CN114075201A - Preparation method of sitagliptin impurity - Google Patents
Preparation method of sitagliptin impurity Download PDFInfo
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- CN114075201A CN114075201A CN202010845130.0A CN202010845130A CN114075201A CN 114075201 A CN114075201 A CN 114075201A CN 202010845130 A CN202010845130 A CN 202010845130A CN 114075201 A CN114075201 A CN 114075201A
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Abstract
The invention provides a preparation method of a sitagliptin impurity compound, belonging to the field of chemical pharmacy. According to the method, racemic and/or chiral sitagliptin is used as a substrate, reduction amination is carried out firstly, then Cope elimination is carried out, and the sitagliptin impurity compound is obtained. The method is rigorous in operation, practical, scientific and reliable, the required materials are easy to store, no harm is caused, the product is easy to purify, the yield and purity are high, the preparation requirement of the impurity can be met, a new thought is provided for the synthesis of the sitagliptin impurity (XGT062-05), and the method has important significance for the research of the sitagliptin impurity.
Description
Technical Field
The invention relates to the field of chemical pharmacy, and particularly relates to a preparation method of sitagliptin impurity.
Background
Sitagliptin is a novel orally administered Dipeptidyl peptidase-4 (DPP-4) inhibitor drug developed by american merck corporation, has the same position as other effective antihyperglycemic drugs (such as sulfonylureas, GLP-1 receptor agonists, thiazolidinediones, insulin, and the like) as a second-line hypoglycemic drug after metformin therapy is used for treating type 2 diabetes, is a highly selective DPP-4 inhibitor, is the DPP-4 inhibitor on the market at the 1 st global level, and is approved for sale by the food and drug administration in china in 2009, and has a trade name: jienowei. The sitagliptin can improve the blood sugar by being taken alone, and can enhance the curative effect by being taken together with metformin, insulin, sulfonylureas and thiazolidinediones, and the risk of hypoglycemia is not increased, and the body mass of a patient is not increased.
Sitagliptin chemical name (3R) -3-amino-1- [3- (trifluoromethyl) -5,6,7, 8-tetrahydro-1, 2, 4-triazolo [4,3-a ] pyrazin-7- (8H) -yl ] -4- (2,4, 5-trifluorophenyl) butan-1-one, having the following structural formula:
during the production process and the preparation stability standing process of sitagliptin, impurities are inevitably generated: (2E) -1- [5, 6-dihydro-3- (trifluoromethyl) -1,2, 4-triazolo [4,3-a ] pyrazin-7 (8H) -yl ] -4- (2,4, 5-trifluorophenyl) -2-buten-1-one (hereinafter referred to as sitagliptin impurity), the structural formula of which is shown as compound XGT062-05, and the impurity has important significance for the quality control and impurity research of sitagliptin.
Chemistry select (2018,3,2723-2729) reports a preparation method of sitagliptin impurities, wherein sitagliptin impurities are obtained by degrading sitagliptin acetate through n-butanol at high temperature, and the preparation method comprises the following steps:
comparing the product nuclear magnetism with the product nuclear magnetism, repeating the preparation method of the literature, and confirming the structure of the obtained product to be actually double bond position isomeric impurity (XGT062-04), wherein the structure is as follows:
chinese patent document CN105130999A reports a synthesis method of sitagliptin impurities, the reaction route is long, and by comparing the nuclear magnetism of the product provided by the method, the actual structure of the obtained product can be judged to be double-bond position isomeric impurities (XGT 062-04). The preparation method comprises the following steps:
ACS Omega [ (2020),5(10),5356-5364] reports the preparation method of sitagliptin impurity, which comprises the following steps:
through verification and discovery, the first step of the method uses a format reagent and CoBr2The method needs strict control of anhydrous and anaerobic conditions, and is complex to operate and difficult to repeat. And the third step repeats the optimal conditions, the generation of double bond isomers cannot be avoided, the purification cost is greatly increased, the purity is difficult to reach more than 95 percent, and the quality research requirements cannot be met.
PCT application WO2015120111A2 discloses a report on sitagliptin impurities, but the obtained structure of the report is a sitagliptin impurity double-bond cis-trans isomeric mixture or four compounds containing double bond position isomerism and cis-trans isomerism, and because the four compounds are similar in property, the four compounds cannot be separated by a conventional means, and the purification cost is greatly increased. In the experimental process, acetic anhydride which is easy to prepare toxic auxiliary materials and sodium borohydride which is a dangerous chemical are used, so the application range of the method is limited. The preparation method comprises the following steps:
disclosure of Invention
In order to improve the technical problem, the invention provides a preparation method of a sitagliptin impurity compound XGTT 062-05, which comprises the following steps:
1) compounds XGTT 062-05-001 and R1C(O)R2In the presence of a reducing agent, carrying out reductive amination reaction in a solvent I to prepare a compound XGTT 062-05-002;
2) subjecting the compound XGT062-05-002 prepared in step 1) to Cope elimination in solvent II in the presence of an oxidizing agent to obtain the sitagliptin impurity (XGT 062-05);
wherein R is1And R2Are identical or different and are independently selected from hydrogen or C1-6An alkyl group;
according to an embodiment of the invention, said R1C(O)R2May be selected from at least one of formaldehyde, paraformaldehyde, acetaldehyde, acetone, methyl ethyl ketone;
according to an embodiment of the present invention, the reducing agent in step 1) is selected from at least one of sodium cyanoborohydride, sodium borohydride or sodium triacetoxyborohydride, preferably sodium cyanoborohydride;
according to an embodiment of the present invention, the solvent I in step 1) is selected from at least one of methanol, ethanol, tetrahydrofuran and toluene, preferably methanol.
According to an embodiment of the invention, the compound XGT062-05-001 with R in step 1)1C(O)R2In a molar ratio of 1 (1-10), such as 1 (2-8), illustratively 1: 4.
According to an embodiment of the invention, the molar ratio of the compound XGT062-05-001 to the reducing agent in step 1) is 1 (1-10), such as 1 (2-8), illustratively 1: 4.
According to an embodiment of the invention, the mass to volume ratio of compound XGT062-05-001 to solvent I in step 1) may be 1 (2-30) g/mL, for example 1 (5-20) g/mL, illustratively 1:10 g/mL.
According to an embodiment of the present invention, the oxidizing agent in step 2) is selected from at least one of m-chloroperoxybenzoic acid, hydrogen peroxide, potassium permanganate and tert-butyl hydroperoxide, preferably m-chloroperoxybenzoic acid;
according to an embodiment of the present invention, the solvent II in step 2) is selected from at least one of dichloromethane, chloroform, ethyl acetate, and tetrahydrofuran, preferably dichloromethane.
According to an embodiment of the invention, the molar ratio of the compound XGT062-05-002 to the oxidizing agent in step 2) is 1 (0.8-3), such as 1 (1-2), illustratively 1: 1.5.
According to an embodiment of the invention, the mass to volume ratio of the compound XGT062-05-002 to solvent II in step 2) may be 1 (2-30) g/mL, such as 1 (5-20) g/mL, with 1:10g/mL being exemplary.
According to an embodiment of the invention, the reaction temperature in step 2) may be in the range of-80 ℃ to 10 ℃, for example-70 ℃ to-65 ℃, 50 ℃ to-45 ℃, 30 ℃ to 5 ℃, exemplary 0 ℃ to 5 ℃.
According to an embodiment of the invention, the reaction time of step 2) may be 0.1 to 12h, for example 0.5 to 6 h.
The invention also provides application of the preparation method in pharmaceutical process research, and the preparation method can be used for sitagliptin impurity research.
Advantageous effects
The synthesis method provided by the invention provides a new idea for synthesizing sitagliptin impurities (XGT062-05), is easy to obtain starting materials, is simple to operate, can effectively control the generation of double-bond isomeric impurities in the reaction process, and is convenient and fast to purify. The method is rigorous in operation, practical, scientific and reliable, the required materials are easy to store and harmless, the product is easy to purify, the yield and purity are high, the preparation requirement of the impurity can be met, and the method has important significance for researching the sitagliptin impurity.
Drawings
FIG. 1 shows an example2 XGTT 062-05 Compound obtained1H NMR spectrum (deuterated reagent is d)6-DMSO)；
FIG. 2 is an MS map of the XGT062-05 compound obtained in example 2;
FIG. 3 is an HPLC chromatogram of the XGT062-05 compound obtained in example 2;
FIG. 4 shows the XGTT 062-05 compound obtained in example 21H NMR spectrum (deuterated reagent is CDCl)3)。
Definition and description of terms
The term "C1-6Alkyl "denotes straight-chain and branched alkyl groups having 1,2, 3, 4,5 or 6 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a 1, 2-dimethylpropyl group, a neopentyl group, a 1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3, 3-dimethylbutyl group, a2, 2-dimethylbutyl group, a 1, 1-dimethylbutyl group, a2, 3-dimethylbutyl group, a 1, 3-dimethylbutyl group or a 1, 2-dimethylbutyl group, or the like, or isomers thereof.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1 Synthesis of Compound XGTT 062-05-01
XGTT 062-05-001(30g, 1.0eq), formaldehyde (23.8g, 4.0eq), methanol (300mL), sodium cyanoborocyanide (18.45g, 4.0eq) were added to a 500mL three-necked flask, then replaced with argon three times, stirred at room temperature overnight, and the progress of the reaction was monitored by TLC. Stopping the reaction after the basic reaction of the raw materials is finished, adding water and stirring, extracting for 3 times by DCM, combining organic phases, washing by saturated sodium chloride, draining to obtain a yellow oily crude product, purifying by column chromatography, collecting eluent, draining to obtain 16.4g of a light yellow oily product, wherein the volume ratio of the eluent is DCM/MeOH-20/1. Yield: 52 percent.
Example 2 Synthesis of Compound XGTT 062-05
Dissolving the compound XGTT 062-05-01(16.4g, 1.0eq) obtained in the step 1 in dichloromethane (165mL), adding the dichloromethane (165mL) into a three-necked bottle, cooling and stirring, adding a DCM solution of m-chloroperoxybenzoic acid (11.6g, 1.5eq) dropwise at the temperature of 0-5 ℃, preserving the temperature for 1h after the dropwise addition is finished, and monitoring the reaction progress by TLC. The raw materials are reacted completely, saturated sodium bicarbonate aqueous solution is added, stirring and liquid separation are carried out, the organic phase is washed for 3 times by sodium sulfite aqueous solution, m-chloroperoxybenzoic acid is removed, and the organic phase is dried and concentrated to obtain 17g of light yellow oily crude product. Purifying the crude product by column chromatography, and eluting the eluent: DCM: MeOH 40:1, the eluate was collected and concentrated to dryness under reduced pressure to give sitagliptin as an impurity: 13g, yield: 87.2% (HPLC: 96.8%).
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of sitagliptin impurity compound XGTT 062-05 comprises the following steps:
1) compounds XGTT 062-05-001 and R1C(O)R2In the presence of a reducing agent, carrying out reductive amination reaction in a solvent I to prepare a compound XGTT 062-05-002;
2) carrying out Cope elimination on the compound XGT062-05-002 prepared in the step 1) in a solvent II in the presence of an oxidant to obtain the sitagliptin impurity XGT 062-05;
wherein R is1And R2Are identical or different and are independently selected from hydrogen or C1-6An alkyl group.
2. The method of claim 1, wherein R is1C(O)R2May be at least one selected from the group consisting of formaldehyde, paraformaldehyde, acetaldehyde, acetone, and methyl ethyl ketone.
3. The preparation method according to claim 1 or 2, characterized in that the reducing agent in step 1) is selected from at least one of sodium cyanoborohydride, sodium borohydride or sodium triacetoxyborohydride, preferably sodium cyanoborohydride;
preferably, the solvent I in step 1) is selected from at least one of methanol, ethanol, tetrahydrofuran and toluene, and is preferably methanol.
4. The method according to any one of claims 1 to 3, wherein the compounds XGT062-05-001 and R in step 1)1C(O)R2The molar ratio of (A) to (B) is 1 (1-10), for example 1 (2-8).
5. The process of any one of claims 1 to 4, wherein the compound XGT062-05-001 and the reducing agent are present in step 1) in a molar ratio of 1 (1-10), such as 1 (2-8).
6. The method according to any one of claims 1 to 5, wherein the ratio of XGT062-05-001 to solvent I in step 1) may be 1 (2 to 30) g/mL, for example 1 (5 to 20) g/mL.
7. The production method according to any one of claims 1 to 6, wherein the oxidizing agent in step 2) is selected from at least one of m-chloroperoxybenzoic acid, hydrogen peroxide, potassium permanganate, and tert-butyl hydroperoxide, preferably m-chloroperoxybenzoic acid;
preferably, the solvent II in step 2) is at least one selected from dichloromethane, chloroform, ethyl acetate and tetrahydrofuran.
8. The process of any of claims 1-7, wherein the compound XGT062-05-002 is present in step 2) in a molar ratio to the oxidizing agent of 1 (0.8-3), such as 1 (1-2);
preferably, the mass-to-volume ratio of the compound XGT062-05-002 to the solvent II in step 2) may be 1 (2-30) g/mL, for example 1 (5-20) g/mL.
9. The process of any one of claims 1 to 8, wherein the reaction temperature of step 2) may be from-80 ℃ to 10 ℃, such as from-70 ℃ to-65 ℃, from-50 ℃ to 45 ℃, from 30 ℃ to 5 ℃;
preferably, the reaction time of step 2) may be from 0.1 to 12h, for example from 0.5 to 6 h.
10. Use of the preparation method of any one of claims 1-9 in pharmaceutical technology research, which can be used for sitagliptin impurity research.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115611708A (en) * | 2022-11-08 | 2023-01-17 | 北京福元医药股份有限公司沧州分公司 | Preparation method of rotigotine impurity K |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010122578A2 (en) * | 2009-04-20 | 2010-10-28 | Msn Laboratories Limited | Process for the preparation of sitagliptin and its intermediates |
| CN105130999A (en) * | 2015-10-15 | 2015-12-09 | 合肥华方医药科技有限公司 | Synthesis method of Sitagliptin impurities |
| CN106478637A (en) * | 2016-08-30 | 2017-03-08 | 南京正大天晴制药有限公司 | A kind of impurity of sitagliptin and its preparation, detection method |
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2020
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010122578A2 (en) * | 2009-04-20 | 2010-10-28 | Msn Laboratories Limited | Process for the preparation of sitagliptin and its intermediates |
| CN105130999A (en) * | 2015-10-15 | 2015-12-09 | 合肥华方医药科技有限公司 | Synthesis method of Sitagliptin impurities |
| CN106478637A (en) * | 2016-08-30 | 2017-03-08 | 南京正大天晴制药有限公司 | A kind of impurity of sitagliptin and its preparation, detection method |
Non-Patent Citations (3)
| Title |
|---|
| DATTATRAY S. METI ET AL.: "Efficient and Convenient Synthetic Routes for Sitagliptin Impurities", 《CHEMISTRYSELECT》 * |
| LUKAS JEDINAK ET AL.: "Use of Silver Carbonate in the Wittig Reaction", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| 周航等: "(－)-Frontalin 的形式合成", 《有机化学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115611708A (en) * | 2022-11-08 | 2023-01-17 | 北京福元医药股份有限公司沧州分公司 | Preparation method of rotigotine impurity K |
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