CN114195664A - Preparation method of sitagliptin phosphate key intermediate - Google Patents
Preparation method of sitagliptin phosphate key intermediate Download PDFInfo
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- CN114195664A CN114195664A CN202111669204.0A CN202111669204A CN114195664A CN 114195664 A CN114195664 A CN 114195664A CN 202111669204 A CN202111669204 A CN 202111669204A CN 114195664 A CN114195664 A CN 114195664A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Abstract
The invention discloses a preparation method of a sitagliptin phosphate key intermediate. The preparation method adopts 3-oxo-4- (2,4, 5-trifluorophenyl) -ethyl butyrate and 2, 4-dichloroaniline as starting materials, and obtains a sitagliptin phosphate key intermediate (R) -3-amino-4- (2,4, 5-trifluorophenyl) -butyric acid through three-step reaction, wherein the purity of the finally obtained product is more than 99.0%, the chiral purity is more than 99.5%, and the total molar yield is more than 80%. The reagents adopted by the invention are conventional reagents, and are safe, easy to obtain and low in price. The method has the advantages of high atom economy, less three wastes, simple operation, short production period and low cost, and is very suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of preparation of pharmaceutical intermediates, and particularly relates to a preparation method of a sitagliptin phosphate key intermediate.
Background
Sitagliptin phosphate (1) is a novel anti-type 2 diabetes drug, developed by the company of majoritan, and approved by FDA in us for marketing at 10 months in 2006, and is the 1 st dipeptidyl peptidase iv (DPP-4) inhibitor drug for treating type 2 diabetes. The effect of the sitagliptin phosphate on treating type 2 diabetes is very ideal. As a novel antidiabetic medicament, sitagliptin phosphate has the advantages of blood sugar dependence, moderate blood sugar reduction effect, no hypoglycemia while increasing insulin secretion, capability of effectively relieving hunger sensation and the like, and no side effects of nausea, vomiting, edema, body mass increase and the like.
The basic information of the compound is as follows:
chemical name: chemical name: 7- [ (3R) -3-amino-1-oxo-4- (2,4, 5-trifluorophenyl) butyl ] -5, 6, 7, 8-tetrahydro-3- (trifluoromethyl) -1, 2, 4-triazolone [4, 3-a ] pyrazine phosphate (1: 1) monohydrate;
the name of English: sitagliptin phosphate monohydrate
CAS number: 654671-77-9
The chemical structure is as follows:
in most of the current processes for the preparation of sitagliptin phosphate, a key compound (R) -3-amino-4- (2,4, 5-trifluorophenyl) -butyric acid is involved, and the structure is as follows:
the compound is used as a core fragment of sitagliptin phosphate and is also an introduced fragment of a chiral center of the compound, so that the preparation of the compound is crucial to the whole process.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the preparation method of the sitagliptin phosphate key intermediate (R) -3-amino-4- (2,4, 5-trifluorophenyl) -butyric acid, which is environment-friendly, high in yield and suitable for industrial production.
The reaction formula of the preparation method of the sitagliptin phosphate key intermediate is as follows:
the preparation method of the sitagliptin phosphate key intermediate comprises the following steps:
(1) adding 3-oxo-4- (2,4, 5-trifluorophenyl) -ethyl butyrate, 2, 4-dichloroaniline, cation exchange resin and an organic solvent into a reaction bottle, stirring, heating for reflux reaction, and filtering and concentrating to obtain an intermediate 1 after the reaction is finished;
(2) adding the intermediate 1 and isopropylamine hydrochloride into a buffer solution, adjusting the pH to 8-9 by using an isopropylamine aqueous solution, and then adding immobilized transaminase for reaction; after the reaction is finished, adding an organic solvent, filtering to remove solids, extracting, drying, filtering and concentrating to obtain an intermediate 2;
(3) adding the intermediate 2 into water, adding alkali, heating for reflux reaction to hydrolyze amido bonds, extracting and washing reaction liquid by using an organic solvent after the reaction is finished, recovering 2, 4-dichloroaniline and removing impurities, then adjusting acid, crystallizing, filtering, washing with water and drying to obtain (R) -3-amino-4- (2,4, 5-trifluorophenyl) -butyric acid, wherein the purity of the obtained product is more than 99.0 percent, and the chiral purity is more than 99.5 percent;
(4) and (3) combining the organic phases obtained by washing in the step (3), adding water, acidifying, collecting a water phase, washing with an organic solvent, adjusting the pH of the water phase to 8-9 by using inorganic base, filtering, drying to obtain the recovered 2, 4-dichloroaniline, and continuously using the 2, 4-dichloroaniline in the step (1).
The cation exchange resin in the step (1) is 001X7Na type strong cation exchange resin, and the organic solvent is one or more of acetonitrile, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether and acetone.
And (3) the buffer solution in the step (2) is dipotassium phosphate or disodium phosphate solution.
The alkali in the step (3) is sodium hydroxide or potassium hydroxide, the organic solvent used for extraction is ethyl acetate or dichloromethane, the acid adjusting reagent is hydrochloric acid, and the pH value of crystallization is 7.0-7.3.
And (4) the acidified reagent is hydrochloric acid.
The invention adopts 3-oxo-4- (2,4, 5-trifluorophenyl) -ethyl butyrate and 2, 4-dichloroaniline as starting materials, and obtains the sitagliptin phosphate key intermediate (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid through three-step reaction, wherein the purity of the finally obtained product is more than 99.0%, the chiral purity is more than 99.5%, and the total molar yield is more than 80%. The reagents adopted by the invention are conventional reagents, and are safe, easy to obtain and low in price. The method has the advantages of high atom economy, less three wastes, simple operation, short production period and low cost, and is very suitable for large-scale industrial production.
Detailed Description
For a better understanding of the present invention, reference will now be made to the following examples. The examples are provided only for illustrating the present invention and not for limiting the present invention.
Example 1:
(1) a1000 ml reaction flask was charged with 500ml of acetonitrile, 100g of 3-oxo-4- (2,4, 5-trifluorophenyl) -ethyl butyrate, and 65.4g of 2, 4-dichloroaniline, and then 5.0g of a 001X7Na type strong cation exchange resin, and stirred, heated to reflux and reacted for 10 hours. After completion of the reaction, insoluble matter was removed by filtration, and the obtained filtrate was concentrated under reduced pressure to obtain 146.0g in total of intermediate 1, and the crude yield was 101.0%.
(2) To a 2000ml reaction flask was added 1200ml of a dipotassium hydrogenphosphate buffer solution (pH6.8), a total of 146.0g of intermediate 1 and 102g of isopropylamine hydrochloride, the pH was adjusted to 8.0 using an aqueous isopropylamine solution, and then 3.0g of immobilized ω -transaminase was added, the temperature was controlled at 20 to 25 ℃, pH: 7.8-8.2 (controlled by using an isopropylamine aqueous solution) for 10 h; after the reaction is finished, adding 500ml of ethyl acetate, stirring for 1h, filtering to remove solids, collecting organic phases in a layering manner, extracting an aqueous phase twice by using 500ml of ethyl acetate, combining the organic phases, and washing twice by using purified water, wherein the amount of the purified water is 300 ml; the organic phase was dried over 20g of anhydrous sodium sulfate, filtered and concentrated to obtain 132.2g of intermediate 2 in total, with a yield of 90.3%.
(3) Adding 600ml of purified water into a 1000ml reaction bottle, adding 132.2g of the intermediate 2, then adding 35.1g of sodium hydroxide under stirring, and heating to reflux for reaction for 12 hours; after the reaction is finished, cooling to room temperature, washing the reaction solution twice by using dichloromethane, using 300ml of dichloromethane each time (recovering 2, 4-dichloroaniline and removing impurities), controlling the temperature of a water phase to be 20-25 ℃, using hydrochloric acid to adjust the pH value to be 7.12, then cooling to 5-10 ℃, stirring and crystallizing for 2h, filtering to obtain a wet product, and carrying out forced air drying for 16h at 55-60 ℃ to obtain 73.1g of a key intermediate (R) -3-amino-4- (2,4, 5-trifluorophenyl) -butyric acid, wherein the yield is 89.4%, the purity of the obtained product is 99.3%, and the chiral purity is 99.8%.
(4) Combining the dichloromethane organic phases obtained by washing, adding 500ml of purified water, adjusting the pH value to 2 by using hydrochloric acid, collecting water phases in a layering manner, and washing 2 times by using ethyl acetate, wherein 200ml of the ethyl acetate is used for each time; controlling the temperature of the washed water phase at 20-30 ℃, stirring, adjusting the pH value to 8-9 by using 25% sodium hydroxide solution, filtering, and carrying out forced air drying on a wet product at 55-60 ℃ for 16h to obtain 55.2g of recovered 2, 4-dichloroaniline.
Claims (5)
1. A preparation method of a sitagliptin phosphate key intermediate is characterized by comprising the following specific steps:
(1) adding 3-oxo-4- (2,4, 5-trifluorophenyl) -ethyl butyrate, 2, 4-dichloroaniline, cation exchange resin and an organic solvent into a reaction bottle, stirring, heating for reflux reaction, and filtering and concentrating to obtain an intermediate 1 after the reaction is finished;
(2) adding the intermediate 1 and isopropylamine hydrochloride into a buffer solution, adjusting the pH to 8-9 by using an isopropylamine aqueous solution, and then adding immobilized transaminase for reaction; after the reaction is finished, adding an organic solvent, filtering to remove solids, extracting, drying, filtering and concentrating to obtain an intermediate 2;
(3) adding the intermediate 2 into water, adding alkali, heating for reflux reaction to hydrolyze amido bonds, extracting and washing reaction liquid by using an organic solvent after the reaction is finished, recovering 2, 4-dichloroaniline and removing impurities, then adjusting acid, crystallizing, filtering, washing with water and drying to obtain (R) -3-amino-4- (2,4, 5-trifluorophenyl) -butyric acid, wherein the purity of the obtained product is more than 99.0 percent, and the chiral purity is more than 99.5 percent;
(4) and (3) combining the organic phases obtained by washing in the step (3), adding water, acidifying, collecting a water phase, washing with an organic solvent, adjusting the pH of the water phase to 8-9 by using inorganic base, filtering, drying to obtain the recovered 2, 4-dichloroaniline, and continuously using the 2, 4-dichloroaniline in the step (1).
2. The method for preparing sitagliptin phosphate key intermediate according to claim 1, wherein the cation exchange resin in step (1) is 001X7Na type strong cation exchange resin, and the organic solvent is one or more of acetonitrile, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether and acetone.
3. The method for preparing sitagliptin phosphate key intermediate according to claim 1, wherein the buffer solution in step (2) is dipotassium hydrogen phosphate or disodium hydrogen phosphate solution.
4. The method for preparing sitagliptin phosphate key intermediate according to claim 1, wherein the base in step (3) is sodium hydroxide or potassium hydroxide, the organic solvent used for extraction is ethyl acetate or dichloromethane, the acid adjusting reagent is hydrochloric acid, and the pH value of crystallization is 7.0-7.3.
5. The method for preparing sitagliptin phosphate key intermediate according to claim 1, wherein the acidifying reagent of step (4) is hydrochloric acid.
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| CN104805069A (en) * | 2015-02-06 | 2015-07-29 | 南京博优康远生物医药科技有限公司 | Immobilized transaminase and applications thereof in synthesizing of Sitagliptin intermediate |
| CN105018440A (en) * | 2014-04-24 | 2015-11-04 | 南京博优康远生物医药科技有限公司 | Aminotransferase and application thereof to synthesis of sitagliptin intermediate |
| CN105219745A (en) * | 2014-06-12 | 2016-01-06 | 南京博优康远生物医药科技有限公司 | A kind of immobilization transaminase and the application in synthesis sitagliptin intermediate thereof |
| CN105331651A (en) * | 2015-11-25 | 2016-02-17 | 尚科生物医药（上海）有限公司 | Sitagliptin and enzyme-chemical preparation method of intermediate of sitagliptin |
| CN107686852A (en) * | 2016-08-04 | 2018-02-13 | 上海朴颐化学科技有限公司 | A kind of preparation method of moxifloxacin intermediate compound |
| CN109234327A (en) * | 2017-07-11 | 2019-01-18 | 上海弈柯莱生物医药科技有限公司 | A kind of application of the transaminase of stereoselectivity in asymmetric syntheses Chiral Amine |
| CN110129306A (en) * | 2018-02-08 | 2019-08-16 | 广东东阳光药业有限公司 | Immobilization transaminase and its application |
| WO2020089828A1 (en) * | 2018-11-01 | 2020-05-07 | Stereokem Pvt. Ltd. | An improved process for the preparation of sitagliptin and its intermediates |
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2021
- 2021-12-30 CN CN202111669204.0A patent/CN114195664A/en active Pending
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