CN107417585B - A kind of synthetic method of pharmaceutical intermediate - Google Patents
A kind of synthetic method of pharmaceutical intermediate Download PDFInfo
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- CN107417585B CN107417585B CN201710481790.3A CN201710481790A CN107417585B CN 107417585 B CN107417585 B CN 107417585B CN 201710481790 A CN201710481790 A CN 201710481790A CN 107417585 B CN107417585 B CN 107417585B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/06—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to a kind of synthetic method of pharmaceutical intermediate, a kind of method preparing (2S, 3R) -2- amino -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate (I).The method includes by compound (2R; 3R) -2- amino -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate (II) is in organic solvent; after being reacted with aldehyde and resolving agent heating; cold filtration obtains the compound of target product Formulas I through alkali is free in solvent.Method product yield high of the invention, simple process are conducive to industrialized production.
Description
Technical field
The invention belongs to chemicals technical fields, and in particular to one kind (2S, 3R) -2- amino -3- hydroxyl -3- (4- first
Sulfonvlphenyl) ethyl propionate (I) synthetic method.
Background technique
(2S, 3R) -2- amino -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate (I) is Thiamphenicol
(Thiamphenicol) and the crucial chiral intermediate of the drugs such as Florfenicol (Florfenicol), abbreviation d- ethyl ester.Its
Structural formula is as follows:
United States Patent (USP) US3927054A is described from racemic Soviet Union's formula 2- amino -3- hydroxyl -3- (4- mesyl benzene
Base) ethyl propionate splits to obtain required (2S, 3R) -2- amino -3- hydroxyl -3- (4- methanesulfonylphenYl) by d- tartaric acid
Ethyl propionate (I), but because being traditional chemical resolution, theoretical yield is less than 50%.
Article (J.Agric.Food Chem., 2013,61 (1), pp 157-166) is disclosed with racemic Soviet Union's formula 2-
Amino -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate is raw material, by the fractionation of 435 enzyme of Novezyme, final
The product for being 35.13% to ee value.
Patent CN101265220A is reported with L- Su-Type -2 -- amino-3- hydroxyl-3- (4- methanesulfonylphenYl) propionic acid second
Ester is starting material, obtains required (2S, 3R) -2- amino-by acylation, cyclisation hydroxyl overturning, amino configuration reversal, hydrolysis
3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate (I), this route is longer, and in this step of the amino configuration reversal of alkali effect
It overturns and is not thorough.
Above-mentioned (2S, 3R) -2- amino -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate (I) reported in the literature is universal
Yield is not high, and chiral selectivity is poor, complex operation, is unfavorable for industrialized production, and therefore, this field needs to develop one
Kind of technological operation is simple, higher (2S, 3R) -2- amino -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate (I) of yield
Synthetic method.
Summary of the invention
The purpose of the present invention is to overcome the deficiency in the prior art, provides a kind of (2S, 3R) -2- ammonia being convenient for industrialized production
The synthetic method of base -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate (I).
The route of synthetic method of the present invention is as shown in lower section:
The present invention is using Formula II compound as raw material, the specific steps of synthesis are as follows:
After Formula II compound is reacted with aldehyde and resolving agent heating in organic solvent, cold filtration, by filter residue in solvent
It is middle to obtain compound of formula I through alkali is free.
Preferably, Formula II compound, aldehyde and resolving agent are mixed with organic solvent, is heated to reflux and slow cooling is to room
Temperature, filtering, filter residue is added to the water, and alkali is added, pH is adjusted to 7~9, and then cooling, filtering obtains compound of formula I.
Preferably, the molar ratio of Formula II compound and aldehyde used is 1:(0.02~1)；Preferably 1:(0.05~0.5).
Preferably, the molar ratio of Formula II compound and resolving agent used is 1:(0.5~1.5)；Preferably 1:(0.8~
1.2)。
Preferably, the ratio of the compound and organic solvent of Formula II is 1mmol:(1mL~100mL), more preferably
1mmol:(1mL~5mL).
Preferably, the aldehyde is selected from salicylide and its derivative, preferably includes salicylide, 5- nitrosalicylaldehyde, 3- methyl
One of salicylide and o-vanillin are a variety of, more preferably salicylide or 5- nitrosalicylaldehyde.
Preferably, the resolving agent is selected from L-TARTARIC ACID and its derivative, preferably L-TARTARIC ACID and L- dibenzoyl wine
One of stone acid is a variety of, more preferably L-TARTARIC ACID.
Preferably, organic solvent is alcohols solvent, preferably includes the short chain alcohol with 1~7 carbon atom, more preferable first
One of alcohol, ethyl alcohol, isopropanol, the tert-butyl alcohol and n-butanol are a variety of, most preferably methanol or ethyl alcohol.
Preferably, the free used alkali be selected from the conventional use of inorganic base that tartaric acid or derivatives thereof can be made free or
Organic base is preferably selected from bicarbonate, carbonate, hydroxide and the organic amine of potassium and sodium, is more preferably selected from sodium bicarbonate, carbon
Sour sodium and sodium hydroxide.
The main component of filter residue is the tartrate of compound of formula I in the method for the present invention.
In the present invention, filter residue is dissociated in solvent through alkali using acid-base neutralization method commonly used in the art, wherein institute
It is the commonly used in the art solvent for keeping tartrate mesotartaric acid free, preferably water or alcoholic solvent with solvent, more preferably
For water.
Reaction temperature in the method for the present invention by can make use solvent refluxing temperature；Reacting heating time is from heating
Start that a large amount of solids are precipitated into system and amount of solid no longer obviously increases the required time.
In the method for the invention, Formula II compound carries out schiff bases condensation with aldehyde first, then acid stronger ester group
α-the hydrogen at ortho position is seized and racemization by alkali, forms the diastereoisomer for being configured as R type and S type for generating amino, the two can
With free conversion.Then by the addition of L-TARTARIC ACID or derivatives thereof, induced product is converted to S type product (i.e. D- ethyl ester),
Ultimately generate the tartrate of target compound I:
The beneficial effects of the present invention are the reaction yields for greatly improving target product compound of formula I (to reach as high as
86%), and present invention process operation is simple, reacting the configuration conversion being related to, to belong to Dynamic Resolution process, reaction speed fast,
Suitable for industrialized production.
Specific embodiment
Various raw materials and reagents used in the embodiment of the present invention are commercially available purchase, manufacturer's packet unless otherwise instructed
Acros, Greagent, Adamas and TCI etc. are included, reagent purity is in addition to 3- cresotinic acid aldehyde > 98%, remaining is >=99%.
The amount of product compound of formula I is detected by AD-H chirality HPLC in embodiment.Chirality HPLC instrument is Shimadzu Corporation
SPD-10A type liquid chromatograph.
Embodiment 1 is by Formula II compound (2R, 3R) -2- amino -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate
(2.87g, 10mmol), 5- nitrosalicylaldehyde (0.17g, 1mmol), L-TARTARIC ACID (1.50g, 10mmol) and methanol (10mL) are mixed
It closes, is heated to reflux and a large amount of solids are no longer precipitated within 30 minutes into reaction system, water is added in slow cooling to room temperature, filtering, filter cake
In (15mL).Sodium carbonate is added and adjusts pH value to 8, is filtered after being placed in ice-water bath cooling 1h, obtains compound of formula I (2S, 3R) -2-
Amino -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate 2.45g, yield 85.4%.
Embodiment 2 by Formula II compound (2.87g, 10mmol), salicylide (0.12g, 1mmol), L-TARTARIC ACID (1.50g,
It 10mmol) is mixed with ethyl alcohol (10mL), is heated to reflux and a large amount of solids are no longer precipitated within 30 minutes into reaction system, slow cooling is extremely
Room temperature, filtering, filter cake are added in water (15mL).Sodium bicarbonate is added and adjusts pH value to 8, is taken out after being placed in ice-water bath cooling 1h
Filter, obtains compound of formula I 2.17g, yield 75.6%.
Embodiment 3 is by Formula II compound (2.87g, 10mmol), salicylide (0.06g, 0.5mmol), L-TARTARIC ACID
(1.20g, 8mmol) is mixed with methanol (20mL), is heated to reflux 30 minutes and a large amount of solids are no longer precipitated into reaction system, slowly
It is cooled to room temperature, filtering, filter cake are added in water (15mL).Sodium bicarbonate is added and adjusts pH value to 8, is placed in ice-water bath cooling 1h
After filter, obtain compound of formula I 2.32g, yield 80.8%.
Embodiment 4 is by Formula II compound (2.87g, 10mmol), o-vanillin (0.76g, 5mmol), L-TARTARIC ACID
(1.80g, 12mmol) is mixed with isopropanol (50mL), is heated to reflux 30 minutes and a large amount of solids are no longer precipitated into reaction system,
Slow cooling to room temperature, filtering, filter cake is added in water (15mL).Sodium hydroxide is added and adjusts pH value to 8, is placed in cold in ice-water bath
But it is filtered after 1h, obtains compound of formula I 2.21g, yield 77.0%.
Embodiment 5 is by Formula II compound (2.87g, 10mmol), 5- nitrosalicylaldehyde (0.033g, 0.2mmol), L- hexichol
Formyl tartaric acid (5.38g, 15mmol) is mixed with ethyl alcohol (200mL), is heated to reflux 30 minutes and is no longer precipitated into reaction system
A large amount of solids, slow cooling to room temperature, filtering, filter cake are added in water (15mL).Sodium bicarbonate is added and adjusts pH value to 8, is placed in
It is filtered after cooling 1h in ice-water bath, obtains compound of formula I 1.98g, yield 69.1%.
Embodiment 6 is by Formula II compound (2.87g, 10mmol), 5- nitrosalicylaldehyde (1.67g, 10mmol), L-TARTARIC ACID
(0.75g, 5mmol) is mixed with n-butanol (1000mL), is heated to reflux 30 minutes and a large amount of solids are no longer precipitated into reaction system,
Slow cooling to room temperature, filtering, filter cake is added in water (15mL).Sodium hydroxide is added and adjusts pH value to 8, is placed in cold in ice-water bath
But it is filtered after 1h, obtains compound of formula I 2.09g, yield 72.9%.
Embodiment 7 is by Formula II compound (2.87g, 10mmol), 3- cresotinic acid aldehyde (0.27g, 2mmol), L- hexichol first
Acyl tartaric acid (3.58g, 10mmol) is mixed with the tert-butyl alcohol (50mL), is heated to reflux 30 minutes and is no longer precipitated greatly into reaction system
Solid, slow cooling to room temperature are measured, filtering, filter cake are added in water (15mL).Sodium hydroxide is added and adjusts pH value to 8, is placed in ice
It is filtered after cooling 1h in water-bath, obtains compound of formula I 2.15g, yield 75.1%.
Claims (17)
1. a kind of method of synthetic compound of formula i, comprising the following steps:
In organic solvent by Formula II compound, after reacting with aldehyde and resolving agent heating, cold filtration passes through filter residue in solvent
Alkali is free to obtain compound of formula I,
Wherein the aldehyde is selected from one of salicylide, 5- nitrosalicylaldehyde, 3- cresotinic acid aldehyde and o-vanillin or a variety of；
The resolving agent is one or both of L-TARTARIC ACID and L- dibenzoyl tartaric acid.
2. the method according to claim 1, wherein Formula II compound, aldehyde and resolving agent and organic solvent are mixed
It closes, is heated to reflux and slow cooling is to room temperature, filter residue is added to the water by filtering, and alkali is added, pH is adjusted to 7~9, then cold
But, filtering obtains compound of formula I.
3. the method according to claim 1, wherein the molar ratio of the Formula II compound and aldehyde is 1:(0.02
~1).
4. according to the method described in claim 3, it is characterized in that, the molar ratio of the Formula II compound and aldehyde is 1:(0.05
~0.5).
5. method described in any one of claim 1 to 3, which is characterized in that the Formula II compound and resolving agent
Molar ratio is 1:(0.5~1.5).
6. according to the method described in claim 5, it is characterized in that, the molar ratio of the Formula II compound and resolving agent is 1:
(0.8~1.2).
7. method described in any one of claim 1 to 3, which is characterized in that the Formula II compound and organic solvent
Ratio be 1mmol:(1mL~100mL).
8. the method according to the description of claim 7 is characterized in that the ratio of the Formula II compound and organic solvent is
1mmol:(1mL~5mL).
9. method described in any one of claim 1 to 3, which is characterized in that the aldehyde is salicylide or 5- nitro water
Poplar aldehyde.
10. method described in any one of claim 1 to 3, which is characterized in that the resolving agent is L-TARTARIC ACID.
11. method described in any one of claim 1 to 3, which is characterized in that the organic solvent is alcohols solvent.
12. according to the method for claim 11, which is characterized in that the alcohols solvent is short with 1~7 carbon atom
Chain alcohol.
13. according to the method for claim 11, which is characterized in that the alcohols solvent be selected from methanol, ethyl alcohol, isopropanol,
One of the tert-butyl alcohol and n-butanol are a variety of.
14. according to the method for claim 11, which is characterized in that the alcohols solvent is methanol or ethyl alcohol.
15. method described in any one of claim 1 to 3, which is characterized in that the alkali, which is selected from, can make the resolving agent
Free inorganic base or organic base.
16. according to the method for claim 15, which is characterized in that the alkali is selected from bicarbonate, the carbonate of potassium and sodium
And hydroxide and organic amine.
17. according to the method for claim 15, which is characterized in that the alkali is selected from sodium bicarbonate, sodium carbonate and hydroxide
Sodium.
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| CN109705003B (en) * | 2019-01-25 | 2020-12-25 | 湖北中牧安达药业有限公司 | Racemization method of L-p-methylsulfonyl phenyl serine ethyl ester |
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| US3733352A (en) * | 1969-07-29 | 1973-05-15 | Sumitomo Chemical Co | Preparation of d-threo-1-p-methyl-sulfonylphenyl-2-dichloro-acet-amidopropane-1,3-diol |
| CN1095832C (en) * | 2000-12-12 | 2002-12-11 | 吉林大学 | Splitting of DL-threo-p-methylsulfonyl methyl serine ester |
| CN1173933C (en) * | 2001-06-01 | 2004-11-03 | 中国科学院上海有机化学研究所 | Preparing D-(-)-Su's 1-R-substituted phenyl-2-difluoro acetoamino-3-fluoro-1-propanol from L type substituted phenyl serine ester |
| CN102503810B (en) * | 2011-11-02 | 2014-05-21 | 浙江科技学院 | Method for recovering and recycling L-tartaric acid |
| CN104355990B (en) * | 2014-10-16 | 2016-09-07 | 安徽扬子化工有限公司 | Method for recycling and mechanically using L- (+) -tartaric acid in D-ethyl ester production |
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