WO2023226902A1 - 一种kras g12c抑制剂的制备方法及其中间体 - Google Patents
一种kras g12c抑制剂的制备方法及其中间体 Download PDFInfo
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- WO2023226902A1 WO2023226902A1 PCT/CN2023/095362 CN2023095362W WO2023226902A1 WO 2023226902 A1 WO2023226902 A1 WO 2023226902A1 CN 2023095362 W CN2023095362 W CN 2023095362W WO 2023226902 A1 WO2023226902 A1 WO 2023226902A1
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- Prior art keywords
- compound
- inert solvent
- base
- obtain compound
- reacts
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- QHHHYLFZGYIBCX-UHFFFAOYSA-N n,n'-bis[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]methanediimine Chemical compound O1C(C)(C)OCC1CN=C=NCC1OC(C)(C)OC1 QHHHYLFZGYIBCX-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- PKVRJCUKSNFIBN-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 PKVRJCUKSNFIBN-UHFFFAOYSA-N 0.000 description 1
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical group [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108700042226 ras Genes Proteins 0.000 description 1
- 108010014186 ras Proteins Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to the field of drug synthesis, specifically, to a preparation method of KRAS G12C inhibitor and its intermediates.
- RAS is the most commonly mutated oncogene in human cancers, and 20 to 30% of human tumors contain RAS mutations, especially in cancer types such as lung cancer, colon cancer, and pancreatic cancer.
- RAS genes There are currently three known RAS genes, namely HRAS, NRAS and KRAS.
- RAS plays the role of a molecular switch. By binding to GTP (Guanosine Triphosphate) or GDP (Guanosine Diphosphate), it shows activation or inactivation in cells. , thereby regulating downstream signaling pathways. Under normal circumstances, the RAS protein is in an inactive state. After mutation, the conformation changes, RAS is in a continuously activated state, and the downstream signaling pathways are also continuously activated, leading to the occurrence of various cancers.
- GTP Guanosine Triphosphate
- GDP Guanosine Diphosphate
- KRAS is the most common subtype in the RAS family, and the KRAS gene accounts for 86% of the total RAS gene mutations.
- the most common mutation mode of KRAS is point mutation, which mostly occurs in G12, G13 in p-loop (aa 10-17) and Q61 in Switch II region (aa 59-76), among which G12 mutation is the most common (83%).
- KRAS G12C mutation accounts for 14.5% of KRAS mutations and is common in lung cancer (4.3%), followed by colorectal cancer (2.5%) and biliary tract cancer (2.3%). Since lung cancer is the number one cancer in China, there are more than 600,000 non-small cell lung cancer patients every year, which means that about 20,000 to 30,000 non-small cell lung cancer patients in China have clinical needs for KRAS G12C target drugs every year.
- This synthesis route uses B01 as the starting material and the ring-closing reaction with S-methylisothiourea sulfate under alkaline conditions to generate B02, and the chlorination reaction in the presence of phosphorus oxychloride to generate B03, which is reacted with S-methylisothiourea sulfate under alkaline conditions respectively.
- the starting material B01 of this synthesis route is not widely commercialized and is expensive; the intermediates B02, B03, B04, B05, B06 and B07 all have thioether structures, so they have pungent odor and are not environmentally friendly.
- the process of preparing B07 from B06 In the process, the palladium catalyst is easily poisoned due to the existing thioether structure, and more catalyst needs to be consumed; in the process of preparing B08 through the oxidation reaction of B07, B07 and B08 are easily oxidized into aromatization by-products; this route has multiple columns Chromatographic purification.
- this synthesis method has technical problems such as high cost, high pollution, low yield, and difficulty in mass production. Therefore, there is an urgent need to develop a simple, efficient, low-cost, low-pollution, column-free chromatography purification operation suitable for industrialization. Synthetic route for production.
- the object of the present invention is to provide a (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-((di Methylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piper
- a first aspect of the present invention provides a method for preparing KRAS G12C inhibitor A16, wherein the method includes the steps
- compound A13 In an inert solvent and in the presence of a condensing agent, compound A13 reacts with 2-fluoroacrylic acid to obtain compound A16.
- the method further includes the following steps
- Boc is removed from compound A12 to obtain compound A13.
- the method further includes the following steps
- the method further includes the following steps
- the method further includes the step
- the method further includes the step
- compound A07 is reacted with (S)-2-(piperazin-2-yl)acetonitrile or a salt thereof to obtain compound A08;
- R 1 is each independently a halogen (such as chlorine, bromine, iodine);
- R 2 is each independently selected from the following group of substituted or unsubstituted groups: C1-C10 alkyl, C3-C10 cycloalkyl, phenyl, benzyl; wherein, the substitution is one or more selected from the following group Group substitution: C1-C6 alkyl, C3-C6 cycloalkyl.
- the present invention provides a method for preparing intermediate compound A08, which includes the following steps:
- compound A07 reacts with (S)-2-(piperazin-2-yl)acetonitrile or its salt to obtain chemical compound Compound A08;
- R 1 is each independently a halogen (such as chlorine, bromine, iodine);
- R 2 is each independently selected from the following group of substituted or unsubstituted groups: C1-C10 alkyl, C3-C10 cycloalkyl, phenyl, benzyl; wherein, the substitution is one or more selected from the following group Group substitution: C1-C6 alkyl, C3-C6 cycloalkyl.
- R 2 is each independently selected from methyl, ethyl, isopropyl, and benzyl; preferably, it is methyl or ethyl.
- the inert solvent is selected from: dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-Methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetone, acetonitrile, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, N,N-dimethylformamide (DMF ), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), benzene, toluene, chlorobenzene, or A combination thereof; preferably, the inert solvent is selected from: dichloromethane, 1,2-dichloroethane, chlor
- the base is selected from: sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, triethylamine, 1-methylpyrrolidine, 1 -Methylpiperidine, dimethylisopropylamine, N,N-diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4 -Dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) ), 1,5-diazabicyclo[4.3.0]undec-7-ene (DBN), or a combination thereof; preferably, the base is selected from: sodium carbonate, potassium carbonate, cesium carbonate, triethyl Amine, 1-methylpyrrolidine, 1 -Methylpipe
- the molar equivalent of the base is 0.1 to 10 equivalents of compound A01, preferably 0.5 to 5 equivalents, and more preferably 1 to 3 equivalents.
- the inert solvent is selected from: dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-Methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetone, acetonitrile, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, N,N-dimethylformamide (DMF ), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), benzene, toluene, chlorobenzene, or A combination thereof; preferably, the inert solvent is selected from: toluene,
- step s2) compound A02 and compound A15 are first alkylated and then ring-closed to obtain compound A03.
- the base is selected from: sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, 1-methyl pyrrolidine, 1-methylpiperidine, dimethylisopropylamine, N,N-diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, 2-methylpyridine, 2,6-di Methylpyridine, 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undecane- 7-ene (DBU), 1,5-diazabicyclo[4.3.0]undec-7-ene (DBN), or a combination thereof; preferably, the base is selected from: sodium carbonate, potassium carbonate, Sodium methoxide,
- the molar equivalent of the base used is 0.1 to 10 equivalents of compound A02, preferably 0.5 to 5 equivalents, and more preferably 1 to 3 equivalents.
- the inert solvent is selected from: tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetone, acetonitrile, ethanol, methanol, isopropyl alcohol , tert-butanol, pentanol, n-butanol, N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), benzene, toluene, chlorobenzene, or combinations thereof; preferably, the inert solvent is selected From: Tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethanol, methanol, isopropanol, tert-butanol, pentanol, n-butanol, ethylene glycol dimethyl ether (DME), benzene, toluene, chlorobenzene , or combinations thereof; preferably, the inert solvent
- the base is selected from: sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyloxide, 1,4-diazabicyclo [2.2.
- the base is selected from: sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyloxide, 2,2,6,6-tetramethyl Lithium piperidine, lithium hexamethyldisilazide (LHMDS), potassium hexamethyldisilamide (KHMDS), or a combination thereof; more preferably, the base is selected from: sodium methoxide, sodium ethoxide, Sodium ethoxide, Sodium
- the molar equivalent of the base used is 0.1 to 10 equivalents of compound A03, preferably 0.5 to 5 equivalents, and more preferably 1 to 3 equivalents.
- the reaction temperature is 30°C to 120°C; preferably, the reaction temperature is 50°C to 100°C, and more preferably, the reaction temperature is 60°C to 90°C.
- the chlorinating reagent is selected from: oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, or combinations thereof, more preferably The ground is phosphorus oxychloride.
- the debenzylation reagent is selected from: ceric ammonium nitrate (CAN), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), 1 -Chloroethyl chloroformate, or combinations thereof.
- the inert solvent is selected from: tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether (DME), dichloroethane, carbon tetrachloride, chloroform, benzene , toluene, chlorobenzene, or a combination thereof; preferably, the inert solvent is selected from: tetrahydrofuran, 2-methyltetrahydrofuran, dichloroethane, carbon tetrachloride, chloroform, toluene, chlorobenzene, or a combination thereof; more Preferably, the inert solvent is selected from: dichloroethane, carbon tetrachloride, chloroform, toluene, or combinations thereof.
- the inert solvent is selected from: dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-Methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetone, acetonitrile, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, N,N-dimethylformamide (DMF ), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), benzene, toluene, chlorobenzene, or A combination thereof; preferably, the inert solvent is selected from: toluene,
- the base is selected from: sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, hydrogen Potassium oxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, 1-methylpyrrolidine, 1-methylpiperidine, dimethylisopropylamine, N,N-diisopropylethylamine, N- Methylmorpholine, imidazole, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane ( DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]undec-7-ene (DBN) , or a combination thereof
- the molar equivalent of the base is 0.1 to 10 equivalents of compound A06, preferably 0.5 to 5 equivalents, and more preferably 1 to 3 equivalents.
- the inert solvent is selected from: dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-Methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetone, acetonitrile, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, N,N-dimethylformamide (DMF ), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), benzene, toluene, chlorobenzene, or its combination;
- the inert solvent is selected from: toluene,
- step s7) the salt of (S)-2-(piperazin-2-yl)acetonitrile is (2S,3S)-2,3-dihydroxysuccinate.
- the base is selected from: sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, hydrogen Potassium oxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, 1-methylpyrrolidine, 1-methylpiperidine, dimethylisopropylamine, N,N-diisopropylethylamine, N- Methylmorpholine, imidazole, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane ( DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]undec-7-ene (DBN) , or a combination thereof
- the molar equivalent of the base is 0.1 to 10 equivalents of compound A07, preferably 0.5 to 5 equivalents, and more preferably 1 to 3 equivalents.
- the present invention provides a method for preparing KRAS G12C inhibitor A16, which method includes the steps
- compound A09 In an inert solvent, in the presence of a base and a catalyst, compound A09 reacts with (1-((dimethylamino)methyl)cyclopropyl)methanol to obtain compound A10;
- compound A13 In an inert solvent, in the presence of a base and a condensing agent, compound A13 reacts with 2-fluoroacrylic acid to obtain compound A16.
- the base is selected from: sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tert.
- the base is selected from: sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbon
- the molar equivalent of the base is 0.1 to 10 equivalents of compound A08, preferably 0.5 to 5 equivalents, and more preferably 1 to 3 equivalents.
- the inert solvent is selected from: tetrahydrofuran (922.0kg), dioxane, acetonitrile, water, or a combination thereof.
- the catalyst is selected from: palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, bis( Dibenzylideneacetone) palladium, bis(acetonitrile)palladium dichloride, bis(triphenylphosphine)palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride , 1,1'-bis(diphenylphosphino)ferrocene palladium dichloromethane complex, bis(benzonitrile)palladium dichloride, 1,4-bis(diphenylphosphine)butane -Palladium chloride, bis(acetonitrile)palladium dichloride, allyl palladium chloride dimer, [1,3-bis(2,6-diisopropy
- the catalyst is selected from: palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, tris(triphenylphosphine)palladium, (Dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, bis(acetonitrile)palladium dichloride, bis(triphenylphosphine)palladium chloride, [1,1'-bis(diphenyl) Phosphino)ferrocene] dichloride Palladium, 1,1'-bis(diphenylphosphino)ferrocene dichloride palladium dichloromethane complex, RuPhos Pd G1, RuPhos Pd G2, RuPhos Pd G3, Xphos Pd G1, Xphos Pd G2,
- the molar equivalent of the catalyst is 0.01-5 equivalents of compound A09; preferably 0.01-2 equivalents, preferably 0.01-1 equivalents, more preferably 0.01 ⁇ 0.05 equivalent.
- the base is selected from: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, tert-butyl alcohol Potassium, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-bis Azabicyclo[4.3.0]undec-7-ene (DBN), lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidine, hexamethyldisilyl Lithium amide (LHMDS), potassium hexamethyldisilazide (KHMDS), or a combination thereof; preferably, the base is selected from: sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide , 1,4-diazabicyclo
- the molar equivalent of the base is 0.1 to 10 equivalents of compound A09; preferably, it is 1 to 3 equivalents.
- the inert solvent is selected from: tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, dioxane, benzene, toluene, N,N-bis Methylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), or other Combination;
- the inert solvent is selected from: tetrahydrofuran, dimethyltetrahydrofuran, dioxane, toluene, or a combination thereof.
- the reaction temperature is 30°C to 130°C; preferably, the reaction temperature is 50°C to 100°C; more preferably, the reaction temperature is 60°C to 90°C.
- the catalyst in step s'3), is selected from: palladium carbon, platinum dioxide, platinum carbon, palladium hydroxide, palladium chloride, Raney nickel, or a combination thereof; preferably, the The catalyst is selected from: palladium carbon, platinum carbon, palladium hydroxide, or combinations thereof.
- the weight of the catalyst is 1% to 100% of the weight of A10; preferably 5% to 20%.
- the catalyst is selected from: palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, bis(di(dibenzylideneacetone)dipalladium) Benzylideneacetone) palladium, bis(acetonitrile)palladium dichloride, bis(triphenylphosphine)palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 1,1'-Bis(diphenylphosphine)ferrocene palladium dichloride dichloromethane complex, bis(benzonitrile)palladium dichloride, 1,4-bis(diphenylphosphine)butane- Palladium chloride, bis(acetonitrile)palladium dichloride, allyl palladium chloride, bis(acetonitrile)pal
- the molar equivalent of the catalyst is 0.01-5 equivalents of compound A11; preferably, it is 0.01-2 equivalents.
- the base is selected from: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, tert-butyl alcohol Potassium, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-bis Azabicyclo[4.3.0]undec-7-ene (DBN), lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidine, hexamethyldisilyl Lithium amide (LHMDS), potassium hexamethyldisilazide (KHMDS), or a combination thereof; preferably, the base is selected from: sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide , 1,4-diazabicyclo
- the molar equivalent of the base is 0.1 to 10 equivalents of compound A11; preferably, it is 1 to 3 equivalents.
- the inert solvent is selected from: tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, dioxane, benzene, toluene, N,N-dimethyl Formamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), or combinations thereof ;
- it is tetrahydrofuran, dimethyltetrahydrofuran, dioxane, toluene, or a combination thereof.
- the reaction temperature is 0°C to 130°C; preferably the reaction temperature is 50°C to 100°C, and more preferably the reaction temperature is 60°C to 90°C (such as 75-85 °C).
- the acid is selected from: hydrochloric acid, hydrogen chloride, hydrobromic acid, trifluoroacetic acid, phosphoric acid, or a combination thereof.
- the inert solvent is selected from: ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, Acetone, acetonitrile, ethanol, methanol, isopropyl alcohol, tert-butanol, pentanol, n-butanol, benzene, toluene, chlorobenzene, ethylene glycol dimethyl ether (DME), or combinations thereof; preferably, the inert The solvent is selected from: ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethanol, methanol, isopropyl alcohol, tert-butanol, pentanol, n-butanol, toluene,
- the condensation agent is selected from: carbodiimide condensation agent (DCC, DIC, EDCI, BDDC, P-EDC), phosphine salt condensation agent (BOP- Cl, BOP, PyBOP, AOP, PyAOP), urea salt/ammonium salt condensation agents (HATU, HBTU, TATU, TBTU, COMU, HOTU), other types of condensation agents (T3P, BOP-Cl, FDP, FDDP, DEBT, EDQ), or a combination thereof; preferably, the condensation agent is selected from: EDCI, BOP, HATU, T3P, or a combination thereof.
- the molar equivalent of the condensation agent is 0.1 to 10 equivalents of compound A13; preferably, it is 1 to 3 equivalents.
- the inert solvent is selected from: dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, Tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetonitrile, acetone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dioxane Methyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol dimethyl ether (DME), benzene, toluene, chlorobenzene, or combinations thereof; preferably, the inert solvent is selected from: methylene chloride , Ethyl acetate, isopropyl acetate, tetrahydrofuran, dimethyltetrahydr
- the base is selected from: sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tert.
- the base is selected from: sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbon
- step s'6) also includes a recrystallization step of compound A16, wherein the crystallization solvent is selected from: ethyl acetate, isopropyl acetate, dichloromethane, 1,2-dichloro Ethane, chloroform, carbon tetrachloride, acetonitrile, acetone, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, diethyl ether, methyl ethyl ether, dioxane, petroleum ether, n-heptane, n-hexane, pentane, cyclohexane, methylcyclohexane, ethylene glycol dimethyl ether (DME), benzene, toluene, chlorobenzene, methanol, ethanol, isopropyl alcohol, tert-butanol, propanol, or
- the HPLC purity of compound A16 is greater than 95% and the ee value is greater than 95%.
- the HPLC purity is greater than 98% and the ee value is greater than 98%. More preferably, the HPLC purity is greater than 99% and the ee value is greater than 99%. Greater than 99%.
- the fourth aspect of the present invention provides a KRAS G12C inhibitor intermediate, the intermediate being selected from:
- the present invention provides a method for preparing KRAS G12C inhibitor A16, which method includes the steps
- compound A13 In an inert solvent, in the presence of a base and a condensing agent, compound A13 reacts with 2-fluoroacrylic acid to obtain compound A16.
- the sixth aspect of the present invention provides a method for preparing intermediate A13, which includes the following steps
- Boc is removed from compound A12 to obtain compound A13.
- the seventh aspect of the present invention provides a method for preparing intermediate A12, which includes the following steps
- the eighth aspect of the present invention provides a method for preparing intermediate A11, which includes the following steps:
- the method further includes the step
- the method further includes the step
- compound A07 is reacted with (S)-2-(piperazin-2-yl)acetonitrile or a salt thereof to obtain compound A08;
- R 1 is each independently a halogen (such as chlorine, bromine, iodine);
- R 2 is each independently selected from the following group of substituted or unsubstituted groups: C1-C10 alkyl, C3-C10 cycloalkyl, phenyl, benzyl; wherein, the substitution is one or more selected from the following group Group substitution: C1-C6 alkyl, C3-C6 cycloalkyl.
- the present invention provides a method for preparing intermediate A05, which method includes the steps
- the inventor developed a new KRAS G12C inhibitor intermediate, It can synthesize KRAS G12C inhibitors with high efficiency, and has the advantages of low cost, safe and environmentally friendly process, and column-free chromatography operation, which is more suitable for industrial production. On this basis, the present invention was completed.
- inert solvent refers to a reagent that does not react with the reaction substrate.
- Intermediates refer to semi-finished products, which are products formed during the production of the required products. Typically, inventors can proceed to the production of products from intermediates as starting materials. Therefore, screening suitable intermediates can optimize the process route, thereby increasing the yield and saving time and cost.
- the intermediate refers to the following compounds
- the preparation method of intermediate A8 includes the steps
- compound A07 is reacted with (S)-2-(piperazin-2-yl)acetonitrile or a salt thereof to obtain compound A08;
- R 1 is each independently a halogen (such as chlorine, bromine, iodine);
- R 2 is each independently selected from the following group of substituted or unsubstituted groups: C1-C10 alkyl, C3-C10 cycloalkyl, phenyl, benzyl; wherein, the substitution is one or more selected from the following group Substituted by groups: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, preferably, R 2 is each independently selected from methyl, ethyl, isopropyl, benzyl; preferably methyl or ethyl .
- the preparation method of intermediate A10 includes the steps
- the preparation of intermediate A10 also includes the preparation of the above-mentioned intermediate A8.
- the preparation method of intermediate A11 includes the following steps
- the preparation of intermediate A11 also includes the preparation of the above-mentioned intermediate A10.
- the preparation method of intermediate A12 includes the following steps
- the preparation of intermediate A12 also includes the preparation of the above-mentioned intermediate A11.
- the preparation method of intermediate A13 includes the following steps
- Boc is removed from compound A12 to obtain compound A13.
- the acid is hydrochloric acid.
- the preparation of intermediate A13 also includes the preparation of the above-mentioned intermediate A12.
- the KRAS G12C inhibitor described in the present invention refers to a component containing a structural part Compounds, such as compound A16
- the preparation of compound A16 includes the following steps
- compound A13 In an inert solvent, in the presence of a base and a condensing agent, compound A13 reacts with 2-fluoroacrylic acid to obtain compound A16.
- the preparation of compound A16 also includes the preparation of the above-mentioned intermediate A13.
- the present invention provides a new intermediate
- the intermediate of the present invention can efficiently synthesize KRAS G12C inhibitors, such as (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-(1-(( Dimethylamino)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl) Piperazin-2-yl)acetonitrile;
- the process of the present invention avoids a series of process problems caused by preparing intermediates containing thioether structures
- the process of the present invention avoids the use of oxidants and the introduction of aromatization impurities that are difficult to remove;
- the process of the present invention can avoid the use of multiple column chromatography purification operations and is suitable for industrial production;
- the process of the present invention is simple to operate, easy to purify and obtain high-quality, high-purity intermediates and KRAS G12C inhibitors;
- the new route of the present invention has greater advantages and stronger industrialization prospects than the existing methods.
- the present invention is further described below by means of examples, but the present invention is not limited to the scope of the described examples.
- the solutions of the present invention described above are all technical solutions that can achieve the purpose of the present invention.
- the temperatures and reagents used in the following examples can be replaced by the corresponding temperatures and reagents mentioned above to achieve the purpose of the present invention.
- Carboxylic acid ester (171.2kg, 1.0eq), add (2S, 3S)-2,3-dihydroxysuccinate of (S)-2-(piperazin-2-yl)acetonitrile at 0 to 5°C (236.7kg, 1.1eq), slowly add N,N-diisopropylethylamine (321.7kg, 5.0eq) after 10 minutes, stir at 0 ⁇ 5°C for 3 hours, adjust the temperature to 20 ⁇ 25°C and stir for 16 hours .
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Abstract
涉及一种KRAS G12C抑制剂的制备方法及其中间体。所述方法工艺路线简洁、高效、低成本、低污染、安全性高、无柱层析纯化操作,制备的目标产物HPLC纯度大于99.0%,产物的ee值大于99.0%,适合工业化应用。
Description
本发明涉及药物合成领域,具体地,涉及一种KRAS G12C抑制剂的制备方法及其中间体。
RAS是人类癌症中最常出现突变的致癌基因,20~30%的人类肿瘤都存在RAS突变,尤其是在肺癌、结肠癌和胰腺癌等癌症种类中。目前已知的RAS基因有三种分别为HRAS、NRAS和KRAS,RAS起着分子开关的作用,通过结合GTP(Guanosine Triphosphate)或GDP(Guanosine Diphosphate),在细胞中分别表现出激活或失活的状态,以此调控下游的信号通路。正常情况下,RAS蛋白处于非活化状态,突变后构象发生改变,RAS处于持续激活状态,且下游信号通路也被持续激活,从而导致多种癌症的发生。而KRAS是RAS家族中最常见的亚型,KRAS基因占RAS基因突变总数的86%。KRAS最常见的突变方式为点突变,多发生在p-loop(aa 10~17)中的G12、G13和Switch II区(aa 59-76)的Q61,其中G12突变最为常见(83%)。KRAS G12C突变在KRAS突变中占14.5%,常见于肺癌(4.3%)、其次结直肠癌(2.5%)和胆道癌(2.3%)。由于肺癌是中国第一大癌症,每年有60多万非小细胞肺癌患者,意味着中国每年约有2~3万非小细胞肺癌患者有基于KRAS G12C靶点药物的临床需求。
(S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-(1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈或其盐作为基于KRAS G12C抑制剂的原料药,专利WO2021078312、WO2021078285与CN112694475等均报道了该化合物的合成方法,合成路线如下:
该合成路线以B01为起始原料与S-甲基异硫脲硫酸盐在碱性条件下关环反应生成B02,在三氯氧磷存在下氯代反应生成B03,在碱性条件下分别与(S)-2-(哌嗪-2-基)乙腈和(Boc)2O反应生成B05,接着B05脱除苄基与8-氯-7-氟萘-1-基三氟甲烷磺酸酯通过Buchwald反应生成B07,然后B07的甲硫醚氧化后再与(1-((二甲氨基)甲基)环丙基)甲醇在碱性条件下反应生成A12,最后A12脱除Boc保护后再与2-氟丙烯酰氯缩合反应生成A16。
该合成路线的起始原料B01未广泛商业化、价格昂贵;中间体B02、B03、B04、B05、B06与B07均存在硫醚结构,因此存在刺激性异味、不环保,在B06制备B07的过程中,由于存在的硫醚结构而导致钯催化剂容易中毒,则需要消耗更多的催化剂;在B07氧化反应制备B08过程中,B07与B08容易氧化为芳构化副产物;该路线存在多次柱层析纯化。
综上所述,该合成方法存在成本高、污染大、收率低、难以批量生产等技术问题,因此迫切需要开发一种简洁、高效、低成本、低污染、无柱层析纯化操作适合工业化生产的合成路线。
发明内容
针对背景技术中的问题,本发明的目的在于提供一种(S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-(1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈及其中间体的合成方法,该合成方法成本低、工艺安全环保、无柱层析操作更适合工业化生产。
本发明的第一方面,提供一种KRAS G12C抑制剂A16的制备方法,其中,所述方法包括步骤
s’6)在惰性溶剂中,缩合剂存在下,化合物A13与2-氟丙烯酸反应,得到化合物A16。
在另一优选例中,所述方法还包括如下步骤
s’5)在惰性溶剂中,酸存在下,化合物A12脱除Boc,得到化合物A13。
在另一优选例中,所述方法还包括如下步骤
s’4)在惰性溶剂中,碱和催化剂存在下,化合物A11与8-氯-7-氟萘-1-基三氟甲烷磺酸酯反应,得到化合物A12。
在另一优选例中,所述方法还包括如下步骤
s’3)在惰性溶剂中,催化剂和氢气存在下,化合物A10脱除Cbz,得到化合物A11。
在另一优选例中,所述方法还包括步骤
s’1)在惰性溶剂中,碱存在下,化合物A08与(Boc)2O反应,得到化合物A09;
s’2)在惰性溶剂中,碱和催化剂存在下,化合物A09与(1-((二甲氨基)甲基)环丙基)甲醇反应,得到化合物A10。
在另一优选例中,所述方法还包括步骤
s1)在惰性溶剂中,碱存在下,化合物A01与化合物A14反应,得到化合物A02;
s2)在惰性溶剂中,碱存在下,化合物A02与化合物A15反应,得到化合物A03;
s3)在惰性溶剂中,碱存在下,化合物A03与尿素反应,得到化合物A04;
s4)化合物A04与氯化试剂反应,得到化合物A05;
s5)在惰性溶剂中,脱苄基试剂存在下,化合物A05脱除苄基,得到化合物A06;
s6)在惰性溶剂中,化合物A06与CbzCl反应,得到化合物A07;
s7)在惰性溶剂中,化合物A07与(S)-2-(哌嗪-2-基)乙腈或其盐反应,得到化合物A08;
R1各自独立为卤素(如氯、溴、碘);
R2各自独立选自取代或未取代的下组基团:C1-C10烷基、C3-C10环烷基、苯基、苄基;其中,所述取代是被选自下组的一个或多个基团取代:C1-C6烷基、C3-C6环烷基。
本发明第二方面,提供一种中间体化合物A08的制备方法,其包括以下步骤
s1)在惰性溶剂中,碱存在下,化合物A01与化合物A14反应,得到化合物A02;
s2)在惰性溶剂中,碱存在下,化合物A02与化合物A15反应,得到化合物A03;
s3)在惰性溶剂中,碱存在下,化合物A03与尿素反应,得到化合物A04;
s4)化合物A04与氯化试剂反应,得到化合物A05;
s5)在惰性溶剂中,脱苄基试剂存在下,化合物A05脱除苄基,得到化合物A06;
s6)在惰性溶剂中,化合物A06与CbzCl反应,得到化合物A07;
s7)在惰性溶剂中,化合物A07与(S)-2-(哌嗪-2-基)乙腈或其盐反应,得到化
合物A08;
R1各自独立为卤素(如氯、溴、碘);
R2各自独立选自取代或未取代的下组基团:C1-C10烷基、C3-C10环烷基、苯基、苄基;其中,所述取代是被选自下组的一个或多个基团取代:C1-C6烷基、C3-C6环烷基。
在另一优选例中,R2各自独立选自甲基、乙基、异丙基、苄基;优选地为甲基或者乙基。
在另一优选例中,步骤s1)中,所述惰性溶剂选自:二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、乙酸乙酯、乙酸异丙酯、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、二氧六环、丙酮、乙腈、石油醚、正庚烷、正己烷、戊烷、环己烷、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙二醇二甲醚(DME)、苯、甲苯、氯苯、或其组合;优选地,所述惰性溶剂选自:二氯甲烷、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、乙腈、二氧六环、N,N-二甲基甲酰胺、N-甲基吡咯烷酮(NMP)、或其组合;更优选地,所述惰性溶剂选自:二氯甲烷、四氢呋喃、二甲基四氢呋喃、乙腈、N,N-二甲基甲酰胺、或其组合。
在另一优选例中,步骤s1)中,所述的碱选自:碳酸钠、碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、三乙胺、1-甲基吡咯烷、1-甲基哌啶、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、咪唑、吡啶、2-甲基吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶(DMAP)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]十一碳-7-烯(DBN)、或其组合;优选地,所述碱选自:碳酸钠、碳酸钾、碳酸铯、三乙胺、1-甲基吡咯烷、1-甲基哌啶、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、咪唑、吡啶、2-甲基吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶(DMAP)、或其组合;更优选地,所述碱选自:碳酸钠、碳酸钾、三乙胺、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、或其组合。
在另一优选例中,步骤s1)中,所述碱的摩尔当量为化合物A01的0.1~10当量,优选地为0.5~5当量,更优选地为1~3当量。
在另一优选例中,步骤s2)中,所述惰性溶剂选自:二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、乙酸乙酯、乙酸异丙酯、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、二氧六环、丙酮、乙腈、石油醚、正庚烷、正己烷、戊烷、环己烷、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙二醇二甲醚(DME)、苯、甲苯、氯苯、或其组合;优选地,所述惰性溶剂选自:甲苯、四氢呋喃、2-甲基四氢呋喃、二氧六环、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、
或其组合;更优选地,所述惰性溶剂选自:甲苯、四氢呋喃、2-甲基四氢呋喃、二氧六环、N-甲基吡咯烷酮(NMP)、或其组合。
在另一优选例中,步骤s2)中,化合物A02与化合物A15先烷基化反应后,再关环反应,得到化合物A03。
在另一优选例中,步骤s2)中,所述碱选自:碳酸钠、碳酸钾、碳酸铯、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、三乙胺、1-甲基吡咯烷、1-甲基哌啶、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、咪唑、吡啶、2-甲基吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶(DMAP)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]十一碳-7-烯(DBN)、或其组合;优选地,所述碱选自:碳酸钠、碳酸钾、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、三乙胺、1-甲基吡咯烷、1-甲基哌啶、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、咪唑、吡啶、2-甲基吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶(DMAP)、或其组合;更优选地,所述碱选自:碳酸钾、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、三乙胺、N,N-二异丙基乙胺、或其组合。
在另一优选例中,步骤s2)中,所用碱的摩尔当量为化合物A02的0.1~10当量,优选地为0.5~5当量,更优选地为1~3当量。
在另一优选例中,步骤s3)中,所述惰性溶剂选自:四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、二氧六环、丙酮、乙腈、乙醇、甲醇、异丙醇、叔丁醇、戊醇、正丁醇、N-甲基吡咯烷酮(NMP)、乙二醇二甲醚(DME)、苯、甲苯、氯苯、或其组合;优选地,所述惰性溶剂选自:四氢呋喃、2-甲基四氢呋喃、二氧六环、乙醇、甲醇、异丙醇、叔丁醇、戊醇、正丁醇、乙二醇二甲醚(DME)、苯、甲苯、氯苯、或其组合;更优选地,所述惰性溶剂选自:四氢呋喃、2-甲基四氢呋喃、乙醇、甲醇、异丙醇、叔丁醇、戊醇、正丁醇、或其组合。
在另一优选例中,步骤s3)中,所述碱选自:甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、叔戊醇钠、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]十一碳-7-烯(DBN)、二异丙基氨基锂(LDA)、2,2,6,6-四甲基哌啶锂、六甲基二硅基氨基锂(LHMDS)、六甲基二硅基胺基钾(KHMDS)、或其组合;优选地,所述碱选自:甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、叔戊醇钠、2,2,6,6-四甲基哌啶锂、六甲基二硅基氨基锂(LHMDS)、六甲基二硅基胺基钾(KHMDS)、或其组合;更优选地,所述碱选自:甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、叔戊醇钠、或其组合。
在另一优选例中,步骤s3)中,所用碱的摩尔当量为化合物A03的0.1~10当量,优选地为0.5~5当量,更优选地为1~3当量。
在另一优选例中,步骤s3)中,反应温度为30℃至120℃;优选地,反应温度为50℃至100℃,更优选地,反应温度为60℃至90℃。
在另一优选例中,步骤s4)中,所述的氯化试剂选自:草酰氯、氯化亚砜、三氯氧磷、三氯化磷、五氯化磷、或其组合,更优选地为三氯氧磷。
在另一优选例中,步骤s5)中,所述的脱苄基试剂选自:硝酸铈铵(CAN)、2,3-二氯-5,6-二氰对苯醌(DDQ)、1-氯甲酸氯乙酯、或其组合。
在另一优选例中,步骤s5)中,所述惰性溶剂选自:四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚(DME)、二氯乙烷、四氯化碳、氯仿、苯、甲苯、氯苯、或其组合;优选地,所述惰性溶剂选自:四氢呋喃、2-甲基四氢呋喃、二氯乙烷、四氯化碳、氯仿、甲苯、氯苯、或其组合;更优选地,所述惰性溶剂选自:二氯乙烷、四氯化碳、氯仿、甲苯、或其组合。
在另一优选例中,步骤s6)中,所述惰性溶剂选自:二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、乙酸乙酯、乙酸异丙酯、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、二氧六环、丙酮、乙腈、石油醚、正庚烷、正己烷、戊烷、环己烷、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙二醇二甲醚(DME)、苯、甲苯、氯苯、或其组合;优选地,所述惰性溶剂选自:甲苯、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、氯仿、四氢呋喃、2-甲基四氢呋喃、二氧六环、乙腈、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、或其组合;更优选地,所述惰性溶剂选自:甲苯、二氯甲烷、乙腈、四氢呋喃、2-甲基四氢呋喃、二氧六环、N,N-二甲基甲酰胺(DMF)、或其组合。
在另一优选例中,步骤s6)中,所述碱选自:碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯、甲醇钠、乙醇钠、氢氧化锂、氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾、三乙胺、1-甲基吡咯烷、1-甲基哌啶、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、咪唑、吡啶、2-甲基吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶(DMAP)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]十一碳-7-烯(DBN)、或其组合;优选地,所述碱选自:碳酸钠、碳酸钾、三乙胺、1-甲基哌啶、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、或其组合;更优选地,所述碱选自:碳酸钠、碳酸钾、三乙胺、N,N-二异丙基乙胺、或其组合。
在另一优选例中,步骤s6)中,所述碱的摩尔当量为化合物A06的0.1~10当量,优选地为0.5~5当量,更优选地为1~3当量。
在另一优选例中,步骤s7)中,所述惰性溶剂选自:二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、乙酸乙酯、乙酸异丙酯、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、二氧六环、丙酮、乙腈、石油醚、正庚烷、正己烷、戊烷、环己烷、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙二醇二甲醚(DME)、苯、甲苯、氯苯、或其组合;
优选地,所述惰性溶剂选自:甲苯、乙酸乙酯、二氯甲烷、1,2-二氯乙烷、氯仿、四氢呋喃、2-甲基四氢呋喃、二氧六环、乙腈、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、或其组合;更优选地,所述惰性溶剂选自:甲苯、二氯甲烷、乙腈、四氢呋喃、2-甲基四氢呋喃、二氧六环、N,N-二甲基甲酰胺(DMF)、或其组合。
在另一优选例中,步骤s7)中,(S)-2-(哌嗪-2-基)乙腈的盐为(2S,3S)-2,3-二羟基琥珀酸盐。
在另一优选例中,步骤s7)中,所述碱选自:碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯、甲醇钠、乙醇钠、氢氧化锂、氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾、三乙胺、1-甲基吡咯烷、1-甲基哌啶、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、咪唑、吡啶、2-甲基吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶(DMAP)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]十一碳-7-烯(DBN)、或其组合;优选地,所述碱选自:碳酸钠、碳酸钾、三乙胺、1-甲基哌啶、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、或其组合;更优选地,所述碱选自:碳酸钠、碳酸钾、三乙胺、N,N-二异丙基乙胺、或其组合。
在另一优选例中,步骤s7)中,所述碱的摩尔当量为化合物A07的0.1~10当量,优选地为0.5~5当量,更优选地为1~3当量。
本发明第三方面,提供一种KRAS G12C抑制剂A16的制备方法,所述方法包括步骤
s’1)在惰性溶剂中,碱存在下,化合物A08与(Boc)2O反应,得到化合物A09;
s’2)在惰性溶剂中,碱和催化剂存在下,化合物A09与(1-((二甲氨基)甲基)环丙基)甲醇反应,得到化合物A10;
s’3)在惰性溶剂中,催化剂和氢气存在下,化合物A10脱除Cbz,得到化合物A11;
s’4)在惰性溶剂中,碱和催化剂存在下,化合物A11与8-氯-7-氟萘-1-基三氟甲
烷磺酸酯反应,得到化合物A12;
s’5)在惰性溶剂中,酸存在下,化合物A12脱除Boc,得到化合物A13;
s’6)在惰性溶剂中,碱和缩合剂存在下,化合物A13与2-氟丙烯酸反应,得到化合物A16。
在另一优选例中,步骤s’1)中,所述碱选自:碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯、氢氧化锂、氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾、三乙胺、1-甲基吡咯烷、1-甲基哌啶、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、咪唑、吡啶、2-甲基吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶(DMAP)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]十一碳-7-烯(DBN)、或其组合;优选地,所述碱选自:碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、或其组合;更优选地,所述碱选自:碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、N,N-二异丙基乙胺、或其组合。
在另一优选例中,步骤s’1)中,所述碱的摩尔当量为化合物A08的0.1~10当量,优选地为0.5~5当量,更优选地为1~3当量。
在另一优选例中,步骤s’1)中,惰性溶剂选自:四氢呋喃(922.0kg)、二氧六环、乙腈、水,或其组合。
在另一优选例中,步骤s’2)中,所述的催化剂选自:醋酸钯、氯化钯、四(三苯基膦)钯、三(二亚苄基丙酮)二钯、双(二亚苄基丙酮)钯、双(乙腈)二氯化钯、二(三苯基膦)氯化钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1'-双(二苯基膦基)二茂铁二氯化钯二氯甲烷复合物、二(苯腈)二氯化钯、1,4-双(二苯基膦)丁烷-氯化钯、双(乙腈)二氯化钯、烯丙基氯化钯二聚物、[1,3-双(2,6-二异丙基苯基)咪唑亚基](3-氯吡啶基)二氯化钯、[二叔丁基(氯化)膦]二氯化钯二聚体、双(甲基二苯基膦)二氯化钯、苄基双(三苯基膦)氯化钯、1,3-双(二异丙基苯基)-2-咪唑啉亚基氯化钯二聚体、(三叔丁基膦)(2'-氨基联苯基)氯化钯、[(R)-(+)-2,2'-双(二苯基膦)-1,1'-联萘]二氯化钯、氯化钯(π-肉桂基)二聚物、[1,3-双(2,6-二异丙基苯基)咪唑-2(3H)-亚基](3-氯-1-吡啶基)氯化钯、1,1'-双(二叔丁基膦)二茂铁二氧化钯、双(三环己基膦)二氯化钯、[1,2-双(二苯基膦)乙烷]二氯化钯、[1,3-双(二苯基膦)丙烷]氯化钯、二氯双[二叔丁基(4-二甲氨基苯基)膦]钯、二(三叔丁基膦)钯、二氯双(二叔丁基苯基膦)钯、RuPhos Pd G1、RuPhos Pd G2、RuPhos Pd G3、Xphos Pd G1、Xphos Pd G2、Xphos Pd G3、BrettPhos Pd G1、BrettPhos Pd G3、XantPhos Pd G3、DavePhos-Pd-G3、APhos Pd G3、Pd G3、,1'-联萘-2,2'-双二苯膦、或其组合;优选地,所述催化剂选自:醋酸钯、氯化钯、四(三苯基膦)钯、三(二亚苄基丙酮)二钯、双(二亚苄基丙酮)钯、双(乙腈)二氯化钯、二(三苯基膦)氯化钯、[1,1'-双(二苯基膦基)二茂铁]二氯化
钯、1,1'-双(二苯基膦基)二茂铁二氯化钯二氯甲烷复合物、RuPhos Pd G1、RuPhos Pd G2、RuPhos Pd G3、Xphos Pd G1、Xphos Pd G2、Xphos Pd G3、BrettPhos Pd G1、BrettPhos Pd G3、XantPhos Pd G3、DavePhos-Pd-G3、或其组合;更优选地,所述催化剂选自:醋酸钯、三(二亚苄基丙酮)二钯、双(二亚苄基丙酮)钯、或其组合。
在另一优选例中,步骤s’2)中,所述催化剂的摩尔当量为化合物A09的0.01~5当量;优选地为0.01~2当量,优选地为0.01~1当量,更优选地为0.01~0.05当量。
在另一优选例中,步骤s’2)中,所述的碱选自:碳酸钠、碳酸钾、碳酸铯、氢氧化锂、氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]十一碳-7-烯(DBN)、二异丙基氨基锂(LDA)、2,2,6,6-四甲基哌啶锂、六甲基二硅基氨基锂(LHMDS)、六甲基二硅基胺基钾(KHMDS)、或其组合;优选地,所述碱选自:碳酸钠、碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基氨基锂(LHMDS)、六甲基二硅基胺基钾(KHMDS)、或其组合;更优选地,所述碱选自:碳酸钠、碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、或其组合。
在另一优选例中,步骤s’2)中,所述的碱的摩尔当量为化合物A09的0.1~10当量;优选地为1~3当量。
在另一优选例中,步骤s’2)中,所述的惰性溶剂选自:四氢呋喃、二甲基四氢呋喃、甲基叔丁基醚、二氧六环、苯、甲苯、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙二醇二甲醚(DME)、或其组合;优选地,所述惰性溶剂选自:四氢呋喃、二甲基四氢呋喃、二氧六环、甲苯、或其组合。
在另一优选例中,步骤s’2)中,反应温度为30℃至130℃;优选地,反应温度为50℃至100℃;更优选地,反应温度为60℃至90℃。
在另一优选例中,步骤s’3)中,所述催化剂选自:钯炭、二氧化铂、铂炭、氢氧化钯、氯化钯、雷尼镍、或其组合;优选地,所述催化剂选自:钯炭、铂炭、氢氧化钯、或其组合。
在另一优选例中,步骤s’3)中,所述催化剂的重量为A10重量的1%至100%;优选地为5%至20%。
在另一优选例中,步骤s’4)中,所述催化剂选自:醋酸钯、氯化钯、四(三苯基膦)钯、三(二亚苄基丙酮)二钯、双(二亚苄基丙酮)钯、双(乙腈)二氯化钯、二(三苯基膦)氯化钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1'-双(二苯基膦基)二茂铁二氯化钯二氯甲烷复合物、二(苯腈)二氯化钯、1,4-双(二苯基膦)丁烷-氯化钯、双(乙腈)二氯化钯、烯丙基氯化钯二聚物、[1,3-双(2,6-二异丙基苯基)咪唑亚基](3-氯吡啶基)二氯化钯、[二叔丁基(氯化)膦]二氯化钯二聚体、双(甲基二苯基膦)二氯化钯、
苄基双(三苯基膦)氯化钯、1,3-双(二异丙基苯基)-2-咪唑啉亚基氯化钯二聚体、(三叔丁基膦)(2'-氨基联苯基)氯化钯、[(R)-(+)-2,2'-双(二苯基膦)-1,1'-联萘]二氯化钯、氯化钯(π-肉桂基)二聚物、[1,3-双(2,6-二异丙基苯基)咪唑-2(3H)-亚基](3-氯-1-吡啶基)氯化钯、1,1'-双(二叔丁基膦)二茂铁二氧化钯、双(三环己基膦)二氯化钯、[1,2-双(二苯基膦)乙烷]二氯化钯、[1,3-双(二苯基膦)丙烷]氯化钯、二氯双[二叔丁基(4-二甲氨基苯基)膦]钯、二(三叔丁基膦)钯、二氯双(二叔丁基苯基膦)钯、RuPhos Pd G1、RuPhos Pd G2、RuPhos Pd G3、Xphos Pd G1、Xphos Pd G2、Xphos Pd G3、BrettPhos Pd G1、BrettPhos Pd G3、XantPhos Pd G3、DavePhos-Pd-G3、APhos Pd G3、Pd G3、或其组合;优选地,所述催化剂选自:醋酸钯、氯化钯、四(三苯基膦)钯、三(二亚苄基丙酮)二钯、双(二亚苄基丙酮)钯、双(乙腈)二氯化钯、二(三苯基膦)氯化钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1'-双(二苯基膦基)二茂铁二氯化钯二氯甲烷复合物、RuPhos Pd G1、RuPhos Pd G2、RuPhos Pd G3、Xphos Pd G1、Xphos Pd G2、Xphos Pd G3、BrettPhos Pd G1、BrettPhos Pd G3、XantPhos Pd G3、DavePhos-Pd-G3、或其组合;更优选地,所述催化剂选自:醋酸钯、三(二亚苄基丙酮)二钯、双(二亚苄基丙酮)钯、或其组合。
在另一优选例中,步骤s’4)中,所述催化剂的摩尔当量为化合物A11的0.01~5当量;较优的是0.01~2当量。
在另一优选例中,步骤s’4)中,所述的碱选自:碳酸钠、碳酸钾、碳酸铯、氢氧化锂、氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]十一碳-7-烯(DBN)、二异丙基氨基锂(LDA)、2,2,6,6-四甲基哌啶锂、六甲基二硅基氨基锂(LHMDS)、六甲基二硅基胺基钾(KHMDS)、或其组合;优选地,所述碱选自:碳酸钠、碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基氨基锂(LHMDS)、六甲基二硅基胺基钾(KHMDS)、或其组合;更优选地,所述碱选自:碳酸钠、碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、或其组合。
在另一优选例中,步骤s’4)中,所述碱的摩尔当量为化合物A11的0.1~10当量;优选地为1~3当量。
在另一优选例中,步骤s’4)中,所述惰性溶剂选自:四氢呋喃、二甲基四氢呋喃、甲基叔丁基醚、二氧六环、苯、甲苯、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙二醇二甲醚(DME)、或其组合;优选地为四氢呋喃、二甲基四氢呋喃、二氧六环、甲苯、或其组合。
在另一优选例中,步骤s’4)中,反应温度为0℃至130℃;优选地反应温度为50℃至100℃,更优选地反应温度为60℃至90℃(如75~85℃)。
在另一优选例中,步骤s’5)中,所述酸选自:盐酸、氯化氢、氢溴酸、三氟乙酸、磷酸、或其组合。
在另一优选例中,步骤s’5)中,所述惰性溶剂选自:乙酸乙酯、乙酸异丙酯、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、二氧六环、丙酮、乙腈、乙醇、甲醇、异丙醇、叔丁醇、戊醇、正丁醇、苯、甲苯、氯苯、乙二醇二甲醚(DME)、或其组合;优选地,所述惰性溶剂选自:乙酸乙酯、乙酸异丙酯、四氢呋喃、2-甲基四氢呋喃、二氧六环、乙醇、甲醇、异丙醇、叔丁醇、戊醇、正丁醇、甲苯、乙二醇二甲醚(DME)、或其组合;更优选地,所述惰性溶剂选自:乙酸乙酯、乙酸异丙酯、四氢呋喃、2-甲基四氢呋喃、二氧六环、乙醇、异丙醇、或其组合。
在另一优选例中,步骤s’6)中,所述缩合剂选自:碳二亚胺型缩合剂(DCC、DIC、EDCI、BDDC、P-EDC)、膦盐类缩合剂(BOP-Cl、BOP、PyBOP、AOP、PyAOP)、脲盐/铵盐类缩合剂(HATU、HBTU、TATU、TBTU、COMU、HOTU)、其它类型缩合剂(T3P、BOP-Cl、FDP、FDDP、DEBT、EDQ)、或其组合;优选地,所述缩合剂选自:EDCI、BOP、HATU、T3P,或其组合。
在另一优选例中,步骤s’6)中,所述缩合剂的摩尔当量为化合物A13的0.1~10当量;优选地为1~3当量。
在另一优选例中,步骤s’6)中,所述惰性溶剂选自:二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、乙酸乙酯、乙酸异丙酯、四氢呋喃、二甲基四氢呋喃、甲基叔丁基醚、二氧六环、乙腈、丙酮、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙二醇二甲醚(DME)、苯、甲苯、氯苯、或其组合;优选地,所述惰性溶剂选自:二氯甲烷、乙酸乙酯、乙酸异丙酯、四氢呋喃、二甲基四氢呋喃、二氧六环、乙腈、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙二醇二甲醚(DME)、或其组合;更优选地,所述惰性溶剂选自:二氯甲烷、乙酸乙酯、四氢呋喃、乙腈、N,N-二甲基甲酰胺(DMF)、二甲亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、或其组合。
在另一优选例中,步骤s’6)中,所述碱选自:碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯、氢氧化锂、氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾、三乙胺、1-甲基吡咯烷、1-甲基哌啶、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、咪唑、吡啶、2-甲基吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶(DMAP)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]十一碳-7-烯(DBN)、或其组合;优选地,所述碱选自:碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、二甲基异丙胺、N,N-二异丙基乙胺、N-甲基吗啉、或其组合;更优选地,所述碱选自:碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺、N,N-二异丙基乙胺、或其组合。
在另一优选例中,步骤s’6)还包括对化合物A16的重结晶步骤,其中,所述结晶溶剂选自:乙酸乙酯、乙酸异丙酯、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、乙腈、丙酮、四氢呋喃、二甲基四氢呋喃、甲基叔丁基醚、异丙醚、乙醚、甲乙基醚、二氧六环、石油醚、正庚烷、正己烷、戊烷、环己烷、甲基环己烷、乙二醇二甲醚(DME)、苯、甲苯、氯苯、甲醇、乙醇、异丙醇、叔丁醇、丙醇、或其组合;优选地,所述溶剂选自:乙酸乙酯、乙酸异丙酯、二氯甲烷、甲醇、乙醇、异丙醇、叔丁醇、丙醇、或其组合。
在另一优选例中,化合物A16的HPLC纯度大于95%以及ee值大于95%,优选地,HPLC纯度大于98%以及ee值大于98%,更优选地,的HPLC纯度大于99%以及ee值大于99%。
本发明第四方面,提供一种KRAS G12C抑制剂中间体,所述中间体选自:
本发明第五方面,提供一种KRAS G12C抑制剂A16的制备方法,所述方法包括步骤
s’6)在惰性溶剂中,碱和缩合剂存在下,化合物A13与2-氟丙烯酸反应,得到化合物A16。
本发明第六方面,提供一种中间体A13的制备方法,其包括如下步骤
s’5)在惰性溶剂中,酸存在下,化合物A12脱除Boc,得到化合物A13。
本发明第七方面,提供一种中间体A12的制备方法,其包括如下步骤
s’4)在惰性溶剂中,碱和催化剂存在下,化合物A11与8-氯-7-氟萘-1-基三氟甲烷磺酸酯反应,得到化合物A12。
本发明第八方面,提供一种中间体A11的制备方法,其包括如下步骤
s’3)在惰性溶剂中,催化剂和氢气存在下,化合物A10脱除Cbz,得到化合物A11。
在另一优选例中,所述方法还包括步骤
s’1)在惰性溶剂中,碱存在下,化合物A08与(Boc)2O反应,得到化合物A09;
s’2)在惰性溶剂中,碱和催化剂存在下,化合物A09与(1-((二甲氨基)甲基)环丙基)甲醇反应,得到化合物A10。
在另一优选例中,所述方法还包括步骤
s1)在惰性溶剂中,碱存在下,化合物A01与化合物A14反应,得到化合物A02;
s2)在惰性溶剂中,碱存在下,化合物A02与化合物A15反应,得到化合物A03;
s3)在惰性溶剂中,碱存在下,化合物A03与尿素反应,得到化合物A04;
s4)化合物A04与氯化试剂反应,得到化合物A05;
s5)在惰性溶剂中,脱苄基试剂存在下,化合物A05脱除苄基,得到化合物A06;
s6)在惰性溶剂中,化合物A06与CbzCl反应,得到化合物A07;
s7)在惰性溶剂中,化合物A07与(S)-2-(哌嗪-2-基)乙腈或其盐反应,得到化合物A08;
R1各自独立为卤素(如氯、溴、碘);
R2各自独立选自取代或未取代的下组基团:C1-C10烷基、C3-C10环烷基、苯基、苄基;其中,所述取代是被选自下组的一个或多个基团取代:C1-C6烷基、C3-C6环烷基。
本发明第九方面,提供一种中间体A05的制备方法,所述方法包括步骤
s1)在惰性溶剂中,碱存在下,化合物A01与化合物A14反应,得到化合物A02;
s2)在惰性溶剂中,碱存在下,化合物A02与化合物A15反应,得到化合物A03;
s3)在惰性溶剂中,碱存在下,化合物A03与尿素反应,得到化合物A04;
s4)化合物A04与氯化试剂反应,得到化合物A05。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
本发明人经过长期深入的研究,开发一种新的KRAS G12C抑制剂中间体,
其可高效率地合成KRAS G12C抑制剂,具有成本低、工艺安全环保、无柱层析操作更适合工业化生产等优势。在此基础上完成了本发明。
术语
本发明中,“惰性溶剂”是指不与反应底物发生反应的试剂。
中间体
中间体是指半成品,是生产所需要的产品过程中形成的产物。通常,发明人可以从中间体作为起始原料进行产品的生产。因此,筛选合适的中间体可以优化工艺路线,进而达到提高收率,节约时间、成本的目的。
本发明中,所述中间体是指以下化合物
上述中间体可用于制备KRAS G12C抑制剂。
本发明中间体的制备方法
优选地,中间体A8的制备方法包括步骤
s1)在惰性溶剂中,碱存在下,化合物A01与化合物A14反应,得到化合物A02;
s2)在惰性溶剂中,碱存在下,化合物A02与化合物A15反应,得到化合物A03;
s3)在惰性溶剂中,碱存在下,化合物A03与尿素反应,得到化合物A04;
s4)化合物A04与氯化试剂反应,得到化合物A05;
s5)在惰性溶剂中,碱和脱苄基试剂存在下,化合物A05脱除苄基,得到化合
物A06;
s6)在惰性溶剂中,化合物A06与CbzCl反应,得到化合物A07;
s7)在惰性溶剂中,化合物A07与(S)-2-(哌嗪-2-基)乙腈或其盐反应,得到化合物A08;
R1各自独立为卤素(如氯、溴、碘);
R2各自独立选自取代或未取代的下组基团:C1-C10烷基、C3-C10环烷基、苯基、苄基;其中,所述取代是被选自下组的一个或多个基团取代:卤素、C1-C6烷基、C3-C6环烷基,优选地,R2各自独立选自甲基、乙基、异丙基、苄基;优选地为甲基或者乙基。
优选地,中间体A10的制备方法包括步骤
s’1)在惰性溶剂中,碱存在下,化合物A08与(Boc)2O反应,得到化合物A09;
s’2)在惰性溶剂中,碱和催化剂存在下,化合物A09与(1-((二甲氨基)甲基)环丙基)甲醇反应,得到化合物A10。
优选地,中间体A10的制备还包括上述中间体A8的制备。
优选地,中间体A11的制备方法包括如下步骤
s’3)在惰性溶剂中,催化剂和氢气存在下,化合物A10脱除Cbz,得到化合物A11。
优选地,中间体A11的制备还包括上述中间体A10的制备。
优选地,中间体A12的制备方法包括如下步骤
s’4)在惰性溶剂中,碱和催化剂存在下,化合物A11与8-氯-7-氟萘-1-基三氟甲
烷磺酸酯反应,得到化合物A12。
优选地,中间体A12的制备还包括上述中间体A11的制备。
优选地,中间体A13的制备方法包括如下步骤
s’5)在惰性溶剂中,酸存在下,化合物A12脱除Boc,得到化合物A13。
优选地,所述酸为盐酸。
优选地,中间体A13的制备还包括上述中间体A12的制备。
KRAS G12C抑制剂
本发明中所述的KRAS G12C抑制剂是指含有结构部分的化合物,例如化合物A16
本发明中,化合物A16的制备包括如下步骤
s’6)在惰性溶剂中,碱和缩合剂存在下,化合物A13与2-氟丙烯酸反应,得到化合物A16。
优选地,化合物化合物A16的制备还包括上述中间体A13的制备。
相对于现有技术,本发明的有益效果如下:
1.本发明提供了一种新的中间体;
2.本发明的中间体高效地合成KRAS G12C抑制剂,如(S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-(1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈;
3.相比于现有的合成路线,本发明工艺所采用的起始原料价格便宜、易得;
4.本发明工艺避免制备含有硫醚结构中间体而导致一系列工艺问题;
5.本发明工艺避免使用氧化剂而引入难以除去的芳构化杂质;
6.本发明工艺可以避免使用多次柱层析纯化操作,适用于工业化生产;
7.本发明工艺操作简便,易纯化和获得高质量、高纯度的中间体和KRAS G12C抑制剂;
8.本发明的新路线较现有方法具有较大优势以及更强的工业化前景。
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。所述本发明的方案均为可实现本发明目的之技术方案。以下实施例所辖用温度和试剂,均可以用上述相应温度和试剂替代以实现本发明之目的。
实施例中未注明具体条件的实验方法,按照常规方法和条件,或者按照商品说明书选择。
实施例1乙基苄基甘氨酸酯的制备
反应釜中氮气置换,20~25℃下加入四氢呋喃(50g)、苄胺(10g,1.0eq)和三乙胺(11.3g,1.2eq),在30~45℃下缓慢加入2-氯乙酸乙酯(17.2g,1.5eq),加完后保温搅拌20小时。中控合格后,过滤,向滤液加入水,用盐酸调节反应液pH至6~7,分出有机层,减压脱除溶剂后。残余物经柱层析纯化后得到标题化合物(12.6g),收率70%,GC纯度96%。
1H NMR(400MHz,CDCl3):δ7.22-7.31(m,5H),4.17(q,J=7.1Hz,2H),3.78(s,2H),3.38(s,2H),1.89(br,1H),1.25(t,J=7.1Hz,3H).
实施例2乙基苄基甘氨酸酯的制备
反应釜中氮气置换,20~25℃下加入二氯甲烷(1500kg)、苄胺(300kg,1.0eq)和三乙胺(508.9kg,1.8eq),在30~45℃下缓慢加入2-氯乙酸乙酯(480kg,1.4eq),加完后保温搅拌16小时。中控合格后,过滤,向滤液加入水,用盐酸调节反应液pH至6~7,分出有机层,减压脱除溶剂后,再减压蒸馏得到标题化合物(432.8kg),
收率80%,GC纯度96.0%。
1H NMR(400MHz,CDCl3):δ7.22-7.31(m,5H),4.17(q,J=7.1Hz,2H),3.78(s,2H),3.38(s,2H),1.89(br,1H),1.25(t,J=7.1Hz,3H).
实施例3乙基苄基甘氨酸乙酯-1-苄基-3-氧哌啶-4-羧酸酯盐酸盐的制备
反应釜中氮气置换,20~25℃下加入甲苯(2000kg)、乙基苄基甘氨酸酯(430kg,1.0eq)和三乙胺(337.7kg,1.5eq),在95~100℃下缓慢加入4-溴丁酸乙酯(651.0kg,1.5eq),加完保温搅拌16小时。中控合格后,调温至25~35℃,过滤,向滤液分批加入乙醇钠(302.8kg,2.0eq),回流搅拌3.5小时。中控合格后,调温至0~5℃,缓慢加入冰醋酸调节pH至7~8。加入水,分出有机层,用甲苯反复减压带出水,直到水分<0.2%。调温至20~25℃,缓慢加入一定量的25%氯化氢的乙醇溶液。0.5小时后大量固体析出后,再缓慢加入正庚烷溶液搅拌5小时,过滤、洗涤、取出滤饼干燥后得到标题化合物(463.8kg),收率70%,HPLC纯度99%。
1H NMR(400MHz,CDCl3):δ11.68(s,1H),7.72-7.62(m,2H),7.49-7.43(m,3H),4.46-4.33(m,2H),4.23(q,J=8.0Hz,2H),3.96-3.80(m,1H),3.72-3.28(m,3H),3.15-2.98(m,1H),2.69-2.54(m,1H),1.25(t,J=8.0Hz,3H).
实施例4 7-苄基-5,6,7,8-四氢吡啶[3,4-d]嘧啶-2,4-二醇的制备
反应釜中氮气置换,20~25℃下加入乙醇(4500kg)、尿素(226.9kg,2.5eq)和乙醇钠(359.9kg,3.5eq),溶清后加入乙基苄基甘氨酸乙酯-1-苄基-3-氧哌啶-4-羧酸酯盐酸盐(450kg,1.0eq),回流搅拌48小时。中控合格后,调温至20~25℃,加入水,再缓慢加入18%的盐酸水溶液调pH=6,大量固体析出,继续加入水,保温搅拌1小时。过滤,取出滤饼加入水甲基叔丁基醚打浆1小时。过滤、取出滤饼干燥后得到标题化合物(260.5kg),收率67%,HPLC纯度99%。
1H NMR(DMSO-d6):δ10.94(s,1H),10.62(s,1H),7.37-7.26(m,5H),3.62(s,2H),3.13(s,2H),2.61(t,2H),2.23(t,2H).
实施例5 7-苄基-2,4-二氯-5,6,7,8-四氢吡啶[3,4-d]嘧啶的制备
反应釜中氮气置换,20~25℃下加入三氯氧磷(160g,8.0w/w)后,分批加入7-苄基-5,6,7,8-四氢吡啶[3,4-d]嘧啶-2,4-二醇(20g,1.0w/w),在105~110℃下搅拌反应16小时。中控合格后,调温至50~60℃,减压脱除大部分三氯氧磷,加入二氯甲烷减压蒸馏置换出三氯氧磷。加入二氯甲烷,调温至0~5℃,缓慢加入9%的碳酸钠水溶液,调节反应液至pH=8~9,保持内温小于20℃,搅拌、静置、分层,有机层留存,水层用二氯甲烷萃取两次,合并有机层。向有机层加入活性炭脱色,过滤,滤液减压脱除溶剂。残余物经柱层析纯化后得到标题化合物(16g),收率70%,HPLC纯度99%。
1H NMR(DMSO-d6):δ7.36-7.27(m,5H),3.72(s,2H),3.61(s,2H),2.77(m,4H).
实施例6 7-苄基-2,4-二氯-5,6,7,8-四氢吡啶[3,4-d]嘧啶的制备
反应釜中氮气置换,20~25℃下加入三氯氧磷(2040kg,8.0w/w)后,分批加入7-苄基-5,6,7,8-四氢吡啶[3,4-d]嘧啶-2,4-二醇(255kg,1.0w/w),在105~110℃下搅拌反应16小时。中控合格后,调温至50~60℃,减压脱除大部分三氯氧磷,加入二氯甲烷减压蒸馏置换出三氯氧磷。加入二氯甲烷,调温至0~5℃,缓慢加入9%的碳酸钠水溶液,调节反应液至pH=8~9,保持内温小于20℃,搅拌、静置、分层,有机层留存,水层用二氯甲烷萃取两次,合并有机层。向有机层加入活性炭脱色,过滤,滤液减压脱除溶剂,用甲基叔丁醚置换原来溶剂至一定的体积。调温至50~60℃,溶清后缓慢加入正庚烷,缓慢降温析出。过滤、取出滤饼干燥后得合格的标题化合物(236.2kg),收率81%,HPLC纯度99%。
1H NMR(DMSO-d6):δ7.36-7.27(m,5H),3.72(s,2H),3.61(s,2H),2.77(m,4H).
实施例7 2,4-二氯-5,6,7,8-四氢吡啶[3,4-d]嘧啶盐酸盐的制备
反应釜中氮气置换,20~25℃下加入二氯乙烷(1200kg)与7-苄基-2,4-二氯-5,6,7,8-四氢吡啶[3,4-d]嘧啶(230kg,1.0eq),缓慢加入1-氯甲酸氯乙酯(201.2kg,1.8eq),在室温下搅拌0.5小时,再回流搅拌15小时。中控合格后,调温至30~40℃,减压脱除大部分溶剂,加入甲苯减压蒸馏置换出二氯乙烷和多余的1-氯甲酸氯乙酯。在室温下加入甲醇(1000kg),回流搅拌2小时,中控合格后,缓慢降温
至0~5℃。过滤、取出滤饼干燥后得到标题化合物(156.1kg),收率83%,HPLC纯度99%。
1H NMR(DMSO-d6):δ10.23(s,2H),4.35(s,2H),3.44(m,2H),3.00(t,2H).
实施例8苄基-1,4-二氯-5-8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸酯的制备
反应釜中氮气置换,20~25℃下加入乙腈(610.0kg)与2,4-二氯-5,6,7,8-四氢吡啶[3,4-d]嘧啶盐酸盐(152.0kg,1.0eq),缓慢加入苄氧甲酰氯(118.7kg,1.1eq),在室温下搅拌10分钟,0~5℃下再缓慢加入N,N-二异丙基乙胺(203.9kg,2.5eq),20~25℃下搅拌16小时。中控合格后,减压脱除大部分溶剂,加入甲叔醚减压蒸馏置换出乙腈。向浓缩残余物中加入甲叔醚,并用稀盐酸洗涤有机相,分出有机相浓缩至一定体积后缓慢加入正庚烷,析出固体。过滤、取出滤饼干燥后得到标题化合物(181.6kg),收率85%,HPLC纯度97%。
1H NMR(DMSO-d6):δ7.41-7.30(m,5H),5.14(s,2H),4.64(s,2H),3.74(s,2H),2.74(d,2H).
实施例9苄基(S)-2-氯-4-(3-(氰甲基)哌嗪-1-基)-5,8-二氢吡啶[3,4-d]嘧啶-7(6H)-羧酸酯的制备
反应釜中氮气置换,20~25℃下加入乙腈(836.0kg)与苄基-1,4-二氯-5-8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸酯(171.2kg,1.0eq),在0~5℃下,加入(S)-2-(哌嗪-2-基)乙腈的(2S,3S)-2,3-二羟基琥珀酸盐(236.7kg,1.1eq),10分钟后缓慢加入N,N-二异丙基乙胺(321.7kg,5.0eq),在0~5℃搅拌3小时,调温至20~25℃搅拌16小时。中控合格后,加入水和二氯甲烷,在0~5℃下加入10%的氢氧化钠水溶液调pH=8~9,分出有机层,水层用二氯甲烷萃取,合并有机层。减压脱除溶剂,加入二氯甲烷和乙醇并调温至50~55℃,溶清后缓慢加入正庚烷,缓慢降温至15~20℃搅拌1小时。过滤、取出滤饼干燥后得到标题化合物(185.9kg),收率86%,HPLC纯度99%,手性纯度99.5%。
1H NMR(DMSO-d6):δ7.40-7.33(m,5H),5.13(s,2H),4.48(m,2H),3.89(dd,2H),3.51(d,2H),2.94(m,3H),2.81-2.66(m,6H).
实施例10苄基(S)-4-(4-(叔丁氧羰基)-3-(氰甲基)哌嗪-1-基)-2-氯-5,8-二氢吡啶[3,4-d]嘧啶-7(6H)-羧酸酯的制备
反应釜中氮气置换,20~25℃加入四氢呋喃(922.0kg)、水、苄基(S)-2-氯-4-(3-(氰甲基)哌嗪-1-基)-5,8-二氢吡啶[3,4-d]嘧啶-7(6H)-羧酸酯(172.8kg,1.0eq)与碳酸氢钠(69.1kg,2.1eq),10分钟后缓慢加入Boc酸酐(105.4kg,1.2eq),在20~25℃搅拌16小时。中控合格后,加入水和二氯甲烷,分出有机层,水层用二氯甲烷萃取,合并有机层。减压脱除溶剂,用乙酸乙酯减压置换其它溶剂。加入乙酸乙酯回流,缓慢加入正庚烷,缓慢降温至15~20℃,搅拌6小时。过滤、取出滤饼干燥后得到标题化合物(191.9kg),收率90%,HPLC纯度99%,手性纯度99.5%。
1H NMR(DMSO-d6):δ7.40-7.33(m,5H),5.14(s,2H),4.58-4.34(m,3H),3.90(m,3H),3.71(m,1H),3.40(bs,1H),3.19(m,2H),3.00-2.81(m,3H),2.72(b,2H),1.44(s,9H).
实施例11苯甲基(S)-4-(4-(叔-丁氧基羰基)-3-(氰基甲基)哌嗪-1-基)-2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸酯的制备
反应釜中氮气置换并氮气保护,在20~25℃下,依次加入苄基(S)-4-(4-(叔丁氧羰基)-3-(氰甲基)哌嗪-1-基)-2-氯-5,8-二氢吡啶[3,4-d]嘧啶-7(6H)-羧酸酯(190kg,1.0eq)、(1-((二甲氨基)甲基)环丙基)甲醇(55.9kg,1.2eq)、2-甲基四氢呋喃(950kg)、碳酸铯(234.9kg,2.0eq)、1,1'-联萘-2,2'-双二苯膦(11.2kg,0.05eq)和醋酸钯(4.0kg,0.05eq),在75~85℃搅拌24小时。中控合格后,加入水和二氯甲烷,分出有机层,向有机层加入水和稀盐酸调pH=2~3,分出水层,水层用乙酸乙酯萃取除去杂质,分出水层用碱水调pH=9~11,水层再用乙酸乙酯萃取,分出有机层减压脱除溶剂,用乙醇减压置换其它溶剂。向残余物加入乙醇,调温至60~70℃,缓慢加入水,缓慢降温至20~25℃,搅拌3小时。过滤、取出滤饼
干燥后得到标题化合物(167.6kg),收率75%,HPLC纯度99%,手性纯度99.5%。
1H NMR(400MHz,DMSO-d6)δ7.39-7.32(m,5H),5.13(s,2H),4.49-4.32(m,3H),4.06(s,2H),3.85-3.67(m,4H),3.44-3.41(m,1H),3.30-3.17(m,1H),3.07-3.03(m,2H),2.87-2.81(m,2H),2.64(s,2H),2.18(s,2H),2.13(s,6H),1.44(s,9H),0.56(m,2H),0.36(m,2H).
实施例12叔-丁基(S)-2-(氰基甲基)-4-(2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-1-羧酸酯的制备
反应釜中氮气置换并保护,在20~25℃下,依次加入苯甲基(S)-4-(4-(叔-丁氧基羰基)-3-(氰基甲基)哌嗪-1-基)-2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸酯(10g,1.0w/w)、乙醇(50g)、铂炭(10g,0.1w/w),氢气置换并保护(氢气压力1~2atm),调温至20~30℃下搅拌反应8小时。中控合格后,过滤,用甲基叔丁基醚置换乙醇,在15~25℃下缓慢加入甲基环己烷,搅拌10小时。过滤、取出滤饼干燥后得到标题化合物(6.3g),收率80%,HPLC纯度99.0%,手性纯度99.5%。
1H NMR(400MHz,DMSO-d6)δ4.50(s,1H),4.03(s,2H),3.89-3.76(m,3H),3.67(s,2H),3.31-2.72(m,10H),2.18(s,2H),2.14(s,6H),1.44(s,9H),0.56(m,2H),0.36(m,2H).
实施例13叔-丁基(S)-2-(氰基甲基)-4-(2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-1-羧酸酯的制备
反应釜中氮气置换并保护,在20~25℃下,依次加入苯甲基(S)-4-(4-(叔-丁氧基羰基)-3-(氰基甲基)哌嗪-1-基)-2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸酯(165.0kg,1.0w/w)、乙醇(600kg)、钯炭(16.5kg,0.1w/w),氢气置换并保护(氢气压力1~2atm),调温至20~30℃下搅拌反应8小
时。中控合格后,过滤,用甲基叔丁基醚置换乙醇,在15~25℃下缓慢加入甲基环己烷,搅拌10小时。过滤、取出滤饼干燥后得到标题化合物(111.2kg),收率86%,HPLC纯度99%,手性纯度99.5%。
1H NMR(400MHz,DMSO-d6)δ4.50(s,1H),4.03(s,2H),3.89-3.76(m,3H),3.67(s,2H),3.31-2.72(m,10H),2.18(s,2H),2.14(s,6H),1.44(s,9H),0.56(m,2H),0.36(m,2H).
实施例14(S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
反应釜中氮气置换并保护,在20~25℃下,依次加入叔-丁基(S)-2-(氰基甲基)-4-(2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-1-羧酸酯(110.0kg,1.0eq)、8-氯-7-氟萘-1-基三氟甲烷磺酸酯(111.7kg,1.5eq)、2-甲基四氢呋喃(1000kg)、碳酸铯(221.4kg,3.0eq)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(14.4kg,0.11eq)、三(二苯亚甲基丙酮)二钯(10.4kg,0.05eq),在75~85℃搅拌20小时。中控合格后,过滤,加入N-乙酰-L-半胱氨酸(73.9kg,2.0eq)搅拌3小时,再用5%的碳酸钠水溶液洗涤,分出有机层,向有机层加入水和稀盐酸调pH=2~3,分出水层,水层用乙酸乙酯萃取除去杂质,分出水层用碱水调pH=9~11,水层再用乙酸乙酯萃取,分出有机层减压脱除溶剂,用异丙醇减压置换其它溶剂。向残余物加入异丙醇,缓慢滴加浓盐酸(40.2kg,1.7eq),在20~30℃搅拌30小时。中控合格后,缓慢加入碱水,调节pH=7~9,加入水与乙酸乙酯,分出有机层,再用5%硫酸钠水溶液洗涤有机相,分出有机相,并用乙醇减压置换其它溶剂。升温至60~70℃,溶清后缓慢降温至15~20℃搅拌3小时。过滤、取出滤饼干燥后得到标题化合物(102.2kg),收率80%,HPLC纯度99.0%,手性纯度99.5%。
1H NMR(400MHz,DMSO-d6)δ8.03-7.99(m,1H),7.78(d,J=8Hz,1H),7.62-7.51(m,2H),7.40(d,J=7.6Hz,1H),4.16-3.69(m,6H),3.46-3.44(m,1H),3.09-2.47(m,11H),2.20-2.18(m,2H),2.14(s,6H),0.57(m,2H),0.36(m,2H).
实施例15(S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-(1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-1-(2-氟丙烯酰)哌嗪-2-基)乙腈或其乙醇合物的制备
反应釜中氮气置换并氮气保护,在5~10℃下,依次加入(S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈(100.0kg,1.0eq)、2-氟丙烯酸(23.9kg,1.5eq)、N,N-二异丙基乙胺(114.3kg,5.0eq),二氯甲烷(500kg),缓慢加入正三丙基环磷酸酐50%乙酸乙酯溶液(248.2kg,2.2eq),在5~10℃搅拌5小时。中控合格后,过滤,有机相用5%的碳酸钠水溶液洗涤,分出有机层,用乙醇减压置换其它溶剂。升温至60~70℃,溶清后缓慢降温至0~5℃搅拌10小时。过滤、取出滤饼干燥后得到标题化合物(90.2kg),收率80%,HPLC纯度99.5%,手性纯度99.5%。
1H NMR(400MHz,DMSO-d6)δ8.03-7.99(m,1H),7.79-7.77(m,1H),7.61-7.50(m,2H),7.44-7.38(m,1H),5.43-5.24(m,2H),4.88(br,1H),4.38-4.36(m,1H),4.20-3.74(m,7H),3.50-2.53(m,16H),2.19(s,2H),2.14(s,6H),0.58(m,2H),0.37(m,2H).
对比例
对比例1叔-丁基(S)-2-(氰基甲基)-4-(2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-1-羧酸酯的制备
反应釜中氮气置换并保护,在20~25℃下,依次加入叔丁基(S)-4-(7-苄基-2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸酯(10.0g,1.0w/w)、乙醇(50g)、钯炭(1.0g,0.1w/w),氢气置换并保护(氢气压力3~5atm),调温至20~30℃下搅拌反应72小时。中控合格后,过滤,减压浓缩。残余物经柱层析纯化后得到标题化合物(6.2g),收率74%,HPLC纯度95%,手性纯度99.5%。
1H NMR(400MHz,DMSO-d6)δ4.50(s,1H),4.03(s,2H),3.89-3.76(m,3H),3.67(s,2H),3.31-2.72(m,10H),2.18(s,2H),2.14(s,6H),1.44(s,9H),0.56(m,2H),0.36(m,2H).
对比例2叔-丁基(S)-2-(氰基甲基)-4-(2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-1-羧酸酯的制备
反应釜中氮气置换并保护,在20~25℃下,依次加入叔丁基(S)-4-(7-苄基-2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰甲基)哌嗪-1-羧酸酯(10.0g,1.0eq)、硝酸铈铵(28.6g,3.0eq),乙腈(100g)和水(20g),调温至20~30℃下搅拌反应48小时。中控合格后,二氯甲烷萃取,有机相减压浓缩。残余物经柱层析纯化后得到标题化合物(0.8g),收率10%,HPLC纯度95%,手性纯度99.5%。
1H NMR(400MHz,DMSO-d6)δ4.50(s,1H),4.03(s,2H),3.89-3.76(m,3H),3.67(s,2H),3.31-2.72(m,10H),2.18(s,2H),2.14(s,6H),1.44(s,9H),0.56(m,2H),0.36(m,2H).
对比例3(S)-2-(4-(7-(8-氯-7-氟萘-1-基)-2-((1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈的制备
反应釜中氮气置换并保护,在20~25℃下,依次加入苄基(S)-4-(7-(8-氯-7-氟萘-1-基)-2-(1-((二甲氨基)甲基)环丙基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-2-(氰基甲基)哌嗪-1-羧酸盐(10.0g,1.0w/w)、乙醇(50g)、钯炭(1.0g,0.1w/w),氢气置换并保护(氢气压力1~3atm),调温至20~30℃下搅拌反应30小时。中控合格后,过滤,减压浓缩。残余物经柱层析纯化后得到标题化合物(5.4g),收率67%,HPLC纯度92%,手性纯度99.5%。
1H NMR(400MHz,DMSO-d6)δ8.03-7.99(m,1H),7.78(d,J=8Hz,1H),7.62-7.51(m,2H),7.40(d,J=7.6Hz,1H),4.16-3.69(m,6H),3.46-3.44(m,1H),3.09-2.47(m,11H),2.20-2.18(m,2H),2.14(s,6H),0.57(m,2H),0.36(m,2
H).
值得注意的是,发明人对于保护基的选择及脱保护进行了大量的研究和多次的反复尝试,例如,对于A08中哌嗪N采用苄基保护时,发现使用钯炭加氢脱除苄基,需要加热加压长时间反应才能脱除苄基,出现大量氰基被还原的杂质,反应收率低并且该杂质难以除尽,最终得不到高纯度的A16;使用硝酸铈铵(CAN)或者2,3-二氯-5,6-二氰对苯醌(DDQ)等氧化剂脱除苄基,产生大量芳构化杂质,反应收率低并且该杂质难以除尽,最终也得不到高纯度的A16;使用1-氯甲酸氯乙酯与甲醇脱除苄基,会产生大量N,N-二甲基脱掉一个甲基的杂质,反应收率低并且该杂质难以除尽,最终也不能得到合格的原料药。对于A12中哌嗪N采用Cbz保护时,使用钯炭氢化脱除Cbz,产生脱氯杂质,反应收率低并且该杂质难以除尽,最终不能得到高纯度的A16。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
- 一种KRAS G12C抑制剂A16的制备方法,其特征在于,所述方法包括步骤
在惰性溶剂中,缩合剂存在下,化合物A13与2-氟丙烯酸反应,得到化合物A16。 - 如权利要求1所述的制备方法,其特征在于,所述方法还包括如下步骤
在惰性溶剂中,酸存在下,化合物A12脱除Boc,得到化合物A13。 - 如权利要求1或2所述的制备方法,其特征在于,所述方法还包括如下步骤
在惰性溶剂中,碱和催化剂存在下,化合物A11与8-氯-7-氟萘-1-基三氟甲烷磺酸酯反应,得到化合物A12。 - 如权利要求1-3中任一项所述的制备方法,其特征在于,所述方法还包括如下步骤
在惰性溶剂中,催化剂和氢气存在下,化合物A10脱除Cbz,得到化合物A11。 - 如权利要求1-4中任一项所述的制备方法,其特征在于,所述方法还包括步 骤
s’1)在惰性溶剂中,碱存在下,化合物A08与(Boc)2O反应,得到化合物A09;s’2)在惰性溶剂中,碱和催化剂存在下,化合物A09与(1-((二甲氨基)甲基)环丙基)甲醇反应,得到化合物A10。 - 如权利要求1-5中任一项所述的制备方法,其特征在于,所述方法还包括步骤
s1)在惰性溶剂中,碱存在下,化合物A01与化合物A14反应,得到化合物A02;s2)在惰性溶剂中,碱存在下,化合物A02与化合物A15反应,得到化合物A03;s3)在惰性溶剂中,碱存在下,化合物A03与尿素反应,得到化合物A04;s4)化合物A04与氯化试剂反应,得到化合物A05;s5)在惰性溶剂中,脱苄基试剂存在下,化合物A05脱除苄基,得到化合物A06;s6)在惰性溶剂中,化合物A06与CbzCl反应,得到化合物A07;s7)在惰性溶剂中,化合物A07与(S)-2-(哌嗪-2-基)乙腈或其盐反应,得到化合物A08;R1各自独立为卤素(如氯、溴、碘);R2各自独立选自取代或未取代的下组基团:C1-C10烷基、C3-C10环烷基、苯基、苄基;其中,所述取代是被选自下组的一个或多个基团取代:C1-C6烷基、C3-C6环烷基。 - 一种中间体化合物A08的制备方法,其特征在于,包括以下步骤
s1)在惰性溶剂中,碱存在下,化合物A01与化合物A14反应,得到化合物A02;s2)在惰性溶剂中,碱存在下,化合物A02与化合物A15反应,得到化合物A03;s3)在惰性溶剂中,碱存在下,化合物A03与尿素反应,得到化合物A04;s4)化合物A04与氯化试剂反应,得到化合物A05;s5)在惰性溶剂中,脱苄基试剂存在下,化合物A05脱除苄基,得到化合物A06;s6)在惰性溶剂中,化合物A06与CbzCl反应,得到化合物A07;s7)在惰性溶剂中,化合物A07与(S)-2-(哌嗪-2-基)乙腈或其盐反应,得到化合物A08;R1各自独立为卤素(如氯、溴、碘);R2各自独立选自取代或未取代的下组基团:C1-C10烷基、C3-C10环烷基、苯基、苄基;其中,所述取代是被选自下组的一个或多个基团取代:C1-C6烷基、C3-C6环烷基。 - 一种KRAS G12C抑制剂A16的制备方法,其特征在于,所述方法包括步骤
s’1)在惰性溶剂中,碱存在下,化合物A08与(Boc)2O反应,得到化合物A09;s’2)在惰性溶剂中,碱和催化剂存在下,化合物A09与(1-((二甲氨基)甲基)环丙基)甲醇反应,得到化合物A10;s’3)在惰性溶剂中,催化剂和氢气存在下,化合物A10脱除Cbz,得到化合物A11;s’4)在惰性溶剂中,碱和催化剂存在下,化合物A11与8-氯-7-氟萘-1-基三氟甲 烷磺酸酯反应,得到化合物A12;s’5)在惰性溶剂中,酸存在下,化合物A12脱除Boc,得到化合物A13;s’6)在惰性溶剂中,碱和缩合剂存在下,化合物A13与2-氟丙烯酸反应,得到化合物A16。 - 一种KRAS G12C抑制剂中间体,其特征在于,所述中间体选自:
- 一种中间体A05的制备方法,其特征在于,所述方法包括步骤
s1)在惰性溶剂中,碱存在下,化合物A01与化合物A14反应,得到化合物A02;s2)在惰性溶剂中,碱存在下,化合物A02与化合物A15反应,得到化合物A03;s3)在惰性溶剂中,碱存在下,化合物A03与尿素反应,得到化合物A04;s4)化合物A04与氯化试剂反应,得到化合物A05。
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