JP2002114791A - Method for producing galanthamine type lycoris alkaloids - Google Patents

Abstract

PROBLEM TO BE SOLVED: To develop a method for chemically synthesizing a galanthamine type alkaloid efficiently, more concretely, capable of extremely improving a chemical yield of an intramolecular coupling reaction being the most important in a synthetic process. SOLUTION: This production method is a structural improvement of a substrate of an intramolecular coupling reaction, a phenol derivative is used as one of two kinds of phenyl groups and a pyrogallol derivative symmetrically containing three oxygen-substituted groups is used as the other. A reaction yield can be more extremely improved than a conventional method by the reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing galantamine-type amaryllidaceae alkaloids, which comprises a method for synthesizing a novel intramolecularly coupled product in high yield.

[0002]

2. Description of the Related Art As humanity ages, senile dementia has become a social problem. Most of this senile dementia is Alzheimer's disease, and it is known that substances having acetylcholinesterase inhibitory activity are effective for the treatment. Galantamine has the above-mentioned inhibitory activity and is currently in a clinical trial stage. Therefore, it is desired to establish an efficient chemical synthesis method of galantamine and its derivatives.

[0003] Studies on the chemical synthesis of galantamine-type alkaloids have been reported since the 1960s, but in recent years there have been many reports on new chemical synthesis from the above background. For example, N- (4-hydroxypheneth)
yl) -N- (2-bromo-5-hydroxy-
4-methyoxybenzyl) formamide or N- (3-bromo-4-hydroxyphene)
thyl) -N- (2-bromo-5-hydroxy)
y-4-methoxybenzyl) formam-
Oxidative coupling reaction with potassium ferricyanide using ide as a substrate (Szewczyk, et al.,
J. Heterocyclic Chem. 1995,
32 , 195; Szewczyk, et al. , J. et al.
Heterocyclic Chem. 1988, 2
5 , 1809; Czollner, et al. , Te
Trahedron Letters, 1998, 3
9 , 2087; Henshirwood, et al. ,
US Patent 6,084,094), and
N- [2,2-diphenyl-6- (trimet
hyl-silanyl) benzo [1,3] dio
xol-5-ylmethyl] -2,2,2-tri
fluoro-N- [2- (4-hydroxy-ph
phenyliodine (III) bis (trifluoroacetate) (Kita, Y., et al., J. Or)
g. Chem. , 1998, 63 , 6625; Yasuyuki Kita et al., JP-A-11-80170). The biggest problem with these known synthetic methods is the chemical yield of the intramolecular coupling reaction, which is 50%.
At present, there is no report of a yield exceeding that, and at present, it is extremely difficult to chemically synthesize an industrially effective galantamine-type Amaryllidaceae alkanoid with high yield, simplicity of the production process, and the like. It can be said that it was an issue.

[0004]

SUMMARY OF THE INVENTION The present invention is directed to the development of an efficient chemical synthesis of galantamine-type alkaloids. More specifically, the present invention is intended to reduce the chemical yield of the most important intramolecular coupling reaction during the synthesis process. The task is to greatly improve it.

[0005]

Means for Solving the Problems The invention of this application is based on a general formula for solving the above problems.

Wherein R ₁ represents a protecting group for a hydrocarbon or a hydrocarbon containing an oxygen atom or a trialkylsilyl group, and R ₂ represents a protecting group comprising an amide bond. After reacting with a hypervalent iodine reagent, the general formula

A method for producing an intramolecularly coupled compound (claim 1), which comprises producing the compound of the formula (1), is provided. The invention of this application, the reaction in the production method as hypervalent iodine (III) reagent, phenyl iodide emissions (III) bis (trifluoroacetate represented by the following formula PhI (OCOCF _{3) 2} ) :( phenyliodine (II)
I) The protecting group of R ₁ may be benzyl, benzyloxymethyl, methoxy, or the like, including bis (trifluoroacetate) (claim 2) and a method using a fluoro-substituted alcohol as a solvent (claim 3). Methyl group, methoxyethyl group, methoxybenzyl group,
An allyl group or a protective group consisting of an amide bond of R ₂ , which is represented by the following formula: R ₃ R ₄ R ₅ Si— (R ₃ , R ₄ and R ₅ represent a hydrocarbon) (claim 4) Is represented by the following formula: R ₆ —CO— (R ₆ represents a hydrogen atom or a fluoro-substituted hydrocarbon)
A method (claim 5) and the like represented by the following formula (1) is also provided as the embodiment. In addition, the present invention has a general formula

## STR3 ## (R ₇ in the formula represents a hydroxyl group, an optionally substituted alkoxy group, an oxygen atom to form an acyloxy group or an acyl group or a carbonyl group together with the carbon atoms of the ring structure, R ₉ Represents a hydrogen atom or a hydrocarbon group which may have a substituent)) galantamine-type amaryllidaceae alkaloid (Amaryllidaceae alkalo)
A method for producing galantamine-type amaryllidaceae alkaloids (claim 6), which comprises a method for producing any of the above-mentioned intramolecularly coupled products (claim 6). The general formula

Wherein R represents a hydrocarbon or a hydrocarbon containing an oxygen atom or a protecting group for an organosilicon group, and a phenol derivative represented by the following formula:
I) A method for producing galantamine-type amaryllidaceae alkaloids which form an intramolecularly coupled product by reacting with bis (trifluoroacetate) (claim 7) is also provided as a characteristic feature.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The invention of this application has the above-mentioned features, but basically, norverazine (n) which is a common biosynthesis intermediate of amaryllidaceae alkaloids
orbelladine), which generates various kinds of skeletons depending on the reaction site of the intramolecular coupling reaction. Galantamine-type amaryllidaceae alkaloids are produced by the po 'coupling reaction of norverazine.

The method of the present invention aims at synthesizing a galanthamine-type skeleton with high yield by designing and synthesizing a norverazine derivative in which the above p-o 'coupling reaction proceeds selectively and using it for the coupling reaction. It is a big feature. A phenol derivative designed and synthesized is used for the coupling reaction, and a hypervalent iodine (III) reagent such as phenyliodin (III) bis (trifluoroacetate of the following formula PhI (OCOCF ₃ ) ₂ is used as the coupling reagent. And the above-mentioned compound as an intramolecular coupling product

This is carried out by producing the compound of the following formula.

The hypervalent iodine (III) reagent includes:
Not only the above-mentioned phenyliodin (III) bis (trifluoroacetate) but also, for example, PhI (OAc)
₂ , PhI = O, PhI (OH) (OTs), PhIC
those of l _2, etc. are considered.

[0009]

The symbol R ₁ in the formula represents a hydrocarbon or a protecting group for a hydrocarbon group containing an oxygen atom or an organosilicon group, wherein the hydrocarbon group is an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, Aliphatic hydrocarbons such as alkenyl groups, aralkyl groups such as benzyl and trityl groups, and aliphatic hydrocarbons and aralkyl groups containing oxygen atoms such as methoxymethyl and methoxybenzyl groups are also exemplified. There may be various kinds, such as an organic silyl group and an organic silyloxy group. Among them, the above-mentioned silyl group R ₃ R ₄ R ₅ Si— (R ₃ , R ₄ and R ₅ represent hydrocarbons) is preferred. Exemplified as preferred.

The protecting group consisting of an amide bond of R ₂ serves as a protecting group for a nitrogen atom, and has the following formula: R ₆ —CO— (R ₆ is a hydrogen atom or a hydrocarbon group or a fluoro-substituted hydrocarbon) And formyl group and trifluoroacetyl group are exemplified as preferable.

The phenol derivative of the formula is converted, for example, to the above-mentioned phenyliodin (III) bis (trifluoroacetate)
When reacting, usually the reaction temperature is -50 to
The temperature can be about 10 ° C., and the molar ratio of both can be about 1/3 to 3/1, and this is not limited. Examples of the reaction solvent include acetonitrile, dichloromethane, trifluoroacetic acid, and fluoro-substituted alcohols, and trifluoroethanol is preferably used. The above coupling reaction is more specifically described in the present invention.

This is effectively adopted as one step for the production of galantamine-type amaryllidaceae alkaloids represented by the following formula. In the coupling reaction in this case, for example, as described above,

A phenol derivative of the formula is used as a reaction substrate.

The amaryllidaceae alkaloid galantham, whose synthesis is illustrated in the examples which follow.
ine (1), nearwedine (2), lycor
As for amine (3), an example of synthesis has already been reported.
The synthesis method according to the present invention has the following features as compared with the conventional method. 1) The chemical yield of the intramolecular coupling reaction by the conventional method has not been reported to exceed 50%, whereas the chemical yield of the reaction of the present invention exceeds 80%. The chemical yield has been greatly improved.

The aim of improving the chemical yield of the intramolecular coupling reaction is to improve the structure of the conventional reaction substrate by using a phenol derivative for one of the two phenyl groups and a phenol derivative for the other.
The point is that a pyrogallol derivative having two oxygen substituents symmetrically is used. That is, the binding site in the coupling reaction of the reaction substrate is limited to the two unsubstituted carbon positions (o-positions) of the phenol derivative and the pyrogallol derivative, and the two carbon positions are equivalent. This is because they are designed to generate the same coupling body even when they are combined. The use of pyrogallol derivatives as substrates for coupling reactions has been described by Shimizu et al.
al. Chem. Pharm. Bull. , 197
8, 26 , 3765; Shimizu, et al. ,
Heterocycles, 1997, 8 , 277), but in the case of Shimizu et al., The synthesis route is complicated due to the asymmetric synthesis using L-tyrosine in the phenol moiety, and the coupling reagent is also used in this synthesis. Is different from the law. Reagents for the above coupling reaction have already been reported by Kita et al. (Kita, et al., Chem. Co.)
mmun. Kita, et a, 1996 , 1481;
l. , J. et al. Org. Chem. , 1996, 61 , 58
57) Phenyliod, a less toxic oxidizing agent
ine (III) bis (trifluoroacet)
ate) (PIFA), and one of the features is that a conventionally used highly toxic heavy metal oxidizing agent or the like is not used.

From the reaction mixture of the above coupling reaction, a coupling product

The isolation operation of the formula is extremely simple. That is, as exemplified in the examples described below,
After the coupling reaction, the reaction solvent is distilled off under reduced pressure.

Is isolated. This is a coupling product of the above reaction substrate

This is due to the fact that ## STR2 ## is extremely insoluble in organic solvents, and is economically excellent and particularly useful for mass synthesis. The production of the coupling product is an indispensable step in the production of the galantamine-type alkaloids of the present invention.However, the production of the reaction substrate for the coupling reaction, and the various galantamine-type alkaloids are chemically synthesized from the obtained coupling product. Is done. Representative galantamine-type alkaloids synthesized in high yield by the novel coupling reaction disclosed in this patent are shown in FIG. 1 along with their structural formulas. In producing these final products, various unit reaction operations known in chemical synthesis are appropriately employed. The characteristics of these individual reactions can be described in the following examples.

[0014]

According to the synthesis method of the present invention, in the synthesis of Amaryllidaceae alkaloid, a high chemical yield of intramolecular coupling of 80% or more can be obtained, and a single product of the coupled product from the reaction product can be obtained. It has the feature that the separation operation is extremely easy.

[0015]

Example 1 Synthesis of a galanthamine-type alkaloid skeleton by a coupling reaction of a norbelladine derivative In order to perform a coupling reaction of a norbelladine derivative regioselectively, norbelladine was used.
Using a pyrogallol derivative protected with various substituents for the catechol part of e, a reaction substrate (12) in which the secondary amine part of norbelladine was protected with two kinds of substituents was synthesized. In these syntheses, tyramines are condensed with aldehyde 10 derived from a commercially available gallic acid methyl ester 6 and then sodium borohydride according to a known method carried out with a catechol derivative.
The secondary amine produced by the reduction reaction with e was trifluoroacetylated or formylated to obtain a good yield.
These reaction processes are shown in FIG. In addition, the substrate 12a ~
12i are all new compounds.

Next, the substrate 12 is replaced with phenyliodi.
ne (III) bis (trifluoroaceta
te) By reacting with (PIFA), regioselectively reacted po-coupling derivative 13 or 14 was obtained.
The reaction process is shown in FIG. When trifluoroethanol (CF ₃ CH ₂ OH) was used as a reaction solvent, the yield of the reaction was generally higher than the yield reported in the conventional reports. Particularly, a methyl group is used for R and a formyl group is used for R ′.
With b, 13b was obtained in a quantitative yield, and even with 12d using a benzyl group for R, the target compound 13d was formed with a very high chemical yield of 82%. Various compounds of substrate 12 (1
Table 1 shows the reaction yields of various types of coupling products (13 or 14) obtained from 2a-12i).

From the coupling body 13 galantha
In order to synthesize a min-type alkaloid skeleton, it is necessary to deprotect the pyrogallol moiety and reductively remove excess hydroxyl groups. 13b where the coupling reaction proceeded in high yield
Since demethylation of 13c and 13c generates a by-product with boron tribromide, deprotection of the pyrogallol portion of 13d to 13i was studied. As a result, for example, as shown in the next reaction step, the benzyl group of 13d could be removed in good yield by using boron trichloride at -78 ° C or by mixing trifluoroacetic acid and dimethyl sulfide at room temperature. . One of the two phenolic hydroxyl groups generated by the above reaction simultaneously causes a Michael-type addition to the dienone moiety to give 14b. Gal) by a reduction reaction with formic acid using
Anthamine-type alkaloid skeleton 16 was obtained in high yield. These reaction processes are shown in FIG.

<Synthesis 1-1> N-3 ', 5'-Dihydroxy-4'-meth
oxyphenylmethyl-4-hydroxy
Synthesis of phenylethylamine (11a) Dr of 10a (840 mg, 5 mmol) under nitrogen stream
Thyram in y methanol (15ml) solution
Ine (720 mg, 5.25 mmol) was added, and the mixture was stirred at room temperature for 25 minutes. After completion of the reaction, add s
odiumborohydride (190mg, 5m
mol) was slowly added, and the mixture was stirred under ice cooling for 20 minutes, and then stirred at room temperature for 50 minutes. After completion of the reaction, dry ice was added to the reaction solution, and the precipitate was collected by filtration. The solvent of the filtrate was distilled off, and the obtained crude product was purified by silica gel column chromatography to obtain 11a (1.43 g, 99%).
I got Colorless crystals; ¹ H-NMR (d ₆ -DMSO) δ: 6.9
7 and 6.65 (AB type, J = 8.5H
z, 4H, Ar-H), 6.26 (s, 2H, Ar-
H), 3.65 (s, 3H, OMe), 3.50 (s,
_{2H, CH 2), 2.7-2.6 (} m, 4H, CH 2 C
H _2).

<Synthesis 1-2> N-3 ', 5'-Dibenzyloxy-4'-me
thoxyphenylmethyl-4-hydro
Synthesis of xyphenylethylamine (11c) A solution of 10c (5.0 g, 14.4 mmol) in dry methanol (100 ml) was added under a nitrogen stream.
Ramine (3.9 g, 28.7 mmol) was added,
Reflux at 70 ° C. for 70 minutes. After the reaction was completed, sodium borohydride (0.6%) was added to the reaction solution under ice cooling.
g, 15.8 mmol), and the mixture was stirred under ice-cooling for 30 minutes, and then stirred at room temperature for 40 minutes. After completion of the reaction, the crude product obtained by distilling off the solvent was purified with ethylac
Eate was extracted. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off. A crude product obtained was crystallized from methanol to obtain 11c.
(5.5 g, 81%). Colorless crystals; ¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 7.41-7.26 (m, 10H), 6.96
(D, J = 8.4 Hz, 2H), 6.66 (d, J =
8.4 Hz, 2H), 6.54 (s, 2H, Ar-
H), 5.02 (s, 4H), 3.86 (s, 3H),
3.64 (s, 2H), 2.78 (t, J = 6.0H)
z, 2H), 2.70 (t, J = 6.2 Hz, 2H).

<Synthesis 1-3> N-3 ', 5'-Dihydroxy-4'-meth
oxyphenylmethyl-N- (4-ydro
xyphenylethyl) trifluoroac
Synthesis of etoamide (12a) A solution of 11a (1.43 g, 4.9 mmol) in pyridine (15 ml) under a nitrogen stream was stirred under ice-cooling and stirring.
Fluoroacetic anhydride (2.
(07 ml, 15 mmol) was added dropwise and stirred at 0 ° C. for 20 minutes. After completion of the reaction, the solvent was distilled off, and the crude product obtained was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. The resulting crude product was subjected to silica gel column chromatography (chloroform: methanol = 10:
Purification in 1) gave 12a (1.17 g, 63%) as a crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 7.00 (d, J =
8.8 Hz, 2H, Ar-H), 6.78 and
6.76 (d, J = 8.8 Hz, 2H, Ar-H),
6.38 and 6.28 (s, 2H, Ar-H),
5.64 (brs, 2H, OH), 4.98 (brs,
1H, OH), 4.48 and 4.22 (s, 2H,
CH ₂ ), 3.88 and 3.87 (s, 3H, O
Me), 3.52-5.42 (m, 2H , CH 2),
_{2.84-2.74 (m, 2H, CH 2} ).

<Synthesis 1-4> N-3 ', 4', 5'-Trimethyphenphen
ylmethyl-N- (4-hydroxyphen)
Synthesis of ylethyl) formamide (12b) Commercially available 3,4,5-trimethoxy under nitrogen stream
Benzaldehyde (10b) (2.0 g, 0.
01mol) in methanol (15ml) solution under ice-cooling, commercially available thymine hydrochloro
ride (1.74 g, 0.01 mol), molec
ultra sieves 4A (2.5 g), trie
thylamine (1.39 mL, 0.01 mol)
Was added and stirred at room temperature for 48 hours. After completion of the reaction, the insolubles were removed by filtration, and the filtrate was added with sodium hydroxide under ice-cooling.
orohydride (756mg, 0.02mol)
Was added and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into 1N-HCl for neutralization, and the solvent was distilled off under reduced pressure.
After the residue was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
After filtration, the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product is subjected to silica gel column chromatography (el
uent; hexane: ethyl acetate
= 1: 1) to give 11b. 11b under nitrogen flow
(1.10 g) to formic acid (0.5 m
L), ethyl format (74 mL, 1 mo
l) was added and the mixture was refluxed at 70 ° C. for 10 hours. After completion of the reaction, insolubles were removed by filtration, and the crude product obtained by evaporating the solvent from the filtrate was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate).
ate = 1: 1) and purified to 12b (1.475 g, 42).
% From 10b) was obtained. Colorless crystals; ¹ H-NMR (CDCl ₃ , 300 MHz)
δ: 8.24 and 7.83 (2s, 1H), 7.0
2 (d, J: 8.0 Hz, 1H), 6.90 (d, J =
8.0 Hz, 1 H), 6.77 and 6.33 (2
s, 2H), 4.49 and 4.20 (2s, 2
H), 3.48 and 3.38 (t, J = 7.0H)
z, 2H); IR (CHCl ₃ ): 1595,330
5,3030,3008,2963,2356,234
1,1663,1593,1515,1350c
m ^-1 ; MS (70 eV): m / z 354 (M +, 1
1), 255 (64), 181 (100), 148
(8), 120 (9), 107 (8), 91 (6), 7
7 (7), 44 (18); HRMS (70 eV) cal
cd for C19H23N05 (M +) 345.1
576, found: 345.1580.

<Synthesis 1-5> N-3 ', 4', 5'-Trimethyphenphen
ylmethyl-N- (4-hydroxyphen)
ylethyl) trifluoroacetoami
Synthesis of de (12c) 11b (110 mg, 0.35 mmol) under nitrogen stream
To a pyridine (1 ml) solution under ice cooling
oroacetic acid anhydride
(0.127 ml, 0.9 mmol) and add 1 at the same temperature.
Stirred for hours. After the completion of the reaction, the reaction solution was added to ethyl ac
Extracted with eate. The extract was washed with 1N-HCl, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off to obtain 12c (9%).
(6.5 mg, 95%). Colorless crystals; ¹ H-NMR (CDCl ₃ , 300 MHz)
δ: 7.02 (d, J = 8.0 Hz, 1H), 6.90
(D, J = 8.0 Hz, 1H), 6.77 and
6,74 (2d, J = 8.0 Hz, 2H), 6.77
and 6.33 (2s, 2H), 4.49 and
4.20 (2s, 2H), 3.88 and 3.87
(2s, 3H), 3.84 (s, 3H), 3.83a
nd 3.81 (2s, 3H), 3.48 and
3.38 (2t, J = 7.0 Hz, 2H), 2.73
and 2.20 (2t, J = 7.0 Hz, 2H); I
R (CHCl ₃ ): 2937,2361,2341,1
688, 1595, 1508, 1464, 1234, 1
198 cm ^-1 .

<Synthesis 1-6> N-3 ', 5'-Dibennzyloxy-4'-m
ethoxyphenylmethyl-N- (4-h
hydroxyphenylethyl) formami
Synthesis of de (12d) A solution of 11c (1.96 g, 4.2 mmol) in ethyl formate (40 ml) was placed under a nitrogen stream at 65 ° C.
For 1 day. After completion of the reaction, the crude product obtained by evaporating the solvent was subjected to silica gel column chromatography (c
Purification by chloroform: methanol = 20: 1) gave 12d (2.0 g, 97%). Colorless crystals; ¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 8.13 and 7.74 (s, 1H), 7.43
−7.26 (m, 10H), 6.92 and 6.7
1,6.82 and 6.74 (AB type,
q, J = 8.5 Hz, 4H), 6.48 and 6.
33 (s, 2H, Ar-H), 5.10 (s, 4H),
4.36 and 4.06 (s, 2H), 3.900
and 3.895 (s, 3H), 3.30 and
3.14 (t, J = 6.9 Hz, 2H), 2.61 a
nd 2.54 (t, J = 6.9 Hz, 2H).

<Synthesis 1-7> N-3 ', 5'-Dibenzyloxy-4'-me
thoxyphenylmethyl-N- (4-hy
(doxyphenylethyl) trifluor
Synthesis of oacetoamide (12e) 11c (500 mg, 1.06 mmol) under nitrogen stream
In pyridine (5 ml) solution
aceticanhydride (0.36 ml, 2.
56 mmol) was added dropwise and the mixture was stirred at 0 ° C. for 10 minutes.
After completion of the reaction, methanol (5 ml) was added dropwise to the reaction solution, and the mixture was stirred for 10 minutes. The crude product obtained by distilling off the solvent was subjected to silica gel column chromatography (ethyl).
Purified by l acetate: hexane = 1: 2) to obtain 12e (543 mg, 91%). ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.4
2-7.28 (m, 10H), 6.92-6.88
(M, 2H), 6.76-6.72 (m, 2H), 6.
43 and 6.29 (s, 1H), 5.12 an
d 5.10 (s, 4H), 4.45 and 4.1
6 (s, 2H), 3.909 and 3.900
(S, 3H), 3.32-3.25 (m, 2H), 2.
67-2.62 (m, 2H).

<Synthesis 1-8> 6,7,8-Trimethyoxy-2-formyl
-1,2,3,4-tetrahydro-5H-
[2] benzazepine-5-spiro-1 ′
-Cyclohexa-2 ', 5'-dien-4'-
Synthesis of one [13b] Under a nitrogen stream, 12b (35 mg, 0.1 mmol) of 2,2,2-trifluoroethanol (0.
Phenyliodine (III) b
is (trifluoroacetate) (47m
g, 0.11 mmol) of 2,2,2-trifluo
ethanol (0.5 ml) solution was added dropwise.
Stirred at 0 ° C. for 15 minutes. After completion of the reaction, the crude product obtained by evaporating the solvent was subjected to silica gel column chromatography (chloroform: methanol = 1).
5: 1), and the obtained crude product is ethyl.
Crystallized from acetate to give 13b (32.8 mg, 96
%). Colorless crystals; ¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 8.24 and 8.19 (s, 1H), 7.01
and 6.96 (eachd, J = 10.1 Hz,
2H), 6.62 and 6.47 (s, 1H),
6.30 (d, J = 10.1 Hz, 2H), 4.70
and 4.63 (s, 2H), 3.884 and
3.876 (s, 3H), 3.78 and 3.76
(S, 3H), 3.75-3.66 (m, 2H), 3.
63 and 3.61 (s, 3H), 2.34-2.
27 (m, 2H).

<Synthesis 1-9> 6,7,8-Trimethyoxy-2-triflu
oroacetyl-1, 2,3,4-tetrahy
dro-5H- [2] benzazepine-5-s
piro-1'-cyclohexa-2 ', 5'-d
Synthesis of ie-4′-one [13c] 12c (0.186 mg, 0.45 mmol) under a nitrogen stream
l) 2,2,2-trifluoroethanol
(3 ml) solution at -40 ° C under phenyliodin
e (III) bis (trifluoroacetat
e) (0.213 g, 0.495 mmol) of 2,2
2-Trifluoroethanol (5 ml) solution was added dropwise, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the crude product obtained by distilling off the solvent was subjected to silica gel column chromatography (eluent; hexane: ethyl).
acetate = 1: 1) and purified to 13c (0.13
9g, 75%). Colorless crystals; ¹ H-NMR (CDCl ₃ , 300 MHz)
d: 7.98 and 6.94 (2d, J = 10.0H
z, 2H), 6.63 and 6.45 (2s, 1
H), 6.32 (d, J = 10.0 Hz, 2H), 4.
82 and 4.78 (2s, 2H), 3.89 an
d 3.88 (2s, 3H), 3.87-3.84
(M, 2H), 3.79, 3.77, 3.64 and
3.63 (4s, 6H), 2.34 (t, J = 6.0)
Hz, 2H); IR (CHCl ₃ ): 3030, 300
5,2941,359,2341,1690,166
1,1622, 1595, 1464, 1333, 123
6,1198 cm ^-1 ; MS (70 eV): m / z 41
1 (M +, 58), 380 (12), 285 (10
0), 271 (45), 254 (29), 181 (1
5); HRMS (70 eV) calcd for C2
0H20F3N05 (M +) 411.1293, fou
nd: 411.1285.

<Synthesis 1-10> 6,8-Dibenzyloxy-7-methox
y-2-formyl-1,2,3,4-tetrah
ydro-5H- [2] benzazepine-5-
spiro-1'-cyclohexa-2 ', 5'-
Synthesis of dien-4′-one [13d] Under nitrogen stream, 12d (2.0 g, 4.0 mmol) of 2,2,2-trifluoroethanol (10
0 ml) solution to phenyliodine (III) b
is (trifluoroacetate) (1.9
g, 4.4 mmol) of 2,2,2-trifluor
oethanol (10 ml) solution was added dropwise at -40 ° C.
For 1 hour. After completion of the reaction, the crude product obtained by distilling off the solvent was crystallized from ethyl acetate to obtain 13d (1.29 g, 65%). The mother liquor was subjected to silica gel column chromatography (chloroform:
The resulting crude product was crystallized from ethyl acetate to obtain 13d.
(341.5 mg, 17%). Colorless crystals; ¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 8.21 and 8.19 (s, 1H), 7.47
-7.22 (m, 10H), 7.05 and 6.1
4, 6.98 and 6.14 (AB type,
q, J = 10.2 Hz, 4H), 6.76 and
6.57 (s, 1H, Ar-H), 5.15 and
5.14 (s, 2H), 4.88 and 4.84
(S, 2H), 4.69 and 4.60 (s, 2
H), 3.75 and 3.74 (s, 3H), 3.
71 and 3.65 (t, J = 6.2 Hz, 2
H), 2.29 and 2.26 (t, J = 6.2H)
z, 2H).

<Synthesis 1-11> 6,8-Dibenzyloxy-7-methox
y-2-trifluoroacetyl-1,2,2
3,4-tetrahydro-5H- [2] benz
azpine-5-spiro-1'-cycloh
exe-2 ′, 5′-dien-4′-one [13
Synthesis of 12e (1.8 g, 3.2 mmol) of 2,2,2-trifluoroethanol (15
phenyliodine (III) bi
s (trifluoroacetate) (1.7 g,
3.8 mmol) of 2,2,2-trifluoroe
Then, a toluene (15 ml) solution was added dropwise, and the mixture was stirred at -40 ° C for 1 hour. After completion of the reaction, the crude product obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purification by 0) afforded 13e (960.7 mg, 53%). 1H-NMR (CDCl3, 400 MHz) δ: 7.4
7-7.22 (m, 10H), 7.01 and 6.
5. 94 (each d, J = 10.1 Hz, 2H);
77 and 6.55 (s, 1H), 6.14 (d,
J = 10.1 Hz, 2H), 5.14 (s, 2H),
4.91 and 4.89 (s, 2H), 4.80
and 4.74 (s, 2H), 3.88-3.80
(M, 2H), 3.76 and 3.75 (each
s, 3H), 2.32-2.04 (m, 2H).

<Synthesis 1-12> (±) -3-Hydroxy-N-trifluoro
acetyl-N-nornarwedine (14
Synthesis of a) 12a (198 mg, 0.5 mmol) of 2,2,2-trifluoroethanol (4 m
l) The solution was stirred at -15 to -20 ° C with phenylio.
dine (III) bis (trifluoroace)
date) (322 mg, 0.75 mmol) of 2,
2,2-trifluoroethanol (1 ml)
The solution was added dropwise and stirred at the same temperature for 10 minutes. After completion of the reaction, the crude product obtained by evaporating the solvent was crushed.
ice and a 5% aqueous solution of sodium hydrogencarbonate were added thereto, followed by stirring.
0 mg was obtained. The powder was purified by silica gel column chromatography to obtain 14a (23 mg, 12%). ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 6.8
5 and 6.09, 6.79 and 6.07
(AB type, q, J = 10.3 Hz, 4H),
6.56 and 6.40 (s, 1H, Ar-H),
5.21 and 4.09, 4.81 and 4.5
0 (AB type, q, J = 16.0 Hz, 2H),
4.79, 4.37-4.33, 3.73-3.66,
3.33 (m, 2H), 4.73 (brs, 1H),
3.97 and 3.95 (s, 3H), 3.15-
3.11, 2.81-2.74 (m, 2H), 2.23
-2.08 (m, 2H). Under a nitrogen stream, a solution of 13e (284 mg, 0.5 mmol) in dimethyl sulfide (1 ml) was added to the solution.
rifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 5 days. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (ethyl acetate: hexa).
ne = 1: 2) to give 14a (163 mg, 85
%).

<Synthesis 1-13> (±) -3-Hydroxy = N-formyl-N-
Synthesis of nornarwedine (14b) 13d (1.0 g, 2.0 mmol) of d under a nitrogen stream
Ichlomethane (10ml) solution with bo
rontrichloride (6.1 ml, 1 Mi
n dichloromethane, 6.1mmo
l) was added and the mixture was stirred at -78 ° C for 20 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was stirred for 30 minutes.
form was extracted. The extract was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off.
It is crystallized with ylacetate and 14b (605.3m
g, 95%). Colorless crystals; ¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 8.18 and 8.15 (s, 1H), 6.87
and 6.07, 6.83 and 6.06 (A
B type, q, J = 10.3 Hz, 4H), 6.5
4 and 6.39 (s, 1H, Ar-H), 5.18
−5.14, 4.63, 4.04−4.00 (m, 2
H), 4.71-4.69 (m, 1H), 4.65-
4.61, 4.02-3.95, 3.69-3.62,
3.27-3.20 (m, 2H), 3.95 and
3.92 (s, 3H), 3.15-3.09, 2.81
-2.74 (m, 2H), 2.24-1.94 (m, 2
H). Trifluoroacetic acid (1 m) was added to a 13 d (35 mg, 0.07 mmol) solution of dimethyl sulfide (0.5 ml) under a nitrogen stream.
l) was added and the mixture was stirred at room temperature for 4 days. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (ethyl acetate o).
nly) to give 14b (17.9 mg, 81%).

<Synthesis 1-14> (±) -3-Trifluoromethanesuf
onyloxy-N-trifluoroacetyl
Synthesis of -N-nornarwedine (15) 14b (200 mg, 0.63 mmol) under a nitrogen stream
In a pyridine (4 ml) solution of
omethanesulfonic anhydrid
e (0.26 ml, 1.52 mmol) was added dropwise at 0 ° C.
For 1 hour. After the reaction is completed, add
Nol (4 ml) was added dropwise, and the mixture was stirred for 10 minutes. The solvent was distilled off, and the resulting crude product was subjected to silica gel column chromatography (chloroform: methanol =
5: 1), and the obtained crude product is ethyl.
Acetate crystallized 15 (278.3 mg, 98
%). ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.1
9 and 8.16 (s, 1H), 6.89-6.8
04 (m, 1H), 6.798-6.67 (s, 1
H), 6.17-6.12 (m, 1H), 5.22-
5.18, 4.67-4.61, 4.07-4.01,
3.73-3.70, 3.28 (m, 4H), 4.00
and 3.99 (s, 3H), 3.19-3.1
7, 3.14-3.12, 2.83-2.76 (m, 2
H), 2.34-2.00 (m, 2H).

<Synthesis 1-15> (±) -N-formyl-N-nornarwedi
Synthesis of ne (16) 15 (30 mg, 0.067 mmol),
triethylamine (20mg, 0.2mmo
l), palladium acetate (0.29m
g, 0.0013 mmol), triphenylph
ospine (0.7mg, 0.0027mmol)
N, N-dimethylformamide (0.
5 ml) solution to formic acid (6.17 m)
g, 0.134 mmol) was added dropwise and stirred at 60 ° C. for 3 hours. After completion of the reaction, a saturated saline solution was added to the reaction solution, and e was added.
Ther was extracted. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. A crude product (88.8 mg) obtained was subjected to silica gel column chromatography (chloroform: methan).
ol = 15: 1) and purified to 16 (19.4 mg, 97
%). Colorless crystals; ¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 8.18 and 8.15 (s, 1H), 6.90
and 6.10, 6.85 and 6.09 (A
B type, q, J = 10.6 Hz, 2H), 6.8
96-6.88, 6.74-6.72, 6.736
(M, 2H, Ar-H), 5.29-5.25, 4.6
1-4.50, 4.07-4.04 (m, 2H), 4.
73-4.70 (m, 1H), 4.68-4.65,
4.03-3.99, 3.73-3.66, 3.28-
3.21 (m, 2H), 3.86 and 3.85
(S, 3H), 3.23-3.17, 2.80-2.7.
3 (m, 2H), 2.12-1.98 (m, 2H).

<Synthesis 1-16> Synthesis of (±) -Galantamine 16 (15 mg, 0.05 mmol) of t under nitrogen stream
Add the Etrahydrofuran (1 ml) solution to -78
Stirred at ° C for 20 minutes. L-Selectr is added to the solution.
ide (0.21 ml, 1M in tetrahyd
rofuran, 0.21 mmol) was added dropwise.
Stirred at C for 3 hours. After the reaction is completed, lit
high aluminum hydride (4.6
mg, 0.12 mmol) of tetrahydrofu
A ran (1 ml) solution was added dropwise, and the mixture was stirred at 0 ° C. for 1 day. After completion of the reaction, water and a 10% aqueous sodium hydroxide solution were added to the reaction solution. After the mixture was filtered, the solvent was distilled off, and the resulting crude product was subjected to silica gel column chromatography (chloroform: methanol = 5: 1).
And purified by galantamine (6.5 mg, 45
%). White crystal; ¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 6.68 (d, J = 8.1 Hz, 1H, H-8),
6.64 (d, J = 8.2 Hz, 1H, H-7);
06 (d, J = 10.3 Hz, 1H, H-4a);
02 (dd, J = 10.5 Hz, 4.1 Hz, 1H, H
-4), 4.62 (brs, 1H, H-1), 4.15
(T, J = 4.8 Hz, 1H, H-3), 4.14
(D, J = 15.4 Hz, 1H, H-6), 3.84
(S, 3H, OMe), 3.73 (d, J = 14.7H)
z, 1H, H-6), 3.32 (t, J = 13.0H)
z, 1H, H-12), 3.09 (d, J = 14.5H)
z, 1H, H-12), 2.72-2.67 (m, 1
H, H-2), 2.43 (s, 3H, NMe) 2.31.
-2.06 (m, 1H, H-2), 2.04-1.89
(M, 1H, H-11), 1.70-1.60 (m, 1
H, H-11).

<Synthesis 1-17> Synthesis of (±) -Narwedine Ethylene glycol was added to 16 (20 mg, 0.067 mmol) of benzene solution under a nitrogen stream.
And pyridiniump-toluenesulfo
The mixture was refluxed at 110 ° C. for 2 days. After the completion of the reaction, the reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, and the solvent was distilled off.
rm extracted. After the extract was dried over anhydrous sodium sulfate and filtered, the solvent was distilled off to obtain a crude product (45.4 m
g) by silica gel column chromatography (chlo)
Roform: methanol = 10: 1) to give 17 (21.2 mg, 92%). Under nitrogen flow, 1
7 (13.2 mg, 0.05 mmol) in tetrah
ydrofuran (0.5ml) solution under ice-cooling
thium aluminum hydride (4.
4mg, 0.12mmol) tetrahydrof
Uran (1 ml) solution was added dropwise and stirred at room temperature for 19 hours. After completion of the reaction, a saturated aqueous solution of sodium sulfate was added to the reaction solution, and the mixture was dried over anhydrous sodium sulfate. After the mixture was filtered, the solvent was distilled off to obtain a crude product (20.7%).
mg) in tetrahydrofuran (0.5m
l) was added thereto, and 1N-HCl was added dropwise with stirring.
Stir for 2 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added dropwise to the reaction solution, followed by extraction with chloroform. After the extract was dried over anhydrous sodium sulfate and filtered, the solvent was distilled off, and the resulting crude product (18.0 mg) was subjected to silica gel column chromatography (chloroform: meth).
nanol = 10: 1)
(5.9 mg, 54%). These reaction processes are shown in FIG. White crystal; ¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 6.95 (d, J = 10.3 Hz, 1H, en
e), 6.70 (d, = 8.2 Hz, 1H, Ar-
H), 6.66 (d, J = 8.2 Hz, 1H, Ar-
H), 6.05 (d, J = 10.4, 1H, en
e),. 75-4.73 (m, 1H), 4.10 (d,
J = 15.4 Hz, 1H), 3.85 (s, 3H, OM)
e), 3.75 (d, J = 15.4 Hz, H), 3.1.
9 (m, 3H), 2.75 (dd, J = 17.9 Hz,
3.8Hz, 1H), 2.45 (s, 3H, NMe),
2.28 (dt, J = 13.2 Hz, 3.5 Hz, 1
H), 1.89-1.84 (m, 1H).

Table 1 Reaction yields of various coupling products obtained from the coupling reaction

[Table 1]

[Brief description of the drawings]

FIG. 1 A representative galantamine-type alkaloid synthesized in high yield according to the present invention.

Fig. 2 Reaction process for synthesizing various coupling reaction substrates from gallic acid methyl ester

Fig. 3 Coupling reaction process

FIG. 4 Galantamine-type skeleton formation reaction process

FIG. 5: Galantamine and nalwezin formation reaction process

Claims (13)

[Claims] 1. A compound of the general formula (Wherein R ₁ represents a protecting group for a hydrocarbon group or a hydrocarbon group containing an oxygen atom or an organosilicon group, and R ₂ represents a protecting group comprising an amide bond). Phenyliodine (III) bis (trifluoroacetate) represented by (OCOCF ₃ ) ₂
By reacting with a hypervalent iodine (III) reagent such as A method for producing an intramolecularly coupled product, which comprises producing the compound of formula (I). 2. The hypervalent iodine (III) reagent has the formula P
hI (OCOCF ₃₎ phenyl iodide emissions represented by ₂ (III) The method of manufacturing according to claim 1 which is bis (trifluoroacetate). 3. The method according to claim 1, wherein the reaction is carried out using a fluoro-substituted alcohol as a solvent. 4. The protecting group for R ₁ is a benzyl group, an allyl group, a tert-butyl group, a benzyloxymethyl group, a methoxymethyl group, a methoxyethyl group, a methoxybenzyl group, or a compound represented by the following formula: R ₃ R ₄ R ₅ Si _{-, (R 3,} R ₄ and _{R 5} is a hydrocarbon), in the manufacturing method according to claim 1 or 2 represented. 5. The method according to claim 1, wherein the protecting group comprising an amide bond of R ₂ is represented by the following formula: R ₆ —CO— (R ₆ represents a hydrogen atom or a fluoro-substituted hydrocarbon). 6. A compound of the general formula (Wherein R ₇ represents a hydroxyl group, an alkoxy group which may have a substituent, an acyloxy group or an oxygen atom which forms a carbonyl group together with an acyl group or a carbon atom constituting a ring, and R ₈ represents a hydrogen atom Or a hydrocarbon group which may have a substituent) or a galantamine-type amaryllidaceae alkaloid (Amaryllidaceaealkalo)
A method for producing galantamine-type amaryllidaceae alkaloids, which comprises a process for producing the intramolecularly coupled product according to any one of claims 1 to 5, which is a method for producing id). 7. A compound of the general formula (Wherein R represents a hydrocarbon group, a hydrocarbon group containing an oxygen atom or a protecting group for an organosilicon group) represented by the following formula:
7. The method for producing a galantamine-type amaryllidaceae alkaloid according to claim 6, wherein the reaction is carried out with bis (trifluoroacetate) to form an intramolecularly coupled product. 8. The following formula obtained by the coupling reaction according to claim 7. (Wherein R represents a hydrocarbon group, a hydrocarbon group containing an oxygen atom, or a protecting group for an organosilicon group). 6] And the phenolic hydroxyl group is converted to the following formula by trifluoromethanesulfonylation. And the triflate group is subjected to a reductive elimination reaction by the following formula: A method for producing galantamine-type amaryllidaceae alkaloids for producing the compound of formula (I). 9. A compound obtained by the method of claim 8, wherein the carbonyl group is stereoselectively reduced and the formyl group is reduced to give the following compound: A method for producing galantamine-type amaryllidaceae alkaloids for producing galantamine. 10. The compound obtained by the method of claim 8 wherein the carbonyl group is acetalized to give a compound of the general formula (Wherein R represents a hydrocarbon), and the compound is converted into a cyclic or acyclic acetal compound by reducing the formyl group and hydrolyzing the acetal group to obtain the following formula: A method for producing galantamine-type amaryllidaceae alkaloids for producing narwedine. 11. The compound obtained by the method according to claim 9, wherein the olefin site thereof is hydrogen-reduced to obtain the following formula: A method for producing galantamine-type amaryllidaceae alkaloids for producing lycoramine. 12. The compound obtained by the method of claim 8 by hydrolysis of the formyl group and a stereoselective reduction reaction of the carbonyl group to obtain the following compound: Norgalantamine
A method for producing galantamine-type amaryllidaceae alkaloids for producing e). 13. The compound obtained by the method according to claim 8, wherein after demethylation of the methoxy group, reduction of the formyl group and stereoselective reduction of the carbonyl group give the following formula: A method for producing galantamine-type amaryllidaceae alkaloids for producing sanguinine.