CN111171007A

CN111171007A - Synthetic method of sitagliptin intermediate

Info

Publication number: CN111171007A
Application number: CN202010118115.6A
Authority: CN
Inventors: 陈伟翰; 陆煜东; 饶龙意
Original assignee: GUANGZHOU DAGUANG PHARMACEUTICAL CO Ltd
Current assignee: GUANGZHOU DAGUANG PHARMACEUTICAL CO Ltd
Priority date: 2020-02-26
Filing date: 2020-02-26
Publication date: 2020-05-19

Abstract

The invention provides a preparation method of a sitaxel intermediate, which comprises the steps of carrying out an activation reaction on 5, 7-dichloro-2-BOC-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid under the action of acid, and then carrying out a condensation reaction on the activated carboxylic acid and benzofuran-6-carboxylic acid to prepare 2- (benzofuran-6-carbonyl) -5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid. The method has the advantages of cheap and easily-obtained raw materials, few reaction byproducts, high yield, high purity of the final product, no damage to the environment, greenness, environmental protection, simple and convenient operation, mild reaction conditions, no need of column separation of the product and easy realization of industrialization.

Description

Synthetic method of sitagliptin intermediate

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry synthesis, and relates to a synthesis method of a sitagliptest intermediate.

Background

Dry eye, also known as keratoconjunctival xerosis, refers to a general term for a variety of diseases characterized by abnormal quality or quantity of tear fluid or abnormal kinetics, resulting in decreased stability of tear film, and associated ocular discomfort and/or ocular surface tissue changes. It is a common ocular surface disease at present, and the main treatment method is to use artificial tears. Dry eye is a chronic ocular disease with inflammation that may ultimately lead to damage to the surface of the eye.

The ritastemide eye drops are the first therapeutic drug for signs of chronic inflammatory diseases of eyes, are designed and developed by SARcodeBioscience, are approved by the FDA in the United states and are sold on the market in 2016, 07, 11, and the active ingredient of the ritastemide eye drops is under the trade name Xiidra and the specification of 50mg/ml and is used for dry eye diseases of adults. The sitagliptin is a novel small molecule T cell inhibitor, and the combination of the two is effectively blocked by simulating the structure of the connecting part of a cell adhesion molecule and a lymphocyte function-related antigen, so that the T cell mediated inflammatory reaction is inhibited. The sitagliptin eye drops are the first new medicine in the field of dry eye disease treatment since 2003 and have good clinical development prospects.

The traditional Chinese chemical name of the sitaxel is (S) -2- [2- (benzofuran-6-carbonyl) -5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-formamido ] -3- (3-methylsulfonylphenyl) propionic acid, and the chemical structural formula is as follows:

。

through the reverse synthetic analysis of the structure of the sitaxel, the structure of the intermediate is found to be composed of three parts of important intermediates, and the structures of the important intermediates are as follows:

。

the intermediate II is an important difficulty in synthesizing the sitagliptin, and two synthetic routes are mainly adopted at present.

Patent document AU2006247136B2 discloses a method for preparing an intermediate II, which is prepared from benzofuran-6-carboxylic acid as a starting material by acylation, condensation, and esterification. The method has the disadvantages that the acylation reaction conditions are harsh, the product obtained in the first step of reaction is unstable, other impurities are easily introduced, and the synthetic intermediate II needs to be purified by passing through a column, which is not beneficial to industrial production.

Patent document CA2985444C discloses another method for preparing intermediate II, which uses benzofuran-6-carboxylic acid as starting material, and first activates with CDI to form active intermediate, and then reacts with 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid to obtain intermediate II.

Disclosure of Invention

The invention aims to provide a preparation method of a sitagliptin intermediate II aiming at the defects in the prior synthesis technology, and the method has the advantages of easily available raw materials, simple process, environmental protection, economy, easy purification and suitability for industrial production.

The invention aims to realize the preparation method of the sitagliptin intermediate II, which adopts the following synthetic route: 5, 7-dichloro-2-BOC-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid (compound 2) is subjected to an activation reaction under the action of acid to prepare 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid (compound 3); the compound 3 reacts with benzofuran-6-carboxylic acid (compound 4) activated by an acid-binding agent under the catalysis of a condensing agent to prepare 2- (benzofuran-6-carbonyl) -5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid (target compound 1), and the reaction formula is as follows:

。

further, the acid used for activating the compound 2 is selected from hydrochloric acid, trifluoroacetic acid, formic acid, citric acid and methanesulfonic acid, and the concentration of the acid is 5% -35%, and preferably 20% trifluoroacetic acid solution.

The reaction solvent in the step is dichloromethane, the reaction temperature is 20-60 ℃, and the reaction time is 2-8 hours.

In order to reduce the influence of impurities on the next condensation reaction, the activated crude compound 3 needs to be refined, and the high-purity compound 3 is obtained after refining.

Further, the compound 3 reacts with the compound 4 activated by the acid-binding agent under the catalysis of the condensing agent to prepare a crude compound 1.

The acid-binding agent is selected from N, N-diisopropylethylamine and triethylamine, and preferably N, N-diisopropylethylamine.

The molar ratio of the compound 4 to the acid-binding agent is 1: (1-1.5), preferably in a molar ratio of 1: 1.2.

the condensing agent is selected from 2- (7-azabenzotriazole) -N, N, N ', N ' -tetramethylurea Hexafluorophosphate (HATU), 1-hydroxy-7-azabenzotriazole (HOAt), N, N ' -Carbonyldiimidazole (CDI), preferably HOAt; the molar ratio of compound 3 to condensing agent is 1: (1-1.5), preferably in a molar ratio of 1: 1.05.

the molar ratio of the compound 3 to the compound 4 is 1: (0.8-1.2), preferably in a molar ratio of 1: 1.05.

the reaction solvent in the step is selected from dichloromethane, tetrahydrofuran, chloroform, dimethyl sulfoxide and N, N-dimethylformamide, and dichloromethane is preferred; the mass-to-volume ratio of the compound 3 to the reaction solvent is 12.5-50% (g/mL), and the preferred mass-to-volume ratio is 20% (g/mL).

The reaction temperature in the step is 10-60 ℃, and the reaction time is 5-15 hours. The reaction temperature is preferably 30 ℃ and the reaction time is preferably 5 hours.

In order to reduce the influence of impurities on subsequent reactions, the crude compound 1 needs to be refined, and the refining method comprises the following steps: dissolving the crude product of the compound 1 in an organic solvent, heating to a certain temperature, keeping the temperature, stirring, cooling to a low temperature, crystallizing, filtering and drying to obtain a solid, namely the compound 1. Wherein the organic solvent is selected from anhydrous methanol, anhydrous ethanol and anhydrous acetonitrile, and preferably the anhydrous ethanol; the mass-volume ratio of the crude compound 1 to the organic solvent is 12.5-50% (g/mL), preferably 20% (g/mL); raising the temperature to a certain temperature of 40-80 ℃, and stirring for 1-4 hours; the temperature is reduced to 0-20 ℃ for crystallization.

The advantages of the invention are as follows: the invention provides a preparation method of a sitaxel intermediate II, and used benzofuran-6-carboxylic acid does not need acylation, so that experimental steps and generated by-product pollution are reduced. The method has the advantages of cheap and easily-obtained raw materials, few reaction byproducts, high yield, high purity of the final product, simplified reaction steps, mild reaction conditions, no need of column separation of the product and easy realization of industrialization.

Drawings

FIG. 1 is an HPLC chromatogram of Compound 3 prepared in example 1 of the present invention;

FIG. 2 is a mass spectrum of Compound 3 prepared in example 1 of the present invention;

FIG. 3 is an HPLC chromatogram of Compound 1 prepared in example 1 of the present invention;

FIG. 4 is a mass spectrum of Compound 1 prepared in example 1 of the present invention.

Detailed Description

In order to make the objects and technical solutions of the present invention clearer, preferred embodiments of the present invention are described in detail below. It is to be noted that: the following examples are intended to illustrate the invention further and are not to be construed as limiting the scope of the invention. The invention is not limited to the embodiments described above, but rather, many modifications and variations may be made by one skilled in the art without departing from the scope of the invention. The raw materials and reagents used in the invention are all commercial products.

Example 1

1) Preparation of compound 3:

3.46g (0.01mol) of Compound 2 was placed in a three-necked flask, 34.6g of a 30% trifluoroacetic acid in methylene chloride was added, nitrogen gas was purged three times to keep the system under a nitrogen atmosphere, stirring was started, reaction was carried out at 25 ℃ for 6 hours, and after the reaction was completed, suction filtration was carried out to obtain 3.25g of a white solid. Dissolving the solid with 10ml petroleum ether, heating to 30 ℃, stirring for reaction for 2 hours, cooling to 10 ℃, filtering and drying to obtain solid, namely the compound 3, the weight of which is 3.05g, the yield of which is 88 percent, the HPLC purity is 99.73 percent, and the MS [ M + +1, ESI + ]: 247.00;

2) preparation of compound 1:

1.45g (0.01mol) of Compound 4 was placed in a three-necked flask, 10ml of methylene chloride was added, then 3.39g (0.009mol) of HATU and 1.31g (0.01mol) of N, N-diisopropylethylamine were added, nitrogen gas was purged three times, the system was placed under a nitrogen atmosphere, stirring was turned on, the temperature was decreased to 0 ℃ for reaction for 3 hours, then 3.05g (0.008 mol) of Compound 3 was added, the temperature was raised to 30 ℃ for reaction for 8 hours, methylene chloride was distilled off under reduced pressure to give a white solid, which was dried and the solid weighed 3.08 g. Adding the obtained solid into 15ml of absolute ethyl alcohol, keeping the temperature at 60 ℃, stirring for 2 hours, cooling to 10 ℃, filtering to obtain a white solid, and drying to obtain the solid, wherein the obtained solid is the compound 1, the weight is 2.68g, the yield is 87.01%, the purity is 99.28%, and MS [ M + +1, ESI + ]: 391.03.

Example 2

1) Preparation of compound 3:

placing 15g (0.043 mol) of the compound 2 in a three-neck flask, adding 150g of 25% dichloromethane hydrochloride solution, pumping nitrogen for three times to ensure that the system is in a nitrogen atmosphere, starting stirring, keeping the temperature at 25 ℃ for reacting for 5 hours, stirring after the reaction is finished, and performing suction filtration to obtain a white solid. Dissolving the solid with 75ml of methyl tert-butyl ether, heating to 50 ℃, keeping the temperature for reaction for 1 hour, cooling to 10 ℃, and filtering to obtain a solid, namely a compound 3, the weight of which is 11.26g, the yield of which is 92%, the HPLC purity is 99.85%, and the MS [ M + +1, ESI + ]: 247.01;

2) preparation of compound 1:

placing 7.78g (0.048mol) of compound 4 in a three-necked flask, adding 50ml of tetrahydrofuran, then adding 6.53g (0.048mol) of HOAt and 7.75g (0.06mol) of N, N-diisopropylethylamine, pumping nitrogen for three times, keeping the system under nitrogen atmosphere, starting stirring, cooling to 3 ℃ for reaction for 1 hour, then adding 11.26g (0.04 mol) of compound 3, raising the temperature to 25 ℃ for reaction for 9 hours, carrying out reduced pressure distillation to spin-dry tetrahydrofuran to obtain a crude product, adding 50ml of anhydrous methanol, heating to 50 ℃, keeping the temperature and stirring for 2 hours, cooling to 7 ℃, carrying out suction filtration to obtain a white solid, and drying to obtain the solid which is compound 1, 11.52g in weight, 74% in yield, 99.21% in purity, and MS [ M + +1, ESI + ]: 391.08.

Example 3

1) Preparation of compound 3:

placing 15g (0.043 mol) of the compound 2 in a three-neck flask, adding 150g of 20% formic acid dichloromethane solution, pumping nitrogen for three times, keeping the system in a nitrogen atmosphere, starting stirring, keeping the temperature at 30 ℃ for reaction for 7 hours, after the reaction is finished, carrying out suction filtration to obtain a white solid, dissolving the solid with 75ml of diethyl ether, heating to 45 ℃, carrying out heat preservation reaction for 1 hour, cooling to 10 ℃, and filtering to obtain a solid, namely the compound 3, wherein the weight is 11.52g, the yield is 92%, the HPLC purity is 99.85%, and the MS [ M + +1, ESI + ]: 247.02;

2) preparation of compound 1:

placing 7.78g (0.048mol) of the compound 4 in a three-neck flask, adding 50ml of dichloromethane, then adding 7.78g (0.048mol) of CDI and 6.07g (0.06mol) of triethylamine, pumping nitrogen for three times, leading the system to be in a nitrogen atmosphere, starting stirring, reducing the temperature to 3 ℃ for reaction for 1 hour, then adding 11.52g (0.04 mol) of the compound 3, raising the temperature to 40 ℃ for reaction for 6 hours, distilling under reduced pressure to spin dry the dichloromethane to obtain a crude product, adding 50ml of anhydrous methanol, raising the temperature to 50 ℃, keeping the temperature and stirring for 1.5 hours, reducing the temperature to 10 ℃, carrying out suction filtration to obtain a white solid, drying, and obtaining the solid which is the compound 1, 12.14g in weight, the yield of 78 percent, the purity of 99.56 percent MS [ M + +1, ESI + ]: 391.02.

Claims

1. A preparation method of a sitagliptin intermediate is characterized in that a compound 2 is subjected to an activation reaction under the action of acid to prepare a compound 3; the compound 3 and a compound 4 activated by an acid binding agent react under the catalysis of a condensing agent to prepare an intermediate compound 1; the preparation method also comprises a refining method of the compound 1; the reaction formula is shown as follows:

。

2. a preparation method of a sitagliptin intermediate as claimed in claim 1, characterized in that the acid used for activating the compound 2 is selected from hydrochloric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, and the concentration of the acid is 5-35%.

3. The preparation method of a sitagliptin intermediate as claimed in claim 1, wherein the acid scavenger is selected from N, N-diisopropylethylamine and triethylamine, and the molar ratio of the compound 4 to the acid scavenger is 1: (1-1.5), preferably in a molar ratio of 1: 1.2.

4. a process for the preparation of a sitagliptin intermediate according to claim 1, wherein the condensing agent is selected from HATU, HOAt, CDI, the molar ratio of compound 3 to condensing agent is 1: (1-1.5), preferably in a molar ratio of 1: 1.05.

5. the preparation method of a sitagliptin intermediate according to claim 1, wherein the molar ratio of the compound 3 to the compound 4 is 1: (0.8-1.2), preferably in a molar ratio of 1: 1.05.

6. a process for preparing a sitagliptin intermediate according to claim 1, characterized in that the reaction solvent of the compound 3 and the compound 4 is selected from dichloromethane, tetrahydrofuran, chloroform, dimethyl sulfoxide, N-dimethylformamide; the mass-to-volume ratio of the compound 3 to the reaction solvent is 12.5-50% (g/mL), and the preferred mass-to-volume ratio is 20% (g/mL).

7. The method for preparing a sitagliptin intermediate according to claim 1, wherein the method for purifying the compound 1 comprises the following steps: dissolving the compound 1 in an organic solvent, heating to a certain temperature, keeping the temperature, stirring, cooling to a low temperature, crystallizing, filtering and drying.

8. The method for purifying the compound 1 according to claim 7, wherein the organic solvent used for purification is selected from methanol, ethanol and acetonitrile, and the mass volume ratio of the compound 1 to the organic solvent is 12.5% to 50% (g/mL).

9. The method according to claim 7, wherein the organic solvent used for purification is an anhydrous solvent.

10. The method for refining the compound 1 according to claim 7, wherein the temperature is raised to 40 ℃ to 80 ℃, and the stirring time is 1 to 4 hours; the temperature is reduced to 0-20 ℃ for crystallization.