CN114105745A - Siponimod intermediate and preparation method thereof - Google Patents
Siponimod intermediate and preparation method thereof Download PDFInfo
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- CN114105745A CN114105745A CN202110993567.3A CN202110993567A CN114105745A CN 114105745 A CN114105745 A CN 114105745A CN 202110993567 A CN202110993567 A CN 202110993567A CN 114105745 A CN114105745 A CN 114105745A
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- 238000002360 preparation method Methods 0.000 title abstract description 32
- KIHYPELVXPAIDH-HNSNBQBZSA-N 1-[[4-[(e)-n-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-c-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid Chemical compound CCC1=CC(C(\C)=N\OCC=2C=C(C(C3CCCCC3)=CC=2)C(F)(F)F)=CC=C1CN1CC(C(O)=O)C1 KIHYPELVXPAIDH-HNSNBQBZSA-N 0.000 title abstract description 12
- 229950005693 siponimod Drugs 0.000 title abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 109
- 238000000034 method Methods 0.000 claims abstract description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 46
- 229940125797 compound 12 Drugs 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 41
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 27
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000012074 organic phase Substances 0.000 claims description 24
- 229940125773 compound 10 Drugs 0.000 claims description 23
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 20
- 229940126543 compound 14 Drugs 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 16
- 239000007810 chemical reaction solvent Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 15
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 14
- 239000003638 chemical reducing agent Substances 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 238000006722 reduction reaction Methods 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000005917 acylation reaction Methods 0.000 claims description 6
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 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 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 238000012805 post-processing Methods 0.000 claims description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 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
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 3
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 2
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000013341 scale-up Methods 0.000 abstract description 2
- 238000003541 multi-stage reaction Methods 0.000 abstract 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- YOHLABDNVQLZIA-UHFFFAOYSA-N 4-amino-3-ethylbenzonitrile Chemical compound CCC1=CC(C#N)=CC=C1N YOHLABDNVQLZIA-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 description 1
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/20—Free hydroxyl or mercaptan
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
Abstract
The invention relates to a siponimod intermediate and a preparation method thereof, belonging to the field of pharmaceutical chemistry. The preparation method comprises the steps of taking bromoacetophenone as a starting material, and carrying out multi-step reaction to obtain 1- (3-ethyl-4-hydroxymethyl) acetophenone; the method has the advantages of high yield, simple and easily obtained raw materials, low cost, controllable reaction condition and temperature, and suitability for industrial scale-up production.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a siponimod intermediate and a preparation method thereof.
Background
SiponiMod (SiponiMod), whose chemical name is: 1- {4- [1- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -ethyl-benzyl (benzyl) } -azetidine-3-carboxylic acid, wherein the chemical structural formula is shown as a formula (I). Siponimod is an oral sphingosine-1-phosphate receptor modulator and can be used to treat multiple sclerosis.
1- (3-ethyl-4-hydroxymethyl) acetophenone is a common intermediate for synthesizing siponimod, and the chemical structural formula of the intermediate is shown as formula 4:
patent WO2004103306a2 discloses a synthetic route for the preparation of 1- (3-ethyl-4-hydroxymethyl) acetophenone: the compound is prepared by taking 4-amino-3-ethyl benzonitrile as a raw material and performing diazotization, formylation, sodium borohydride reduction and Grignard reaction. Because the method needs to use the explosive diazonium salt and the Grignard reagent with higher activity, the reaction safety coefficient is lower; and the substrate 4-amino-3-ethyl benzonitrile is high in cost, so that the industrial application of the route is limited.
Therefore, research on the preparation method of siponimod intermediate is still needed to obtain the method which has the advantages of safe and simple operation, short production period, low cost, high yield, high purity and environmental friendliness.
Disclosure of Invention
The present invention provides various intermediates useful in the preparation of siponimod.
The invention also provides a preparation method of the intermediates.
Compound 4, 1- (3-ethyl-4-hydroxymethyl) acetophenone, has the structure shown in formula 4 below:
the present invention provides a process for preparing compound 4. According to the method for preparing the compound 4, the compound 9 is used as an initial material, a reaction is carried out to obtain a compound 10, the compound 10 is subjected to an acylation reaction to obtain a compound 11, the compound 11 is subjected to a reduction reaction to obtain a compound 12, the compound 12 is subjected to a substitution reaction to obtain a compound 13, the compound 13 is subjected to a reduction reaction to obtain a compound 14, and the compound 14 is subjected to a deprotection reaction to obtain the compound 4; the reaction route is as follows:
in one aspect, the present invention provides a process for the preparation of compound 4, comprising step (F): reacting the compound 14 in a reaction solvent in the presence of an acid at 30-60 ℃ to obtain a compound 4,
the acid is at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid or methanesulfonic acid.
The feed molar ratio of compound 14 to the acid can be from 1:2.0 to 1: 5.0. In some embodiments, the dosing molar ratio of compound 14 to the acid is from 1:2.5 to 1: 4.0. In some embodiments, the acid is at least one of hydrochloric acid, p-toluenesulfonic acid, or methanesulfonic acid.
In the reaction of compound 14 to produce compound 4, in some embodiments, the reaction solvent is selected from at least one of methanol, ethanol, isopropanol, or tetrahydrofuran; in some embodiments, the reaction solvent is methanol, which facilitates the reaction.
In the reaction for preparing compound 4 from compound 14, after completion of the reaction, the reaction is optionally subjected to a post-treatment.
In some embodiments, the post-processing comprises: stopping the reaction, concentrating the reaction solution, adding water and ethyl acetate for extraction, and combining organic phases to remove the solvent to obtain a compound 4.
In some embodiments, compound 14 is reacted in methanol at 30 ℃ to 60 ℃ with the addition of hydrochloric acid, and after the reaction is completed, post-treatment is performed to obtain compound 4; the post-treatment comprises the following steps: stopping the reaction, concentrating the reaction solution, adding water and ethyl acetate for extraction, and combining organic phases to remove the solvent to obtain a compound 4.
A process for the preparation of compound 14 comprising step (E): compound 13 is reacted in a solvent in the presence of a reducing agent to give compound 14,
the reducing agent is at least one of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, palladium carbon/hydrogen, raney nickel/hydrogen and formic acid.
The feeding molar ratio of the reducing agent to the compound 13 is 1:1-4.0: 1; or the molar ratio is 1:1-3.0: 1. In some embodiments, the reducing agent is at least one of sodium borohydride, sodium cyanoborohydride, palladium on carbon/hydrogen, raney nickel/hydrogen.
In some embodiments, in step (E), the solvent is selected from at least one of methanol, ethanol, isopropanol, or tetrahydrofuran.
In some embodiments, the reaction of compound 13 to compound 14 is at a reaction temperature of from-5 ℃ to-10 ℃.
In the reaction for producing compound 14 from compound 13, after completion of the reaction, the reaction may be optionally subjected to a post-treatment.
In some embodiments, the reaction of compound 13 to compound 14 is post-treated, said post-treatment comprising: stopping the reaction, concentrating the reaction solution, adding water and ethyl acetate for extraction, and combining organic phases to remove the solvent to obtain the compound 14.
In some embodiments, compound 13 is reacted with sodium borohydride in methanol at-5 ℃ to-10 ℃, the temperature is raised to room temperature for further reaction, after the reaction is completed, the reaction is stopped, water and ethyl acetate are added for extraction after the reaction solution is concentrated, and the organic phases are combined to remove the solvent, so that compound 14 is obtained.
A process for the preparation of compound 13 comprising step (D): reacting compound 12 with DMF (dimethyl formamide) represented by compound (01) in a reaction solvent at low temperature in the presence of a base to obtain compound 13,
in some embodiments, in step (D), the base is selected from at least one of n-butyllithium, t-butyllithium. In some embodiments, in step (D), the base is n-butyllithium, which facilitates production and availability of the desired product.
In some embodiments, compound 12 is reacted with DMF represented by compound (01), and the reaction solvent is an organic solvent and may be at least one selected from THF, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, or diethyl ether; in some embodiments, the reaction solvent is THF, facilitating the reaction and work-up.
In some embodiments, the molar ratio of compound 12 to base is 1:1.0 to 1: 2.0; or the molar ratio is 1:1.0-1: 1.5.
In some embodiments, the molar ratio of compound 12 to DMF present in compound (01) is 1:1.5 to 1: 5.0; or the molar ratio is 1:2.0-1: 4.0; or the molar ratio is 1:2.5-1: 3.0.
In some embodiments, the low temperature is from-60 ℃ to-80 ℃; or-65 ℃ to-75 ℃; or-78 ℃.
In some embodiments, the reaction time for reacting compound 12 with DMF as represented by compound (01) is 30min-5 h; or the reaction time is 1h-3 h.
In the reaction for producing compound 13 from compound 12, after completion of the reaction, the reaction may be optionally post-treated.
In some embodiments, compound 12 is post-treated after the reaction with DMF, said post-treatment comprising: quenching the reaction by ammonium chloride, heating to room temperature, adding hydrochloric acid to adjust pH, adding ethyl acetate for extraction, combining organic phases, and concentrating under reduced pressure to obtain a compound 13. In some embodiments, compound 12 is reacted with DMF followed by a post-treatment comprising: quenching the reaction with ammonium chloride, warming to room temperature, adding 10% hydrochloric acid to adjust the pH to 4-6, adding ethyl acetate for extraction, combining the organic phases and concentrating under reduced pressure to obtain compound 13.
In some embodiments, a method of making compound 13 comprises: reacting compound 12 with DMF (dimethyl formamide) shown as compound (01) at-60 to-80 ℃ in a reaction solvent in the presence of alkali, quenching the reaction by ammonium chloride after the reaction is finished, heating to room temperature, adding hydrochloric acid to adjust the pH, adding ethyl acetate to extract, combining organic phases, and concentrating under reduced pressure to obtain compound 13; the reaction solvent is at least one of THF, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether or diethyl ether; the alkali is selected from at least one of n-butyl lithium and tert-butyl lithium.
In some embodiments, a method of making compound 13 comprises: reacting compound 12 with DMF (dimethyl formamide) shown as compound (01) at-60 to-80 ℃ in THF (tetrahydrofuran) in the presence of n-butyllithium, quenching the reaction with ammonium chloride after the reaction is finished, heating to room temperature, adding 10% hydrochloric acid to adjust the pH, adding ethyl acetate to extract, combining organic phases, and concentrating under reduced pressure to obtain compound 13.
In some embodiments, a method of making compound 13 comprises: reacting compound 12 with DMF (dimethyl formamide) shown as compound (01) at-60 to-80 ℃ in THF (tetrahydrofuran) in the presence of n-butyllithium, quenching the reaction by ammonium chloride after the reaction is finished, heating to room temperature, adding 10% hydrochloric acid to adjust the pH to 4-6, adding ethyl acetate for extraction, combining organic phases, and concentrating under reduced pressure to obtain compound 13; the molar ratio of the compound 12 to the alkali is 1:0.5-1: 2.0; the molar ratio of the compound 12 to DMF shown in the compound (01) is 1:1.5-1: 5.0.
The method for preparing the compound 13 from the compound 12 and the compound (01) has high yield and simple post-treatment, and is suitable for industrial amplification.
The method for preparing the compound 13 is simple to operate, high in yield and suitable for industrial amplification.
A process for the preparation of compound 12 comprising step (C): carrying out reduction reaction on the compound 11 in a reaction solvent in the presence of a reducing agent and alkali to obtain a compound 12,
the reducing agent is at least one of hydrazine hydrate, a combination of aluminum trichloride and sodium borohydride and a combination of triethylsilane and boron trifluoride diethyl etherate.
In the preparation method of the compound 12, the feeding molar ratio of the reducing agent to the compound 11 is 2.0:1-5.0: 1; or the molar ratio is 2.5:1-4.0: 1. In some embodiments, in the preparation of compound 12, the reducing agent is hydrazine hydrate, which facilitates the reduction reaction.
In the preparation method of the compound 12, the base is at least one of sodium hydroxide, potassium hydroxide and potassium tert-butoxide.
In the preparation method of the compound 12, the charging molar ratio of the alkali to the compound 11 is 2.0:1-5.0: 1; or the molar ratio is 2.5:1-4.0: 1. In some embodiments, in the method of preparing compound 12, the base is sodium hydroxide, which facilitates the reduction reaction.
In the preparation method of the compound 12, the reaction solvent is at least one selected from ethylene glycol, diethylene glycol and triethylene glycol. In some embodiments, in the preparation method of compound 12, the reaction solvent is ethylene glycol, which facilitates the reaction.
In the reaction for preparing the compound 12 from the compound 11, the reaction temperature can be 120-180 ℃. In the reaction of compound 11 to compound 12, in some embodiments, the reaction temperature is 130 ℃ to 170 ℃. In the reaction of compound 11 to compound 12, in some embodiments, the reaction temperature is in the range of 140 ℃ to 160 ℃. In the reaction of compound 11 to compound 12, in some embodiments, the reaction temperature is 150 ℃.
In the reaction of compound 11 to produce compound 12, the reaction time may be 1 hour to 10 hours. Compound 11 reaction to produce compound 12, in some embodiments, the reaction time is from 2 hours to 8 hours. Compound 11 reaction to produce compound 12, in some embodiments, the reaction time is 3 hours to 6 hours.
In the reaction for producing compound 12 from compound 11, after completion of the reaction, the reaction may be optionally subjected to a post-treatment. In some embodiments, in the reaction of compound 11 to compound 12, after completion of the reaction, the post-treatment comprises: water and ethyl acetate are added into the reaction liquid for extraction, organic phases are combined, and the solvent is removed to obtain the compound 12.
In some embodiments, hydrazine hydrate and sodium hydroxide are added into the compound 11 in ethylene glycol to react at 120-180 ℃, after the reaction is finished, the reaction is stopped, and after post-treatment, the compound 12 is obtained; the post-treatment comprises the following steps: water and ethyl acetate were added to the reaction solution for extraction, and the organic phases were combined and the solvent was removed to obtain compound 12.
A process for the preparation of compound 11 comprising step (B): the compound 10 is subjected to acylation reaction with formamide and thionyl chloride in a solvent to obtain a compound 11,
in the preparation method of the compound 11, the solvent is at least one of dichloromethane, dichloroethane, chloroform, diethyl ether, n-hexane and petroleum ether.
The feeding molar ratio of the formamide to the compound 10 is 0.5:1-4.0: 1; or the molar ratio is 1.0:1-3.0: 1.
The feeding molar ratio of the thionyl chloride to the compound 10 is 1.0:1-4.0: 1; or the molar ratio is 1:1.0-3.0: 1; or a molar ratio of 2.0: 1.
In some embodiments, in the method of making compound 11, the reaction temperature of the acylation reaction is from 10 ℃ to 40 ℃. In some embodiments, the reaction temperature of the acylation reaction is from 20 ℃ to 30 ℃. In some embodiments, the reaction temperature of the acylation reaction is 25 ℃.
In the reaction for producing compound 11 from compound 10, after completion of the reaction, the reaction may be optionally post-treated. In some embodiments, in the reaction of compound 10 to compound 11, after completion of the reaction, the post-treatment comprises: water was added to the reaction solution for extraction, and the organic phases were combined and the solvent was removed to give compound 11. In some embodiments, in the reaction of compound 10 to compound 11, after completion of the reaction, the post-treatment comprises: adding water into the reaction liquid for extraction, combining organic phases, removing the solvent, and optionally recrystallizing by ethanol to obtain the compound 11.
In some embodiments, compound 10 is reacted in dichloromethane at 10 ℃ to 40 ℃ with formamide and thionyl chloride, and after the reaction is completed, the reaction is stopped, water is added into the reaction solution for extraction, and the organic phases are combined to remove the solvent, so that compound 11 is obtained.
A process for preparing the aforementioned compound 10, comprising step (a): the protecting group on the compound 9 can obtain a compound 10,
in some embodiments, a method of making compound 10, comprises: reacting the compound 9 in ethylene glycol at 80-120 ℃ in the presence of toluene and p-toluenesulfonic acid, adding water after the reaction is finished, combining organic phases, washing with water, and concentrating the organic phases under reduced pressure to obtain a compound 10.
In some embodiments, a method of preparing compound 4 comprises at least one of the foregoing steps (a), (B), (C), (D), (E), and (F). In some embodiments, a method of preparing compound 4, comprises any one of the foregoing steps (a), step (B), step (C), step (D), step (E), step (F), or any two steps, or any three steps, or four steps, or any five steps, or any six steps. In some embodiments, a method of preparing compound 4, comprises steps (B) and (C) as previously described.
In another aspect of the present invention, there is provided an intermediate compound having a structure represented by formula 11 or 12 below:
in the invention, the intermediate compound 12 of siponimod can be quickly and conveniently prepared by using the cheap raw material compound 9, and the compound 12 is further deprotected to obtain an important intermediate compound 4; the siponimod intermediate and the preparation method thereof have the advantages of simple and easily obtained raw materials, controllable reaction condition and temperature, easy operation and implementation, high yield and lower cost, and are suitable for industrial scale-up production.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound A" and "compound represented by formula A" and "formula A" means the same compound.
In the present invention, "optional" or "optionally" means that it may or may not be present; or may not be performed; the phrase "optionally adding a reaction solvent to the crude product obtained in step (C)" means that the reaction solvent may or may not be added to the crude product obtained in step (C).
In the present invention, the reaction is considered complete when the remaining amount of the raw materials does not exceed 5%, 3%, 2%, 1% or 0.5% of the charged amount in the reaction.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol; min represents minutes; h represents an hour; g represents g; ml means ml; DMF for N, N-dimethylformamide, THF for tetrahydrofuran; DCM denotes dichloromethane.
In the present invention, n-BuLi represents n-butyllithium.
EXAMPLE 1 preparation of Compound 10
Compound (9) (10.00g), ethylene glycol (6.53g), p-toluenesulfonic acid (0.86g), toluene (100mL) were added to a reaction flask, heated to 100 ℃ and stirred for 12 hours, water (50mL) was added after the reaction was completed for extraction, water (20mL) was added for washing, the organic phases were combined, and the organic phase was concentrated under reduced pressure to give compound 10(7.32g) in 59.9% yield, purity: 96.5 percent.
MS:[M+1]＝243.0，1H NMR(400MHz,CDCl3):δ7.50-7.45(m,2H)；7.40-7.33(m,2H)；4.11-3.98(m,2H)；3.81-3.70(m,2H)；1.65(s,3H)。
EXAMPLE 2 preparation of Compound 10
Adding the compound 9(20.00g), ethylene glycol (13.06g), p-toluenesulfonic acid (1.72g) and toluene (200ml) into a reaction flask, stirring at 100 ℃ for reaction for 12 hours, after the reaction is completed, adding water (100ml), extracting once, washing once (40ml), concentrating and evaporating to dryness to obtain the compound 10(15.13g), wherein the yield is 62.7%, and the purity: 97.2 percent.
EXAMPLE 3 preparation of Compound 10
Adding the compound 9(50.00g), ethylene glycol (32.65g), p-toluenesulfonic acid (4.30g) and toluene (500ml) into a reaction flask, stirring at 100 ℃ for reaction for 12 hours, after the reaction is completed, adding water (250ml), extracting once, washing once (100ml), concentrating and evaporating to dryness to obtain the compound 10(38.02g), wherein the yield is 62.3%, and the purity: 95.2 percent.
EXAMPLE 4 preparation of Compound 11
Adding the compound 10(10.00g), formamide (1.85g), thionyl chloride (7.34g) and dichloromethane (100mL) into a reaction bottle, stirring at 25 ℃ for reaction for 1h, adding water (50mL) after the reaction is completed, extracting twice, adding water (20mL), washing once, and concentrating and evaporating dichloromethane to obtain a crude product. The crude product was recrystallized from ethanol to give compound 11(5.02g) in 42.8% yield and purity: 93.2 percent.
MS:[M+1]＝285.0，1H NMR(400MHz,CDCl3):δ7.67-7.64(m,2H)；7.44-7.41(m,1H)；4.12-3.98(m,2H)；3.83-3.71(m,2H)；2.55(s,3H)；1.70(s,3H)。
EXAMPLE 5 preparation of Compound 11
Adding the compound 10(15.00g), formamide (2.78g), thionyl chloride (11.01g) and dichloromethane (150ml) into a reaction bottle, stirring at 25 ℃ for reaction for 1h, adding water (75ml) after the reaction is completed, extracting twice, washing once (30ml), concentrating and evaporating dichloromethane to obtain a crude product. The crude product was recrystallized from ethanol to give compound 11(7.86g) in 44.7% yield, purity: 95.6 percent.
EXAMPLE 6 preparation of Compound 11
Adding the compound 10(30.00g), formamide (5.55g), thionyl chloride (22.02g) and dichloromethane (300ml) into a reaction bottle, stirring at 25 ℃ for reaction for 1h, adding water (150ml) after the reaction is completed, extracting twice, washing once (60ml), concentrating and evaporating to dryness to obtain a crude product. The crude product was recrystallized from ethanol to give compound 11(16.73g) in 47.6% yield, purity: 95.6 percent.
EXAMPLE 7 preparation of Compound 12
Compound 11(10.00g), hydrazine hydrate (50%, 7.02g), sodium hydroxide (2.81g), ethylene glycol (150ml) were added to a reaction flask, stirred at 150 ℃ for reaction for 3 hours, after completion of the reaction, water (50ml) was added, ethyl acetate (50ml) was extracted once, water washed once (20ml), the organic phases were combined and concentrated under reduced pressure to give compound 12(6.74g), yield 70.8%, purity: 92.5 percent.
MS:[M+1]＝271.0，1H NMR(400MHz,CDCl3):δ7.44-7.34(m,2H)；7.24-7.21(m,1H)；4.11-3.97(m,2H)；3.81-3.70(m,2H)；2.65(q,2H)；1.65(s,3H)；1.25(t,3H)。
EXAMPLE 8 preparation of Compound 13
Adding the compound 12(10.00g) and tetrahydrofuran (150ml) into a reaction bottle, cooling to-60 ℃ to-80 ℃, dropwise adding n-BuLi (1.6mol/L, 25.3ml), and stirring for 1h at-78 ℃ after dropwise adding. DMF (8.08g) was added dropwise thereto, and after the addition was completed, the temperature was controlled to-78 ℃ and stirring was carried out for 1 hour. After the reaction was completed, the reaction was quenched with ammonium chloride (1.97g), warmed to room temperature, adjusted to pH ≈ 5 with 10% hydrochloric acid, extracted three times with ethyl acetate (50ml), combined organic phases were concentrated under reduced pressure to give a yellow oily substance, and subjected to column chromatography (ethyl acetate: n-hexane ═ 1:4 to 1:20) to give compound 13(5.85g) in a yield of 72.1% purity: 95.7 percent.
MS:[M+1]＝221.3，1H NMR(400MHz,CDCl3)δ10.10(s,1H),7.68-7.81(d,1H),7.40(s,1H),7.30-7.40.(d,1H),3.90-4.10(m,4H),2.55-2.65(q,2H),1.80(s,3H),1.28-1.20(t,3H)。
EXAMPLE 9 preparation of Compound 14
Adding the compound 13(10.00g) and methanol (150ml) into a reaction bottle, cooling to-5 ℃ to-10 ℃, adding sodium borohydride (1.89g) in batches, heating to 25 ℃ after adding, and reacting for 2 hours. After the reaction, water (10ml) was added, the reaction solution was concentrated under reduced pressure, ethyl acetate (100ml) was added for extraction twice, and the organic phases were combined and concentrated under reduced pressure to give compound 14, which was used directly in the next reaction.
EXAMPLE 10 preparation of Compound 4
Compound 14(10.00g, prepared as in example 9), methanol (150mL) was added to a reaction flask, hydrochloric acid (3mol/L, 20mL) was added, the temperature was raised to 30 ℃ to 60 ℃ and stirred for 2h, after the reaction was completed, concentration was performed under reduced pressure, water (50mL) was added after concentration, ethyl acetate (50mL) was added to extract twice, the organic phases were combined, concentration was performed under reduced pressure to obtain a yellow oil, and recrystallization was performed with ethanol to obtain compound 4(6.82g), yield 85.0%, purity 94.3%.
MS:[M+1]＝179.2，1H NMR(400MHz,CDCl3)δ7.75-7.78(m,2H),7.51-7.52(d,1H),4.77.(s,2H),2.69-2.70(q,2H),2.58(s,3H),1.24-1.26(t,3H)。
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A method of preparing compound 12, comprising: carrying out reduction reaction on the compound 11 in a reaction solvent in the presence of a reducing agent and alkali to obtain a compound 12,
wherein the reducing agent is at least one of hydrazine hydrate, a combination of aluminum trichloride and sodium borohydride, and a combination of triethylsilane and boron trifluoride ethyl ether.
2. The method of claim 1, the base is at least one of sodium hydroxide, potassium hydroxide, and potassium tert-butoxide; and/or the reaction solvent is at least one of ethylene glycol, diethylene glycol and triethylene glycol.
3. The method according to claim 1, wherein the charging molar ratio of the reducing agent to the compound 11 is 2.0:1-5.0: 1; and/or the charging molar ratio of the alkali to the compound 11 is 2.0:1-5.0: 1.
4. A method according to any one of claims 1 to 3, wherein post-processing is performed, said post-processing comprising: water and ethyl acetate are added into the reaction liquid for extraction, and the organic phases are combined to remove the solvent, so that the compound 12 is obtained.
5. The method of any of claims 1-4, further comprising: the compound 10 is subjected to acylation reaction with formamide and thionyl chloride in a solvent under the condition of reaction temperature to obtain a compound 11,
6. the method of claim 5, wherein the solvent is at least one of dichloromethane, dichloroethane, chloroform, diethyl ether, n-hexane, and petroleum ether.
7. The process of claim 5, wherein the reaction temperature is 10 ℃ to 40 ℃.
8. The method according to any one of claims 5-7, further comprising a post-processing comprising: water was added to the reaction solution, and the organic phases were combined and the solvent was removed to obtain compound 11.
9. A method of preparing compound 4, comprising: compound 12, prepared according to any one of claims 1 to 8, is reacted with DMF of compound (01) in a reaction solvent in the presence of a base at low temperature to produce compound 13, wherein the base is at least one of n-butyllithium and t-butyllithium; reacting the compound 13 in a solvent in the presence of a reducing agent to obtain a compound 14, wherein the reducing agent is at least one of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, palladium-carbon/hydrogen, raney nickel/hydrogen and formic acid; reacting the compound 14 in a solvent in the presence of an acid at 30-60 ℃ to obtain a compound 4, wherein the acid is at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid and methanesulfonic acid;
10. a compound having the structure shown in formula 11 or 12 below:
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