CN106008513A - Preparation method of tofacitinib citrate degradation impurity - Google Patents
Preparation method of tofacitinib citrate degradation impurity Download PDFInfo
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- CN106008513A CN106008513A CN201610335785.7A CN201610335785A CN106008513A CN 106008513 A CN106008513 A CN 106008513A CN 201610335785 A CN201610335785 A CN 201610335785A CN 106008513 A CN106008513 A CN 106008513A
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- methyl
- pyrrolo
- tofacitinib citrate
- pyrimidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a preparation method of tofacitinib citrate degradation impurities. The method is characterized in that: with 3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2, 3-d)]Pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropanenitrile as a starting material is used for preparing tofacitinib citrate degradation impurity N- ((3R,4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d under the action of an oxidant]Pyrimidine-4-amine oxide (I).
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a preparation method of tofacitinib citrate degradation impurities for treating rheumatoid arthritis.
Background
Rheumatoid arthritis is an autoimmune disease that causes inflammation of joints and surrounding tissues due to the human immune system mistakenly attacking healthy tissues. Tofacitinib citrate is a drug developed by the American pfeiffer pharmaceutical company for treating rheumatoid arthritis, is named as Xeljanz, is a Janus kinase inhibitor and is used for adult patients with moderate to severe active Rheumatoid Arthritis (RA) with insufficient or intolerant response to methotrexate treatment.
The company pfeiffe discloses two routes of preparation in patent WO2007012953 (see route 1 and route 2). Route 1 uses (4-methylpyridin-3-yl) methyl carbamate (compound I) as a starting material, benzyl is firstly introduced to obtain a compound II, the compound II is reduced by sodium borohydride to obtain a compound III, the compound III is reduced by chiral rhodium catalysis, salifying and purifying by L-ditoluoyltartaric acid to obtain a key intermediate IV, the key intermediate IV is condensed with 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine, subjected to reductive dechlorination and debenzylation, and finally acylated with cyanoacetyl chloride to obtain tofacitinib. In the method, sodium borohydride (which easily generates a large amount of gas during reduction) and an expensive chiral rhodium catalyst are used for preparing the key intermediate IV, so that the industrial application is extremely limited.
Route 2 is substantially different from the above routes except that 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine is used as a raw material, pyrrole is protected by tosyl chloride, and then the raw material is condensed with a compound IV to obtain IX, the protecting group of Tos of IX is removed by 50% sodium hydroxide solution, and then the IX is hydrogenated and debenzylated to obtain VI, and finally the VI is acylated with ethyl cyanoacetate to obtain tofacitinib.
N- ((3R,4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine oxide is a degradation impurity of tofacitinib citrate, is a nitrogen oxide, and can influence the quality of tofacib citrate. Therefore, it is necessary to find a method for easily synthesizing the impurities.
Disclosure of Invention
The invention aims to provide a preparation method of tofacitinib citrate degradation impurities. The preparation method has simple operation and high yield.
In order to achieve the purpose, the invention adopts the technical scheme that: a preparation method of tofacitinib citrate degradation impurities comprises the following steps:
dissolving 3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropanenitrile serving as a starting material in an organic solvent, and under the action of an oxidant, preparing the tofacitinib citrate degradation impurity N- ((3R,4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine oxide.
In the technical scheme, the used organic solvent is C1-4Alcohol, C2-8Ether and dichloromethane, and the like.
In the technical scheme, the reaction temperature is 0-50 ℃.
In the technical scheme, the used oxidant is 30% of hydrogen peroxide, tert-butyl peroxy alcohol, m-chloroperoxybenzoic acid (m-CPBA) and the like.
In the technical scheme, the molar ratio of the 3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropanenitrile to the oxidant is 1: 1-1: 10.
In the technical scheme, the reaction time is 40-70 h.
In the preferred technical scheme, the used organic solvents are ethanol, isopropanol and dichloromethane.
In a preferred technical scheme, the reaction temperature is 10-30 ℃.
In a preferred technical scheme, the used oxidant is m-chloroperoxybenzoic acid (m-CPBA).
In a preferred technical scheme, the molar ratio of 3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile to m-chloroperoxybenzoic acid is 1: 3-1: 7.
In a preferred technical scheme, the reaction time is 45-55 h.
The reaction process can be expressed as:
the invention has the advantages that: the oxidant is easy to obtain, the reaction condition is mild, and the operation is simple.
The invention is further illustrated by the following examplesThe following examples are given for illustrative purposes only and are not to be construed as limiting the scope of the present invention. The corresponding alterations and modifications made according to the ordinary skill in the art and the conventional means without departing from the scope of the invention are all included in the scope of the invention。
The first embodiment is as follows:
mixing 3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile (10.0g, 32.01mmol), dichloromethane (700ml), m-CPBA (27.6g, 160.1mmol) was added to a 1L single-neck flask (undissolved, milky white) and reacted at 25 ℃. The solution gradually changed from milky white to light yellow and gradually dissolved clear as the reaction proceeded, and the reaction was monitored by TLC, and after 50h, TLC showed that the starting material was substantially completely reacted. Dichloromethane was removed by rotary evaporation to obtain a yellow solid, and the product was separated and purified by column chromatography to obtain 5.1g of a pale yellow solid.1HNMR (DMSO- d6, 400MHz) δ 8.38 (d, J = 5.3 Hz, 1H), 7.30 (d, J = 2.6 Hz, 1H), 6.76 (d, J = 3.1 Hz, 1H), 4.73 (s, 1H), 4.13 (m, 2H), 3.94 (m, 1H), 3.77 (m, 1H), 3.66 (d, J = 11.4 Hz, 1H), 3.43 (d, J = 18.8 Hz, 2H), 3.17 (s, 3H), 2.38 (d, J = 5.0 Hz, 1H), 1.82 (s, 1H), 1.58 (s, 1H), 1.01 (d, J = 6.9 Hz, 3H)；ESI-MS(m/z): 328.9[M+H]+。
Example two:
3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile (10.0g, 32.01mmol), ethanol (700ml), m-CPBA (27.6g, 160.1mmol) was added to a 1L one-neck flask (undissolved, milky white) and reacted at 25 ℃. The solution gradually changed from milky white to light yellow and gradually dissolved clear as the reaction proceeded, and the reaction was monitored by TLC, and after 40h, TLC showed that the starting material was substantially completely reacted. And (3) removing ethanol by rotary evaporation to obtain a yellow solid, and separating and purifying the product by utilizing column chromatography to obtain 6g of a light yellow solid.
Example three:
3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile (10.0g, 32.01mmol), isopropanol (700ml), m-CPBA (27.6g, 160.1mmol) was added to a 1L one-neck flask (undissolved, milky white) and reacted at 25 ℃. The solution gradually changed from milky white to light yellow and gradually dissolved clear as the reaction proceeded, and the reaction was monitored by TLC, and after 50h, TLC showed that the starting material was substantially completely reacted. The isopropanol is removed by rotary evaporation to obtain a yellow solid, and the product is separated and purified by column chromatography to obtain 5.5g of a light yellow solid.
Example four:
3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile (10.0g, 32.01mmol), ethanol (700ml), m-CPBA (27.6g, 160.1mmol) was added to a 1L one-neck flask (undissolved, milky white) and reacted at 30 ℃. The solution gradually changed from milky white to light yellow and gradually dissolved clear as the reaction proceeded, and the reaction was monitored by TLC, and after 40h, TLC showed that the starting material was substantially completely reacted. And (3) removing ethanol by rotary evaporation to obtain a yellow solid, and separating and purifying the product by utilizing column chromatography to obtain 5.2g of a light yellow solid.
Example five:
3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile (10.0g, 32.01mmol), ethanol (700ml), m-CPBA (16.6g, 96.0mmol) was added to a 1L one-neck flask (undissolved, milky white) and reacted at 25 ℃. The solution gradually changed from milky white to light yellow and gradually dissolved clear as the reaction proceeded, and the reaction was monitored by TLC, and after 55h, TLC showed that the starting material was substantially completely reacted. And (4) removing ethanol by rotary evaporation to obtain a yellow solid, and separating and purifying the product by utilizing column chromatography to obtain 4.9g of a light yellow solid.
Example six:
3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile (10.0g, 32.01mmol), dichloromethane (700ml), m-CPBA (27.6g, 160.1mmol) was added to a 1L one-neck flask (undissolved, milky white) and reacted at 25 ℃. The solution gradually changed from milky white to light yellow and gradually dissolved clear as the reaction proceeded, and the reaction was monitored by TLC, and after 50h, TLC showed that the starting material was substantially completely reacted. Dichloromethane was removed by rotary evaporation to obtain a yellow solid, and the product was separated and purified by column chromatography to obtain 5.4g of a pale yellow solid.
Claims (6)
1. A preparation method of tofacitinib citrate degradation impurities is characterized in that 3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropanenitrile is used as a starting material and is dissolved in an organic solvent to prepare tofacitinib citrate degradation impurities N- ((3R,4R) -1- (2-cyanoacetyl) -4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine oxide under the action of an oxidant.
2. The production method according to claim 1: characterized in that the organic solvent is C1-4Alcohol, C2-8Ether and dichloromethane, and the like.
3. The production method according to claim 1: it is characterized in that the reaction temperature is 0-50 ℃.
4. The production method according to claim 1: the method is characterized in that the used oxidant is 30% of hydrogen peroxide, tert-butyl peroxy alcohol, m-chloroperoxybenzoic acid (m-CPBA) and the like.
5. The production method according to claim 1: the method is characterized in that the molar ratio of 3- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropanenitrile to an oxidant is 1: 1-1: 10.
6. The production method according to claim 1: it is characterized in that the reaction time is 40-70 h.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109053771A (en) * | 2018-08-22 | 2018-12-21 | 珠海优润医药科技有限公司 | A kind of support method replaces the related substance and its preparation method and application of cloth |
| CN110606846A (en) * | 2019-07-30 | 2019-12-24 | 石药集团中奇制药技术（石家庄）有限公司 | Tofacitinib citrate impurity and analysis method and application thereof |
| CN112574206A (en) * | 2019-09-28 | 2021-03-30 | 鲁南制药集团股份有限公司 | Preparation method of tofacitinib methylated impurities |
| CN114957264A (en) * | 2022-06-29 | 2022-08-30 | 华润双鹤药业股份有限公司 | Tofacitinib citrate impurity and preparation method and application thereof |
-
2016
- 2016-05-20 CN CN201610335785.7A patent/CN106008513A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| SAMPATH KUMAR REDDY GOVIND ET AL.: "Stability indicating HPLC method for the quantification of tofacitinib citrate and its related substances", 《DER PHARMA CHEMICA》 * |
| 梁晓东等: "达沙替尼原料中的杂质研究", 《CHINESE JOURNAL OF NEW DRUGS》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109053771A (en) * | 2018-08-22 | 2018-12-21 | 珠海优润医药科技有限公司 | A kind of support method replaces the related substance and its preparation method and application of cloth |
| CN109053771B (en) * | 2018-08-22 | 2020-02-28 | 珠海优润医药科技有限公司 | Related substance of tofacitinib and preparation method and application thereof |
| CN110606846A (en) * | 2019-07-30 | 2019-12-24 | 石药集团中奇制药技术（石家庄）有限公司 | Tofacitinib citrate impurity and analysis method and application thereof |
| CN112574206A (en) * | 2019-09-28 | 2021-03-30 | 鲁南制药集团股份有限公司 | Preparation method of tofacitinib methylated impurities |
| CN114957264A (en) * | 2022-06-29 | 2022-08-30 | 华润双鹤药业股份有限公司 | Tofacitinib citrate impurity and preparation method and application thereof |
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