CN114437085B - Preparation method of rebamipa intermediate - Google Patents
Preparation method of rebamipa intermediate Download PDFInfo
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- CN114437085B CN114437085B CN202011209954.5A CN202011209954A CN114437085B CN 114437085 B CN114437085 B CN 114437085B CN 202011209954 A CN202011209954 A CN 202011209954A CN 114437085 B CN114437085 B CN 114437085B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 99
- 238000000034 method Methods 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
- 150000001875 compounds Chemical class 0.000 claims description 81
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 45
- 238000003756 stirring Methods 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000003054 catalyst Substances 0.000 claims description 29
- 238000001914 filtration Methods 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 18
- 230000035484 reaction time Effects 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- 238000007363 ring formation reaction Methods 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 9
- 229910052759 nickel Inorganic materials 0.000 claims description 9
- 230000009467 reduction Effects 0.000 claims description 9
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 230000018044 dehydration Effects 0.000 claims description 8
- 238000006297 dehydration reaction Methods 0.000 claims description 8
- 229910017604 nitric acid Inorganic materials 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- 238000004537 pulping Methods 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 6
- 239000012670 alkaline solution Substances 0.000 claims description 5
- 239000012752 auxiliary agent Substances 0.000 claims description 5
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 claims description 5
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003637 basic solution Substances 0.000 claims description 3
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 3
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 230000001546 nitrifying effect Effects 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 27
- 238000009776 industrial production Methods 0.000 abstract description 5
- 125000001041 indolyl group Chemical group 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 230000007935 neutral effect Effects 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 239000000047 product Substances 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 238000001035 drying Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- IIFDQESZTDBKEM-UHFFFAOYSA-N 3-(4-fluorophenyl)propan-1-amine Chemical compound NCCCC1=CC=C(F)C=C1 IIFDQESZTDBKEM-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- WVWTVBZOOBKCKI-UHFFFAOYSA-N 3-(4-fluorophenyl)prop-2-enenitrile Chemical compound FC1=CC=C(C=CC#N)C=C1 WVWTVBZOOBKCKI-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- 239000005457 ice water Substances 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 6
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 description 5
- 238000004821 distillation Methods 0.000 description 4
- QOEAMLSLLJPIRF-UHFFFAOYSA-N methyl 5-fluoro-2-methyl-3-nitrobenzoate Chemical compound COC(=O)C1=CC(F)=CC([N+]([O-])=O)=C1C QOEAMLSLLJPIRF-UHFFFAOYSA-N 0.000 description 4
- 239000003444 phase transfer catalyst Substances 0.000 description 4
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- HMABYWSNWIZPAG-UHFFFAOYSA-N rucaparib Chemical compound C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 HMABYWSNWIZPAG-UHFFFAOYSA-N 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- JKOVQYWMFZTKMX-ONEGZZNKSA-N (e)-n,n-dimethyl-2-nitroethenamine Chemical group CN(C)\C=C\[N+]([O-])=O JKOVQYWMFZTKMX-ONEGZZNKSA-N 0.000 description 2
- JVBLXLBINTYFPR-UHFFFAOYSA-N 5-fluoro-2-methylbenzoic acid Chemical compound CC1=CC=C(F)C=C1C(O)=O JVBLXLBINTYFPR-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000005629 indol-6-ones Chemical class 0.000 description 2
- NHNMRJSHULPMIM-UHFFFAOYSA-N methyl chlorate Chemical compound COCl(=O)=O NHNMRJSHULPMIM-UHFFFAOYSA-N 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229950004707 rucaparib Drugs 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SPBWDKFNGQZARC-UHFFFAOYSA-N COCOC.C(=O)N(C)C Chemical compound COCOC.C(=O)N(C)C SPBWDKFNGQZARC-UHFFFAOYSA-N 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application provides a preparation method of a repairam intermediate shown in a formula (II), which comprises the steps of constructing a benzolactam ring and then constructing an indole ring, so as to prepare the repairam intermediate. The preparation method uses the raw materialsThe method has the advantages of low price and easy acquisition of materials, low production cost of products, good raw material safety, effective prevention of safety accidents, simple preparation process, mild preparation conditions, high reaction yield and purity, and can be applied to industrial production on a large scale.
Description
Technical Field
The application relates to the technical field of pharmaceutical chemistry, in particular to a preparation method of a repairable intermediate.
Background
Rucaparib (racaparib) is a poly (adenosine diphosphate) ribose polymerase (PARP) inhibitor used to treat advanced ovarian cancer associated with BRCA gene mutations in two or more lines of chemotherapy, and is known by the chemical name: 8-fluoro-2- {4- [ (methylamino) methyl]Phenyl } -1,3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ]]Indol-6-ones of the formula: c (C) 19 H 18 FN 3 O, CAS NO:283173-50-2, the structural formula is shown as (I):
the chemical name of a key intermediate for preparing Rucaparib is 8-fluoro-1, 3,4, 5-tetrahydro-6H-azepino [5,4,3-cd ]]Indol-6-ones of the formula: c (C) 11 H 9 FN 2 O, CAS NO:1408282-26-7, the structural formula is shown as (II):
for the synthetic route of intermediate (II), the prior art provides the following three:
scheme 1
In the synthetic route 1, 5-fluoro-2-methylbenzoic acid is taken as a raw material, 5-fluoro-3-nitro-2-methylbenzoic acid methyl ester is obtained through nitration and esterification, the 5-fluoro-3-nitro-2-methylbenzoic acid methyl ester reacts with DMFDMA and is hydrogenated to obtain 6-fluoro-1H-indole-4-methyl formate, the 6-fluoro-1H-indole-4-methyl formate reacts with 1-dimethylamino-2-nitroethylene, and then the intermediate (II) is obtained through reduction and catalytic hydrogenation.
The 1-dimethylamino-2-nitroethylene used in the synthetic route 1 is expensive, the yield from the reduction of the compound 7 to the compound 8 is low, and the intermediate has high cost and is unfavorable for industrial production.
Scheme 2 differs from scheme 1 in the step of synthesizing intermediate (II) at compound 6, specifically as follows:
scheme 2
The steps from compounds 6 to 11 in synthetic route 2 have low yields and the raw material TFA TES used is also expensive, which results in high cost of the products in the route and is unfavorable for industrial production.
Scheme 3
In the synthetic route 3, 5-fluoro-2-methylbenzoic acid is used as a raw material, 5-fluoro-3-nitro-2-methylbenzoic acid methyl ester is obtained through nitration and esterification, the 5-fluoro-3-nitro-2-methylbenzoic acid methyl ester is reacted with DMFDMA and hydrogenated to obtain 6-fluoro-1H-indole-4-methyl formate, then the 6-fluoro-3-formyl-1H-indole-4-methyl formate is obtained through velsmeier reaction, and then the 6-fluoro-3-formyl-1H-indole-4-methyl formate is reacted with nitromethane to obtain an intermediate (II) through reduction and catalytic hydrogenation, the nitromethane is needed in the synthetic route 2, great potential safety hazards exist in industrial production, the route reaction steps are longer, and the overall yield is lower.
Based on the problems existing in the prior art, the development of a novel preparation method of the Ruicalpab intermediate (II) is a technical problem to be solved urgently by the person skilled in the art.
Disclosure of Invention
In view of the above problems in the prior art, an object of the present application is to provide a preparation method of a repaira intermediate, which is used for solving the problems of complex preparation process, expensive production raw materials or explosiveness.
The application provides a preparation method of a repairamate intermediate shown in a formula (II), which comprises the following steps:
(1) Reacting a compound shown in a formula (III) with acetonitrile in an alkaline solution to generate a compound shown in a formula (IV);
(2) The compound shown in the formula (IV) is subjected to hydrogenation reaction with hydrogen in the presence of a catalyst and an alkaline auxiliary agent to generate a compound shown in the formula (V);
(3) Reacting a compound shown in a formula (V) with chloroformate to generate a compound shown in a formula (VI);
(4) A compound shown in a formula (VI) undergoes a dehydration cyclization reaction in the presence of a dehydration cyclization catalyst to generate a compound shown in a formula (VII);
(5) Nitrifying the compound shown in the formula (VII) with mixed acid to generate a compound shown in the formula (VIII);
(6) Reacting a compound shown in a formula (VIII) with N, N-dimethylformamide dimethyl acetal to generate a compound shown in a formula (IX);
(7) The compound shown in the formula (IX) is subjected to reduction cyclization to generate a rebamipa intermediate shown in the formula (II);
further, the mass ratio of the compound shown in the formula (III) to acetonitrile is (1.8-2.4): 1, and the mass ratio of acetonitrile to alkaline solution is 1: (3-5).
Preferably, the basic solution comprises acetonitrile, water, potassium hydroxide and phase transfer catalyst dodecyltrimethylammonium chloride, wherein the basic solution comprises acetonitrile: water: potassium hydroxide: the mass ratio of the dodecyl trimethyl ammonium chloride is 35:05:14:1. In this application, the person skilled in the art may choose other alkaline solutions according to the actual situation, as long as the purpose of this application is met.
Further, the mass ratio between the compound shown in the formula (IV), the catalyst and the alkaline auxiliary agent is 54: (0.2-6): (0.5-4).
Further, the molar ratio of the compound represented by formula (V) to chloroformate is (0.7-1.3): 1.
further, the ratio of the mass of the compound represented by the formula (VI) to the volume of the dehydration cyclization catalyst is 1: (2-5) g/ml.
Further, the mixed acid comprises nitric acid and sulfuric acid, and the molar ratio of the nitric acid to the sulfuric acid is 1 (2.5-5).
Further, the molar ratio of the compound represented by formula (VII) to nitric acid is (0.5-1): the molar ratio of the compound shown in the formula (VII) to sulfuric acid is (2.5-5): 1.
further, the molar ratio of the compound represented by the formula (VIII) to N, N-dimethylformamide methylal is (0.5-1): 1.
Further, the alkaline auxiliary agent is at least one selected from potassium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide and ammonia water.
Further, the methyl chlorate is selected from any one of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate and tert-butyl chloroformate.
Further, the dehydration cyclization catalyst is at least one selected from polyphosphoric acid, phosphorus oxychloride, phosphorus pentachloride and tin chloride.
Further, the reduction method in step (7) includes: (a) Hydrogenation with a hydrogen source under the action of a catalyst, or (b) reduction with a chemical reducing agent;
the catalyst is at least one of palladium-based catalyst, platinum-based catalyst and nickel-based catalyst, preferably palladium carbon or skeleton nickel;
the hydrogen source is at least one selected from hydrogen, formic acid, sodium formate, ammonium formate and hydrazine hydrate;
the chemical reducing agent is at least one selected from iron powder, zinc powder and sodium hydrosulfite (commonly known as sodium hydrosulfite).
Further, the reaction temperature in the step (1) is 75-85 ℃ and the reaction time is 1-3h;
the reaction temperature in the step (2) is 80-110 ℃, the reaction time is 4-10h, and hydrogen is introduced until the pressure is 2-3MPa;
the reaction temperature in the step (3) is 0-10 ℃ and the reaction time is 1-3h;
the reaction temperature in the step (4) is 60-100 ℃ and the reaction time is 6-10h;
the reaction temperature in the step (5) is 0-10 ℃ and the reaction time is 1-3h;
the reaction temperature in the step (6) is 80-140 ℃ and the reaction time is 3-10h; preferably, the reactants react for 0 to 2 hours at the reaction temperature of 80 to 100 ℃ under the protection of nitrogen, then the temperature is continuously increased to 110 to 140 ℃, and the reactants react for 3 to 5 hours at the reaction temperature of 110 to 140 ℃;
in the step (7), the reaction temperature of the reaction under the action of the catalyst is 20-100 ℃, the reaction time is 4-10h, and the reaction temperature of the reaction under the action of the chemical reducing agent is 20-110 ℃ and the reaction time is 4-8h.
Further, after the compound shown in the formula (III) is mixed with acetonitrile, an alkaline solution is added dropwise to react, and the temperature of a reaction system is controlled to be 0-80 ℃ during the dropwise addition.
Further, methyl chlorate is dripped into the reaction system, and the temperature of the reaction system is controlled to be 0-10 ℃ during dripping.
Further, when the mixed acid is added dropwise to the reaction solution in the step (5), the temperature of the reaction solution is 0 ℃, and after the completion of the dropwise addition, the reaction is carried out at 0-10 ℃ for 1-3 hours, preferably 2 hours.
Further, the preparation method of the application further comprises the following purification steps:
adding the repairam intermediate shown in the formula (II) into a solvent, stirring and pulping, and then filtering to obtain a purified repairam intermediate shown in the formula (II);
wherein the solvent is at least one selected from ethyl acetate, dichloromethane, n-hexane, n-heptane, methyl tert-butyl ether and methanol. Dichloromethane and methanol are preferred.
Further, stirring and pulping at 30-40deg.C for 1-3 hr, preferably 2 hr, cooling to below 10deg.C, and filtering.
Through the above purification steps, the purity of the repairable intermediate represented by formula (ii) can be improved.
According to the preparation method of the repairane intermediate shown in the formula (II), p-fluoro cinnamonitrile shown in the formula (IV) is synthesized, a benzolactam ring is constructed through catalytic hydrogenation, amidation and cyclization, and an indole ring is constructed, so that the repairane intermediate is prepared.
Of course, not all of the above-described advantages need be achieved simultaneously in practicing any one of the products or methods of the present application.
Detailed Description
For further explanation of the present application, the present application will be specifically explained below with reference to examples, but the scope of protection of the present application is not limited to the specific examples.
Example 1
(1) 70g of acetonitrile, 10g of water, 28g of potassium hydroxide and 2g of phase transfer catalyst dodecyl trimethyl ammonium chloride are added into a 500ml reaction bottle, after stirring until potassium hydroxide is uniformly dispersed, 63g of a mixed solution of a compound (p-fluorobenzaldehyde) shown in a formula (III) and 30g of acetonitrile is dropwise added, after the addition is finished, the mixture is reacted for 2 hours at 80 ℃, 100ml of toluene is added to cool to 10 ℃, 100ml of water is added, layering is carried out, an organic phase is washed to be neutral by saturated saline, drying and desolventizing are carried out, and 54.5g of a compound (p-fluoro cinnamonitrile) shown in a formula (IV) is obtained after rectification under reduced pressure (yield 73%), and purity is 95%.
(2) 54.5g of p-fluoro cinnamonitrile, 200ml of ethanol, 3g of skeleton nickel and 1g of potassium hydroxide are added into an autoclave, hydrogen is introduced to the autoclave to 2.5MPa after nitrogen replacement, the temperature is raised to 95 ℃ for reaction for 7 hours, the pressure is kept at 2.5MPa, after the reaction is finished, the temperature is reduced, the catalyst is removed by filtration, the filtrate is desolvated, and then the compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) is obtained by reduced pressure distillation, wherein the yield is 85%, and the purity is 94%.
(3) 48g of 3- (4-fluorophenyl) propylamine is dissolved in 300ml of dichloromethane, 37.7g of triethylamine is added, the temperature is reduced to 10 ℃ by stirring, 36g of ethyl chloroformate is added dropwise, the dropwise adding temperature is controlled to be 10 ℃, the reaction is carried out at 5 ℃ for 2 hours after the completion of the dropwise adding, 100ml of water is added after the detection reaction is finished, layering is carried out, an organic phase is washed to be neutral by water, anhydrous magnesium sulfate is dried, filtration and desolventizing are carried out, 67.7g of a compound shown in a formula (VI) are obtained (yield 96%), and purity is 95%.
(4) 67.7g of the compound of formula (VI) are added into a reaction bottle, 250ml of PPA (polyphosphoric acid) is added, stirring and heating are carried out to 80 ℃, the temperature is kept for reaction for 8 hours, the residual content of the raw material is detected to be less than 1 percent (the conversion rate of the raw material is 98 percent), 300ml of ice water and 300ml of dichloromethane are added, stirring, standing and layering are carried out, the aqueous phase is extracted once by 100ml of dichloromethane, the organic phases are combined, water is washed to be neutral, and the next step is directly carried out after drying.
(5) Cooling the solution obtained in the previous step to 0 ℃, dropwise adding a mixed acid solution prepared from 150g of 98wt% concentrated sulfuric acid and 33g of 70wt% concentrated nitric acid, continuing to react at 5 ℃ for 2 hours after the dropwise adding, pouring the reaction solution into 300ml of ice water for hydrolysis after detecting that the raw materials react, layering, extracting the water phase once with 100ml of dichloromethane, merging the organic phases, washing with water to be neutral, drying with anhydrous magnesium sulfate, desolvating, and recrystallizing the obtained solid with 150ml of ethanol to obtain 52.6g of a compound shown in a formula (VIII) (two-step yield 78%) with purity of 99.2%.
(6) To 52.6g of the compound of formula (VIII), 200ml of DMF (N, N-dimethylformamide), 41.3g of DMFDMA (N, N-dimethylformamide dimethyl acetal), 35g of triethylamine were added, the reaction was continued under nitrogen protection at a temperature of 90℃for 1 hour, the reaction was continued at a temperature of 120℃for 4 hours, after the completion of the reaction of the starting materials, about 190ml of the solvent was distilled off under reduced pressure, and 225ml of methanol was added to the residue to conduct the subsequent reaction directly.
(7) Adding the solution obtained in the last step into a hydrogenation kettle, adding 2.5g of 5wt% palladium carbon, replacing nitrogen for three times, introducing hydrogen to the pressure of 0.2MPa, stirring, reacting for exothermic heat, introducing circulating water to control the reaction temperature to be 50 ℃, reacting for 7 hours at 40 ℃, sampling, detecting that the raw materials are reacted, replacing hydrogen in the kettle by nitrogen, filtering to remove the palladium carbon, adding 370ml of water, stirring for 30 minutes, filtering, pulping the obtained solid by using 40ml of dichloromethane and 200ml of methanol at 40 ℃, cooling to below 0 ℃, filtering and drying to obtain 40.2g of white solid (the Rakappab intermediate shown as a formula (II) (yield 85%), product purity is 99.4%, and total yield is 39.4%.
Example 2
(1) 70g of acetonitrile, 10g of water, 28g of potassium hydroxide and 2g of phase transfer catalyst dodecyl trimethyl ammonium chloride are added into a 500ml reaction bottle, after stirring until potassium hydroxide is uniformly dispersed, 63g of mixed solution of a compound (p-fluorobenzaldehyde) shown in a formula (III) and 30g of acetonitrile are added dropwise, after the addition is finished, the mixture is reacted for 3 hours at 75 ℃, 100ml of toluene is added to cool to 5 ℃, 100ml of water is added, layering is carried out, an organic phase is washed to be neutral by saturated saline, drying and desolventizing are carried out, and 54g of a compound (p-fluoro cinnamonitrile) shown in a formula (IV) is obtained after rectification under reduced pressure (yield 73%), and purity is 95%.
(2) 54g of p-fluoro cinnamonitrile and 200ml of ethanol are added into an autoclave, 3g of skeleton nickel and 0.5g of potassium hydroxide are added, hydrogen is introduced to the autoclave until the pressure is 2.0MPa after nitrogen replacement, the temperature is raised to 90 ℃ for reaction for 10 hours, the pressure is kept at 2.0MPa, after the reaction is finished, the temperature is reduced, the catalyst is removed by filtration, the filtrate is desolvated, and then the compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) is obtained through reduced pressure distillation, wherein the yield is 80 percent, and the purity is 92 percent.
(3) 45g of 3- (4-fluorophenyl) propylamine is dissolved in 280ml of dichloromethane, 35.3g of triethylamine is added, stirring and cooling are carried out to 5 ℃, 34g of ethyl chloroformate is dropwise added, the dropwise heating temperature is controlled to 5 ℃, the reaction is carried out at 0 ℃ for 3 hours after the completion of the addition, 100ml of water is added after the detection reaction, layering is carried out, an organic phase is washed to be neutral by water, anhydrous magnesium sulfate is dried, filtering is carried out, and a solvent is removed to obtain 63.1g of a compound shown as a formula (VI) (the yield is 96 percent), and the purity is 93 percent.
(4) 63.1g of the compound of formula (VI) are placed in a reaction flask, 225ml of PPA is added, the mixture is stirred and heated to 60 ℃ for reaction for 10 hours, the residual content of the raw material is detected to be less than 1 percent (the conversion rate of the raw material is 98 percent), 280ml of ice water and 280ml of dichloromethane are added, the mixture is stirred and kept stand for delamination, the aqueous phase is extracted once by 90ml of dichloromethane, the organic phases are combined, the mixture is washed to be neutral by water, and the mixture is dried and then directly subjected to the next step.
(5) Cooling the solution obtained in the previous step to 0 ℃, dropwise adding a mixed acid solution prepared from 140g of 98wt% concentrated sulfuric acid and 31g of 70wt% concentrated nitric acid, continuing to react at 0 ℃ for 3 hours after the dropwise adding, pouring the reaction solution into 280ml of ice water for hydrolysis after detecting that the raw materials react, layering, extracting the water phase once with 95ml of dichloromethane, merging the organic phases, washing with water to be neutral, drying with anhydrous magnesium sulfate, desolvating, and recrystallizing the obtained solid with 140ml of ethanol to obtain 47.1g of a compound shown in a formula (VIII) (two-step yield 78%) and purity of 99.1%.
(6) 47.1g of the compound of formula (VIII) (0.23 mol) were added with 180ml of DMF, 37g of DMFDMA,31.5g of triethylamine, reacted at 80℃for 6 hours under nitrogen protection, further reacted at 120℃for 4 hours, after the completion of the reaction of the starting materials, about 170ml of the solvent was distilled off under reduced pressure, and 190ml of methanol was added to the residue to conduct the subsequent reaction directly.
(7) Adding the solution obtained in the last step into a hydrogenation kettle, adding 2.2g of 5wt% palladium-carbon, replacing nitrogen for three times, introducing hydrogen to the pressure of 0.2MPa, stirring, reacting for exothermic heat, introducing circulating water to control the reaction temperature to 20 ℃, reacting for 10 hours at 30 ℃, sampling, detecting that the raw materials are reacted, replacing hydrogen in the kettle by nitrogen, filtering to remove the palladium-carbon, adding 330ml of water, stirring for 30 minutes, filtering, pulping the obtained solid by 34ml of dichloromethane and 180ml of methanol at 40 ℃, cooling to below 0 ℃, filtering and drying to obtain 33.7g of white solid (the Rakappab intermediate shown in a formula (II) (yield 85%), total yield of 35.7%, and product purity of 99.3%.
Example 3
(1) 70g of acetonitrile, 10g of water, 28g of potassium hydroxide and 2g of phase transfer catalyst dodecyl trimethyl ammonium chloride are added into a 500ml reaction bottle, after stirring until potassium hydroxide is uniformly dispersed, 63g of mixed solution of a compound (p-fluorobenzaldehyde) shown in a formula (III) and 30g of acetonitrile are added dropwise, after the addition, the mixture is reacted for 1h at 85 ℃, 100ml of toluene is added to cool to 10 ℃, 100ml of water is added, layering is carried out, an organic phase is washed to be neutral by saturated saline, drying and desolventizing are carried out, and 54g of a compound (p-fluoro cinnamonitrile) shown in a formula (IV) is obtained after rectification under reduced pressure (yield 73%), and purity is 95%.
(2) 54g of p-fluoro cinnamonitrile and 200ml of ethanol are added into an autoclave, 3g of skeleton nickel and 2g of potassium hydroxide are added, hydrogen is introduced to the autoclave until the pressure is 3.0MPa after nitrogen replacement, the temperature is raised to 100 ℃ for reaction for 4 hours, the pressure is kept at 3.0MPa, after the reaction is finished, the catalyst is removed by cooling and filtering, the filtrate is desolvated, and then the 3- (4-fluorophenyl) propylamine (yield is 76%) of the compound shown in the formula (V) is obtained by reduced pressure distillation, and the purity is 87%.
(3) 43g of 3- (4-fluorophenyl) propylamine are dissolved in 270ml of dichloromethane, 33.8g of triethylamine is added, the temperature is reduced to 0 ℃ by stirring, 33g of ethyl chloroformate (0.33 mol) is added dropwise, the dropwise addition temperature is controlled to be 10 ℃, the reaction is carried out at 10 ℃ for 1h after the addition is finished, 100ml of water is added after the detection reaction is finished, layering is carried out, an organic phase is washed to be neutral by water, anhydrous magnesium sulfate is dried, filtration and desolventizing are carried out, and 60.2g of a compound shown as a formula (VI) is obtained (yield 96%), and purity is 88%.
(4) 60.2g of the compound of formula (VI) are added into a reaction bottle, 225ml of PPA is added, the mixture is stirred and heated to 100 ℃ for reaction for 6 hours, the residual content of the raw materials is detected to be less than 1 percent (the conversion rate of the raw materials is 98 percent), 270ml of ice water and 270ml of dichloromethane are added, the mixture is stirred and kept stand for layering, the aqueous phase is extracted once by 100ml of dichloromethane, the organic phases are combined, the mixture is washed to be neutral by water, and the next step is directly carried out after the mixture is dried.
(5) Cooling the solution obtained in the previous step to 0 ℃, dropwise adding a mixed acid solution prepared from 135g of 98wt% concentrated sulfuric acid and 30g of 70wt% concentrated nitric acid, continuing to react at 10 ℃ for 1h after the dropwise adding, pouring the reaction solution into 300ml of ice water for hydrolysis after detecting that the raw materials react, layering, extracting the water phase once with 90ml of dichloromethane, merging the organic phases, washing with water to be neutral, drying with anhydrous magnesium sulfate, desolvating, and recrystallizing the obtained solid with 140ml of ethanol to obtain 45.1g of a compound shown in a formula (VIII) (two-step yield 70%) and purity of 99.1%.
(6) 45.1g of the compound represented by the formula (VIII), 170ml of DMF, 35.4g of DMFDMA,30g of triethylamine and nitrogen are added, the temperature is raised to 100 ℃ for reaction for 2 hours, the temperature is raised to 140 ℃ for reaction for 1 hour, after the reaction of the raw materials is detected, about 160ml of solvent is distilled off under reduced pressure, and 190ml of methanol is added to the residue for direct next reaction.
(7) Adding the solution obtained in the last step into a hydrogenation kettle, adding 2.1g of 5wt% palladium carbon, replacing nitrogen for three times, introducing hydrogen to the pressure of 0.2MPa, stirring, reacting for exothermic heat, introducing circulating water to control the reaction temperature to be 50 ℃, reacting for 4 hours at 50 ℃, sampling, detecting that the raw materials are reacted, replacing hydrogen in the kettle by nitrogen, filtering to remove the palladium carbon, adding 330ml of water, stirring for 30 minutes, filtering, pulping the obtained solid by 35ml of dichloromethane and 170ml of methanol at 40 ℃, cooling to below 0 ℃, filtering and drying to obtain 34.6g of white solid (the Rakappab intermediate shown as a formula (II)), wherein the yield is 85%, the total yield is 31.6%, and the product purity is 99.3%.
Example 4
(1) The same as in example 1.
(2) 54.5g of p-fluoro cinnamonitrile and 200ml of ethanol are added into an autoclave, 3g of skeleton nickel and 1g of sodium methoxide are added, hydrogen is introduced to the pressure of 2.0MPa after nitrogen replacement, the temperature is raised to 95 ℃ for reaction for 7 hours, the pressure is kept at 2.0MPa, after the reaction is finished, the temperature is reduced, the catalyst is removed by filtration, the filtrate is desolvated and then distilled under reduced pressure, thus obtaining 40.2g of compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) (yield 71%), and purity is 93.5%.
(3) - (7) is the same as in example 1. The total yield is 32.5 percent and the purity of the product is 99.1 percent.
Example 5
(1) The same as in example 1.
(2) 54.5g of p-fluoro cinnamonitrile and 200ml of ethanol are added into an autoclave, 3g of skeleton nickel and 4g of ammonia water are added, hydrogen is introduced to the autoclave until the pressure is 2.0MPa after nitrogen replacement, the temperature is raised to 95 ℃ for reaction for 7 hours, the pressure is kept at 2.0MPa, after the reaction is finished, the temperature is reduced, the catalyst is removed by filtration, the filtrate is desolvated, and then the reduced pressure distillation is carried out to obtain 44.2g of the compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) (yield 78%), and purity is 93%.
(3) - (7) is the same as in example 1. The total yield is 36.2 percent and the purity of the product is 99.4 percent.
Example 6
(1) The same as in example 1.
(2) 54.5g of p-fluoro cinnamonitrile and 200ml of ethanol are added into an autoclave, 6g of skeleton nickel and 1g of potassium hydroxide are added, hydrogen is introduced to the autoclave until the pressure is 2.0MPa after nitrogen replacement, the temperature is raised to 95 ℃ for reaction for 7 hours, the pressure is kept at 2.0MPa, after the reaction is finished, the temperature is reduced, the catalyst is removed by filtration, the filtrate is desolvated and then distilled under reduced pressure, thus 48g of compound (3- (4-fluorophenyl) propylamine shown in the formula (V) is obtained (yield is 85%), and the purity is 94%.
(3) - (7) is the same as in example 1. The total yield is 39.5 percent and the purity of the product is 99.5 percent.
Example 7
(1) The same as in example 1.
(2) 54.5g of p-fluoro cinnamonitrile and 200ml of ethanol are added into an autoclave, 0.2g of palladium-carbon and 1g of potassium hydroxide are added, hydrogen is introduced to the pressure of 2.0MPa after nitrogen replacement, the temperature is raised to 95 ℃ for reaction for 7 hours, the pressure is kept at 2.0MPa, after the reaction is finished, the temperature is reduced, the catalyst is removed by filtration, the filtrate is desolvated and then distilled under reduced pressure, 48g of compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) is obtained (yield 83%), and the purity is 94%.
(3) - (7) is the same as in example 1. The total yield is 38.1 percent and the purity of the product is 99.5 percent.
Example 8
(1) - (3) is the same as in example 1.
(4) 67.3g of the compound shown in the formula (VI) is added into a reaction bottle, 250ml of phosphorus oxychloride is added, stirring and heating are carried out to 80 ℃, heat preservation is carried out for 8 hours, the residual content of the raw materials is detected to be less than 1 percent (the raw material conversion rate is 60 percent), 300ml of ice water and 300ml of dichloromethane are added, stirring, standing and layering are carried out, the aqueous phase is extracted once by 100ml of dichloromethane, the organic phases are combined, water washing is carried out to be neutral, and the compound shown in the formula (VII) is obtained after drying.
(5) - (7) is the same as in example 1. The total yield is 19.2 percent and the purity of the product is 98.8 percent.
Example 9
(1) - (3) is the same as in example 1.
(4) 67.3g of the compound shown in the formula (VI) is added into a reaction bottle, 250ml of phosphorus oxychloride and 70g of phosphorus pentoxide are added, stirring and heating are carried out to 80 ℃, the temperature is kept for reaction for 8 hours, the residual content of the raw materials is detected to be less than 1 percent (the conversion rate of the raw materials is 92 percent), 300ml of ice water and 300ml of dichloromethane are added, stirring and standing and layering are carried out, the aqueous phase is extracted once by 100ml of dichloromethane, the organic phases are combined, water is washed to be neutral, and the compound shown in the formula (VII) is obtained after drying.
(5) - (7) is the same as in example 1. The total yield is 33.7 percent and the purity of the product is 99.1 percent.
Example 10
(1) - (3) is the same as in example 1.
(4) 67.3g of the compound shown in the formula (VI) is added into a reaction bottle, 250ml of phosphorus oxychloride and 100g of stannic chloride are added, stirring and heating are carried out to 80 ℃, the temperature is kept for reaction for 8 hours, the residual content of the raw materials is detected to be less than 1 percent (the conversion rate of the raw materials is 95 percent), 300ml of ice water and 300ml of dichloromethane are added, stirring and standing are carried out for layering, the aqueous phase is extracted once by 100ml of dichloromethane, the organic phases are combined, water is used for washing to be neutral, and the compound shown in the formula (VII) is obtained after drying.
(5) - (7) is the same as in example 1. The total yield is 34.3 percent and the purity of the product is 99.1 percent.
Example 11
(1) - (3) is the same as in example 1.
(4) 67.3g of the compound shown in the formula (VI) is added into a reaction bottle, 250ml of phosphorus oxychloride and 70g of phosphorus pentachloride are added, stirring and heating are carried out to 80 ℃, the temperature is kept for reaction for 8 hours, the residual content of the raw materials is detected to be less than 1 percent (86 percent of raw material conversion), 300ml of ice water and 300ml of dichloromethane are added, stirring and standing and layering are carried out, the aqueous phase is extracted once by 100ml of dichloromethane, the organic phases are combined, water is used for washing to be neutral, and the compound shown in the formula (VII) is obtained after drying.
(5) - (7) is the same as in example 1. The total yield is 31.4 percent and the purity of the product is 98.7 percent.
Example 12
(1) - (2) the same as in example 1.
(3) 48g of 3- (4-fluorophenyl) propylamine is dissolved in 300ml of dichloromethane, 37.7g of triethylamine is added, the temperature is reduced to 10 ℃ by stirring, 31.2g of methyl chloroformate (0.33 mol) is dropwise added, the dropwise adding temperature is controlled to be 10 ℃, the reaction is carried out for 2 hours at 5 ℃ after the dropwise adding is finished, 100ml of water is added after the reaction is detected, the layers are separated, an organic phase is washed to be neutral by water, anhydrous magnesium sulfate is dried, the filtration and the solvent removal are carried out, and 64.8g of a compound shown as a formula (VI) (the yield is 98%) and the purity is 95%.
(4) - (7) is the same as in example 1. The total yield is 40.2 percent and the purity of the product is 99.3 percent.
Example 13
(1) - (2) the same as in example 1.
(3) 48g of 3- (4-fluorophenyl) propylamine is dissolved in 300ml of dichloromethane, 37.7g of triethylamine is added, the temperature is reduced to 10 ℃ by stirring, 40.4g of isopropyl chloroformate (0.33 mol) is dropwise added, the dropwise adding temperature is controlled to be 10 ℃, the reaction is carried out for 2 hours at 5 ℃ after the dropwise adding is finished, 100ml of water is added after the reaction is detected, the layers are separated, an organic phase is washed to be neutral by water, anhydrous magnesium sulfate is dried, the filtration and the solvent removal are carried out, and 70.4g of a compound shown as a formula (VI) (the yield is 94%) and the purity is 95%.
(4) - (7) is the same as in example 1. The total yield is 32.8 percent, and the purity of the product is 99.1 percent.
Example 14
(1) - (2) the same as in example 1.
(3) 48g of 3- (4-fluorophenyl) propylamine is dissolved in 300ml of dichloromethane, 37.7g of triethylamine is added, the temperature is reduced to 10 ℃ by stirring, 50.7g of tert-butyl chloroformate (0.33 mol) is dropwise added, the dropwise adding temperature is controlled to be 10 ℃, the reaction is carried out for 2 hours at 5 ℃ after the dropwise adding is finished, 100ml of water is added after the reaction is detected, the layers are separated, an organic phase is washed to be neutral by water, anhydrous magnesium sulfate is dried and filtered, and 73.8g of a compound shown as a formula (VI) is obtained after the solvent is removed (yield is 93 percent), and the purity is 95 percent.
(4) - (7) is the same as in example 1. The total yield is 29.6 percent and the purity of the product is 98.8 percent.
Example 15
(1) - (6) is the same as in example 1.
(7) Sequentially adding the solution obtained in the previous step and 70g of iron powder into 250ml of four-neck flask with a thermometer and a stirring device, stirring to fully mix, heating the four-neck flask to 90 ℃, slowly dropwise adding 60g of glacial acetic acid, heating and refluxing after the addition is finished for reaction, filtering while hot to remove the iron powder after the reaction is 6h, adding 370ml of water into filtrate for dilution, filtering, stirring and pulping the obtained solid with 40ml of dichloromethane and 200ml of methanol at 35 ℃ for 2h, cooling to 10 ℃, filtering and drying to obtain 34.6g of white solid (a Ruicapa intermediate shown as a formula (II) (the yield is 73%), and the product purity is 99.4% and the total yield is 33.8%.
According to the embodiment, the preparation method of the repairamate intermediate shown in the formula (II) does not need to use expensive or explosive raw materials in the preparation process, and is mild in preparation conditions and high in reaction yield and purity. By using the preparation method provided by the application, the production cost of the product is low, and the occurrence of safety accidents can be effectively avoided, so that the preparation method can be widely applied to industrial production.
The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the scope of the present application. Any modifications, equivalent substitutions, improvements, etc. that are within the spirit and principles of the present application are intended to be included within the scope of the present application.
Claims (13)
1. A method for preparing a repairam intermediate represented by formula (ii), comprising the steps of:
(1) Reacting a compound shown in a formula (III) with acetonitrile in an alkaline solution to generate a compound shown in a formula (IV);
(2) The compound shown in the formula (IV) is subjected to hydrogenation reaction with hydrogen in the presence of a catalyst and an alkaline auxiliary agent to generate a compound shown in the formula (V);
(3) Reacting a compound shown in a formula (V) with chloroformate to generate a compound shown in a formula (VI); the chloroformate is selected from any one of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate and tert-butyl chloroformate;
(4) A compound shown in a formula (VI) undergoes a dehydration cyclization reaction in the presence of a dehydration cyclization catalyst to generate a compound shown in a formula (VII);
(5) Nitrifying the compound shown in the formula (VII) with mixed acid to generate a compound shown in the formula (VIII);
(6) Reacting a compound shown in a formula (VIII) with N, N-dimethylformamide dimethyl acetal to generate a compound shown in a formula (IX);
(7) The compound shown in the formula (IX) is subjected to reduction cyclization to generate a rebamipa intermediate shown in the formula (II);
2. the process according to claim 1, wherein the mass ratio of the compound represented by the formula (III) to acetonitrile is (1.8-2.4): 1, and the mass ratio of acetonitrile to basic solution is 1: (3-5).
3. The preparation method according to claim 1, wherein the mass ratio between the compound represented by the formula (IV), the catalyst and the alkaline auxiliary agent is 54: (0.2-6): (0.5-4).
4. The production process according to claim 1, wherein the molar ratio of the compound represented by the formula (V) to chloroformate is (0.7-1.3): 1.
5. the process according to claim 1, wherein the ratio of the mass of the compound represented by the formula (VI) to the volume of the dehydration cyclization catalyst is 1: (2-5) g/ml.
6. The preparation method according to claim 1, wherein the mixed acid comprises nitric acid and sulfuric acid in a molar ratio of 1 (2.5-5).
7. The process according to claim 6, wherein the molar ratio of the compound represented by the formula (VII) to nitric acid is (0.5-1): the molar ratio of the compound shown in the formula (VII) to sulfuric acid is (2.5-5): 1.
8. the process according to claim 1, wherein the molar ratio of the compound of formula (VIII) to N, N-dimethylformamide dimethyl acetal is from (0.5 to 1): 1.
9. The preparation method according to claim 1, wherein the alkaline auxiliary is at least one selected from potassium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide and aqueous ammonia.
10. The process according to claim 1, wherein the dehydration cyclization catalyst is at least one selected from the group consisting of polyphosphoric acid, phosphorus oxychloride, phosphorus pentachloride, and tin chloride.
11. The production method according to claim 1, wherein the reduction method in step (7) comprises: (a) Hydrogenation with a hydrogen source under the action of a catalyst, or (b) reduction with a chemical reducing agent;
the catalyst is at least one selected from palladium-based catalyst, platinum-based catalyst and nickel-based catalyst;
the hydrogen source is at least one selected from hydrogen, formic acid, sodium formate, ammonium formate and hydrazine hydrate;
the chemical reducing agent is at least one selected from iron powder, zinc powder and sodium dithionite.
12. The preparation method according to claim 7, wherein,
the reaction temperature in the step (1) is 75-85 ℃ and the reaction time is 1-3h;
the reaction temperature in the step (2) is 80-110 ℃, the reaction time is 4-10h, and hydrogen is introduced until the pressure is 2-3MPa;
the reaction temperature in the step (3) is 0-10 ℃ and the reaction time is 1-3h;
the reaction temperature in the step (4) is 60-100 ℃ and the reaction time is 6-10h;
the reaction temperature in the step (5) is 0-10 ℃ and the reaction time is 1-3h;
the reaction temperature in the step (6) is 80-140 ℃ and the reaction time is 3-10h;
in the step (7), the reaction temperature of the reaction under the action of the catalyst is 20-100 ℃, the reaction time is 4-10h, and the reaction temperature of the reaction under the action of the chemical reducing agent is 20-110 ℃ and the reaction time is 4-8h.
13. The preparation method according to claim 1, further comprising the following purification steps:
adding the repairam intermediate shown in the formula (II) into a solvent, stirring and pulping, and then filtering to obtain a purified repairam intermediate shown in the formula (II);
wherein the solvent is at least one selected from ethyl acetate, dichloromethane, n-hexane, n-heptane, methyl tert-butyl ether and methanol.
Priority Applications (1)
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