CN109053771B - Related substance of tofacitinib and preparation method and application thereof - Google Patents
Related substance of tofacitinib and preparation method and application thereof Download PDFInfo
- Publication number
- CN109053771B CN109053771B CN201810961994.1A CN201810961994A CN109053771B CN 109053771 B CN109053771 B CN 109053771B CN 201810961994 A CN201810961994 A CN 201810961994A CN 109053771 B CN109053771 B CN 109053771B
- Authority
- CN
- China
- Prior art keywords
- acid
- tofacitinib
- preparation
- organic phase
- taking
- 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.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- 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
- G01N30/02—Column chromatography
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Detergent Compositions (AREA)
Abstract
The invention discloses a related substance of tofacitinib, a preparation method and application thereof, wherein the system name of the substance is as follows: n, N' -diacetyl { (3R,4R) -4-methyl-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidin-1-yl } imine. The impurity is low in generation level in the condensation reaction process, but because the impurity is consistent with the main functional group of tofacitinib, the removal effect in the subsequent salification and refining processes is limited, and the quality of tofacitinib raw material medicaments and finished product preparations is greatly influenced. By detecting the presence of the impurities, the quality of the tofacitinib raw material and the preparation can be effectively determined.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a related substance of tofacitinib (chemical name: 3- { (3R,4R) -4-methyl-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino ] piperidine-1-yl } -3-oxopropanenitrile), and a preparation method and application thereof.
Background
Tofacitinib (Tofacitinib, pharmaceutically acceptable citrate thereof, trade name: Xeljanz) is a novel oral JAK3 inhibitor developed by the drug of Perey in America, is approved by FDA to be marketed in 11 months of 2012, and can be used for adult patients with moderate and severe active rheumatoid arthritis who have insufficient response or intolerance to methotrexate treatment.
Acetylation of the N-nitrile on the piperidine ring is an essential step in the synthesis of tofacitinib. In view of efficiency and cost control in practical production, the strategy of preparing the intermediate TF-M7 (chemical name: 3R,4R) -4-methyl-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidine) and then conducting N-nitrile acetylation on the piperidine ring is frequently adopted at present. The prior published reports of the tofacitinib synthesis process are mainly as follows:
method one (US6627754, CN1409712C)
The method takes benzyl-protected 4-methyl-piperidine-3-ketone as an initial raw material, firstly performs reduction and ammoniation reaction on methylamino through ketone, and then performs resolution after N-alkylation, hydrogenolysis debenzylation and piperidine N-nitrile acetylation to obtain tofacitinib.
Method two (WO2007012953, CN101233138A)
The method takes 3-amido-4-methylpyridine as a raw material, obtains a substituted piperidine fragment protected by benzyl through 4 steps of reaction and 1 time of resolution, and then obtains tofacitinib through N-alkylation, hydrogenolysis debenzylation and piperidine N-nitrile acetylation.
In addition, various published reports (CN1195755C, CN106146517A, CN105440039A, CN101233138A, Chem Med Chem,2014:9(11),2516-2527, Tetrahedron Letters,2013:54(37),5096-5098, Journal of Medicinal Chemistry 2010:53(24),8468-8484) also adopt the synthesis strategy to prepare the tofacitinib by taking tofacitinib intermediate TF-M7 as a starting material or performing condensation reaction on a key intermediate and nitriloacetic acid.
According to the above published reports, the intermediate TF-M7 and nitriloacetic acid or nitriloacetyl chloride (which is mainly prepared by chlorination of nitriloacetic acid as a raw material in production) are important raw materials for the production process of tofacitinib, so that the quality of the intermediate TF-M7 and nitriloacetic acid greatly influences the quality of tofacitinib raw materials and preparations.
Pharmaceutical researchers have conducted systematic studies on the impurity profile of tofacitinib, such as:
wu X, Zeng X F, Wang L, et al, identification of related substations in intercititinib citrate by LC-MS techniques for synthesizing process optimization [ J ]. Journal of pharmaceutical and biological analysis 2017,143:17-25. Using a specific LC-MS method, separation, identification and characterization of process impurities and degradation impurities of the washout (using destruction conditions such as acid-base hydrolysis, oxidation, strong light, high humidity and high temperature) were performed, and 5 process impurities and 6 degradation impurities were identified by TOF-MS, 3 of which were verified by further directed synthesis.
Iqbal J.B. Alassadi et al.Stablility indicating HPLC method for the identification of tofacitinib citrate and its related details [ J ]. DerPharma Chemica,2014,6(2):11-19. developed the reverse phase liquid chromatography analysis method for tofacitinib, which proves that the crude drug can be used for detecting process impurities and degradation impurities in the conventional quality control of tofacitinib, but only verifies part of impurities published in the pharmacopoeia.
The two groups of researches still have obvious defects, for example, the research on the impurity part of the process is not sufficient, and the impurities with lower content are not well separated and identified, so that the existing quality research work of tofacitinib still has certain improvement space.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a tofacitinib related substance, and a preparation method and application thereof.
The technical scheme adopted by the invention is as follows:
a tofacitinib substance has a structural formula shown in formula I:
wherein R is a carboxyl protecting group, and PG is an amino protecting group;
the method comprises the following steps:
1) preparation of 2, 2' -PG imino-diacetate: mixing iminodiacetic acid and a carboxyl protective agent, performing catalytic reaction to protect carboxyl, and then adding an amino protective agent to obtain 2, 2' -PG imino-diacetate (Int 01 in a synthetic route) under the action of a catalyst;
2) preparation of 2, 2' -PG imino-diacetic acid: removing the carboxyl protecting group of Int 01 to obtain 2, 2' -PG imino-diacetic acid (Int 02 in the synthetic route);
3) preparation of a compound of formula I: dissolving Int 02 and TF-M7, performing complete condensation reaction under the action of an alkali catalyst and a condensing agent, removing amino protecting groups, and performing post-treatment to obtain the compound shown in the formula I.
As a further improvement of the above preparation method, R is selected from alkyl of C1-C3; PG is selected from Cbz, Boc, Fmoc, Pmb, Bzl.
As a further improvement of the above preparation method, in the step 3), the base catalyst is at least one selected from pyridine, 4-dimethylaminopyridine and 4-pyrrolidinylpyridine.
As a further improvement of the above production method, in the step 3), the condensing agent is at least one selected from dicyclohexylcarbodiimide and diisopropylcarbodiimide.
As a further improvement of the preparation method, in the step 3), the temperature of the condensation reaction is 0-40 ℃.
As a further improvement of the preparation method, in the step 3), after removing the amino protecting group, adding acid for neutralization, separating liquid, taking an organic phase, cooling to minus 10 +/-5 ℃, filtering, and adding an acid alcohol solution into the filtrate until no solid is separated out; separating the solid, suspending the solid in dichloromethane, adding alkali to neutralize the solid, taking an organic phase, drying, filtering and concentrating the organic phase to dryness to obtain the compound shown in the formula I.
As a further improvement of the above preparation method, in the alcoholic solution of the acid, the acid is selected from one of hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid.
As a further improvement of the above preparation method, in the alcoholic solution of the acid, the alcohol is selected from one of methanol, ethanol, n-propanol and isopropanol.
The invention has the beneficial effects that:
in the process of developing the processes of tofacitinib bulk drug and preparation, the inventor finds that an unreported impurity (M/z (M + H) can be detected in the condensation reaction process of intermediate TF-M7 and nitriloacetic acid+) 588.6). Further study confirmed that the impurity has the structure shown in formula I.
Although the impurity is generated at a low level in the condensation reaction process, the impurity is consistent with the main functional groups of tofacitinib, so that the removal effect in the subsequent salifying and refining processes is limited, and the quality of tofacitinib raw material medicaments and finished products of preparations is greatly influenced. By detecting the existence of the impurities, the quality of the tofacitinib raw material and the preparation can be effectively determined, so that more intensive quality research work on the tofacitinib raw material medicine and the preparation is facilitated.
The novel impurity preparation method provided by the invention has the advantages of simple synthesis process, high purity (purity is more than 98.0%), good stability, long-term storage for standby application and the like, and can be used as an impurity reference substance of tofacitinib raw material medicines and preparations.
Drawings
FIG. 1 is a mass spectrum (ESI-MS) of tofacitinib impurity I obtained according to the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of tofacitinib impurity I obtained according to the present invention;
FIG. 3 is a partial enlarged view of the hydrogen nuclear magnetic resonance spectrum of tofacitinib impurity I obtained according to the invention
FIG. 4 is a nuclear magnetic resonance carbon spectrum of tofacitinib impurity I obtained according to the present invention;
FIG. 5 is a high performance liquid chromatogram of tofacitinib impurity I obtained according to the present invention.
Detailed Description
In the process of developing the processes of tofacitinib bulk drug and preparation, the inventor finds that an unreported impurity (M/z (M + H) can be detected in the condensation reaction process of intermediate TF-M7 and nitriloacetic acid+) 588.6). Further study confirmed that the impurity has the structure shown in formula I.
The inventors analyzed the cause as follows:
1) the industrial preparation method of the nitriloacetic acid generally comprises the steps of taking chloroacetic acid and sodium cyanide as raw materials, condensing, acidifying and the like to prepare the nitriloacetic acid;
2) the industrial production methods of sodium cyanide mainly include an acrylonitrile by-product method (obtained by alkalizing hydrocyanic acid which is a by-product in the process of preparing acrylonitrile by a propylene ammoxidation method), an anderson method (using natural gas as a carbon source and ammonia as a nitrogen source) and a light oil cracking method (using light oil as a carbon source and ammonia as a nitrogen source), and the three production methods inevitably cause ammonia (ammonia cyanide) to remain in sodium cyanide;
3) residual ammonia in sodium cyanide and chloroacetic acid are subjected to N-alkylation reaction in the preparation process of the nitriloacetic acid to generate iminodiacetic acid and the iminodiacetic acid is remained in the nitriloacetic acid;
4) the iminodiacetic acid remaining in the nitriloacetic acid was condensed with TF-M7 in the N-nitrile acetylation reaction of TF-M7 to give the impurity named N, N' -diacetyl { (3R,4R) -4-methyl-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidin-1-yl } imine.
Possible generation routes are as follows:
the inventors found no report on the study of the compound after searching databases such as CAS (scientific), real, TLC (Pharmaceutical Standards) and the like and documents for systematic quality study of tofacitinib (J.pharm.biomed.anal.,143(2017): 17-25; Der Pharmaceutical Chemica,2014,6(2):11-19), and confirmed that the compound is a novel compound.
Although the impurity is generated at a low level in the condensation reaction process, the impurity is consistent with the main functional groups of tofacitinib, so that the removal effect in the subsequent salifying and refining processes is limited, and the quality of tofacitinib raw material medicaments and finished products of preparations is greatly influenced. Therefore, a method capable of simply and effectively synthesizing the impurities is developed, so that the impurity can be used as a reference substance for quality research of the tofacitinib bulk drug and the preparation, and further quality research work on the tofacitinib bulk drug and the preparation is facilitated.
A tofacitinib substance has a structural formula shown in formula I:
wherein R is a carboxyl protecting group, and PG is an amino protecting group;
the method comprises the following steps:
1) preparation of 2, 2' -PG imino-diacetate: mixing iminodiacetic acid and a carboxyl protective agent, performing catalytic reaction to protect carboxyl, and then adding an amino protective agent to obtain 2, 2' -PG imino-diacetate (Int 01 in a synthetic route) under the action of a catalyst;
2) preparation of 2, 2' -PG imino-diacetic acid: removing the carboxyl protecting group of Int 01 to obtain 2, 2' -PG imino-diacetic acid (Int 02 in the synthetic route);
3) preparation of a compound of formula I: dissolving Int 02 and TF-M7, performing complete condensation reaction under the action of an alkali catalyst and a condensing agent, removing amino protecting groups, and performing post-treatment to obtain the compound shown in the formula I.
The carboxyl protecting group and the amino protecting group may be those described in textbooks or known to those skilled in the art. As a further improvement of the above preparation method, in consideration of the source of the protective agent, cost and the like, R is selected from the group consisting of C1-C3 alkyl; PG is selected from Cbz, Boc, Fmoc, Pmb, Bzl.
As a further improvement of the above preparation method, in the step 3), the base catalyst is at least one selected from pyridine, 4-dimethylaminopyridine and 4-pyrrolidinylpyridine. Of course, other catalysts may be used.
As a further improvement of the above production method, in the step 3), the condensing agent is at least one selected from dicyclohexylcarbodiimide and diisopropylcarbodiimide.
As a further improvement of the preparation method, in the step 3), the temperature of the condensation reaction is 0-40 ℃. The optimum reaction temperature can be determined by those skilled in the art according to the details of the actual reaction.
As a further improvement of the preparation method, in the step 3), after removing the amino protecting group, adding acid for neutralization, separating liquid, taking an organic phase, cooling to minus 10 +/-5 ℃, filtering, and adding an acid alcohol solution into the filtrate until no solid is separated out; separating the solid, suspending the solid in dichloromethane, adding alkali to neutralize the solid, taking an organic phase, drying, filtering and concentrating the organic phase to dryness to obtain the compound shown in the formula I.
The amino-protecting group can be removed by a method described in a textbook. Or, illustratively, as follows:
① PG ═ Boc (tert-butyloxycarbonyl), adding an aqueous solution of an acid until the pH value is 2-4, stirring and reacting for 2-3 hours, adding an alkali for neutralization, separating liquid, taking an organic phase, cooling to-10 +/-5 ℃, and quickly filtering;
② PG ═ Cbz/Pmb/Bzl (benzyloxycarbonyl/4-methoxybenzyl/benzyl), adding Pd/C catalyst to react for 8-10 hours under the hydrogen pressure of 0.5-2.0 MPa, cooling to-10 +/-5 ℃, and rapidly filtering;
③ when Fmoc (fluorene methoxycarbonyl), piperidine or diethylamine was added and stirred for reaction for 6-8 hours, followed by neutralization with acid and liquid separation, and the organic phase was taken, cooled to-10. + -. 5 ℃ and then rapidly filtered.
As a further improvement of the above preparation method, in the alcoholic solution of the acid, the acid is selected from one of hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid.
As a further improvement of the above preparation method, in the alcoholic solution of the acid, the alcohol is selected from one of methanol, ethanol, n-propanol and isopropanol.
The present invention will be further described with reference to the following examples.
Example 1
(1) Preparation of 2, 2' -tert-butoxycarbonylimino-diacetic acid methyl ester
Adding iminodiacetic acid (1.33g), methanol (30ml) and methanesulfonic acid (0.3g) into a reaction bottle, heating until reflux and stirring for reaction for 7-8 hours, and concentrating under reduced pressure to remove the solvent; adding a sodium carbonate solution to neutralize the solution until the pH value is 6-7, extracting and separating the solution by using dichloromethane (2 x 20ml), taking an organic phase, drying the organic phase, cooling the organic phase to 0-5 ℃, adding triethylamine (0.5g), slowly dropwise adding di-tert-butyl dicarbonate (3.3g, 1.5eq), continuously stirring the mixture at the temperature of 25-35 ℃ for reacting for 3-5 hours, and concentrating the mixture under reduced pressure to remove the solvent to obtain an oily substance.
(2) Preparation of 2, 2' -tert-butoxycarbonylimino-diacetic acid
And (2) adding tetrahydrofuran (30ml) into the oily substance obtained in the step (1), uniformly stirring, cooling to-10 ℃, slowly adding a lithium hydroxide aqueous solution (14ml, 5%), stirring for reacting for 1-2 hours, adding sodium chloride (2.0g), continuously stirring until the solution is completely dissolved, separating the solution, taking an organic phase, drying and filtering.
(3) Preparation of Compound of formula I (impurity I)
And (3) adding tofacitinib intermediate TF-M7(5.4g, 2.2eq) and 4-dimethylaminopyridine (0.3g) into the filtrate obtained in the step (2), stirring and dissolving, then controlling the temperature to be 5-10 ℃, adding dicyclohexylcarbodiimide (5.0g) in batches, heating to 20-30 ℃, continuing to stir overnight until the reaction is not continued, cooling to-10 ℃, and then filtering. Taking the filtrate, adding dilute hydrochloric acid (0.1M) to the pH value of 3-4, stirring and reacting for 2-3 hours, adding alkali to neutralize, taking the upper organic phase, cooling to-15 ℃, and quickly filtering.
Taking the filtrate, dropwise adding a phosphoric acid/methanol (10%) solution while stirring until no solid is precipitated, cooling to room temperature, filtering, drying, suspending in dichloromethane (30ml), adding alkali for neutralization, taking the organic phase, drying, filtering, concentrating to dryness to obtain white powder (3.0g, impurity I, yield 43.7%, purity 99.4%).
Example 2
(1) Preparation of 2, 2' -benzyloxycarbonylimino-diacetic acid ethyl ester
Adding iminodiacetic acid (0.66g), ethanol (30ml) and p-toluenesulfonic acid (0.2g) into a reaction bottle, heating until reflux and stirring for reaction for 5-6 hours, and concentrating under reduced pressure to remove the solvent; adding a sodium carbonate solution to neutralize the solution to pH 6-7, extracting and separating the solution by using dichloromethane (2 x 20ml), taking an organic phase, drying the organic phase, cooling the organic phase to 0-5 ℃, adding N, N-diisopropylethylamine (1.0g), slowly dropwise adding benzyl chloroformate (1.1g, 1.3eq), continuously stirring the mixture at the temperature of 30-40 ℃ for reacting for 3-4 hours, and concentrating the mixture under reduced pressure to remove the solvent to obtain an oily substance.
(2) Preparation of 2, 2' -benzyloxycarbonylimino-diacetic acid
And (2) adding 1, 4-dioxane (30ml) into the oily substance obtained in the step (1), uniformly stirring, cooling to-5 ℃, slowly adding a potassium hydroxide aqueous solution (20ml, 5%), stirring for reacting for 1-2 hours, adding sodium chloride (3.1g), continuously stirring until the solution is completely dissolved, separating the solution, taking an organic phase, drying and filtering.
(3) Preparation of Compound of formula I (impurity I)
And (3) adding the tofacitinib intermediate TF-M7(2.2g, 1.8eq) and pyridine (0.1g) into the filtrate obtained in the step (2), stirring and dissolving, then controlling the temperature to be 0-5 ℃, adding diisopropylcarbodiimide (1.8g) in batches, heating to 25-35 ℃, continuing stirring overnight until the reaction is not continued, cooling to-5 ℃, and then filtering. Taking the filtrate, adding a Pd/C catalyst (0.2g), reacting for 8 hours under the hydrogen pressure of 0.5MPa, cooling to-5 ℃, and quickly filtering.
Taking the filtrate, dropwise adding a sulfuric acid/n-propanol (10%) solution while stirring until no solid is precipitated, cooling to room temperature, filtering, drying, suspending in dichloromethane (20ml), adding alkali for neutralization, taking the organic phase, drying, filtering, concentrating to dryness to obtain white powder (0.5g, impurity I, yield 14.5%, purity 99.0%).
Example 3
(1) Preparation of 2, 2' -fluorenyl methoxy carbonyl imino-propyl diacetate
Adding iminodiacetic acid (0.66g), n-propanol (30ml) and sulfuric acid (0.2g) into a reaction bottle, heating until reflux and stirring for reaction for 4-5 hours, and concentrating under reduced pressure to remove the solvent; adding a sodium carbonate solution to neutralize to pH 6-7, extracting with dichloromethane (2 × 20ml), separating liquid, taking an organic phase, drying, cooling to 0-5 ℃, adding triethylamine (0.8g), slowly dropwise adding fluorenyl methoxy carbonyl chloride (1.6g, 1.2eq), continuing to stir at 20-30 ℃ for reaction for 3-4 hours, and concentrating under reduced pressure to remove the solvent to obtain an oily substance.
(2) Preparation of 2, 2' -fluorenyl methoxy carbonyl imino-diacetic acid
And (2) adding methyltetrahydrofuran (30ml) into the oily substance obtained in the step (1), uniformly stirring, cooling to-15 ℃, slowly adding a sodium hydroxide aqueous solution (12ml, 5%), stirring for reacting for 2-3 hours, adding sodium chloride (2.0g), continuously stirring until the sodium hydroxide aqueous solution is completely dissolved, separating, taking an organic phase, drying and filtering.
(3) Preparation of Compound of formula I (impurity I)
And (3) adding the tofacitinib intermediate TF-M7(2.5g, 2.0eq) and 4-pyrrolidinylpyridine (0.3g) into the filtrate obtained in the step (2), stirring and dissolving, then controlling the temperature to be 5-10 ℃, adding dicyclohexylcarbodiimide (2.1g) in batches, heating to 30-40 ℃, continuing to stir overnight until the reaction is not continued, cooling to-15 ℃, and then filtering. Taking the filtrate, adding piperidine (0.5g), stirring and reacting for 6 hours, adding acid for neutralization, separating liquid, taking an organic phase, cooling to-15 ℃, and quickly filtering.
Taking the filtrate, dropwise adding a methanesulfonic acid/isopropanol (10%) solution while stirring until no solid is precipitated, cooling to room temperature, filtering, drying, suspending in dichloromethane (20ml), adding alkali for neutralization, taking the organic phase, drying, filtering, concentrating to dryness to obtain white powder (1.2g, tofacitinib impurity I, yield 35.0%, purity 98.0%).
Example 4
(1) Preparation of isopropyl 2, 2' - (4-methoxybenzyl) imino-diacetate
Adding iminodiacetic acid (0.66g), isopropanol (30ml) and methanesulfonic acid (0.3g) into a reaction bottle, heating until reflux and stirring for reaction for 5-6 hours, and carrying out reduced pressure concentration to remove the solvent; adding a sodium carbonate solution to neutralize the solution until the pH value is 6-7, extracting and separating the solution by using dichloromethane (2 x 20ml), taking an organic phase, drying the organic phase, cooling the organic phase to 0-5 ℃, adding N, N-diisopropylethylamine (1.0g), slowly dropwise adding 4-methoxybenzyl chloride (1.2g, 1.5eq), continuously stirring the mixture at the temperature of 25-30 ℃ for reacting for 3-4 hours, and concentrating the mixture under reduced pressure to remove the solvent to obtain an oily substance.
(2) Preparation of 2, 2' - (4-methoxybenzyl) imino-diacetic acid
And (2) adding methyl tetrahydrofuran (30ml) into the oily substance obtained in the step (1), uniformly stirring, cooling to-10 ℃, slowly adding a lithium hydroxide aqueous solution (8ml, 5%), stirring for reacting for 2-3 hours, adding sodium chloride (1.2g), continuously stirring until the solution is completely dissolved, separating, taking an organic phase, drying and filtering.
(3) Preparation of Compound of formula I (impurity I)
And (3) adding the tofacitinib intermediate TF-M7(2.5g, 2.0eq) and 4-dimethylaminopyridine (0.2g) into the filtrate obtained in the step (2), stirring and dissolving, then controlling the temperature to be 10-20 ℃, adding 2.1g of dicyclohexylcarbodiimide in batches, heating to 25-35 ℃ after the addition is finished, continuing stirring overnight until the reaction is not continued, cooling to-10 ℃ and then filtering. Taking the filtrate, adding a Pd/C catalyst (0.3g), reacting for 10 hours under the hydrogen pressure of 1.5MPa, cooling to-10 ℃, and quickly filtering.
Taking the filtrate, dropwise adding a phosphoric acid/ethanol (10%) solution while stirring until no solid is precipitated, cooling to room temperature, filtering, drying, suspending in dichloromethane (20ml), adding alkali for neutralization, taking the organic phase, drying, filtering, concentrating to dryness to obtain white powder (1.4g, tofacitinib impurity I, yield 40.8%, purity 98.6%).
Example 5
(1) Preparation of 2, 2' -benzylimino-diacetic acid methyl ester
Adding iminodiacetic acid (0.66g), methanol (30ml) and methanesulfonic acid (0.3g) into a reaction bottle, heating until reflux and stirring for reaction for 4-5 hours, and concentrating under reduced pressure to remove the solvent; adding a sodium carbonate solution to neutralize the solution until the pH value is 6-7, extracting and separating the solution by using dichloromethane (2 x 20ml), taking an organic phase, drying the organic phase, cooling the organic phase to 0-5 ℃, adding triethylamine (0.8g), slowly dropwise adding benzyl chloride (0.9g, 1.4eq), continuously stirring the mixture at the temperature of 25-35 ℃ for reacting for 3-4 hours, and concentrating the mixture under reduced pressure to remove a solvent to obtain an oily substance.
(2) Preparation of 2, 2' -benzylimino-diacetic acid
And (2) adding tetrahydrofuran (30ml) into the oily substance obtained in the step (1), uniformly stirring, cooling to-10 ℃, slowly adding a lithium hydroxide aqueous solution (7ml, 5%), stirring for reacting for 2-3 hours, adding sodium chloride (1.5g), continuously stirring until the solution is completely dissolved, separating, taking an organic phase, drying and filtering.
(3) Preparation of Compound of formula I (impurity I)
And (3) adding the tofacitinib intermediate TF-M7(2.3g, 1.9eq) and 4-dimethylaminopyridine (0.2g) into the filtrate obtained in the step (2), stirring and dissolving, then controlling the temperature to be 10-20 ℃, adding dicyclohexylcarbodiimide (2.2g) in batches, heating to 25-35 ℃ after the addition is finished, continuing to stir overnight until the reaction is not continued, cooling to-10 ℃ and then filtering. Taking the filtrate, adding a Pd/C catalyst (0.2g), reacting for 10 hours under the hydrogen pressure of 2.0MPa, cooling to-15 ℃, and quickly filtering.
Taking the filtrate, dropwise adding a phosphoric acid/methanol (10%) solution while stirring until no solid is precipitated, cooling to room temperature, filtering, drying, suspending in dichloromethane (20ml), adding alkali for neutralization, taking the organic phase, drying, filtering, concentrating to dryness to obtain white powder (1.0g, impurity I, yield 29.1%, purity 98.5%).
Example 6
(1) Preparation of 2, 2' -benzylimino-diacetic acid methyl ester
Adding iminodiacetic acid (0.66g), methanol (30ml) and methanesulfonic acid (0.3g) into a reaction bottle, heating until reflux and stirring for reaction for 4-5 hours, and concentrating under reduced pressure to remove the solvent; adding a sodium carbonate solution to neutralize the solution to pH 6-7, extracting and separating the solution by using dichloromethane (2 x 20ml), taking an organic phase, drying the organic phase, cooling the organic phase to 0-5 ℃, adding N, N-diisopropylethylamine (0.9g), slowly dropwise adding benzyl bromide (1.2g, 1.4eq), continuously stirring the mixture at the temperature of 25-35 ℃ for reacting for 3-4 hours, and concentrating the mixture under reduced pressure to remove a solvent to obtain an oily substance.
(2) Preparation of 2, 2' -benzylimino-diacetic acid
And (2) adding methyl tetrahydrofuran (30ml) into the oily substance obtained in the step (1), uniformly stirring, cooling to-10 ℃, slowly adding a lithium hydroxide aqueous solution (7ml, 5%), stirring for reacting for 2-3 hours, adding sodium chloride (1.5g), continuously stirring until the solution is completely dissolved, separating, taking an organic phase, drying and filtering.
(3) Preparation of Compound of formula I (impurity I)
And (3) adding the tofacitinib intermediate TF-M7(2.5g, 2.0eq) and 4-dimethylaminopyridine (0.2g) into the filtrate obtained in the step (2), stirring and dissolving, then controlling the temperature to be 10-20 ℃, adding dicyclohexylcarbodiimide (2.4g) in batches, heating to 20-30 ℃, continuing to stir overnight until the reaction is not continued, cooling to-15 ℃, and then filtering. Taking the filtrate, adding a Pd/C catalyst (0.3g), reacting for 10 hours under the hydrogen pressure of 2.0MPa, cooling to-10 ℃, and quickly filtering.
Taking the filtrate, dropwise adding a phosphoric acid/isopropanol (10%) solution while stirring until no solid is precipitated, cooling to room temperature, filtering, drying, suspending in dichloromethane (20ml), adding alkali for neutralization, taking the organic phase, drying, filtering, concentrating to dryness to obtain white powder (1.1g, impurity I, yield 32.0%, purity 98.9%).
Example 7
(1) Preparation of 2, 2' -tert-butoxycarbonylimino-diacetic acid methyl ester
Adding iminodiacetic acid (0.66g), methanol (30ml) and methanesulfonic acid (0.1g) into a reaction bottle, heating until reflux and stirring for reaction for 5-6 hours, and concentrating under reduced pressure to remove the solvent; adding a sodium carbonate solution to neutralize the solution until the pH value is 6-7, extracting and separating the solution by using dichloromethane (2 x 20ml), taking an organic phase, drying the organic phase, cooling the organic phase to 0-5 ℃, adding triethylamine (0.5g), slowly dropwise adding di-tert-butyl dicarbonate (1.1g, 1.0eq), continuously stirring the mixture at the temperature of 30-40 ℃ for reacting for 3-4 hours, and concentrating the mixture under reduced pressure to remove the solvent to obtain an oily substance.
(2) Preparation of 2, 2' -tert-butoxycarbonylimino-diacetic acid
And (2) adding tetrahydrofuran (30ml) into the oily substance obtained in the step (1), uniformly stirring, cooling to-10 ℃, slowly adding a lithium hydroxide aqueous solution (14ml, 5%), stirring for reacting for 1-2 hours, adding sodium chloride (2.0g), continuously stirring until the solution is completely dissolved, separating the solution, taking an organic phase, drying and filtering.
(3) Preparation of Compound of formula I (impurity I)
And (3) adding the Tofacitinib intermediate TF-M7(2.7g, 2.2eq) and 4-dimethylaminopyridine (0.3g) into the filtrate obtained in the step (2), stirring and dissolving, then controlling the temperature to be 5-10 ℃, adding diisopropylcarbodiimide (1.8g) in batches, heating to 20-30 ℃, continuing to stir overnight until the reaction is not continued, cooling to-10 ℃, and then filtering. Taking the filtrate, adding dilute sulfuric acid (0.1M) to the pH value of 3-4, stirring and reacting for 2-3 hours, adding alkali to neutralize, taking an upper layer organic phase, cooling to-15 ℃, and quickly filtering.
Taking the filtrate, dropwise adding a phosphoric acid/ethanol (10%) solution while stirring until no solid is precipitated, cooling to room temperature, filtering, drying, suspending in dichloromethane (30ml), adding alkali for neutralization, taking the organic phase, drying, filtering, concentrating to dryness to obtain white powder (1.0g, impurity I, yield 29.1%, purity 99.0%).
Example 8
(1) Preparation of 2, 2' -tert-butoxycarbonylimino-diacetic acid ethyl ester
Adding iminodiacetic acid (0.66g), ethanol (30ml) and methanesulfonic acid (0.2g) into a reaction bottle, heating until reflux and stirring for reaction for 5-6 hours, and concentrating under reduced pressure to remove the solvent; adding a sodium carbonate solution to neutralize the solution until the pH value is 6-7, extracting and separating the solution by using dichloromethane (2 x 20ml), taking an organic phase, drying the organic phase, cooling the organic phase to 0-5 ℃, adding triethylamine (0.5g), slowly dropwise adding di-tert-butyl dicarbonate (1.3g, 1.2eq), continuously stirring the mixture at the temperature of 30-40 ℃ for reacting for 3-4 hours, and concentrating the mixture under reduced pressure to remove the solvent to obtain an oily substance.
(2) Preparation of 2, 2' -tert-butoxycarbonylimino-diacetic acid
And (2) adding methyltetrahydrofuran (30ml) into the oily substance obtained in the step (1), uniformly stirring, cooling to-10 ℃, slowly adding a lithium hydroxide aqueous solution (14ml, 5%), stirring for reacting for 2-3 hours, adding sodium chloride (2.0g), continuously stirring until the solution is completely dissolved, separating the solution, taking an organic phase, drying and filtering.
(3) Preparation of Compound of formula I (impurity I)
And (3) adding the tofacitinib intermediate TF-M7(2.5g, 2.0eq) and 4-dimethylaminopyridine (0.3g) into the filtrate obtained in the step (2), stirring and dissolving, then controlling the temperature to be 10-20 ℃, adding dicyclohexylcarbodiimide (2.4g) in batches, heating to 25-40 ℃, continuing to stir overnight until the reaction is not continued, cooling to-10 ℃, and then filtering. Taking the filtrate, adding dilute phosphoric acid (0.1M) to the pH value of 3-4, stirring and reacting for 2-3 hours, adding alkali to neutralize, taking the upper organic phase, cooling to-15 ℃, and quickly filtering.
Taking the filtrate, dropwise adding a phosphoric acid/ethanol (10%) solution while stirring until no solid is precipitated, cooling to room temperature, filtering, drying, suspending in dichloromethane (30ml), adding alkali for neutralization, taking the organic phase, drying, filtering, concentrating to dryness to obtain white powder (1.2g, impurity I, yield 34.9%, purity 99.2%).
Example 9
(1) Preparation of 2, 2' -tert-butoxycarbonylimino-diacetic acid ethyl ester
Adding iminodiacetic acid (0.66g), ethanol (30ml) and methanesulfonic acid (0.2g) into a reaction bottle, heating until reflux and stirring for reacting for 6-7 hours, and concentrating under reduced pressure to remove the solvent; adding a sodium carbonate solution to neutralize the solution until the pH value is 6-7, extracting and separating the solution by using dichloromethane (2 x 20ml), taking an organic phase, drying the organic phase, cooling the organic phase to 0-5 ℃, adding N, N-diisopropylethylamine (0.9g), slowly dropwise adding di-tert-butyl dicarbonate (1.3g, 1.2eq), continuously stirring the mixture at the temperature of 20-30 ℃ for reacting for 3-4 hours, and concentrating the mixture under reduced pressure to remove the solvent to obtain an oily substance.
(2) Preparation of 2, 2' -tert-butoxycarbonylimino-diacetic acid
And (2) adding methyl tetrahydrofuran (30ml) into the oily substance obtained in the step (1), uniformly stirring, cooling to-10 ℃, slowly adding a potassium hydroxide aqueous solution (8ml, 5%), stirring for reacting for 1-2 hours, adding sodium chloride (1.3g), continuously stirring until the sodium chloride is completely dissolved, separating liquid, taking an organic phase, drying and filtering.
(3) Preparation of Compound of formula I (impurity I)
And (3) adding the tofacitinib intermediate TF-M7(2.3g, 1.8eq) and 4-dimethylaminopyridine (0.3g) into the filtrate obtained in the step (2), stirring and dissolving, then controlling the temperature to be 10-15 ℃, adding dicyclohexylcarbodiimide (2.4g) in batches, heating to 25-35 ℃ after the addition is finished, continuing stirring overnight until the reaction is not continued, cooling to-10 ℃ and then filtering. And (3) taking the filtrate, adding a methanesulfonic acid aqueous solution (0.1M) to the pH value of 3-4, stirring for reacting for 2-3 hours, adding alkali for neutralization, taking an upper layer organic phase, cooling to-15 ℃, and quickly filtering.
Taking the filtrate, dropwise adding a phosphoric acid/ethanol (10%) solution while stirring until no solid is precipitated, cooling to room temperature, filtering, drying, suspending in dichloromethane (30ml), adding alkali for neutralization, taking the organic phase, drying, filtering, concentrating to dryness to obtain white powder (1.1g, impurity I, yield 32.0%, purity 99.1%).
Example 10
(1) Preparation of 2, 2' -fluorenyl methoxy carbonyl imino-diacetic acid methyl ester
Adding iminodiacetic acid (0.66g), methanol (30ml) and methanesulfonic acid (0.2g) into a reaction bottle, heating until reflux and stirring for reaction for 4-5 hours, and concentrating under reduced pressure to remove the solvent; adding a sodium carbonate solution to neutralize to pH 6-7, extracting with dichloromethane (2 × 20ml), separating liquid, taking an organic phase, drying, cooling to 0-5 ℃, adding triethylamine (0.8g), slowly dropwise adding fluorenyl methoxy carbonyl chloride (1.6g, 1.2eq), continuing to stir at 20-30 ℃ for reaction for 3-4 hours, and concentrating under reduced pressure to remove the solvent to obtain an oily substance.
(2) Preparation of 2, 2' -fluorenyl methoxy carbonyl imino-diacetic acid
And (2) adding methyltetrahydrofuran (30ml) into the oily substance obtained in the step (1), uniformly stirring, cooling to-15 ℃, slowly adding a lithium hydroxide aqueous solution (14ml, 5%), stirring for reacting for 2-3 hours, adding sodium chloride (2.0g), continuously stirring until the solution is completely dissolved, separating the solution, taking an organic phase, drying and filtering.
(3) Preparation of Compound of formula I (impurity I)
And (3) adding tofacitinib intermediate TF-M7(2.5g, 2.0eq) and 4-pyrrolidinylpyridine (0.3g) into the filtrate obtained in the step (2), stirring and dissolving, then controlling the temperature to be 20-35 ℃, adding dicyclohexylcarbodiimide (2.1g) in batches, continuing to stir overnight after the addition is finished until the reaction is not continued, cooling to-15 ℃, and then filtering. Adding diethylamine (0.5g) into the filtrate, stirring and reacting for 8 hours, adding acid to neutralize, separating liquid, taking the organic phase, cooling to-15 ℃, and rapidly filtering.
Taking the filtrate, dropwise adding a phosphoric acid/n-propanol (10%) solution while stirring until no solid is precipitated, cooling to room temperature, filtering, drying, suspending in dichloromethane (20ml), adding alkali for neutralization, taking the organic phase, drying, filtering, concentrating to dryness to obtain white powder (0.8g, tofacitinib impurity I, yield 23.3%, purity 98.3%).
Detection of impurity I obtained in example 1
(1) Mass spectrometric detection
ESI-MS of impurity I obtained in example 1, as shown in FIG. 1: m/z (M + H)+)＝588.6。
(2) Hydrogen spectroscopy detection
As shown in FIGS. 2 and 3, of the impurity I obtained in example 11HNMR(500MHz，DMSO-d6)，δ(ppm)：11.66(s,2H)，8.10～8.12(d,2H)，7.14(s,2H)，6.53～6.56(d,2H)，4.82～4.90(d,2H)，3.65～4.00(m,5H)，3.42～3.57(m,6H)，3.33～3.42(m,2H)，3.24～3.26(d,5H)。
(3) Carbon spectrum detection
As shown in FIG. 4, example 1Of the resulting impurity I13CNMR (125MHz, DMSO-d6), delta (ppm): 168.02, 156.86, 151.67, 150.47, 120.71, 102.17, 101.67, 54.89 (residual DCM), 53.38, 52.99, 49.19 (residual MeOH), 44.26, 40.90(DMSO), 37.88, 34.22, 33.91, 30.31, 13.65.
(4) Liquid phase detection
The detection method comprises the following steps: the detection was performed by a reversed phase liquid chromatography column (packed with C18 bonded silica gel), an ultraviolet detector (λ 210nm), and a gradient elution procedure using acetonitrile and perchloric acid aqueous solution (0.1%) as mobile phases, and the test results are shown in fig. 5.
And (3) testing conditions are as follows: a column (InertSustain, C18,5 μm. times.4.6 mm. times.250 mm) at a column temperature of 40 ℃ and a flow rate of 1.2 ml/min; mobile phase (a: 0.1% perchloric acid, B: acetonitrile), gradient program:
the test results are shown in fig. 5. As can be seen from the figure, the purity of the impurity I prepared by the method of the invention is as high as 99.4%.
Claims (10)
1. A substance related to tofacitinib, which has a structural formula shown in formula I:
2. the process for preparing the tofacitinib related substance as claimed in claim 1, wherein the synthetic route is as follows:
wherein R is a carboxyl protecting group, and PG is an amino protecting group;
the method comprises the following steps:
1) preparation of compound Int 01: mixing iminodiacetic acid and a carboxyl protective agent, performing catalytic reaction to protect carboxyl, adding an amino protective agent, and obtaining a compound Int 01 under the action of a catalyst;
2) preparation of compound Int 02: removing a carboxyl protecting group of a compound Int 01 to obtain a compound Int 02;
3) preparation of a compound of formula I: reacting compound Int 02 and TF-M7(3R,4R) -4-methyl-3- [ methyl (7)H-pyrrolo [2,3-d]Pyrimidin-4-yl) amino]Dissolving piperidine, performing condensation reaction completely under the action of an alkali catalyst and a condensing agent, removing an amino protecting group, and performing post-treatment to obtain the compound shown in the formula I.
3. The method of claim 2, wherein: r is selected from alkyl of C1-C3; PG is selected from Cbz, Boc, Fmoc, Pmb or Bzl.
4. The method of claim 2, wherein: in the step 3), the base catalyst is at least one selected from pyridine, 4-dimethylaminopyridine and 4-pyrrolidinylpyridine.
5. The method of claim 2, wherein: in the step 3), the condensing agent is at least one selected from dicyclohexylcarbodiimide and diisopropylcarbodiimide.
6. The method of claim 2, wherein: in the step 3), the temperature of the condensation reaction is 0-40 ℃.
7. The method of claim 2, wherein: in the step 3), after amino protecting groups are removed, adding acid for neutralization, separating liquid, taking an organic phase, cooling to minus 10 +/-5 ℃, filtering, and adding an acid alcohol solution into the filtrate until no solid is separated out; separating the solid, suspending the solid in dichloromethane, adding alkali to neutralize the solid, taking an organic phase, drying, filtering and concentrating the organic phase to dryness to obtain the compound shown in the formula I.
8. The method of claim 7, wherein: in the alcoholic solution of the acid, the acid is selected from one of hydrochloric acid, sulfuric acid, phosphoric acid or methanesulfonic acid.
9. The method of claim 7, wherein: in the alcoholic acid solution, the alcohol is selected from methanol, ethanol, n-propanol or isopropanol.
10. The use of tofacitinib-related substance as set forth in claim 1 in the detection and analysis of tofacitinib bulk drug and preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810961994.1A CN109053771B (en) | 2018-08-22 | 2018-08-22 | Related substance of tofacitinib and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810961994.1A CN109053771B (en) | 2018-08-22 | 2018-08-22 | Related substance of tofacitinib and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109053771A CN109053771A (en) | 2018-12-21 |
| CN109053771B true CN109053771B (en) | 2020-02-28 |
Family
ID=64687919
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810961994.1A Active CN109053771B (en) | 2018-08-22 | 2018-08-22 | Related substance of tofacitinib and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109053771B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101243081A (en) * | 2005-07-21 | 2008-08-13 | 霍夫曼-拉罗奇有限公司 | Pyrido[2,3-d]pyrimidine-2,4-diamine compounds as PTP1B inhibitors |
| CN104447751A (en) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Tofacitinib compound |
| CN104788461A (en) * | 2015-04-30 | 2015-07-22 | 南京臣功制药股份有限公司 | Industrial production method applicable to citric acid tofacitinib |
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014011540A1 (en) * | 2012-07-09 | 2014-01-16 | Emory University | Bone morphogenetic protein pathway activation, compositions for ossification, and methods related thereto |
-
2018
- 2018-08-22 CN CN201810961994.1A patent/CN109053771B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101243081A (en) * | 2005-07-21 | 2008-08-13 | 霍夫曼-拉罗奇有限公司 | Pyrido[2,3-d]pyrimidine-2,4-diamine compounds as PTP1B inhibitors |
| CN104447751A (en) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Tofacitinib compound |
| CN104788461A (en) * | 2015-04-30 | 2015-07-22 | 南京臣功制药股份有限公司 | Industrial production method applicable to citric acid tofacitinib |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109053771A (en) | 2018-12-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN115505051A (en) | Method for refining sugammadex sodium | |
| EP3658540B1 (en) | Process for the preparation of aripiprazole lauroxil | |
| CA2931606A1 (en) | Improved process for the preparation of pomalidomide and its purification | |
| CN109053771B (en) | Related substance of tofacitinib and preparation method and application thereof | |
| BRPI1014070B1 (en) | processes for the production of dipeptidyl peptidase-iv inhibitor and intermediate | |
| CN114671867B (en) | Preparation method of tocartinib intermediate 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine | |
| CN112876502B (en) | Preparation method of N-trimethylsiloxyethoxycarbonyl-N-methyl-L/D-leucine | |
| CN114437043B (en) | Preparation method of anti-new crown drug Nirmatrelvir | |
| AU2021388369B2 (en) | Preparation method for S-configuration phenylethylamine hydrochloride compound | |
| WO2021180023A1 (en) | Elastase inhibitor prodrug and use thereof | |
| CN109824534B (en) | Synthesis method of N-alkanoyl memantine | |
| CN111518152B (en) | Preparation method and application of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholane-24-aldehyde | |
| WO2022145444A1 (en) | Method for supporting amino acid on resin for solid-phase synthesis | |
| KR20030022270A (en) | Thrombin inhibitors comprising an aminoisoquinoline group | |
| CN114163348A (en) | Synthesis method of aminoacyl-substituted L-phenylalanine | |
| CN108129404B (en) | Synthesis method of chiral piperazinone derivative | |
| CN115093365B (en) | Synthesis method of raffinacine | |
| CN113636980B (en) | Preparation method of dexrazoxane | |
| JP5397706B2 (en) | Method for producing high purity 1-benzyl-3-aminopyrrolidine | |
| CN108641075B (en) | Rapamycin and double short-chain polyethylene glycol prodrug of rapamycin derivative and application of rapamycin and double short-chain polyethylene glycol prodrug | |
| CN106279165A (en) | A kind of synthesis preparation method of tadanafil | |
| CN114105790A (en) | Preparation method of 3-amino-4, 5-dibromobenzoic acid methyl ester | |
| CN105481860A (en) | Refinement technique of tadalafil I crystal | |
| CN116120395A (en) | Preparation method of Nemactetvir intermediate | |
| CN114539134A (en) | Synthetic method of prucalopride intermediate 1- (3-methoxypropyl) -4-piperidinamine |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |