CN117105862A - Preparation method of roflumilast and intermediate thereof - Google Patents
Preparation method of roflumilast and intermediate thereof Download PDFInfo
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- CN117105862A CN117105862A CN202310922765.XA CN202310922765A CN117105862A CN 117105862 A CN117105862 A CN 117105862A CN 202310922765 A CN202310922765 A CN 202310922765A CN 117105862 A CN117105862 A CN 117105862A
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- roflumilast
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- roflumilast intermediate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229960002586 roflumilast Drugs 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 73
- AHVVCELVGCPYGI-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde Chemical compound FC(F)OC1=CC=C(C=O)C=C1OCC1CC1 AHVVCELVGCPYGI-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000007037 hydroformylation reaction Methods 0.000 claims abstract description 14
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006722 reduction reaction Methods 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000007858 starting material Substances 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 239000007810 chemical reaction solvent Substances 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 20
- 230000008569 process Effects 0.000 claims description 20
- 239000007795 chemical reaction product Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000007800 oxidant agent Substances 0.000 claims description 12
- 239000003444 phase transfer catalyst Substances 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- 150000002431 hydrogen Chemical group 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical group [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 10
- 238000007670 refining Methods 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 claims description 7
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims description 7
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 238000005917 acylation reaction Methods 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 3
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methyl-N-phenylamine Natural products CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 claims description 3
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- 229920002866 paraformaldehyde Polymers 0.000 claims description 3
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 4
- 150000001448 anilines Chemical class 0.000 abstract description 2
- 125000004122 cyclic group Chemical group 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- 238000000746 purification Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 7
- 230000002194 synthesizing effect Effects 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 230000001590 oxidative effect Effects 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 150000002537 isoquinolines Chemical class 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
- IUSPXLCLQIZFHL-UHFFFAOYSA-N 5-bromo-3h-2-benzofuran-1-one Chemical compound BrC1=CC=C2C(=O)OCC2=C1 IUSPXLCLQIZFHL-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 229940113151 HIF prolyl hydroxylase inhibitor Drugs 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- VVOCYQDSDXLBEA-UHFFFAOYSA-N dimethyl 2-oxopropanedioate Chemical compound COC(=O)C(=O)C(=O)OC VVOCYQDSDXLBEA-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- WJGPMRFWBJZJOQ-UHFFFAOYSA-N methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate Chemical compound C1=CC2=C(O)C(C(=O)OC)=NC(C)=C2C=C1OC1=CC=CC=C1 WJGPMRFWBJZJOQ-UHFFFAOYSA-N 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The application provides a preparation method of a key intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline formate (LT-D3) of roflumilast, which is prepared by using 3-oxo-3- (4-phenoxyphenyl) propionate (MQC) as a starting material through hydroformylation, imidization and reduction reaction. The application has novel circuit and relatively simple synthetic circuit, all raw material reagents used are easy to obtain or prepare, the reagent used in the imidization step, namely the substituted aniline, can be obtained through reduction reaction, can realize the cyclic utilization of aniline reagents, realize the atomic economy of green chemistry, do not use reagents with high danger and high pollution in the preparation method, are safe and environment-friendly, have mild reaction conditions, are convenient and controllable to operate, and the prepared roflumilast intermediate LT-D3 has better purity and yield and is suitable for industrial production.
Description
Technical Field
The application relates to the technical field of medicines, in particular to a preparation method of roflumilast and an intermediate thereof.
Background
Roflumilast is the first small molecule hypoxia inducible factor prolyl hydroxylase inhibitor worldwide developed by febugen (fibogen) in the united states for use in the treatment of anemia arising from chronic disease in patients undergoing dialysis therapy. The 12-month roflumilast in 2018 is marketed in China for the first time, and a new treatment means is provided for anemic patients caused by chronic kidney disease.
Luo Shasi he has a framework structure of isoquinoline compounds, and the chemical name is: 2- (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamide) acetic acid having the structural formula:
isoquinoline compounds of the following structural formula LT-D3 are chemically named: 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester, which is a key intermediate for synthesizing Luo Shasi, and the synthesis of the intermediate is also a difficult point for synthesizing raw materials of roxat.
In the prior art, the original research company discloses a synthesis process of a roflumilast intermediate LT-D3 in a Chinese patent application CN103435546A, wherein the process of the route involves an ether formation process of 5-bromophthalide and phenol, the process has high requirement on moisture, and more byproducts are easily generated by ring opening, so that the yield and purity of the roflumilast intermediate LT-D3 are not ideal.
The Beijing Bemeituo new drug research and development limited company discloses a method for synthesizing a roflumilast intermediate LT-D3 in Chinese patent application CN104024227A, the reaction condition for generating an isoquinoline ring is mild, but a large number of experimental steps are needed to introduce a 1-methyl group on the isoquinoline ring, and the introducing process usually needs ultralow temperature conditions; in addition, the yield of partial reaction steps in the synthesis method is low, the purification is needed by adopting a column chromatography method, the cost is high, and the large-scale production is not easy.
The Shenzhen Tajirui biological medicine Co., ltd, in Chinese patent application CN106083720A, discloses a synthetic method of a roflumilast intermediate LT-D3, and the reaction condition of the patent method is mild; the reaction selectivity is high, no isomer is generated, and column purification is not needed. However, in the synthetic method, a solvent carbon tetrachloride is used to generate benzene sulfonate which is a genotoxic impurity; and the multi-step reaction intermediate is directly fed without purification, which is unfavorable for quality control.
The Shanghai gazan and medical science and technology limited company in China patent application CN106478503A discloses a method for synthesizing a roflumilast intermediate LT-D3, the reaction steps of the method are shorter, but the used ketomalonic acid dimethyl ester is not easy to obtain, the cyclization reaction needs to reach high temperature of about 200 ℃, and the industrialization operation difficulty is higher.
In view of the importance of treating and preventing HIF-related diseases, there is always an interest in the industry to develop a method for synthesizing the key intermediate LT-D3 of roflumilast, which has a simple process route and mild reaction conditions and is suitable for industrial production, wherein the method is cost-effective and novel for preparing Luo Shasi, especially for preparing the key intermediate LT-D3 of the key intermediate.
Disclosure of Invention
Aiming at the defects existing in the prior art, the application provides the preparation method of the roflumilast intermediate LT-D3, which has the advantages of mild reaction conditions, low heavy metal content, high product purity and yield, and strong operability, and is suitable for industrial production.
The application provides a preparation method of a roflumilast intermediate LT-D3, which comprises the following synthetic routes:
wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and halogen.
The preparation method of the Luo Shasi intermediate LT-D3 comprises the following steps:
(1) The compound LT-D1 is prepared by using a compound MQC as a starting material through an hydroformylation reaction;
(2) The compound LT-D1 in the step (1) is subjected to imidization reaction to prepare a compound LT-D2;
(3) And (3) carrying out reduction reaction on the compound LT-D2 in the step (2) to prepare the roflumilast intermediate LT-D3.
In the preparation method, the hydroformylation reaction product LT-D1 of the step (1) can be refined and then subjected to the step (2) reaction; the reaction may be carried out in step (2) without purification.
In the preparation method, the step (2) also comprises a process of refining the imidization reaction product LT-D2.
Preferably, in the step (1), the reaction route is as follows:
the reaction process comprises the following steps: the method is characterized in that a compound MQC is used as an initial raw material, and is subjected to an hydroformylation reaction with a compound B1 in an aprotic reaction solvent A1 under the action of a phase transfer catalyst, wherein a reaction product is LT-D1.
Wherein the compound B1 in the step (1) is selected from one of paraformaldehyde and trioxane; preferably, the compound B1 is trioxane.
Further, the hydroformylation reaction of the step (1) also comprises a process of adding an oxidant to act as an activating compound B1; the oxidant is one or more selected from sodium persulfate and potassium persulfate; preferably, the oxidizing agent is sodium persulfate.
Wherein the phase transfer catalyst of step (1) is selected from quaternary ammonium salt phase transfer catalysts; specifically, the quaternary ammonium salt phase transfer catalyst is tetrabutylammonium chloride.
Wherein the aprotic solvent A1 in the step (1) is selected from one or more of tetrahydrofuran, 1, 2-dichloroethane and acetonitrile; preferably, the reaction solvent A1 is acetonitrile.
Further, the molar ratio of the starting material MQC to the catalyst in step (1) is 1:1.5 to 3.5; preferably, the molar ratio of the starting material MQC to the catalyst is 1:2.5; still further, the molar ratio of the starting material MQC to the oxidizing agent in step (1) is 1:1.5 to 3.5; preferably, the molar ratio of the starting material MQC to the oxidizing agent is 1:1.5.
preferably, in step (2), the reaction route is as follows:
wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and halogen.
The reaction process comprises the following steps: imidizing the reaction product LT-D1 obtained in the step (1) with a compound B2 in an aprotic reaction solvent A2, wherein the reaction product is LT-D2; further, the step (2) further comprises a process of refining the reaction product LT-D2.
Wherein the compound B2 in the step (2) is selected from aniline, p-methoxyaniline, p-bromoaniline or p-toluidine.
Wherein the aprotic solvent A2 in the step (2) is selected from one or more of ethyl acetate, acetonitrile, N-dimethylformamide and dichloromethane; preferably, the reaction solvent A2 is dichloromethane.
Further, the refining process of the reaction product LT-D2 in the step (2) comprises the processes of reduced pressure concentration, extraction, crystallization and the like; preferably, the refining process of the reaction product LT-D2 in the step (2) is reduced pressure concentration and concentrate recrystallization; more specifically, the refining process of the reaction product LT-D2 in the step (2) comprises the following steps: concentrating the reaction product LT-D2 under reduced pressure until no fraction is obtained, and crystallizing the concentrate by using ethyl acetate/n-heptane; or crystallizing the concentrate from ethyl acetate/petroleum ether, etc.
It should be noted that the refining process in the step (1) and the step (2) may be performed by common purification methods including, but not limited to, filtration, washing, extraction, purification, drying, etc., and may also be performed by other auxiliary steps for collecting the product, improving the yield, improving the purity of the product, removing impurities, etc.
Preferably, in step (3), the reaction route is as follows:
wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and halogen.
The reaction process comprises the following steps: and (3) introducing hydrogen into the reaction product LT-D2 obtained after refining in the step (2) in an aprotic reaction solvent A3 under the action of a metal catalyst to perform a reduction reaction to generate a roflumilast intermediate LT-D3.
Wherein the aprotic solvent A3 in the step (3) is selected from one or more of tetrahydrofuran, ethyl acetate, ethanol and 1, 4-dioxane; preferably, the reaction solvent A3 is ethyl acetate.
Wherein the metal catalyst in the step (3) is selected from one or more of palladium carbon, palladium acetate and Raney nickel; preferably, the catalyst is palladium on carbon; more preferably, the catalyst is 10% palladium on carbon, wherein 10% refers to the molar ratio of metallic palladium in the palladium on carbon catalyst.
Further, the molar usage ratio of LT-D2 to the catalyst in the step (3) is 1:0.05-0.2; preferably, the molar ratio of LT-D2 to catalyst is 1:0.1.
The application also provides a preparation method of the roflumilast, which comprises the following specific synthetic route:
wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and halogen.
Specifically, the preparation method of Luo Shasi comprises the steps of preparing Luo Shasi of the key intermediate LT-D3 of the synthesized roflumilast through further acylation reaction; specifically, the acylation reaction is to prepare the roflumilast by reacting LT-D3 with glycine in the presence of a catalyst DBU.
The application also provides a compound LT-D1 prepared by the step (1), which has the following structural formula:
the application also provides a compound LT-D2 prepared by the step (2), which has the following structural formula:
wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and halogen.
Further, the compound LT-D2 in the present application may be specifically:
the compound LT-D1 and the compound LT-D2 can be used as intermediates for synthesizing roflumilast.
The application also provides application of the compound LT-D1 and the compound LT-D2 in preparing key intermediates LT-D3 and roflumilast of the roflumilast.
The application has the following beneficial effects:
the application provides a preparation method of a key intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline formate (LT-D3) of roflumilast, which is prepared by using 3-oxo-3- (4-phenoxyphenyl) propionate (MQC) as a starting material through hydroformylation, imidization and reduction reaction. The application has novel circuit and relatively simple synthetic circuit, all raw material reagents used are easy to obtain or prepare, the reagent used in the imidization step, namely the substituted aniline, can be obtained through reduction reaction, can realize the recycling of aniline reagents, realize the atomic economy of green chemistry, do not use reagents with high danger and high pollution in the preparation method, are safe and environment-friendly, have mild reaction conditions and convenient and controllable operation, and the prepared roflumilast intermediate has higher purity and yield and is suitable for industrial production.
Detailed Description
The technical scheme of the present application will be further described with reference to specific examples, but the present application is not limited thereto.
The foregoing description of the preferred embodiments of the application is not intended to limit the application to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the application are intended to be included within the scope of the application.
Example 1 a preparation method of a roflumilast intermediate LT-D3, the synthetic route of which is specifically as follows:
1.1 hydroformylation reaction to produce LT-D1, the reaction equation is as follows:
adding 250.00g of reaction solvent acetonitrile, 50.00g of raw material MQC, 94.12g of phase transfer catalyst tetrabutylammonium chloride, 60.48g of oxidant sodium persulfate and 152.53g of trioxane into a reaction bottle, heating to 70-80 ℃, keeping the temperature, stirring for reacting for 5 hours, adding 2500.00g of water into the reaction solution, cooling to room temperature for crystallization, and filtering; the filter cake was purified with 500.00g of tetrahydrofuran and 1000.00g of water to obtain 47.30g of a pale yellow solid, namely compound LT-D1, with a yield of 86.4% and an HPLC purity of 95.169%.
Compound LT-D1: melting point 174.0-174.8 ℃; LCMS [ M+H ]] + (m/z: 324.05); nuclear magnetic data 1 H NMR(400MHz,DMSO)：δ12.086(s,1H)，9.910(s,1H)，8.429(d,J＝69.6Hz,1H)，7.638～7.249(m,6H)，4.019(s,3H)。
1.2 imidization to form LT-D4, the reaction equation is as follows:
40ml of reaction solvent methylene dichloride, 2.00g of LT-D and 1.14g of p-methoxyaniline are added into a reaction bottle, the reaction is stirred at room temperature for 20 hours, TLC (thin layer chromatography) detects the end point of the reaction, the reaction is concentrated under reduced pressure until no fraction exists, the concentrate is crystallized by ethyl acetate/petroleum ether, and 2.29g of yellow crystals are obtained, namely the compound LT-D4, the yield is 86.4%, and the HPLC purity is 99.405%.
Compound LT-D4: melting point 167.5-168.8 ℃; LCMS [ M+H ]] + (m/z: 429.16); nuclear magnetic data 1 H NMR(400MHz,DMSO)：δ11.792(s,1H),9.313(s,1H),8.719(s,1H),8.399(d,J＝8.8Hz,1H),7.712(dd,J＝2.0,9.2Hz,1H),7.587～7.548(m,2H),7.403(t,J＝7.2Hz,1H),7.303(d,J＝8.0Hz,2H),6.957(d,J＝8.8Hz,2H),3.999(s,3H),3.796(s,3H)。
1.3 reduction reaction to give roflumilast intermediate LT-D3, the reaction equation is as follows:
2.00g of LT-D4, 50ml of solvent ethanol and 0.10g of metal catalyst palladium acetate are added into a reaction bottle, reducing agent hydrogen is introduced, the pressure is increased to 0.3-0.4 Mpa, the temperature is increased to 50-60 ℃ for reaction for 8 hours, filtration is carried out, the filtrate is washed twice with water, reduced pressure concentration is carried out, methanol is used for pulping, 1.22g of pale yellow solid is obtained, namely compound LT-D3, the yield is 84.7%, and the HPLC purity is 96.381%.
Example 2A preparation method of a roflumilast intermediate LT-D3 comprises the following specific synthetic routes:
2.1 hydroformylation reaction to form LT-D1, the reaction equation is as follows:
250.00g of tetrahydrofuran, 50.00g of MQC, 133.56g of tetrabutylammonium fluoride serving as a phase transfer catalyst, 68.66g of potassium persulfate serving as an oxidant and 228.82g of paraformaldehyde are added into a reaction bottle, the temperature is raised to 70-80 ℃, the reaction is carried out for 5 hours under the condition of heat preservation and stirring, 2500.00g of water is added into the reaction liquid, the temperature is reduced to room temperature for crystallization, and the filtration is carried out, thus obtaining 45.22g of light yellow solid which is the compound LT-D1, the yield is 82.6%, and the HPLC purity is 93.524%.
2.2 imidization to form LT-D5, the reaction equation is as follows:
40ml of ethyl acetate, 2.00g of LT-D and 0.87g of aniline as reaction solvents are added into a reaction bottle, the mixture is reacted for 20 hours at room temperature, the mixture is concentrated under reduced pressure until no fraction exists, the concentrate is crystallized by ethyl acetate/n-heptane, and 2.08g of yellow powder is obtained, namely the compound LT-D5, the yield is 84.6%, and the HPLC purity is 97.461%.
Compound LT-D5: melting point 113.8-115.9 ℃; LCMS [ M+H ]] + (m/z: 399.16); nuclear magnetic data 1 H NMR(400MHz,DMSO)：δ11.402(s,1H)，9.089(s,1H)，8.500(s,1H)，8.175(d,J＝9.2Hz,1H)，7.549～7.492(m,3H)，7.395～7.336(m,3H)，7.284～7.210(m,3H)，7.022(d,J＝6.8Hz,2H)，3.954(s,3H)。
2.3 reduction reaction to give roflumilast intermediate LT-D3, the reaction equation is as follows:
2.00g of LT-D2, 40ml of tetrahydrofuran as a reaction solvent and 0.20g of palladium-carbon with 10% of metal catalyst are added into a reaction bottle, reducing agent hydrogen is introduced, the mixture is pressurized to 0.3-0.4 Mpa, the temperature is raised to 50-60 ℃ for reaction for 8 hours, the mixture is filtered, the filtrate is washed twice with water and concentrated under reduced pressure, and methanol is used for pulping to obtain 1.32g of light yellow solid, namely LT-D3, the yield is 85.2%, and the HPLC purity is 96.134%.
Example 3a method for preparing the intermediate LT-D3 of roflumilast, the synthetic route of which is specifically as follows:
3.1 hydroformylation reaction to form LT-D1, the reaction equation is as follows:
adding 500.00g of reaction solvent 1, 2-dichloroethane, 50.00g of raw material MQC, 141.18g of phase transfer catalyst tetrabutylammonium chloride, 100.79g of oxidant sodium persulfate and 152.53g of trioxane into a reaction bottle, heating to 50-60 ℃, stirring for reacting for 12 hours under heat preservation, cooling to room temperature after the reaction is finished, adding water (300.00 g multiplied by 3) into the reaction solution, washing once with saturated sodium bicarbonate solution (100.00 g), washing once with saturated saline solution (100.00 g), concentrating the organic phase under reduced pressure until no fraction exists, crystallizing the residue with ethyl acetate and petroleum ether to obtain a light yellow solid 46.91g which is the compound LT-D1, wherein the yield is 85.7%, and the HPLC purity is 91.342%.
3.2 imidization to form LT-D6, the reaction equation is as follows:
40ml of acetonitrile, 2.00g of LT-D and 1.60g of p-bromoaniline as reaction solvents are added into a reaction bottle, stirred at room temperature for reaction for 20 hours, solids are gradually separated out, TLC (thin layer chromatography) detects the end point of the reaction, the reaction is concentrated under reduced pressure until no fraction exists, the concentrate is crystallized by ethyl acetate/petroleum ether, 2.48g of pale yellow crystals are obtained, namely the compound LT-D6, the yield is 84.1%, and the HPLC purity is 93.919%.
Compound LT-D6: melting point 209.4-210.5 ℃; ESI [ M+H ]] + (m/z: 477.0443, 479.0422); nuclear magnetic data 1 H NMR(400MHz,DMSO)：δ11.944(s,1H),9.243(d,J＝2.8Hz,1H),8.734(s,1H),8.446(d,J＝9.2Hz,1H),7.739(dd,J＝2.4,9.2Hz,1H),7.605～7.541(m,4H),7.411～7.374(m,1H),7.297(d,J＝8.0Hz,2H),7.090(d,J＝8.4Hz,2H),4.006(s,3H)。
3.3 reduction reaction to give roflumilast intermediate LT-D3, the reaction equation is as follows:
2.00g of LT-D6, 50ml of 1, 4-dioxane as a reaction solvent and 0.40g of Raney nickel as a metal catalyst are added into a reaction bottle, a reducing agent hydrogen is introduced, the pressure is increased to 0.3-0.4 Mpa, the temperature is increased to 50-60 ℃ for reaction for 8 hours, the filtration is carried out, the filtrate is washed twice by water and concentrated under reduced pressure, and the methanol is used for pulping, thus obtaining 1.08g of light yellow solid, namely LT-D3, the yield is 83.1%, and the HPLC purity is 97.864%.
Example 4A preparation method of roflumilast intermediate LT-D3, the synthetic route of which is specifically as follows:
4.1 hydroformylation reaction to produce LT-D1, the reaction equation is as follows:
adding 250.00g of reaction solvent acetonitrile, 50.00g of raw material MQC, 117.65g of phase transfer catalyst tetrabutylammonium chloride, 60.48g of oxidant sodium persulfate and 152.53g of trioxane into a reaction bottle, heating to 70-80 ℃, keeping the temperature, stirring for reacting for 5 hours, adding 2500.00g of water into the reaction solution, cooling to room temperature for crystallization, and filtering; the filter cake was purified with 500.00g and 1000.00g of acetonitrile to obtain 49.1g of pale yellow solid, namely compound LT-D1, whose yield was 89.7% and HPLC purity was 96.341%.
4.2 imidization to form LT-D7, the reaction equation is as follows:
40ml of N, N-dimethylformamide as a reaction solvent was added to a reaction flask, stirred, added with 2.00g of LT-D and 0.99g of p-toluidine, stirred at room temperature for reaction for 20 hours, TLC was used to detect the end point of the reaction, 50ml of water was added to the reaction solution, extraction was performed three times with ethyl acetate (50 ml. Times.3), and the concentrate was crystallized from ethyl acetate/petroleum ether to give 2.16g of a pale yellow solid, compound LT-D7, yield of which was 84.7%, and HPLC purity of which was 99.342%.
Compound LT-D7: melting point 147.8-149.2 ℃; LCMS [ M+H ]] + (m/z: 413.17); nuclear magnetic data 1 H NMR(400MHz,DMSO)：δ11.749(s,1H),9.272(s,1H),8.678(s,1H),8.375(d,J＝9.2Hz,1H),7.690(d,J＝8.4Hz,1H),7.550(t,J＝7.6Hz,2H),7.376(t,J＝7.2Hz,1H),7.291(d,J＝7.6Hz,2H),7.199(d,J＝8.0Hz,2H),7.010(d,J＝7.6Hz,2H),3.992(s,3H),2.327(s,3H)。
4.3 reduction reaction to give roflumilast intermediate LT-D3, the reaction equation is as follows:
adding LT-D7.00 g, ethyl acetate 40ml, metal catalyst 10% palladium carbon 0.10g into a reaction bottle, introducing reducing agent hydrogen, pressurizing to 0.3-0.4 Mpa, heating to 50-60 ℃ for reaction for 8 hours, filtering, washing filtrate twice, concentrating under reduced pressure, pulping with methanol to obtain light yellow solid 1.30g, namely LT-D3, wherein the yield is 86.7%, and the purity is 98.352%.
Example 5 preparation method of roflumilast
On the basis of the key intermediate LT-D3 of the synthesized roflumilast, luo Shasi he is prepared by further acylation reaction, and the reaction equation is as follows:
20g of absolute ethyl alcohol, 2.00g of LT-D3, 14.00g of anhydrous sodium thiosulfate and 0.82g of glycine are added into a reaction bottle, the catalyst DBU (1, 8-diazacyclo [5,4,0] undecene-7) is added under the protection of nitrogen, the reaction is stirred and reacted at the temperature of 70-80 ℃ after the addition, the reaction is cooled to room temperature, 6.00g of 10% hydrochloric acid is added, the mixture is stirred and filtered, and the yellow solid is obtained by drying, namely Luo Shasi he, the yield is 94.4%, and the HPLC purity is 96.876%.
Luo Shasi he: melting point 219.9-223.4 ℃; LCMS [ M+H ]] + (m/z: 353.11); nuclear magnetic data 1 H NMR(400MHz,DMSO)：δ13.298(s,1H)，12.788(br,1H)，9.095(t,J＝6.0Hz,1H)，8.283(d,J＝9.0Hz,1H)，7.606(d,J＝2.4Hz,1H)，7.521(dd,J 1 ＝9.0Hz,J 2 ＝2.4Hz,1H)，7.470(t,J＝7.8Hz,2H)，7.246(t,J＝7.2Hz,1H)，7.171(d,J＝7.8Hz,2H)，4.042(d,J＝6.0Hz,2H)，2.693(s,3H)。
In the above-mentioned process for synthesizing Luo Shasi intermediate LT-D3, the purification process in the hydroformylation reaction step and the imidization reaction step may be performed by common purification means including, but not limited to, filtration, washing, extraction, purification, drying, etc., and may be performed by other auxiliary steps for collecting the product, improving the yield, improving the purity of the product, removing impurities, etc.
The foregoing is only a preferred embodiment of the present application, but the scope of the present application is not limited thereto, and any person skilled in the art, who is within the scope of the present application, should make equivalent substitutions or modifications according to the technical scheme of the present application and the inventive concept thereof, and should be covered by the scope of the present application.
Claims (18)
1. A preparation method of a roflumilast intermediate LT-D3 is characterized by comprising the following synthetic routes:
wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and halogen;
the method specifically comprises the following steps:
(1) The compound LT-D1 is prepared by using a compound MQC as a starting material through an hydroformylation reaction;
(2) The compound LT-D1 in the step (1) is subjected to imidization reaction to prepare a compound LT-D2;
(3) And (3) carrying out reduction reaction on the compound LT-D2 in the step (2) to prepare the roflumilast intermediate LT-D3.
2. The method for preparing a roflumilast intermediate LT-D3 according to claim 1, wherein the step (2) further comprises a process of refining the imidization reaction product LT-D2.
3. The preparation method of the roflumilast intermediate LT-D3 according to claim 1, wherein the reaction route of the step (1) is as follows:
the reaction process comprises the following steps: the method is characterized in that a compound MQC is used as an initial raw material, and is subjected to an hydroformylation reaction with a compound B1 in an aprotic reaction solvent A1 under the action of a phase transfer catalyst, wherein a reaction product is LT-D1.
4. A process for the preparation of a roflumilast intermediate LT-D3 according to claim 3, wherein compound B1 in step (1) is selected from one of paraformaldehyde, trioxane; preferably, the compound B1 is trioxane.
5. A process for the preparation of a roflumilast intermediate LT-D3 according to claim 3, wherein the hydroformylation reaction of step (1) further comprises the addition of an oxidising agent.
6. A method for preparing a roflumilast intermediate LT-D3 according to claim 3, wherein the oxidizing agent is one or more selected from sodium persulfate and potassium persulfate; preferably, the oxidizing agent is sodium persulfate.
7. A process for the preparation of roflumilast intermediate LT-D3 according to claim 3, wherein the phase transfer catalyst in step (1) is selected from quaternary ammonium salt phase transfer catalysts; preferably, the quaternary ammonium salt phase transfer catalyst is tetrabutylammonium chloride.
8. A process for the preparation of a roflumilast intermediate LT-D3 according to claim 3, characterized in that the aprotic solvent A1 of step (1) is selected from one or more of tetrahydrofuran, 1, 2-dichloroethane, acetonitrile; preferably, the reaction solvent A1 is acetonitrile.
9. The preparation method of the roflumilast intermediate LT-D3 according to claim 1, wherein the reaction route of the step (2) is as follows:
wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and halogen;
the reaction process comprises the following steps: and (3) carrying out imidization reaction on the reaction product LT-D1 obtained in the step (1) and the compound B2 in an aprotic reaction solvent A2, wherein the reaction product is LT-D2.
10. The method for preparing a roflumilast intermediate LT-D3 according to claim 9, wherein the compound B2 in the step (2) is selected from aniline, p-methoxyaniline, p-bromoaniline or p-toluidine.
11. The preparation method of the roflumilast intermediate LT-D3 according to claim 9, wherein the aprotic solvent A2 in the step (2) is one or more selected from ethyl acetate, acetonitrile, N-dimethylformamide and dichloromethane; preferably, the reaction solvent A2 is dichloromethane.
12. The preparation method of the roflumilast intermediate LT-D3 according to claim 1, wherein the reaction route of the step (3) is as follows:
wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and halogen;
the reaction process comprises the following steps: and (3) introducing hydrogen into the reaction product LT-D2 obtained after refining in the step (2) in an aprotic reaction solvent A3 under the action of a metal catalyst to perform reduction reaction to generate a roflumilast intermediate LT-D3.
13. The preparation method of the roflumilast intermediate LT-D3 according to claim 12, wherein the aprotic solvent A3 in the step (3) is one or more selected from tetrahydrofuran, ethyl acetate, ethanol and 1, 4-dioxane; preferably, the reaction solvent A3 is ethyl acetate.
14. The preparation method of the roflumilast intermediate LT-D3 according to claim 12, wherein the metal catalyst in the step (3) is one or more selected from palladium carbon, palladium acetate and Raney nickel; preferably, the catalyst is palladium on carbon; more preferably, the catalyst is 10% palladium on carbon.
15. The preparation method of the roflumilast is characterized by comprising the following synthetic route:
wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and halogen;
the method specifically comprises the following steps:
(1) Preparing a roflumilast intermediate LT-D3 according to the preparation method of any one of claims 1-15;
(2) The roflumilast intermediate LT-D3 is subjected to an acylation reaction to prepare the roflumilast; specifically, the acylation reaction is to prepare the roflumilast by reacting LT-D3 with glycine in the presence of a catalyst DBU.
16. A compound LT-D1 is characterized by the following specific structural formula:
17. a compound LT-D2 is characterized by the following specific structural formula:
wherein R is selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and halogen.
18. The compound LT-D2 of claim 17, wherein the compound LT-D2 is:
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