CN107417585A - A kind of synthetic method of pharmaceutical intermediate - Google Patents
A kind of synthetic method of pharmaceutical intermediate Download PDFInfo
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- CN107417585A CN107417585A CN201710481790.3A CN201710481790A CN107417585A CN 107417585 A CN107417585 A CN 107417585A CN 201710481790 A CN201710481790 A CN 201710481790A CN 107417585 A CN107417585 A CN 107417585A
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- formula
- compound
- aldehyde
- salicylide
- tartaric acid
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- CEEHCOWSYFANRT-WDEREUQCSA-N CCOC([C@H]([C@@H](c(cc1)ccc1S(C)(=O)=O)O)N)=O Chemical compound CCOC([C@H]([C@@H](c(cc1)ccc1S(C)(=O)=O)O)N)=O CEEHCOWSYFANRT-WDEREUQCSA-N 0.000 description 1
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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, method that one kind prepares (4 methanesulfonylphenYl) ethyl propionate (I) of 3 hydroxyl of (2S, 3R) 2 amino 3.Methods described is included compound (2R; 3R) (4 methanesulfonylphenYl) ethyl propionate (II) of 2 amino, 3 hydroxyl 3 is in organic solvent; after aldehyde and resolving agent heating response; cold filtration, the compound of target product Formulas I is obtained through alkali is free in solvent.The method product yield high of the present invention, simple process, beneficial to industrialized production.
Description
Technical field
The invention belongs to chemicals technical field, and in particular to one kind (2S, 3R) -2- amino -3- hydroxyls -3- (4- first
Sulfonvlphenyl) ethyl propionate (I) synthetic method.
Background technology
(2S, 3R) -2- amino -3- hydroxyls -3- (4- methanesulfonylphenYls) ethyl propionates (I) are Thiamphenicols
(Thiamphenicol) and the medicine such as Florfenicol (Florfenicol) crucial chiral intermediate, abbreviation d- ethyl esters.Its
Structural formula is as follows：
United States Patent (USP) US3927054A is described from racemic Soviet Union's formula 2- amino -3- hydroxyls -3- (4- mesyl benzene
Base) ethyl propionate splits to obtain required (2S, 3R) -2- amino -3- hydroxyls -3- (4- methanesulfonylphenYls) by d- tartaric acid
Ethyl propionate (I), but because be traditional chemical resolution, therefore 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- hydroxyls -3- (4- methanesulfonylphenYls) ethyl propionate is raw material, by the fractionation of the enzymes of Novezyme 435, final
To the product that ee values are 35.13%.
Patent CN101265220A is reported with L- Su-Type -2 -- amino-3- hydroxyls-3- (4- methanesulfonylphenYls) propionic acid second
Ester is initiation material, by acylation, cyclisation hydroxyl upset, amino configuration reversal, hydrolyze obtain required (2S, 3R) -2- amino -
3- hydroxyls -3- (4- methanesulfonylphenYls) ethyl propionate (I), this route is longer, and in this step of the amino configuration reversal of alkali effect
Upset is not thorough.
(2S, 3R) -2- amino -3- hydroxyls -3- (4- methanesulfonylphenYls) ethyl propionates (I) of above-mentioned document report are universal
Yield is not high, and chiral selectivity is poor, complex operation, is unfavorable for industrialized production, and therefore, this area needs exploitation one
(2S, 3R) -2- amino -3- hydroxyls -3- (4- methanesulfonylphenYls) ethyl propionate (I) that kind technological operation is simple, yield is higher
Synthetic method.
The content of the invention
A kind of present invention aims to overcome that the deficiencies in the prior art, there is provided (2S, 3R) -2- ammonia for being easy to industrialized production
The synthetic method of base -3- hydroxyls -3- (4- methanesulfonylphenYls) ethyl propionates (I).
The route of synthetic method of the present invention is for example shown below：
Using Formula II compound as raw material, synthesis concretely comprises the following steps the present invention：
By Formula II compound in organic solvent with after aldehyde and resolving agent heating response, cold filtration, by filter residue in solvent
It is middle free through alkali and obtain compound of formula I.
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 is added alkali and adjusted pH to 7~9, is then cooled down, is filtered and obtain compound of formula I.
Preferably, Formula II compound and the mol ratio of aldehyde used are 1:(0.02~1)；Preferably 1：(0.05~0.5).
Preferably, Formula II compound and the mol ratio of resolving agent used are 1:(0.5~1.5)；Preferably 1:(0.8~
1.2)。
Preferably, the compound of Formula II and the ratio of organic solvent are 1mmol:(1mL~100mL), more preferably
1mmol:(1mL~5mL).
Preferably, the aldehyde is selected from salicylide and its derivative, preferably includes salicylide, 5- nitrosalicylaldehydes, 3- methyl
One or more in salicylide and o-vanillin, more preferably salicylide or 5- nitrosalicylaldehydes.
Preferably, the resolving agent is selected from L-TARTARIC ACID and its derivative, preferably L-TARTARIC ACID and L- dibenzoyl wine
One or more in stone acid, more preferably L-TARTARIC ACID.
Preferably, organic solvent is alcohols solvent, preferably includes the short chain alcohol with 1~7 carbon atom, more preferably first
One or more in alcohol, ethanol, isopropanol, the tert-butyl alcohol and n-butanol, most preferably methanol or ethanol.
Preferably, the free used alkali be selected from conventional use of inorganic base that tartaric acid or derivatives thereof can be made free or
Organic base, bicarbonate, carbonate, hydroxide and the organic amine of potassium and sodium are preferably selected from, is more preferably selected from sodium acid carbonate, carbon
Sour sodium and sodium hydroxide.
The main component of filter residue is the tartrate of compound of formula I in the inventive method.
In the present invention, filter residue is dissociated in solvent through alkali using acid-base neutralization method commonly used in the art, wherein institute
Make the free solvent of tartrate mesotartaric acid, preferably water or alcoholic solvent with solvent for commonly used in the art, more preferably
For water.
Reaction temperature in the inventive method by can make use solvent refluxing temperature；It is from heating to react the heat time
Start to separate out a large amount of solids into system and amount of solid no longer substantially 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 types and S types of generation amino, Liang Zheke
With free conversion.Then converted by the addition of L-TARTARIC ACID or derivatives thereof, induced product to S types product (i.e. D- ethyl esters),
Ultimately generate target compound I tartrate：
The beneficial effects of the present invention are the reaction yield for greatly improving target product compound of formula I (to reach as high as
86%), and present invention process operation is simple, it is fast to react configuration conversion category Dynamic Resolution process, the reaction speed being related to,
Suitable for industrialized production.
Embodiment
Various raw materials and reagent used are commercially available purchase unless otherwise instructed in the embodiment of the present invention, and manufacturer wraps
Acros, Greagent, Adamas and TCI etc. are included, reagent purity removes 3- cresotinic acid aldehyde>Outside 98%, remaining is >=99%.
The amount of product compound of formula I is detected by AD-H chiralitys HPLC in embodiment.The chiral HPLC instruments are Shimadzu Corporation
SPD-10A type liquid chromatographs.
Embodiment 1 is by Formula II compound (2R, 3R) -2- amino -3- hydroxyls -3- (4- methanesulfonylphenYls) ethyl propionate
(2.87g, 10mmol), 5- nitrosalicylaldehydes (0.17g, 1mmol), L-TARTARIC ACID (1.50g, 10mmol) and methanol (10mL) are mixed
Close, be heated to reflux no longer separating out within 30 minutes a large amount of solids, slow cooling to room temperature into reaction system, filtering, filter cake add water
In (15mL).Add sodium carbonate and adjust pH value to 8, be placed in ice-water bath after cooling down 1h and filter, obtain compound of formula I (2S, 3R) -2-
Amino -3- hydroxyls -3- (4- methanesulfonylphenYls) 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,
10mmol) mixed with ethanol (10mL), be heated to reflux no longer separating out within 30 minutes a large amount of solids into reaction system, slow cooling is extremely
Room temperature, filtering, filter cake are added in water (15mL).Add sodium acid carbonate and adjust pH value to 8, be placed in ice-water bath after cooling down 1h and take out
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) mixes with methanol (20mL), is heated to reflux no longer separating out a large amount of solids into reaction system in 30 minutes, slowly
Room temperature is cooled to, filtering, filter cake are added in water (15mL).Add sodium acid carbonate and adjust pH value to 8, be placed in ice-water bath and cool down 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) mixes with isopropanol (50mL), is heated to reflux no longer separating out a large amount of solids into reaction system in 30 minutes,
Slow cooling to room temperature, filtering, filter cake is added in water (15mL).Add sodium hydroxide and adjust pH value to 8, be placed in cold in ice-water bath
But filtered after 1h, obtain compound of formula I 2.21g, yield 77.0%.
Embodiment 5 is by Formula II compound (2.87g, 10mmol), 5- nitrosalicylaldehydes (0.033g, 0.2mmol), L- hexichol
Formyl tartaric acid (5.38g, 15mmol) mixes with ethanol (200mL), is heated to reflux no longer separating out into reaction system for 30 minutes
A large amount of solids, slow cooling to room temperature, filtering, filter cake are added in water (15mL).Add sodium acid carbonate and adjust pH value to 8, be placed in
Filtered after cooling down 1h in ice-water bath, obtain compound of formula I 1.98g, yield 69.1%.
Embodiment 6 is by Formula II compound (2.87g, 10mmol), 5- nitrosalicylaldehydes (1.67g, 10mmol), L-TARTARIC ACID
(0.75g, 5mmol) mixes with n-butanol (1000mL), is heated to reflux no longer separating out a large amount of solids into reaction system in 30 minutes,
Slow cooling to room temperature, filtering, filter cake is added in water (15mL).Add sodium hydroxide and adjust pH value to 8, be placed in cold in ice-water bath
But filtered after 1h, obtain compound of formula I 2.09g, yield 72.9%.
Embodiment 7 is by Formula II compound (2.87g, 10mmol), 3- cresotinic acids aldehyde (0.27g, 2mmol), L- hexichol first
Acyl tartaric acid (3.58g, 10mmol) mixes with the tert-butyl alcohol (50mL), is heated to reflux no longer separating out greatly into reaction system for 30 minutes
Solid, slow cooling to room temperature are measured, filtering, filter cake are added in water (15mL).Add sodium hydroxide and adjust pH value to 8, be placed in ice
Filtered after cooling down 1h in water-bath, obtain compound of formula I 2.15g, yield 75.1%.
Claims (10)
1. a kind of method of synthetic compound of formula i, comprises the following steps：
By Formula II compound in organic solvent, with after aldehyde and resolving agent heating response, cold filtration, filter residue being passed through in solvent
Alkali is free and obtains compound of formula I.
2. according to the method for claim 1, it is characterised in that mix Formula II compound, aldehyde and resolving agent and organic solvent
Close, be heated to reflux and slow cooling is to room temperature, filtering, filter residue is added to the water, and add alkali and adjust pH to 7~9, it is then cold
But, filter and obtain compound of formula I.
3. according to the method for claim 1, it is characterised in that the Formula II compound and the mol ratio of aldehyde are 1:(0.02
~1)；Preferably 1：(0.05~0.5).
4. according to method according to any one of claims 1 to 3, it is characterised in that the Formula II compound and resolving agent
Mol ratio is 1:(0.5~1.5)；Preferably 1:(0.8~1.2).
5. according to method according to any one of claims 1 to 4, it is characterised in that the Formula II compound and organic solvent
Ratio be 1mmol:(1mL~100mL), more preferably 1mmol:(1mL~5mL).
6. according to method according to any one of claims 1 to 5, it is characterised in that the aldehyde is selected from salicylide and its derivative
Thing.
7. according to the method for claim 6, it is characterised in that the salicylide and its derivative include salicylide, 5- nitre
One or more in base salicylide, 3- cresotinic acids aldehyde and o-vanillin, preferably salicylide or 5- nitrosalicylaldehydes.
8. according to method according to any one of claims 1 to 7, it is characterised in that the resolving agent be selected from L-TARTARIC ACID and
One or more in its derivative, preferably L-TARTARIC ACID and L- dibenzoyl tartaric acids, more preferably L-TARTARIC ACID.
9. according to method according to any one of claims 1 to 8, it is characterised in that the organic solvent is alcohols solvent；It is excellent
Selecting the alcohols solvent includes the short chain alcohol with 1~7 carbon atom, more preferably methanol, ethanol, isopropanol, the tert-butyl alcohol and just
One or more in butanol, most preferably methanol or ethanol.
10. according to method according to any one of claims 1 to 9, it is characterised in that the alkali be selected from can make tartaric acid or its
Derivative free inorganic base or organic base, the preferably bicarbonate of potassium and sodium, carbonate, hydroxide and organic amine, it is more excellent
Choosing is selected from sodium acid carbonate, sodium carbonate, sodium hydroxide.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109705003A (en) * | 2019-01-25 | 2019-05-03 | 湖北中牧安达药业有限公司 | A kind of racemization method of L- D-4-methylsulfonylphserine serine ethyl ester |
| CN116041271A (en) * | 2022-12-29 | 2023-05-02 | 山东微研生物科技有限公司 | Preparation method of florfenicol intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN1302798A (en) * | 2000-12-12 | 2001-07-11 | 吉林大学 | Splitting of DL-threo-p-methylsulfonyl methyl serine ester |
| CN1326926A (en) * | 2001-06-01 | 2001-12-19 | 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 |
| CN102503810A (en) * | 2011-11-02 | 2012-06-20 | 浙江科技学院 | Method for recovering and recycling L-tartaric acid |
| CN104355990A (en) * | 2014-10-16 | 2015-02-18 | 安徽扬子化工有限公司 | Method for recycling and mechanically using L- (+) -tartaric acid in D-ethyl ester production |
-
2017
- 2017-06-22 CN CN201710481790.3A patent/CN107417585B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN1302798A (en) * | 2000-12-12 | 2001-07-11 | 吉林大学 | Splitting of DL-threo-p-methylsulfonyl methyl serine ester |
| CN1326926A (en) * | 2001-06-01 | 2001-12-19 | 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 |
| CN102503810A (en) * | 2011-11-02 | 2012-06-20 | 浙江科技学院 | Method for recovering and recycling L-tartaric acid |
| CN104355990A (en) * | 2014-10-16 | 2015-02-18 | 安徽扬子化工有限公司 | Method for recycling and mechanically using L- (+) -tartaric acid in D-ethyl ester production |
Non-Patent Citations (1)
| Title |
|---|
| RUI GUO ET AL.: "Chiral Resolution of Racemic p‑Methylsulfonylphenyl Serine Ethyl Ester with Lipases: The Mechanism of Side Reaction and Its Suppression", 《JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109705003A (en) * | 2019-01-25 | 2019-05-03 | 湖北中牧安达药业有限公司 | A kind of racemization method of L- D-4-methylsulfonylphserine serine ethyl ester |
| CN116041271A (en) * | 2022-12-29 | 2023-05-02 | 山东微研生物科技有限公司 | Preparation method of florfenicol intermediate |
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| CN107417585B (en) | 2019-05-03 |
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