CN100398512C - Method for preparing (+-)-alpha-[(substituted amino) methyl]-benzene ring substituted group-phenylmethanol type compounds - Google Patents
Method for preparing (+-)-alpha-[(substituted amino) methyl]-benzene ring substituted group-phenylmethanol type compounds Download PDFInfo
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Abstract
The present invention relates to the field of medicine compounds, particularly to a method for preparing (+-)-alpha-[(substituted amino) methyl]-benzene ring substituted group-phenylmethanol type compounds. In the present invention, a protective reaction is carried out to 3, 4 or 5 position hydroxyl groups on a substituted acetophenone benzene ring, an ammonia substituting reaction is carried out to the halogen atoms in the obtained compound, a reduction reaction is carried out to the carbonyl in the obtained compound, and the protection of the compound is eliminated in order to obtain (+-)-alpha-[(substituted amino) methyl]-benzene ring substituted group-phenylmethanol type compounds. The method can be used for synthesizing a series of epinephrine medicines having a structure which is the same or similar to that of the compounds, and recovery is kept in the process of synthesis with little environmental pollution.
Description
Technical field
The present invention relates to the medical compounds field, be specifically related to the preparation method of (±) α-[(substituted amido) methyl]-benzene ring substitution group-phenylcarbinol compounds.
Background technology
(±) α-[(substituted amido) methyl]-benzene ring substitution group-phenylcarbinol and pharmacologically acceptable salt thereof are used as suprarenin in pharmaceutical industries, and it is clinical to be usually used in antishock and to relieving asthma, and especially the shock that penicillin anaphylaxis is caused is first-selected medicine.
Suprarenin all has directly powerful excitation to α and beta receptor, thereby can increase cardiac contractile force, accelerates heart rate, and cardiac output is increased, and systolic pressure raises.Simultaneously, suprarenin also has the positivity conduction to heart.Low dose of suprarenin is biphasic reaction to blood vessel, and at first excited α acceptor makes vasoconstriction, then presents persistent beta receptor excitation, causes vasodilation, and the blood vessel total peripheral resistance reduces.
Suprarenin can excited β
2Acceptor is removed bronchial muscular spasm rapidly, but diastole gastrointestinal smooth muscle also slows down gastrointestinal peristalsis, and the pupil radial muscle is also had excitation, can produce the mydriasis effect.Its blood sugar that can also raise can be used for treating hypoglycemic coma.
The chemical structure of adrenoceptor excitomotor and receptor-selective
As from the foregoing, by it to the selectivity of different adrenoceptors and be divided into three major types: 1. α receptor agonism medicine (α-adrenoceptor agonists).2. α, beta receptor excitomotor (α, β-adrenoceptor agonists).3. beta receptor excitomotor (β-adrenoceptor agonists).
The preparation of (±) α-[(substituted amido) methyl]-benzene ring substitution group-phenylcarbinol class pharmacologically acceptable salt is market and buys and carry out the composite of corresponding salify or solvent on the basis of this compound, and related methods of synthesis does not have description.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of (±) α-[(substituted amido) methyl]-benzene ring substitution group-phenylcarbinol compounds.
To achieve these goals, the present invention adopts following technical scheme:
The preparation method of (±) of the present invention α-[(substituted amido) methyl]-benzene ring substitution group-phenylcarbinol compounds comprises the steps:
(1) 3,4 or 5 hydroxyl on the substituting group methyl phenyl ketone phenyl ring is carried out protective reaction, the compound that obtains is suc as formula (I),
The protecting group of PFG representation hydroxy, protecting group is :-OCH
3,-OCH
2OCH
3,-OCH
2OCH
2C
6H
5,-OCH
2OCH
2CH
2OCH
3,-OCH
2OCH
2CH
2Si (CH
3)
3,-OCH
2SCH
3,-OCH (CH
3)
2,-O-c-C
6H
11,-OC (CH
3) ,-CH
2C
6H
5, 4-CH
3OC
6H
4CH
2O-,-OSi (CH
3)
3,-OSi (CH
3)
2C (CH
3)
3,-O
2CH ,-OCOCH
3,-OCOC
6H
5Or-O
2CC (CH
3)
3R
2Be methoxyl group or hydrogen;
The preparation of formula (I) compound is a starting raw material with the substituting group methyl phenyl ketone, uses a kind of organic solvent dissolution, and agitation condition drips corresponding protection reagent down and carries out the protective reaction of functional group.The solvent that uses can be ethanol, acetone, N; dinethylformamide, methylene dichloride, tetrahydrofuran (THF), pyridine; protection reagent is both can be the halo derivatives of above-mentioned protecting group; it also can be carboxylic acid derivative; the temperature of reaction is-20 ℃ of certain temperature of solvent boiling point so far, and this reaction can finish in 1 to 24 hour.
(2) halogenating reaction is carried out at the ortho position of carbonyl in formula (I) compound, the compound that obtains is suc as formula (II),
X represents halogen atom, can be chlorine, bromine or iodine;
Preparation to formula (II) compound is a starting raw material with formula (I) compound, uses a kind of organic solvent dissolution, drips corresponding halogenating agent under the intense agitation and carries out carbonyl adjacent halogenating reaction.The solvent that uses can be methylene dichloride, trichloromethane, tetracol phenixin, ethyl acetate, acetate, triethylamine, N, dinethylformamide, water, halogenating agent can be chlorine, simple substance bromine, iodine, cupric chloride, cupric bromide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, thionyl chloride, pyridine hydrobromide salt, temperature of reaction is-20 ℃ of certain temperature of solvent boiling point so far, and reaction can finish in 1 to 24 hour.
(3) halogen atom in formula (II) compound is carried out ammoniating reaction, the compound that obtains is suc as formula (III),
NR
5Represent substituted amido, substituted amido can be amino, methylamine, dimethylamine, ethamine, diethylamine, propylamine, Isopropylamine, butylamine, 2-methyl propylamine or TERTIARY BUTYL AMINE;
The preparation of formula (III) compound is a starting raw material with formula (II) compound, uses a kind of organic solvent dissolution, and agitation condition drips corresponding ammonia carries out halogen on the carbonyl ortho position for reagent replacement(metathesis)reaction down.The solvent that uses can be methylene dichloride, trichloromethane, ethyl acetate, acetone, ethanol, ammonia can be liquefied ammonia, methylamine, dimethylamine, ethamine, diethylamine, propylamine, Isopropylamine, butylamine, 2-methyl propylamine, TERTIARY BUTYL AMINE for reagent, temperature of reaction is-20 ℃ of certain temperature of solvent boiling point so far, and reaction can finish in 1 to 24 hour.
(4) carbonyl in formula (III) compound is carried out reduction reaction, the compound that obtains is suc as formula (IV);
The preparation of formula (IV) compound is a starting raw material with formula (III) compound, uses a kind of organic solvent dissolution, carries out the carbonyl reduction reaction to go back original reagent accordingly under the agitation condition.The solvent that uses can be ethanol, Virahol, the trimethyl carbinol, acetate, tetrahydrofuran (THF), trifluoroacetic acid, also original reagent can be liquefied ammonia, sodium Metal 99.5, potassium, lithium, sodium borohydride, borine, diisobutyl lithium hydride, aluminium lithium hydrogen, hydrogen, temperature of reaction is-78 ℃ of certain temperature of solvent boiling point so far, and reaction can finish in 1 to 24 hour.
(5) formula (IV) compound is gone protection, can obtain (±) α-[(substituted amido) methyl]-benzene ring substitution group-phenylcarbinol compounds, shown in formula V.
Wherein, R
1Representation hydroxy or hydrogen, R
2Representation methoxy or hydrogen, R
3Representation hydroxy or hydrogen, R4 representation hydroxy, methoxyl group or hydrogen, NR5 represents substituted amido.
The acquisition of target compound shown in the formula V is a starting raw material with formula (IV) compound, uses a kind of organic solvent dissolution, under the agitation condition to go protecting reagent to carry out the protective reaction of functional group accordingly.The solvent that uses can be methylene dichloride, trichloromethane, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, N; dinethylformamide, tetrahydrofuran (THF), toluene, methyl-sulphoxide, acetate, trifluoroacetic acid; removing to protect reagent can be iodo trimethyl silane, liquefied ammonia, sodium Metal 99.5, potassium, lithium, sodium cyanide, lithium iodide, aluminum chloride, alchlor, hydrofluoric acid, Hydrogen bromide, hydrochloric acid, pyridine hydrochloride, salt of wormwood, sodium bicarbonate, hydrogen; temperature of reaction is-50 ℃ of certain temperature of solvent boiling point so far, and reaction can finish in 1 to 24 hour.
The salify of target compound shown in the formula V is regulated the pH mode with mineral acid, hydrochloric acid or sulfuric acid and is carried out in organic solvent.The pH regulator scope reclaims the pharmacologically acceptable salt that the solid of separating out behind the organic solvent is (±) α-[(substituted amido) methyl]-benzene ring substitution group-phenylcarbinol between 1～5.
Preparation method of the present invention has following beneficial effect: preparation method of the present invention can synthesize that structure conforms to it or approaching serial suprarenin medicine, keeps in the building-up process reclaiming, and environmental pollution is little.
Embodiment
Embodiment 1
One, protective group
Getting 2-methoxyl group-4-hydroxy acetophenone 23 grams (0.139 mole) is put in 250 milliliters of three mouthfuls of glass reaction bottles of exsiccant; agitation condition adds 200 milliliters of pyridines for following 40 ℃; drip aceticanhydride 17 grams (0.147 mole) with dropping funnel subsequently; termination reaction after 2 hours; last handling process adopts the mode that strengthens water gaging to carry out; when pyridine is removed in washing, precipitate the product 4-ethanoyl-3-methoxyl group that is protected-phenylacetate crude product 28 grams (0.125 mole, yield 96%).
Two, carbonyl adjacent halogenating reaction
Getting 4-ethanoyl-3-methoxyl group-phenylacetate 25 grams (0.120 mole) is put in tail and connects in three mouthfuls of glass reaction bottles of sodium hydroxide absorption bottle; room temperature adds 200 milliliters of trichloromethanes under the agitation condition; feeding chlorine reaction termination reaction after 4 hours; last handling process is that the trichloromethane solvent is reclaimed in the rotatory evaporator evaporation; get final product to such an extent that 4-alpha-chloro ethanoyl-3-methoxyl group-phenylacetate crude product 23.3 restrains (0.096 mole, yield 80%).
Three, the amine of α-halogen is for displacement
Getting 4-alpha-chloro ethanoyl-3-methoxyl group-phenylacetate 20 grams (0.082 mole) is put in three mouthfuls of glass reaction bottles; room temperature adds 200 milliliters of ethyl acetate under the agitation condition; be warming up to reflux state after half an hour; drip Isopropylamine reaction 3 hours; last handling process is that ethyl acetate solvent is reclaimed in the rotatory evaporator evaporation; obtain 4-α-isopropylamine base-ethanoyl-3-methoxyl group-phenylacetate 17.4 gram crude products (0.067 mole, yield 80%).
Four, the reduction of carbonyl
Getting 4-α-isopropylamine base-ethanoyl-3-methoxyl group-phenylacetate 15 grams (0.057 mole) is put in three mouthfuls of glass reaction bottles; room temperature adds 150 milliliters of tetrahydrofuran (THF)s under the agitation condition; add sodium borohydride 5.39 gram (0.14 mole) reactions 6 hours; last handling process is for adding the less water termination reaction; subsequently with ethyl acetate extraction; ethyl acetate solvent is reclaimed in the rotatory evaporator evaporation; obtain (±) 4-(1-hydroxyl-2-isopropylamine base-ethyl)-3-methoxyacetic acid phenyl ester 12.8 gram crude products (0.048 mole, yield 84%).
Five, functional group go the protection
Getting 4-(1-hydroxyl-2-isopropylamine base-ethyl)-3-methoxyacetic acid phenyl ester 10 grams (0.037 mole) is put in three mouthfuls of glass reaction bottles, room temperature adds 100 milliliters of ethanol under the agitation condition, add salt of wormwood 2.01 gram (0.019 mole) reactions 8 hours, last handling process is for adding the less water termination reaction, subsequently with ethyl acetate extraction, ethyl acetate and alcohol solvent are reclaimed in the rotatory evaporator evaporation, obtain (±) α-[(isopropylamine base) methyl]-2-methoxyl group-4-hydroxyl-phenylcarbinol 7.5 and restrain (0.048 mole of crude product, yield 90%).
Embodiment 2
One, protective group
Getting 2-methoxyl group-4-hydroxy acetophenone 23 grams (0.139 mole) is put in 250 milliliters of three mouthfuls of glass reaction bottles of exsiccant; room temperature adds 200 milliliters of N under the agitation condition; dinethylformamide; add sodium hydride 3.65 gram (0.153 mole) reactions after 1 hour; drip methoxymethyl chlorine 12.3 grams (0.153 mole) with dropping funnel; termination reaction after 3 hours; last handling process adopts the mode that strengthens water gaging to carry out; remove N in washing; in the time of dinethylformamide; precipitate the product 2-methoxyl group-4-methoxymethyl ether that is protected-methyl phenyl ketone crude product 26.3 grams (0.125 mole, yield 90%).
Two, carbonyl adjacent halogenating reaction
Getting 2-methoxyl group-4-methoxymethyl ether-methyl phenyl ketone 20 grams (0.095 mole) is put in three mouthfuls of glass reaction bottles, room temperature adds 150 milliliters of acetate under the agitation condition, drip simple substance bromine 16 grams (0.10 mole) with dropping funnel, termination reaction after 4 hours, after last handling process adopts and strengthens the water gaging dilution, with ethyl acetate extraction, ethyl acetate solvent is reclaimed in the rotatory evaporator evaporation, obtain 2-methoxyl group-4-methoxymethyl ether-alpha-brominated methyl phenyl ketone crude product 19.2 grams (0.067 mole, yield 70%).
Three, the amine of α-halogen is for displacement
Getting 2-methoxyl group-4-methoxymethyl ether-methyl phenyl ketone 15 grams (0.052 mole) is put in three mouthfuls of glass reaction bottles, room temperature adds 200 milliliters in acetone under the agitation condition, be warming up to reflux state after half an hour, drip Isopropylamine reaction 3 hours, last handling process is that acetone solvent is reclaimed in the rotatory evaporator evaporation, obtain 2-methoxyl group-4-methoxymethyl ether-α-isopropylamine base methyl phenyl ketone 11.82 gram crude products (0.044 mole, yield 85%).
Four, the reduction of carbonyl
Getting 2-methoxyl group-4-methoxymethyl ether-α-isopropylamine base methyl phenyl ketone 10 grams (0.037 mole) is put in three mouthfuls of glass reaction bottles, room temperature adds 150 milliliters of ethanol under the agitation condition, add sodium 2.13 gram (0.093 mole) reactions 4 hours, last handling process adds the less water termination reaction, subsequently with ethyl acetate extraction, ethyl acetate solvent is reclaimed in the rotatory evaporator evaporation, obtain (±) 2-methoxyl group-4-methoxymethyl ether-α-isopropylamine base methyl phenyl ketone 5.48 and restrain (0.02 mole of crude product, yield 54%).
Five, functional group go the protection
Getting 2-methoxyl group-4-methoxymethyl ether-α-isopropylamine base methyl phenyl ketone 5 grams (0.019 mole) is put in three mouthfuls of glass reaction bottles, room temperature adds 100 milliliters of methylene dichloride under the agitation condition, dripping bromine was for trimethyl silane 5.81 gram (0.038 mole) reactions 4 hours, last handling process adds the less water termination reaction, subsequently with dichloromethane extraction, rotatory evaporator evaporation dichloromethane solvent, obtain (±) α-[(isopropylamine base) methyl]-2-methoxyl group-4-hydroxyl-phenylcarbinol 3.64 and restrain (0.016 mole of crude product, yield 84%).
The salify of embodiment 3 (±) α-[(isopropylamine base) methyl]-2-methoxyl group-4-hydroxyl-phenylcarbinol
Getting 5 gram (±) α-[(isopropylamine base) methyl]-2-methoxyl group-4-hydroxyl-phenylcarbinols is dissolved in 200 milliliters of ethanol, regulating pH with concentrated hydrochloric acid is 1, reclaim alcohol solvent with the rotatory evaporator evaporation subsequently, the solid of separating out is (±) α-[(substituted amido) methyl]-benzene ring substitution group-benzyl alcohol hydrochloride.
The salify of embodiment 4 (±) α-[(isopropylamine base) methyl]-2-methoxyl group-4-hydroxyl-phenylcarbinol
Getting 5 gram (±) α-[(isopropylamine base) methyl]-2-methoxyl group-4-hydroxyl-phenylcarbinols is dissolved in 200 milliliters of acetone, regulating pH with the vitriol oil is 2, reclaim acetone solvent with the rotatory evaporator evaporation subsequently, the solid of separating out is (±) α-[(substituted amido) methyl]-benzene ring substitution group-phenylcarbinol vitriol.
Claims (6)
1. the preparation method of (±) α-[(substituted amido) methyl]-benzene ring substitution group-phenylcarbinol compounds comprises the steps:
(1) 4 hydroxyl on the hydroxyl-substituted ethyl ketone phenyl ring is carried out protective reaction, the compound that obtains is suc as formula (I),
The protecting group of PFG representation hydroxy, protecting group is :-OCH
3,-OCH
2OCH
3,-OCH
2OCH
2C
6H
5,-OCH
2OCH
2CH
2OCH
3,-OCH
2OCH
2CH
2Si (CH
3)
3,-OCH
2SCH
3,-OCH (CH
3)
2,-O-c-C
6H
11,-OC (CH
3) ,-CH
2C
6H
5, 4-CH
3OC
6H
4CH
2O-,-OSi (CH
3)
3,-OSi (CH
3)
2C (CH
3)
3,-O
2CH ,-OCOCH
3,-OCOC
6H
5Or-O
2CC (CH
3)
3R
2Be methoxyl group or hydrogen;
(2) halogenating reaction is carried out at the ortho position of carbonyl in formula (I) compound, the compound that obtains is suc as formula (II),
X represents halogen atom, is chlorine, bromine or iodine;
(3) halogen atom in formula (II) compound is carried out ammoniating reaction, the compound that obtains is suc as formula (III),
NR
5Represent substituted amido, substituted amido is amino, methylamine, dimethylamine, ethamine, diethylamine, propylamine, Isopropylamine, butylamine, 2-methyl propylamine or TERTIARY BUTYL AMINE;
(4) carbonyl in formula (III) compound is carried out reduction reaction, the compound that obtains is suc as formula (IV);
(5) formula (IV) compound is gone protection, promptly obtain (±) α-[(substituted amido) methyl]-benzene ring substitution group-phenylcarbinol compounds, shown in formula V.
Wherein, R
1Representation hydroxy or hydrogen, R
2Representation methoxy or hydrogen, R
3Representation hydroxy or hydrogen, R
4Representation hydroxy, methoxyl group or hydrogen, NR
5Represent substituted amido.
2. preparation method according to claim 1, it is characterized in that the described hydroxyl protection reaction of step (1) is: with hydroxyl-substituted ethyl ketone is starting raw material, use organic solvent dissolution, agitation condition drips corresponding protection reagent down and carries out the protective reaction of functional group; Described organic solvent is ethanol, acetone, N, dinethylformamide, methylene dichloride, tetrahydrofuran (THF) or pyridine; Halo derivatives or carboxylic acid derivative that described protection reagent is above-mentioned protecting group, the temperature of reaction be-20 ℃ to the solvent for use boiling temperature, the reaction times is 1～24 hour.
3. preparation method according to claim 1, it is characterized in that the described halogenating reaction of step (2) is: with formula (I) compound is starting raw material, uses dissolution with solvents, drips corresponding halogenating agent under the intense agitation and carries out carbonyl adjacent halogenating reaction; Described solvent is methylene dichloride, trichloromethane, tetracol phenixin, ethyl acetate, acetate, triethylamine, N, dinethylformamide or water; Described halogenating agent is chlorine, simple substance bromine, iodine, cupric chloride, cupric bromide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, thionyl chloride or pyridine hydrobromide salt; Temperature of reaction be-20 ℃ to the solvent for use boiling temperature, the reaction times is 1～24 hour.
4. preparation method according to claim 1, it is characterized in that the described ammoniating reaction of step (3) is: with formula (II) compound is starting raw material, use dissolution with solvents, agitation condition drips corresponding ammonia carries out halogen on the carbonyl ortho position for reagent replacement(metathesis)reaction down; Described solvent is methylene dichloride, trichloromethane, ethyl acetate, acetone or alcohol; Described ammonia is liquefied ammonia, methylamine, dimethylamine, ethamine, diethylamine, propylamine, Isopropylamine, butylamine, 2-methyl propylamine or TERTIARY BUTYL AMINE for reagent; Temperature of reaction be-20 ℃ to the solvent for use boiling temperature, the reaction times is 1～24 hour.
5. preparation method according to claim 1, it is characterized in that the described reduction reaction of step (4) is: with formula (III) compound is starting raw material, uses dissolution with solvents, carries out the carbonyl reduction reaction to go back original reagent accordingly under the agitation condition; Described solvent is ethanol, Virahol, the trimethyl carbinol, acetate, tetrahydrofuran (THF) or trifluoroacetic acid; The described original reagent of going back is liquefied ammonia, sodium Metal 99.5, potassium, lithium, sodium borohydride, borine, diisobutyl lithium hydride, aluminium lithium hydrogen or hydrogen; Described temperature of reaction be-78 ℃ to the solvent for use boiling temperature, the reaction times is 1～24 hour.
6. preparation method according to claim 1, it is characterized in that the described reduction reaction of step (5) is: with formula (IV) compound is starting raw material, uses dissolution with solvents, under the agitation condition to go protecting reagent to carry out the protective reaction of functional group accordingly; Described solvent is methylene dichloride, trichloromethane, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, N, dinethylformamide, tetrahydrofuran (THF), toluene, methyl-sulphoxide, acetate or trifluoroacetic acid; It is described that to remove to protect reagent be iodo trimethyl silane, liquefied ammonia, sodium Metal 99.5, potassium, lithium, sodium cyanide, lithium iodide, aluminum chloride, alchlor, hydrofluoric acid, Hydrogen bromide, hydrochloric acid, pyridine hydrochloride, salt of wormwood, sodium bicarbonate or hydrogen; Temperature of reaction be-50 ℃ to the solvent for use boiling temperature, the reaction times is 1～24 hour.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US364896A (en) * | 1887-06-14 | Door-sill | ||
| US3644353A (en) * | 1966-09-23 | 1972-02-22 | Allen & Hanburys Ltd | 4 hydroxy-alpha'aminomethyl-m-xylene-alpha' alpha**3-diols |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US364896A (en) * | 1887-06-14 | Door-sill | ||
| US3644353A (en) * | 1966-09-23 | 1972-02-22 | Allen & Hanburys Ltd | 4 hydroxy-alpha'aminomethyl-m-xylene-alpha' alpha**3-diols |
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Granted publication date: 20080702 Termination date: 20160421 |