CN110655496A - 手性化合物的合成方法 - Google Patents
手性化合物的合成方法 Download PDFInfo
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- CN110655496A CN110655496A CN201811555598.5A CN201811555598A CN110655496A CN 110655496 A CN110655496 A CN 110655496A CN 201811555598 A CN201811555598 A CN 201811555598A CN 110655496 A CN110655496 A CN 110655496A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 82
- 238000000034 method Methods 0.000 title claims abstract description 31
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 34
- 230000009467 reduction Effects 0.000 claims abstract description 21
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 19
- 238000001308 synthesis method Methods 0.000 claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 17
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims abstract description 16
- 239000011592 zinc chloride Substances 0.000 claims abstract description 8
- 235000005074 zinc chloride Nutrition 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 93
- 239000002904 solvent Substances 0.000 claims description 75
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 66
- 238000006243 chemical reaction Methods 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 32
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 238000005804 alkylation reaction Methods 0.000 claims description 24
- 150000001266 acyl halides Chemical class 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 238000001953 recrystallisation Methods 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 18
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 17
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims description 16
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 16
- 229960003767 alanine Drugs 0.000 claims description 16
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 15
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 15
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 claims description 14
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 14
- 239000002168 alkylating agent Substances 0.000 claims description 13
- 229940100198 alkylating agent Drugs 0.000 claims description 13
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 12
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- 230000029936 alkylation Effects 0.000 claims description 12
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- 230000002140 halogenating effect Effects 0.000 claims description 12
- -1 p-toluenesulfonyloxy Chemical group 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- 230000002152 alkylating effect Effects 0.000 claims description 11
- 230000010933 acylation Effects 0.000 claims description 10
- 238000005917 acylation reaction Methods 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 9
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 9
- 238000011033 desalting Methods 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 239000008096 xylene Substances 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 150000008282 halocarbons Chemical class 0.000 claims description 8
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 239000012452 mother liquor Substances 0.000 claims description 7
- 150000002825 nitriles Chemical class 0.000 claims description 7
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 229940102001 zinc bromide Drugs 0.000 claims description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 6
- 229940011051 isopropyl acetate Drugs 0.000 claims description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 claims description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 5
- 239000012752 auxiliary agent Substances 0.000 claims description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 5
- 229940071870 hydroiodic acid Drugs 0.000 claims description 5
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 claims description 4
- KJDRSWPQXHESDQ-UHFFFAOYSA-N 1,4-dichlorobutane Chemical group ClCCCCCl KJDRSWPQXHESDQ-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 229960001270 d- tartaric acid Drugs 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- ROUYUBHVBIKMQO-UHFFFAOYSA-N 1,4-diiodobutane Chemical compound ICCCCI ROUYUBHVBIKMQO-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000005456 alcohol based solvent Substances 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 239000004210 ether based solvent Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 239000005453 ketone based solvent Substances 0.000 claims description 3
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 3
- 125000005905 mesyloxy group Chemical group 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 239000003039 volatile agent Substances 0.000 claims description 3
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims description 2
- JYLNVJYYQQXNEK-UHFFFAOYSA-N 3-amino-2-(4-chlorophenyl)-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(CN)C1=CC=C(Cl)C=C1 JYLNVJYYQQXNEK-UHFFFAOYSA-N 0.000 claims description 2
- BTOJSYRZQZOMOK-UHFFFAOYSA-N 4-chloro-7-(4-methylphenyl)sulfonylpyrrolo[2,3-d]pyrimidine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=NC(Cl)=C2C=C1 BTOJSYRZQZOMOK-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- PBLPPTNKAUFZJW-RNKHSWPKSA-N C(C1=CC=CC=C1)(=O)O.C(C1=CC=CC=C1)(=O)O.C([C@@H](O)[C@H](O)C(=O)O)(=O)O Chemical compound C(C1=CC=CC=C1)(=O)O.C(C1=CC=CC=C1)(=O)O.C([C@@H](O)[C@H](O)C(=O)O)(=O)O PBLPPTNKAUFZJW-RNKHSWPKSA-N 0.000 claims description 2
- PBLPPTNKAUFZJW-CEAXSRTFSA-N C(C1=CC=CC=C1)(=O)O.C(C1=CC=CC=C1)(=O)O.C([C@H](O)[C@@H](O)C(=O)O)(=O)O Chemical compound C(C1=CC=CC=C1)(=O)O.C(C1=CC=CC=C1)(=O)O.C([C@H](O)[C@@H](O)C(=O)O)(=O)O PBLPPTNKAUFZJW-CEAXSRTFSA-N 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 229930182843 D-Lactic acid Natural products 0.000 claims description 2
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000004645 aluminates Chemical class 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 2
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 229940117975 chromium trioxide Drugs 0.000 claims description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 229940022769 d- lactic acid Drugs 0.000 claims description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- BNSOYWDFFBDEFB-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O BNSOYWDFFBDEFB-UHFFFAOYSA-L 0.000 claims description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 229940116298 l- malic acid Drugs 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 claims description 2
- 239000011654 magnesium acetate Substances 0.000 claims description 2
- 229940069446 magnesium acetate Drugs 0.000 claims description 2
- 235000011285 magnesium acetate Nutrition 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940032330 sulfuric acid Drugs 0.000 claims description 2
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于化学合成技术领域,涉及手性化合物的合成方法,具体是(1R,2S)‑1‑苯基‑2‑(吡咯烷‑1‑基)丙‑1‑醇的合成方法。本发明的巧妙合成策略,使得羰基还原时能够实现不对称还原,直接高收率得到目标化合物。改善了现有工艺中无法通过不对称还原高收率得到目标化合物的问题。而且,本发明使用廉价的盐酸、氯化锌即可实现高纯度化合物(A)的合成;此外,本发明无任何异构体浪费;另外,本发明方法避免了使用去甲麻黄碱管控品;本发明的原料廉价易得,降低了合成成本;并且,本发明的制备方法易于工业化大生产。
Description
技术领域
本发明属于化学合成技术领域,涉及手性化合物的合成方法,具体是(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的合成方法。
背景技术
手性化合物的合成,特别是具有多个手性中心的化合物的合成,一般存在产率低的问题。在设计多手性中心化合物的合成时,合成路线的选择至关重要,尤其是工业化大生产的合成路线。
手性配体,(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇,在生产治疗艾滋病药物依非韦仑(Efavirenz)的手性控制中起到至关重要的作用(US6015926A),工艺流程如下式所示。
US5856492A公开了用去甲麻黄碱[L-(-)-Norephdrine,(1R,2S)-2-氨基-1-苯基丙-1-醇]和1,4-二溴丁烷制备手性配体。去甲麻黄碱属管控品,有规模化和商业化难度。工艺流程如下式所示。
WO2015063795A2公开了制备光学纯手性配体方法,该方法经过卤代、胺代、硼氢化钠还原、D-酒石酸拆分、酒石酸盐重结晶纯化、脱除酒石酸六个步骤实现。该方法理论上仅有50%是所要的手性配体,很不经济。工艺流程如下式所示。
发明内容
为改善上述问题,本发明提供一种下式(II)所示手性化合物的合成方法,
其中,所述合成方法包括烷基化步骤,具体为:L-丙氨酸(Ⅰ)与烷基化试剂进行烷基化反应,得到化合物(Ⅱ)。
根据本发明,所述烷基化试剂为被一个或多个离去基团(X)取代的烷烃;所述离去基团选自卤素、甲磺酰氧基或对甲苯磺酰氧基;
优选地,所述烷基化试剂选自被一个或多个卤素取代的烷烃,例如卤代烷烃,优选为二卤代烷烃;所述卤素选自氯、溴或碘;
例如,所述烷基化试剂可以为1,4-二氯丁烷、1,4-二溴丁烷、1,4-二碘丁烷;
根据本发明,所述反应的温度为20℃~150℃,优选为50℃~100℃;
根据本发明,所述反应可以在溶剂中进行,所述溶剂可以是芳烃类溶剂、醚类溶剂、腈类溶剂、酮类溶剂、酰胺类溶剂、醇类溶剂的一种、两种或更多种,优选为甲苯、二甲苯、四氢呋喃、二氧六环、乙腈、丙腈、丙酮、丁酮、甲基异丙基酮、N,N-二甲基甲酰胺、甲醇、乙醇、丙醇、异丙醇、丁醇、叔丁醇的任一种或其组合;
根据本发明,所述反应可以在碱的存在下进行;所述的碱可以是氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠的任一种或其组合;
根据本发明,L-丙氨酸(Ⅰ)与烷基化试剂的摩尔比为1:(1-3),优选为1:1;
根据本发明,化合物(Ⅱ)中的HX是离去基团所对应的酸,例如氢氯酸、氢溴酸、氢碘酸的任一种或其组合。
上述化合物(II)可作为合成(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的中间体,(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇可作为依非韦仑(Efavirenz)合成过程中的手性配体。
本发明还提供下式(III)所示手性化合物的合成方法,
其中,所述合成方法包括以下步骤:
(1)烷基化:L-丙氨酸(Ⅰ)与烷基化试剂进行烷基化反应,得到化合物(Ⅱ);
(2)酰基化:化合物(Ⅱ)与卤化剂反应转化为酰卤,随后酰卤与苯进行傅克酰基化反应,得到化合物(Ⅲ)。
根据本发明,步骤(1)中,
所述烷基化试剂为被一个或多个离去基团(X)取代的烷烃;所述离去基团选自卤素、甲磺酰氧基或对甲苯磺酰氧基;
优选地,所述烷基化试剂选自被一个或多个卤素取代的烷烃,例如卤代烷烃,优选为二卤代烷烃;所述卤素选自氯、溴或碘;
例如,所述烷基化试剂可以为1,4-二氯丁烷、1,4-二溴丁烷、1,4-二碘丁烷;
根据本发明,所述反应的温度为20℃~150℃,优选为50℃~100℃;
根据本发明,所述反应可以在溶剂中进行,所述的溶剂可以是芳烃类溶剂、醚类溶剂、腈类溶剂、酮类溶剂、酰胺类溶剂、醇类溶剂的一种、两种或更多种,优选为甲苯、二甲苯、四氢呋喃、二氧六环、乙腈、丙腈、丙酮、丁酮、甲基异丙基酮、N,N-二甲基甲酰胺、甲醇、乙醇、丙醇、异丙醇、丁醇、叔丁醇的任一种或其组合;
根据本发明,所述反应可以在碱的存在下进行;所述的碱可以是氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠的任一种或其组合;
根据本发明,L-丙氨酸(Ⅰ)与烷基化试剂的摩尔比为1:(1-3),优选为1:1;
根据本发明,化合物(Ⅱ)中的HX是离去基团所对应的酸,例如氢氯酸、氢溴酸、氢碘酸的任一种或其组合;
根据本发明,步骤(2)合成酰卤的步骤中,
所述反应的温度为10℃~100℃,优选为20℃~80℃;
所述反应可以在溶剂中进行,所述溶剂可以是卤代烃类溶剂,例如二氯甲烷、1,2-二氯乙烷的任一种或其组合;
根据本发明,所述反应可以加入催化剂,例如N,N-二甲基甲酰胺;
根据本发明,所述卤化剂可以是草酰氯、草酰溴、氯化亚砜、溴化亚砜、双(三氯甲基)碳酸酯的任一种或其组合;
根据本发明,步骤(2)酰卤与苯进行傅克酰基化反应的步骤中,
所述反应的温度为10℃~100℃,优选为20℃~80℃;
根据本发明,所述反应可以加入催化剂,所述催化剂可以是三氯化铝、三氯化铁、三氟化硼、三氯化铋、活性三氧化二铁(α-Fe2O3)的任一种或其组合;
上述化合物(III)可作为合成(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的中间体,(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇可作为依非韦仑(Efavirenz)合成过程中的手性配体。
本发明还提供下式所示的混合物(IV)的合成方法,
所述合成方法包括以下步骤:
(1)烷基化:L-丙氨酸(Ⅰ)与烷基化试剂进行烷基化反应,得到化合物(Ⅱ);
(2)酰基化:化合物(Ⅱ)与卤化剂反应转化为酰卤,随后酰卤与苯进行傅克酰基化反应,得到化合物(Ⅲ);
(3)还原:化合物(Ⅲ)与还原剂进行反应,得到混合物(Ⅳ)。
其中,步骤(1)、步骤(2)具有上文所述的反应条件;
根据本发明,步骤(3)中,
所述反应的温度为-10℃~100℃,优选为-10℃~60℃,进一步优选为-5℃~10℃;
所述反应可以在溶剂中进行,所述溶剂选自醚类溶剂、醇类溶剂的一种、两种或更多种,例如四氢呋喃、二氧六环、甲醇、乙醇、丙醇、异丙醇、丁醇、叔丁醇的任一种或其组合;
所述还原剂可以是硼氢化锂、硼氢化钠、硼氢化钾、硼氢化锌、四氢铝锂、二氢双(2-甲氧基乙氧基)铝酸钠、二异丁基氢化铝的任一种或其组合,优选为硼氢化钠;
根据本发明,所述反应可以加入还原助剂,所述还原助剂可以是氯化钙、氯化镁、溴化镁、醋酸镁、氯化锌、溴化锌、醋酸锌、硫酸锌、甲磺酸锌、三氟甲磺酸锌的任一种或其组合,优选为氯化锌、溴化锌;
根据本发明,化合物(Ⅲ)与还原剂与还原助剂的摩尔比为1:(1-2):(0-1),优选为1:(1-1.5):(0-0.5);
根据本发明,所述反应的时间为30分钟至20小时,优选为30分钟至8小时;
根据本发明,所得混合物(Ⅳ)的手性纯度为:(1R,2S)93%以上,(1S,2S)7%以下,(1S,2R)0%,(1R,2R)0%;
上述混合物(IV)可作为合成(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的中间体,(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇可作为依非韦仑(Efavirenz)合成过程中的手性配体。
本发明还提供下式所示的粗盐(V)的合成方法,
所述合成方法包括以下步骤:
(1)烷基化:L-丙氨酸(Ⅰ)与烷基化试剂进行烷基化反应,得到化合物(Ⅱ);
(2)酰基化:化合物(Ⅱ)与卤化剂反应转化为酰卤,随后酰卤与苯进行傅克酰基化反应,得到化合物(Ⅲ);
(3)还原:化合物(Ⅲ)与还原剂进行反应,得到混合物(Ⅳ);
(4)成盐:混合物(Ⅳ)与拆分剂(HY)反应,得到粗盐(Ⅴ)。
其中,步骤(1)、步骤(2)、步骤(3)具有上文所述的反应条件;
根据本发明,步骤(4)中,
所述反应的温度为0℃~100℃,优选为0℃~80℃;
所述反应可以在溶剂中进行,所述溶剂可以是醚类溶剂、腈类溶剂、酮类溶剂、醇类溶剂的一种、两种或更多种,例如四氢呋喃、二氧六环、乙腈、丙腈、丙酮、丁酮、甲基异丙基酮、甲醇、乙醇、丙醇、异丙醇、丁醇、叔丁醇的任一种或其组合;
所述拆分剂可以选自D-酒石酸、D-苹果酸、D-乳酸、(S)-扁桃酸、(R)-樟脑磺酸、D-酒石酸二苯甲酸酯、L-酒石酸、L-苹果酸、L-乳酸、(S)-樟脑磺酸、L-酒石酸二苯甲酸酯、盐酸、氢溴酸、氢碘酸、硫酸、甲磺酸、三氟甲磺酸、对甲苯磺酸的任一种或其组合;
所述反应的时间可以为30分钟至两天,优选为30分钟至30小时;
所得粗盐(Ⅴ)的手性纯度为:(1R,2S)大于99.8%,(1S,2S)小于0.2%,(1S,2R)0%,(1R,2R)0%;
上述粗盐(V)可作为合成(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的中间体,(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇可作为依非韦仑(Efavirenz)合成过程中的手性配体。
本发明还提供下式所示的光学纯盐(VI)的合成方法,
所述合成方法包括以下步骤:
(1)烷基化:L-丙氨酸(Ⅰ)与烷基化试剂进行烷基化反应,得到化合物(Ⅱ);
(2)酰基化:化合物(Ⅱ)与卤化剂反应转化为酰卤,随后酰卤与苯进行傅克酰基化反应,得到化合物(Ⅲ);
(3)还原:化合物(Ⅲ)与还原剂进行反应,得到混合物(Ⅳ);
(4)成盐:混合物(Ⅳ)与拆分剂(HY)反应,得到粗盐(Ⅴ);
(5)重结晶:将粗盐(Ⅴ)进行重结晶,得到光学纯盐(Ⅵ)。
其中,步骤(1)、步骤(2)、步骤(3)、步骤(4)具有上文所述的反应条件;
根据本发明,步骤(5)中,
所述重结晶的操作可以为:将粗盐(Ⅴ)与溶剂混合,加热溶解,降温,搅拌,析出晶体,得到光学纯盐(Ⅵ);
重结晶步骤所述加热的温度为0℃~100℃,优选为0℃~80℃;
重结晶步骤所述的溶剂选自醚类溶剂、腈类溶剂、酮类溶剂、醇类溶剂的一种、两种或更多种,例如四氢呋喃、二氧六环、乙腈、丙腈、丙酮、丁酮、甲基异丙基酮、甲醇、乙醇、丙醇、异丙醇、丁醇、叔丁醇的任一种或其组合;
重结晶步骤中加热的时间和降温的时间相同或不同,彼此独立地选自30分钟至两天,优选为30分钟至30小时;
重结晶所得光学纯盐(Ⅵ)的手性纯度为:(1R,2S)100%,(1S,2S)0%,(1S,2R)0%,(1R,2R)0%;
上述光学纯盐(VI)可作为合成(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的中间体,(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇可作为依非韦仑(Efavirenz)合成过程中的手性配体。
本发明还提供下式所示的化合物(A)的合成方法,
所述合成方法包括以下步骤:
(1)烷基化:L-丙氨酸(Ⅰ)与烷基化试剂进行烷基化反应,得到化合物(Ⅱ);
(2)酰基化:化合物(Ⅱ)与卤化剂反应转化为酰卤,随后酰卤与苯进行傅克酰基化反应,得到化合物(Ⅲ);
(3)还原:化合物(Ⅲ)与还原剂进行反应,得到混合物(Ⅳ);
(4)成盐:混合物(Ⅳ)与拆分剂(HY)反应,得到粗盐(Ⅴ);
(5)重结晶:将粗盐(Ⅴ)进行重结晶,得到光学纯盐(Ⅵ);
(6)脱盐:光学纯盐(Ⅵ)进行脱盐步骤,得到光学纯化合物(A)。
其中,步骤(1)、步骤(2)、步骤(3)、步骤(4)、步骤(5)具有上文所述的反应条件;
根据本发明,步骤(6)中,
所述反应的温度为0℃~100℃,优选为20℃~50℃;
所述反应可以在溶剂中进行,所述溶剂可以为卤代烃类溶剂、芳烃类溶剂、醚类溶剂、酯类溶剂、烷烃类溶剂、水中的一种、两种或更多种,例如二氯甲烷、1,2-二氯乙烷、甲苯、二甲苯、乙醚、异丙醚、甲基叔丁醚、乙二醇二甲醚、乙酸乙酯、乙酸异丙酯、己烷、环己烷、庚烷、水中的任一种或其组合;
所述反应可以加入碱,所述碱可以为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、氨水中的任一种或其组合;
脱盐所得化合物(A)的手性纯度为:(1R,2S)100%;
上述化合物(A)可作为依非韦仑(Efavirenz)合成过程中的手性配体。
本发明还提供一种由上述成盐步骤母液、上述重结晶步骤母液合成化合物(Ⅲ)的方法,包括下述步骤:
1)脱盐:将上述成盐步骤母液、上述重结晶步骤母液合并,减压蒸除挥发物,残留物与碱反应,得到混合物(IV);
2)氧化:混合物(IV)与氧化剂反应,得到化合物(Ⅲ)。
根据本发明,步骤1)中,
所述反应的温度为0℃~100℃,优选为20℃~50℃;
所述反应可以在溶剂中进行,所述溶剂可以为卤代烃类溶剂、芳烃类溶剂、醚类溶剂、酯类溶剂、烷烃类溶剂、水的一种、两种或更多种,例如二氯甲烷、1,2-二氯乙烷、甲苯、二甲苯、乙醚、异丙醚、甲基叔丁醚、乙二醇二甲醚、乙酸乙酯、乙酸异丙酯、己烷、环己烷、庚烷、水的任一种或其组合;
所述的碱可以是氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、氨水的任一种或其组合;
脱盐所得混合物(IV)的纯度为:(1R,2S)~27%,(1S,2S)~73%;
根据本发明,步骤2)中,
所述反应的温度为-10℃~100℃,优选为0℃~50℃;
所述反应可以在溶剂中进行,所述溶剂可以是卤代烃类溶剂、芳烃类溶剂、醚类溶剂、酯类溶剂、烷烃类溶剂、水的一种、两种或更多种,例如二氯甲烷、1,2-二氯乙烷、甲苯、二甲苯、乙醚、异丙醚、甲基叔丁醚、乙二醇二甲醚、乙酸乙酯、乙酸异丙酯、己烷、环己烷、庚烷、水的任一种或其组合;
所述氧化剂可以是三氧化铬、重铬酸钠、重铬酸钾、高锰酸钾、高锰酸钠、重铬酸吡啶、Dess-Martin试剂、二氧化锰的任一种或其组合,优选为重铬酸钠;
根据本发明,所述反应可以先在酸性条件下进行,随后用碱调节溶液的pH。
根据本发明,可以将溶液的pH调节至8-11,例如10;
所述的酸可以选自硫酸、盐酸、磷酸的任一种或其组合;
所述的碱可以是氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、氨水的任一种或其组合;
上述化合物(III)可作为合成(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的中间体,(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇可作为依非韦仑(Efavirenz)合成过程中的手性配体。
本发明所述化合物的化学名称为:
化合物(Ⅰ):L-丙氨酸;
化合物(Ⅱ):(2S)-2-(吡咯烷-1-基)丙酸酸加成盐;
化合物(Ⅲ):(2S)-1-苯基-2-(吡咯烷-1-基)丙-1-酮;
混合物(Ⅳ):(1R/S,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇;
化合物(Ⅴ):(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇酸加成盐粗盐;
化合物(Ⅵ):(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇酸加成盐光学纯盐;
化合物(A):(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇。
与现有技术相比,本发明具有下述有益技术效果:
1)高收率;本发明的巧妙合成设计,使得羰基还原时能够实现不对称还原,直接高收率得到目标化合物。改善了现有工艺中无法通过不对称还原高收率得到目标化合物的问题。
2)高纯度;本发明使用廉价的盐酸、氯化锌即可实现高纯度化合物(A)的合成(WO2015063795A2技术使用较贵的酒石酸和溴化锌);
3)无任何异构体浪费(WO2015063795A2技术不经济,损失一半);
4)本发明方法避免了使用去甲麻黄碱管控品;本发明的原料廉价易得,降低了合成成本;
5)易于工业化大生产。
具体实施方式
下文将结合具体实施例对本发明做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
本发明所使用的高压液相色谱(HPLC)参数是:柱子,Chialpak IA,250X4.6mm X 5μm;柱温,30℃;流速,0.8ml/min;样品浓度,1mg/ml;进样体积,20μm;流动相,正己烷:乙醇:二乙胺(95:5:0.1,v/v/v);洗脱模式,等度洗脱;检测波长,220nm。
除非另有说明,本发明涉及液体与液体之间的百分比时,所述的百分比为体积/体积百分比;本发明涉及液体与固体之间的百分比时,所述百分比为体积/重量百分比;本发明涉及固体与液体之间的百分比时,所述百分比为重量/体积百分比;其余为重量/重量百分比。
实施例1(2S)-2-(吡咯烷-1-基)丙酸盐酸盐的制备
将L-丙氨酸(500克)、碳酸氢钠(1500克)和乙醇(10升)的混合物搅拌回流1小时后,于回流状态下滴加1,4-二氯丁烷(713克)和乙醇(1升)的混合物,4小时滴加完毕。继续搅拌回流16小时后,将反应混合物温度降至室温,浓盐酸酸化(~500毫升),过滤。滤饼用乙醇打浆、过滤(3x1升)。合并滤液,减压浓缩至干,加入新鲜乙醇(3升)升温溶解,硅藻土过滤。滤液再次减压浓缩至干后,用异丙醇于0℃~5℃结晶即得(2S)-2-(吡咯烷-1-基)丙酸盐酸盐(920克),收率91%,纯度98%。
实施例2(2S)-1-苯基-2-(吡咯烷-1-基)丙-1-酮的制备
将实施例1合成的(2S)-2-(吡咯烷-1-基)丙酸盐酸盐(900克)、1,2-二氯乙烷(6升)和N,N-二甲基甲酰胺(5毫升)搅拌混合,于室温下滴加草酰氯(650克)。1小时滴加完毕后,将反应混合物缓慢升温至回流,然后保持回流16小时。将反应混合物温度降至室温,减压浓缩彻除挥发物后,加入苯(5升)和活性α-Fe2O3(10克)。将此混合物缓慢升温至回流,然后保持回流18小时。将反应混合物温度降至室温,加入硅藻土(50克),浓氨水碱化,过滤。滤液经水洗两次后减压浓缩彻除挥发物,即得(2S)-1-苯基-2-(吡咯烷-1-基)丙-1-酮粗品(1010克),产率99%,纯度96%。
实施例3(1R/S,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的制备(溴化锌催化)
室温下将溴化锌(140克)和乙醇(2升)搅拌混合。待体系温度降至0℃~5℃,分批加入硼氢化钠(110克)。0℃~5℃下搅拌30分钟后,加入实施例2所得粗品(500克)的乙醇(1升)溶液。于0℃~5℃下继续搅拌8小时后,加入丙酮(100毫升)终止反应,加入稀盐酸调节pH~5。55℃下减压浓缩彻除挥发物后,加入水(4升),加盐酸调节pH~2,加甲苯(2升)。20℃~30℃下继续1小时后静置分层。有机层回收甲苯套用。水层用氨水碱化至pH~10,甲苯(2x1.5升)萃取。合并甲苯层,55℃下减压浓缩除甲苯,即得(1R/S,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇粗品(482克),产率99%,化学纯度95%,手性纯度:(1R,2S)93.67%,(1S,2S)6.33%,(1S,2R)0%,(1R,2R)0%。
实施例4(1R/S,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的制备(氯化锌催化)
室温下将氯化锌(90克)和乙醇(2升)搅拌混合。待体系温度降至0℃~5℃,分批加入硼氢化钠(110克)。0℃~5℃下搅拌30分钟后,加入实施例2所得粗品(500克)的乙醇(1升)溶液。于0℃~5℃下继续搅拌8小时后,加入丙酮(100毫升)终止反应,加入稀盐酸调节pH~5。55℃下减压浓缩彻除挥发物后,加入水(4升),加盐酸调节pH~2,加甲苯(2升)。20℃~30℃下继续1小时后静置分层。有机层回收甲苯套用。水层用氨水碱化至pH~10,甲苯(2x1.5升)萃取。合并甲苯层,55℃下减压浓缩除甲苯,即得(1R/S,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇粗品(480克),产率99%,化学纯度95%,手性纯度:(1R,2S)93.58%,(1S,2S)6.42%,(1S,2R)0%,(1R,2R)0%。
实施例5(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇D-酒石酸盐的制备
将D-酒石酸(340克)和乙醇(2升)的混合物搅拌回流直至透明澄清,然后加入实施例3所得粗品(475克)和乙醇(500毫升)的溶液,缓慢降温至20℃~30℃并继续搅拌2小时。过滤,滤饼用冷的乙醇洗涤,50℃~55℃下真空干燥,即得(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇D-酒石酸盐(760克),产率97%,手性纯度:(1R,2S)99.94%,(1S,2S)0.06%,(1S,2R)0%,(1R,2R)0%。
实施例6(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇盐酸盐的制备
将实施例4所得粗品(475克)溶于乙醇(3升),于20℃~30℃下缓缓滴入浓盐酸(190毫升)并继续搅拌1小时。于55℃下减压浓缩除去挥发物,加入乙醇(2.5升),加热回流至透明澄清后继续回流30分钟。缓慢降温至20℃~30℃并继续搅拌2小时。过滤,滤饼用冷的乙醇洗涤,50℃~55℃下真空干燥,即得(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇盐酸盐(510克)。产率96%,手性纯度:(1R,2S)99.84%,(1S,2S)0.16%,(1S,2R)0%,(1R,2R)0%。
实施例7(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇D-酒石酸盐的重结晶
将实施例5所得D-酒石酸盐(750克)和乙醇(3升)的混合物搅拌回流至透明澄清,继续搅拌回流30分钟后,缓慢降温至20℃~30℃并继续搅拌2小时。再于0℃~5℃下搅拌1小时。过滤,滤饼用冷的乙醇洗涤,50℃~55℃下真空干燥,即得(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇D-酒石酸盐(742克)。产率99%,手性纯度:(1R,2S)100%。
实施例8(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇盐酸盐的重结晶
将实施例6所得盐酸盐(510克)和乙醇(1.5升)的混合物搅拌回流至透明澄清,继续搅拌回流30分钟后,缓慢降温至20℃~30℃并继续搅拌2小时。再于0℃~5℃下搅拌1小时。过滤,滤饼用冷的乙醇洗涤,50℃~55℃下真空干燥,即得(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇盐酸盐(496克)。产率97%,手性纯度:(1R,2S)100%。
实施例9母液回收(2S)-1-苯基-2-(吡咯烷-1-基)丙-1-酮
将实施例5~8所得母液合并、减压浓缩彻除挥发物。将所得残留物、水(500毫升)和甲苯(500毫升)充分搅拌混合,于20℃~35℃下用浓氨水碱化至pH~10。静置分层,水相用甲苯(500毫升)萃取一次。合并的甲苯层,用稀氨水(500毫升)洗涤一次。于55℃下减压浓缩除去挥发物,即得(1R/S,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇粗品(~90克),纯度96%,手性纯度:(1R,2S)27.17%,(1S,2S)72.83%。
将上述所得粗品(~90克)溶于稀硫酸(100克硫酸溶于250毫升水),于20℃~25℃搅拌下滴加重铬酸钠溶液(110克重铬酸钠溶于110克水)。滴毕,继续搅拌6小时。加入水(100毫升)和甲苯(250毫升),于0℃~5℃下用浓氨水碱化至pH~10,继续搅拌30分钟。过滤,甲苯洗涤滤饼。滤液静置分层,甲苯层用稀氨水洗涤。于50℃~55℃下减压浓缩去除挥发物,即得(2S)-1-苯基-2-(吡咯烷-1-基)丙-1-酮产品(85克),产率99%,纯度97%。
此粗品不需要进一步纯化,可直接用于实施例3或4,进行下一循环套用。
实施例10光学纯手性配体(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的制备(D-酒石酸盐脱盐)
将实施例7所得的D-酒石酸盐(740克)、水(800毫升)和甲苯(800毫升)充分搅拌混合,于20℃~35℃下用浓氨水碱化至pH~10。静置分层,水相用甲苯(500毫升)萃取一次。合并的甲苯层,用稀氨水(500毫升)洗涤一次。于55℃下减压浓缩除去挥发物,即得光学纯手性配体(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇(426克),产率99%。手性纯度:(1R,2S)100%。
实施例11光学纯手性配体(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇的制备(盐酸盐脱盐)
将实施例8所得的盐酸盐(490克)、水(800毫升)和甲苯(800毫升)充分搅拌混合,于20℃~35℃下用浓氨水碱化至pH~10。静置分层,水相用甲苯(500毫升)萃取一次。合并的甲苯层,用稀氨水(500毫升)洗涤一次。于55℃下减压浓缩除去挥发物,即得光学纯手性配体(1R,2S)-1-苯基-2-(吡咯烷-1-基)丙-1-醇(415克),产率~100%。手性纯度:(1R,2S)100%。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述的合成方法,其中,所述烷基化试剂为被一个或多个离去基团(X)取代的烷烃;所述离去基团选自卤素、甲磺酰氧基或对甲苯磺酰氧基;
优选地,所述烷基化试剂选自被一个或多个卤素取代的烷烃,例如卤代烷烃,优选为二卤代烷;所述卤素选自氯、溴或碘;
例如,所述烷基化试剂为1,4-二氯丁烷、1,4-二溴丁烷、1,4-二碘丁烷;
所述反应的温度为20℃~150℃,优选为50℃~100℃;
所述反应在溶剂中进行,所述的溶剂选自芳烃类溶剂、醚类溶剂、腈类溶剂、酮类溶剂、酰胺类溶剂、醇类溶剂的一种、两种或更多种,优选为甲苯、二甲苯、四氢呋喃、二氧六环、乙腈、丙腈、丙酮、丁酮、甲基异丙基酮、N,N-二甲基甲酰胺、甲醇、乙醇、丙醇、异丙醇、丁醇、叔丁醇的任一种或其组合;
优选地,所述反应在碱的存在下进行;所述的碱选自氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠的任一种或其组合;
L-丙氨酸(Ⅰ)与烷基化试剂的摩尔比为1:(1-3),优选为1:1;
化合物(Ⅱ)中的HX是离去基团所对应的酸,例如氢氯酸、氢溴酸、氢碘酸的任一种或其组合。
4.根据权利要求3所述的合成方法,其中,步骤(2)合成酰卤的步骤中,
所述反应的温度为10℃~100℃,优选为20℃~80℃;
所述反应在溶剂中进行,所述溶剂选自卤代烃类溶剂,例如二氯甲烷、1,2-二氯乙烷的任一种或其组合;
所述反应可以加入催化剂,例如N,N-二甲基甲酰胺;
所述卤化剂选自草酰氯、草酰溴、氯化亚砜、溴化亚砜、双(三氯甲基)碳酸酯的任一种或其组合;
步骤(2)酰卤与苯进行傅克酰基化反应的步骤中,
所述反应的温度为10℃~100℃,优选为20℃~80℃;
所述反应可以加入催化剂,所述催化剂选自三氯化铝、三氯化铁、三氟化硼、三氯化铋、活性三氧化二铁(α-Fe2O3)的任一种或其组合。
6.根据权利要求5所述的合成方法,其中,步骤(3)中,
所述反应的温度为-10℃~100℃,优选为-10℃~60℃,进一步优选为-5℃~10℃;
所述反应可以在溶剂中进行,所述溶剂选自醚类溶剂、醇类溶剂的一种、两种或更多种,例如四氢呋喃、二氧六环、甲醇、乙醇、丙醇、异丙醇、丁醇、叔丁醇的任一种或其组合;
所述还原剂可以是硼氢化锂、硼氢化钠、硼氢化钾、硼氢化锌、四氢铝锂、二氢双(2-甲氧基乙氧基)铝酸钠、二异丁基氢化铝的任一种或其组合,优选为硼氢化钠;
所述反应可以加入还原助剂,所述还原助剂可以是氯化钙、氯化镁、溴化镁、醋酸镁、氯化锌、溴化锌、醋酸锌、硫酸锌、甲磺酸锌、三氟甲磺酸锌的任一种或其组合,优选为氯化锌、溴化锌;
化合物(Ⅲ)与还原剂与还原助剂的摩尔比为1:(1-2):(0-1),优选为1:(1-1.5):(0-0.5);
所述反应的时间为30分钟至20小时,优选为30分钟至8小时。
7.粗盐(V)的合成方法,
其中,所述合成方法包括以下步骤:
(1)烷基化:L-丙氨酸(Ⅰ)与烷基化试剂进行烷基化反应,得到化合物(Ⅱ);
(2)酰基化:化合物(Ⅱ)与卤化剂反应转化为酰卤,随后酰卤与苯进行傅克酰基化反应,得到化合物(Ⅲ);
(3)还原:化合物(Ⅲ)与还原剂进行反应,得到混合物(Ⅳ);
(4)成盐:混合物(Ⅳ)与拆分剂(HY)反应,得到粗盐(Ⅴ);
步骤(4)中,
所述反应的温度为0℃~100℃,优选为0℃~80℃;
所述反应可以在溶剂中进行,所述溶剂可以是醚类溶剂、腈类溶剂、酮类溶剂、醇类溶剂的一种、两种或更多种,例如四氢呋喃、二氧六环、乙腈、丙腈、丙酮、丁酮、甲基异丙基酮、甲醇、乙醇、丙醇、异丙醇、丁醇、叔丁醇的任一种或其组合;
所述拆分剂可以选自D-酒石酸、D-苹果酸、D-乳酸、(S)-扁桃酸、(R)-樟脑磺酸、D-酒石酸二苯甲酸酯、L-酒石酸、L-苹果酸、L-乳酸、(S)-樟脑磺酸、L-酒石酸二苯甲酸酯、盐酸、氢溴酸、氢碘酸、硫酸、甲磺酸、三氟甲磺酸、对甲苯磺酸的任一种或其组合;
所述反应的时间可以为30分钟至两天,优选为30分钟至30小时。
8.光学纯盐(VI)的合成方法,
其中,所述合成方法包括以下步骤:
(1)烷基化:L-丙氨酸(Ⅰ)与烷基化试剂进行烷基化反应,得到化合物(Ⅱ);
(2)酰基化:化合物(Ⅱ)与卤化剂反应转化为酰卤,随后酰卤与苯进行傅克酰基化反应,得到化合物(Ⅲ);
(3)还原:化合物(Ⅲ)与还原剂进行反应,得到混合物(Ⅳ);
(4)成盐:混合物(Ⅳ)与拆分剂(HY)反应,得到粗盐(Ⅴ);
(5)重结晶:将粗盐(Ⅴ)进行重结晶,得到光学纯盐(Ⅵ);
步骤(5)中,
所述重结晶的操作可以为:将粗盐(Ⅴ)与溶剂混合,加热溶解,降温,搅拌,析出晶体,得到光学纯盐(Ⅵ);
重结晶步骤所述加热的温度为0℃~100℃,优选为0℃~80℃;
重结晶步骤所述的溶剂选自醚类溶剂、腈类溶剂、酮类溶剂、醇类溶剂的一种、两种或更多种,例如四氢呋喃、二氧六环、乙腈、丙腈、丙酮、丁酮、甲基异丙基酮、甲醇、乙醇、丙醇、异丙醇、丁醇、叔丁醇的任一种或其组合;
重结晶步骤中加热的时间和降温的时间相同或不同,彼此独立地选自30分钟至两天,优选为30分钟至30小时。
9.化合物(A)的合成方法,
其中,所述合成方法包括以下步骤:
(1)烷基化:L-丙氨酸(Ⅰ)与烷基化试剂进行烷基化反应,得到化合物(Ⅱ);
(2)酰基化:化合物(Ⅱ)与卤化剂反应转化为酰卤,随后酰卤与苯进行傅克酰基化反应,得到化合物(Ⅲ);
(3)还原:化合物(Ⅲ)与还原剂进行反应,得到混合物(Ⅳ);
(4)成盐:混合物(Ⅳ)与拆分剂(HY)反应,得到粗盐(Ⅴ);
(5)重结晶:将粗盐(Ⅴ)进行重结晶,得到光学纯盐(Ⅵ);
(6)脱盐:光学纯盐(Ⅵ)进行脱盐步骤,得到光学纯化合物(A);
步骤(6)中,
所述反应的温度为0℃~100℃,优选为20℃~50℃;
所述反应可以在溶剂中进行,所述溶剂可以为卤代烃类溶剂、芳烃类溶剂、醚类溶剂、酯类溶剂、烷烃类溶剂、水中的一种、两种或更多种,例如二氯甲烷、1,2-二氯乙烷、甲苯、二甲苯、乙醚、异丙醚、甲基叔丁醚、乙二醇二甲醚、乙酸乙酯、乙酸异丙酯、己烷、环己烷、庚烷、水中的任一种或其组合;
所述反应可以加入碱,所述碱可以为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、氨水中的任一种或其组合。
10.化合物(Ⅲ)的合成方法,
其中,所述合成方法包括以下步骤:
1)脱盐:将权利要求7-9任一项中成盐步骤母液、权利要求8或9中重结晶步骤母液合并,减压蒸除挥发物,残留物与碱反应,得到混合物(IV);
2)氧化:混合物(IV)与氧化剂反应,得到化合物(Ⅲ);
步骤1)中,
所述反应的温度为0℃~100℃,优选为20℃~50℃;
所述反应可以在溶剂中进行,所述溶剂可以为卤代烃类溶剂、芳烃类溶剂、醚类溶剂、酯类溶剂、烷烃类溶剂、水的一种、两种或更多种,例如二氯甲烷、1,2-二氯乙烷、甲苯、二甲苯、乙醚、异丙醚、甲基叔丁醚、乙二醇二甲醚、乙酸乙酯、乙酸异丙酯、己烷、环己烷、庚烷、水的任一种或其组合;
所述的碱可以是氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、氨水的任一种或其组合;
步骤2)中,
所述反应的温度为-10℃~100℃,优选为0℃~50℃;
所述反应可以在溶剂中进行,所述溶剂可以是卤代烃类溶剂、芳烃类溶剂、醚类溶剂、酯类溶剂、烷烃类溶剂、水的一种、两种或更多种,例如二氯甲烷、1,2-二氯乙烷、甲苯、二甲苯、乙醚、异丙醚、甲基叔丁醚、乙二醇二甲醚、乙酸乙酯、乙酸异丙酯、己烷、环己烷、庚烷、水的任一种或其组合;
所述氧化剂可以是三氧化铬、重铬酸钠、重铬酸钾、高锰酸钾、高锰酸钠、重铬酸吡啶、Dess-Martin试剂、二氧化锰的任一种或其组合,优选为重铬酸钠;
优选地,所述反应可以先在酸性条件下进行,随后用碱调节溶液的pH;
优选地,可以将溶液的pH调节至8-11,例如10;
所述的酸可以选自硫酸、盐酸、磷酸的任一种或其组合;
所述的碱可以是氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、氨水的任一种或其组合。
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---|---|---|---|---|
CN101239937A (zh) * | 2007-02-07 | 2008-08-13 | 上海雅本化学有限公司 | 一种光学活性r-(-)-1-苄氧羰基-3-氨基吡咯烷及其盐酸盐的制备方法 |
CN101412670A (zh) * | 2007-10-19 | 2009-04-22 | 浙江普洛医药科技有限公司 | 洛索洛芬钠的合成方法 |
CN101759665A (zh) * | 2008-12-23 | 2010-06-30 | 江苏恩华药业股份有限公司 | 取代苯基哌嗪芳烷醇衍生物及其在制备镇痛药物中的应用 |
CN104072381A (zh) * | 2013-03-26 | 2014-10-01 | 安徽贝克联合制药有限公司 | 光学纯氨基醇盐酸盐的制备方法 |
WO2015063795A2 (en) * | 2013-10-31 | 2015-05-07 | Laurus Labs Private Limited | Novel process for preparation of optically pure norephedrine and its derivatives |
-
2018
- 2018-12-18 CN CN201811555598.5A patent/CN110655496A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101239937A (zh) * | 2007-02-07 | 2008-08-13 | 上海雅本化学有限公司 | 一种光学活性r-(-)-1-苄氧羰基-3-氨基吡咯烷及其盐酸盐的制备方法 |
CN101412670A (zh) * | 2007-10-19 | 2009-04-22 | 浙江普洛医药科技有限公司 | 洛索洛芬钠的合成方法 |
CN101759665A (zh) * | 2008-12-23 | 2010-06-30 | 江苏恩华药业股份有限公司 | 取代苯基哌嗪芳烷醇衍生物及其在制备镇痛药物中的应用 |
CN104072381A (zh) * | 2013-03-26 | 2014-10-01 | 安徽贝克联合制药有限公司 | 光学纯氨基醇盐酸盐的制备方法 |
WO2015063795A2 (en) * | 2013-10-31 | 2015-05-07 | Laurus Labs Private Limited | Novel process for preparation of optically pure norephedrine and its derivatives |
Non-Patent Citations (1)
Title |
---|
WINCENTY KWAPISZEWSKI ET AL.: "synthesis of optically active 2-(pyrrolidino-and 4-methylpiperzino) alkanoic acids", 《ACTA POLONIAE PHARMACEUTICA-DRUG RESEARCH》 * |
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