CN114437085A - Preparation method of Ruicapa intermediate - Google Patents
Preparation method of Ruicapa intermediate Download PDFInfo
- Publication number
- CN114437085A CN114437085A CN202011209954.5A CN202011209954A CN114437085A CN 114437085 A CN114437085 A CN 114437085A CN 202011209954 A CN202011209954 A CN 202011209954A CN 114437085 A CN114437085 A CN 114437085A
- Authority
- CN
- China
- Prior art keywords
- formula
- reaction
- compound shown
- catalyst
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 94
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 30
- 239000003054 catalyst Substances 0.000 claims description 29
- 238000001914 filtration Methods 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 25
- 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 15
- 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
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 9
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 9
- 229910052759 nickel Inorganic materials 0.000 claims description 9
- 229910017604 nitric acid Inorganic materials 0.000 claims description 9
- 238000006722 reduction reaction Methods 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 8
- 230000018044 dehydration Effects 0.000 claims description 8
- 238000006297 dehydration reaction Methods 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- 238000004537 pulping Methods 0.000 claims description 7
- 230000009467 reduction Effects 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
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- 239000012670 alkaline solution Substances 0.000 claims description 5
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 5
- 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
- 238000006396 nitration reaction Methods 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
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 239000012752 auxiliary agent 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
- 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
- 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
- 239000003637 basic solution Substances 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
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 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
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 30
- 238000009776 industrial production Methods 0.000 abstract description 5
- 125000001041 indolyl group Chemical group 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 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
- 238000001816 cooling Methods 0.000 description 23
- 238000001035 drying Methods 0.000 description 21
- 230000007935 neutral effect Effects 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 238000010438 heat treatment Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 238000005406 washing Methods 0.000 description 14
- IIFDQESZTDBKEM-UHFFFAOYSA-N 3-(4-fluorophenyl)propan-1-amine Chemical compound NCCCC1=CC=C(F)C=C1 IIFDQESZTDBKEM-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 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
- 239000005457 ice water Substances 0.000 description 10
- 239000012071 phase 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 8
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001514 detection method 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
- 238000003786 synthesis reaction Methods 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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 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
- 238000004321 preservation Methods 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
- 150000003839 salts Chemical class 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000126 substance Substances 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
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- NHNMRJSHULPMIM-UHFFFAOYSA-N methyl chlorate Chemical compound COCl(=O)=O NHNMRJSHULPMIM-UHFFFAOYSA-N 0.000 description 2
- XXKDRTXIEZBWPZ-UHFFFAOYSA-N molport-035-774-070 Chemical group O=C1NCCC2=CNC3=CC(F)=CC1=C32 XXKDRTXIEZBWPZ-UHFFFAOYSA-N 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 229950004707 rucaparib Drugs 0.000 description 2
- -1 (methylamino) methyl Chemical group 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000035772 mutation Effects 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
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux 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 Ruipab intermediate shown in a formula (II), wherein the preparation method comprises the steps of constructing a benzolactam ring and then constructing an indole ring, so that the Ruipab intermediate is prepared. The preparation method has the advantages of cheap and easily-obtained raw materials, low production cost of products, good safety of the raw materials, simple preparation process, mild preparation conditions, high reaction yield and purity, and capability of effectively avoiding safety accidents, so that the preparation method can be applied to industrial production on a large scale.
Description
Technical Field
The application relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of a Ruipab intermediate.
Background
Rucaparib (rucapaib) is a poly adenosine diphosphate ribose polymerase (PARP) inhibitor used for the treatment of advanced ovarian cancer associated with two-or more-line chemotherapy and with mutations in the BRCA gene, and has the chemical name: 8-fluoro-2- {4- [ (methylamino) methyl group]Phenyl } -1,3,4, 5-tetrahydro-6H-azepino [5,4,3-cd]Indol-6-one, formula: c19H18FN3O, 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-one, formula: c11H9FN2O，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:
synthesis scheme 1
In the synthetic route 1, 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 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 an intermediate (II) is obtained through reduction and catalytic hydrogenation.
The 1-dimethylamino-2-nitroethylene used in the synthetic route 1 is expensive, and the yield from the reduction of the compound 7 to the reduction of the compound 8 is low, so that the cost of the intermediate is high, and the industrial production is not facilitated.
Scheme 2 differs from scheme 1 in the steps for the synthesis of intermediate (II) in compound 6, as follows:
synthesis scheme 2
The steps from compound 6 to 11 in the synthetic route 2 have low yield, and the price of the used TFA TES raw material is also high, so that the product cost of the route is high, and the method is not beneficial to industrial production.
Synthesis 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 reacts with DMFDMA and is hydrogenated to obtain 6-fluoro-1H-indole-4-methyl formate, the 6-fluoro-3-formyl-1H-indole-4-methyl formate is obtained through a velsmeier reaction, and then the 6-fluoro-1H-indole-4-methyl formate reacts with nitromethane, is reduced and is catalytically hydrogenated to obtain an intermediate (II), nitromethane is required to be used in the synthetic route 2, great potential safety hazards exist in industrial production, the route reaction steps are long, and the overall yield is low.
Based on the problems in the prior art, the development of a new preparation method of the Ruipab intermediate (II) becomes a technical problem to be solved by the technical personnel in the field.
Disclosure of Invention
In view of the above problems in the prior art, the present application aims to provide a preparation method of a Ruipab intermediate, which is used for solving the problems of complex preparation process, expensive production raw materials or explosive property.
The application provides a preparation method of a Ruicapalb 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) carrying out hydrogenation reaction on the compound shown in the formula (IV) and hydrogen in the presence of a catalyst and a basic auxiliary agent to generate a compound shown in a formula (V);
(3) reacting the compound shown in the formula (V) with chloroformate to generate a compound shown in a formula (VI);
(4) carrying out dehydration cyclization reaction on the compound shown in the formula (VI) in the presence of a dehydration cyclization catalyst to generate a compound shown in a formula (VII);
(5) carrying out nitration reaction on the compound shown in the formula (VII) and mixed acid to generate a compound shown in a formula (VIII);
(6) reacting the compound shown in the formula (VIII) with N, N-dimethylformamide dimethyl acetal to generate a compound shown in the formula (IX);
(7) carrying out reduction cyclization on the compound shown in the formula (IX) to generate a Ruicapab intermediate shown in the formula (II);
further, 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 the alkaline solution is 1: (3-5).
Preferably, the basic solution comprises acetonitrile, water, potassium hydroxide and a phase transfer catalyst, dodecyl trimethyl ammonium chloride, wherein the ratio of acetonitrile: water: potassium hydroxide: the mass ratio of the dodecyl trimethyl ammonium chloride is 35:05:14: 1. In the present application, those skilled in the art can select other alkaline solutions according to practical situations as long as the purpose of the present application is satisfied.
Further, the mass ratio of the compound represented by the formula (IV), the catalyst and the basic auxiliary agent is 54: (0.2-6): (0.5-4).
Further, the molar ratio of the compound represented by the formula (V) to the chloroformate is (0.7 to 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 the formula (VII) to nitric acid is (0.5-1):1, the molar ratio of the compound shown as the formula (VII) to the sulfuric acid is (2.5-5): 1.
further, the molar ratio of the compound represented by the formula (VIII) to N, N-dimethylformamide formal is (0.5-1): 1.
Further, the alkaline assistant 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 alcohol chloroformate.
Further, the dehydration cyclization catalyst is selected from at least one of polyphosphoric acid, phosphorus oxychloride, phosphorus pentachloride and stannic chloride.
Further, the reduction method in the step (7) comprises: (a) carrying out hydrogenation reaction with hydrogen source under the action of catalyst, or (b) carrying out reduction reaction under the action of chemical reducing agent;
the catalyst is at least one of palladium-based catalyst, platinum-based catalyst and nickel-based catalyst, preferably palladium carbon or skeletal nickel;
the hydrogen source is selected from at least one of hydrogen, formic acid, sodium formate, ammonium formate and hydrazine hydrate;
the chemical reducing agent is selected from at least one of iron powder, zinc powder and sodium hydrosulfite (commonly called sodium hydrosulfite).
Further, the reaction temperature in the step (1) is 75-85 ℃, and the reaction time is 1-3 h;
the reaction temperature in the step (2) is 80-110 ℃, the reaction time is 4-10h, and hydrogen is introduced until the pressure is 2-3 MPa;
the reaction temperature in the step (3) is 0-10 ℃, and the reaction time is 1-3 h;
the reaction temperature in the step (4) is 60-100 ℃, and the reaction time is 6-10 h;
the reaction temperature in the step (5) is 0-10 ℃, and the reaction time is 1-3 h;
the reaction temperature of the step (6) is 80-140 ℃, and the reaction time is 3-10 h; preferably, the reactants are reacted for 0-2h at the reaction temperature of 80-100 ℃ under the protection of nitrogen, then are continuously heated to 110-;
in the step (7), the reaction temperature is 20-100 ℃ and the reaction time is 4-10h under the action of the catalyst, and the reaction temperature is 20-110 ℃ and the reaction time is 4-8h under the action of the chemical reducing agent.
Further, after the compound shown in the formula (III) is mixed with acetonitrile, dropwise adding an alkaline solution to react, and controlling the temperature of a reaction system to be 0-80 ℃ during dropwise adding.
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 dropwise addition is completed, the reaction is carried out for 1 to 3 hours, preferably 2 hours, at the temperature of 0 to 10 ℃.
Further, the preparation method of the present application further comprises the following purification steps:
adding the intermediate of the Ruipab shown in the formula (II) into a solvent, stirring and pulping, and then filtering to obtain a purified intermediate of the Ruipab 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 30-40 deg.C for 1-3 hr, preferably 2 hr, cooling to below 10 deg.C, and filtering.
Through the purification steps, the purity of the Ruipab intermediate shown in the formula (II) can be improved.
The preparation method of the Ruipab intermediate shown in the formula (II) comprises the steps of firstly synthesizing p-fluoro cinnamonitrile shown in the formula (IV), constructing a benzolactam ring through catalytic hydrogenation, amidation and cyclization, and then constructing an indole ring, so that the Ruipab intermediate is prepared.
Of course, not all advantages described above need to be achieved at the same time in the practice of any one product or method of the present application.
Detailed Description
To further illustrate the present application, the present application will be specifically described with reference to examples, but the scope of the present application is not limited to the specific examples.
Example 1
(1) Adding 70g of acetonitrile, 10g of water, 28g of potassium hydroxide and 2g of dodecyl trimethyl ammonium chloride serving as a phase transfer catalyst into a 500ml reaction bottle, stirring until the potassium hydroxide is uniformly dispersed, dropwise adding a mixed solution of 63g of a compound (p-fluorobenzaldehyde) shown in the formula (III) and 30g of acetonitrile, reacting at 80 ℃ for 2 hours after the addition is finished, adding 100ml of toluene, cooling to 10 ℃, adding 100ml of water, layering, washing an organic phase with saturated salt water to be neutral, drying, removing a solvent, and performing reduced pressure rectification to obtain 54.5g of a compound (p-fluorocinnamonitrile) shown in the formula (IV) (yield is 73%) and purity is 95%.
(2) Adding 54.5g of p-fluorocinnamonitrile, 200ml of ethanol, 3g of skeletal nickel and 1g of potassium hydroxide into an autoclave, introducing hydrogen to the autoclave until the pressure is 2.5MPa after nitrogen replacement, heating to 95 ℃ for reaction for 7 hours, keeping the pressure at 2.5MPa, cooling and filtering to remove the catalyst after the reaction is finished, removing the solvent from the filtrate, and distilling under reduced pressure to obtain 48g of the compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) (the yield is 85%) and the purity is 94%.
(3) Dissolving 48g of 3- (4-fluorophenyl) propylamine in 300ml of dichloromethane, adding 37.7g of triethylamine, stirring, cooling to 10 ℃, dropwise adding 36g of ethyl chloroformate, controlling the dropwise adding temperature to be 10 ℃, keeping the temperature at 5 ℃ after the addition is finished, reacting for 2 hours, after the detection reaction is finished, adding 100ml of water, layering, washing an organic phase to be neutral, drying over anhydrous magnesium sulfate, filtering, and removing a solvent to obtain 67.7g of the compound shown in the formula (VI) (the yield is 96 percent) and the purity is 95 percent.
(4)67.7g of the compound shown in the formula (VI) is added into a reaction bottle, 250ml of PPA (polyphosphoric acid) is added, the temperature is raised to 80 ℃ by stirring, the reaction is kept for 8 hours, the residual 1 percent of the raw material is detected (the conversion rate of the raw material is 98 percent), 300ml of ice water and 300ml of dichloromethane are added, the mixture is stirred, the mixture is kept stand for layering, the water 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 drying.
(5) Cooling the solution obtained in the previous step to 0 ℃, dropwise adding a mixed acid solution prepared from 150g of 98 wt% concentrated sulfuric acid and 33g of 70 wt% concentrated nitric acid, continuing to perform heat preservation reaction at 5 ℃ for 2 hours after dropwise adding, pouring the reaction solution into 300ml of ice water for hydrolysis and layering after detecting the reaction of the raw materials, extracting the water phase once by using 100ml of dichloromethane, combining organic phases, washing to be neutral, drying by using anhydrous magnesium sulfate, removing the solvent, and recrystallizing the obtained solid by using 150ml of ethanol to obtain 52.6g of the compound shown in the formula (VIII) (the two-step yield is 78%) with the purity of 99.2%.
(6) Adding 200ml of DMF (N, N-dimethylformamide), 41.3g of DMFDMA (N, N-dimethylformamide dimethyl acetal) and 35g of triethylamine into 52.6g of the compound shown by the formula (VIII), heating to 90 ℃ under the protection of nitrogen, reacting for 1 hour, continuously heating to 120 ℃ for reacting for 4 hours, after the reaction of the raw materials is detected, distilling about 190ml of solvent under reduced pressure, and adding 225ml of methanol into the residue to directly carry out the next reaction.
(7) Adding the solution in the previous step into a hydrogenation kettle, adding 2.5g of 5 wt% palladium-carbon, introducing hydrogen to the pressure of 0.2MPa after nitrogen replacement for three times, stirring, reacting to release heat, introducing circulating water to control the reaction temperature to be 50 ℃, reacting for 7 hours at 40 ℃, sampling, detecting the reaction completion of raw materials, introducing hydrogen in the nitrogen replacement kettle, filtering to remove the palladium-carbon, adding 370ml of water, stirring for 30 minutes, filtering, stirring and pulping the obtained solid for 2 hours at 40 ℃ by using 40ml of dichloromethane and 200ml of methanol, cooling to below 0 ℃, filtering and drying to obtain 40.2g of white solid (Ruika intermediate shown in formula (II)) (yield is 85%, the product purity is 99.4%, and the total yield is 39.4%.
Example 2
(1) Adding 70g of acetonitrile, 10g of water, 28g of potassium hydroxide and 2g of dodecyl trimethyl ammonium chloride serving as a phase transfer catalyst into a 500ml reaction bottle, stirring until the potassium hydroxide is uniformly dispersed, dropwise adding a mixed solution of 63g of a compound (p-fluorobenzaldehyde) shown in a formula (III) and 30g of acetonitrile, reacting at 75 ℃ for 3 hours after the addition, adding 100ml of toluene, cooling to 5 ℃, adding 100ml of water, layering, washing an organic phase to be neutral by using saturated salt water, drying, removing a solvent, and carrying out reduced pressure rectification to obtain 54g of a compound (p-fluorocinnamonitrile) shown in a formula (IV) (yield is 73%) with purity of 95%.
(2) Adding 54g of p-fluorocinnamonitrile and 200ml of ethanol into an autoclave, adding 3g of skeletal nickel and 0.5g of potassium hydroxide, introducing hydrogen to the autoclave until the pressure is 2.0MPa after nitrogen replacement, heating to 90 ℃ for reaction for 10 hours, keeping the pressure at 2.0MPa, cooling and filtering to remove the catalyst after the reaction is finished, removing the solvent from the filtrate, and distilling under reduced pressure to obtain 45g of the compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) (yield 80%) with purity of 92%.
(3) Dissolving 45g of 3- (4-fluorophenyl) propylamine in 280ml of dichloromethane, adding 35.3g of triethylamine, stirring, cooling to 5 ℃, dropwise adding 34g of ethyl chloroformate, controlling the dropwise adding temperature to be 5 ℃, keeping the temperature at 0 ℃ after the addition is finished, reacting for 3 hours, after the detection reaction is finished, adding 100ml of water, layering, washing an organic phase to be neutral, drying over anhydrous magnesium sulfate, filtering, and removing a solvent 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 shown as the formula (VI) is added into a reaction bottle, 225ml of PPA is added, the mixture is stirred and heated to 60 ℃, the temperature is kept for 10 hours for reaction, the residual 1 percent of the raw material is detected (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 layering, the water phase is extracted once by 90ml of dichloromethane, the organic phases are combined, washed to be neutral by water and dried, and then the next step is directly carried out.
(5) Cooling the solution obtained in the previous step to 0 ℃, dropwise adding a mixed acid solution prepared from 140g of 98 wt% concentrated sulfuric acid and 31g of 70 wt% concentrated nitric acid, continuing to perform heat preservation reaction at 0 ℃ for 3 hours after dropwise adding, pouring the reaction solution into 280ml of ice water for hydrolysis and layering after detecting the reaction of the raw materials, extracting the water phase once by 95ml of dichloromethane, combining organic phases, washing to be neutral, drying by anhydrous magnesium sulfate, removing the solvent, and recrystallizing the obtained solid by 140ml of ethanol to obtain 47.1g of the compound shown in the formula (VIII) (the two-step yield is 78%) with the purity of 99.1%.
(6)47.1g of the compound (0.23mol) shown in the formula (VIII), adding 180ml of DMF, 37g of DMFDMA and 31.5g of triethylamine, heating to 80 ℃ under the protection of nitrogen for reacting for 6 hours, continuously heating to 120 ℃ for reacting for 4 hours, after detecting that the raw materials are reacted, distilling out about 170ml of solvent under reduced pressure, and adding 190ml of methanol into residues to directly carry out the next reaction.
(7) Adding the solution in the previous step into a hydrogenation kettle, adding 2.2g of 5 wt% palladium-carbon, introducing hydrogen to the pressure of 0.2MPa after nitrogen replacement for three times, stirring, reacting to release heat, introducing circulating water to control the reaction temperature to be 20 ℃, reacting at 30 ℃ for 10 hours, sampling, detecting the reaction completion of raw materials, introducing hydrogen in the nitrogen replacement kettle, filtering to remove the palladium-carbon, adding 330ml of water, stirring for 30 minutes, filtering, stirring and pulping the obtained solid for 2 hours at 40 ℃ by using 34ml of dichloromethane and 180ml of methanol, cooling to below 0 ℃, filtering and drying to obtain 33.7g of white solid (Ruika intermediate shown in formula (II)) (yield is 85%, the total yield is 35.7%, and the product purity is 99.3%.
Example 3
(1) Adding 70g of acetonitrile, 10g of water, 28g of potassium hydroxide and 2g of dodecyl trimethyl ammonium chloride serving as a phase transfer catalyst into a 500ml reaction bottle, stirring until the potassium hydroxide is uniformly dispersed, dropwise adding a mixed solution of 63g of a compound (p-fluorobenzaldehyde) shown in the formula (III) and 30g of acetonitrile, reacting at 85 ℃ for 1h after the addition is finished, adding 100ml of toluene, cooling to 10 ℃, adding 100ml of water, layering, washing an organic phase to be neutral by using saturated salt water, drying, removing a solvent, and carrying out reduced pressure rectification to obtain 54g of a compound (p-fluorocinnamonitrile) shown in the formula (IV) (yield is 73%) with purity of 95%.
(2) Adding 54g of p-fluorocinnamonitrile and 200ml of ethanol into an autoclave, adding 3g of skeletal nickel and 2g of potassium hydroxide, introducing hydrogen to the autoclave until the pressure is 3.0MPa after nitrogen replacement, heating to 100 ℃ for reaction for 4 hours, keeping the pressure at 3.0MPa, cooling and filtering to remove the catalyst after the reaction is finished, removing the solvent from the filtrate, and distilling under reduced pressure to obtain 43g of a compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) (the yield is 76%) with the purity of 87%.
(3)43g of 3- (4-fluorophenyl) propylamine is dissolved in 270ml of dichloromethane, 33.8g of triethylamine is added, the temperature is reduced to 0 ℃ by stirring, 33g of ethyl chloroformate (0.33mol) is dropwise added, the dropwise adding temperature is controlled to be 10 ℃, after the addition is finished, the temperature is kept at 10 ℃ for reaction for 1h, 100ml of water is added after the detection reaction is finished, the mixture is layered, an organic phase is washed to be neutral by water, anhydrous magnesium sulfate is dried, and the mixture is filtered and desolventized to obtain 60.2g of a compound shown in a formula (VI) (the yield is 96 percent) and the purity is 88 percent.
(4) Adding 60.2g of the compound shown as the formula (VI) into a reaction bottle, adding 225ml of PPA, stirring, heating to 100 ℃, keeping the temperature for reaction for 6 hours, detecting the residual 1% of the raw material (the conversion rate of the raw material is 98%), adding 270ml of ice water and 270ml of dichloromethane, stirring, standing for layering, extracting the water phase once by using 100ml of dichloromethane, combining the organic phases, washing to be neutral, and directly carrying out the next step after drying.
(5) Cooling the solution obtained in the previous step to 0 ℃, dropwise adding a mixed acid solution prepared from 135g of 98 wt% concentrated sulfuric acid and 30g of 70 wt% concentrated nitric acid, continuing to perform heat preservation reaction at 10 ℃ for 1h after dropwise adding, pouring the reaction solution into 300ml of ice water for hydrolysis and layering after detecting the reaction of the raw materials, extracting the water phase once by 90ml of dichloromethane, combining organic phases, washing to be neutral, drying by anhydrous magnesium sulfate, removing the solvent, recrystallizing the obtained solid by 140ml of ethanol to obtain 45.1g of the compound shown in the formula (VIII) (the two-step yield is 70%), and the purity is 99.1%.
(6) Adding 170ml of DMF, 35.4g of DMFDMA and 30g of triethylamine into 45.1g of the compound shown in the formula (VIII), heating to 100 ℃ under the protection of nitrogen for reacting for 2 hours, continuously heating to 140 ℃ for reacting for 1 hour, after the reaction of the raw materials is detected, distilling under reduced pressure to obtain about 160ml of solvent, and adding 190ml of methanol into the residue to directly carry out the next reaction.
(7) Adding the solution in the previous step into a hydrogenation kettle, adding 2.1g of 5 wt% palladium-carbon, introducing hydrogen to the pressure of 0.2MPa after nitrogen replacement for three times, stirring, reacting to release heat, introducing circulating water to control the reaction temperature to be 50 ℃, reacting for 4 hours at 50 ℃, sampling, detecting the reaction completion of raw materials, introducing hydrogen in the nitrogen replacement kettle, filtering to remove the palladium-carbon, adding 330ml of water, stirring for 30 minutes, filtering, stirring and pulping the obtained solid for 2 hours at 40 ℃ by using 35ml of dichloromethane and 170ml of methanol, cooling to below 0 ℃, filtering and drying to obtain 34.6g of white solid (Ruika intermediate shown in formula (II)) (yield 85%, total yield 31.6% and product purity of 99.3%.
Example 4
(1) Same as in example 1.
(2) Adding 54.5g of p-fluorocinnamonitrile and 200ml of ethanol into an autoclave, adding 3g of skeletal nickel and 1g of sodium methoxide, introducing hydrogen to the autoclave until the pressure is 2.0MPa after nitrogen replacement, heating to 95 ℃ for reaction for 7 hours, keeping the pressure at 2.0MPa, cooling and filtering to remove the catalyst after the reaction is finished, removing the solvent from the filtrate, and distilling under reduced pressure to obtain 40.2g of a compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) (the yield is 71%) with the purity of 93.5%.
(3) - (7) is the same as in example 1. The total yield is 32.5 percent, and the product purity is 99.1 percent.
Example 5
(1) Same as in example 1.
(2) Adding 54.5g of p-fluorocinnamonitrile and 200ml of ethanol into an autoclave, adding 3g of skeletal nickel and 4g of ammonia water, introducing hydrogen to the autoclave until the pressure is 2.0MPa after nitrogen replacement, heating to 95 ℃ for reaction for 7 hours, keeping the pressure at 2.0MPa, cooling and filtering to remove the catalyst after the reaction is finished, removing the solvent from the filtrate, and distilling under reduced pressure to obtain 44.2g of a compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) (the yield is 78%) with the purity of 93%.
(3) - (7) is the same as in example 1. The total yield is 36.2 percent, and the product purity is 99.4 percent.
Example 6
(1) Same as in example 1.
(2) Adding 54.5g of p-fluorocinnamonitrile and 200ml of ethanol into an autoclave, adding 6g of skeletal nickel and 1g of potassium hydroxide, introducing hydrogen to the autoclave until the pressure is 2.0MPa after nitrogen replacement, heating to 95 ℃ for reaction for 7 hours, keeping the pressure at 2.0MPa, cooling and filtering to remove the catalyst after the reaction is finished, removing the solvent from the filtrate, and distilling under reduced pressure to obtain 48g of the compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) (the 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 product purity is 99.5 percent.
Example 7
(1) Same as in example 1.
(2) Adding 54.5g of p-fluorocinnamonitrile and 200ml of ethanol into an autoclave, adding 0.2g of palladium carbon and 1g of potassium hydroxide, introducing hydrogen to the autoclave until the pressure is 2.0MPa after nitrogen replacement, heating to 95 ℃ for reaction for 7 hours, keeping the pressure at 2.0MPa, cooling and filtering the mixture to remove the catalyst after the reaction is finished, removing the solvent from the filtrate, and distilling the filtrate under reduced pressure to obtain 48g of the compound (3- (4-fluorophenyl) propylamine) shown in the formula (V) (yield 83%) with the purity of 94%.
(3) - (7) is the same as in example 1. The total yield is 38.1 percent, and the product purity 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, the mixture is stirred and heated to 80 ℃, the temperature is kept and the reaction is carried out for 8 hours, the residual 1 percent of the raw material is detected (the conversion rate of the raw material is 60 percent), 300ml of ice water and 300ml of dichloromethane are added, the mixture is stirred, the mixture is kept stand and layered, the water phase is extracted once by 100ml of dichloromethane, the organic phases are combined, the mixture is washed to be neutral by water, 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 product purity is 98.8 percent.
Example 9
(1) - (3) is the same as in example 1.
(4) Adding 67.3g of the compound shown in the formula (VI) into a reaction bottle, adding 250ml of phosphorus oxychloride and 70g of phosphorus pentoxide, stirring, heating to 80 ℃, keeping the temperature for reaction for 8 hours, detecting that the content of the raw material is less than 1% (the conversion rate of the raw material is 92%), adding 300ml of ice water and 300ml of dichloromethane, stirring, standing for layering, extracting the water phase once by using 100ml of dichloromethane, combining the organic phases, washing to be neutral, and drying to obtain the compound shown in the formula (VII).
(5) - (7) is the same as in example 1. The total yield is 33.7 percent, and the product purity is 99.1 percent.
Example 10
(1) - (3) is the same as in example 1.
(4) And (2) adding 67.3g of the compound shown in the formula (VI) into a reaction bottle, adding 250ml of phosphorus oxychloride and 100g of stannic chloride, stirring, heating to 80 ℃, keeping the temperature for reaction for 8 hours, detecting that the content of the raw materials is less than 1% (the conversion rate of the raw materials is 95%), adding 300ml of ice water and 300ml of dichloromethane, stirring, standing for layering, extracting the water phase once by using 100ml of dichloromethane, combining the organic phases, washing to be neutral, and drying to obtain the compound shown in the formula (VII).
(5) - (7) is the same as in example 1. The total yield is 34.3 percent, and the product purity 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, the mixture is stirred and heated to 80 ℃, the temperature is kept for reaction for 8 hours, the residual 1 percent of the raw material is detected (the conversion rate of the raw material is 86 percent), 300ml of ice water and 300ml of dichloromethane are added, the mixture is stirred, the mixture is kept stand for layering, the water phase is extracted once by 100ml of dichloromethane, the organic phase is combined, the mixture 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 31.4 percent, and the product purity is 98.7 percent.
Example 12
(1) - (2) is the same as in example 1.
(3) Dissolving 48g of 3- (4-fluorophenyl) propylamine in 300ml of dichloromethane, adding 37.7g of triethylamine, stirring and cooling to 10 ℃, dropwise adding 31.2g of methyl chloroformate (0.33mol), controlling the dropwise adding temperature to be 10 ℃, keeping the temperature at 5 ℃ after the addition is finished, reacting for 2 hours, detecting the reaction is finished, adding 100ml of water, layering, washing an organic phase to be neutral, drying with anhydrous magnesium sulfate, filtering, and removing a solvent to obtain 64.8g of a compound shown in a formula (VI) (the yield is 98%) with the purity of 95%.
(4) - (7) is the same as in example 1. The total yield is 40.2 percent, and the product purity is 99.3 percent.
Example 13
(1) - (2) is the same as in example 1.
(3) Dissolving 48g of 3- (4-fluorophenyl) propylamine in 300ml of dichloromethane, adding 37.7g of triethylamine, stirring and cooling to 10 ℃, dropwise adding 40.4g of isopropyl chloride (0.33mol), controlling the dropwise adding temperature to be 10 ℃, keeping the temperature at 5 ℃ after the addition is finished, reacting for 2 hours, detecting the reaction is finished, adding 100ml of water, layering, washing an organic phase to be neutral, drying with anhydrous magnesium sulfate, filtering, and removing a solvent to obtain 70.4g of a compound shown in a formula (VI) (the yield is 94%) with the purity of 95%.
(4) - (7) is the same as in example 1. The total yield is 32.8 percent, and the product purity is 99.1 percent.
Example 14
(1) - (2) is the same as in example 1.
(3) Dissolving 48g of 3- (4-fluorophenyl) propylamine in 300ml of dichloromethane, adding 37.7g of triethylamine, stirring and cooling to 10 ℃, dropwise adding 50.7g of tert-butyl chloroformate (0.33mol), controlling the dropwise adding temperature to be 10 ℃, keeping the temperature at 5 ℃ after the addition for reaction for 2 hours, after the detection reaction is finished, adding 100ml of water, layering, washing an organic phase to be neutral, drying with anhydrous magnesium sulfate, filtering, and removing a solvent to obtain 73.8g of a compound shown in a formula (VI) (the 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 product purity is 98.8 percent.
Example 15
(1) - (6) is the same as in example 1.
(7) And sequentially adding the solution and 70g of iron powder into a 250ml four-neck flask with a thermometer and a stirring device, stirring to fully mix the solution and the iron powder, heating the four-neck flask to 90 ℃, slowly dropwise adding 60g of glacial acetic acid, heating and refluxing after the addition to react, filtering to remove the iron powder when the solution is hot after 6 hours of reaction, adding 370ml of water into filtrate to dilute and filter, pulping the obtained solid with 40ml of dichloromethane and 200ml of methanol at 35 ℃ for 2 hours, cooling to 10 ℃, filtering and drying to obtain 34.6g of white solid (the Ruicapa intermediate shown in the formula (II)) (the yield is 73%), the product purity is 99.4%, and the total yield is 33.8%.
As can be seen from the above examples, the preparation method of the licarpa intermediate represented by formula (ii) provided in the present application does not require expensive or explosive raw materials in the preparation process, and has mild preparation conditions, high reaction yield and high purity. By using the preparation method provided by the application, the production cost of the product is low, and safety accidents can be effectively avoided, so that the preparation method can be widely applied to industrial production.
The above description is only for the preferred embodiment of the present application and is not intended to limit the scope of the present application. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application are included in the protection scope of the present application.
Claims (14)
1. A preparation method of a Ruicapa intermediate shown in a formula (II) 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) carrying out hydrogenation reaction on the compound shown in the formula (IV) and hydrogen in the presence of a catalyst and a basic auxiliary agent to generate a compound shown in a formula (V);
(3) reacting the compound shown in the formula (V) with chloroformate to generate a compound shown in a formula (VI);
(4) carrying out dehydration cyclization reaction on the compound shown in the formula (VI) in the presence of a dehydration cyclization catalyst to generate a compound shown in a formula (VII);
(5) carrying out nitration reaction on the compound shown in the formula (VII) and mixed acid to generate a compound shown in a formula (VIII);
(6) reacting the compound shown in the formula (VIII) with N, N-dimethylformamide dimethyl acetal to generate a compound shown in the formula (IX);
(7) carrying out reduction cyclization on the compound shown in the formula (IX) to generate a Ruipab intermediate shown in a formula (II);
2. the production method 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 the basic solution is 1: (3-5).
3. The production method according to claim 1, wherein the mass ratio of the compound represented by the formula (IV), the catalyst and the basic auxiliary is 54: (0.2-6): (0.5-4).
4. The production method according to claim 1, wherein the molar ratio of the compound represented by the formula (V) to the chloroformate is (0.7 to 1.3): 1.
5. the production 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 production method according to claim 1, wherein the mixed acid comprises nitric acid and sulfuric acid, and the molar ratio of nitric acid to sulfuric acid is 1 (2.5-5).
7. The production method according to claim 6, wherein the molar ratio of the compound represented by the formula (VII) to nitric acid is (0.5-1):1, the molar ratio of the compound shown as the formula (VII) to the sulfuric acid is (2.5-5): 1.
8. the process according to claim 1, wherein the molar ratio of the compound represented by the formula (VIII) to N, N-dimethylformamide dimethyl acetal is (0.5-1): 1.
9. The production method according to claim 1, wherein the basic auxiliary is at least one selected from the group consisting of potassium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, and ammonia water.
10. The preparation method according to claim 1, wherein the chloroformate is selected from any one of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, and tert-butyl chloroformate.
11. The preparation method according to claim 1, wherein the dehydration cyclization catalyst is at least one selected from polyphosphoric acid, phosphorus oxychloride, phosphorus pentachloride and stannic chloride.
12. The production method according to claim 1, wherein the reduction method in the step (7) includes: (a) carrying out hydrogenation reaction with hydrogen source under the action of catalyst, or (b) carrying out reduction reaction under the action of chemical reducing agent;
the catalyst is at least one of palladium-based catalyst, platinum-based catalyst and nickel-based catalyst;
the hydrogen source is selected from at least one of hydrogen, formic acid, sodium formate, ammonium formate and hydrazine hydrate;
the chemical reducing agent is selected from at least one of iron powder, zinc powder and sodium hydrosulfite.
13. The production method according to claim 7, wherein,
the reaction temperature in the step (1) is 75-85 ℃, and the reaction time is 1-3 h;
the reaction temperature in the step (2) is 80-110 ℃, the reaction time is 4-10h, and hydrogen is introduced until the pressure is 2-3 MPa;
the reaction temperature in the step (3) is 0-10 ℃, and the reaction time is 1-3 h;
the reaction temperature in the step (4) is 60-100 ℃, and the reaction time is 6-10 h;
the reaction temperature in the step (5) is 0-10 ℃, and the reaction time is 1-3 h;
the reaction temperature of the step (6) is 80-140 ℃, and the reaction time is 3-10 h;
in the step (7), the reaction temperature is 20-100 ℃ and the reaction time is 4-10h under the action of the catalyst, and the reaction temperature is 20-110 ℃ and the reaction time is 4-8h under the action of the chemical reducing agent.
14. The method of claim 1, further comprising the following purification steps:
adding the Ruipab intermediate shown in the formula (II) into a solvent, stirring and pulping, and then filtering to obtain a purified Ruipab 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)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011209954.5A CN114437085B (en) | 2020-11-03 | 2020-11-03 | Preparation method of rebamipa intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011209954.5A CN114437085B (en) | 2020-11-03 | 2020-11-03 | Preparation method of rebamipa intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114437085A true CN114437085A (en) | 2022-05-06 |
| CN114437085B CN114437085B (en) | 2023-06-23 |
Family
ID=81361250
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011209954.5A Active CN114437085B (en) | 2020-11-03 | 2020-11-03 | Preparation method of rebamipa intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114437085B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114516877A (en) * | 2020-11-20 | 2022-05-20 | 烟台弘邦医药科技有限公司 | Preparation method of Ruipab intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000037443A1 (en) * | 1998-12-22 | 2000-06-29 | Pentech Pharmaceuticals, Inc. | Process for preparing arylpiperidine carbinol intermediates and derivatives |
| CN107954919A (en) * | 2018-01-08 | 2018-04-24 | 南京奇可药业有限公司 | A kind of preparation method of Rucaparib key intermediates |
| CN109824677A (en) * | 2019-04-03 | 2019-05-31 | 江苏开元药业有限公司 | The preparation method for treating ovarian cancer Rui Kapabu |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3898212A (en) * | 1974-08-09 | 1975-08-05 | Squibb & Sons Inc | Triazino(4,3-D) (1,4) benzodiazepine-3,4,7-triones |
| WO2019130229A1 (en) * | 2017-12-28 | 2019-07-04 | Mylan Laboratories Ltd | Methods and intermediates for preparing rucaparib |
-
2020
- 2020-11-03 CN CN202011209954.5A patent/CN114437085B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000037443A1 (en) * | 1998-12-22 | 2000-06-29 | Pentech Pharmaceuticals, Inc. | Process for preparing arylpiperidine carbinol intermediates and derivatives |
| CN107954919A (en) * | 2018-01-08 | 2018-04-24 | 南京奇可药业有限公司 | A kind of preparation method of Rucaparib key intermediates |
| CN109824677A (en) * | 2019-04-03 | 2019-05-31 | 江苏开元药业有限公司 | The preparation method for treating ovarian cancer Rui Kapabu |
Non-Patent Citations (2)
| Title |
|---|
| HIROAKI KUROUCHI ET AL.: "Activation of Electrophilicity of Stable Y‑Delocalized Carbamate Cations in Intramolecular Aromatic Substitution Reaction: Evidence for Formation of Diprotonated Carbamates Leading to Generation of Isocyanates", 《J. ORG. CHEM.》 * |
| W. HAEFLIGER ET AL.: "BENZ[c,d]INDOLES - I. THE USE OF TERT-BUTOXY-BIS(DIMETHYLAMINO)METHANE AS CONDENSATION REAGENT", 《TETRAHEDRON LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114516877A (en) * | 2020-11-20 | 2022-05-20 | 烟台弘邦医药科技有限公司 | Preparation method of Ruipab intermediate |
| CN114516877B (en) * | 2020-11-20 | 2023-10-27 | 烟台弘邦医药科技有限公司 | Preparation method of rebamipa intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114437085B (en) | 2023-06-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108658857B (en) | Method for synthesizing carboxylic acid derivative | |
| CN114437085A (en) | Preparation method of Ruicapa intermediate | |
| WO2022199226A1 (en) | Method for preparing 3,3',4,4'-tetraaminobiphenyl | |
| CN107235891B (en) | Preparation method of 4-bromocarbazole | |
| CN112300072A (en) | High-yield synthesis method of 5-iodoisoquinoline compounds | |
| CN114751852B (en) | Preparation method of silodosin key intermediate | |
| CN111320548A (en) | Synthesis method of anticancer drug intermediate 2-fluoro-3-methyl aminobenzoate | |
| CN114920699B (en) | Method for preparing 6-chloro-2-methyl-2H-indazol-5-amine | |
| WO2023039940A1 (en) | Method for preparing n,n,n-tripivaloyl-1,3,5-triaminobenzene | |
| CN115403577A (en) | Synthesis method of carboxyl azaindole | |
| CN109956877B (en) | Synthesis method of 1, 3-bis (3-aminophenoxy) benzene | |
| CN112341313A (en) | Preparation method of 3, 5-dichlorobenzyl alcohol and carboxyamidotriazole intermediate | |
| CN111620788A (en) | Method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formic ether | |
| CN115677559B (en) | One-step synthesis method of ondansetron intermediate tetrahydrocarbazolone | |
| CN106117200B (en) | Prevention or the preparation method for the treatment of joint replacement phlebothrombosis medicine Eliquis | |
| CN114516877B (en) | Preparation method of rebamipa intermediate | |
| CN112920054A (en) | Preparation method of 3,3 ', 4, 4' -tetraaminobiphenyl | |
| JP3160439B2 (en) | Method for producing acetylguanine | |
| CN108863900A (en) | A kind of preparation method of 5- fluoro indole -2- ketone | |
| CN114591176B (en) | Preparation method of 3-nitrophthalic acid | |
| CN101717342A (en) | Method for synthesizing 2,5-diamino phenyl ethanol | |
| CN117720464A (en) | Preparation method of 2-chloro-5, 6-dihydro-cyclopentyl [ B ] pyridine-7-ketone | |
| CN115536494B (en) | Synthesis method of 1- (4-bromophenyl) -1, 4-butanediol | |
| CN113336780B (en) | Preparation method of 2-formyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester | |
| CN115611768B (en) | Synthesis method of 3, 4-dichlorobenzonitrile |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240104 Address after: Branch No. 7, Building 5, No. 8 Xiangshan Road, Economic and Technological Development Zone, Yantai City, Shandong Province, 265599 Patentee after: Yantai Lide New Materials Technology Co.,Ltd. Address before: No.49-2, Tiancheng West Lane, Laishan District, Yantai City, Shandong Province 264003 Patentee before: Yantai Hongbang Medical Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right |