AU2018102141A4 - Method for preparing Baricitinib - Google Patents
Method for preparing Baricitinib Download PDFInfo
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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
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- 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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Abstract The present application discloses a method for preparing Baricitinib and belongs to the technical field of drug preparation. In the method, 4-Chloropyrrolo[2,3-d]pyrimidine is used as the starting material and subjected to amino protection first, and then the material is reacted with hydrazine 5 hydrate and acraldehyde to form an intermediate 4 through replacement and ring formation based on a method of "one pot process"; and starting material 1,3-dibromoacetone is reacted with ethanediol to form an intermediate 5 through condensation, the intermediate 5 is reacted with ethanesulfonamide to form an intermediate 6 through condensation, the intermediate 6 is reacted with diethyl cyanomethylphosphonate in the presence of strong alkali to form an intermediate 7, 10 and the intermediate 4 and the intermediate 7 are reacted to form target products 1 through addition and deprotection in the presence of a catalyst. By this method, the reaction conditions are mild, the intermediates are easy to purify, and the total yield is up to 40 to 55%. Thus, the method is very suitable for industrial production.
Description
Abstract
The present application discloses a method for preparing Baricitinib and belongs to the technical field of drug preparation. In the method, 4-Chloropyrrolo[2,3-d]pyrimidine is used as the starting material and subjected to amino protection first, and then the material is reacted with hydrazine hydrate and acraldehyde to form an intermediate 4 through replacement and ring formation based on a method of “one pot process”; and starting material 1,3-dibromoacetone is reacted with ethanediol to form an intermediate 5 through condensation, the intermediate 5 is reacted with ethanesulfonamide to form an intermediate 6 through condensation, the intermediate 6 is reacted with diethyl cyanomethylphosphonate in the presence of strong alkali to form an intermediate 7, and the intermediate 4 and the intermediate 7 are reacted to form target products 1 through addition and deprotection in the presence of a catalyst. By this method, the reaction conditions are mild, the intermediates are easy to purify, and the total yield is up to 40 to 55%. Thus, the method is very suitable for industrial production.
2018102141 03 Jul2018
Description
METHOD FOR PREPARING BARICITINIB
Technical Field
The present application belongs to the technical field of drug preparation, and more particularly relates to a method for preparing Baricitinib which is an optional JAK1 and JAK2 inhibitor.
Background Art
Baricitinib, chemically described as
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(ethylsulfonyl)azetidin-3-yl)acetoni trile, is jointly developed by Eli Lilly and IncyteCompany as an selective oral JAK1/JAK2 inhibitor that can inhibit the intracellular signal transduction of various inflammatory cytokines like IL-6 and IL-23. The product can be used to treat moderate and severe rheumatoid arthritis. In a research project that involves more than 1,300 patients, Baricitinib developed by Eli Lilly and IncyteCompany showed better performance than placebo on rheumatoid arthritis (RA) in a treatment period of 12 weeks and thereby met key purpose. In clinic, Baricitinib is also proved to be superior to Humira in 2 common clinical indexes of RA and thereby also meets the secondary purpose of the project. Recent clinic research result shows that Baricitinib has good treatment effect. Nowadays, countries including China and the USA have completed 3 periods of clinic research, which makes Baricitinib the first oral medicine over common standard injection treatment method (Humira and Enbrel). The structural formula is as follows:
At present, a few methods are available to prepare Baricitinib, which mainly include patent 25 CN105294699 and PCT patent W02009114512 (corresponding Chinese patent CN102026999A or CN102026999B).
2018102141 03 Jul2018
In CN 105294699, a method for preparing Baricitinib is as follows:
In this method, Pyrazole-4-boronicacid pinacol ester and l-Boc-3-(cyanomethylene)azetidine are used as starting materials to form a compound 9 through Michael addition reaction; the compound
9 is reacted with a starting material compound 10 to form an intermediate 11 through coupling reaction in the presence of a catalyst; the intermediate 11 is reacted to lose 2 carboxylate molecules per molecule and form an intermediate 12; and the intermediate 12 is reacted with Ethanesulfonyl chloride in an organic solvent to form the final product Baricitinib (compound 1) through amidation of sulphonyl. In the process, a compound 7 and a compound 8 are difficult to get, and in the last reaction with ethanesulfonyl chloride, 2 active aminos make it easy for double replacement to happen or ethanesulfonyl chloride is likely to react with the amino on the pyrrole ring and thereby forms side products. In addition, the noble metal palladium used in the method is relatively expensive and not favorable for industrial production.
In the PCT patent W02009114512 (corresponding Chinese patent CN102026999A or
CN102026999B), the method for preparing Baricitinib is as follows:
2018102141 03 Jul2018
In this process, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine is used as the starting material and is first protected by 2-(Trimethylsilyl)ethoxymethyl chloride (SEMC1) to form SEM-protected 4-chloro-7H-pyrrolo[2,3-d]pyrimidine; the SEM-protected 4-chloro-7H-pyrrolo[2,3-d]pyrimidine is then reacted with borate (compound 17) to obtain a compound 18 through Suzuki coupling ; the compound 18 is reacted in aqueous hydrochloric acid solution to remove 1 -ethoxyethyl and form a pyrazole (compound 19); the compound 19 is reacted with a compound 6 to form a compound 20 through Michael addition reaction in the presence of a catalyst DBU; and the compound 20 is subjected to 2 deprotection processes by LIBF4 and NH4OH to form Baricitinib.
The process route is long, the yield is low, the operation is complicated, and the cost is high which the palladium is used twice. Thus, the method is not good for industrial production.
2018102141 03 Jul2018
Summary of the Invention
To overcome the above-mentioned shortcomings, the present application provides a method for preparing Baricitinib, which uses easy-to-get materials, is easy to operate and reduces cost of products.
In the present application, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine is used as the starting material and subjected to amino protection first, and then amino-protected product is directly or after removal of solvent reacted with hydrazine hydrate and acraldehyde through replacement and ring formation based on a “one-pot process” to form an intermediate 4; starting material
1,3-dibromoacetone and ethanediol are reacted to form an intermediate 5 through condensation;
the intermediate 5 and ethanesulfonamid are reacted to form an intermediate 6 through condensation; the intermediate 6 is reacted with diethyl cyanomethylphosphonate in the presence of strong alkali to form an intermediate 7, and the intermediate 4 and the intermediate 7 are reacted to form target products 1 through addition and deprotection in the presence of a catalyst.
By this method, yield is up to 40 to 55%, the process route is short, the operation is simple, raw materials are easy to get, and cost of products is reduced without using noble metal palladium in
Michael addition reaction.
On this basis, the present application provides a method for preparing Baricitinib.
Technical solution to realize the method is as follows:
A method for preparing Baricitinib comprises the following steps that:
(1) 4-chloro-7H-pyrrolo[2,3-d]pyrimidine is used as the starting material and is subjected to amino protection to form an intermediate compound 3; the intermediate compound 3 is reacted with hydrazine hydrate and acraldehyde in the presence of oxygen and organic solvent according to a certain ratio to form a compound 4 through replacement, ring formation and recrystallization based on an “one-pot process”; and the structural formula of the compound 4 is as below:
R’ represents amino-protected compound, such as alkoxycarbonyls including di-tert butyl
2018102141 03 Jul2018 dicarbonate ((Boc)2O), Fmoc-Cl and Cbz-Cl; acyls including TS-C1 and Tfa-Cl; alkyls including Trt-Cl, and PMB-Br or PMB-C1.
R’ represents the protecting group for R, such as Boc, Fomc, Cbz, TS, Tfa, Trt and PMB.
(2) 1,3-dibromoacetone and ethanediol are used as raw materials and reacted in the presence of a strong acid to form an amino-protected compound 5 though condensation; and the structural formula of the compound 5 is as below:
Br Br
O O
VJ (3)The compound 5 obtained in step (2) is reacted with ethane sulfonamide in the presence of an alkali to form a compound 6 through ring formation under heat; and the structural formula of the compound 6 is as below:
(4) Diethyl cyanomethylphosphonate is used as the raw material to react with the compound 6 obtained in the step (3) in the presence of a strong alkali to form a compound 7; and the structural formula of the compound 7 is as below:
O
II
(5) The compound 4 obtained in step (1) and the compound 7 obtained in step (4) are reacted to form target products 1 through addition and removal of amino-protecting group in the presence of a catalyst and solvent to form Baricitinib.
In some embodiments, organic solvent in the step (1) is tetrahydrofuran, methylbenzene, 20 dimethylbenzene or o-dichlorobenzene;
In some embodiments, the mol ratio of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine to hydrazine hydrate to acraldehyde in the step (1) is 1:1:11-1:4:4;
In some embodiments, the strong acid catalyst in the step (2) is p-toluenesulfonic acid or sulfuric acid;
In some embodiments, the alkali in the step (3) is potassium carbonate, sodium carbonate or 5
2018102141 03 Jul2018 cesium carbonate, preferably the cesium carbonate, and the reaction temperature is 50 to 80°C;
In some embodiments, the strong alkali in the step (3) is cesium carbonate and the reaction temperature is 65 °C;
In some embodiments, the strong alkali in the step (4) is sodium hydride, potassium hydride, 5 sodium methoxide or sodium ethoxide and the reaction temperature is 10 to 40°C;
In some embodiments, the catalyst in the step (5) is DBU, TBAB or TEBA, and the reaction temperature is 40 to 70°C.
Benefits:
(1) The present application reduces cost compared to the conventional synthesis methods for 10 Baricitinib by avoiding using palladium in Suzuki coupling reaction;
(2) The present application lowers possibility of forming side products by using amino-protecting group to prevent the amino in the pyrrole ring from participating reaction and thereby offers better quality and yield of intermediates and products;
(3) The present application comprises fewer steps by removing solvent through steaming and 15 reacting the amino-protected compound 2, ammonium hydroxide and acraldehyde to obtain the intermediate 4 through replacement and ring formation based on a “one-pot process”;
(4) The present application uses cheap and easy-to-get starting materials, shorter process routes compared to conventional processes, and mild reaction conditions and thereby is suitable for industrial production.
Brief Description of the Drawings
Fig.l is a hydrogen spectrum of Baricitinib in Embodiment 1;
Fig.2 is a liquid chromatogram of Baricitinib in Embodiment 1.
Detailed Description of the Embodiments
Embodiment 1
Synthesis of compound 4
15.4 g (O.lmol) of compound 2, 11.4 g (0.05mol) of dipotassium hydrogen phosphate, 26.2 g (0.12mol) of di-tert butyl dicarbonate, 300 g of tetrahydrofuran and 70 g of water wereadded into a 1-L reaction flask and stirred for 12 hours at room temperature; after raw materials reacted completely as monitored, liquid was separated, and the water layer was extracted by using 200 g 6
2018102141 03 Jul2018 of tetrahydro furan; and organic layers were mixed and the mixture was kept for next step.
5.1 g (O.lmol) of hydrazine hydrate and 5.6 g (O.lmol) of acraldehyde were added into the system and were refluxed in oxygen atmosphere to allow materials to reactfor 8 hours; heating was stopped after raw materials under central control reacted completely, and the system was cooled down till room temperature; the system was poured into 100 g of icy water while stirring; the mixture was stirred for 10 minutes and then was separated; the organic layer was dried and filtered; and the filtrate was subjected to rotary evaporation to obtain a crude sticky material; and the crude product was recrystallized by using methyl tert-butyl ether and n-hexane to obtain around 24.9 g of the compound 4 (yield:87.2% and HPLC>98.0%).
Synthesis of compound 5
500 g of methylbenzene was added into a 2-L reaction flask, and then while stirring, 43.2 g (0.2mol) of 1,3-dibromoacetone, 24.3 g (0.4mol) of ethanediol and 0.3 g of p-toluenesulfonic acid were added; the system was heated to 110°C and then refluxed, water generated was separated by using a water segregator during refluxing; the temperature was held to allow the reaction continue for 12 hours and the mixture was evaporated under reduced pressure to obtain methylbenzene; after no liquid drips out, 450 g of acetic ether was added into the system, the system was washed twice by using 450g of water and the organic layer was dried; the organic layer was treated with fiber active carbon and then diatomite; and the filtrate was evaporated to obtain an acetic ether, and finally 41.9 g of transparent liquid (HPLC>99.0%, yield:80.7%, 'HNMR (400MHz, CDCI3),
5ppm3.61(s,4H), 4.14(s,4H) was obtained.
Synthesis of compound 6
500 g of 1,4-dioxane, 39.0 g (0.15mol) of compound 5, 97.7 g (0.3mol) of cesium carbonate and 18.0 g (0.17mol) of ethane sulfonamide were added into a 2-L reaction flask; the system was heated to 80°C, and the temperature was held to allow the materials to react for 20 hours; the mixture was put in central control; reaction was stopped after the raw material compound 5 basically reacted completely, and the system was cooled down to room temperature; 500 g of water and 500 g of acetic ether were added into the system; the materials were stirred, the mixture was separated; the water layer was extracted with acetic ether, per time 300 g, twice; the organic layers were mixed and washed with 500 g of water; the organic layer was put into a clean 2-L reaction flask; 30.4 g of concentrated hydrochloric acid was dripped into the flask while stirring at 7
2018102141 03 Jul2018 room temperature; the mixture was stirred for 1 hour after dripping; the mixture was separated; the organic layer was washed with 500 g of water and dried; the mixture was filtered, the filtrate was condensed to half amount and 300 g of n-heptane was added; the systemwas cooled down to 0 to 10°C; the temperature was held and the system was stirred for 2 hours and then filtered; and the filter cake was dried to obtain around 22.6 g of compound 6 (yield:92.4%, HPLC>98.0%). m/z = 164.1(M+1), 'HNMR(300MHz ,CDC13):54 .08(d,J=2.4Hz,2H),3.94(d,J =
2.6Hz ,2H),3.35-3.10(m,2H), 1.40-1.20(m,3H)ppm
Synthesis of compound 7
450 g of tetrahydro furan and 21.3 g (0.12mol) of diethyl cyanomethylphosphonate were added 10 into a 2-L reaction flask; the system was cooled down to -5-5°C and 5.3 g (0.13mol) of 60% sodium hydride was added batch by batch under protection of nitrogen within 30 minutes; and the system was heated gradually to 20°C; the system was stirred for 45 minutes and solution that was prepared by using 16.3 g (0.1 mol) of compound 6 and 80 g of tetrahydrofuran was dripped into the system within 1 hour; the mixture was stirred at room temperature for 12 hours, and the mixture was put in central control till raw materials basically reacted completely; the system was cooled down to 0°C, 500 g of acetic ether and 300 g of saturated saline solution were added, and the mixture was stirred for 5 minutes and then was separated; the water layer was extracted with acetic ether, per time 300 g, three times; the organic layers were mixed; the organic layer was washed with 500 g of water and then dried; the mixture was filtered and the filtrate was condensed to obtain crude compound 7; and the crude product was rinsed by using a small amount of n-hexane, the crude product was dried to obtain 15.2 g of compound 7 (yield:88.2%, HPLC>98.0%).
Synthesis of target products 1
200 g of acetonitrile and 14.3 g (0.05mol) of compound 4 were added into a 1-L reaction flask;
and then while stirring, 6.9 g (0.05mol) of potassium carbonate was added; the mixture was stirred at room temperature for 30 minutes and then 9.3 g (0.05mol) of compound 7 and 8.1 g (0.025mol) of TBAB were added; the system was heated to 40°C and the materials reacted for 8 hours; the reaction was stopped when materials reacted completely as monitored; the solvent was removed by evaporation under reduced pressure and then 100 g of water was added into the system to quench the reaction; 200 g of acetic ether was added, and the mixture was stirred and separated; 8
2018102141 03 Jul2018 the water layer was extracted with acetic ether, per time 300 g, three times; organic layers extracted were mixed, 10.2 g of concentrated hydrochloric acid was added at room temperature, and the mixture was stirred for 30 minutes; the mixture was filtered, and 300 g of fresh acetic ether was added into the filter cake; 10% solution of potassium carbonate was added while stirring to adjust the pH value to 7; the mixture was separated; the organic layer was dried and filtered, the filter cake was dried to obtain 16.6 g of white solid (HPLC>99.0%, see Fig.2, HPLC:99.82%, yield:89.3%, Fig.l is the 'HNMR of the target product.
Embodiment!
Synthesis of compound 4
15.4 g (O.lmol) of compound 2, 11.4 g (0.05mol) of dipotassium hydrogen phosphate, 31.0 g (0.12mol) of Fmoc-Cl and 400 g of dichloromethane were added into a 1-L reaction flask, and the mixture was stirred for 12 hours at room temperature and was put in central control; after raw materials reacted completely, the mixture was filtered, 300 g of icy water was added into filtrate, the mixture was stirred for 10 minutes, liquid was separated and the water layer was extracted by using 200 g of tetrahydrofuran; and organic layers were mixed, the organic layer was spin-dried, and the obtained system was kept for next step.
10.2 g (0.2mol) of hydrazine hydrate, 500 g of methylbenzene and 11.2 g (0.2mol) of acraldehyde were added into the system and refluxed in oxygen atmosphere to allow materials to react for 8 hours; heating was stopped after raw materials under central control reacted completely, and the system was cooled down till room temperature; while stirring, the system was poured into 100 g of icy water and the mixture was stirred for 10 minutes and then the mixture was layered; the organic layer was dried and filtered; and the filtrate was subjected to rotary evaporation to obtain a crude sticky material; and the crude product was recrystallized by using methyl tert-butyl ether and n-hexane to obtain around 41.7 g of the compound 4 (yield:80.5% and HPLC>98.0%).
Synthesis of compound 5
500g of methylbenzene was added into a 2-L reaction flask, and then while stirring, 43.2 g (0.2mol) of 1,3-dibromoacetone, 24.3 g (0.4mol) of ethanediol and 2.0 g of concentrated sulfuric acid were added; the system was heated to 110°C and refluxed and water generated was separated by using a water segregator during refluxing; the temperature was held to allow the reaction continue for 12 hours and the mixture was evaporated under reduced pressure to obtain 9
2018102141 03 Jul2018 methylbenzene; after no liquid drips out, 450 g of acetic ether was added into the system, the system was washed twice by using 450 g of water and the organic layer was dried; the organic layer was treated with fiber active carbon and then diatomite; and the filtrate was evaporated to obtain an acetic ether layer, and finally 42.1 g of transparent liquid (HPLC>99.0%, yield:81.1%) was obtained.
Synthesis of compound 6
500 g of 1,4-dioxane, 39.0 g (0.15mol) of compound 5, 41.5g (0.3mol) of potassium carbonate and 18.0 g (0.17mol) of ethane sulfonamide were added into a 2-L reaction flask; the system was heated to 70 °C, and the temperature was held to allow the materials to react for 20 hours; the mixture was put in central control; reaction was stopped after the raw material compound 5 basically reacted completely and the system was cooled down to room temperature; 500 g of water and 500 g of acetic ether were added into the system; the mixture was stirred and separated; the water layer was extracted with acetic ether, per time 300 g, twice; the organic layers were mixed and washed with 500 g of water; the organic layer was added into a clean 2-L reaction flask; 30.4 g of concentrated hydrochloric acid was dripped into the flask while stirring at room temperature; the mixture was stirred for 1 hour after dripping; the mixture was separated; the organic layer was washed with 500 g of water and dried; the mixture was filtered and the filtrate was condensed to half amount and 300 g of n-heptane was added; the system was cooled down to 0 to 10°C; the temperature was held and the system was stirredfor 2 hours; and the filter cake was filtered and dried to obtain around 22.8g of compound 6 (yield:93.1%, HPLC>98.0%).
Synthesis of compound 7
450 g of tetrahydro furan and 21.3 g (0.12mol) of diethyl cyanomethylphosphonate were added into a 2-L reaction flask; the system was cooled down to 10°C and 7.0g (0.13mol) of sodium methoxide was added under protection of nitrogen and then the system was gradually heated to
20°C and stirred for 45 minutes, and solution that was prepared by using 16.3 g (0.1 mol) of compound 6 and 80 g of tetrahydrofuran was dripped into the system within 1 hour; the mixture was stirred and reacted for 10 hours at 30°C and the mixture was put in central control till raw materials basically reacted completely; the system was cooled down to 10°C, 500 g of acetic ether and 300 g of saturated saline solution were added, the mixture was stirred for 5 minutes and was separated; the water layer was extracted with acetic ether, per time 300g, three times; the organic 10
2018102141 03 Jul2018 layers were mixed; the organic layer was washed with 500 g of water and then dried; the mixture was filtered and the filtrate was condensed to obtain crude compound 7; and the crude product was rinsed by using a small amount of n-hexane, and the crude product was dried to obtain 16.6 g of compound 7 (yield:96.4%, HPLC>98.0%).
Synthesis of target products 1
200 g of acetonitrile and 20.4 g (0.05mol) of compound 4 were added into a 1-L reaction flask; and then while stirring, 6.9 g (0.05mol) of potassium carbonate was added; the mixture was stirred at room temperature for 30 minutes and then 9.3 g (0.05mol) of compound 7 and 8 g (0.05mol) of
DBU were added; the system was heated to 40°C and the materials reacted for 8 hours; the mixture was put in central control and reaction was stopped when materials reacted completely; the solvent was removed by evaporation under reduced pressure and then 100 g of water was added into the system to quench the reaction; 200 g of acetic ether was added, the mixture was stirred for 30 minutes, the mixture was filtered and the filter cake was rinsed by using 100 g of fresh acetic ether; and the filter cake was dried to obtain 17.0 g of white solid (HPLC>99.0%, yield:91.2%).
Embodiment 3
Synthesis of compound 4
15.4 g (O.lmol) of compound 2, 27.6 g (0.2mol) of potassium carbonate, 19.lg (O.lmol) of paratoluensulfonyl chloride and 500 g of acetonitrile were added into a 1-L reaction flask; the mixture was stirred for 8 hours at room temperature and was put in central control; after raw materials reacted completely, the mixture was filtered, and the filtrate was spin-dried under reduced pressure and then was kept for next step;
20.4 g (0.4mol) of hydrazine hydrate, 450 g of o-dichlorobenzene and 22.4 g (0.4mol) of acraldehyde were added into the system and refluxed in oxygen atmosphere to allow materials to react for 4 hours; heating was stopped after raw materials under central control reacted completely, and the system was cooled down till room temperature; the system was poured into 100 g of icy water while stirring; the mixture was stirred for 10 minutes and then was separated; the organic layer was dried and filtered; and the filtrate was subjected to rotary evaporation to obtain a crude sticky material; and the crude product was recrystallized by using methyl tert-butyl ether and 11
2018102141 03 Jul2018 n-hexane to obtain around 27.7 g of the compound 4 (yield:81.6% and HPLC>98.0%).
Synthesis of compound 5
500 g of methylbenzene was added into a 2-L reaction flask, and then while mixing, 43.2g (0.2mol) of 1,3-dibromoacetone, 24.3 g (0.4mol) of ethanediol and 0.3 g of p-toluenesulfonic acid were added; the system was heated to 110°C and refluxed and water generated was separated by using a water segregator during refluxing; the temperature was held to allow the reaction continue for 12 hours and the mixture was evaporated under reduced pressure to obtain methylbenzene; after no liquid drips out, 450g of acetic ether was added into the system, the system was washed twice by using 450 g of water and the organic layer was dried; the organic layer was treated with fiber active carbon and then diatomite; and the filtrate was evaporated to obtain an acetic ether, and finally 42.6 g of transparent liquid (HPLC>99.0%, yield:82.0%, 'HNMR(400MHz, CDC13),5ppm3.61 (s,4H), 4.14(s,4H) was obtained.
Synthesis of compound 6
500 g of 1,4-dioxane, 39.0 g (0.15mol) of compound 5, 31.8 g (0.3mol) of sodium carbonate and
18.0 g (0.17mol) of ethane sulfonamide were added into a 2-L reaction flask; the system was heated to 65 °C, and the temperature was held to allow the materials to react for 16 hours; the mixture was put in central control; reaction was stopped after the raw material compound 5 basically reacted completely and the system was cooled down to room temperature; 500 g of water and 500 g of acetic ether were added into the system; the materials were stirred, and the mixture was separated; the water layer was extracted with acetic ether, per time 300 g, twice; the organic layers were mixed and the organic layer was washed with 500 g of water; the organic layer was added into a clean 2-L reaction flask; 30.4 g of concentrated hydrochloric acid was dripped into the flask while stirring at room temperature and; the mixture was stirred for 1 hour after dripping; the mixture was separated; the organic layer was washed with 500 g of water and then dried; the mixture was filtered, the filtrate was condensed to half amount and 300 g of n-heptane was added; the system was cooled down to 0 to 10°C; the temperature was held and the system was stirred for 2 hours; and the filter cake was dried to obtain around 23.0 g of compound 6 (yield:94.1%, HPLC>98.0%).
Synthesis of compound 7
450 g of tetrahydro furan and 21.3 g (0.12mol) of diethyl cyanomethylphosphonate were added
2018102141 03 Jul2018 into a 2-L reaction flask; the system was cooled down to 10°C, 10.2 g (0.15mol) of sodium ethoxide was added under protection of nitrogen and then the system was gradually heated to 20°C; the mixture was stirred for 45 minutes and solution that was prepared by using 16.3 g (O.lmol) of compound 6 and 80 g of tetrahydro furan was dripped into the system within 1 hour;
the mixture was stirred to react at 40°C for 10 hours and the mixture was put in central control till raw materials basically reacted completely; the system was cooled down to 10°C, 500 g of acetic ether and 300 g of saturated saline solution were added, and the mixture was stirred for 5 minutes and then separated; the water layer was extracted with acetic ether, per time 300 g, three times; the organic layers were mixed; the organic layer was washed with 500 g of water and then the organic layer was dried; the mixture was filtered and the filtrate was condensed to obtain crude compound 7; and the crude product was rinsed by using a small amount of n-hexane, and then dried to obtain
16.3 g of compound 7 (yield:94.3%, HPLC>98.0%).
Synthesis of target products 1
200 g of acetonitrile and 17.0 g (0.05mol) of compound 4 were added into a 1-L reaction flask; 15 and then while mixing, 6.9 g (0.05mol) of potassium carbonate was added; the mixture was stirred at room temperature for 30 minutes and then 9.3 g (0.05mol) of compound 7 and 5.7 g (0.05mol) of TEBA were added; the system was heated to 70 °C and the materials reacted for 6 hours; the mixture was put in central control and reaction was stopped when materials reacted completely; the solvent was removed by evaporation under reduced pressure and then 100 g of water was added into the system to quench the reaction; 400 g of acetone was added and 9.8 g (O.lmol) of concentrated sulfuric acid was dripped at room temperature, the mixture was stirred at40°C for 1 hour, the mixture was cooled down to 0°C, the mixture was filtered and the filter cake was rinsed by using 50 g of acetone; and the filtrate was dried completely by rotary evaporation under reduced pressure, 300 g of acetic ether was added, the mixture was stirred at room temperature for
2 hours, and the filter cake was dried to obtain 16.0 g of white solid (HPLC>99.0%, yield:85.9%).
Embodiment 4
Synthesis of compound 4
15.4 g (O.lmol) of compound 2, 20.2 g (0.2mol) of triethylamine, 27.9 g (O.lmol) of triphenylmethyl chloride and 600 g of acetonitrile were added into a 1-L reaction flask; the mixture was stirred for 4 hours at room temperature and the mixture was put in central control; 13
2018102141 03 Jul2018 after raw materials reacted completely, the mixture was filtered, the filtrate was spin-dried and the mixture was kept for next step;
20.4 g (0.4mol) of hydrazine hydrate, 450 g of o-dichlorobenzene and 22.4 g (0.4mol) of acraldehyde were added into the system and refluxed in oxygen atmosphere to allow materials to react for 4 hours; heating was stopped after raw materials under central control reacted completely, and the system was cooled down till room temperature; the system was poured into 100 g of icy water while stirring; the mixture was stirred for 10 minutes and then was separated; the organic layer was dried and filtered; and the filtrate was subjected to rotary evaporation to obtain a crude sticky material; and the crude product was recrystallized by using ether and n-hexane to obtain around 35.6 g of the compound 4 (yield:83.2% and HPLC>98.0%).
Synthesis of compound 5
500 g of methylbenzene was added into a 2-L reaction flask, and then while stirring, 43.2 g of (0.2mol) 1,3-dibromoacetone, 24.3 g of (0.4mol) ethanediol and 0.3 g of p-toluenesulfonic acid were added; the system was heated to 110°C and refluxed, and water generated was separated by using a water segregator during refluxing; the temperature was held to allow the reaction continue for 12 hours and the mixture was evaporated under reduced pressure to obtain methylbenzene; after no liquid drips out, 450 g of acetic ether was added into the system, the system was washed twice by using 450 g of water and the organic layer was dried; the organic layer was treated with fiber active carbon and then diatomite; and the filtrate was evaporated to obtain an acetic ether layer, and finally 42.6 g of transparent liquid (HPLC>99.0%, yield:82.0%) was obtained.
Synthesis of compound 6
500 g of 1,4-dioxane, 39.0 g (0.15mol) of compound 5, 31.8 g (0.3mol) of sodium carbonate and 18.0 g (0.17mol) of ethane sulfonamide were added into a 2-L reaction flask; the system was heated to 50°C, and the temperature was held to allow the materials to react for 16 hours; the mixture was put in central control; reaction was stopped after the raw material compound 5 basically reacted completely and the system was cooled down to room temperature; 500 g of water and 500 g of acetic ether were added into the system; the materials were stirred, the mixture was separated; the water layer was extracted with acetic ether, per time 300 g, twice; the organic layers were mixed and the organic layer was washed with 500 g of water; the organic layer was added into a clean 2-L reaction flask; 30.4 g of concentrated hydrochloric acid was dripped into the flask 14
2018102141 03 Jul2018 while stirring at room temperature; the mixture was stirred for 1 hour after dripping; the mixture was separated; the organic layer was washed with 500 g of water and then dried; the mixture was filtered, the filtrate was condensed to half amount and 300 g of n-heptane was added; the system was cooled down to 0 to 10°C; the temperature was held, the system was stirred for 2 hours and then filtered; and the filter cake was dried to obtain around 22.1 g of compound 6 (yield:90.2%,
HPLC>98.0%).
Synthesis of compound 7
450 g of tetrahydro furan and 21.3 g (0.12mol) of diethyl cyanomethylphosphonate were added into a 2-L reaction flask; the system was cooled down to 10°C and 10.2 g (0.15mol) of sodium ethoxide was added under protection of nitrogen and then the system was gradually heated to 20°C; the mixture was stirred for 45 minutes and solution that was prepared by using 16.3 g (O.lmol) of compound 6 and 80 g of tetrahydro furan was dripped into the system within 1 hour; the mixture was stirred to react at 40°C for 10 hours and the mixture was put in central control till raw materials basically reacted completely; the system was cooled down to 10°C, 500 g of acetic ether and 300 g of saturated saline solution were added, and the mixture was stirred for 5 minutes and then separated; the water layer was extracted with acetic ether, per time 300g> three times; the organic layers were mixed; the organic layer was washed with 500 g of water and then dried; the mixture was filtered and the filtrate was condensed to obtain crude compound 7; and the crude product was rinsed by using a small amount of n-hexane, and the crude product was dried to obtain 16.3 g of compound 7 (yield:94.3%, HPLC>98.0%).
Synthesis of target products 1
400 g of acetonitrile and 21.4 g (0.05mol) of compound 4 were added into a 1-L reaction flask; and then while mixing, 6.9 g (0.05mol) of potassium carbonate was added; the mixture was stirred at room temperature for 30 minutes and then 9.3 g (0.05mol) of compound 7 and 5.7 g (0.025 mol) of TEBA were added; the system was heated to 70 °C and the materials reacted for 6 hours; the mixture was put in central control and reaction was stopped when materials reacted completely;
the solvent was removed by evaporation under reduced pressure and then 100 g of water was added into the system to quench the reaction; 400 g of acetone was added, and 19.6g (0.2mol) of concentrated sulfuric acid was dripped, the mixture was stirred at 40°C for 1 hour, the mixture was cooled down to 0°C, the temperature was held and the mixture was stirred for 1 to 2 hours, the 15
2018102141 03 Jul2018 mixture was filtered and the filter cake was rinsed by using 50 g of acetone; and the filtratewas dried completely by rotary evaporation under reduced pressure, 300 g of acetic etherwasadded, the mixture was stirred at room temperature for 2 hours, and the filter cake was dried to obtain 16.7 g of white solid (HPLC>99.0%, yield:89.6%).
Embodiment 5
Synthesis of compound 4
15.4 g (O.lmol) of compound 2, 20.2 g (O.lmol) of potassium carbonate, 24.1 g (0.12mol) of 4-methoxybenzyl bromide and 500 g of acetonitrile were added into a 1-L reaction flask; the mixture was stirred for 4 hours at room temperature and the mixture was put in central control;
after raw materials reacted completely, the mixture was filtered, the filtrate was spin-dried, and the mixture was kept for next step;
20.4 g (0.4mol) of hydrazine hydrate, 450 g of o-dichlorobenzene and 22.4 g (0.4mol) of acraldehyde were added into the system and refluxed in oxygen atmosphere to allow materials to react for 4 hours; heating was stopped after raw materials under central control reacted completely, and the system was cooled down till room temperature; the system was poured into 100 g of icy water while stirring; the mixture was stirred for 10 minutes and then layered; the organic layer was dried and filtered; and the filtrate was subjected to rotary evaporation to obtain a crude sticky material; and the crude product was recrystallized by using methyl tert-butyl ether and n-hexane to obtain around 24.6 g of the compound 4 (yield:80.5% and HPLC>98.0%).
Synthesis of compound 5
500 g of methylbenzene was added into a 2-L reaction flask, and then while mixing, 43.2 g (0.2mol) of 1,3-dibromoacetone, 24.3 g (0.4mol) of ethanediol and 0.3 g of p-toluenesulfonic acid were added; the system was heated to 110°C and then refluxed, and water generated was separated by using a water segregator during refluxing; the temperature was held to allow the reaction continue for 12 hours and the mixture was evaporated under reduced pressure to obtain methylbenzene; after no liquid drips out, 450 g of acetic ether was added into the system, the system was washed twice by using 450 g of water and the organic layer was dried; the organic layer was treated with fiber active carbon and then diatomite; and the filtrate was evaporated to obtain an acetic ether layer, and finally 42.6 g of transparent liquid (HPLC>99.0%, yield:82.0%) was obtained.
2018102141 03 Jul2018
Synthesis of compound 6
500 g of 1,4-dioxane, 39.0 g (0.15mol) of compound 5, 31.8 g (0.3mol) of sodium carbonate and 18.0 g (0.17mol) of ethyl sulfonamide were added into a 2-L reaction flask; the system was heated to 60°C, and the temperature was held to allow the materials to react for 16 hours; the mixture was put in central control; reaction was stopped after the raw material compound 5 basically reacted completely and the system was cooled down to room temperature; 500 g of water and 500 g of acetic ether were added into the system; the materials were stirred, and the mixture was separated; the water layer was extracted with acetic ether, per time 300 g, twice; the organic layers were mixed and then washed with 500 g of water; the organic layer was added into a clean 2-L reaction flask; 30.4 g of concentrated hydrochloric acid was dripped into the flask while stirring at room temperature; the mixture was stirred for 1 hour after dripping; the mixture was separated; the organic layer was washed with 500 g of water and then dried; the mixture was filtered, the filtrate was condensed to half amount and 300 g of n-heptane was added; the system was cooled down to 0 to 10 °C; the temperature was held and the system was stirred for 2 hours and then filtered; and the filter cake was dried to obtain around 24.5 g of compound 6 (yield:93.4%, HPLC>98.0%).
Synthesis of compound 7
450 g of tetrahydrofuran and 21.3g (0.12mol) of diethyl cyanomethylphosphonate were added into a 2-L reaction flask; the system was cooled down to 10°C and 10.2 g (0.15mol) of sodium ethoxide was added under protection of nitrogen and then the system was gradually heated to
20°C; the system was stirred for 45 minutes and solution that was prepared by using 16.3 g (O.lmol) of compound 6 and 80 g of tetrahydrofuran was dripped into the system within 1 hour; the mixture was stirred to react at 40°C for 10 hours and the mixture was put in central control till raw materials basically reacted completely; the system was cooled down to 10°C, 500 g of acetic ether and 300 g of saturated saline solution were added, and the mixture was stirred for 5 minutes and then separated; the water layer was extracted with acetic ether, per time 300g, three times; the organic layers were mixed; the organic layer was washed with 500 g of water and then dried; the mixture was filtered and the filtrate was condensed to obtain crude compound 7; and the crude product was rinsed by using a small amount of n-hexane, and the crude product was dried to obtain 16.3 g of compound 7 (yield:94.3%, HPLC>98.0%).
Synthesis of target products 1
2018102141 03 Jul2018
400 g of acetonitrile and 15.3 g (0.05mol) of compound 4 were added into a 1-L reaction flask; and then while mixing, 6.9 g (0.05mol) of potassium carbonate was added; the mixture was stirred at room temperature for 30 minutes and then 9.3 g (0.05mol) of compound 7 and 5.7 g (0.025 mol) of TEBA were added; the system was heated to 70°C to allow the materials to react for 6 hours;
the mixture was put in central control and reaction was stopped when materials reacted completely; the solvent was removed by evaporation under reduced pressure and then 100 g of water was added into the system to quench the reaction; 400 g of ethanol was added , the system was cooled down to 0 to 10°C, the temperature was held and 17.1 g (0.15mol) of trifluoroacetic acid was dripped and the mixture was stirred at room temperature for 1 hour, the mixture was cooled down to 0°C, the temperature was held and the mixture was stirred for 1 to 2 hours and then filtered; the filter cake was rinsed by using 50 g of ethanol; 400 g of dichloromethane was added into the system, the system was cooled down to 0 to 10°C, and the mixture was stirred for 2 hours and then filtered, the filter cake was dried to obtainl5.2 g of white solid (HPLC>99.0%, yield:81.8%).
2018102141 03 Jul2018
Claims
Claims (4)
1. A method for preparing Baricitinib,
4 7 wherein method comprising:
(1) 4-chloro-7H-pyrrolo[2,3-d]pyrimidine is used as the rawmaterial and is subjected to amino protection by amino-protecting group R to form an intermediate compound 3; the intermediate
10 compound 3 is reacted with hydrazine hydrate and acraldehyde in the presence of oxygen and organic solvent to form a compound 4 through replacement, ring formation and recrystallization based on an one-pot process”;
wherein, R represents amino-protected compound, including di-tert butyl dicarbonate ((BocfiO), Fmoc-Cl and Cbz-Cl; TS-C1 and Tfa-Cl; Trt-Cl, and PMB-Br or PMB-C1;
15 wherein, R’ represents the protecting group for R, such as Boc, Fomc, Cbz, TS, Tfa, Trt and PMB;
(2) 1,3-dibromoacetone and ethanediol are used as the raw material and reacted in the presence of a strong acid to form a carbonyl-protected compound 5 though condensation;
2018102141 03 Jul2018
(3) the compound 5 obtained in step (2) is reacted with ethane sulfonamide in the presence of an alkali to form a compound 6 through ring formation under heat;
(4) diethylcyanomethylphosphonate is used as the raw material to react with the compound 6 obtained in the step (3) in the presence of a strong alkali to form a compound 7;
5 (5) the compound 4 obtained in step (l)and the compound 7 obtained in step (4) are reacted through addition and removal of amino-protecting group in the presence of a catalyst and solvent to form Baricitinib.
2. The method for preparing Baricitinib as recited in claim 1, wherein the organic solvent in the step (1) is one of tetrahydrofuran, methylbenzene, dimethylbenzene or o-dichlorobenzene.
10 3. The method for preparing Baricitinib as recited in claim 1, wherein the mol ratio of
4-chloro-7H-pyrrolo[2,3-d]pyrimidine to hydrazine hydrate to acraldehyde in the step (1) is
1:1:1-1:4:4.
4. The method for preparing Baricitinib as recited in claim 1, wherein the recrystallization solvent in the step (1) is MTBE/n-hexane, MTBE/n-heptane, diethyl ether/n-hexane or diethyl
15 ether/n-heptane.
5. The method for preparing Baricitinib as recited in claim 1, wherein the strong acid catalyst in the step (2) is one of p-toluenesulfonic acid or sulfuric acid.
6. The method for preparing Baricitinib as recited in claim 1, wherein the alkali in the step (3) is one of potassium carbonate, sodium carbonate or cesium carbonate, and the reaction temperature
20 is 50 to 80°C.
7. The method for preparing Baricitinib as recited in claim 6, wherein the alkali in the step (3) is cesium carbonate and the reaction temperature is 65 °C.
8. The method for preparing Baricitinib as recited in claim 1, wherein the strong alkali in the step (4) is one of sodium hydride, potassium hydride, sodium methoxide or sodium ethoxide and the
25 reaction temperature is 10 to 40 °C.
9. The method for preparing Baricitinib as recited in claim 1, wherein the catalyst in the step (5) is one of DBU, TBAB or TEBA, and the reaction temperature is 40 to 70°C.
Drawings
2018102141 03 Jul2018
BRTN-01 1H-NMR DMSO 303K 500MHz
CO OJ tO - co r» to © © κ r< K
V«C0f^’-’-’-tO©^,h'’-O>tO©^,b- >^ησί'-οοοοίΰοιηοωοιιη’-ιο'- © woin’joiirtOjiS'fM’-soNiS’t © i£i<£)iNWSinn«qwqq-ifiCJNPj ©
I / IV Ψ ex?
BRUKER
CXJ
NAME zbzy
EXPNO 87
PROCNO 1
Date. 20170803 Time 9.12
INSTRUM WNMR-l-SOOMHz PULPROG s1pul30
NUC1
PL1
SFO1
50.000 usee 30.00 usee 303.1 K
120.00 dB 500.1302729 MHz
32768
500.1260401 MHz
1/2
Drawings
2018102141 03 Jul2018
StMu&Mariual lntegration/Temporary
2017/08/02 15:31:14 1 /1 .J LabSdutions Analysis Report
Jiangsu Zhongbang Pharmaceutical Co., Ltd.
<Sample Inforraation>
Sample Name : Baridtimb
Sample ID : Baridtimb
Data file name : BaricitiniKlcd
Method file flame : Baridtimb Related Materials.lcm
Batch file flame : 2Q170802,lcb
Batch file same : 1-23
Sample introduction volume : 20pL
Analysis Date : 2017/06/02 14:25:10 Analyst
Process Date : 2017/06/02 15:00:12 Processor
Instrument No, : JSY-024 <Chromatogram>
nV <Feak Table>
Detector A 250 nm
JS Rivaroxaban-16-20/16-95 -1 -baricitinib-lcd
FIG. 2
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711334329.1 | 2017-12-13 | ||
| CN201711334329.1A CN108129482A (en) | 2017-12-13 | 2017-12-13 | A kind of Ba Rui replaces the preparation method of Buddhist nun |
| CN201810667443.4A CN108586465B (en) | 2017-12-13 | 2018-06-25 | Preparation method of barretinib |
| CN201810667443.4 | 2018-06-25 |
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| AU2018366342A Pending AU2018366342A1 (en) | 2017-12-13 | 2018-07-03 | Method for preparing Baricitinib |
| AU2018102141A Active AU2018102141A4 (en) | 2017-12-13 | 2018-07-03 | Method for preparing Baricitinib |
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| AU2018366342A Pending AU2018366342A1 (en) | 2017-12-13 | 2018-07-03 | Method for preparing Baricitinib |
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| CN (2) | CN108129482A (en) |
| AU (2) | AU2018366342A1 (en) |
| WO (1) | WO2019114258A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2021053690A1 (en) * | 2019-09-17 | 2021-03-25 | Natco Pharma Limited | An improved process for the preparation of baricitinib |
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| CN108129482A (en) * | 2017-12-13 | 2018-06-08 | 江苏中邦制药有限公司 | A kind of Ba Rui replaces the preparation method of Buddhist nun |
| CN111362853A (en) * | 2020-04-27 | 2020-07-03 | 安徽大学 | Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester |
| CN112898306B (en) * | 2021-02-02 | 2022-04-08 | 山东四环药业股份有限公司 | Preparation method of barretinib |
| CN115124537A (en) * | 2022-07-13 | 2022-09-30 | 山东大学 | Preparation method of JAK inhibitor britinib |
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| DE3035395A1 (en) * | 1980-09-19 | 1982-05-06 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING PYRAZOLE |
| ZA200905371B (en) * | 2007-02-28 | 2010-10-27 | Leo Pharma As | Novel phosphodiesterase Inhibitors |
| ES2602577T3 (en) * | 2008-03-11 | 2017-02-21 | Incyte Holdings Corporation | Azetidine and cyclobutane derivatives as JAK inhibitors |
| EP3227298A4 (en) * | 2014-12-05 | 2018-05-23 | Sun Pharmaceutical Industries Ltd | Process for the preparation of baricitinib and an intermediate thereof |
| WO2016125080A2 (en) * | 2015-02-02 | 2016-08-11 | Sun Pharmaceutical Industries Limited | Process for the preparation of baricitinib and an intermediate thereof |
| AR104918A1 (en) * | 2015-06-19 | 2017-08-23 | Lilly Co Eli | PROCESSES AND INTERMEDIARIES FOR THE PREPARATION OF {1- (ETILSULFONIL) -3- [4- (7H-PIRROLO [2,3-D] PIRIMIDIN-4-IL) -1H-PIRAZOL-1-IL] AZETIDIN-3-IL } ACETONITRILE |
| CN105294699B (en) * | 2015-12-04 | 2019-06-11 | 上海勋和医药科技有限公司 | Ba Rui replaces the preparation method of Buddhist nun |
| CN105541891B (en) * | 2016-02-04 | 2017-11-28 | 东南大学 | Ba Rui prepares methods of the Ba Rui for Buddhist nun for intermediate of Buddhist nun and preparation method thereof and by the intermediate |
| CN106496195B (en) * | 2016-10-18 | 2019-03-08 | 杭州科巢生物科技有限公司 | Ba Rui is for Buddhist nun and its synthetic method of intermediate |
| CN106946917B (en) * | 2017-03-20 | 2019-06-11 | 杭州科巢生物科技有限公司 | A kind of JAK inhibitor Ba Rui replaces the novel synthesis of Buddhist nun and its intermediate |
| CN107176955B (en) * | 2017-03-24 | 2019-04-09 | 南京优科制药有限公司 | A kind of Ba Rui replaces the preparation method of Buddhist nun |
| CN107739328B (en) * | 2017-11-22 | 2020-03-20 | 海化生命(厦门)科技有限公司 | Preparation method of key intermediate 1 for synthesizing barretinib |
| CN108129482A (en) * | 2017-12-13 | 2018-06-08 | 江苏中邦制药有限公司 | A kind of Ba Rui replaces the preparation method of Buddhist nun |
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- 2018-07-03 WO PCT/CN2018/094160 patent/WO2019114258A1/en active Application Filing
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| WO2021053690A1 (en) * | 2019-09-17 | 2021-03-25 | Natco Pharma Limited | An improved process for the preparation of baricitinib |
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| CN108586465A (en) | 2018-09-28 |
| AU2018366342A1 (en) | 2019-07-04 |
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| CN108129482A (en) | 2018-06-08 |
| WO2019114258A1 (en) | 2019-06-20 |
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