CN114516847A - Preparation method of sitagliptin intermediate - Google Patents

Preparation method of sitagliptin intermediate Download PDF

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CN114516847A
CN114516847A CN202210231639.5A CN202210231639A CN114516847A CN 114516847 A CN114516847 A CN 114516847A CN 202210231639 A CN202210231639 A CN 202210231639A CN 114516847 A CN114516847 A CN 114516847A
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preparation
sitagliptin intermediate
sitagliptin
formula
solvent
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CN114516847B (en
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陈云华
周魏魏
谭建德
缪炳林
徐龙
叶海伟
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Taizhou Da Chen Pharmaceutical Co ltd
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Taizhou Da Chen Pharmaceutical Co ltd
Taizhou Vocational and Technical College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to a preparation method of a sitagliptin intermediate, belonging to the technical field of synthesis of pharmaceutical intermediates. In order to solve the existing problems of high pollution and unsafe problem, the method for preparing the sitagliptin intermediate is provided. The method can effectively avoid high-temperature reaction and reduce environmental pollution, and the substrate dihydrazide can be efficiently removed to form closed rings to obtain a corresponding final product under the action of the chloromethylene dimethyl ammonium chloride, and the obtained product has the effects of high yield, high purity and high quality.

Description

Preparation method of sitagliptin intermediate
Technical Field
The invention relates to a preparation method of a sitagliptin intermediate, belonging to the technical field of synthesis of drug intermediates.
Background
Sitagliptin is a dipeptidyl peptidase-1V (DPP-1V) inhibitor developed by the company mershato usa, and has the chemical name of (3R) -3-amino-1- [3- (trifluoromethyl) -5,6,7, 8-tetrahydro-1, 2, 4-triazolo [4,3-a ] pyrazin-7-yl ] -4- (2,4, 5-trifluorophenyl) butan-1-one, and the CAS number of 486460-32-6. In 2006, 10 months, sitagliptin was approved by the FDA in the united states for marketing as the first dipeptidyl enzyme-4 (DPP-4) inhibitor type ii diabetes treatment drug.
The 3-trifluoromethyl-5, 6,7, 8-tetrahydro-1, 2, 4-triazolo [4, 3-a ] pyrazine hydrochloride is a key intermediate used in the synthesis of sitagliptin, and the structural formula is shown as follows:
Figure BDA0003538564900000011
currently, there are several main ways for the synthesis of the sitagliptin intermediate. For example, the synthetic route disclosed in the patent (publication No. WO2004103276A) is that glycine methyl ester and 2- (N-tert-butoxycarbonyl) aminoacetaldehyde are subjected to reductive amination, benzyloxycarbonyl chloride protects a secondary amino group, tert-butoxycarbonyl is removed under acidic conditions, cyclization is performed under the action of trimethylaluminum, and methylation, cyclization and the like are performed after deprotection by hydrogenolysis, and the synthetic route is as follows:
Figure BDA0003538564900000021
the reaction steps of the route are more and complicated, and expensive methylating reagent (trimethyl oxonium tetrafluoroborate) and palladium carbon are needed.
As reported in the prior literature, the synthetic route of the method is as follows, wherein pyrazine chloride is used as a raw material to be subjected to hydrazinolysis, trifluoroacetic anhydride acylation, polyphosphoric acid cyclization and palladium-carbon catalytic hydrogenation reduction with hydrazine hydrate:
Figure BDA0003538564900000022
however, the synthesis route also uses expensive palladium-carbon, and the use of hydrogen has certain danger, which is not beneficial to safe production.
As another example, the conventional synthesis route is shown in org.Lett.,2005, (6):1039-1042, which is prepared by hydrazinolysis, phosphorus oxychloride cyclization, ethylenediamine nucleophilic substitution and methanol hydrochloride cyclization from ethyl trifluoroacetate, hydrazine hydrate and chloroacetyl chloride as raw materials, and comprises the following steps:
Figure BDA0003538564900000023
The synthesis route is mainly adopted in domestic enterprises and has the advantage of short synthesis route, but the reaction conditions during dehydration and cyclization are severe, phosphorus oxychloride with strong corrosivity and high toxicity is used, dehydration and cyclization can be completed only at high temperature, and after-treatment is carried out, the cracking by using ice water is dangerous to a certain extent, a large amount of phosphorus-containing wastewater which is difficult to treat is generated, and the problem of great environmental pollution is solved.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of a sitagliptin intermediate, and solves the problems of mild reaction of a synthetic route and little environmental pollution.
The invention aims to realize the preparation method of the sitagliptin intermediate through the following technical scheme, and is characterized by comprising the following steps of:
in the presence of an acid-binding agent, carrying out cyclization reaction on a substrate compound shown in a formula II under the action of a compound shown in a formula III, namely chloromethylene dimethyl ammonium chloride to obtain a corresponding sitagliptin intermediate compound shown in a formula I;
Figure BDA0003538564900000031
under the action of the compound of the formula III, the compound of the formula II with a dihydrazide structure (hereinafter referred to as dihydrazide) can be subjected to dehydration cyclization to form a corresponding product, and meanwhile, the reaction system can effectively remove small molecular acid generated by the reaction under the action of an acid binding agent, so that the reaction is more effectively carried out. More specifically, the substrate dihydrazide can be effectively promoted to remove the micromolecular water and cyclize to form the annular structure of the product under the action of the chloromethylene dimethyl ammonium chloride, and the method can realize the reaction under mild conditions, avoid the reaction at high temperature, reduce the generation of impurities and improve the yield and purity quality of the product; on the other hand, the problem of generating a large amount of wastewater by adopting phosphorus oxychloride and the like is solved, the pollution to the environment caused by the phosphorus-containing wastewater is greatly reduced, and the method is more favorable for realizing the advantage of less environmental pollution.
In the above method for preparing a sitagliptin intermediate, preferably, the temperature of the cyclization reaction is carried out at 20 to 35 ℃. By adopting the synthetic route, the reaction is carried out under the action of the compound shown in the formula III, so that the dehydration cyclization of the dihydrazide can be realized under the milder temperature condition, the reaction is carried out under the milder condition, the severe danger of the reaction at high temperature is avoided, the long-time reaction at high temperature is also avoided, the generation of other impurities is more effectively avoided, and the effect of high purity and yield of the product is more favorably realized. More preferably, the temperature of the ring-closure reaction is 25 to 30 ℃.
In the above method for preparing a sitagliptin intermediate, preferably, the acid scavenger is selected from an organic base or an inorganic base. Aims to effectively remove the small molecular acid produced in the reaction process, is more beneficial to the reaction, improves the conversion rate of raw materials and the yield of products, and is also beneficial to improving the purity and quality of the products. The reaction is preferably carried out using an organic base, which is more advantageous in that the reaction proceeds mildly. As a further preference, the organic amine is selected from triethylamine, diethylamine or pyridine; the inorganic alkali is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
In the above preparation method of sitagliptin intermediate, the cyclization reaction is carried out in an organic solvent. Further, the cyclization reaction is carried out in one or more of halogenated alkane solvents, ether solvents, aromatic hydrocarbon solvents and nitrile solvents. The haloalkane here may be C1-C4Halogenated alkanes such as dichloromethane, trichloromethane, dichloroethane, etc.; ether solvents such as tetrahydrofuran, methyl t-butyl ether, 2-methyltetrahydrofuran, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; the above-mentionedNitrile solvents such as acetonitrile and the like. The solvents are more favorable for the reaction to be carried out, so that the reaction is carried out uniformly. Preferably, the cyclization reaction is carried out in one or more of tetrahydrofuran, dichloromethane, toluene and acetonitrile. The amount of the solvent may be any amount according to the usual amount.
In the preparation method of the sitagliptin intermediate, the molar ratio of the substrate compound shown as the formula II to the compound shown as the formula III, namely chloromethylene dimethyl ammonium chloride, is preferably 1: 1.0 to 1.3. The method can make more effective use of raw materials, reduce the waste of the raw materials, improve the conversion rate and better ensure the effects of product yield and purity quality.
In the above preparation method of sitagliptin intermediate, preferably, the compound of formula ii: the mol ratio of the acid-binding agent is 1: 1.0 to 1.5. The reaction can be better guaranteed to be carried out, the utilization rate of raw materials can be better improved, and waste is reduced.
In the above method for preparing a sitagliptin intermediate, preferably, after the cyclization reaction is completed, the solvent in the reaction solution is removed, and water and a water-insoluble solvent are added to the residue for treatment. The water-soluble impurities such as salt and the like in the system can be better removed, and the water-insoluble solvent can better extract the product, so that the purity and the quality of the product can be better ensured. As a further preference, the water-insoluble solvent is selected from toluene, ethyl acetate or dichloromethane. By adopting a two-phase solvent system, the effects of extracting the product and ensuring the purity and quality of the product are more facilitated. Further, it is preferable that the mass ratio of the water to the water-insoluble solvent to be added is 1: 1 to 1.2.
The preparation method of the sitagliptin intermediate has the following specific reaction equation:
Figure BDA0003538564900000051
in summary, compared with the prior art, the invention has the following advantages:
the raw materials are synthesized, so that high-temperature reaction can be effectively avoided, the environmental pollution can be reduced, the substrate dihydrazide can be efficiently subjected to ring closure by removing small molecular water under the action of the chloromethylene dimethyl ammonium chloride to obtain a corresponding final product, the obtained product has the effects of high yield and high purity and quality, and the molar yield reaches over 90 percent; meanwhile, the adopted reagent can reduce the corrosion to equipment and improve the operation safety.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.
Example 1
The structural formulae of the respective raw materials and products in this example are shown below (the structural formulae of the respective raw materials and products in other examples are the same):
Figure BDA0003538564900000061
the preparation method comprises the following steps: dissolving 1mol of raw material bishydrazide of a compound shown as a formula II in 500ml of acetonitrile, adding 1.0mol of chloromethylene dimethyl ammonium chloride (Vilsmeier Reagent) of a compound shown as a formula III and 1.0mol of triethylamine, controlling the reaction temperature of the system to react for 8 hours at room temperature, after the reaction is finished, decompressing and concentrating to recover acetonitrile to obtain a product residue, adding 200ml of ethyl acetate and 200ml of ethyl acetate into the residue to extract a product, standing, layering, collecting an organic phase, washing the organic phase with 100ml of brine for 2 times, collecting the organic phase, adding 2.0g of anhydrous sodium sulfate to dehydrate and dry, filtering, collecting filtrate, concentrating and removing the solvent to obtain a final product of a sitagliptin intermediate of the compound shown as the formula I, wherein the molar yield is 90.5%, and the purity of the product is more than 99.2%.
Example 2
Dissolving 1mol of dihydrazide of a compound shown as a formula II serving as a raw material in 400ml of acetonitrile, adding 1.2mol of chloromethylene dimethyl ammonium chloride (Vilsmeier Reagent) of a compound shown as a formula III and 1.3mol of triethylamine, controlling the reaction temperature of a system to react at 30 ℃ for 6 hours, after the reaction is finished, concentrating under reduced pressure to recover the acetonitrile to obtain a product residue, adding 200ml of water and 200ml of ethyl acetate into the residue to extract a product, standing, layering, collecting an organic phase, washing the organic phase with 100ml of brine for 2 times, collecting the organic phase, adding 2.0g of anhydrous sodium sulfate to dehydrate and dry, filtering, collecting filtrate, concentrating and removing the solvent to obtain a final product, namely a sitagliptin intermediate of the compound shown as the formula I, wherein the molar yield is 92.1%, and the product purity is over 99.4%.
Example 3
Dissolving 1mol of raw material bishydrazide of a compound shown as a formula II in 400ml of acetonitrile, adding 1.3mol of chloromethylene dimethyl ammonium chloride (Vilsmeier Reagent) of a compound shown as a formula III and 1.5mol of triethylamine, controlling the reaction temperature of a system to react at 25 ℃ for 8 hours, after the reaction is finished, decompressing and concentrating to recover acetonitrile to obtain a product residue, adding 200ml of water and 200ml of ethyl acetate into the residue to extract a product, standing and layering, collecting an organic phase, washing the organic phase with 100ml of brine for 2 times, collecting the organic phase, adding 2.0g of anhydrous sodium sulfate to dehydrate and dry, filtering, collecting filtrate, concentrating and removing a solvent to obtain a final product, namely a sitagliptin intermediate of the compound shown as the formula I, wherein the molar yield is 92.4%, and the product purity is over 99.3%.
Example 4
Dissolving 1mol of raw material bishydrazide of a compound shown as a formula II in 500ml of tetrahydrofuran, adding 1.1mol of chloromethylene dimethyl ammonium chloride (Vilsmeier Reagent) of a compound shown as a formula III and 1.2mol of triethylamine, controlling the reaction temperature of a system to react at 30 ℃ for 7 hours, after the reaction is finished, decompressing and concentrating to recover tetrahydrofuran to obtain a product residue, adding 200ml of dichloromethane and 200ml of dichloromethane into the residue to extract a product, standing and layering, collecting an organic phase, washing the organic phase with 100ml of brine for 2 times, collecting the organic phase, adding 2.0g of anhydrous sodium sulfate to dehydrate and dry, filtering, collecting filtrate, concentrating and removing a solvent to obtain a final product, namely a sitagliptin intermediate of the compound shown as the formula I, wherein the molar yield is 91.8%, and the purity of the product is over 99.2%.
Example 5
Dissolving 1mol of raw material bishydrazide of a compound shown as a formula II in 500ml of acetonitrile, adding 1.1mol of chloromethylene dimethyl ammonium chloride (Vilsmeier Reagent) of a compound shown as a formula III and 1.2mol of pyridine, controlling the reaction temperature of a system to react at 20 ℃ for 10 hours, after the reaction is finished, decompressing and concentrating to recover acetonitrile to obtain a product residue, adding 200ml of dichloromethane and 200ml of dichloromethane into the residue to extract a product, standing, layering, collecting an organic phase, washing the organic phase with 100ml of brine for 2 times, collecting the organic phase, adding 2.0g of anhydrous sodium sulfate to dehydrate and dry, filtering, collecting filtrate, concentrating and removing a solvent to obtain a final product, namely a sitagliptin intermediate of the compound shown as the formula I, wherein the molar yield is 92.1%, and the product purity is over 99.2%.
Example 6
Dissolving 1mol of dihydrazide of a compound shown as a formula II serving as a raw material in 500ml of acetonitrile, adding 1.0mol of chloromethylene dimethyl ammonium chloride (Vilsmeier Reagent) of a compound shown as a formula III and 1.1mol of triethylamine, controlling the reaction temperature of a system to react at 35 ℃ for 6 hours, after the reaction is finished, decompressing and concentrating to recover the acetonitrile to obtain a product residue, adding 200ml and 200ml of toluene into the residue to extract a product, standing, layering, collecting an organic phase, washing the organic phase with 100ml of brine for 2 times, collecting the organic phase, adding 2.0g of anhydrous sodium sulfate to dehydrate and dry, filtering, collecting filtrate, concentrating and removing the solvent to obtain a final product, namely a sitagliptin intermediate of the compound shown as the formula I, wherein the molar yield is 91.6%, and the purity of the product reaches over 99.1%.
Example 7
Dissolving 1mol of dihydrazide of a compound shown as a formula II serving as a raw material in 500ml of acetonitrile, adding 1.1mol of chloromethylene dimethyl ammonium chloride (Vilsmeier Reagent) of a compound shown as a formula III and 1.2mol of sodium bicarbonate, controlling the reaction temperature of a system to react at 32 ℃ for 5 hours, after the reaction is finished, concentrating under reduced pressure to recover the acetonitrile to obtain a product residue, adding 200ml of water and 240ml of ethyl acetate into the residue to extract a product, standing, layering, collecting an organic phase, washing the organic phase with 100ml of brine for 2 times, collecting the organic phase, adding 1.5g of anhydrous sodium sulfate to dehydrate and dry, filtering, collecting filtrate, concentrating and removing the solvent to obtain a final product, namely a sitagliptin intermediate of the compound shown as the formula I, wherein the molar yield is 90.2%, and the product purity is over 99.0%.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims (10)

1. A preparation method of a sitagliptin intermediate is characterized by comprising the following steps:
in the presence of an acid-binding agent, carrying out cyclization reaction on a substrate compound shown in a formula II under the action of a compound shown in a formula III, namely chloromethylene dimethyl ammonium chloride to obtain a corresponding sitagliptin intermediate shown in a formula I;
Figure FDA0003538564890000011
2. the preparation method of sitagliptin intermediate according to claim 1, characterized in that the cyclization reaction is carried out at a temperature of 20 ℃ to 35 ℃.
3. The preparation method of sitagliptin intermediate according to claim 1, characterized in that the acid scavenger is selected from organic base or inorganic base.
4. The preparation method of sitagliptin intermediate as claimed in claim 3, wherein the organic base is selected from triethylamine, diethylamine or pyridine; the inorganic base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
5. The preparation method of sitagliptin intermediate according to any one of claims 1 to 4, characterized in that the cyclization reaction is carried out in one or more of halogenated alkane solvent, ether solvent, aromatic hydrocarbon solvent and nitrile solvent.
6. The preparation method of sitagliptin intermediate according to any one of claims 1 to 4, characterized in that the cyclization reaction is carried out in one or more of tetrahydrofuran, dichloromethane, toluene and acetonitrile.
7. The preparation method of sitagliptin intermediate as claimed in any one of claims 1 to 4, wherein the molar ratio of the substrate compound of formula II to the compound of formula III, namely chloromethylene dimethyl ammonium chloride, is 1: 1.0 to 1.3.
8. The preparation method of sitagliptin intermediates according to any one of claims 1 to 4, wherein the compound of formula II: the mol ratio of the acid-binding agent is 1: 1.0 to 1.5.
9. The preparation method of a sitagliptin intermediate according to any one of claims 1 to 4, characterized in that after the cyclization reaction is finished, the solvent in the reaction solution is removed, and water and a water-insoluble solvent are added to the residue for treatment.
10. The method for preparing sitagliptin intermediate according to claim 9, wherein the water-insoluble solvent is selected from toluene, ethyl acetate or dichloromethane.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097733A1 (en) * 2004-04-05 2005-10-20 Merck & Co., Inc. Process for the preparation of enantiomerically enriched beta amino acid derivatives
CN103923087A (en) * 2014-04-21 2014-07-16 南京靖龙药物研发有限公司 Method for preparing deuterium-labeled sitagliptin
CN112480021A (en) * 2020-12-01 2021-03-12 台州达辰药业有限公司 Preparation method of 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097733A1 (en) * 2004-04-05 2005-10-20 Merck & Co., Inc. Process for the preparation of enantiomerically enriched beta amino acid derivatives
CN103923087A (en) * 2014-04-21 2014-07-16 南京靖龙药物研发有限公司 Method for preparing deuterium-labeled sitagliptin
CN112480021A (en) * 2020-12-01 2021-03-12 台州达辰药业有限公司 Preparation method of 5- (chloromethyl) -2- (trifluoromethyl) -1,3,4 oxadiazole

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MAAROOF ZAREI, ET AL.: "Convenient Vilsmeier Reagent Mediated One-Pot Synthesis of Symmetrical and Asymmetrical 1, 3, 4- Oxadiazoles", 《ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL》, pages 97 - 98 *
朱高峰;周艳;: "5, 6, 7, 8-四氢-3-三氟甲基-1, 2, 4-三唑并[4, 3-a]吡嗪盐酸盐的合成", 广州化工, no. 13, pages 355 *

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