CN115368389A - Preparation method of Filgotinib intermediate - Google Patents
Preparation method of Filgotinib intermediate Download PDFInfo
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- CN115368389A CN115368389A CN202110543322.0A CN202110543322A CN115368389A CN 115368389 A CN115368389 A CN 115368389A CN 202110543322 A CN202110543322 A CN 202110543322A CN 115368389 A CN115368389 A CN 115368389A
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- methylphenylboronic acid
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- RIJLVEAXPNLDTC-UHFFFAOYSA-N n-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide Chemical compound C1CC1C(=O)NC(=NN12)N=C1C=CC=C2C(C=C1)=CC=C1CN1CCS(=O)(=O)CC1 RIJLVEAXPNLDTC-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 229950006663 filgotinib Drugs 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 89
- 239000002904 solvent Substances 0.000 claims abstract description 89
- BIWQNIMLAISTBV-UHFFFAOYSA-N (4-methylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C=C1 BIWQNIMLAISTBV-UHFFFAOYSA-N 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims abstract description 32
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 230000002140 halogenating effect Effects 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 77
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- 239000007787 solid Substances 0.000 claims description 26
- 238000001816 cooling Methods 0.000 claims description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- 238000005406 washing Methods 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 15
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 12
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 10
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 10
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 9
- 150000001340 alkali metals Chemical class 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 150000008282 halocarbons Chemical class 0.000 claims description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052792 caesium Inorganic materials 0.000 claims description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000002894 organic compounds Chemical class 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 30
- 239000000243 solution Substances 0.000 description 26
- 239000000047 product Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 11
- 238000010828 elution Methods 0.000 description 9
- CBUOGMOTDGNEAW-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(CBr)C=C1 CBUOGMOTDGNEAW-UHFFFAOYSA-N 0.000 description 8
- 239000012295 chemical reaction liquid Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
- 102000042838 JAK family Human genes 0.000 description 1
- 108091082332 JAK family Proteins 0.000 description 1
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a Filgotinib intermediate. The preparation method comprises the following steps: (a) In a solvent A, 4-methyl phenylboronic acid, pinacol and a halogenating reagent are subjected to the following reaction and pretreated to obtain a compound N-1; (b) In a solvent B, in the presence of alkali, reacting the compound N-1 with thiomorpholine-1,1-dioxide to obtain a compound N. The preparation method provided by the invention is simple and convenient to operate, cheap and easily available in raw materials, mild in reaction conditions, high in product purity and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of a Filgotinib intermediate.
Background
Filgotinib is a JAK1 inhibitor and has the chemical name of N- [5- [4- [ (1,1-dioxo-4-thiomorpholinyl) methyl ] phenyl ] [1,2,4] triazolo [1,5-A ] pyridin-2-yl ] cyclopropanecarboxamide, and the chemical structural formula is as follows:
filgotinib is a novel once daily oral JAK kinase inhibitor that preferentially inhibits JAK1. Approved by the committee of the European Union and the labor province of Japan,
(filigotinib maleate 200mg and 100mg in tablets) was marketed in the European Union and Japan in 11 months of 2020 for the treatment of Rheumatoid Arthritis (RA). In addition, a new indication application for the oral JAK1 inhibitor Jyseleca (filigotib, 200 mg) has been accepted and has been under scrutiny by the European Medicines Authority (EMA), which is intended for the treatment of: adult patients with moderate to severe Ulcerative Colitis (UC) who are inadequately responsive, unresponsive, or intolerant to conventional or biological therapies.
The compound N is a key intermediate in the synthesis of Filgotinib, and the methods for preparing the compound N disclosed in WO2010010190 and WO2010149769 by the original manufacturers are as follows: 4-bromomethylbenzeneboronic acid pinacol ester is used as a raw material to react with thiomorpholine-1,1-dioxide.
Among them, 4-bromomethylbenzeneboronic acid pinacol ester (N-1) is expensive, and its general synthetic method is as follows: the synthetic method needs to separate to obtain N-1', N-1 is obtained by NBS bromination, and due to the generation of dibrominated byproducts, the separation and purification of N-1 are difficult, the purity is not high, the yield is low,
according to the reports of documents WO2008148867, WO2017133423, CN110627775 and the like, the compounds can be synthesized according to the following routes: the synthesis method uses the expensive Pd catalyst, has higher cost of raw materials,
therefore, the development of a novel process for preparing the Filgotinib intermediate compound N, which is environment-friendly, lower in cost and better in quality control, is urgently needed in the field.
Disclosure of Invention
The invention aims to solve the technical problems of high cost, complex treatment, low yield and the like in the synthesis of a compound N in the prior art, and provides a preparation method of a Filgotinib intermediate. The preparation method has the advantages of environmental friendliness, low cost, simplicity in operation, contribution to industrialization and the like.
The invention provides a preparation method of a Filgotinib intermediate, which comprises the following steps:
(a) In a solvent A, 4-methyl phenylboronic acid, pinacol and a halogenating reagent are subjected to the following reaction and pretreated to obtain a compound N-1;
(b) In a solvent B, in the presence of alkali, reacting the compound N-1 with thiomorpholine-1,1-dioxide to obtain a compound N;
the pretreatment does not include column chromatography purification.
In step (a), the reaction conditions and methods may be those conventional in such reactions in the art, and the following methods and conditions are particularly preferred in the present invention:
the solvent A is ester solvent, halogenated hydrocarbon solvent, ether solvent, aromatic hydrocarbon solvent and C 5-8 One or more alkane solvents. The ester solvent is preferably ethyl acetate. The halogenated hydrocarbon solvent is preferably dichloromethane. The ether solvent is preferably tetrahydrofuran. The aromatic hydrocarbon solvent is preferably toluene. Said C 5-8 The alkane solvent is preferably n-heptane and/or n-hexane. SaidThe volume-to-mass ratio of the solvent A to the 4-methylphenylboronic acid is 5 to 50mL/g, preferably 15 to 25mL/g, for example, 20mL/g or 18mL/g.
The halogenating agent is one or more of liquid bromine, NBS, dibromohydantoin and NCS.
The molar ratio of the halogenating agent to 4-methylphenylboronic acid is from 1.0 to 3.0, more preferably from 1.2 to 2.0, for example 1.49 or 1.39.
The molar ratio of AIBN to 4-methylphenylboronic acid is 0.05 to 0.2, for example, 0.11, 0.1 or 0.09.
The molar ratio of pinacol to 4-methylphenylboronic acid is from 1.0 to 3.0, more preferably from 1.0 to 1.5, for example, 1.19.
The reaction temperature of the reaction is 40-80 ℃, preferably 50-60 ℃.
The progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC, or NMR), typically by monitoring the disappearance of the 4-methylphenylboronic acid as the end point of the reaction.
The pretreatment comprises the following steps: after the reaction is finished, cooling, filtering or washing the reaction system to obtain the compound N-1.
The pretreatment usually requires only simple treatment, and does not require column chromatography or recrystallization for purification.
In the pretreatment, when a solid is precipitated after the cooling, the pretreatment is preferably carried out by filtration.
When the pretreatment is conducted by filtration, the filtration may comprise rinsing the solids with a solvent and combining the rinse with the filtrate. Wherein the solvent is preferably selected from ether solvents, aromatic hydrocarbon solvents and C 5-8 One or more of alkane solvents; the ether solvent, the aromatic hydrocarbon solvent and C 5-8 The alkane solvent is as defined above.
When the pretreatment is carried out by washing, the washing is preferably carried out by washing with an aqueous alkaline solution and then washing with water. The alkaline aqueous solution is preferably a saturated aqueous sodium carbonate solution.
When the solvent A and the solvent B are the same solvent, the pretreatment is preferably water washing; no further solvent is added in step (b);
when the solvent A and the solvent B are different solvents, concentration is further included after the pretreatment to remove most of the solvents.
In step (b), the reaction conditions and methods may be those conventional in the art for such reactions, and the following are particularly preferred in the present invention:
the solvent B is one or more of an ester solvent, a halogenated hydrocarbon solvent, an ether solvent, an aromatic hydrocarbon solvent, a nitrile solvent and a ketone solvent. The ester solvent is preferably ethyl acetate. The halogenated hydrocarbon solvent is preferably dichloromethane. The ether solvent is preferably tetrahydrofuran. The aromatic hydrocarbon solvent is preferably toluene. The nitrile solvent is preferably acetonitrile. The ketone solvent is preferably acetone. The volume-to-mass ratio of the solvent B to the 4-methylphenylboronic acid is 5 to 50mL/g, preferably 10 to 30mL/g, for example, 20mL/g or 18mL/g.
The alkali is organic alkali and/or inorganic alkali. The organic base is preferably an organic compound containing 1 to 3 nitrogens and 3 to 20 carbons, more preferably triethylamine and/or diisopropylethylamine. The inorganic base is preferably one or more of an alkali metal hydroxide, carbonate and bicarbonate. The alkali metal is preferably sodium, potassium or cesium. The hydroxide of the alkali metal is preferably sodium hydroxide and/or potassium hydroxide. The carbonate of the alkali metal is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate. The bicarbonate of an alkali metal is preferably sodium bicarbonate and/or potassium bicarbonate.
The molar ratio of the base to the 4-methylphenylboronic acid is from 0.8 to 2.0, preferably from 0.8 to 1.1, for example 1.0 or 0.86.
The molar ratio of thiomorpholine-1,1-dioxide to 4-methylbenzeneboronic acid is 0.8 to 1.2, for example, 1.0 or 1.10.
The reaction temperature of the reaction is 0 to 100 ℃, preferably 10 to 70 ℃, for example, 15 to 30 ℃ or 40 to 50 ℃.
The progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC, or NMR), typically by monitoring the disappearance of the compound N-1 as the end point of the reaction.
The reaction may further comprise a post-treatment, which preferably comprises the steps of: after the reaction was completed, the organic phase was concentrated by water washing, and the residue was recrystallized. The solvent for recrystallization is preferably an ester solvent and/or C 5～8 An alkane solvent. The ester solvent is preferably ethyl acetate and/or isopropyl acetate. Said C 5～8 The alkane solvent is preferably n-heptane and/or n-hexane. The temperature of recrystallization is preferably 70 to 77 ℃.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The positive progress effects of the invention are as follows:
the preparation method of the invention has the advantages of simple operation, cheap and easily obtained raw materials, mild reaction conditions and high product purity, and is suitable for industrial production.
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and the spirit and scope of the present invention are not limited thereto. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Example 1:
4-Methylphenylboronic acid (5.0g, 37mmol), pinacol (5.2g, 44mmol), NBS (9.8g, 55mmol), AIBN (0.6g, 4 mmol) and n-heptane (100 mL) were charged into a reaction flask, the temperature was raised to 50 to 60 ℃ for 1694s of reaction, and HPLC was followed until the reaction was complete.
Cooling the reaction solution to 15-25 deg.C, and stirring for 1hr. Filtering to obtain filtrate and filter cake; the filter cake was rinsed with N-heptane (100 mL. Times.2) and the rinse was combined with the filtrate to give a solution of compound N-1 in N-heptane. Most of the solvent was removed by concentration under reduced pressure to obtain a pretreated product.
To the pretreated product was added ethyl acetate (100 mL), thiomorpholine-1,1-dioxide (5.6g, 41mmol) and diisopropylethylamine (4.2g, 32mmol), the reaction was stirred at 15-30 ℃ for 16946 hrs and HPLC followed until the reaction was complete.
The reaction mixture was washed with water (30 mL. Times.2), the organic phases were combined, and the organic phase was concentrated to about 80mL, warmed to 70-77 deg.C until the system became a clear solution (i.e., a clear solution), and n-heptane (50 mL) was added, cooled to 0-10 deg.C and stirred for 1hr to precipitate a solid. Filtration and elution with n-heptane (10 mL. Times.2) gave 9.3g of an off-white solid with an HPLC purity of 98.0% and a yield of 72.0%.
Example 2:
4-Methylphenylboronic acid (10.0g, 74mmol), pinacol (10.4g, 88mmol), NBS (18.3g, 103mmol), AIBN (1.2g, 7mmol) and ethyl acetate (180 mL) were added to a reaction flask, the temperature was raised to 50-60 ℃ for 169rs of reaction, and HPLC was followed until the reaction was complete.
The reaction solution was cooled to 15-25 ℃ and washed with a saturated aqueous solution of sodium carbonate (30 mL) and water (30 mL), respectively, to obtain an ethyl acetate solution (pretreated product) containing compound N-1.
To the pretreated product, thiomorpholine-1,1-dioxide (9.9 g, 74mmol) and diisopropylethylamine (9.5 g, 74mmol) were added, the reaction was stirred at 15-30 ℃ for 1694 hrs, followed by HPLC until the reaction was complete.
Cooling the reaction liquid to 15-25 ℃, washing the reaction mixture with water (30 mL multiplied by 2), combining organic phases, concentrating the organic phases to about 160mL, heating to 70-77 ℃, adding n-heptane (100 mL) after the system is dissolved, cooling to 0-10 ℃, stirring for 1hr, and separating out solids. Filtration and elution with n-heptane (20 mL. Times.2) gave 18.0g of an off-white solid with an HPLC purity of 98.5% and a yield of 69.5%.
Example 3:
4-Methylphenylboronic acid (5.0g, 37mmol), pinacol (5.2g, 44mmol), AIBN (0.6g, 4mmol) and ethyl acetate (90 mL) were added to a reaction flask, and Br was added dropwise at room temperature 2 (7.7g, 48mmol), heating to 50-60 ℃ for reaction 1ihrs, and HPLC tracking until the reaction is complete.
The reaction solution was cooled to 15-25 ℃ and washed with a saturated aqueous solution of sodium carbonate (20 mL) and water (20 mL), respectively, to obtain an ethyl acetate solution (pretreated product) containing the compound N-1.
To the pretreated product, thiomorpholine-1,1-dioxide (5.0g, 37mmol) and diisopropylethylamine (4.8g, 37mmol) were added, the reaction was stirred at 15-30 ℃ for 1694 hrs, and HPLC tracing was performed until the reaction was completed.
Cooling the reaction liquid to 15-25 deg.c, washing the reaction mixture with water (20 mL × 2), concentrating the organic phase to 80mL, heating to 70-77 deg.c, dissolving the system, adding n-heptane (50 mL), cooling to 0-10 deg.c, stirring for 1hr to separate out solid. Filtration and n-heptane (10 mL. Times.2) elution gave 8.5g of off-white solid with an HPLC purity of 97.9% and a yield of 65.9%.
Example 4:
4-Methylphenylboronic acid (5.0g, 37mmol), pinacol (5.2g, 44mmol), dibromohydantoin (14.9g, 52mmol), AIBN (0.6g, 4mmol) and ethyl acetate (90 mL) were added to a reaction flask, the temperature was raised to 50-60 ℃ for 1694s of reaction, and HPLC followed until the reaction was complete.
The reaction solution was cooled to 15-25 ℃ and washed with a saturated aqueous solution of sodium carbonate (20 mL) and water (20 mL), respectively, to obtain an ethyl acetate solution (pretreated product) containing the compound N-1.
To the pretreated product, thiomorpholine-1,1-dioxide (5.0g, 37mmol) and diisopropylethylamine (4.8g, 37mmol) were added, the reaction was stirred at 15 to 30 ℃ for 1694 hrs, and HPLC tracing was performed until the reaction was completed.
Cooling the reaction liquid to 15-25 ℃, washing the reaction mixture with water (20 mL multiplied by 2), concentrating the organic phase to about 80mL, heating to 70-77 ℃, adding n-heptane (50 mL) after the system is dissolved, cooling to 0-10 ℃, stirring for 1hr, and separating out the solid. Filtration and elution with n-heptane (10 mL. Times.2) gave 8.8g of an off-white solid with an HPLC purity of 98.3% and a yield of 68.2%.
Example 5:
4-Methylphenylboronic acid (5.0g, 37mmol), pinacol (5.2g, 44mmol), NCS (chlorosuccinimide) (6.9g, 52mmol), AIBN (0.6g, 4mmol) and ethyl acetate (90 mL) were added to a reaction flask, the temperature was raised to 50-60 ℃ for 1694s of reaction, and HPLC followed until the reaction was complete.
The reaction solution was cooled to 15-25 ℃ and washed with saturated aqueous sodium carbonate solution (20 mL) and water (20 mL), respectively, to obtain an ethyl acetate solution (pretreated product) containing compound N-1.
To the pretreated product, thiomorpholine-1,1-dioxide (5.0g, 37mmol) and diisopropylethylamine (4.8g, 37mmol) were added, the reaction was stirred at 15 to 30 ℃ for 1694 hrs, and HPLC tracing was performed until the reaction was completed.
Cooling the reaction liquid to 15-25 ℃, washing the reaction mixture with water (20 mL multiplied by 2), concentrating the organic phase to about 80mL, heating to 70-77 ℃, adding n-heptane (50 mL) after the system is dissolved, cooling to 0-10 ℃, stirring for 1hr, and separating out the solid. Filtration and elution with n-heptane (10 mL. Times.2) gave 8.6g of an off-white solid with an HPLC purity of 98.0% and a yield of 66.7%.
Example 6
4-Methylphenylboronic acid (50.0 g, 0.37mol), pinacol (52.2 g, 0.44mol), NBS (91.6 g, 0.51mol), AIBN (6.0 g, 37mmol) and ethyl acetate (900 mL) were added to a reaction flask, the temperature was raised to 50-60 ℃ for reaction 169rs, and HPLC followed until the reaction was complete.
The reaction solution was cooled to 15-25 ℃ and washed with a saturated aqueous sodium carbonate solution (250 mL) and water (250 mL), respectively, to obtain an ethyl acetate solution (pretreated product) containing compound N-1.
Adding thiomorpholine-1,1-dioxide (49.7 g, 0.37mol) and diisopropylethylamine (47.5 g, 0.37mol) into the pretreated product, heating to 40-50 ℃, stirring for reaction for 6hrs, and tracking by HPLC until the reaction is complete.
Cooling the reaction liquid to 15-25 ℃, washing the reaction mixture with water (250 mL multiplied by 2), concentrating the organic phase to about 800mL, heating to 70-77 ℃, adding n-heptane (500 mL) after the system is dissolved, cooling to 0-10 ℃, stirring for 1hr, and separating out the solid. Filtration and elution with n-heptane (100 mL. Times.2) gave 92.3g of an off-white solid with an HPLC purity of 98.8% and a yield of 70.5%.
Example 7
4-Methylphenylboronic acid (100.0g, 0.74mol), pinacol (104.3g, 0.88mol), NBS (183.3g, 1.03mol), AIBN (12.1g, 74mmol) and ethyl acetate (1800 mL) were added to a reaction flask, the temperature was raised to 50-60 ℃ for 6hrs, and HPLC was followed until the reaction was complete.
The reaction solution was cooled to 15-25 ℃ and washed with saturated aqueous sodium carbonate (5000 mL) and water (300 mL), respectively, to obtain an ethyl acetate solution (pretreated product) containing compound N-1.
To the pretreated product, thiomorpholine-1,1-dioxide (99.4 g, 0.74mol) and diisopropylethylamine (95.0 g, 0.74mol) were added, the temperature was raised to 40 to 50 ℃, the reaction was stirred for 6hrs, and hplc traces were made until the reaction was complete.
Cooling the reaction liquid to 15-25 ℃, washing the reaction mixture twice by water (500mL, 300mL), concentrating the organic phase to about 1600mL, heating to 70-77 ℃, adding n-heptane (1000 mL) after the system is dissolved, cooling to 0-10 ℃, stirring for 1hr, and separating out the solid. Filtration and elution with n-heptane (100 mL. Times.2) gave 181.6g of an off-white solid with an HPLC purity of 98.6% and a yield of 70.3%.
Comparative example 1
4-Methylphenylboronic acid (5.0g, 37mmol), pinacol (5.2g, 44mmol), NBS (9.8g, 55mmol), AIBN (0.6g, 4 mmol) and n-heptane (100 mL) were added to a reaction flask, the temperature was raised to 50-60 ℃ for 169rs of reaction, and HPLC followed until the reaction was complete.
Cooling the reaction solution to 15-25 deg.C, and stirring for 1hr. Filtering to obtain filtrate and filter cake; the filter cake was rinsed with N-heptane (100 mL. Times.2) and the rinse was combined with the filtrate to give a solution of compound N-1 in N-heptane. Concentrating under reduced pressure to remove most solvent to obtain crude compound N-1, and performing column chromatography (PE/CH) 2 Cl 2 = 10/1) purification gives 7.2g of white solid (compound N-1) 94.1% hplc purity, yield 66.1%.
Comparative example 2
4-Methylphenylboronic acid (5.0g, 37mmol), pinacol (5.2g, 44mmol), NBS (9.8g, 55mmol), AIBN (0.6g, 4 mmol) and ethyl acetate (90 mL) were added to a reaction flask, the temperature was raised to 50-60 ℃ for 1694, and HPLC was followed until the reaction was complete.
The reaction solution was cooled to 15-25 deg.C, thiomorpholine-1,1-dioxide (5.0g, 37mmol) and diisopropylethylamine (7.1g, 56mmol) were added, the temperature was raised to 40-50 deg.C, the reaction was stirred for 2 hrs, and HPLC tracking was performed until the reaction was complete.
Cooling the reaction liquid to 15-25 ℃, washing the reaction mixture with water (50 mL multiplied by 2), concentrating the organic phase to about 80mL, heating to 70-77 ℃, adding n-heptane (50 mL) after the system becomes clear solution (namely, clearness), cooling to 0-10 ℃, stirring for 1hr, and separating out solid. Filtration and elution with n-heptane (10 mL. Times.2) gave 7.8g of an off-white solid with an HPLC purity of 97.5% and a yield of 57.7%.
Comparative example 3
C3.1.N-1 isolation test:
4-Methylphenylboronic acid (100.0g, 0.74mol), pinacol (104.3g, 0.88mol), NBS (196.4g, 1.10mol), AIBN (12.11g, 74mmol) and n-heptane (2L) were charged into a reaction flask, the temperature was raised to 50 to 60 ℃ for 169rs of reaction, and HPLC was followed until the reaction was complete.
Cooling the reaction solution to 15-25 deg.C, and stirring for 1hr. Filtering to obtain filtrate and filter cake; the filter cake was rinsed with N-heptane (100 mL. Times.2) and the rinse was combined with the filtrate to give a solution of compound N-1 in N-heptane. Concentrating the organic phase under reduced pressure to about 1L, heating to 50-60 deg.C, cooling to 0-10 deg.C after the system is dissolved, stirring for 1hr, and separating out solid. Filtration and N-heptane (50 mL. Times.2) rinsing gave 133.4g of white solid compound N-1, 90.0% HPLC purity and 61.0% yield.
C3.2. Compound N was synthesized from N-1 solid:
the compound N-1 (30.0g, 0.10mol), thiomorpholine-1,1-dioxide (15.0g, 0.11mol), diisopropylethylamine (14.0g, 0.11mol) and ethyl acetate (300 mL) were added into a reaction bottle, the temperature was raised to 40-50 ℃, the reaction was stirred for 5hrs, and HPLC was followed until the reaction was completed. Washing the reaction mixture with water (100 mL × 2), concentrating the organic phase under reduced pressure until no solvent exists, adding ethyl acetate (150 mL) and n-heptane (150 mL), heating to 70-78 ℃, cooling to 0-10 ℃ after the system is clear, stirring for 1hr, and precipitating a solid. Filtration and N-heptane (60 mL. Times.2) elution gave 33.0g of an off-white solid (Compound N) with an HPLC purity of 98.1% and a yield of 91.5%.
The results showed that the final product yield was 55.8% when purified for each reaction.
Claims (10)
1. A preparation method of a Filgotinib intermediate is characterized by comprising the following steps:
(a) In a solvent A, 4-methyl phenylboronic acid, pinacol and a halogenating reagent are subjected to the following reaction and pretreated to obtain a compound N-1;
(b) In a solvent B, in the presence of alkali, reacting the compound N-1 with thiomorpholine-1,1-dioxide to obtain a compound N;
the pretreatment does not include column chromatography purification.
2. The method according to claim 1, wherein the reaction mixture,
in the step (a), the solvent A is ester solvent, halogenated hydrocarbon solvent, ether solvent, aromatic hydrocarbon solvent and C 5-8 One or more of alkane solvents;
and/or in the step (a), the volume mass ratio of the solvent A to the 4-methylphenylboronic acid is 5-50 mL/g;
and/or, in step (a), the halogenating agent is one or more of liquid bromine, NBS, dibromohydantoin and NCS;
and/or, in the step (a), the molar ratio of the halogenating agent to the 4-methylphenylboronic acid is 1.0-3.0;
and/or, in the step (a), the molar ratio of the AIBN to the 4-methyl phenylboronic acid is 0.05-0.2;
and/or, in the step (a), the molar ratio of the pinacol to the 4-methylphenylboronic acid is 1.0-3.0;
and/or in the step (a), the reaction temperature of the reaction is 40-80 ℃.
3. The method according to claim 2,
in the step (a), the ester solvent is ethyl acetate;
and/or, in step (a), the halogenated hydrocarbon solvent is dichloromethane;
and/or, in the step (a), the ether solvent is preferably tetrahydrofuran;
and/or, in step (a), the aromatic hydrocarbon solvent is toluene;
and/or, in step (a), said C 5-8 The alkane solvent is n-heptane and/or n-hexane;
and/or in the step (a), the volume-mass ratio of the solvent A to the 4-methylphenylboronic acid is 15-25 mL/g;
and/or, in the step (a), the molar ratio of the halogenating agent to the 4-methylphenylboronic acid is 1.2-2.0;
and/or, in the step (a), the molar ratio of the pinacol to the 4-methylphenylboronic acid is 1.0-1.5;
and/or in the step (a), the reaction temperature of the reaction is 50-60 ℃.
4. The method according to claim 1, wherein the reaction mixture,
in step (a), the pretreatment comprises the following steps: after the reaction is finished, cooling, filtering or washing the reaction system to obtain the compound N-1.
5. The method according to claim 4,
in the step (a), in the pretreatment, when a solid is precipitated after the cooling, the pretreatment is filtration;
and/or, in step (a), when the pretreatment employs filtration, the filtration comprises rinsing the solids with a solvent, and combining the rinse and the filtrate;
and/or, in the step (a), when the pretreatment adopts water washing operation, the water washing is carried out by firstly washing with alkaline aqueous solution and then washing with water.
6. The method according to claim 5,
in the step (a), in the filtering, the solvent is an ether solvent, an aromatic hydrocarbon solvent and C 5-8 One or more of alkane solvents; the ether solvent, the aromatic hydrocarbon solvent and C 5-8 The alkane solvent is defined in claim 3;
and/or the alkaline aqueous solution is saturated sodium carbonate aqueous solution.
7. The method according to claim 1, wherein when the solvent A and the solvent B are the same solvent, the pretreatment is water washing; no further solvent is added in step (b);
and/or, when the solvent A and the solvent B are different solvents, concentrating to remove most of the solvent after the pretreatment.
8. The method according to claim 1, wherein the reaction mixture,
in the step (B), the solvent B is one or more of an ester solvent, a halogenated hydrocarbon solvent, an ether solvent, an aromatic hydrocarbon solvent, a nitrile solvent and a ketone solvent;
and/or in the step (B), the volume mass ratio of the solvent B to the 4-methylphenylboronic acid is 5-50 mL/g;
and/or, in the step (b), the alkali is organic alkali and/or inorganic alkali;
and/or, in the step (b), the molar ratio of the alkali to the 4-methylphenylboronic acid is 0.8-2.0;
and/or, in the step (b), the molar ratio of the thiomorpholine-1,1-dioxide to the 4-methylbenzeneboronic acid is 0.8-1.2;
and/or, in the step (b), the reaction temperature of the reaction is 0-100 ℃.
9. The method according to claim 6,
in the step (b), the ester solvent is ethyl acetate;
and/or, in the step (b), the halogenated hydrocarbon solvent is dichloromethane;
and/or, in the step (b), the ether solvent is tetrahydrofuran;
and/or, in the step (b), the aromatic hydrocarbon solvent is toluene;
and/or, in step (b), the nitrile solvent is acetonitrile;
and/or, in step (b), the ketone solvent is acetone;
and/or in the step (B), the volume mass ratio of the solvent B to the 4-methylphenylboronic acid is 10-30 mL/g;
and/or, in the step (b), the organic base is an organic compound containing 1 to 3 nitrogen and 3 to 20 carbon atoms;
and/or, in the step (b), the inorganic base is one or more of hydroxide, carbonate and bicarbonate of alkali metal;
and/or the reaction temperature of the reaction in the step (b) is 10-70 ℃.
10. The method according to claim 7,
in the step (b), the organic base is triethylamine and/or diisopropylethylamine;
and/or, in step (b), the alkali metal is sodium, potassium or cesium;
and/or, in the step (b), the hydroxide of the alkali metal is sodium hydroxide and/or potassium hydroxide;
and/or in the step (b), the carbonate of the alkali metal is one or more of sodium carbonate, potassium carbonate and cesium carbonate;
and/or, in the step (b), the bicarbonate of the alkali metal is sodium bicarbonate and/or potassium bicarbonate.
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