CN114835714A - Preparation method of tofacitinib - Google Patents
Preparation method of tofacitinib Download PDFInfo
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- CN114835714A CN114835714A CN202210372067.2A CN202210372067A CN114835714A CN 114835714 A CN114835714 A CN 114835714A CN 202210372067 A CN202210372067 A CN 202210372067A CN 114835714 A CN114835714 A CN 114835714A
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- tofacitinib
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- 239000004012 Tofacitinib Substances 0.000 title claims abstract description 27
- 229960001350 tofacitinib Drugs 0.000 title claims abstract description 27
- 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 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 238000006482 condensation reaction Methods 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- UOBCYTOUXLAABU-UHFFFAOYSA-N 2-chloro-4-methylpyridin-3-amine Chemical compound CC1=CC=NC(Cl)=C1N UOBCYTOUXLAABU-UHFFFAOYSA-N 0.000 claims abstract description 5
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229940073608 benzyl chloride Drugs 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 4
- 238000006640 acetylation reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 8
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012346 acetyl chloride Substances 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 4
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims description 4
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 claims description 4
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000005576 amination reaction Methods 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 230000002829 reductive effect Effects 0.000 abstract description 15
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000000047 product Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- 238000006268 reductive amination reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000010924 continuous production Methods 0.000 abstract description 2
- 238000006264 debenzylation reaction Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- NVKDDQBZODSEIN-UHFFFAOYSA-N 1-benzyl-n,4-dimethylpiperidin-3-amine Chemical compound C1CC(C)C(NC)CN1CC1=CC=CC=C1 NVKDDQBZODSEIN-UHFFFAOYSA-N 0.000 abstract 1
- BTOJSYRZQZOMOK-UHFFFAOYSA-N 4-chloro-7-(4-methylphenyl)sulfonylpyrrolo[2,3-d]pyrimidine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=NC(Cl)=C2C=C1 BTOJSYRZQZOMOK-UHFFFAOYSA-N 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000004811 liquid chromatography Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 9
- 230000006872 improvement Effects 0.000 description 7
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000000622 liquid--liquid extraction Methods 0.000 description 6
- 238000000638 solvent extraction Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- -1 lithium aluminum hydride Chemical compound 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- HKJYVRJHDIPMQB-UHFFFAOYSA-N propan-1-olate;titanium(4+) Chemical compound CCCO[Ti](OCCC)(OCCC)OCCC HKJYVRJHDIPMQB-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- IBKMZYWDWWIWEL-UHFFFAOYSA-N 4-methylpyridin-3-amine Chemical compound CC1=CC=NC=C1N IBKMZYWDWWIWEL-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 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
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940122245 Janus kinase inhibitor Drugs 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
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000010898 silica gel chromatography 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
-
- 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
Abstract
The invention relates to the technical field of drug synthesis, in particular to a preparation method of tofacitinib, which comprises the steps of taking 2-chloro-3-amino-4-methylpyridine as a raw material, carrying out catalytic hydrogenation and acetylation reaction, then generating quaternary ammonium salt with benzyl chloride, carrying out reduction, hydrolysis and reductive amination to generate an intermediate N-benzyl-3-methylamino-4-methylpiperidine, splitting, condensing with 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidine, and carrying out deprotection and debenzylation to obtain tofacitinib. The raw materials and reagents used in the preparation method have low cost; the reaction conditions in the process route are mild, so that the energy consumption is low, the byproducts generated in each step of reaction are few, the purity of the intermediate and the final product is good, and the yield is high, so that the preparation method is suitable for industrial production. Products of the hydrolysis reaction, the reductive amination reaction and the condensation reaction can directly enter the next reaction without purification, so that the process steps are reduced and the production efficiency is improved in industrial continuous production.
Description
[ technical field ] A method for producing a semiconductor device
The invention relates to the technical field of drug synthesis, in particular to a preparation method of tofacitinib.
[ background of the invention ]
Tofacitinib (tofacitinib), which is named as [ (3R, 4R) -1-cyanoacetyl-4-methylpiperidin-3-yl ] -N-methyl-7H-pyrrolo [2,3D ] pyrimidin-4-amine, is a JAK inhibitor developed by Perey company, can effectively inhibit the activity of JAK1 and JAK3, and blocks signal transduction of various inflammatory cytokines. Research shows that tofacitinib has good treatment effect on various inflammation-related diseases such as rheumatoid arthritis, ulcerative colitis, psoriasis and the like.
The preparation method of tofacitinib in the prior art comprises the following synthetic routes:
the preparation route disclosed in patent WO2007012953 is as follows:
the method comprises the steps of taking 3-amino-4-methylpyridine as a raw material, obtaining an intermediate cis-1-benzyl-3-methylamino-4-methylpiperidine through amino protection, rhodium catalytic reduction of the pyridine and lithium aluminum hydride reduction, and obtaining tofacitinib through resolution, coupling, debenzylation protection and amidation. In the route, metal rhodium is used as a catalyst in the reduction reaction, so that the raw material cost is high, lithium aluminum hydride is used in the reduction reaction, the post-treatment is complex, rainwater can quickly release heat, and the route has certain danger and is not suitable for industrial large-scale production.
The preparation route disclosed in patent CN106146507 is as follows:
The method takes (4-methylpyridine-3-yl) methyl carbamate as a raw material, and prepares tofacitinib by catalytic hydrogenation, benzyl protection, reduction, salification, resolution, deprotection and amidation salification. Although the preparation method has the advantages of easily available raw materials and low raw material cost, the preparation method still uses the lithium aluminum hydride with certain danger, and is not suitable for industrial scale-up production.
[ summary of the invention ]
The invention aims to provide a preparation method of tofacitinib, which has the characteristics of readily available raw materials, mild reaction conditions and high yield and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of tofacitinib is characterized by comprising the following steps: comprises the following steps of (a) carrying out,
s1: adding raw materials of 2-chloro-3-amino-4-methylpyridine, an alcohol solvent and palladium carbon into a high-pressure reaction kettle, introducing hydrogen, and reacting for 8-12 hours under the pressure of 0.2-0.6 MPa to obtain a compound I;
s2: performing acetylation reaction on the compound I and acetyl chloride to obtain a compound II;
s3: reacting the compound II with benzyl chloride to obtain a compound III, adding sodium borohydride, and reacting at the temperature lower than 0 ℃ to obtain a compound IV;
S4: carrying out hydrolysis reaction on the compound IV under an acidic condition to obtain a compound V;
s5: carrying out amination reduction reaction on the compound V and methylamine methanol to obtain an intermediate VI;
s6: splitting the intermediate VI by using a chiral splitting reagent to obtain an intermediate VII;
s7: carrying out condensation reaction on 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and p-toluenesulfonyl chloride under the action of a condensing agent I and a solvent to obtain a compound VIII;
s8: carrying out condensation reaction on the intermediate VII and the compound VIII under the action of a condensing agent II and a solvent to obtain a compound IX;
s9: carrying out deprotection reaction on a compound IX under an alkaline condition to obtain a compound X;
s10: mixing a compound X, an alcohol solvent and palladium hydroxide carbon, introducing hydrogen, and carrying out hydrogenation reaction to obtain a compound XI;
s11: and carrying out condensation reaction on the compound IX and ethyl cyanoacetate to obtain the tofacitinib.
As a further improvement of the invention, the alcohol solvent is one or more than two of methanol, ethanol and isopropanol.
In a further improvement of the present invention, in the step S4, the alkaline condition is to adjust the pH of the reaction solution to 11-13 with an alkaline solution, and the alkaline solution is a hydroxide solution or a potassium hydroxide solution.
In a further improvement of the present invention, the chiral resolving agent in step S6 is one or more of L-di-p-methylbenzoyltartaric acid, L-dibenzoyltartaric acid, and tartaric acid.
In a further improvement of the present invention, the condensing agent i in step S7 is a sodium hydroxide solution, and the solvent is acetone.
In a further improvement of the present invention, the condensing agent ii in step S8 is potassium carbonate, and the solvent is water and tetrahydrofuran.
As a further improvement of the invention, the alkali in the step S9 is sodium hydroxide or potassium hydroxide, and the mass ratio of the alkali to the compound IX is 1: 3.5-5.
In a further improvement of the invention, the mass ratio of the palladium hydroxide carbon to the compound X in the step S10 is 1: 20-30.
Compared with the prior art, the invention has the beneficial effects that: the raw materials and reagents used in the preparation method have low cost; the reaction conditions in the process route are mild, so that the energy consumption is low, the byproducts generated in each step of reaction are few, the purity of the intermediate and the final product is good, and the yield is high, so that the preparation method is suitable for industrial production. The products of the hydrolysis reaction, the reductive amination reaction and the condensation reaction can directly enter the next reaction without purification, so that the process steps are reduced and the production efficiency is improved in the industrial continuous production.
[ detailed description ] A
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A preparation method of tofacitinib specifically comprises the following steps:
s1: adding 600L of methanol, 100Kg of raw material 2-chloro-3-amino-4-methylpyridine and 2Kg of 5% wet palladium carbon in a high-pressure reaction kettle in sequence, stirring uniformly, introducing hydrogen, and reacting for 10-12 hours under 0.3-0.4 MPa. After the reaction was completed, the palladium-carbon was removed by filtration by liquid chromatography, and the reaction solution was concentrated under reduced pressure to obtain 76Kg of compound i as a white solid.
S2: adding 800L of dichloromethane serving as a solvent into a reaction kettle, adding 76Kg of a compound I while stirring, cooling the temperature of the reaction kettle to 0 ℃, slowly dropwise adding 76Kg of acetyl chloride, and reacting for 12 hours after dropwise adding. After the reaction is completely detected by liquid chromatography, 30 percent sodium hydroxide solution is added, the pH value is adjusted to 12, an organic phase is separated, and the organic phase is decompressed and concentrated to obtain 100Kg of light yellow solid compound II.
S3: adding 100Kg of compound II, 500L of acetonitrile and 90Kg of benzyl chloride, heating to 70-80 ℃, and reacting for 11-12 hours. And (3) after the reaction is completely detected by liquid chromatography, carrying out reduced pressure concentration, and removing 80-90% of acetonitrile to obtain a compound III. Adding 700L of methanol, reducing the temperature of the reaction kettle to 0 ℃, adding 72Kg of sodium borohydride in batches, and reacting at the temperature lower than 0 ℃. After the reaction is completely detected by liquid chromatography, reduced pressure concentration is carried out, 80-90% of methanol is removed, and 500L of water is added to obtain 155Kg of precipitated white solid compound IV.
S4: adding 350L of hydrochloric acid, adding 155Kg of compound IV in batches, and carrying out hydrolysis reaction at the reaction temperature of 70-80 ℃. After the reaction is completed, the reaction temperature is reduced to below 10 ℃, 30% sodium hydroxide solution is added, the pH value is adjusted to 12, toluene is added for liquid-liquid extraction, and anhydrous magnesium sulfate is added for drying, so that the compound V in the organic phase is obtained.
S5: adding 620L of toluene, mixing with the compound V, adding 250Kg of tetrapropyl titanate at the reaction temperature of 0 ℃, and dropwise adding 250L of 33 percent methylamine methanol solution for reaction. After the reaction is completed, 66Kg of solid sodium borohydride is added at the reaction temperature of 0 ℃ for reaction. After the reaction is completed, 100L of water is added, liquid-liquid extraction is carried out by using 200L of dichloromethane for 3 times, organic phases are combined, and the solvent is concentrated to be dry, so that 100Kg of intermediate VI is obtained.
S6: 100Kg of intermediate VI, 500Kg of methanol, 500Kg of water and 100Kg of L-di-p-methylbenzoyl tartaric acid were added to a reaction vessel and stirred at room temperature to be completely dissolved. And continuously stirring for 15-20 minutes until solid is separated out, heating to 60-70 ℃, and reacting for 4-5 hours. After the reaction is completed, cooling to 20 ℃, and performing suction filtration and drying to obtain a crude product. Mixing methanol, isopropanol and water in a ratio of 1:3:4, recrystallizing the solid with a mixed solvent, recrystallizing the solid for 4 times to obtain a crude product, extracting the crude product with dichloromethane, and performing rotary evaporation to obtain 40Kg of oily liquid intermediate VII.
S7: 50Kg of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and 70Kg of p-toluenesulfonyl chloride are dissolved in 350L of acetone solvent, and 150L of 5% sodium hydroxide solution is slowly added dropwise. Stirring at room temperature, and reacting for 10-14 hours. 200L of water is added into the reaction liquid, a large amount of solid is separated out, and 98.5Kg of green solid compound VIII is obtained after suction filtration and drying.
S8: adding 375L of water and 125L of tetrahydrofuran into a reaction kettle, stirring for 20-30 minutes at room temperature, adding 56Kg of intermediate VII, 50Kg of compound VIII and 200Kg of potassium carbonate, and reacting for 10-14 hours at the reaction temperature of 70-80 ℃. And (3) detecting the reaction by liquid chromatography, concentrating under reduced pressure to remove 70-80% of tetrahydrofuran, extracting the concentrated solution by using ethyl acetate, and concentrating the solvent to dryness to obtain 70Kg of light yellow solid compound IX.
S9: dissolving 20Kg of compound IX in methanol, adding 5Kg of sodium hydroxide in batches, reacting at 40-50 ℃ for 3-4 hours, and removing the methanol by vacuum concentration. Adding 100L of water and 100L of ethyl acetate, carrying out liquid-liquid extraction, concentrating the organic phase of the extract liquid to 35-40L, and standing overnight to obtain 12Kg of a compound X.
S10: adding 10Kg of compound X, 70L of ethanol and 2Kg of 20% sodium hydroxide palladium carbon into a reaction kettle, and introducing hydrogen at the reaction temperature of 50-60 ℃ to perform catalytic hydrogenation reaction. After completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated to dryness by rotation and recrystallized from ethyl acetate to obtain 6.24Kg of the compound XI.
S11: 6Kg of the compound XI, 1.9Kg of 1, 8-diazabicycloundecen-7-ene (DBU) as a catalyst, 5.6Kg of ethyl cyanoacetate and 20L of ethanol were added to a reaction vessel and reacted at room temperature for 7 to 8 hours. After the reaction is completed, dichloromethane is added, and after washing with water, the mixture is concentrated to dryness under reduced pressure, so that 6.7Kg of target product tofacitinib is obtained.
Example 2
A preparation method of tofacitinib specifically comprises the following steps:
s1: adding 600L of ethanol, 100Kg of raw material 2-chloro-3-amino-4-methylpyridine and 2Kg of 5% wet palladium carbon into a high-pressure reaction kettle in sequence, stirring uniformly, introducing hydrogen, and reacting for 9-11 hours under 0.4-0.5 MPa. After the reaction was completed as detected by liquid chromatography, the palladium-carbon was removed by filtration, and the reaction solution was concentrated under reduced pressure to obtain 73Kg of compound i as a white solid.
S2: adding 800L of dichloromethane serving as a solvent into a reaction kettle, adding 76Kg of a compound I while stirring, cooling the temperature of the reaction kettle to 0 ℃, slowly dropwise adding 76Kg of acetyl chloride, and reacting for 12-14 hours after dropwise adding is finished. After the reaction was completed, the reaction was checked by liquid chromatography, and 35% sodium hydroxide solution was added to adjust the pH to 13, and the organic phase was separated and concentrated under reduced pressure to obtain 95Kg of compound II as a pale yellow solid.
S3: adding 95Kg of compound II, 500L of acetonitrile and 90Kg of benzyl chloride, heating to 80-90 ℃, and reacting for 11-12 hours. And (3) after the reaction is completely detected by liquid chromatography, carrying out reduced pressure concentration, and removing 80-90% of acetonitrile to obtain a compound III. Adding 700L of methanol, reducing the temperature of the reaction kettle to 0 ℃, adding 70Kg of sodium borohydride by 3 times, and reacting at the temperature lower than 0 ℃. After the reaction is completely detected by liquid chromatography, reduced pressure concentration is carried out, 80-90% of methanol is removed, and 500L of water is added to obtain 140Kg of precipitated white solid compound IV.
S4: adding 340L of hydrochloric acid, adding 140Kg of compound IV in batches, and carrying out hydrolysis reaction at the reaction temperature of 70-80 ℃. After the reaction is completed, the reaction temperature is reduced to below 10 ℃, 35% sodium hydroxide solution is added, the pH value is adjusted to 13, toluene is added for liquid-liquid extraction, and anhydrous magnesium sulfate is added for drying, so that the compound V in the organic phase is obtained.
S5: adding 600L of toluene, mixing with the compound V, adding 250Kg of tetrapropyl titanate at the reaction temperature of 0 ℃, and dropwise adding 250L of 33% methylamine methanol solution for reaction. After the reaction is completely detected by liquid chromatography, 66Kg of solid sodium borohydride is added at the reaction temperature of 0 ℃ for reaction. After the reaction is completed, 100L of water is added, liquid-liquid extraction is carried out by using 200L of dichloromethane for 3 times, organic phases are combined, and the solvent is concentrated to be dry, so that 86Kg of intermediate VI is obtained.
S6: 86Kg of intermediate VI, 500Kg of methanol, 500Kg of water and 90Kg of L-dibenzoyltartaric acid are added into a reaction kettle and stirred at normal temperature to be completely dissolved. And continuously stirring for 15-20 minutes until solid is separated out, heating to 60-70 ℃, and reacting for 4-5 hours. After the reaction is completed, cooling to 20 ℃, and performing suction filtration and drying to obtain a crude product. Mixing methanol, isopropanol and water in a ratio of 1:3.2:4.5, recrystallizing the solid with a mixed solvent, recrystallizing the solid for 4 times to obtain a crude product, extracting the crude product with dichloromethane, and performing rotary evaporation to obtain 40Kg of oily liquid intermediate VII.
S7: 50Kg of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and 70Kg of p-toluenesulfonyl chloride are dissolved in 350L of acetone solvent, and 150L of 5% sodium hydroxide solution is slowly added dropwise. Stirring at room temperature, and reacting for 10-14 hours. 200L of water is added into the reaction liquid, a large amount of solid is separated out, and 98.5Kg of green solid compound VIII is obtained after suction filtration and drying.
S8: adding 375L of water and 125L of tetrahydrofuran into a reaction kettle, stirring for 20-30 minutes at room temperature, adding 40Kg of intermediate VII, 40Kg of compound VIII and 200Kg of potassium carbonate, and reacting for 10-14 hours at the reaction temperature of 70-80 ℃. And (3) detecting the reaction by liquid chromatography, concentrating under reduced pressure to remove 70-80% of tetrahydrofuran, extracting the concentrated solution by using ethyl acetate, and concentrating the solvent to dryness to obtain 56Kg of light yellow solid compound IX.
S9: dissolving 20Kg of compound IX in methanol, adding 5.7Kg of sodium hydroxide in batches, reacting at 40-50 ℃ for 3-3.5 hours, and removing the methanol by vacuum concentration. Adding 100L of water and 100L of ethyl acetate, carrying out liquid-liquid extraction, concentrating the organic phase of the extract liquor to 35-40L, and standing overnight to obtain 12.6Kg of compound X.
S10: adding 10Kg of compound X, 70L of ethanol and 2.5Kg of 20% sodium hydroxide palladium carbon into a reaction kettle, and introducing hydrogen at the reaction temperature of 50-60 ℃ to perform catalytic hydrogenation reaction. After completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated to dryness by rotation and recrystallized from ethyl acetate to obtain 6.6Kg of the compound XI.
S11: 6Kg of the compound XI, 2.1Kg of 1, 8-diazabicycloundecen-7-ene (DBU) as a catalyst, 4.6Kg of ethyl cyanoacetate and 20L of ethanol were added to a reaction vessel and reacted at room temperature for 7 to 8 hours. After the reaction is completed, dichloromethane is added, after washing with water, the mixture is concentrated under reduced pressure and is subjected to silica gel chromatography to obtain 6.1Kg of target product tofacitinib.
Claims (8)
1. A preparation method of tofacitinib is characterized by comprising the following steps: comprises the following steps of (a) preparing a solution,
s1: adding raw materials of 2-chloro-3-amino-4-methylpyridine, an alcohol solvent and palladium carbon into a high-pressure reaction kettle, introducing hydrogen, and reacting for 8-12 hours under the pressure of 0.2-0.6 MPa to obtain a compound I;
s2: performing acetylation reaction on the compound I and acetyl chloride to obtain a compound II;
s3: reacting the compound II with benzyl chloride to obtain a compound III, adding sodium borohydride, and reacting at the temperature lower than 0 ℃ to obtain a compound IV;
s4: carrying out hydrolysis reaction on the compound IV under an acidic condition to obtain a compound V;
s5: carrying out amination reduction reaction on the compound V and methylamine methanol to obtain an intermediate VI;
s6: splitting the intermediate VI by using a chiral splitting reagent to obtain an intermediate VII;
s7: carrying out condensation reaction on 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and p-toluenesulfonyl chloride under the action of a condensing agent I and a solvent to obtain a compound VIII;
s8: carrying out condensation reaction on the intermediate VII and the compound VIII under the action of a condensing agent II and a solvent to obtain a compound IX;
s9: carrying out deprotection reaction on a compound IX under an alkaline condition to obtain a compound X;
S10: mixing a compound X, an alcohol solvent and palladium hydroxide carbon, introducing hydrogen, and carrying out hydrogenation reaction to obtain a compound XI;
s11: and carrying out condensation reaction on the compound IX and ethyl cyanoacetate to obtain the tofacitinib.
2. The method for preparing tofacitinib according to claim 1, wherein: the alcohol solvent is one or more than two of methanol, ethanol and isopropanol.
3. The method for preparing tofacitinib according to claim 1, wherein: in the step S4, the alkaline condition is to adjust the pH value of the reaction solution to 11-13 by using an alkaline solution, and the alkaline solution is a hydroxide solution or a potassium hydroxide solution. .
4. The method for preparing tofacitinib according to claim 1, wherein: the chiral resolution reagent in the step S6 is one or more than two of L-di-p-methylbenzoyl tartaric acid, L-dibenzoyl tartaric acid and tartaric acid.
5. The method for preparing tofacitinib according to claim 1, wherein: the condensing agent I in the step S7 is sodium hydroxide solution, and the solvent is acetone.
6. The method for preparing tofacitinib according to claim 1, wherein: the condensing agent II in the step S8 is potassium carbonate, and the solvent is water and tetrahydrofuran.
7. The method for preparing tofacitinib according to claim 1, wherein: the alkali in the step S9 is sodium hydroxide or potassium hydroxide, and the mass ratio of the alkali to the compound IX is 1: 3.5-5.
8. The method for preparing tofacitinib according to claim 1, wherein: in the step S10, the mass ratio of the palladium hydroxide carbon to the compound X is 1: 20-30.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5686618A (en) * | 1993-12-02 | 1997-11-11 | Boehringer Ingelheim Kg | Method for preparing 3-amino-2-chloro-4-alkylpyridine or-4-arylpyridine |
| CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
| CN108484607A (en) * | 2018-03-26 | 2018-09-04 | 山东科兴生物制品有限公司 | Novel preparation method of tofacitinib citrate |
| CN110668995A (en) * | 2018-07-03 | 2020-01-10 | 江苏海悦康医药科技有限公司 | Tofacitinib citrate intermediate and preparation method of tofacitinib citrate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5686618A (en) * | 1993-12-02 | 1997-11-11 | Boehringer Ingelheim Kg | Method for preparing 3-amino-2-chloro-4-alkylpyridine or-4-arylpyridine |
| CN101233138A (en) * | 2005-07-29 | 2008-07-30 | 辉瑞产品公司 | Pyrrolo[2,3-d]pyrimidine derivatives, their intermediates and synthesis |
| CN108484607A (en) * | 2018-03-26 | 2018-09-04 | 山东科兴生物制品有限公司 | Novel preparation method of tofacitinib citrate |
| CN110668995A (en) * | 2018-07-03 | 2020-01-10 | 江苏海悦康医药科技有限公司 | Tofacitinib citrate intermediate and preparation method of tofacitinib citrate |
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