CN112574206A - Preparation method of tofacitinib methylated impurities - Google Patents

Preparation method of tofacitinib methylated impurities Download PDF

Info

Publication number
CN112574206A
CN112574206A CN201910928242.XA CN201910928242A CN112574206A CN 112574206 A CN112574206 A CN 112574206A CN 201910928242 A CN201910928242 A CN 201910928242A CN 112574206 A CN112574206 A CN 112574206A
Authority
CN
China
Prior art keywords
acid
compound
tofacitinib
preparation
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201910928242.XA
Other languages
Chinese (zh)
Inventor
张贵民
翟立海
李振
郭立红
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lunan Pharmaceutical Group Corp
Original Assignee
Lunan Pharmaceutical Group Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lunan Pharmaceutical Group Corp filed Critical Lunan Pharmaceutical Group Corp
Priority to CN201910928242.XA priority Critical patent/CN112574206A/en
Publication of CN112574206A publication Critical patent/CN112574206A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/90—Plate chromatography, e.g. thin layer or paper chromatography

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of tofacitinib methylated impurities. The method takes N-methyl-N- ((3R,4R) -4-methylpiperidine-3-yl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine as a raw material, takes formaldehyde as a methylation reagent, and reacts under the action of protonic acid and a catalyst to obtain the tofacitinib methylated impurities.

Description

Preparation method of tofacitinib methylated impurities
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of tofacitinib methylated impurities.
Background
Tofacitinib citrate (Tofacitinib citrate), chemical name is (3R,4R) -4-methyl-3- (methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamino) -beta-carbonyl-1-piperidinepropanil-2-hydroxy-1, 2, 3-propane tricarboxylate (1: 1). Tofacitinib citrate is a novel oral JAK inhibitor developed by the U.S. fevere company, approved by the U.S. FDA to be on the market at 11 months of 2012, and is under the trade name Xeljanz, and is used for treating adult patients with moderate to severe active rheumatoid arthritis who do not respond sufficiently or are intolerant to methotrexate treatment. The structural formula is as follows:
Figure BDA0002219497470000011
at present, more methods for preparing tofacitinib are reported, and the method is mainly divided into two major steps, wherein the first step is the synthesis of a piperidine ring intermediate containing a protecting group; the second step is that the piperidine ring intermediate and chlorinated 7H-pyrrolo [2,3-d ] pyrimidine-4-group are subjected to coupling reaction to obtain tofacitinib, for example, the original research patent US6627754 and Chinese patent application CN1409712 report a method for obtaining tofacitinib by using benzyl protected 4-methyl-piperidine-3-ketone as an initial raw material, firstly performing reduction and ammoniation reaction on methylamino by ketone, then performing N-alkylation, hydrogenolysis debenzylation and piperidine N-nitrile acetylation, and then performing resolution:
Figure BDA0002219497470000012
the Chinese patent applications CN1195755C, CN106146517A, CN101233138A and the literature (Chem Med Chem,2014:9(11), 2516-:
Figure BDA0002219497470000021
in summary of the above published reports, it is known that the formation of N-methyl-N- [ (3R,4R) -4-methyl-3-piperidinyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (II) by solvent methylation of tofacitinib produces the impurity N-methyl-N- [ (3R,4R) -1, 4-dimethyl-3-piperidinyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-amine as follows:
Figure BDA0002219497470000022
in the process of research and development of new drugs, the quality of drugs is an important standard for measuring the quality of drugs, the quality standard of drugs has strict regulations on the purity of active ingredients of the drugs and the limit of impurities, generally, more than 0.1% of drug impurities should be identified and quantified by a selective method, and for drug research and development personnel, the impurities generated in the efficient impurity synthesis route oriented synthesis process are developed so as to obtain an impurity reference substance, so that the development of quality detection work (such as impurity HPLC positioning, impurity content measurement and the like) of each batch of raw material drugs is also very important work.
With the advancement of the national research work on the drug consistency, the preparation method of the tofacitinib methylated impurities is determined, qualified reference substances are provided, and the method can play a positive role in the quality control of tofacitinib. At present, only the synthesis of tofacitinib citrate related substances (Liushuai, Tangchao, China journal of medical industry [ J ],2017 (3); 382-containing 386) reports on the preparation method of the methylated impurity compound. The process takes N-methyl-N- [ (3R,4R) -4-methyl-3-piperidyl ] -7H-pyrrolo [2,3-d ] pyrimidine-4-amine as a reaction raw material, and obtains the methylation impurity of tofacitinib by palladium hydroxide/carbon catalysis, hydrogenation and column chromatography separation in a methanol solvent. However, the method is complicated to operate, two methylation impurities are difficult to separate, and the yield is low and is only 10%.
Figure BDA0002219497470000031
Therefore, the problem to be solved at present is to explore a process route with low production cost, simple operation and higher yield for the methylated impurities of tofacitinib.
Disclosure of Invention
The invention aims to provide a tofacitinib methylated impurity compound and a preparation method thereof, wherein the impurity compound can be used as an impurity reference substance in a tofacitinib finished product detection standard and is used in a quality control link of impurity qualitative and quantitative analysis in the tofacitinib production process. The preparation method is novel, the raw materials are easy to obtain, the operation is simple, and the sample purity is high.
The specific technical scheme of the invention is as follows:
Figure BDA0002219497470000032
a preparation method of tofacitinib methylated impurity compound comprises the following steps: adding N-methyl-N- ((3R,4R) -4-methylpiperidine-3-yl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine, namely the compound shown in the formula I and formaldehyde into purified water, adding acid and a catalyst into the mixture under stirring, reacting the mixture at room temperature, and after TLC detection reaction is finished, carrying out post-treatment on the reaction solution to obtain a target compound II.
In a preferable embodiment, the feeding molar ratio of the compound I to formaldehyde is 1: 1.8-2.5, and particularly preferably 1: 2.0.
Preferably, the formaldehyde is 35 to 40 mass percent of formaldehyde aqueous solution, and particularly preferably 37 mass percent of formaldehyde aqueous solution.
In a preferred scheme, the acid is protonic acid; one or a combination of hydrochloric acid, sulfuric acid, acetic acid, benzenesulfonic acid and p-toluenesulfonic acid is preferred, and acetic acid is particularly preferred.
In a preferred embodiment, the feeding molar ratio of the compound I to the acid is 1: 2.0-2.6, and particularly preferably 1: 2.4.
Preferably, the catalyst is reducing agent Zn, Fe, Na2SO3Among them, Zn is particularly preferable.
In a preferred embodiment, the feeding molar ratio of the compound I to the catalyst is 1: 1.2-2.0, and particularly preferably 1: 1.5.
Preferably, after the reaction is finished, the reaction solution needs to be post-treated, and the post-treatment steps are as follows: after TLC detection reaction is completed, suction filtration is carried out, filtrate is reserved, the filtrate is washed by 10% NaOH and purified water in sequence, anhydrous sodium sulfate is dried, and the solvent is removed under reduced pressure to obtain the target compound.
The compound of formula II can be converted into pharmaceutically acceptable salts and solvates.
The compound of the formula II, and the salt or solvate thereof can be applied to detection of tofacitinib intermediate, bulk drug and/or preparation.
The invention has the technical effects that:
1. provided is a high purity methylated impurity of tofacitinib, which can be used as an impurity reference substance for controlling the quality of tofacitinib in the production process.
2. The method for preparing the tofacitinib methylated impurity compound II is simple, convenient and efficient, and has the advantages of short route of the whole synthesis method, simple operation steps, high reaction yield and high product purity.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water are added into a reaction bottle, 14.41g (0.24mol) of acetic acid, 16.22g (0.2mol) of 37% formalin solution and 9.65g (0.15mol) of zinc powder are added under stirring, the reaction is carried out at room temperature, TLC detection is carried out, suction filtration is carried out after the reaction is completed, filtrate is retained, the filtrate is washed by 10% NaOH and purified water in turn, anhydrous sodium sulfate is dried, and the solvent is removed under reduced pressure to obtain the target compound with the yield of 99.25% and the HPLC purity of 99.95%.
Example 2
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water were put into a reaction flask, and 12.01g (0.20mol) of acetic acid, 16.22g (0.2mol) of 37% formalin solution and 8.42g (0.15mol) of iron powder were added with stirring, reacted at room temperature, subjected to TLC detection, after completion of the reaction, suction-filtered, the filtrate was retained, washed with 10% NaOH and purified water in this order, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the objective compound with a yield of 94.45% and an HPLC purity of 99.90%.
Example 3
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water were put into a reaction flask, and 11.41g (0.19mol) of acetic acid, 17.14g (0.2mol) of 35% formalin solution and 8.42g (0.15mol) of iron powder were added with stirring, reacted at room temperature, detected by TLC, and after completion of the reaction, suction filtration was performed, the filtrate was retained, and the filtrate was washed with 10% NaOH and purified water in this order, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the objective compound in 85.87% yield and 99.63% HPLC purity.
Example 4
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine and 50ml of purified water were put in a reaction flask, and 15.61g (0.26mol) of acetic acid, 17.14g (0.2mol) of 35% formalin, 18.92g (0.15mol) of Na were added under stirring2SO3Reacting at room temperature, detecting by TLC, performing suction filtration after complete reaction, reserving filtrate, washing the filtrate by using 10% NaOH and purified water in sequence, drying by using anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain the target compound with the yield of 93.46% and the HPLC purity of 99.87%.
Example 5
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water are added into a reaction bottle, 16.21g (0.27mol) of acetic acid, 15.0g (0.2mol) of 40% aqueous formaldehyde solution and 9.65g (0.15mol) of zinc powder are added under stirring, the reaction is carried out at room temperature, TLC detection is carried out, suction filtration is carried out after the reaction is completed, filtrate is retained, the filtrate is washed by 10% NaOH and purified water in turn, anhydrous sodium sulfate is dried, the solvent is removed under reduced pressure to obtain the target compound, the yield is 85.45%, and the HPLC purity is 99.58%.
Example 6
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water were put into a reaction flask, and 8.78g (0.24mol) of hydrochloric acid, 14.61g (0.18mol) of 37% formalin solution and 9.65g (0.15mol) of zinc powder were added with stirring to react at room temperature, followed by TLC detection, suction filtration was performed after completion of the reaction, the filtrate was retained, and the filtrate was washed with 10% NaOH and purified water in this order, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the objective compound in 92.43% yield and 99.82% HPLC purity.
Example 7
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water were put into a reaction flask, and 23.52g (0.24mol) of sulfuric acid, 13.80g (0.17mol) of 37% formalin solution and 9.65g (0.15mol) of zinc powder were added with stirring, reacted at room temperature, subjected to TLC detection, after completion of the reaction, suction-filtered, the filtrate was retained, washed with 10% NaOH and purified water in this order, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the objective compound with a yield of 84.55% and an HPLC purity of 99.69%.
Example 8
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water were put into a reaction flask, 37.96g (0.24mol) of benzenesulfonic acid, 20.29g (0.25mol) of 37% formalin solution and 9.65g (0.15mol) of zinc powder were added with stirring, reacted at room temperature, detected by TLC, after completion of the reaction, suction-filtered, the filtrate was retained, washed with 10% NaOH and purified water in this order, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the objective compound with a yield of 92.45% and an HPLC purity of 99.75%.
Example 9
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water were put into a reaction flask, 41.33g (0.24mol) of p-toluenesulfonic acid, 21.10g (0.26mol) of 37% formalin solution and 9.65g (0.15mol) of zinc powder were added with stirring, reacted at room temperature, subjected to TLC detection, suction filtration was performed after completion of the reaction, the filtrate was retained, washed with 10% NaOH in sequence, purified water and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the objective compound with a yield of 83.35% and an HPLC purity of 99.47%.
Example 10
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water were put into a reaction flask, 14.41g (0.24mol) of acetic acid, 16.22g (0.2mol) of 37% formalin solution and 7.68g (0.12mol) of zinc powder were added with stirring, reacted at room temperature, detected by TLC, after completion of the reaction, suction-filtered, the filtrate was retained, washed with 10% NaOH and purified water in this order, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the objective compound with a yield of 92.22% and an HPLC purity of 99.81%.
Example 11
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water were put into a reaction flask, 14.41g (0.24mol) of acetic acid, 16.22g (0.2mol) of 37% formalin solution and 12.80g (0.20mol) of zinc powder were added with stirring, reacted at room temperature, subjected to TLC detection, after completion of the reaction, suction-filtered, the filtrate was retained, washed with 10% NaOH and purified water in this order, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the objective compound with a yield of 93.58% and an HPLC purity of 99.74%.
Example 12
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water were put into a reaction flask, and 14.41g (0.24mol) of acetic acid, 18.77g (0.2mol) of a 32% formalin solution and 7.04g (0.11mol) of zinc powder were added with stirring, reacted at room temperature, detected by TLC, and after completion of the reaction, suction filtration was performed, the filtrate was retained, washed with 10% NaOH and purified water in this order, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the objective compound in 83.19% yield and 99.58% HPLC purity.
Example 13
24.53g (0.1mol) of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine and 50ml of purified water were put into a reaction flask, and 14.41g (0.24mol) of acetic acid, 14.29g (0.2mol) of 42% formalin solution and 13.44g (0.21mol) of zinc powder were added with stirring, reacted at room temperature, detected by TLC, and after completion of the reaction, suction filtration was performed, the filtrate was retained, and the filtrate was washed with 10% NaOH and purified water in this order, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the objective compound in 82.72% yield and 99.45% HPLC purity.
Comparative examples
Reacting N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine (7g, 28.6mmol), palladium hydroxide on charcoal (0.7g) and methanol (70 g)ml) is added into a hydrogenation kettle, and hydrogen (1.4MPa) is introduced to react for 48 hours at the temperature of 65 ℃. Filtration and concentration of the filtrate under reduced pressure gave a pale yellow oil (7.46 g). The oil (2g) was taken up by column chromatography (eluent: V)Methanol∶VMethylene dichloride1:50) to obtain methylated impurities, the yield is 10%, and the HPLC purity is 93.54%.

Claims (10)

1. A preparation method of tofacitinib methylated impurities is characterized by comprising the following steps: adding a compound I, namely N-methyl-N- ((3R,4R) -4-methylpiperidine-3-yl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine and formaldehyde into purified water, adding acid and a catalyst into the purified water while stirring, reacting at room temperature, and after TLC detection reaction is finished, carrying out post-treatment on a reaction solution to obtain a target compound II, wherein the reaction route is as follows:
Figure FDA0002219497460000011
2. the preparation method according to claim 1, wherein the feeding molar ratio of the compound I to the formaldehyde is 1: 1.8-2.5.
3. The preparation method according to claim 1, wherein the formaldehyde is a 35-40% by mass aqueous formaldehyde solution.
4. The method of claim 1, wherein the acid is a protic acid.
5. The method according to claim 1 or 4, wherein the acid is one or a combination of hydrochloric acid, sulfuric acid, acetic acid, benzenesulfonic acid and p-toluenesulfonic acid, and acetic acid is particularly preferred.
6. The preparation method according to claim 1, wherein the feeding molar ratio of the compound I to the acid is 1: 2.0-2.6.
7. The method of claim 1, wherein the catalyst is Zn, Fe, Na2SO3One or a combination thereof.
8. The preparation method according to claim 1, wherein the feeding molar ratio of the compound I to the catalyst is 1: 1.2-2.0.
9. A pharmaceutically acceptable salt, solvate of a compound of formula II as claimed in claim 1.
10. Use of a compound of formula II as defined in claim 1, and salts or solvates thereof, for the detection of tofacitinib intermediates, drug substances and/or formulations.
CN201910928242.XA 2019-09-28 2019-09-28 Preparation method of tofacitinib methylated impurities Pending CN112574206A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910928242.XA CN112574206A (en) 2019-09-28 2019-09-28 Preparation method of tofacitinib methylated impurities

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910928242.XA CN112574206A (en) 2019-09-28 2019-09-28 Preparation method of tofacitinib methylated impurities

Publications (1)

Publication Number Publication Date
CN112574206A true CN112574206A (en) 2021-03-30

Family

ID=75110170

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910928242.XA Pending CN112574206A (en) 2019-09-28 2019-09-28 Preparation method of tofacitinib methylated impurities

Country Status (1)

Country Link
CN (1) CN112574206A (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160122354A1 (en) * 2013-06-05 2016-05-05 Srinivasan Thirumalai Rajan PROCESS FOR THE PREPARATION OF (3R,4R)-4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL-AMINO)-ß-OXO-1-PIPERIDINEPROPANENITRILE AND ITS SALTS
CN106008513A (en) * 2016-05-20 2016-10-12 江苏正大清江制药有限公司 Preparation method of tofacitinib citrate degradation impurity
CN107698595A (en) * 2017-09-23 2018-02-16 江苏正大清江制药有限公司 Preparation method of tofacitinib citrate substance
CN107793418A (en) * 2017-10-24 2018-03-13 扬子江药业集团有限公司 Industrial production method of tofacitinib citrate
CN108640923A (en) * 2018-07-09 2018-10-12 湖南天地恒制药有限公司 A kind of support method replaces the preparation method of cloth key intermediate
CN109776547A (en) * 2019-03-22 2019-05-21 北京新领先医药科技发展有限公司 Preparation method of tofacitinib citrate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160122354A1 (en) * 2013-06-05 2016-05-05 Srinivasan Thirumalai Rajan PROCESS FOR THE PREPARATION OF (3R,4R)-4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL-AMINO)-ß-OXO-1-PIPERIDINEPROPANENITRILE AND ITS SALTS
CN106008513A (en) * 2016-05-20 2016-10-12 江苏正大清江制药有限公司 Preparation method of tofacitinib citrate degradation impurity
CN107698595A (en) * 2017-09-23 2018-02-16 江苏正大清江制药有限公司 Preparation method of tofacitinib citrate substance
CN107793418A (en) * 2017-10-24 2018-03-13 扬子江药业集团有限公司 Industrial production method of tofacitinib citrate
CN108640923A (en) * 2018-07-09 2018-10-12 湖南天地恒制药有限公司 A kind of support method replaces the preparation method of cloth key intermediate
CN109776547A (en) * 2019-03-22 2019-05-21 北京新领先医药科技发展有限公司 Preparation method of tofacitinib citrate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
刘帅等: "托法替布枸橼酸盐有关物质的合成", 《中国医药工业杂志》, vol. 48, no. 03, pages 382 - 386 *

Similar Documents

Publication Publication Date Title
HU223312B1 (en) Process for preparing aryl-piperazinyl-heterocyclic compounds
CN108948020B (en) Refining method of tofacitinib citrate
KR20100046245A (en) Trazodone and trazodone hydrochloride in purified form
CN104761555A (en) Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method
CN115485282A (en) Oxazaspiro compound, salt form and crystal form thereof
CN112574206A (en) Preparation method of tofacitinib methylated impurities
CN113636973A (en) Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester
EP3424927B1 (en) Efficient process for the preparation of sitagliptin through a very effective preparation of the intermediate 2,4,5-trifluorophenylacetic acid
CN102725288A (en) Method for manufacturing a 6-substituted-1-methyl-1H-benzimidazole derivative, and manufacturing intermediate from said method
CA2673510C (en) Maleic acid monosalt of antiviral agent and pharmaceutical composition containing the same
CA2800324C (en) Zilpaterol and salts thereof for use in increasing the rate of weight gain, improved feed efficiency and/or increasing carcass leanness in a bovine
CN112694465A (en) Novel preparation process of trelagliptin succinate
CN110343111B (en) Preparation method of tofacitinib citrate
US8362006B2 (en) Processes for making zilpaterol and salts thereof
CN112209929A (en) Novel preparation process of linagliptin
CN109912605B (en) Purification method of pemetrexed intermediate
US9090623B2 (en) Compound JK12A and preparation thereof
HU220600B1 (en) Process for preparing 3,7-dialkyl xanthine derivatives from 3-alkyl xanthine derivatives
CN111004255A (en) Preparation method of cefcapene lactone compound or hydrochloride thereof
CN112574205B (en) Preparation method of tofacitinib water-soluble impurities
CN112724181B (en) Method for preparing Cangrelor intermediate adenosine-2-thioketone
CN116789607A (en) Letermopevir related substance, preparation method and detection method thereof
CN110003220B (en) Preparation method of tofacitinib citrate
CN112724140A (en) Novel preparation process of linagliptin
AU2016204871A1 (en) Processes for making zilpaterol and salts thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination