CN114437073A - Preparation method of oral JAK pathway inhibitor - Google Patents
Preparation method of oral JAK pathway inhibitor Download PDFInfo
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- CN114437073A CN114437073A CN202011207231.1A CN202011207231A CN114437073A CN 114437073 A CN114437073 A CN 114437073A CN 202011207231 A CN202011207231 A CN 202011207231A CN 114437073 A CN114437073 A CN 114437073A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 102000042838 JAK family Human genes 0.000 title claims abstract description 8
- 108091082332 JAK family Proteins 0.000 title claims abstract description 8
- 239000003112 inhibitor Substances 0.000 title claims abstract description 6
- 230000037361 pathway Effects 0.000 title claims abstract description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000004280 Sodium formate Substances 0.000 claims abstract description 11
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims abstract description 11
- 235000019254 sodium formate Nutrition 0.000 claims abstract description 11
- MLIREBYILWEBDM-UHFFFAOYSA-M 2-cyanoacetate Chemical compound [O-]C(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-M 0.000 claims abstract description 7
- -1 pyrimidin-4-ylamino Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000000605 extraction Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 230000007935 neutral effect Effects 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 claims description 4
- 239000000852 hydrogen donor Substances 0.000 claims description 3
- MLIREBYILWEBDM-UHFFFAOYSA-N anhydrous cyanoacetic acid Natural products OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims 1
- 239000000010 aprotic solvent Substances 0.000 claims 1
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims 1
- BESQLCCRQYTQQI-UHFFFAOYSA-N propan-2-yl 2-cyanoacetate Chemical compound CC(C)OC(=O)CC#N BESQLCCRQYTQQI-UHFFFAOYSA-N 0.000 claims 1
- 239000003586 protic polar solvent Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 41
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 abstract description 32
- SYIKUFDOYJFGBQ-YLAFAASESA-N tofacitinib citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 SYIKUFDOYJFGBQ-YLAFAASESA-N 0.000 abstract description 18
- 239000003054 catalyst Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract 1
- UMWNXPTXDOVDFE-QAPCUYQASA-N n-[(3r,4r)-1-benzyl-4-methylpiperidin-3-yl]-n-methyl-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C([C@H]([C@H](C1)N(C)C=2C=3C=CNC=3N=CN=2)C)CN1CC1=CC=CC=C1 UMWNXPTXDOVDFE-QAPCUYQASA-N 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 229960004247 tofacitinib citrate Drugs 0.000 description 17
- 238000000967 suction filtration Methods 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- 229960004106 citric acid Drugs 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- WERQQWICVQUZHF-UHFFFAOYSA-M sodium formate dihydrate Chemical compound O.O.[Na+].[O-]C=O WERQQWICVQUZHF-UHFFFAOYSA-M 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 4
- 239000004012 Tofacitinib Substances 0.000 description 4
- 229960002303 citric acid monohydrate Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229960001350 tofacitinib Drugs 0.000 description 4
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000006264 debenzylation reaction Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 description 1
- XIVBKXMBKBOIOC-UHFFFAOYSA-N C(#N)CC(=O)O.ON1C(CCC1=O)=O Chemical compound C(#N)CC(=O)O.ON1C(CCC1=O)=O XIVBKXMBKBOIOC-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000010250 cytokine signaling pathway Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 description 1
- 238000012502 risk assessment Methods 0.000 description 1
- 238000013349 risk mitigation Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method of an oral JAK pathway inhibitor, belonging to the field of organic drug synthesis. In particular to a preparation method of a JAK pathway inhibitor (3R,4R) -4-methyl-3- (methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-ylamino) -beta-oxo-1-piperidinepropanonitrile citrate, which takes N- ((3R,4R) -1-benzyl-4-methylpiperidine-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidine-4-amine as a starting material, is reduced under a Pd/C catalyst and a sodium formate system, condensed with cyanoacetate, salified with citric acid to prepare a final product (3R,4R) -4-methyl-3- (methyl-7H-pyrrolo [2 ], 3-d ] pyrimidin-4-ylamino) - β -oxo-1-piperidinepropanitrile citrate. The preparation method has the advantages of mild reaction conditions, simple and convenient post-treatment and low cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic drug synthesis, and particularly relates to a preparation method of (3R,4R) -4-methyl-3- (methyl-1H-pyrrolo [2,3-d ] pyrimidine-4-amino) -beta-oxy-1-piperidinepropanitrile citrate.
Background
The (3R,4R) -4-methyl-3- (methyl-1H-pyrrolo [2,3-d ] pyrimidine-4-amino) -beta-oxo-1-piperidinepropanenitrile Citrate is commonly known as Tofacitinib Citrate (an English name of Tofacitinib Citrate), is an oral JAK pathway inhibitor developed by the company of Perey, and JAK/STAT is an important cytokine signaling pathway and is related to a plurality of diseases such as blood system diseases, tumors, rheumatoid arthritis, psoriasis and the like. Unlike most other current Rheumatoid Arthritis (RA) treatment drugs that act primarily on extracellular targets: tofacitinib takes an intracellular signal transduction pathway as a target point, acts on a core part of a cytokine network, and not only can relieve symptoms but also can slow down or stop damage of diseases. The inhibition strength of tofacitinib on JAK3 is 5-100 times that of JAK1 and JAK 2.
Tofacitinib citrate tablets were approved by FDA by risk assessment and mitigation strategies (REMS) on day 11/6 of 2012 for the treatment of patients with active adult and moderate to severe Rheumatoid Arthritis (RA) who do not respond well to methotrexate. FDA indicates that tofacitinib citrate may be used in moderate to severe rheumatoid arthritis patients who either fail to benefit from the conventional oral therapeutic methotrexate or cannot tolerate treatment. Tofacitinib may be used alone or in combination with methotrexate and other standard therapeutic agents. Tofacitinib citrate has been approved by more than 80 countries worldwide to market by the present time, and is marketed in china in 2017.
Tofacitinib citrate (chemical name: (3R,4R) -4-methyl-3- (methyl-1H-pyrrolo [2,3-d ] pyrimidine-4-amino) -beta-oxo-1-piperidinepropanitrile, 2-hydroxy-1, 2, 3-propanetricarboxylic acid (1:1)) has the following structure:
at present, the synthetic method of tofacitinib has a plurality of reports in documents, and a piperidine amine structural intermediate and a pyrrolopyrimidine structural intermediate are mainly condensed to obtain a mother ring structure, and the mother ring structure is condensed by cyanoacetyl and then salified with citric acid. For example, the synthetic route reported in WO2001042246A by sequin of the original research company is as follows:
in the route, the debenzylation reaction of the raw material 5 adopts hydrogen reduction, and a high-pressure kettle is needed, so that potential safety hazards exist; meanwhile, the amidation reaction of the raw material 3 adopts cyanoacetic acid-N-hydroxysuccinimide ester, so that the supplier is few, the cost is high, the stability of the active ester material is poor, and the quality of the product after batch amplification is difficult to ensure.
The synthetic route disclosed in patent application CN106146517A adopts a Pd/C and formic acid reduction system for debenzylation, which avoids the use of a high-pressure reaction kettle, but the reaction easily generates formamide impurities in an alcohol solvent, and the impurities are not easily removed in the subsequent process, and are easily introduced into the finished product, so that the product quality does not meet the requirement of pharmaceutical API; meanwhile, the feeding amount of formic acid needs to be strictly controlled in the reaction process.
Patent application CN105693728A discloses debenzylation in alcohol solvent by adopting Pd/C and ammonium formate reduction system, and the drawback of this reaction condition is that in scale-up production, ammonium formate is easy to generate white solid at the reaction kettle mouth to block the reaction kettle, thereby causing potential safety hazard.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for preparing tofacitinib citrate, which has high yield, high purity and low cost and is suitable for industrial amplification production by reacting Pd/C and a hydrogen donor in water.
In one aspect, the present invention provides a method for preparing a compound of formula 3, comprising: reacting the compound of formula 4 in water under the conditions of Pd/C catalyst, acetic acid and sodium formate to prepare the compound of formula 3,
in some embodiments, the mass to volume ratio of the compound of formula 4 to water is 1: 2-20 Kg/L; in some typical embodiments, the mass to volume ratio of the compound of formula 4 to water is 1: 5-20 Kg/L; in some more typical embodiments, the mass to volume ratio of the compound of formula 4 to water is 1: 5-10 Kg/L; in some more typical embodiments, the mass to volume ratio of the compound of formula 4 to water is 1: 5 Kg/L.
In some embodiments, the mass ratio of the compound of formula 4 to the Pd/C catalyst is 1: 0.05 to 0.25; in some typical embodiments, the mass ratio of the compound of formula 4 to the Pd/C catalyst is 1: 0.07 to 0.21; in some more typical embodiments, the mass ratio of the compound of formula 4 to the Pd/C catalyst is 1: 0.21.
in some embodiments, the molar ratio of the compound of formula 4 to acetic acid is 1: 3-10; in some typical embodiments, the molar ratio of the compound of formula 4 to acetic acid is 1: 5-8; in some more typical embodiments, the molar ratio of the compound of formula 4 to acetic acid is 1: 6.
in some embodiments, the molar ratio of the compound of formula 4 to sodium formate is 1: 2-8; in some typical embodiments, the molar ratio of the compound of formula 4 to sodium formate is 1: 2-6; in some more typical embodiments, the molar ratio of the compound of formula 4 to sodium formate is 1: 3.
in some embodiments, the reaction temperature of the above reaction is from 20 ℃ to 70 ℃; in some typical embodiments, the reaction temperature of the above reaction is 20 ℃ to 30 ℃.
In some embodiments, the reaction time of the reaction is 1-5 hours; in some typical embodiments, the reaction time of the reaction is 1-2 h; in some more typical embodiments, the reaction time for the above reaction is 2 h.
In some embodiments, the post-treatment of the above reaction comprises the steps of: adjusting pH of the solution to neutral, adding organic solvent for extraction, mixing organic solvent layers, concentrating to obtain oily substance, adding n-hexane for crystallization, filtering, and drying.
In some embodiments, the organic solvent added in the extraction step is selected from one of ethyl acetate, n-butanol, or dichloromethane; in some typical embodiments, the organic solvent added in the extraction step is one of n-butanol or dichloromethane; in some more typical embodiments, the organic solvent added in the extraction step is dichloromethane.
In some exemplary embodiments, there is provided a method of preparing a compound of formula 3, comprising: reacting the compound of formula 4 in water under the conditions of Pd/C catalyst, acetic acid and sodium formate to prepare a compound of formula 3, adjusting the pH of the solution to be neutral after the reaction is completed, adding an organic solvent for extraction, combining organic solvent layers, concentrating to obtain oily matter, adding n-hexane for crystallization, performing suction filtration and drying,
wherein: the mass-to-volume ratio of the compound of formula 4 to water is 1: 5 Kg/L; the mass ratio of the compound of formula 4 to the Pd/C catalyst is 1: 0.21; the molar ratio of the compound of formula 4 to acetic acid is 1: 6; the molar ratio of the compound of formula 4 to sodium formate is 1: 3; the reaction temperature is 20-30 ℃; the reaction time is 2 h; the organic solvent added in the extraction step is dichloromethane.
In another aspect, the present invention further provides a process for preparing tofacitinib citrate, a compound of formula 3, comprising: reacting the compound shown in the formula 3 with cyanoacetate in tetrahydrofuran under the catalysis of DBU to prepare a compound shown in the formula 2; then further carrying out salt forming reaction with citric acid to prepare tofacitinib citrate,
wherein R is C1-C6 alkyl.
In some embodiments, R is selected from methyl, ethyl, or isopropyl; in some typical embodiments, R is selected from methyl.
In some embodiments, the molar ratio of the compound of formula 3 to cyanoacetate is 1: 1-4; in some typical embodiments, the molar ratio of the compound of formula 3 to cyanoacetate is 1:1 to 2.
In some embodiments, the molar ratio of the compound of formula 3 to DBU is 1: 0.3 to 4; in some typical embodiments, the molar ratio of the compound of formula 3 to DBU is 1: 0.5 to 2; in some more typical embodiments, the molar ratio of the compound of formula 3 to DBU is 1: 1.
in some embodiments, the mass to volume ratio of the compound of formula 3 to tetrahydrofuran is 1: 3-10 Kg/L; in some typical embodiments, the mass to volume ratio of the compound of formula 3 to tetrahydrofuran is 1: 5-10 Kg/L; in some more typical embodiments, the mass to volume ratio of the compound of formula 3 to tetrahydrofuran is 1: 5 Kg/L.
In some embodiments, the molar ratio of the compound of formula 3 to citric acid is 1: 1-4; in some typical embodiments, the molar ratio of the compound of formula 3 to citric acid is 1: 1-2; in some more typical embodiments, the molar ratio of the compound of formula 3 to citric acid is 1: 1.5 to 1.8.
In some embodiments, the temperature of the salt formation reaction is from 20 ℃ to 80 ℃; in some exemplary embodiments, the temperature of the salt formation reaction is 20 ℃ to 30 ℃.
In some embodiments, the solvent for the above salt-forming reaction is selected from one or both of ethanol or water; in some exemplary embodiments, the solvent for the salt forming reaction is a mixed solvent of ethanol and water.
In some embodiments, the volume ratio of ethanol to water is 1-4: 1; in some typical embodiments, the volume ratio of ethanol to water is 1-2.5: 1; in some more typical embodiments, the volume ratio of ethanol to water is 1-1.5: 1.
In some embodiments, the time of the salt forming reaction is 1-4 hours; in some typical embodiments, the above salt formation reaction time is 2 hours.
In some exemplary embodiments, there is provided a process for preparing tofacitinib citrate, comprising: reacting the compound of the formula 3 with cyanoacetate in tetrahydrofuran under the catalysis of DBU, performing suction filtration after the reaction is completed to obtain a compound of the formula 2, performing salt forming reaction on the compound of the formula 2 and citric acid, performing suction filtration, drying to obtain tofacitinib citrate,
wherein R is as defined above.
On the other hand, the invention provides a preparation method of tofacitinib citrate, which comprises the following steps:
(1) reacting the compound of the formula 4 in water under the conditions of Pd/C catalyst, acetic acid and sodium formate to prepare a compound of a formula 3;
(2) the compound of the formula 3 and cyanoacetate react in tetrahydrofuran under the catalysis of DBU to prepare a compound of the formula 2, the compound of the formula 2 and citric acid react to form salt to prepare tofacitinib citrate,
wherein R is as defined above.
The invention provides a novel preparation method of a compound shown in a formula 3 and a compound shown in a formula 1, namely tofacitinib citrate, and the provided preparation method has the characteristics of mild reaction conditions, simple and convenient post-treatment, high yield and high product purity and is suitable for industrial production.
Defining:
the term "C1-C6 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl, examples including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.
The term "sodium formate" includes sodium formate and/or hydrates thereof, such as sodium formate dihydrate.
The term "citric acid" includes citric acid and/or hydrates thereof, such as citric acid monohydrate.
The term "Pd/C" includes Pd/C having a Pd content of 1% to 10%, such as 5% Pd/C or 10% Pd/C.
DBU refers to 1, 8-diazabicycloundecen-7-ene.
h means hours.
Detailed Description
The following specific examples are included to provide a clear understanding of the invention and are set forth to enable those skilled in the art to make and practice the invention. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention. The reagents used in the present invention are all commercially available products. The compound of formula 4 of the present invention can be obtained commercially or prepared according to the method disclosed in CN 200680027901.3.
The HPLC detection conditions were as follows:
a chromatographic column: waters Acquity BEH UPLC 18,2.1 × 100mm size: 1.7 μm
Mobile phase: gradient elution was carried out using 10mmol/L potassium dihydrogen phosphate (pH adjusted to 6.8 with potassium hydroxide) -acetonitrile (92:8) as mobile phase A and acetonitrile as mobile phase B, as shown in the following table.
Wavelength: 210nm
Column temperature: 65 deg.C
Flow rate: 0.360ml per minute
Sample introduction amount: 10ul of
Preparing a test solution: precisely weighing 2mg of the product, placing the product in a 20ml measuring flask, adding a mixed solution of 0.05 percent trifluoroacetic acid aqueous solution and acetonitrile (95:5) as a solvent, dissolving and diluting to a scale
EXAMPLE 1 preparation of the Compound of formula 3
Adding 5.7kg of the compound of formula 4 (with HPLC purity of 98.5%) into a 100L reaction kettle, adding 30L of purified water, adding 6.2kg of acetic acid and 5.3kg of sodium formate dihydrate under stirring at room temperature, adding 1.2kg of 10% Pd/C, reacting for 2h at 25 ℃, monitoring by TLC after the reaction is finished, adjusting the pH of the solution to be neutral, adding dichloromethane for extraction, combining dichloromethane layers, concentrating to obtain an oily substance, adding n-hexane to precipitate a white solid, performing suction filtration and drying to obtain 4.0kg of an intermediate, wherein the yield is 96%, the HPLC purity is 99.7%, and the single impurity content is less than 0.1%.1H-NMR(400MHz，DMSO-d6)δ:11.59(s，1H)，8.08(s，1H)，7.12(d，J＝ 3.3Hz，1H)，6.53(d，J＝3.3Hz，1H)，4.79(s，1H)，3.32(s，3H)，3.12(dd，J＝11.9， 9.1Hz，1H)，2.90～2.72(m，2H)，2.67～2.59(m，1H)，2.37～2.10(m，2H)，1.80～1.68(m， 1H)，1.54～1.41(m，1H)，0.98(d，J＝7.2Hz，3H).
EXAMPLE 2 preparation of the Compound of formula 3
Adding 600g of the compound of the formula 4 (with HPLC purity of 98.2%) into a 30L reaction kettle, adding 1.2L of purified water, adding 800g of acetic acid and 500g of sodium formate dihydrate while stirring at room temperature, adding 60g of 10% Pd/C, reacting at 25 ℃ for 1h, monitoring the reaction by TLC, adjusting the pH of the solution to be neutral, adding dichloromethane for extraction, combining dichloromethane layers, concentrating to obtain an oily substance, adding n-hexane to precipitate a white solid, performing suction filtration and drying to obtain 395g of an intermediate, wherein the yield is 90%, the HPLC purity is 99.5%, and the single impurity content is less than 0.1%.
EXAMPLE 3 preparation of the Compound of formula 3
Adding 600g of the compound of the formula 4 (with HPLC purity of 98.2%) into a 30L reaction kettle, adding 12L of purified water, adding 800g of acetic acid and 500g of sodium formate dihydrate while stirring at room temperature, adding 60g of 10% Pd/C, reacting at 25 ℃ for 1h, monitoring by TLC after the reaction is finished, adjusting the pH of the solution to be neutral, adding dichloromethane for extraction, combining dichloromethane layers, concentrating to obtain an oily substance, adding n-hexane to precipitate a white solid, performing suction filtration and drying to obtain an intermediate 403g, wherein the yield is 92%, the HPLC purity is 99.5%, and the single impurity content is less than 0.1%.
EXAMPLE 4 preparation of the Compound of formula 3
Adding 45g of the compound of the formula 4 (with HPLC purity of 96.4%) into a 1L reaction bottle, adding 500mL of purified water, adding 40g of acetic acid and 70g of sodium formate dihydrate under stirring at room temperature, adding 3g of 10% Pd/C, reacting at 25 ℃ for 1h, monitoring by TLC after the reaction is finished, adjusting the pH of the solution to be neutral, adding dichloromethane for extraction, combining dichloromethane layers, concentrating to obtain an oily substance, adding n-hexane to precipitate a white solid, performing suction filtration and drying to obtain an intermediate 30g, wherein the yield is 91%, and the HPLC purity is 99.2%.
Example 5 preparation of tofacitinib citrate
Adding 3.5kg of the compound of the formula 3 into a 30L reaction kettle, adding 18L of tetrahydrofuran, 2.8kg of methyl cyanoacetate and 2.2kg of DBU, reacting for 7h at room temperature, monitoring the reaction by TLC, performing suction filtration, adding the solid into the 30L reaction kettle, adding 10L of absolute ethanol, 10L of purified water and 4.6kg of citric acid monohydrate, stirring for 2h at 20-30 ℃, performing suction filtration, and drying to obtain 6.6kg of a white solid, wherein the yield is 92%, the HPLC purity is 99.8%, and the single impurity content is less than 0.1%. HNMR (400MHz, DMSO) δ 12.36(s,2H), 11.67 (s,1H), 8.11(d, J ═ 5.9Hz,1H), 7.15(s,1H), 6.57(s,1H), 4.85(s,1H), 4.16-4.02(m,2H), 3.83-3.62(m,1H), 3.40(s,1H), 3.32(s,2H), 3.26(s,3H), 2.70(dd, J ═ 41.1,15.4Hz,2H), 2.38(s,1H), 1.87-1.68(m,1H), 1.61-1.55(m,1H), 1.01(d, J ═ 7.1Hz,3H).
Example 6: preparation of tofacitinib citrate
Adding 75g of the compound shown in the formula 3 into a 3L reaction kettle, adding 375mL of tetrahydrofuran, 32g of methyl cyanoacetate and 47g of DBU, reacting for 5h at room temperature, monitoring the reaction by TLC to be basically finished, performing suction filtration, adding the solid into a 5L reaction kettle, adding 1.5L of absolute ethyl alcohol, 1L of purified water and 120g of citric acid monohydrate, stirring for 2h at 20-30 ℃, performing suction filtration, and drying to obtain 143g of a white solid, wherein the yield is 93%, the HPLC purity is 99.7%, and the single impurity content is less than 0.1%.
Example 7: preparation of tofacitinib citrate
Adding 30g of the intermediate 3 into a 1L reaction kettle, adding 300mL of tetrahydrofuran, 25g of methyl cyanoacetate and DBU19g, reacting for 5h at room temperature, monitoring the reaction by TLC to be basically finished, performing suction filtration, adding the solid into a 2L reaction kettle, adding 500mL of absolute ethanol, 200mL of purified water and 25g of citric acid monohydrate, stirring for 2h at room temperature, performing suction filtration, and drying to obtain 55g of white solid, wherein the yield is 89%, the HPLC purity is 99.5%, and the single impurity content is less than 0.1%.
Claims (6)
1. A preparation method of an oral JAK pathway inhibitor is characterized by comprising the following steps:
(1) reacting a compound of formula 4 in Pd/C with a hydrogen donor in water;
(2) adjusting the pH of the reaction liquid obtained in the step (1) to be neutral, adding an organic solvent for extraction, and carrying out aftertreatment to obtain a compound shown in a formula 3;
(3) the compound of formula 3 is reacted with cyanoacetate in a protic solvent under the catalysis of DBU to prepare the compound of formula 2, and then salified.
2. The method according to claim 1, wherein the hydrogen donor in step (1) is acetic acid or sodium formate.
3. The method according to claim 1, wherein the mass-to-volume ratio of the compound of formula 4 to water in step (1) is 1: 2 to 20 Kg/L.
4. The method according to claim 1, wherein the organic solvent added in the extraction step of step (2) is selected from one of ethyl acetate, n-butanol and dichloromethane.
5. The method according to claim 1, wherein the cyanoacetic acid ester in the step (3) is selected from the group consisting of methyl cyanoacetate, ethyl cyanoacetate and isopropyl cyanoacetate.
6. The method according to claim 1, wherein the aprotic solvent used in step (3) is selected from tetrahydrofuran and dichloromethane.
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