CN116813538A - Nevirapine intermediate compound and preparation method thereof - Google Patents
Nevirapine intermediate compound and preparation method thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 97
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 title claims abstract description 72
- 229960000689 nevirapine Drugs 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 86
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims abstract description 24
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 11
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 101150003085 Pdcl gene Proteins 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 230000002829 reductive effect Effects 0.000 abstract description 24
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 238000007363 ring formation reaction Methods 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 238000001514 detection method Methods 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000012065 filter cake Substances 0.000 description 20
- 239000008213 purified water Substances 0.000 description 20
- 230000001276 controlling effect Effects 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000012295 chemical reaction liquid Substances 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- RXTRRIFWCJEMEL-UHFFFAOYSA-N 2-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- -1 2-chloro-4-methylpyridine-3-yl Chemical group 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JXYPNRIYAMXJSE-UHFFFAOYSA-N 1,4-diazepin-6-one Chemical compound O=C1C=NC=CN=C1 JXYPNRIYAMXJSE-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- AULKGEJDEAKINM-UHFFFAOYSA-N 2,6-dichloro-4-methylpyridin-3-amine Chemical compound CC1=CC(Cl)=NC(Cl)=C1N AULKGEJDEAKINM-UHFFFAOYSA-N 0.000 description 1
- UVCHGYJPZGYMSW-UHFFFAOYSA-N 2-chloro-n-(2-chloro-4-methylpyridin-3-yl)pyridine-3-carboxamide Chemical compound CC1=CC=NC(Cl)=C1NC(=O)C1=CC=CN=C1Cl UVCHGYJPZGYMSW-UHFFFAOYSA-N 0.000 description 1
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 description 1
- IEJSXJLVJOGKMB-UHFFFAOYSA-N 2-methoxy-4-methylpyridin-3-amine Chemical compound COC1=NC=CC(C)=C1N IEJSXJLVJOGKMB-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000006887 Ullmann reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 239000006012 monoammonium phosphate Substances 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a nevirapine intermediate compound and a preparation method thereof. The new intermediate of nevirapine provided by the invention takes 2-bromo-N- (2-hydroxy-4-methylpyridine-3-yl) nicotinamide as a raw material and reacts with trifluoro methane sulfonic anhydride to obtain the new intermediate of nevirapine; the new intermediate reacts with cyclopropylamine to obtain nevirapine. The nevirapine can be prepared by using the intermediate compound and only by one-step cyclization, so that the operation steps are simplified, the reaction temperature is reduced, the use of a dangerous chemical reagent NaH can be effectively avoided, and the operation process is safer.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a nevirapine intermediate compound and a preparation method thereof.
Background
Nevirapine (Nevirapine), chemical name of which is 11-cyclopropyl-4-methyl-5, 11-dihydro-6H-dihydropyrido [3,2-b:2',3' -e ] [1,4] diazepin-6-one, is a high-selectivity and non-competitive HIV-1 virus reverse transfer enzyme inhibitor. The first non-nucleoside reverse transcriptase inhibitors developed by germany Boehringer Ingelheim company. Nevirapine is one of the most widely used anti-aids drugs in the world at present, and can permeate placenta, and can be used for preventing HIV infection and maternal and infant transmission by independently taking the drug, CAS:129618-40-2, the chemical structure is as follows:
the existing synthesis method of nevirapine can be used for mass production technology, namely patent WO2007010352, CN101585836A and the publication 'synthesis of nevirapine', journal of Chinese medicine industry, 2012,43 (6): 411-413 takes CAPIC and 2-chloronicotinyl chloride as raw materials, potassium carbonate is taken as an acid-binding agent, and the 2-chloro-N- (2-chloro-4-methylpyridin-3-yl) nicotinamide is obtained by reaction under heating (75 ℃ to 80 ℃) in toluene, and the yield is about 87.8 percent. Then under the catalysis of cuprous chloride, ullmann reaction is carried out on the N- (2-chloro-4-methylpyridine-3-yl) -2- (cyclopropylamino) nicotinamide and cyclopropylamine, finally, reflux is carried out on the N- (2-chloro-4-methylpyridine-3-yl) -2- (cyclopropylamino) nicotinamide in toluene solvent under the action of potassium tert-butoxide, and nevirapine is obtained through ring closure reaction, wherein the yield of the two steps of reaction is 82%. However, the yield of the synthesis method is general, and for large-scale industrial production, there is still further room for improvement, optimization and perfection. The synthetic route is as follows:
U.S. Pat. No. 3,979 and J.org.chem. 1995,60 (6) were prepared by stirring 1875-877 with 3-amino-2-methoxy-4-methylpyridine as starting material, 2-chloronicotinyl chloride, ethyl acetate and N, N-diisopropylethylamine in a reactor at 0deg.C for 10h, washing with hydrochloric acid, and drying to give 2-chloro-N- (2-methoxy-4-methylpyridin-3-yl) nicotinamide in 88% yield. Then the mixture and cyclopropylamine are placed in a closed container and heated to 110 ℃ to react to obtain 2- (cyclopropylamino) -N- (2-methoxy-4-methylpyridin-3-yl) nicotinamide with 86 percent of yield. And finally, under the protection of argon, ring-closing reaction is carried out on NaH or hexamethyldisilazide in dry pyridine to obtain the target product, wherein the yield is 91%. However, the final product of the synthesis method needs to be purified by chromatography, has strict process conditions and high production cost. The synthetic route is as follows:
chinese patent application CN102127077a and literature hetercycl.chem 1995,32 (1): 259-263 amidation of 2, 6-dichloro-3-amino-4-methylpyridine with 2-chloronicotinyl chloride or 2-chloronicotinic acid to give 2-chloro-N- (2, 6-dichloro-4-methylpyridin-3-yl) nicotinamide. Then heating the mixture with cyclopropylamine in a dimethylbenzene solvent to 120 ℃ for reaction for 48 hours, filtering, washing with water, and drying in vacuum to obtain 2- (cyclopropylamino) -N- (2, 6-dichloro-4-methylpyridin-3-yl) nicotinamide with a yield of 84%. Under the protection of nitrogen, 2-methoxyl diethyl ether is taken as a solvent, strong alkali NaH is added, the mixture is heated to 120 ℃ for reflux reaction, then Pd/C is used for catalytic hydrogenation and dechlorination to obtain a target product, the yield of the two steps of reaction is 55%, and the synthetic route is as follows:
however, the method has the advantages of long reaction steps, more side reactions, long preparation period and low yield.
From the above, the prior process for preparing nevirapine has many disadvantages. Therefore, research and search for a process suitable for industrial production of nevirapine with mild reaction conditions, simple operation process, high product yield and high purity still needs to be solved.
Disclosure of Invention
Aiming at the problems of the existing nevirapine preparation technology, the invention provides a new intermediate compound of nevirapine and a preparation method thereof, and the use of high temperature conditions and sodium hydride can be avoided when the intermediate is used for preparing the nevirapine.
The specific technical scheme of the invention is as follows:
the first aspect of the invention provides a nevirapine intermediate compound, which has a structure shown in a formula I-2:
the second aspect of the invention provides a preparation method of a nevirapine intermediate compound I-2, which comprises the following steps: adding compound I-1 and acid binding agent into dry organic solvent A, and controlling temperature T A1 Adding trifluoromethanesulfonic anhydride, and controlling temperature T A2 After the reaction is finished, the compound I-2 is obtained through post-treatment, and the reaction route is as follows：
Preferably, the organic solvent A is selected from one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and chloroform, and dichloromethane is preferred.
Preferably, the acid binding agent is selected from one of sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, N-diisopropylethylamine, preferably triethylamine.
Preferably, the feeding mole ratio of the compound I-1 to the trifluoromethanesulfonic anhydride to the acid binding agent is 1:1.4 to 2.5:3.5 to 5.5, preferably 1:1.8:4.0.
preferably, the temperature T is controlled A1 Is at-10 to 10 ℃, preferably 0 to 5 ℃; t (T) A2 Is 10 to 40 ℃, preferably 20 to 25 ℃.
In a preferred embodiment, after the reaction is completed, a post-treatment operation is performed, specifically: adding methanol or purified water into the reaction solution, quenching, filtering, washing the filtrate with saturated sodium bicarbonate solution and saturated saline solution, and concentrating the organic phase under reduced pressure until the organic phase is dried to obtain the compound I-2.
Wherein the compound I-1 is prepared as follows: adding compound SM-1 into solvent B at room temperature, and controlling temperature T B1 Adding N, N' -Carbonyl Diimidazole (CDI), controlling the temperature T B2 After the reaction is finished, the compound SM-2 is added after the reaction of the compound SM-1 is detected, and the temperature T is controlled B3 After the reaction is detected, the compound I-1 is prepared by post-treatment, and the reaction route is as follows:
preferably, the solvent B is selected from one or a combination of anhydrous dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, preferably tetrahydrofuran.
Preferably, the feeding mole ratio of the compound SM-1 to CDI to the compound SM-2 is 1:1.0 to 1.3:1.0 to 1.2, preferably 1:1.05:1.05.
preferably, the temperature T is controlled B1 0 to 20 ℃, preferably 10 to 15 ℃; t (T) B2 20 to 40 ℃, preferably 25 to 30 ℃; t (T) B3 Is 30 to 80℃and preferably 40 to 45 ℃.
In a preferred embodiment, after the reaction is completed, a post-treatment operation is performed, specifically: cooling the reaction solution to room temperature, removing the solvent by reduced pressure, adding purified water, stirring for crystallization, filtering, and drying the obtained filter cake under reduced pressure to obtain the compound I-1.
In another preferred embodiment, after the reaction is completed, a post-treatment operation is performed, specifically: pouring the reaction solution into purified water, stirring for crystallization, filtering, and drying the obtained filter cake under reduced pressure to obtain the compound I-1.
In a third aspect, the invention provides the use of a new intermediate compound I-2 of nevirapine for preparing nevirapine.
The preparation of the compound I comprises the following steps: under the protection of inert gas, adding the compound I-2, cyclopropylamine, catalyst, ligand, alkali and organic solvent C into a closed reaction device, and controlling the temperature T C After the reaction is detected, nevirapine I is prepared through post-treatment, and the reaction route is as follows:
preferably, the catalyst is chosen from Pd (OAc) 2 、PdCl 2 、Pd 2 (dba) 3 Preferably Pd (OAc) 2 。
Preferably, the ligand is selected from the group consisting of P (t-Bu) 3 、P(o-tolyl) 3 One of BINAP, xantphos, dppf, preferably BINAP:
preferably, the base is selected from Cs 2 CO 3 One of t-BuOK and t-Buona, preferably Cs 2 CO 3 。
Preferably, the organic solvent C is selected from one or a combination of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether, and preferably diethylene glycol dimethyl ether.
Preferably, the feeding mole ratio of the compound I-2 to cyclopropylamine, catalyst, ligand and alkali is 1:1.4 to 3.5:0.05 to 0.2:0.06 to 0.25:2.2 to 3.6, preferably 1:1.7:0.1:0.12:2.5, the molar amount of catalyst is Pd.
Preferably, the reaction temperature T C 60 to 110℃and preferably 80 to 85 ℃.
Preferably, the post-treatment steps are as follows: and (3) filtering the reaction liquid pad by diatomite, pouring the filtrate into purified water, stirring for crystallization, filtering, and recrystallizing the filter cake by absolute ethyl alcohol to obtain the target product.
Preferably, the inert gas is one of argon, nitrogen or a combination thereof, preferably nitrogen.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a new nevirapine intermediate compound and a preparation method thereof, and the new intermediate and cyclopropylamine can be prepared into nevirapine only by one-step cyclization, so that the operation steps are simplified, the reaction temperature is reduced, meanwhile, the use of a dangerous chemical reagent NaH can be effectively avoided, and the operation process is safer;
(2) the novel intermediate preparation is prepared by taking the compound SM-1 and the compound SM-2 as starting materials, the process can effectively reduce the reaction temperature, and the operation is more suitable for industrial production;
(3) the new process for preparing nevirapine can effectively avoid the use of cyano materials with stronger toxicity in the prior art, the production operation is safer, and the target product obtained by the process has higher purity and yield and is suitable for industrial scale-up production.
In summary, the invention provides a new method for preparing nevirapine, which can effectively avoid the use of dangerous chemical reagents, has simpler synthesis operation and high yield and purity, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
The invention adopts HPLC to measure the purity of nevirapine, and the chromatographic conditions are as follows:
chromatographic column: supelco LC-ABE C 18 Columns (4.6 mm. Times.150 mm,5 μm) or columns of comparable performance;
mobile phase: acetonitrile: 25mmol/L monoammonium phosphate (ph=5.0 with sodium hydroxide) (25:75);
isocratic elution;
column temperature: 35 ℃;
detection wavelength: 220nm;
flow rate: 0.8ml/min;
sample injection amount: 20 μl;
the structure of the compound I-1 obtained by the invention is confirmed as follows:
ESI-HRMS(m/z):308.0026、310.0024[M+H] + ； 1 H NMR(400MHz，DMSO-d 6 )δ：9.65(s,1H),8.16(dd,J＝4.8、1.7Hz,1H),7.74(dd,J＝4.8、1.7Hz,1H),7.39～7.42(m,2H),6.53(d,J＝5.0Hz,1H),3.26(s,1H),2.32(s,3H)； 13 C NMR(125MHz,DMSO-d 6 )δ：166.49,152.73,146.60,145.33,143.92,138.17,137.46 134.54,126.79,122.12,120.26,18.37。
the structure of the compound I-2 obtained by the invention is confirmed as follows:
ESI-HRMS(m/z):439.9514、441.9512[M+H] + ； 1 H NMR(400MHz,DMSO-d 6 )δ：9.80(s,1H),8.28(dd,J＝4.8、1.7Hz,1H),7.65(dd,J＝4.8、1.7Hz,1H),7.48(d,J＝5.0Hz,1H),7.40(t,J＝4.8Hz,1H),6.58(d,J＝5.0Hz,1H),2.36(s,3H)； 13 C NMR(125MHz,DMSO-d 6 )δ：166.37,147.86,147.07,145.43,145.26,138.79,138.24,134.05,127.24,125.38,122.54,119.26,18.37。
the structure of the compound I obtained by the invention is confirmed as follows:
ESI-HRMS(m/z):267.1238[M+H] + ； 1 H NMR(400MHz,DMSO-d 6 )δ：9.88(s,1H),8.40(dd,J＝4.8、1.7Hz,1H),8.22(d,J＝4.8Hz,1H),8.12(dd,J＝7.9、1.7Hz,1H),7.44(d,J＝5.0Hz,1H),6.83(dd,J＝7.6、4.8Hz,1H),2.86～2.92(m,1H),2.25(s,3H),0.72～0.77(m,2H),0.33～0.37(m,2H)； 13 C NMR(125MHz,DMSO-d 6 )δ：166.20,158.74,150.03,149.42,147.34,146.17,136.12,129.57,125.86,111.20,108.38,23.80,18.25,6.52.
in the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
Example 1
Adding compound SM-1 (40.40 g,0.20 mol) into anhydrous tetrahydrofuran (300 ml), controlling the temperature to be 10-15 ℃, adding CDI (34.05 g,0.21 mol), controlling the temperature to be 25-30 ℃ for reaction, detecting that the compound SM-1 is reacted, adding SM-2 (26.07 g,0.21 mol), controlling the temperature to be 40-45 ℃ for reaction, cooling the reaction solution to the room temperature after the detection reaction is finished, pouring the reaction solution into purified water (2500 ml), stirring for crystallization, filtering, drying the obtained filter cake under reduced pressure, and obtaining the compound I-1 with the yield of 96.8% and the HPLC purity of 99.95%.
Example 2
Adding compound SM-1 (40.40 g,0.20 mol) into dry chloroform (300 ml), adding CDI (34.05 g,0.21 mol) at a temperature of 10-15 ℃, reacting at a temperature of 25-30 ℃, detecting that compound SM-1 is reacted, adding compound SM-2 (24.83 g,0.20 mol), refluxing at a temperature, detecting that the reaction is finished, evaporating solvent under reduced pressure, adding purified water (1500 ml), stirring for crystallization, filtering, drying the obtained filter cake under reduced pressure, and obtaining compound I-1 with a yield of 92.1% and an HPLC purity of 99.71%.
Example 3
Adding compound SM-1 (40.40 g,0.20 mol) into dry toluene (300 ml), adding CDI (34.05 g,0.21 mol) at a temperature of 10-15 ℃, controlling the temperature to react at 25-30 ℃, detecting that compound SM-1 is reacted, adding compound SM-2 (29.79 g,0.24 mol) at a temperature of 35-40 ℃ after the reaction is finished, concentrating the reaction solution to dryness under reduced pressure after the detection is finished, adding purified water (1500 ml), stirring for crystallization, filtering, drying the obtained filter cake under reduced pressure, and obtaining the compound I-1 with a yield of 93.5% and an HPLC purity of 99.60%.
Example 4
At room temperature, adding compound SM-1 (40.40 g,0.20 mol) into dry N, N-dimethylformamide (300 ml), controlling the temperature to be between 5 ℃ below zero and 0 ℃ to add CDI (34.05 g,0.21 mol), controlling the temperature to be between 15 ℃ below zero and 20 ℃ for reaction, detecting that compound SM-1 is reacted, adding compound SM-2 (32.28 g,0.26 mol) after the completion of the reaction, controlling the temperature to be between 25 ℃ below zero and 30 ℃ for reaction, pouring the reaction solution into purified water (3000 ml) after the completion of the detection reaction, stirring, crystallizing, filtering, decompressing and drying the obtained filter cake to obtain compound I-1, wherein the yield is 86.6%, and the HPLC purity is 98.65%.
Example 5
Adding compound SM-1 (40.40 g,0.20 mol) into dried dimethylbenzene (300 ml), controlling the temperature to be 10-15 ℃, adding CDI (32.43 g,0.20 mol), controlling the temperature to be 35-40 ℃ for reaction, detecting that compound SM-1 is reacted, adding compound SM-2 (26.07 g,0.21 mol), controlling the temperature to be 75-80 ℃ for reaction, cooling the reaction solution to room temperature after the detection reaction is finished, decompressing and steaming out the solvent, adding purified water (1500 ml), stirring and crystallizing, filtering, and drying the obtained filter cake under reduced pressure to obtain compound I-1 with the yield of 92.6% and the HPLC purity of 99.61%.
Example 6
At room temperature, compound SM-1 (40.40 g,0.20 mol) is added into dry N, N-dimethylacetamide (300 ml), CDI (42.16 g,0.26 mol) is added at 15-20 ℃ and is reacted at 40-45 ℃, compound SM-2 (26.07 g,0.21 mol) is added after the completion of the detection of compound SM-1, the reaction is carried out at 75-80 ℃ and is reacted at 75-80 ℃, the reaction solution is poured into purified water (3000 ml) after the completion of the detection, the mixture is stirred and crystallized and filtered, and the obtained filter cake is dried under reduced pressure to obtain compound I-1, the yield is 93.3%, and the HPLC purity is 99.52%.
Example 7
Adding compound SM-1 (40.40 g,0.20 mol) into dry N-methylpyrrolidone (300 ml), controlling the temperature to be 15-20 ℃, adding CDI (45.40 g,0.28 mol), controlling the temperature to be 40-45 ℃ for reaction, detecting that compound SM-1 is reacted, adding compound SM-2 (26.07 g,0.21 mol), controlling the temperature to be 80-85 ℃ for reaction, pouring the reaction solution into purified water (3000 ml) after the detection reaction is finished, stirring for crystallization, filtering, and drying the obtained filter cake under reduced pressure to obtain the compound I-1 with the yield of 86.3% and the HPLC purity of 98.66%.
Synthesis of Compound I-2
Example 8
Compound I-1 (36.89 g,0.10 mol), triethylamine (40.48 g,0.40 mol) are added into dry dichloromethane (300 ml), trifluoromethanesulfonic anhydride (50.79 g,0.18 mol) is added at the temperature of 0-5 ℃, the reaction is carried out at the temperature of 20-25 ℃ after the addition, methanol is added into the reaction solution to quench the reaction solution after the reaction is detected, the reaction solution is filtered, the filtrate is washed by saturated sodium bicarbonate solution (200 ml multiplied by 3), saturated saline (100 ml) is washed, and the organic phase is concentrated to be dry under reduced pressure, thus obtaining the compound I-2, the yield is 95.3%, and the HPLC purity is 99.88%.
Example 9
Adding compound I-1 (36.89 g,0.10 mol), pyridine (31.64 g,0.40 mol) into dry tetrahydrofuran (300 ml), adding trifluoromethanesulfonic anhydride (39.50 g,0.14 mol) at-10 to-5 ℃, reacting at-10-15 ℃ after the addition, adding purified water into the reaction solution to quench after the detection reaction, regulating the pH to 11 with saturated sodium carbonate solution, stirring for crystallization, filtering, and drying the obtained filter cake under reduced pressure to obtain compound I-2, wherein the yield is 91.2% and the HPLC purity is 99.51%.
Example 10
Compound I-1 (36.89 g,0.10 mol), potassium carbonate (55.28 g,0.40 mol) are added into dry dichloromethane (300 ml), trifluoromethanesulfonic anhydride (70.53 g,0.25 mol) is added at the temperature of-5-0 ℃, the temperature is controlled to be 15-20 ℃ after the addition is finished, the reaction solution is added into methanol for quenching after the detection reaction is finished, the filtration is carried out, the filtrate is washed by saturated sodium bicarbonate solution (200 ml multiplied by 3), saturated saline (100 ml) is washed, the organic phase is concentrated to be dry under reduced pressure, and then the compound I-2 is obtained, the yield is 92.1%, and the HPLC purity is 99.45%.
Example 11
Compound I-1 (36.89 g,0.10 mol), N, N-diisopropylethylamine (45.23 g,0.35 mol) were added to dry 2-methyltetrahydrofuran (300 ml), trifluoromethanesulfonic anhydride (50.79 g,0.18 mol) was added at a temperature of-5 to 0℃and reacted at a temperature of 25 to 30℃after completion of the addition, after completion of the detection reaction, the reaction solution was quenched with methanol, filtered, the filtrate was washed with saturated sodium hydrogencarbonate solution (200 ml. Times.3), saturated brine (100 ml) and the organic phase was concentrated to dryness under reduced pressure to give Compound I-2 in a yield of 90.2% and an HPLC purity of 99.52%.
Example 12
Compound I-1 (36.89 g,0.10 mol), sodium bicarbonate (71.08 g,0.55 mol) are added into dry chloroform (300 ml), trifluoromethanesulfonic anhydride (50.79 g,0.18 mol) is added at the temperature of 0-5 ℃, the reaction is carried out at the temperature of 20-25 ℃ after the addition, methanol is added into the reaction solution to quench the reaction solution after the reaction is detected, the reaction solution is filtered, the filtrate is washed by saturated sodium bicarbonate solution (200 ml multiplied by 3), saturated saline (100 ml) is washed, and the organic phase is concentrated to be dry under reduced pressure, thus obtaining the compound I-2, the yield is 84.3%, and the HPLC purity is 98.38%.
Example 13
Compound I-1 (36.89 g,0.10 mol), potassium bicarbonate (32.04 g,0.32 mol) are added into dry dichloromethane (300 ml), trifluoromethanesulfonic anhydride (33.86 g,0.12 mol) is added at the temperature of minus 15 ℃ to minus 10 ℃, after the addition is finished, the temperature is controlled to 5 ℃ to 10 ℃, after the detection reaction is finished, the reaction solution is added into methanol for quenching, filtration is carried out, the filtrate is washed by saturated sodium bicarbonate solution (200 ml multiplied by 3), saturated saline (100 ml) is washed, and the organic phase is concentrated to be dry under reduced pressure, thus obtaining the compound I-2, the yield is 85.2%, and the HPLC purity is 98.52%.
Example 14
Compound I-1 (36.89 g,0.10 mol), sodium carbonate (60.41 g,0.57 mol) were added to dry dichloromethane (300 ml), trifluoromethanesulfonic anhydride (76.18 g,0.27 mol) was added at a temperature of 10-15℃until the addition was completed, the reaction was carried out at a temperature of 40-45℃until the reaction was completed, the reaction mixture was quenched with methanol after the completion of the detection, filtered, the filtrate was washed with saturated sodium bicarbonate solution (200 ml. Times.3), saturated brine (100 ml) and the organic phase was concentrated to dryness under reduced pressure to give Compound I-2 in a yield of 85.5% and an HPLC purity of 98.44%.
Synthesis of Compound I
Example 15
Under nitrogen, compound I-2 (22.01 g,0.05 mol), cyclopropylamine (4.85 g,0.085 mol), pd (OAc) 2 (1.12g，0.005mol)、BINAP(3.74g，0.006mol)、Cs 2 CO 3 (40.73 g,0.125 mol) and diethylene glycol dimethyl ether (200 ml) are added into a closed reactor to react at the temperature of 80-85 ℃, after the detection reaction is finished, the reaction liquid is filtered by diatomite, the filtrate is poured into purified water (2000 ml), stirred and crystallized and filtered, and the filter cake is recrystallized by absolute ethyl alcohol to obtain the target product I, the yield is 98.6%, and the HPLC purity is 99.98%.
Example 16
Under nitrogen, compound I-2 (22.01 g,0.05 mol), cyclopropylamine (3.99 g,0.07 mol), pd (OAc) 2 (1.12 g,0.005 mol), BINAP (3.74 g, 0.006mol), t-BuOK (14.03 g,0.125 mol) and ethylene glycol dimethyl ether (200 ml) are added into a closed reactor to react at the temperature of 60-65 ℃, after the detection reaction is finished, the reaction liquid is filtered by kieselguhr, the filtrate is poured into purified water (2000 ml), stirred and crystallized and then filtered, and the filter cake is recrystallized by absolute ethyl alcohol to obtain the target product I, the yield is 93.3%, and the HPLC purity is 99.71%.
Example 17
Compound I-2 (22.01 g,0.05 mol) and cyclopropylamine (9) were reacted under nitrogen.99g，0.175mol)、PdCl 2 (0.89g，0.005mol)、Xantphos(3.47g，0.006mol)、Cs 2 CO 3 (40.73 g,0.125 mol) and 1, 4-dioxane (200 ml) are added into a closed reactor to react at the temperature of 75-80 ℃, after the detection reaction is finished, the reaction liquid is filtered by kieselguhr, the filtrate is poured into purified water (2000 ml), stirred and crystallized and filtered, and the filter cake is recrystallized by absolute ethyl alcohol to obtain the target product I, the yield is 94.3 percent, and the HPLC purity is 99.60 percent.
Example 18
Under nitrogen, compound I-2 (22.01 g,0.05 mol), cyclopropylamine (4.85 g,0.085 mol), pd (OAc) 2 (0.56g，0.0025mol)、BINAP(1.87g，0.003mol)、Cs 2 CO 3 (40.73 g,0.125 mol) and toluene (200 ml) are added into a closed reactor to react at the temperature of 95-100 ℃, after the detection reaction is finished, the reaction liquid is filtered by diatomite, the filtrate is concentrated to dryness under reduced pressure and then poured into purified water (1500 ml), stirred and crystallized and filtered, and the filter cake is recrystallized by absolute ethyl alcohol to obtain the target product I, the yield is 93.4 percent and the HPLC purity is 99.66 percent.
Example 19
Under nitrogen, compound I-2 (22.01 g,0.05 mol), cyclopropylamine (4.85 g,0.085 mol), pd (OAc) 2 (2.24g，0.001mol)、BINAP(7.78g，0.0125mol)、Cs 2 CO 3 (40.73 g,0.125 mol) and dimethylbenzene (200 ml) are added into a closed reactor to react at the temperature of 110-115 ℃, after the detection reaction is finished, the reaction liquid is filtered by diatomite, the filtrate is concentrated to dryness under reduced pressure and then poured into purified water (1500 ml), stirred and crystallized and filtered, and the filter cake is recrystallized by absolute ethyl alcohol to obtain the target product I, the yield is 94.6 percent, and the HPLC purity is 99.54 percent.
Example 20
Under nitrogen, compound I-2 (22.01 g,0.05 mol), cyclopropylamine (4.85 g,0.085 mol), pd (OAc) 2 (1.12g，0.005mol)、P(o-tolyl) 3 (1.83g，0.006mol)、Cs 2 CO 3 (35.84 g,0.11 mol) and diethylene glycol dimethyl ether (200 ml) are added into a closed reactor to react at the temperature of 90-95 ℃, after the detection reaction is finished, the reaction liquid is filtered by diatomite, and the filtrate is poured into purified waterIn (2000 ml), stirring, crystallizing, filtering, recrystallizing the filter cake with absolute ethyl alcohol to obtain the target product I, wherein the yield is 93.6%, and the HPLC purity is 99.52%.
Example 21
Under nitrogen, compound I-2 (22.01 g,0.05 mol), cyclopropylamine (4.85 g,0.085 mol), pd (OAc) 2 (1.12g，0.005mol)、P(t-Bu) 3 (1.21g，0.006mol)、Cs 2 CO 3 (58.64 g,0.18 mol) and 2-methyltetrahydrofuran (200 ml) are added into a closed reactor to react at the temperature of 70-75 ℃, after the detection reaction is finished, the reaction liquid is filtered by diatomite, the filtrate is concentrated to dryness under reduced pressure and then poured into purified water (1500 ml), stirred for crystallization and then filtered, and a filter cake is recrystallized by absolute ethyl alcohol to obtain a target product I, wherein the yield is 94.5 percent and the HPLC purity is 99.47 percent.
Example 22
Under nitrogen, compound I-2 (22.01 g,0.05 mol), cyclopropylamine (3.43 g,0.06 mol), pd (OAc) 2 (0.22g，0.001mol)、BINAP(1.25g，0.002mol)、Cs 2 CO 3 (32.58 g,0.1 mol) and tetrahydrofuran (200 ml) are added into a closed reactor to react at the temperature of 55-60 ℃, after the detection reaction is finished, the reaction liquid is filtered by kieselguhr, the filtrate is poured into purified water (2000 ml), stirred and crystallized and filtered, and the filter cake is recrystallized by absolute ethyl alcohol to obtain the target product I, the yield is 87.6%, and the HPLC purity is 98.84%.
Example 23
Under nitrogen, compound I-2 (22.01 g,0.05 mol), cyclopropylamine (10.85 g,0.19 mol), pd (OAc) 2 (4.49g，0.02mol)、BINAP(8.41g，0.014mol)、Cs 2 CO 3 (65.16 g,0.2 mol) and dimethylbenzene (200 ml) are added into a closed reactor to react at the temperature of 110-115 ℃, after the detection reaction is finished, the reaction liquid is filtered by diatomite, the filtrate is poured into purified water (2000 ml), stirred and crystallized and filtered, and the filter cake is recrystallized by absolute ethyl alcohol to obtain a target product I, wherein the yield is 86.3 percent and the HPLC purity is 97.98 percent.
Claims (10)
1. The nevirapine intermediate compound is characterized in that the structure is shown as a formula I-2:
2. a process for the preparation of nevirapine intermediate compound of claim 1, comprising the steps of: adding compound I-1 and acid binding agent into dry organic solvent A, and controlling temperature T A1 Adding trifluoromethanesulfonic anhydride, and controlling temperature T A2 After the reaction is finished, the compound I-2 is obtained through post-treatment, and the reaction route is as follows:
3. the preparation method according to claim 2, wherein the organic solvent A is selected from one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and chloroform; the temperature T is controlled A1 Is at the temperature of-10 to 10 ℃; t (T) A2 Is 10-40 ℃.
4. The method according to claim 2, wherein the acid-binding agent is selected from one of sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, and N, N-diisopropylethylamine.
5. The preparation method according to claim 2, wherein the molar ratio of the compound I-1 to the triflic anhydride to the acid-binding agent is 1:1.4 to 2.5:3.5 to 5.5.
6. The preparation method according to claim 2, wherein the preparation method of the compound I-1 comprises the following steps: adding compound SM-1 into solvent B at room temperature, and controlling temperature T B1 Adding N, N' -carbonyl diimidazole and controlling the temperature T B2 ReactionAfter the SM-1 reaction is detected, SM-2 is added, and the temperature T is controlled B3 After the reaction is detected, the compound I-1 is prepared by post-treatment, and the reaction route is as follows:
7. the preparation method according to claim 6, wherein the solvent B is selected from one or a combination of anhydrous dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone; the feeding mole ratio of the compound SM-1 to the N, N' -carbonyl diimidazole to the compound SM-2 is 1:1.0 to 1.3:1.0 to 1.2; the temperature T is controlled B1 0-20 ℃; t (T) B2 20-40 ℃; t (T) B3 Is 30-80 ℃.
8. Use of a nevirapine intermediate compound of claim 1 for the preparation of nevirapine.
9. Use of a nevirapine intermediate compound according to claim 8 for the preparation of nevirapine, characterized in that the preparation process comprises the steps of: under the protection of inert gas, adding a compound I-2, cyclopropylamine, a catalyst, a ligand, alkali and an organic solvent C into a closed reaction device, and controlling the temperature T C After the reaction is detected, nevirapine I is prepared through post-treatment, and the synthetic route is as follows:
10. the use according to claim 9, wherein the catalyst is selected from Pd (OAc) 2 、PdCl 2 、Pd 2 (dba) 3 One of the following; the ligand is selected fromP(t-Bu) 3 、P(o-tolyl) 3 One of BINAP, xantphos, dppf; the molar ratio of the compound I-2 to the cyclopropylamine, the catalyst, the ligand and the alkali is 1:1.4 to 3.5:0.05 to 0.2:0.06 to 0.25:2.2 to 3.6; the reaction temperature T C 60-110 ℃.
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