, t, J = 6.0Hz), 3.48
(3H, s), 4.67 (2H, d, J = 6.0H
z), 5.18 (2H, s), 6.90-7.10 (3
H, m), 7.28 (1H, t, J = 7.8Hz)

Reference Example 9 5- (3-Methoxymethoxybenzyloxymethyl)-
2,2,8-Trimethyl-4H-1,3-dioxino [4,5-c] pyridine 3-methoxymethoxybenzyl alcohol 2.50 g of methylene chloride in 15 ml of solution was stirred under ice-cooling while stirring with triethylamine 1.50 g and then methanesulfone. Acid chloride 1.7
0 g was added dropwise and reacted for 30 minutes. Methanesulfonic acid 3
-Methoxymethoxybenzyl

Under an argon atmosphere, a solution of 2.39 g of 5-hydroxymethyl-2,2,8-trimethyl-4H-1,3-dioxino [4,5-c] pyridine in 18 ml of dimethyl sulfoxide was added with sodium hydride (60%). Oily) 5
49 mg was added, and the mixture was stirred at room temperature for 30 minutes. Reaction solution
The mixture was cooled to ° C, and the previously synthesized 3-methoxymethoxybenzyl methanesulfonate was added dropwise without isolation. 0
After reacting at 50 ° C. for 10 minutes and then at 50 ° C. for 30 minutes, water was added, the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 5- (3-methoxymethoxybenzyloxymethyl) -2,2,8-trimethyl-4H-1,3-dioxino [4. 1.82 g of 5-c] pyridine was obtained.

Light yellow oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.55 (6H, s), 2.41 (3H, s),
3.48 (3H, s), 4.44 (2H, s), 4.4
7 (2H, s), 4.88 (2H, s), 5.18 (2
H, s), 6.90-7.05 (3H, m), 7.27.
(1H, t, J = 7.7Hz), 7.95 (1H, s)

Reference Example 10 3-hydroxy-5- (3-hydroxybenzyloxymethyl) -4-hydroxymethyl-2-methylpyridine 5- (3-methoxymethoxybenzyloxymethyl)-
To a solution of 1.82 g of 2,2,8-trimethyl-4H-1,3-dioxino [4,5-c] pyridine in 18 ml of tetrahydrofuran was added 18 ml of 2N hydrochloric acid, and the mixture was stirred at 80 ° C. for 1 hour.
Stirred for hours. The reaction solution was neutralized with sodium hydrogen carbonate, extracted with tetrahydrofuran, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-diethyl ether to give 3-hydroxy-5- (3-hydroxybenzyloxymethyl). ) -4-Hydroxymethyl-2-methylpyridine 837.7 mg was obtained.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.34 (3H, s), 3.30 (1H, s),
4.41 (2H, s), 4.51 (2H, s), 4.7
4 (2H, s), 6.60-6.80 (3H, m),
7.13 (1H, t, J = 7.8Hz), 7.89 (1
H, s), 8.60-9.70 (1H, br)

Reference Example 11 4-hydroxymethyl-3-methoxymethoxy-5-
(3-Methoxymethoxybenzyloxymethyl) -2-
Methylpyridine Under an argon atmosphere, 3-hydroxy-5- (3-hydroxybenzyloxymethyl) -4-hydroxymethyl-
To a solution of 830 mg of 2-methylpyridine in 30 ml of N, N-dimethylformamide was added 266 mg of sodium hydride (60% oily), and the mixture was stirred at room temperature for 30 minutes, and then -30
The mixture was cooled to ° C, and a solution of 535 mg of chloromethyl methyl ether in 1 ml of N, N-dimethylformamide was added dropwise.
After reacting at -30 ° C for 30 minutes, water was added and the mixture was extracted with ethyl acetate, washed successively with 1N aqueous sodium hydroxide solution and water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 512 mg of 4-hydroxymethyl-3-methoxymethoxy-5- (3-methoxymethoxybenzyloxymethyl) -2-methylpyridine.

Light yellow oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.55 (3H, s), 3.37 (1H, t, J =
7.1 Hz), 3.48 (3H, s), 3.64 (3
H, s), 4.58 (2H, s), 4.64 (2H,
s), 4.68 (2H, d, J = 7.1Hz), 5.0
9 (2H, s), 5.18 (2H, s), 6.95-
7.10 (3H, m), 7.28 (1H, t, J = 7.
8Hz), 8.24 (1H, s)

Reference Example 12 4-azidomethyl-3-methoxymethoxy-5- (3-
Methoxymethoxybenzyloxymethyl) -2-methylpyridine 4-hydroxymethyl-3-methoxymethoxy-5-
(3-Methoxymethoxybenzyloxymethyl) -2-
To a solution of 50 mg of methylpyridine in 1 ml of N, N-dimethylformamide, 36 mg of triethylamine with stirring under ice cooling,
Next, 38 mg of methanesulfonic acid chloride was added dropwise, and the mixture was stirred for 5 minutes. Sodium azide (22 mg) was added to the reaction solution, the mixture was reacted at room temperature for 30 minutes, water was added, the mixture was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4-azidomethyl-3-methoxymethoxy-5- (3-methoxymethoxybenzyloxymethyl) -2-methylpyridine 64.2 mg.

Colorless oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.56 (3H, s), 3.48 (3H, s),
3.63 (3H, s), 4.55 (4H, s), 4.5
9 (2H, s), 5.03 (2H, s), 5.18 (2
H, s), 6.90-7.10 (3H, m), 7.28.
(1H, t, J = 7.8Hz), 8.29 (1H, s)

Reference Example 13 4-aminomethyl-3-methoxymethoxy-5- (3-
Methoxymethoxybenzyloxymethyl) -2-methylpyridine Under argon atmosphere, lithium aluminum hydride 21m
4-azidomethyl-3-methoxymethoxy-5- (3-methoxymethoxybenzyloxymethyl) -2-methylpyridine 6 in a suspension of 2 g of diethyl ether at room temperature.
A solution of 4.2 mg of diethyl ether in 1 ml was added dropwise 30
Stirred for minutes. Aqueous diethyl ether and 2N aqueous sodium hydroxide solution were added, and the mixture was extracted with diethyl ether and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin layer chromatography to give 4-aminomethyl-3-methoxymethoxy-5-
(3-Methoxymethoxybenzyloxymethyl) -2-
14.6 mg of methylpyridine was obtained.

Colorless amorphous ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.52 (3H, s), 3.48 (3H, s),
3.64 (3H, s), 3.87 (2H, br s),
4.57 (2H, s), 4.58 (2H, s), 5.0
4 (2H, s), 5.18 (2H, s), 6.90-
7.10 (3H, m), 7.27 (1H, t, J = 7.
8Hz), 8.21 (1H, s)

Example 13 4-Aminomethyl-3-hydroxy-5- (3-hydroxybenzyloxymethyl) -2-methylpyridine dihydrochloride 4-Aminomethyl-3-methoxymethoxy-5- (3-
Hydrogen chloride was added to a solution of 34 mg of methoxymethoxybenzyloxymethyl) -2-methylpyridine in 2 ml of methanol.
The ethanol solution was added until it became acidic, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol-diethyl ether to give 4-aminomethyl-3-hydroxy-5-
Thus, 14.2-mg of (3-hydroxybenzyloxymethyl) -2-methylpyridine dihydrochloride was obtained.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.59 (3H, s), 4.14 (2H, br
s), 4.51 (2H, s), 4.72 (2H, s),
6.60-6.80 (3H, m), 7.15 (1H,
t, J = 7.9 Hz), 8.18 (1H, s), 8.2
7 (3H, br s), 9.30-9.65 (1H, b
r)

Example 14 4-Aminomethyl-3-hydroxy-2-methyl-5-
Neopentyloxymethylpyridine Neopentyl bromide was used to synthesize 4-aminomethyl-3-hydroxy-2-methyl-5-neopentyloxymethylpyridine according to the methods of Reference Example 2 to Reference Example 4 and Example 1. did.

Light yellow solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.87 (9H, s), 2.45 (3H, s),
3.02 (2H, s), 4.23 (2H, s), 4.3
8 (2H, s), 7.84 (1H, s)

Reference Example 14 2-Iodoethylcyclopentane Cyclopentaneethanol 4.7 g 30 ml benzene
Thionyl chloride (4.9 ml) and a catalytic amount of pyridine were added to the solution under ice cooling, and the mixture was heated with stirring at 50 ° C. for 1 hour. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed successively with 2N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. . This residue was dissolved in 2-butanone, 8.5 g of sodium iodide was added, and the mixture was heated under reflux overnight. The precipitate was filtered off at room temperature, the filtrate was concentrated under reduced pressure, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4.2 g of 2-iodoethylcyclopentane. .

Yellow oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.8-2.1 (11H, m), 3.19 (2H,
t, J = 7.2 Hz)

Example 15 4-aminomethyl-5- (2-cyclopentylethyloxymethyl) -3-hydroxy-2-methylpyridine Using 2-iodoethylcyclopentane, Reference Examples 2 to 4 and Example 1 were used. 4-aminomethyl-5- (2-cyclopentylethyloxymethyl)-
3-Hydroxy-2-methylpyridine was synthesized.

Light yellow solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.00-1.18 (2H, m), 1.40-1.
67 (6H, m), 1.68-1.90 (3H, m),
2.45 (3H, s), 3.41 (2H, t, J = 6.
8Hz), 4.24 (2H, s), 4.38 (2H,
s), 7.85 (1H, s)

Example 16 4-Aminomethyl-5-cyclohexylmethoxymethyl-3-hydroxy-2-methylpyridine Bromomethylcyclohexane was used, and 4-aminomethyl-5-cyclohexylmethoxymethyl-3-hydroxy-2-methylpyridine was used according to the methods of Reference Examples 2 to 4 and Example 1. Aminomethyl-
5-cyclohexylmethoxymethyl-3-hydroxy-
2-Methylpyridine was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 0.85-0.93 (2H, m), 1.05-
1.23 (3H, m), 1.46-1.58 (1H,
m), 1.59-1.67 (5H, m), 2.25 (3
H, s), 3.16 (2H, d, J = 6.3 Hz),
4.00 (2H, s), 4.31 (2H, s), 7.6
9 (1H, s)

Reference Example 15 Methanesulfonic acid 3,3-dimethylbutyl tert-butylacetic acid 1.0 g of tetrahydrofuran 2
8.6 ml of borane-tetrahydrofuran complex salt (1M tetrahydrofuran solution) was added dropwise to the 0 ml solution under ice cooling, and the mixture was stirred overnight while returning to room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, chloroform was added, the mixture was washed with 10% aqueous citric acid solution and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. 20 methylene chloride residue
Then, 1.2 ml of triethylamine and 0.67 ml of methanesulfonic acid chloride were added dropwise under ice cooling, and the mixture was stirred for 30 minutes. The reaction solution was washed with 10% aqueous citric acid solution, saturated saline solution, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 3,3-dimethylbutyl methanesulfonate. 1.
4 g were obtained.

Colorless oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.96 (9H, s), 1.70 (2H, t, J =
7.5 Hz), 3.01 (3 H, s), 4.29 (2
H, t, J = 7.5 Hz)

Example 17 4-aminomethyl-5- (3,3-dimethylbutoxymethyl) -3-hydroxy-2-methylpyridine 3,3-dimethylbutyl methanesulfonate was used and Reference Examples 2 to 4 were used. And in accordance with the method of Example 1, 4-
Aminomethyl-5- (3,3-dimethylbutoxymethyl) -3-hydroxy-2-methylpyridine was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 0.88 (9H, s), 1.44 (2H, t, J
= 7.3 Hz), 2.25 (3H, s), 3.43 (2
H, t, J = 7.3 Hz), 4.00 (2H, s),
4.33 (2H, s), 7.71 (1H, s)

Example 18 4-Aminomethyl-3-hydroxy-2-methyl-5-
Propoxymethylpyridine 1-Iodopropane was used to synthesize 4-aminomethyl-3-hydroxy-2-methyl-5-propoxymethylpyridine according to the methods of Reference Examples 2 to 4 and Example 1.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.90 (3H, t, J = 7.4Hz), 1.50
-1.65 (2H, m), 2.45 (3H, s), 3.
36 (2H, t, J = 6.6Hz), 4.25 (2H,
s), 4.40 (2H, s), 7.86 (1H, s)

Example 19 4-Aminomethyl-3-hydroxy-2-methyl-5-
Propoxymethylpyridine dihydrochloride According to the method of Example 2, 4-aminomethyl-3-hydroxy-2-methyl-5-propoxymethylpyridine to 4-aminomethyl-3-hydroxy-2-methyl-5.
-Propoxymethylpyridine dihydrochloride was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 0.88 (3H, t, J = 7.4Hz), 1.5
0-1.64 (2H, m), 2.60 (3H, s),
3.45 (2H, t, J = 6.6Hz), 4.14 (2
H, br s), 4.68 (2H, br s), 8.1
8 (1H, br s), 8.20-8.40 (3H, b
r)

Example 20 4-Aminomethyl-3-hydroxy-2-methyl-5-
Pentyloxymethylpyridine 1-Bromopentane was used to synthesize 4-aminomethyl-3-hydroxy-2-methyl-5-pentyloxymethylpyridine according to the methods of Reference Examples 2 to 4 and Example 1. .

Light yellow solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.88 (3H, t, J = 7.0Hz), 1.20
-1.40 (4H, m), 1.50-1.65 (2H,
m), 2.45 (3H, s), 3.38 (2H, t, J
= 6.6 Hz), 4.25 (2H, s), 4.39 (2
H, s), 7.85 (1H, s)

Example 21 4-Aminomethyl-3-hydroxy-2-methyl-5-
Pentyloxymethylpyridine dihydrochloride According to the method of Example 2, 4-aminomethyl-3-hydroxy-2-methyl-5-pentyloxymethylpyridine to 4-aminomethyl-3-hydroxy-2-methyl- 5-Pentyloxymethylpyridine dihydrochloride was synthesized.

Light yellow solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 0.87 (3H, t, J = 6.7Hz), 1.2
0-1.40 (4H, m), 1.50-1.70 (2
H, m), 2.68 (3H, s), 3.50 (2H,
t, J = 6.6 Hz), 4.17 (2H, br s),
4.77 (2H, s), 8.22 (1H, s), 8.5
4 (3H, br s)

Example 22 4-Aminomethyl-5-hexyloxymethyl-3-hydroxy-2-methylpyridine 1-Bromohexane was used according to the methods of Reference Examples 2 to 4 and Example 1 to give 4 -Aminomethyl-5-hexyloxymethyl-3-hydroxy-2-methylpyridine was synthesized.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.88 (3H, t, J = 6.8Hz), 1.20
-1.40 (6H, m), 1.55 (2H, q, J =
6.6 Hz), 2.45 (3H, s), 3.39 (2
H, t, J = 6.6 Hz), 4.25 (2H, s),
4.39 (2H, s), 7.86 (1H, s)

Example 23 4-Aminomethyl-5-heptyloxymethyl-3-hydroxy-2-methylpyridine 1-iodoheptane was used according to the methods of Reference Examples 2 to 4 and Example 1 to give 4 -Aminomethyl-5-heptyloxymethyl-3-hydroxy-2-methylpyridine was synthesized.

Light yellow solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.87 (3H, t, J = 6.9Hz), 1.17
-1.40 (8H, m), 1.49-1.66 (2H,
m), 2.45 (3H, s), 3.38 (2H, t, J
= 6.6 Hz), 4.25 (2H, s), 4.39 (2
H, s), 7.85 (1H, s)

Example 24 4-Aminomethyl-3-hydroxy-2-methyl-5-
(4-Methylpentyloxymethyl) pyridine 1-Bromo-4-methylpentane was used, and 4-aminomethyl-3-hydroxy-2-methyl- was prepared according to the methods of Reference Example 2 to Reference Example 4 and Example 1. 5- (4-methylpentyloxymethyl) pyridine was synthesized.

Light yellow solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.89 (6H, d, J = 6.6Hz), 1.37
-1.45 (1H, m), 1.69-1.77 (4H,
m), 2.46 (3H, s), 3.43 (2H, t, J
= 6.9 Hz), 4.19 (2H, s), 4.51 (2
H, s), 7.83 (1H, s)

Example 25 4-Aminomethyl-3-hydroxy-2-methyl-5-
Octyloxymethylpyridine 1-Bromooctane was used to synthesize 4-aminomethyl-3-hydroxy-2-methyl-5-octyloxymethylpyridine according to the methods of Reference Examples 2 to 4 and Example 1. .

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 0.85 (3H, t, J = 6.9Hz), 1.1
5-1.35 (10H, m), 1.42-1.52 (2
H, m), 2.25 (3H, s), 3.35 (2H,
t, J = 6.5 Hz), 4.00 (2H, s), 4.3
2 (2H, s), 7.70 (1H, s)

Example 26 4-Aminomethyl-3-hydroxy-2-methyl-5-
Octyloxymethylpyridine dihydrochloride According to the method of Example 2, 4-aminomethyl-3-hydroxy-2-methyl-5-octyloxymethylpyridine to 4-aminomethyl-3-hydroxy-2-methyl- 5-Octyloxymethylpyridine dihydrochloride was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 0.85 (3H, t, J = 6.9Hz), 1.1
5-1.35 (10H, m), 1.50-1.60 (2
H, m), 2.62 (3H, s), 3.48 (2H,
t, J = 6.6 Hz), 4.14 (2H, br s),
4.70 (2H, s), 8.20 (1H, s), 8.2
5-8.45 (3H, br)

Example 27 4-Aminomethyl-5-dodecyloxymethyl-3-hydroxy-2-methylpyridine 1-Bromododecane was used according to the methods of Reference Examples 2 to 4 and Example 1 to give 4 -Aminomethyl-5-dodecyloxymethyl-3-hydroxy-2-methylpyridine was synthesized.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.88 (3H, t, J = 6.8Hz), 1.20
-1.35 (18H, m), 1.50 to 1.60 (2
H, m), 2.45 (3H, s), 3.38 (2H,
t, J = 6.6 Hz), 4.24 (2H, s), 4.3
9 (2H, s), 7.85 (1H, s)

Reference Example 16 3-hydroxy-4-hydroxymethyl-5- [2-
(6-hydroxy-2,5,7,8-tetramethyl-
3,4-Dihydro-2H-benzo [b] pyran-2-yl) ethoxymethyl] -2-methylpyridine 5-hydroxymethyl-2,2,8-trimethyl-4H
2.0 g of -1,3-dioxino [4,5-c] pyridine
420 mg of sodium hydride (60% oily) was added to a 15 ml solution of dimethylsulfoxide of and the mixture was stirred at room temperature for 20 minutes. This reaction mixture was prepared according to European Patent Application Publication No. 3877.
No. 71, p-toluenesulfonic acid 2- (6-methoxymethoxy-2,5,7,) synthesized by the method described in
A solution of 0.95 g of 8-tetramethyl-3,4-dihydro-2H-benzo [b] pyran-2-yl) ethyl in 4 ml of dimethylsulfoxide was added, and the mixture was heated with stirring at 70 ° C. for 15 minutes. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dissolve the residue in 20 ml of methanol, add 6 ml of 2N hydrochloric acid, and add 1 at 80 ° C.
The mixture was heated and stirred for an hour. The reaction solution was concentrated under reduced pressure, neutralized with sodium hydrogen carbonate and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-hydroxy-4-hydroxymethyl-5- [2- (6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H. 600 mg of -benzo [b] pyran-2-yl) ethoxymethyl] -2-methylpyridine was obtained.

White amorphous ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.25 (3H, s), 1.75-1.98 (4
H, m), 2.04 (3H, s), 2.10 (3H,
s), 2.16 (3H, s), 2.44 (3H, s),
2.58 (2H, t, J = 6.9Hz), 3.55-
3.70 (2H, m), 4.28-4.38 (2H,
m), 4.98 (2H, s), 7.80 (1H, s)

Reference Example 17 4-hydroxymethyl-3-methoxymethoxy-5-
[2- (6-methoxymethoxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo [b] pyran-2-yl) ethoxymethyl] -2-methylpyridine 3-hydroxy- 4-hydroxymethyl-5- [2-
(5-hydroxy-2,5,7,8-tetramethyl-
3,4-Dihydro-2H-benzo [b] pyran-2-yl) ethoxymethyl] -2-methylpyridine 400 mg
87 mg of sodium hydride (60% oily) was added to a solution of N, N-dimethylformamide in 10 ml under ice cooling.
After 10 minutes at -15 ° C chloromethyl methyl ether 0.
A solution of 17 ml of methylene chloride in 0.34 ml was added dropwise over 10 minutes, and the mixture was stirred for 30 minutes. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4-hydroxymethyl-3-methoxymethoxy-5- [2- (6-methoxymethoxy-2, 5, 7, 8
350 mg of -tetramethyl-3,4-dihydro-2H-benzo [b] pyran-2-yl) ethoxymethyl] -2-methylpyridine were obtained.

White amorphous ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.25 (3H, s), 1.75-2.05 (4
H, m), 2.06 (3H, s), 2.14 (3H,
s), 2.18 (3H, s), 2.54 (3H, s),
2.58 (2H, t, J = 6.9Hz), 3.48 (1
H, br t, J = 6.5 Hz), 3.61 (3H,
s), 3.63 (3H, s), 3.71-3.85 (2
H, m), 4.60 (2H, s), 4.67 (2H,
d, J = 6.5 Hz), 4.85 (2H, s), 5.0
7 (2H, s), 8.24 (1H, s)

Reference Example 18 4-aminomethyl-3-methoxymethoxy-5- [2-
(6-Methoxymethoxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo [b] pyran-2
-Yl) ethoxymethyl] -2-methylpyridine 4-hydroxymethyl-3-methoxymethoxy-5-
[2- (6-Methoxymethoxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo [b] pyran-2-yl) ethoxymethyl] -2-methylpyridine 300 mg, triethylamine 1 To a solution of 0.0 ml of 4-dimethylaminopyridine (1 mg) in methylene chloride (10 ml) was added a solution of methanesulfonic acid chloride (0.075 ml) in methylene chloride (0.5 ml) at -7 ° C, and the mixture was stirred for 40 minutes. After completion of the reaction, water was added and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance was dissolved in 10 ml of N, N-dimethylformaldehyde,
400 mg of sodium azide was added, and the mixture was heated with stirring at 70 ° C. for 40 minutes. After the reaction, the mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol and 10% palladium-carbon powder 150 was added.
mg was added and the mixture was stirred under a hydrogen atmosphere for 30 minutes. After completion of the reaction, the filtrate obtained by suction filtration was concentrated and then purified by silica gel column chromatography to give 4-aminomethyl-
3-Methoxymethoxy-5- [2- (6-methoxymethoxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo [b] pyran-2-yl) ethoxymethyl] -2 -205 mg of methyl pyridine was obtained.

White amorphous ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.26 (3H, s), 1.75-2.05 (4
H, m), 2.04 (3H, s), 2.13 (3H,
s), 2.18 (3H, s), 2.51 (3H, s),
2.59 (2H, t, J = 6.9Hz), 3.61 (3
H, s), 3.64 (3H, s), 3.65-3.82.
(2H, m), 3.84 (2H, br s), 4.45
-4.60 (2H, m), 4.85 (2H, s), 5.
03 (2H, s), 8.21 (1H, s)

Example 28 4-Aminomethyl-3-hydroxy-5- [2- (6-
Hydroxy-2,5,7,8-tetramethyl-3,4-
Dihydro-2H-benzo [b] pyran-2-yl) ethoxymethyl] -2-methylpyridine dihydrochloride 4-aminomethyl-3-methoxymethoxy-5- [2-
(6-Methoxymethoxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo [b] pyran-2
-Yl) ethoxymethyl] -2-methylpyridine 180
To a solution of 2 mg of methanol in 0.5 ml of hydrochloric acid-methanol solution was added and stirred at room temperature for 20 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, diethyl ether was added, and the resulting precipitate was collected by filtration. It is washed with diethyl ether, dried under reduced pressure and treated with 4-aminomethyl-3-hydroxy-5- [2- (6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro- 180 mg of 2H-benzo [b] pyran-2-yl) ethoxymethyl] -2-methylpyridine dihydrochloride was obtained.

Yellow solid ¹ H-NMR (CDCl ₃ + CD ₃ OD, 400 MH
z) δ ppm: 1.28 (3H, s), 1.75-
1.98 (3H, m), 2.01 to 2.08 (4H,
m), 2.11 (3H, s), 2.12 (3H, s),
2.63 (2H, t, J = 6.8Hz), 2.78 (3
H, s), 3.78-3.95 (2H, m), 4.26.
(2H, s), 4.67 (1H, d, J = 12.8H
z), 4.74 (1H, d, J = 12.8 Hz), 8.
10 (1H, s)

Example 29 4-Aminomethyl-3-hydroxy-5- (9-hydroxynonyloxymethyl) -2-methylpyridine 1-Bromononanol was used to prepare the compounds of Reference Examples 2 to 4 and Example 1. According to the method, 4-aminomethyl-3-hydroxy-5- (9-hydroxynonyloxymethyl)
2-Methylpyridine was synthesized.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.20-1.40 (10H, m), 1.45
1.65 (4H, m), 2.45 (3H, s), 3.3
8 (2H, t, J = 6.6Hz), 3.63 (2H,
t, J = 6.6 Hz), 4.24 (2H, s), 4.3
9 (2H, s), 7.85 (1H, s)

Example 30 4-Aminomethyl-3-hydroxy-5- (9-hydroxynonyloxymethyl) -2-methylpyridine dihydrochloride According to the method of Example 2, 4-aminomethyl-3- Hydroxy-5- (9-hydroxynonyloxymethyl)-
2-Methylpyridine to 4-aminomethyl-3-hydroxy-5- (9-hydroxynonyloxymethyl) -2
-Methylpyridine dihydrochloride was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 1.20-1.65 (14H, m), 2.68
(3H, s), 3.45 (2H, t, J = 6.4H
z), 3.48 (2H, t, J = 6.5Hz), 4.1
4 (2H, br s), 4.72 (2H, s), 8.1
3 (1H, s), 8.41 (3H, br s)

Example 31 4-Aminomethyl-3-hydroxy-5- (2-methoxyethoxymethyl) -2-methylpyridine dihydrochloride 2-bromoethyl methyl ether was used, and Reference Examples 2 to 4 were used. According to the method of Example 1 and Example 2, 4-
Aminomethyl-3-hydroxy-5- (2-methoxyethoxymethyl) -2-methylpyridine dihydrochloride was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.57 (3H, br s), 3.25 (3H,
s), 3.48-3.54 (2H, m), 3.60-
3.65 (2H, m), 4.14 (2H, br s),
4.69 (2H, br s), 8.05-8.25 (4
H, m)

Reference Example 19 5- (2-Methoxycarbonylethenyl) -2,2,8
-Trimethyl-4H-1,3-dioxino [4,5-
c] pyridine 5-hydroxymethyl-2,2,8-trimethyl-4H
-1,3-Dioxyno [4,5-c] pyridine 1.04
g of methylene chloride in a solution of 30 g of manganese dioxide 4.3
5 g was added and the mixture was stirred at room temperature for 20 minutes. Manganese dioxide was removed by Celite filtration, and the filtrate was concentrated under reduced pressure.

205 mg of sodium hydride (60% oily) was added to a solution of 0.77 ml of trimethyl phosphonoacetate in 25 ml of tetrahydrofuran under ice cooling in an argon stream, and the mixture was added to 5
After stirring for 5 minutes, 5 m of the above concentrated tetrahydrofuran
1 solution was slowly added dropwise. Stir for 10 minutes,
The mixture was stirred for 30 minutes while warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was collected by filtration, washed successively with diethyl ether and hexane to give 5- (2-methoxycarbonylethenyl) -2,
2,8-trimethyl-4H-1,3-dioxino [4,
850 mg of 5-c] pyridine was obtained.

White crystal ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.56 (6H, s), 2.43 (3H, s),
3.82 (3H, s), 4.92 (2H, s), 6.3
6 (1H, d, J = 16.1Hz), 7.54 (1H,
d, J = 16.1 Hz), 8.25 (1H, s)

Reference Example 20 5- (2-methoxycarbonylethyl) -2,2,8-
Trimethyl-4H-1,3-dioxino [4,5-c]
Pyridine 5- (2-methoxycarbonylethenyl) -2,2,8
-Trimethyl-4H-1,3-dioxino [4,5-
c] In a solution of 850 mg of pyridine in 80 ml of methanol,
The mixture was stirred overnight at room temperature in a hydrogen stream (1 atm) in the presence of 250 mg of 10% palladium-carbon powder. The reaction mixture was filtered through Celite, and the obtained filtrate was evaporated under reduced pressure to give 5- (2
-Methoxycarbonylethyl) -2,2,8-trimethyl-4H-1,3-dioxino [4,5-c] pyridine (602 mg) was obtained.

White crystal ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.55 (6H, s), 2.38 (3H, s),
2.55-2.65 (2H, m), 2.76 (t, 2)
H, J = 7.8 Hz), 3.68 (3H, s), 4.8
3 (2H, s), 7.87 (1H, s)

Reference Example 21 5- (3-Hydroxypropyl) -2,2,8-trimethyl-4H-1,3-dioxino [4,5-c] pyridine 5- (2-methoxycarbonylethyl) -2, 2,8-
Trimethyl-4H-1,3-dioxino [4,5-c]
To a solution of 602 mg of pyridine in 10 ml of tetrahydrofuran, 440 mg of lithium chloride and sodium borohydride 2
Add 75 mg at room temperature to suspend, followed by ethanol 2
0 ml was added and dissolved, and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, the solvent was evaporated under reduced pressure, water was added to this residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether, 5- (3-hydroxypropyl) -2,
2,8-trimethyl-4H-1,3-dioxino [4,
268 mg of 5-c] pyridine was obtained.

White crystal ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.54 (6H, s), 1.81-1.85 (2
H, m), 2.38 (3H, s), 2.54 (2H,
t, J = 7.5 Hz), 3.69 (2H, t, J = 6.
2Hz), 4.82 (2H, s), 7.88 (1H,
s)

Reference Example 22 5- [3- (2,2-dimethylpropoxy) propyl]
-2,2,8-Trimethyl-4H-1,3-dioxino [4,5-c] pyridine 5- (3-hydroxypropyl) -2,2,8-trimethyl-4H-1,3-dioxino [4 , 5-c] Pyridine (268 mg) in anhydrous dimethyl sulfoxide (1 ml) was added with sodium hydride (60% oily) (53 mg) at room temperature and stirred for 30 minutes, then heated to 100 ° C. and slowly added with neopentyl bromide (5 ml) in dimethyl sulfoxide (5 ml). did. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, 5- [3-
(2,2-Dimethylpropoxy) propyl] -2,2
8-Trimethyl-4H-1,3-dioxino [4,5-
c] Pyridine (192 mg) was obtained.

Colorless oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.92 (9H, s), 1.55 (6H, s),
1.79-1.82 (2H, m), 2.38 (3H,
s), 2.53 (2H, t, J = 7.6Hz), 3.0
6 (2H, s), 3.40 (2H, t, J = 6.0H
z), 4.81 (2H, s), 7.87 (1H, s)

Example 32 4-aminomethyl-5- [3- (2,2-dimethylpropoxy) propyl] -3-hydroxy-2-methylpyridine 5- [3- (2,2-dimethylpropoxy) propyl]
Using 2,2,2,8-trimethyl-4H-1,3-dioxino [4,5-c] pyridine according to the methods of Reference Example 2 to Reference Example 4 and Example 1, 4-aminomethyl- 5
-[3- (2,2-Dimethylpropoxy) propyl]-
3-Hydroxy-2-methylpyridine was synthesized.

White crystal ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.92 (9H, s), 1.71-1.76 (2
H, m), 2.42 (3H, s), 2.62 (2H,
t, J = 7.6 Hz), 3.05 (2H, s), 3.3
8 (2H, t, J = 6.0 Hz), 4.19 (2H,
s), 7.78 (1H, s)

Example 33 4-Aminomethyl-3-hydroxy-2-methyl-5-
(3-Phenylpropoxymethyl) pyridine Using 3-phenylpropyl bromide, according to the methods of Reference Example 2 to Reference Example 4 and Example 1, 4-aminomethyl-3-hydroxy-2-methyl-5- ( 3-Phenylpropoxymethyl) pyridine was synthesized.

Light yellow solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.85-1.95 (2H, m), 2.46 (3
H, s), 2.65 (2H, t, J = 7.7 Hz),
3.42 (2H, t, J = 6.4Hz), 4.25 (2
H, s), 4.39 (2H, s), 7.10-7.30.
(5H, m), 7.86 (1H, s)

Reference Example 23 N-phthaloylpyridoxamine Pyridoxamine dihydrochloride monohydrate 4.0 g of a suspension of 4.0 g of methylene chloride in 80 ml of methylene chloride was combined with carboethoxyphthalimide 3.
5 g and triethylamine 6.0 ml were added, and the mixture was stirred at room temperature overnight. After that, the precipitate was filtered off, and this filtrate was added to 400 ml of chloroform-methanol (5: 1) to remove insoluble matter. The obtained filtrate was concentrated under reduced pressure to obtain 2.5 g of N-phthaloylpyridoxamine.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.31 (3H, s), 4.66 (2H, br)
s), 4.82 (2H, s), 5.10 (1H, b
r), 7.83 (4H, s), 7.93 (1H, s),
8.77 (1H, br)

Reference Example 24 5-Hydroxymethyl-3-methoxymethoxy-2-methyl-4-phthalimidomethylpyridine N-phthaloylpyridoxamine 2.5 g of N, N-dimethylformamide 70 ml solution was cooled to -10 ° C. Then, 0.37 g of sodium hydride (60% oily) was added and stirred for 15 minutes. 0.70 ml of chloromethyl methyl ether was added dropwise to the solution over 30 minutes, and the solution was stirred for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate,
The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether to obtain 2.1 g of 5-hydroxymethyl-3-methoxymethoxy-2-methyl-4-phthalimidomethylpyridine.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.52 (3H, s), 3.31 (1H, br),
3.54 (3H, s), 4.83 (2H, br s),
5.01 (2H, s), 5.08 (2H, s), 7.7
2-7.88 (4H, m), 8.32 (1H, s)

Reference Example 25 5-Bromomethyl-3-methoxymethoxy-2-methyl-4-phthalimidomethylpyridine 5-hydroxymethyl-3-methoxymethoxy-2-methyl-4-phthalimidomethylpyridine To a solution of 50 mg of methylene chloride in 10 ml of methylene chloride. , Triphenylphosphine 50
mg and carbon tetrabromide 75 mg were added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography to obtain 5-bromomethyl-3-methoxymethoxy-2-methyl-4-phthalimidomethylpyridine 40 mg.

Colorless oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.54 (3H, s), 3.57 (3H, s),
4.75 (2H, s), 5.01 (2H, s), 5.1
4 (2H, s), 7.65-7.75 (2H, m),
7.75-7.85 (2H, m), 8.29 (1H,
s)

Reference Example 26 3-Methoxymethoxy-5- (4-methoxyphenoxymethyl) -2-methyl-4-phthalimidomethylpyridine 200 mg of 4-methoxyphenol was dissolved in 5 ml of acetone, and 1.0 g of potassium carbonate and 5-bromomethyl were used. 200 mg of -3-methoxymethoxy-2-methyl-4-phthalimidomethylpyridine was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to obtain 3-methoxymethoxy-5- (4-methoxyphenoxymethyl) -2-methyl-4-phthalimidomethylpyridine 100 mg.

Colorless oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.57 (3H, s), 3.59 (3H, s),
3.75 (3H, s), 5.01 (2H, s), 5.1
0 (2H, s), 5.16 (2H, s), 6.66 (2
H, d, J = 9.2 Hz), 6.71 (2H, d, J =
9.2 Hz), 7.60-7.75 (4H, m), 8.
30 (1H, s)

Reference Example 27 4-aminomethyl-3-methoxymethoxy-5- (4-
Methoxyphenoxymethyl) -2-methylpyridine 100 mg of 3-methoxymethoxy-5- (4-methoxyphenoxymethyl) -2-methyl-4-phthalimidomethylpyridine was dissolved in 3 ml of methanol, and 0.5 ml of hydrazine monohydrate was added. , Stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the portion soluble in methanol was purified by silica gel column chromatography to obtain 50 mg of 4-aminomethyl-3-methoxymethoxy-5- (4-methoxyphenoxymethyl) -2-methylpyridine. It was

Colorless oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.54 (3H, s), 3.65 (3H, s),
3.77 (3H, s), 3.91 (2H, s), 5.0
4 (2H, s), 5.06 (2H, s), 6.85 (2
H, s, J = 9.1 Hz), 6.93 (2H, s, J =
9.1 Hz), 8.30 (1H, s)

Example 34 4-Aminomethyl-3-hydroxy-5- (4-methoxyphenoxymethyl) -2-methylpyridine dihydrochloride 4-Aminomethyl-3-methoxymethoxy-5- (4-
Methoxyphenoxymethyl) -2-methylpyridine 45
Hydrochloric acid-methanol solution 1 to 3 mg solution of methanol
ml was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and 4-aminomethyl-3-hydroxy-5- (4
-Methoxyphenoxymethyl) -2-methylpyridine
40 mg of the dihydrochloride were obtained.

White solid ¹ H-NMR (CDCl ₃ + CD ₃ OD, 400 MH
z) δ ppm: 2.80 (3H, s), 3.79 (3
H, s), 4.37 (2H, s), 5.29 (2H,
s), 6.88 (2H, d, J = 9.1 Hz), 7.0
1 (2H, d, J = 9.1 Hz), 8.30 (1H,
s)

Example 35 4-Aminomethyl-3-hydroxy-5- (4-hydroxyphenoxymethyl) -2-methylpyridine dihydrochloride Hydroquinone was used to prepare the compounds of Reference Example 26, Reference Example 27 and Example 34. According to the method, 4-aminomethyl-3-hydroxy-5- (4-hydroxyphenoxymethyl) -2
-Methylpyridine dihydrochloride was obtained.

White solid ¹ H-NMR (CD ₃ OD, 400 MHz) δ pp
m: 2.75 (3H, s), 4.42 (2Hs), 5.
27 (2H, s), 6.75 (2H, d, J = 9.0H
z), 6.95 (2H, d, J = 9.0Hz), 8.4
4 (1H, s)

Example 36 4-Aminomethyl-5-butoxymethyl-3-hydroxy-2-methylpyridine dihydrochloride 1-Bromobutane was used to prepare Reference Examples 2 to 4, Example 1 and Example 2. 4-aminomethyl-5-butoxymethyl-3-hydroxy-2-methylpyridine dihydrochloride was synthesized according to the method described in 1.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 0.89 (3H, t, J = 7.4Hz), 1.2
5-1.40 (2H, m), 1.45-1.65 (2
H, m), 2.61 (3H, br s), 3.49 (2
H, d, J = 6.5 Hz), 4.14 (2H, br
s), 4.69 (2H, brs), 8.18 (1H, b
rs), 8.32 (3H, br s)

Example 37 4-Aminomethyl-3-hydroxy-2-methyl-5-
(3-Methylbutoxymethyl) pyridine 1-Bromo-3-methylbutane was used, and 4-aminomethyl-3-hydroxy-2-methyl-5 was prepared according to the methods of Reference Example 2 to Reference Example 4 and Example 1. -(3-Methylbutoxymethyl) pyridine was synthesized.

Light yellow solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.87 (6H, d, J = 6.6Hz), 1.4-
1.5 (2H, m), 1.6-1.8 (1H, m),
2.5 (3H, s), 3.4 (2H, t, J = 6.7H
z), 4.2 (2H, s), 4.4 (2H, s), 7.
8 (1H, s)

Reference Example 28 5- (2,2-Dimethylpropoxymethyl) -3-hydroxy-2-methyl-4-pyridinecarbaldehyde 2,2-Dimethylpropyl bromide was used to prepare Reference Example 2.
According to the method of Reference Example 3, 5- (2,2-dimethylpropoxymethyl) -3-hydroxy-2-methyl-4
-Pyridine carbaldehyde was synthesized.

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 0.9 (9H, s), 2.5 (3H,
s), 3.1 (2H, s), 4.7 (2H, s), 8.
1 (1H, s), 10.5 (1H, s), 11.5 (1
H, s)

Reference Example 29 5- (2,2-Dimethylpropoxymethyl) -3-hydroxy-2-methyl-4-pyridinecarbaldehyde oxime O-methyl ether 5- (2,2-dimethylpropoxymethyl) -3- Hydroxy-2-methyl-4-pyridine carbaldehyde 1.
A solution of 9 g of methylene chloride in 30 ml of O-methylhydroxyamine hydrochloride 0.73 g) triethylamine 1.7.
ml and an appropriate amount of anhydrous magnesium sulfate were added, and the mixture was stirred overnight at room temperature. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give 5- (2,2-dimethylpropoxymethyl) -3-hydroxy-2-methyl-4-pyridinecarbaldehyde oxime O-methyl ether (1.9 g).
I got

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 0.9 (9H, s), 2.5 (3H,
s), 3.1 (2H, s), 4.0 (3H, s), 4.
5 (2H, s), 8.0 (1H, s), 8.6 (1H,
s), 10.3 (1H, s)

Reference Example 30 4-Acetyl-5- (2,2-dimethylpropoxymethyl) -3-hydroxy-2-methylpyridine 5- (2,2-Dimethylpropoxymethyl) -3-hydroxy-2-methyl- 4-Pyridinecarbaldehyde oxime O-Methyl ether 1.4 g in a tetrahydrofuran 40 ml solution at -78 ° C under a stream of argon methyllithium (1.15 M tetrahydrofuran solution) 18 m
1 was added dropwise, and the mixture was stirred overnight while gradually returning to room temperature. Water was added to the reaction solution, and the liquid was made acidic with 2N hydrochloric acid.
Stirred for minutes. Then, the liquid was made alkaline with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.33 g of 4-acetyl-5- (2,2-dimethylpropoxymethyl) -3-hydroxy-2-methylpyridine.

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 0.9 (9H, s), 2.5 (3H,
s), 2.8 (3H, s), 3.1 (2H, s), 4.
7 (2H, s), 8.0 (1H, s), 11.4 (1
H, br s)

Reference Example 31 5- (2,2-Dimethylpropoxymethyl) -3-hydroxy-2-methyl-4-pyridylmethylketone Oxime 4-acetyl-5- (2,2-dimethylpropoxymethyl) -3- Hydroxy-2-methylpyridine 0.33g
Hydroxylamine hydrochloride (97 mg) and sodium acetate (0.11 g) were added to the ethanol (20 ml) solution, and the mixture was stirred at 60 ° C for 1 hr. Water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 5- (2,2-dimethylpropoxymethyl) -3-hydroxy-2-methyl-4-pyridylmethyl containing E, Z isomers of oxime was mixed. 0.38 g of ketone oxime was obtained.

Yellow amorphous ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 0.9 (9H, s), 2.2-2.4 (3H,
s), 2.5-2.6 (3H, s), 3.0-3.1.
(2H, s), 4.4-4.5 (2H, s), 8.0-
8.1 (1H, s)

Example 38 4- (1-aminoethyl) -5- (2,2-dimethylpropoxymethyl) -3-hydroxy-2-methylpyridine dihydrochloride 5- (2,2-dimethylpropoxymethyl) Zinc dust was added to a solution of 0.32 g of -3-hydroxy-2-methyl-4-pyridylmethylketone oxime in 25 ml of acetic acid, and the mixture was stirred at room temperature for 4 hours. Aqueous sodium hydrogen carbonate solution was added to the reaction solution to make it alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, hydrochloric acid-ethanol solution was added to the purified product, the solvent was evaporated under reduced pressure, and 4- (1-aminoethyl) -5-
0.32 g of (2,2-dimethylpropoxymethyl) -3-hydroxy-2-methylpyridine dihydrochloride was obtained.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 0.9 (9H, s), 1.6 (3H, d, J =
6.9 Hz), 2.7 (3H, s), 3.1 (1H,
d, J = 8.6 Hz), 3.2 (1H, d, J = 8.6)
Hz), 4.5-4.6 (2H, m), 4.7 (1H,
d, J = 12.2 Hz), 8.3 (1H, s), 8.6
(3H, br s)

Example 39 4-Aminomethyl-5- [4- (1,1-dimethylethyl) benzyloxymethyl] -3-hydroxy-2-methylpyridine dihydrochloride 4- (1,1-dimethylethyl) ) To a solution of 5.0 g of benzyl alcohol in 60 ml of methylene chloride, 2.6 ml of methanesulfonyl chloride and 4.6 ml of triethylamine were added, and the mixture was stirred at room temperature for 1 hour. Pour the reaction mixture into water,
The liquid property of this solution was made weakly acidic with a 10% aqueous citric acid solution, and the methylene chloride layer was separated. The organic layer was washed successively with aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Using this residue, Reference Example 2
According to the method of Reference Example 4, Example 1 and Example 2,
4-Aminomethyl-5- [4- (1,1-dimethylethyl) benzyloxymethyl] -3-hydroxy-2-methylpyridine dihydrochloride was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 1.3 (9H, s), 2.7 (3H, s), 4.
1-4.2 (2H, br), 4.6 (2H, s), 4.
9 (2H, s), 7.2-7.3 (2H, m), 7.3
-7.4 (2H, m), 8.2 (1H, s), 8.4-
8.6 (3H, br)

Example 40 4-Aminomethyl-3-hydroxy-2-methyl-5-
(4-Trifluoromethylbenzyloxymethyl) pyridine dihydrochloride Using 4-trifluoromethylbenzyl bromide, according to the methods of Reference Example 2 to Reference Example 4, Example 1 and Example 2, 4-amino Methyl-3-hydroxy-2-methyl-5- (4-trifluoromethylbenzyloxymethyl) pyridine dihydrochloride was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.68 (3H, br s), 4.19 (2H,
br s), 4.72 (2H, s), 4.88 (2H,
brs), 7.61 (2H, d, J = 8.1Hz),
7.73 (2H, d, J = 8.1Hz), 8.30 (1
H, s), 8.4-8.65 (3H, br)

Example 41 4-Aminomethyl-3-hydroxy-2-methyl-5-
(4-Pentenoxymethyl) pyridine 5-Bromo-1-pentene was used according to the methods of Reference Example 2 to Reference Example 4 and Example 1, and 4-aminomethyl-
3-Hydroxy-2-methyl-5- (4-pentenoxymethyl) pyridine was synthesized.

Light yellow solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.6-1.7 (2H, m), 2.0-2.2 (2
H, m), 2.5 (3H, s), 3.4 (2H, t, J
= 6.5 Hz), 4.2 (2H, s), 4.4 (2H,
s), 4.9-5.1 (2H, m), 5.7-5.9.
(1H, m), 7.9 (1H, s)

Reference Example 32 1-Methoxy-2- (2,2,2-trifluoroethoxy) benzene 2-methoxyphenol 93.1 g, 1,1,1-trifluoro-2-iodoethane 105.0 g and potassium carbonate 103.6 g of N, N-dimethylformamide 10
It was added to 00 ml and reacted at 130 ° C. for 22 hours. Water was added to the reaction solution and extracted with toluene. Then, the organic layer was washed with a 2N aqueous sodium hydroxide solution and water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was distilled under reduced pressure to obtain 1-methoxy-2- (2,2,2-trifluoroethoxy) benzene (82.7 g).

Light yellow oil Boiling point: 89 to 93 ° C./13 mmHg ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 3.86 (3H, s), 4.38 (2H, q, J =
8.4 Hz), 6.85-7.1 (4H, m)

Reference Example 33 2- (2,2,2-Trifluoroethoxy) phenol 112 g of 1-methoxy-2- (2,2,2-trifluoroethoxy) benzene in 230 ml of methylene chloride with stirring under ice cooling. Then, a solution of boron tribromide (62 ml) in methylene chloride (110 ml) was added dropwise and reacted for 1 hour. The reaction solution was poured into ice water and neutralized with sodium hydrogen carbonate, insoluble materials were removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 100.5 g of 2- (2,2,2-trifluoroethoxy) phenol.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 4.41 (2H, q, J = 8.1Hz), 5.52
(1H, s), 6.8-6.9 (2H, m), 6.95
-7.0 (2H, m)

Reference Example 34 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethanol 2- (2,2,2-trifluoroethoxy) phenol 100.5 g ethanol 210 ml solution, potassium carbonate 188 g and 2-chloroethanol 55 ml were added. The reaction mixture was reacted at 50 ° C. for 19 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
The residue was distilled under reduced pressure to obtain 115 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethanol.

Colorless oil Boiling point: 85 to 87 ° C./0.1 mmHg ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.32 (1H, t, J = 6.4Hz), 3.9-
4.25 (4H, m), 4.39 (2H, q, J = 8.
4Hz), 6.9-7.15 (4H, m)

Reference Example 35 Methanesulfonic acid 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethanol 115 g of chlorinated salt Methylene 440ml
The solution was stirred under ice-cooling, and 74.6 ml of triethylamine and 39.6 ml of methanesulfonyl chloride were added to the solution of δ pp.
The m0 ml solution was added, and the mixture was stirred at room temperature for 2 hours. 300 ml of methylene chloride and 1000 ml of water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue for crystallization, and methanesulfonic acid 2-
145 g of [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl was obtained.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 3.11 (3H, s), 4.2-4.3 (2H,
m), 4.38 (2H, q, J = 8.3Hz), 4.5
5-4.65 (2H, m), 6.9-7.1 (4H,
m)

Example 42 4-Aminomethyl-3-hydroxy-2-methyl-5-
[2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethoxymethyl] pyridine dihydrochloride methanesulfonate 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl Using 4-aminomethyl-3-hydroxy-2-methyl-5- [2-, according to the methods of Reference Example 2 to Reference Example 4, Example 1 and Example 2.
[2- (2,2,2-trifluoroethoxy) phenoxy] ethoxymethyl] pyridine dihydrochloride was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.68 (3H, s), 3.8-3.95 (2
H, m), 4.1-4.3 (4H, m), 4.72 (2
H, q, J = 9.0 Hz), 4.90 (2H, s),
6.9-7.2 (4H, m), 8.27 (1H, s),
8.50 (3H, br s)

Example 43 4-Aminomethyl-5-geranyloxymethyl-3-hydroxy-2-methylpyridine Using geranyl chloride, according to the method of Reference Examples 2 to 4 and Example 1, 4- Aminomethyl-5-geranyloxymethyl-3-hydroxy-2-methylpyridine was synthesized.

Light yellow solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.60 (3H, s), 1.64 (3H, s),
1.68 (3H, s), 2.05-2.15 (4H,
m), 2.45 (3H, s), 3.94 (2H, d, J
= 6.9 Hz), 4.27 (2H, s), 4.40 (2
H, s), 5.05-5.15 (1H, m), 5.34.
(1H, t, J = 6.9Hz), 7.84 (1H, s)

Example 44 4-Aminomethyl-5- (3,4-dimethylbenzyloxymethyl) -3-hydroxy-2-methylpyridine
Dihydrochloride / 4-aminomethyl-5- (2,3-dimethylbenzyloxymethyl) -3-hydroxy-2-methylpyridine dihydrochloride (2: 1 mixture) 3,4-dimethylbenzyl chloride and 2 chloride 4-aminomethyl-5- (3,4-dimethylbenzyloxy) according to the method of Reference Example 2 to Reference Example 4, Example 1 and Example 2 using a 2: 1 mixture of 3,3-dimethylbenzyl. 2: 1 of methyl) -3-hydroxy-2-methylpyridine dihydrochloride and 4-aminomethyl-5- (2,3-dimethylbenzyloxymethyl) -3-hydroxy-2-methylpyridine dihydrochloride. The mixture was synthesized.

Pale yellow solid 4-aminomethyl-5- (3,4-dimethylbenzyloxymethyl) -3-hydroxy-2-methylpyridine.
Dihydrochloride ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.2 (3H, s), 2.2 (3H, s), 2.
7 (3H, s), 4.5 (2H, s), 4.8 (2H, s)
s), 7.0-7.2 (3H, m), 8.2 (1H,
s), 8.5 (3H, br s) 4-aminomethyl-5- (2,3-dimethylbenzyloxymethyl) -3-hydroxy-2-methylpyridine.
Dihydrochloride ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.2 (3H, s), 2.3 (3H, s), 2.
7 (3H, s), 4.6 (2H, s), 4.8 (2H,
s), 7.0-7.2 (3H, m), 8.2 (1H,
s), 8.5 (3H, br s)

Reference Example 36 5- (4-ethoxycarbonylbutoxymethyl) -2,
2,8-trimethyl-4H-1,3-dioxino [4,
5-c] pyridine 5-hydroxymethyl-2,2,8-trimethyl-4H
-1,3-Dioxyno [4,5-c] pyridine 1 g was dissolved in anhydrous dimethylsulfoxide 5 ml, sodium hydride (60% oily) 210 mg was added at room temperature, and the mixture was stirred for 30 minutes, then heated to 100 ° C. and heated to 5-bromo. 5 ml of a solution of 0.88 ml of ethyl valerate in dimethyl sulfoxide was slowly added dropwise, and the mixture was further stirred for 15 minutes. Add water to the reaction solution,
It was extracted with ethyl acetate. Wash the organic layer with saturated saline,
After drying with magnesium sulfate, the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography, 5- (4-ethoxycarbonylbutoxymethyl)-
440 mg of 2,2,8-trimethyl-4H-1,3-dioxino [4,5-c] pyridine was obtained.

Colorless oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.26 (3H, t, J = 7.1Hz), 1.55
(6H, s), 2.0-2.24 (4H, m), 2.3
8 (3H, s), 2.53 (2H, t, J = 7.2H
z), 3.06 (2H, s), 4.10 (2H, t, J
= 6.2 Hz), 4.14 (2H, q, J = 7.1H)
z), 4.81 (2H, s), 7.87 (1H, s)

Reference Example 37 5- (5-hydroxypentoxymethyl) -2,2,8
-Trimethyl-4H-1,3-dioxino [4,5-
c] pyridine 5- (4-ethoxycarbonylbutoxymethyl) -2,
2,8-Trimethyl-4H-1,3-dioxino [4,
5-c] pyridine 320 mg to tetrahydrofuran 6 m
The solution was dissolved in 1 l, and 400 mg of lithium chloride and 250 mg of sodium borohydride were added at room temperature to suspend the solution. Then, 12 ml of ethanol was added to dissolve the solution, and the mixture was stirred at room temperature overnight. After adding a saturated aqueous ammonium chloride solution to stop the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the solution was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. This residue was purified by silica gel column chromatography, 5- (5-hydroxypentoxymethyl) -2,2,8-trimethyl-4H
-1,3-Dioxyno [4,5-c] pyridine 120m
g was obtained.

Light yellow oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.4-1.5 (2H, m), 1.55 (6H,
s), 1.55-1.75 (4H, m), 2.40 (3
H, s), 3.55-3.65 (2H, m), 3.67.
(2H, t, J = 6.4 Hz), 4.39 (2H,
s), 4.90 (2H, s), 7.94 (1H, s)

Example 45 4-Aminomethyl-3-hydroxy-5- (5-hydroxypentoxymethyl) -2-methylpyridine dihydrochloride 5- (5-hydroxypentoxymethyl) -2,2,8
-Trimethyl-4H-1,3-dioxino [4,5-
c] Using pyridine, Reference Examples 2 to 4 and Example 1
And according to the method of Example 2, 4-aminomethyl-3-
Hydroxy-5- (5-hydroxypentoxymethyl)
2-Methylpyridine dihydrochloride was synthesized.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 1.4-1.5 (2H, m), 1.5-1.6
(2H, m), 1.6-1.7 (2H, m), 2.63
(3H, s), 3.38 (2H, t, J = 6.4H
z), 3.49 (2H, t, J = 6.5Hz), 4.1
-4.2 (2H, br), 4.71 (2H, s), 8.
21 (1H, s), 8.3-8.5 (3H, br)

Reference Example 38 5-Chloromethyl-2,2,8-trimethyl-4H-
1,3-Dioxino [4,5-c] pyridine 5-hydroxymethyl-2,2,8-trimethyl-4H
2.0 g of -1,3-dioxino [4,5-c] pyridine
5 ml of thionyl chloride was added dropwise to a 30 ml solution of diethyl ether under ice-cooling, and the mixture was refluxed for 3 hours. The precipitate was collected by filtration, washed with diethyl ether, and the solvent was evaporated under reduced pressure in the presence of diphosphorus pentoxide to give 5-chloromethyl-2,2,8-
Trimethyl-4H-1,3-dioxino [4,5-c]
2.3 g of pyridine was obtained.

White solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.64 (6H, s), 2.80 (3H, s),
4.59 (2H, s), 5.10 (2H, s), 8.2
6 (1H, s)

Reference Example 39 5-Phenylthiomethyl-2,2,8-trimethyl-4
H-1,3-dioxino [4,5-c] pyridine 5-chloromethyl-2,2,8-trimethyl-4H-
1,3-Dioxino [4,5-c] pyridine 500 mg
And 88 mg of sodium hydride (60% oily) was added to a solution of 0.23 ml of thiophenol and 5 ml of dimethyl sulfoxide at room temperature, and the mixture was stirred at 50 ° C for 14 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography to give 5-phenylthiomethyl-2,2,8-trimethyl-4H-1,3-dioxino [4,5- c] Pyridine (526 mg) was obtained.

Light yellow oil ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 1.54 (6H, s), 2.37 (3H, s),
3.90 (2H, s), 4.91 (2H, s), 7.2
0-7.35 (5H, m), 7.73 (1H, s)

Reference Example 40 3-Hydroxy-4-hydroxymethyl-2-methyl-
5-phenylthiomethylpyridine 5-phenylthiomethyl-2,2,8-trimethyl-4
H-1,3-dioxino [4,5-c] pyridine 526
mg was added to 9 ml of 2N hydrochloric acid, and the mixture was heated under reflux for 2 hours. 11 ml of 2N sodium hydroxide was added to the reaction mixture, and the mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH 9 with 10% citric acid aqueous solution and saturated sodium hydrogen carbonate aqueous solution.
It was adjusted to -10 and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to obtain 342 mg of 3-hydroxy-4-hydroxymethyl-2-methyl-5-phenylthiomethylpyridine.

Light yellow solid ¹ H-NMR (CDCl ₃ , 400 MHz) δ pp
m: 2.43 (3H, s), 3.93 (2H, s),
5.03 (2H, s), 7.0-7.3 (5H, m),
7.66 (1H, s)

Example 46 4-Aminomethyl-3-hydroxy-2-methyl-5-
Phenylthiomethylpyridine 3-hydroxy-4-hydroxymethyl-2-methyl-
4-Aminomethyl-3-hydroxy-2-methyl-5-phenylthiomethylpyridine was synthesized using 5-phenylthiomethylpyridine according to the methods of Reference Examples 3 to 4 and Example 1.

White solid ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ p
pm: 2.21 (3H, s), 4.10 (2H, s),
4.11 (2H, s), 7.15-7.25 (1H,
m), 7.25-7.4 (4H, m), 7.61 (1
H, s)

Example 47 Acute toxicity test Six-week-old male ICR mice (29.5-31.5 g) were fasted overnight and suspended in 0.5% CMC 4-aminomethyl-3-hydroxy-2-. Methyl-5-neopentyloxymethylpyridine (0.2 g / ml) was orally administered so that the amount was 1000 mg / kg body weight. The control group received only 0.5% CMC.

No abnormal behavior was observed within 6 hours after administration,
No individual died by 7 days after administration.

Example 48 Maillard Reaction Inhibitory Activity Test Lysozyme, fructose and test compound were adjusted to 10 mg / ml, 200 mM, 0.2 or 2 mM, respectively, in 0.5 M sodium phosphate buffer (pH 7.4).
, And incubated at 37 ° C. for 1 week.

Incubation samples were SDS-P
Separated by AGE, Coomassie Bril
After staining with lient Blue R-250, the dimer generation rate with respect to the total protein was measured with a densitometer.

The inhibitory activity of the test compound was calculated from the dimer production rate in the presence of the test compound relative to the dimer production rate in the absence of the test compound.

[0255]

[Table 1]

[0256]

[Table 2]

Formulation Example 1 Tablet active ingredient 100 mg Corn starch 50 mg Lactose 70 mg Hydroxypropyl cellulose 7 mg Magnesium stearate 3 mg (total 230 mg)

Formulation Example 2 Fine-grain base drug 100 mg Mannitol 190 mg Corn starch 100 mg Hydroxypropyl cellulose 10 mg (total 400 mg)

Formulation 3 Capsule active ingredient 100 mg Lactose 18 mg Crystalline cellulose 35 mg Corn starch 25 mg Magnesium stearate 2 mg (total 180 mg)

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display area A61K 31/44 ACV A61K 31/44 ACV ADP ADP ADP AED AED // A23L 1/30 A23L 1/30 Z A61K 7 / 00 A61K 7/00 D 7/48 7/48 (72) Inventor Hideki Fujikura 5000-3, Shimauchi, Matsumoto City, Nagano Prefecture Sunlife Inukai A202 (72) Kiyoshi Kasai 1-2-34 Nozomizo, Matsumoto City, Nagano Prefecture Kissei Dainyuuryo (72) Inventor Hiroshi Harada 8054 Nakagawa, Shiga-mura, Higashichikuma-gun, Nagano (72) Inventor Fumiyasu Sato 2-12-3 Chikuma, Matsumoto City, Nagano Prefecture

Claims (2)

[Claims] 1. A compound of the general formula (In the formula, R ¹ , R ² and R ³ may be the same or different and each is a hydrogen atom or a lower alkyl group, A is a lower alkylene group, B is an alkylene group,
Is an alkenylene group or an alkynylene group, R is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a halogen atom as a substituent, a hydroxyl group, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a cyano group An acylamide group, an amino group, a carbamoyl group, an aryl group which may have a lower alkyl-substituted carbamoyl group or a di-lower alkyl-substituted carbamoyl group, an aryloxy group which may have a halo lower alkyl group as a substituent, A cycloalkyl group or a heterocyclic group, or B is an aryl group which may have a hydroxyl group or a lower alkoxy group as a substituent together with R, and Y is an oxygen atom or a sulfur atom). 3-Hydroxy-4-aminomethylpyridine derivatives or them Maillard reaction inhibitor comprising a pharmacologically acceptable salt thereof as an active ingredient. 2. A compound of the general formula [In the formula, R ¹ , R ² and R ^{3, which} may be the same or different, each is a hydrogen atom or a lower alkyl group, A is a lower alkylene group, and Z is a general formula —O—B.
-R (wherein B is an alkynylene group, an alkenylene group or an alkynylene group, R is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a halogen atom as a substituent, a hydroxyl group, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group) , Carboxyl group, lower alkoxycarbonyl group, cyano group, acylamido group, amino group, carbamoyl group,
An aryl group which may have a lower alkyl-substituted carbamoyl group or a di-lower alkyl-substituted carbamoyl group, an aryloxy group which may have a halo-lower alkyl group as a substituent, a cycloalkyl group or a heterocyclic group) Or a group of the formula -Y-E (wherein E is an aryl group which may have a hydroxyl group or a lower alkoxy group as a substituent, and Y is an oxygen atom or a sulfur atom). And R ¹ is a methyl group and R ² and R ³ are hydrogen atoms, Z is not a methoxymethyl group]. Derivatives and their pharmacologically acceptable salts.