CN103880770B - The preparation method of chiral 3 morpholine methanol classes and 3 morpholine formic acid compounds - Google Patents
The preparation method of chiral 3 morpholine methanol classes and 3 morpholine formic acid compounds Download PDFInfo
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- CN103880770B CN103880770B CN201410101239.8A CN201410101239A CN103880770B CN 103880770 B CN103880770 B CN 103880770B CN 201410101239 A CN201410101239 A CN 201410101239A CN 103880770 B CN103880770 B CN 103880770B
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- sodium
- compound
- alcohol
- reaction
- solvent
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- UCDFBOLUCCNTDQ-UHFFFAOYSA-N morpholin-3-ylmethanol Chemical compound OCC1COCCN1 UCDFBOLUCCNTDQ-UHFFFAOYSA-N 0.000 title abstract description 4
- BDHPJXPOQGPUNI-UHFFFAOYSA-N formic acid;morpholine Chemical class [O-]C=O.C1COCC[NH2+]1 BDHPJXPOQGPUNI-UHFFFAOYSA-N 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- -1 serine ester Chemical class 0.000 claims abstract description 51
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 230000004224 protection Effects 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- 150000001298 alcohols Chemical class 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 35
- 239000012074 organic phase Substances 0.000 claims description 35
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000000758 substrate Substances 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 25
- 235000019441 ethanol Nutrition 0.000 claims description 25
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 13
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 12
- 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 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- 239000008346 aqueous phase Substances 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 8
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- 238000000638 solvent extraction Methods 0.000 claims description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical group ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- NBVHDOZEOGAKLK-UHFFFAOYSA-N [N]=O.CC1C(N(CCC1)C)(C)C Chemical group [N]=O.CC1C(N(CCC1)C)(C)C NBVHDOZEOGAKLK-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 3
- 229960002218 sodium chlorite Drugs 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 2
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 2
- 229960004217 benzyl alcohol Drugs 0.000 claims description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 2
- 229940073608 benzyl chloride Drugs 0.000 claims description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Chemical group 0.000 claims description 2
- QXIKMJLSPJFYOI-UHFFFAOYSA-L calcium;dichlorite Chemical compound [Ca+2].[O-]Cl=O.[O-]Cl=O QXIKMJLSPJFYOI-UHFFFAOYSA-L 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229940061627 chloromethyl methyl ether Drugs 0.000 claims description 2
- 125000004989 dicarbonyl group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- VISKNDGJUCDNMS-UHFFFAOYSA-M potassium;chlorite Chemical compound [K+].[O-]Cl=O VISKNDGJUCDNMS-UHFFFAOYSA-M 0.000 claims description 2
- 150000003217 pyrazoles Chemical class 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 2
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 claims description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 2
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 claims 3
- 238000005984 hydrogenation reaction Methods 0.000 claims 2
- 125000001340 2-chloroethyl group Chemical class [H]C([H])(Cl)C([H])([H])* 0.000 claims 1
- SHLDRGRIHSAHQU-UHFFFAOYSA-N C(O)(O)=O.C(OC(C)(C)C)(OC(C)(C)C)=O Chemical compound C(O)(O)=O.C(OC(C)(C)C)(OC(C)(C)C)=O SHLDRGRIHSAHQU-UHFFFAOYSA-N 0.000 claims 1
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- YKSNHLNTLVRITE-UHFFFAOYSA-N [Br].CC(Br)=O Chemical compound [Br].CC(Br)=O YKSNHLNTLVRITE-UHFFFAOYSA-N 0.000 claims 1
- ISZHMRSRZLYGBY-UHFFFAOYSA-N [Si].C(C)(C)(C)Cl(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound [Si].C(C)(C)(C)Cl(C1=CC=CC=C1)C1=CC=CC=C1 ISZHMRSRZLYGBY-UHFFFAOYSA-N 0.000 claims 1
- 150000002220 fluorenes Chemical group 0.000 claims 1
- 238000003682 fluorination reaction Methods 0.000 claims 1
- 150000002240 furans Chemical class 0.000 claims 1
- 238000006197 hydroboration reaction Methods 0.000 claims 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims 1
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims 1
- IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical compound [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 claims 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 claims 1
- 229910001950 potassium oxide Inorganic materials 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 4
- 230000000977 initiatory effect Effects 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- 150000001408 amides Chemical class 0.000 abstract description 2
- 230000032050 esterification Effects 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 18
- 150000002118 epoxides Chemical class 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 235000011152 sodium sulphate Nutrition 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 10
- 235000004400 serine Nutrition 0.000 description 8
- 235000011167 hydrochloric acid Nutrition 0.000 description 7
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 7
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- SGCJRDDJGFXEAB-GSVOUGTGSA-N (2R)-2-[(2-chloroacetyl)amino]-3-hydroxypropanoic acid Chemical class OC[C@H](C(O)=O)NC(=O)CCl SGCJRDDJGFXEAB-GSVOUGTGSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 description 3
- 125000005909 ethyl alcohol group Chemical group 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical class CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
- SGCJRDDJGFXEAB-VKHMYHEASA-N (2s)-2-[(2-chloroacetyl)amino]-3-hydroxypropanoic acid Chemical class OC[C@@H](C(O)=O)NC(=O)CCl SGCJRDDJGFXEAB-VKHMYHEASA-N 0.000 description 2
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 2
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 150000003355 serines Chemical class 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- JUNOWSHJELIDQP-BYPYZUCNSA-N (3s)-morpholin-4-ium-3-carboxylate Chemical compound OC(=O)[C@@H]1COCCN1 JUNOWSHJELIDQP-BYPYZUCNSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- DZAHXNNEQCZPGJ-UHFFFAOYSA-N CCCCOC(OC)=O.COC(O)=O Chemical compound CCCCOC(OC)=O.COC(O)=O DZAHXNNEQCZPGJ-UHFFFAOYSA-N 0.000 description 1
- 239000005046 Chlorosilane Substances 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical class [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical class ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- ANBBXQWFNXMHLD-UHFFFAOYSA-N aluminum;sodium;oxygen(2-) Chemical compound [O-2].[O-2].[Na+].[Al+3] ANBBXQWFNXMHLD-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- YALMXYPQBUJUME-UHFFFAOYSA-L calcium chlorate Chemical compound [Ca+2].[O-]Cl(=O)=O.[O-]Cl(=O)=O YALMXYPQBUJUME-UHFFFAOYSA-L 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- GKCXXDSWWDWUHS-BYPYZUCNSA-N ethyl (2s)-2-amino-3-hydroxypropanoate Chemical compound CCOC(=O)[C@@H](N)CO GKCXXDSWWDWUHS-BYPYZUCNSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 229910001388 sodium aluminate Inorganic materials 0.000 description 1
- PANBYUAFMMOFOV-UHFFFAOYSA-N sodium;sulfuric acid Chemical compound [Na].OS(O)(=O)=O PANBYUAFMMOFOV-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses the new preparation process of a kind of chiral 3 morpholine methanol class and 3 morpholine formic acid compounds; using chiral serine as initiation material; serine ester (III) is obtained by catalyst esterification; reacted in the basic conditions with halogen acetyl halide and obtain compound (IV); compound (V) is obtained by hydroxyl protection; add reducing agent and ester is reduced to alcohol (VI); ring closure reaction obtains compound (VII) in the basic conditions, and the chiral 3 morpholine first alcohol compounds (I) of target product are obtained by reduction of amide, hydroxyl deprotection, N protections；Again chiral 3 morpholine formic acid compound (II) is obtained through peroxidating.This method has the advantages that with low cost, environment-friendly, simple to operate, high income, product purity are high, agents useful for same is simple and safe, often walks the intermediate of reaction without further purifying, enormously simplify experimental implementation, production cost is reduced, is adapted to industrialized production.
Description
Technical field
The present invention relates to technical field of fine, and in particular to a kind of chiral 3- morpholines methanol class and 3- morpholine formic acid classes
The new preparation process of compound.
Background technology
Chiral 3- morpholine methanol class (I) compounds and 3- morpholine formic acid class (II) compound is widely used key
Medicine intermediate, many pharmaceutical factories are all using this series compound in new drug development.Existing synthetic technology is generally present
Expensive starting materials are not easy to obtain, technical sophistication, condition are harsh, yield is extremely low, chiral purity is not high, the shortcomings of be not suitable for industrial production.
Therefore the synthesis of chirality 3- morpholine methanol class (I) compounds and 3- morpholine formic acid class (II) compound increasingly by
The attention of chemists.
Shanghai Chang Feng biological medicines Science and Technology Ltd. discloses one for 2012 on the new side of (S) -3 morpholine carboxylic acid synthesis
The patent of method, its synthetic route is as described in following formula：
The synthetic route is initiation material using serine, and route looks that comparison is short, but the route is needed to use by force
Oxidant perchloric acid, the compound is abnormally dangerous, in addition, that step of cyclization is due to the influence of ester group, amplification yield is very low, no
It is adapted to industrialization.
John D.DiMarco, which are equal to, discloses a patent for being related to (R)-N-Boc-3- morpholine methanol for 2006, and it is closed
Into route as described in following formula：
The synthetic route is also to use serine to be initiation material, and synthetic route is very short, but above yield is extremely low, and uses
The borane dimethylsulf iotade of severe toxicity and expensive palladium carbon catalyst, on the whole the route be not suitable for industrialized production.
The content of the invention
In view of this, present invention aims at provide a kind of with low cost, environment-friendly, simple to operate, high income, product
Purity is high and is adapted to the new preparation process of the chiral 3- morpholines first alcohol compound of industrialized production.
To achieve these goals, the present invention provides following technical scheme：
The preparation method of the chiral 3- morpholines first alcohol compound of the present invention, can be represented with following reaction equation：
R is fluorenylmethyloxycarbonyl, p-toluenesulfonyl, trifluoroacetyl group, trityl, tertbutyloxycarbonyl, benzyloxy carbonyl in formula
Base, benzyl, acetyl group；R1For methyl, ethyl, n-propyl, normal-butyl, benzyl, the tert-butyl group or tertiary pentyl；R2For methoxyl methyl, three
Methylsilyl, t-Butyldimethylsilyl or tert-butyl diphenyl silicon substrate；X is chlorine or bromine.
The present invention obtains serine ester (III), the silk of gained using chiral serine as initiation material by catalyst esterification
Propylhomoserin ester (III) reacts in the basic conditions with halogen acetyl halide obtains compound (IV), and compound (IV) is obtained by hydroxyl protection
To compound (V), compound (V) adds reducing agent and ester is reduced into alcohol (VI), and ring closure reaction is obtained alcohol (VI) in the basic conditions
To compound (VII), compound (VII) obtains target product (I) by reduction of amide, hydroxyl deprotection, N protections.
Specifically, the preparation method of described chiral 3- morpholines first alcohol compound comprises the steps：
(1) chiral serine, alcohol and the first catalyst are added into reaction unit, 0~150 DEG C of reaction 1 after being well mixed
~24 hours, reaction solution was adjusted to alkalescent, after concentration saliferous compound (III), described chiral serine and alcohol rub
You are than being (30: 1)~(1: 30), and the first described catalyst is any one in sulfuric acid, thionyl chloride, hydrochloric acid, phosphoric acid；
It is preferred that, described alcohol is any one in methanol, ethanol, propyl alcohol, butanol, benzylalcohol.
(2) compound (III), alkali (A) and solvent (a) are added into reaction unit, cooling is lower to add halogen acetyl halide, -78
Reacted 1~24 hour at~50 DEG C, after reaction terminates, wash organic phase with saturated nacl aqueous solution, organic phase through drying, be concentrated to give
Compound (IV), described compound (III) and the mol ratio of halogen acetyl halide are (5: 1)~(1: 6)；
It is preferred that, described halogen acetyl halide is chloracetyl chloride or bromoacetyl bromide,
It is preferred that, described alkali (A) is triethylamine, pyridine, DMAP, morpholine, sodium carbonate, potassium carbonate, carbon
At least one of sour hydrogen sodium, sodium hydride, sodium hydroxide, hydrofining, potassium hydroxide.
It is preferred that, described solvent (a) is toluene, tetrahydrofuran, dichloroethanes, chloroform, dichloromethane, acetonitrile,
At least one of ether, methyl tertiary butyl ether(MTBE).
(3) compound (IV), alkali (B) and solvent (b) are added into reaction unit, protection group reagent, -20~60 DEG C is added
Lower reaction 1~24 hour, after reaction terminates, adds saturated sodium-chloride water solution, organic solvent extraction, and organic phase is through drying, dense
Contract to obtain compound (V), and described protection group reagent is trim,ethylchlorosilane, tert-butyl chloro-silicane, tert-butyl diphenyl
Any one in chlorosilane, chloromethyl methyl ether；
It is preferred that, described alkali (B) is triethylamine, pyridine, pyrazoles, DMAP, morpholine, sodium carbonate, carbonic acid
At least one of potassium, sodium acid carbonate, sodium hydride, sodium hydroxide, hydrofining, potassium hydroxide.
It is preferred that, described solvent (b) is dimethyl sulfoxide (DMSO), N, N- dimethylformamides, toluene, tetrahydrofuran, two chloroethenes
At least one of alkane, chloroform, dichloromethane, acetonitrile, ether, methyl tertiary butyl ether(MTBE).
(4) added into reaction unit at compound (V) and solvent (c), -50~100 DEG C and add the first reducing agent, reacted
After end, add water and be quenched, organic extractant phase, organic phase through drying, be concentrated to give compound (VI), the first described reducing agent is boron
At least one of hydrofining, lithium borohydride, sodium borohydride；
It is preferred that, described solvent (c) is methanol, ethanol, isopropanol, propyl alcohol, the tert-butyl alcohol, butanol, toluene, ether, first
At least one of base tertbutyl ether, isopropyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, diethylene glycol dimethyl ether.
At (5) -50~100 DEG C, addition solvent (d), alkali (C) and compound (VI) into reaction unit, stirring reaction 1~
24 hours, reaction terminate after, add water and be quenched, added with machine solvent extraction, organic phase through drying, be concentrated to give compound (VII)；
It is preferred that, described alkali (C) is triethylamine, pyridine, DMAP, morpholine, caustic alcohol, sodium tert-butoxide,
In sodium tert-amyl alcohol, sodium carbonate, potassium carbonate, sodium acid carbonate, sodium hydride, sodium hydroxide, hydrofining, potassium hydroxide, lithium hydroxide
It is at least one.
It is preferred that, described solvent (d) is methanol, ethanol, isopropanol, propyl alcohol, the tert-butyl alcohol, butanol, toluene, ether, first
At least one of base tertbutyl ether, isopropyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, diethylene glycol dimethyl ether.
(6) compound (VII) and solvent (e) are added into reaction unit, cooling is lower to add the second reducing agent, -20~150
Reacted 1~24 hour at DEG C, add water and be quenched, point liquid, gained organic phase through drying, be concentrated to give intermediate, the intermediate is added
Into solvent (f), add at deprotection reagent, -20~150 DEG C and react 1~24 hour, reaction solution adjusts pH value to alkalescence, plus
Enter alkali (d) and N protection group reagents, react 1~24 hour, reaction adds organic solvent after terminating, wash, organic phase through drying,
Be concentrated to give chiral 3- morpholines first alcohol compound (I) crude product, crude product it is purified target chiral product (I), described second also
Former agent is lithium aluminium hydride, sodium borohydride, described deprotection reagent is tetrabutyl ammonium fluoride, boron trifluoride, hydrochloric acid, sulfuric acid or
Potassium fluoride, described N protection groups reagent is fluorenes methoxy dicarbonyl chloride, paratoluensulfonyl chloride, TFAA, trityl chloride, two
Dimethyl dicarbonate butyl ester, benzyl chloroformate, benzyl chloride, cylite or acetic anhydride.
It is preferred that, described alkali (d) is triethylamine, pyridine, DMAP, morpholine, caustic alcohol, sodium tert-butoxide,
In sodium tert-amyl alcohol, sodium carbonate, potassium carbonate, sodium acid carbonate, sodium hydride, sodium hydroxide, hydrofining, potassium hydroxide, lithium hydroxide
It is at least one.
It is preferred that, described solvent (e) and solvent (f) they are tetrahydrofuran.
Based on above-mentioned technical scheme, invention further provides a kind of brand-new of chiral 3- morpholines formic acid compound
Preparation Method, compound (I) obtains compound (II) through peroxidating, is specially：Compound (I) is prepared first, is filled to reaction
Middle addition compound (I), alkali (e), the second catalyst, solvent (g) are put, lower add at oxidant, -20~80 DEG C of cooling reacts 1
~24 hours, reaction was filtered after terminating, and solid washing, liquid phase solvent extraction, aqueous phase is adjusted to acidity, solvent extraction, organic phase
Through drying, it is concentrated to give target chiral product (II).
It is preferred that, described oxidant is sodium chlorite, calcium chlorite, potassium chlorite, postassium hypochlorite, sodium hypochlorite, secondary
At least one of calcium chlorate.
It is preferred that, described alkali (e) is at least one of sodium carbonate, potassium carbonate, saleratus, sodium acid carbonate.
It is preferred that, the second described catalyst is at least one in tetramethyl piperidine nitrogen oxides, KBr, KI
Kind.
It is preferred that, described solvent (g) is at least one in water, acetone, acetonitrile, tetrahydrofuran, N, N- dimethylformamides
Kind.
Compared with prior art, the method that provides of the present invention have with low cost, environment-friendly, simple to operate, high income,
The advantages of product purity is high, agents useful for same is simple and safe, often walks the intermediate of reaction without further purifying, enormously simplify reality
Operation is tested, production cost is reduced, is adapted to industrialized production.
Embodiment
Below in conjunction with the embodiment of the present invention, technical scheme is described in detail, it is clear that described
Embodiment is only a part of embodiment of the invention, rather than whole embodiments.Based on the embodiment in the present invention, this area
The every other embodiment that those of ordinary skill is obtained on the premise of creative work is not made, belongs to guarantor of the present invention
The scope of shield.
Testing raw materials used reagent can be bought by free market, and its purity is pure for chemistry.
Embodiment 1
(1) synthesis of Serine ethyl ester (S- (III))
5kg Serines are added in 50L absolute ethyl alcohols, 0 DEG C of instillation 4.6kg concentrated sulfuric acid, add 78 DEG C of reactions 12 small
When.Reaction solution is added dropwise in the saturated solution that 5kg sodium carbonate is made at 0 DEG C, the mixture of solvent is evaporated off, one is directly cast
Step.
(2) synthesis of (S) -2- chloroacetylamino -3- hydroxypropionates (S- (IV))
Added in above-mentioned product and 5.4kg chloracetyl chlorides are added under 50L dichloromethane, 5.8kg triethylamines, ice bath, add room
Temperature reaction 12 hours, reaction solution 20L washings, after organic phase is dried over sodium sulfate, is concentrated to give 9kg (yield 90.2%) (S) -2- chlorine
Acetyl-amino -3- hydroxypropionates.
(3) synthesis of (S) -2- chloroacetylaminos -3- (trimethyl silicon substrate) epoxide ethyl propionate (S- (V))
9kg (S) -2- chloroacetylamino -3- hydroxypropionates, 4kg pyridines are added in 90L tetrahydrofurans, ice bath
Lower instillation 5kg trim,ethylchlorosilanes, add room temperature reaction 6 hours, and tetrahydrofuran is evaporated off, and add 15L water, 15L dichloromethane extraction
Take, organic phase is dried over sodium sulfate, be concentrated to give 12.1kg (yield 100%) (S) -2- chloroacetylamino -3- (trimethyl silicanes
Base) epoxide ethyl propionate.
(4) synthesis of (R) -2- chloroacetylaminos -3- (trimethyl silicon substrate) epoxide propyl alcohol (R- (VI))
10kg (S) -2- chloroacetylaminos -3- (trimethyl silicon substrate) epoxide ethyl propionate is added in 80L tetrahydrofurans,
4kg potassium borohydrides are added portionwise at room temperature, reacts 24 hours, adds water and reaction is quenched, tetrahydrofuran is evaporated off, 10L water, 15L is added
Dichloromethane is extracted, and organic phase is dried over sodium sulfate, be concentrated to give 7.6kg (yield 89.3%) (R) -2- chloroacetylaminos -3-
(trimethyl silicon substrate) epoxide propyl alcohol.
(5) synthesis of (R) -5- (((trimethyl silicon substrate) epoxide) methyl) morpholine -3- ketone (R- (VII))
7kg (R) -2- chloroacetylaminos -3- (trimethyl silicon substrate) epoxide propyl alcohol is added in 50L tetrahydrofurans, ice bath
Under be added portionwise the sodium hydrides of 1.5kg 50%, react 5 hours, after reaction terminates plus 20L water quenchings are gone out, tetrahydrofuran, aqueous phase be evaporated off
Extracted with 15L dichloromethane, organic phase is dried over sodium sulfate, be concentrated to give 5.3kg (yield 89.3%) (R) -5- (((trimethyl silicanes
Base) epoxide) methyl) morpholine -3- ketone.
(6) synthesis of (S)-N- tertbutyloxycarbonyl -3- morpholines methanol (S- (I))
5kg (R) -5- (((trimethyl silicon substrate) epoxide) methyl) morpholine -3- ketone is added in 30L tetrahydrofurans, at room temperature
Add double (dimethoxy ethyoxyl) the sodium aluminate toluene solutions of 8.5kg 70%2- hydrogen, back flow reaction 12 hours, the lower instillation of cooling
6.5kg concentrated hydrochloric acids, are heated to reflux 5 hours.Room temperature is cooled to, point liquid, aqueous phase is extracted with 20L dichloromethane, and organic phase is through sulfuric acid
Sodium dry after be evaporated intermediate intermediates are added in 30L tetrahydrofurans, add 7.5kg tetrabutyl ammonium fluorides, room temperature reaction
5 hours, cool down, 6.2kg triethylamines and 5.4kg di-tert-butyl dicarbonates are added under ice bath, react at room temperature 24 hours.Organic phase is used
10L is washed, and aqueous phase is extracted with 10L dichloromethane, merges organic phase, dried over sodium sulfate, be concentrated to give 4kg (yield 74.9%)
(S)-N-Boc-3- morpholines methanol.
Characterization of The Products data are as follows：Mp 80℃；(the c 1.1, CHCl of optically-active+60.43)；1H NMR (300MHz, CDCl3)δ
1.47 (9H, s, OC (CH3)3), 2.22 (1H, br s, OH), 3.17 (Ha, td, J=12.7,3.2Hz, NCHaHb), 3.46 (Ha,
Td, J=11.8,3Hz, COCHaHb), 3.57 (Hb, dd, J=11.9,3.6Hz, COCHaHb), 3.87 (5H+Hb, m, COCH2,
NCH, CH2- hydroxyl, NCHaHb).
Embodiment 2
(1) synthesis of D-Ser ethyl ester (R- (III))
5kg Serines are added in 50L absolute ethyl alcohols, 0 DEG C of instillation 4.5kg phosphoric acid, are added 78 DEG C and are reacted 12 hours.0
Reaction solution is added dropwise in the saturated solution that 5kg sodium carbonate is made at DEG C, the mixture of solvent is evaporated off, next step is directly thrown.
(2) synthesis of (R) -2- chloroacetylamino -3- hydroxypropionates (R- (IV))
Added in above-mentioned product and 9.6kg bromoacetyl bromides are added under 50L dichloromethane, 5.8kg triethylamines, ice bath, add room
Temperature reaction 12 hours, reaction solution 20L washings, after organic phase is dried over sodium sulfate, is concentrated to give 9.2kg (yield 92.2%) (R) -2-
Chloroacetylamino -3- hydroxypropionates.
(3) synthesis of (R) -2- chloroacetylaminos -3- (trimethyl silicon substrate) epoxide ethyl propionate (R- (V))
9.2kg (R) -2- chloroacetylamino -3- hydroxypropionates, 5.2kg triethylamines are added to 92L tetrahydrofurans
In, 5kg trim,ethylchlorosilanes are instilled under ice bath, room temperature reaction 6 hours is added, tetrahydrofuran is evaporated off, 15L water, 15L dichloros is added
Methane is extracted, and organic phase is dried over sodium sulfate, be concentrated to give 12kg (yield 97%) (R) -2- chloroacetylamino -3- (trimethyls
Silicon substrate) epoxide ethyl propionate.
(4) synthesis of (S) -2- chloroacetylaminos -3- (trimethyl silicon substrate) epoxide propyl alcohol (S- (VI))
10kg (R) -2- chloroacetylaminos -3- (trimethyl silicon substrate) epoxide ethyl propionate is added in 80L tetrahydrofurans,
3.8kg sodium borohydrides are added portionwise at room temperature, reacts 24 hours, adds water and reaction is quenched, tetrahydrofuran is evaporated off, 10L water is added,
15L dichloromethane is extracted, and organic phase is dried over sodium sulfate, be concentrated to give 8kg (yield 94%) (S) -2- chloroacetylaminos -3-
(trimethyl silicon substrate) epoxide propyl alcohol.
(5) synthesis of (S) -5- (((trimethyl silicon substrate) epoxide) methyl) morpholine -3- ketone (S- (VII))
7kg (S) -2- chloroacetylaminos -3- (trimethyl silicon substrate) epoxide propyl alcohol is added in 50L absolute methanols, ice bath
Under be added portionwise 1.7kg sodium methoxides, react 5 hours, after reaction terminates plus 20L water quenchings are gone out, methanol, aqueous phase 15L dichloros be evaporated off
Methane is extracted, and organic phase is dried over sodium sulfate, be concentrated to give 5.5kg (yield 92.6%) (S) -5- (((trimethyl silicon substrate) epoxide)
Methyl) morpholine -3- ketone.
(6) synthesis of (R)-N- tertbutyloxycarbonyl -3- morpholines methanol (R- (I))
5kg (S) -5- (((trimethyl silicon substrate) epoxide) methyl) morpholine -3- ketone is added in 30L diethylene glycol dimethyl ethers,
1.5kg lithium aluminium hydrides are added at room temperature, and back flow reaction 12 hours, the lower instillation 6.5kg concentrated hydrochloric acids of cooling are heated to reflux 5 hours.It is cold
But to room temperature, point liquid, aqueous phase is extracted with 20L dichloromethane, be evaporated after organic phase is dried over sodium sulfate intermediate intermediates add
Enter into 30L tetrahydrofurans, add 7.5kg tetrabutyl ammonium fluorides, react at room temperature 5 hours, cool down, the second of 3kg tri- is added under ice bath
Amine and 5.4kg di-tert-butyl dicarbonates, are reacted at room temperature 24 hours.Organic phase is washed with 10L, and aqueous phase is extracted with 10L dichloromethane,
Merge organic phase, it is dried over sodium sulfate, be concentrated to give 4kg (yield 74.9%) (R)-N-Boc-3- morpholine methanol.
Characterization of The Products data are as follows：Mp 80℃；Optically-active -60.4 (c1.1, CHCl3)；1H NMR (300MHz, CDCl3)δ
1.47 (9H, s, OC (CH3)3), 2.22 (1H, br s, OH), 3.17 (Ha, td, J=12.7,3.2Hz, NCHaHb), 3.46 (Ha,
Td, J=11.8,3Hz, COCHaHb), 3.57 (Hb, dd, J=11.9,3.6Hz, COCHaHb), 3.87 (5H+Hb, m, COCH2,
NCH, CH2- hydroxyl, NCHaHb).
Embodiment 3
(1) synthesis of (R) -2- chloroacetylaminos -3- (trimethyl silicon substrate) epoxide propyl alcohol (R- (VI))
10kg (S) -2- chloroacetylaminos -3- (trimethyl silicon substrate) epoxide ethyl propionate is added to 80L absolute methanols, room
3.8kg sodium borohydrides are added portionwise under temperature, reacts 24 hours, adds water and reaction is quenched, methanol is evaporated off, 10L water, 15L dichloros is added
Methane is extracted, and organic phase is dried over sodium sulfate, be concentrated to give 7.8kg (yield 91.7%) (R) -2- chloroacetylamino -3- (front threes
Base silicon substrate) epoxide propyl alcohol.
(2) synthesis of (R) -5- (((trimethyl silicon substrate) epoxide) methyl) morpholine -3- ketone (R- (VII))
7kg (R) -2- chloroacetylaminos -3- (trimethyl silicon substrate) epoxide propyl alcohol is added in 50L absolute ethyl alcohols, ice bath
Under be added portionwise 2kg caustic alcohols, react 5 hours, after reaction terminates plus 20L water quenchings are gone out, solvent, aqueous phase 15L dichloromethanes be evaporated off
Alkane is extracted, and organic phase is dried over sodium sulfate, be concentrated to give 5.4kg (yield 91%) (R) -5- (((trimethyl silicon substrate) epoxide) methyl)
Morpholine -3- ketone.
(3) synthesis of (S)-N- tertbutyloxycarbonyl -3- morpholines methanol (S- (I))
5kg (R) -5- (((trimethyl silicon substrate) epoxide) methyl) morpholine -3- ketone is added in 30L glycol dimethyl ethers, room
Lower add under 2kg sodium borohydrides, back flow reaction 24 hours, cooling of temperature instills 6.5kg concentrated hydrochloric acids, is heated to reflux 5 hours.It is cooled to
Room temperature, filtering, solid is washed with 10L dichloromethane, and filtrate point liquid, aqueous phase is extracted with 20L dichloromethane, and organic phase is dry through sodium sulphate
Be evaporated after dry intermediate intermediates are added in 10L tetrahydrofurans and 5L concentrated hydrochloric acids at room temperature, react at room temperature 5 hours, it is cold
But, 6kg sodium hydroxides and 5.4kg di-tert-butyl dicarbonates are added under ice bath, is reacted at room temperature 24 hours.Dichloromethane extracts 20L,
Organic phase is dried over sodium sulfate, be concentrated to give 4kg (yield 74.9%) (S)-N-Boc-3- morpholine methanol.
(4) synthesis of (R)-N-Boc-3- morpholines formic acid (R- (II))
2kg (S)-N-Boc-3- morpholines methanol, 1.5kg sodium acid carbonates, 143g tetramethyl piperidine nitrogen oxides are added to 5L
In tetrahydrofuran, the sodium chlorite aqueous solutions of 13kg 10% are instilled at room temperature, add room temperature reaction 12 hours, reaction solution 2L stones
Oily ether extraction, aqueous phase hydrochloric acid adjusts pH value to 5,10L dichloromethane to extract, and organic phase is dried over sodium sulfate, be concentrated to give 2kg (yields
93.9%) (R)-N-Boc-3- morpholine formic acid.
Characterization of The Products data are as follows：mp 181℃；Optically-active+73 (c 1.1, MeOH)；1H NMR (300MHz, DMSO-d6) d
1.37,1.47 (9H, two s, OC (CH3)3), 2.99 (Ha, td, J=12.7,3.7Hz, NCHaHb), 3.17 (0.5Ha, td, J
=12.4,3.3Hz, NCHaHb), 3.37 (Ha, m, COCHaHb), 3.55 (2Hb, m, COCHaHb, NCHaHb), 3.78 (Hc,
Td, J=14.7,3.3Hz, COCHcHd), 4.15 (Hd, t, J=11.6Hz, COCHcHd), 4.31 (1H, dd, J=15.2,
2.7Hz, NCH).
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit is required rather than described above is limited, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each embodiment is only wrapped
Containing an independent technical scheme, this narrating mode of specification is only that for clarity, those skilled in the art should
Using specification as an entirety, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
It may be appreciated other embodiment.
Claims (9)
1. a kind of preparation method of chiral 3- morpholines first alcohol compound, it is characterised in that comprise the steps：
(1) chiral serine, alcohol and the first catalyst are added into reaction unit, 0~150 DEG C of reaction 1~24 after being well mixed
Hour, reaction solution is adjusted to alkalescent, and the compound (III) of saliferous, described chiral serine and the mol ratio of alcohol are obtained after concentration
For (30: 1)~(1: 30), the first described catalyst is any one in sulfuric acid, thionyl chloride, hydrochloric acid, phosphoric acid；
(2) compound (III), alkali (A) and solvent (a) are added into reaction unit, cooling is lower to add halogen acetyl halide, -78~50
Reacted 1~24 hour at DEG C, after reaction terminates, wash organic phase with saturated nacl aqueous solution, organic phase through drying, be concentrated to give chemical combination
Thing (IV), described compound (III) and the mol ratio of halogen acetyl halide are (5: 1)~(1: 6)；
(3) compound (IV), alkali (B) and solvent (b) are added into reaction unit, is added anti-at protection group reagent, -20~60 DEG C
Answer 1~24 hour, reaction terminate after, add saturated sodium-chloride water solution, organic solvent extraction, organic phase through drying, be concentrated to give
Compound (V), described protection group reagent is trim,ethylchlorosilane, tert-butyl chloro-silicane, tert-butyl diphenyl chlorine silicon
Any one in alkane, chloromethyl methyl ether；
(4) added into reaction unit at compound (V) and solvent (c), -50~100 DEG C and add the first reducing agent, reaction terminates
Afterwards, add water and be quenched, organic extractant phase, organic phase through drying, be concentrated to give compound (VI), the first described reducing agent is hydroboration
At least one of potassium, lithium borohydride, sodium borohydride；
At (5) -50~100 DEG C, solvent (d), alkali (C) and compound (VI) are added into reaction unit, stirring reaction 1~24 is small
When, reaction terminate after, add water and be quenched, added with machine solvent extraction, organic phase through drying, be concentrated to give compound (VII)；
(6) compound (VII) and solvent (e) are added into reaction unit, cooling is lower to be added at the second reducing agent, -20~150 DEG C
Reaction 1~24 hour, adds water and is quenched, point liquid, gained organic phase through drying, be concentrated to give intermediate, the intermediate is added to molten
In agent (f), add at deprotection reagent, -20~150 DEG C and react 1~24 hour, reaction solution adjusts pH value to alkalescence, adds alkali
(d) with N protection group reagents, react 1~24 hour, reaction adds organic solvent after terminating, wash, organic phase is through drying, concentration
Chiral 3- morpholines first alcohol compound (I) crude product is obtained, crude product is purified to obtain target chiral product (I), the second described reducing agent
For lithium aluminium hydride, sodium borohydride, described deprotection reagent is tetrabutyl ammonium fluoride, boron trifluoride, hydrochloric acid, sulfuric acid or fluorination
Potassium, described N protection groups reagent is fluorenes methoxy dicarbonyl chloride, paratoluensulfonyl chloride, TFAA, trityl chloride, two carbonic acid
Di tert butyl carbonate, benzyl chloroformate, benzyl chloride, cylite or acetic anhydride；
R is fluorenylmethyloxycarbonyl, p-toluenesulfonyl, trifluoroacetyl group, trityl, tertbutyloxycarbonyl, benzyloxycarbonyl group, benzyl in formula
Base, acetyl group；R1For methyl, ethyl, n-propyl, normal-butyl, benzyl, the tert-butyl group or tertiary pentyl；R2For methoxyl methyl, trimethyl
Silicon substrate, t-Butyldimethylsilyl or tert-butyl diphenyl silicon substrate；X is chlorine or bromine.
2. preparation method according to claim 1, it is characterised in that：In step (1), described alcohol is methanol, ethanol, third
Any one in alcohol, butanol, benzylalcohol.
3. preparation method according to claim 1, it is characterised in that：In step (2), described halogen acetyl halide is chloracetyl
Chlorine or bromine acetyl bromide；Described alkali (A) is triethylamine, pyridine, DMAP, morpholine, sodium carbonate, potassium carbonate, carbonic acid
At least one of hydrogen sodium, sodium hydride, sodium hydroxide, hydrofining, potassium hydroxide；Described solvent (a) is toluene, tetrahydrochysene furan
Mutter, at least one of dichloroethanes, chloroform, dichloromethane, acetonitrile, ether, methyl tertiary butyl ether(MTBE).
4. preparation method according to claim 1, it is characterised in that：In step (3), described alkali (B) is triethylamine, pyrrole
Pyridine, pyrazoles, DMAP, morpholine, sodium carbonate, potassium carbonate, sodium acid carbonate, sodium hydride, sodium hydroxide, hydrofining, hydrogen
At least one of potassium oxide；Described solvent (b) is dimethyl sulfoxide (DMSO), N, N- dimethylformamides, toluene, tetrahydrofuran, two
At least one of chloroethanes, chloroform, dichloromethane, acetonitrile, ether, methyl tertiary butyl ether(MTBE).
5. preparation method according to claim 1, it is characterised in that：In step (4), described solvent (c) is methanol, second
Alcohol, isopropanol, propyl alcohol, the tert-butyl alcohol, butanol, toluene, ether, methyl tertiary butyl ether(MTBE), isopropyl ether, dioxane, tetrahydrofuran, second
At least one of glycol dimethyl ether, diethylene glycol dimethyl ether.
6. preparation method according to claim 1, it is characterised in that：In step (5), described alkali (C) is triethylamine, pyrrole
Pyridine, DMAP, morpholine, caustic alcohol, sodium tert-butoxide, sodium tert-amyl alcohol, sodium carbonate, potassium carbonate, sodium acid carbonate, hydrogenation
At least one of sodium, sodium hydroxide, hydrofining, potassium hydroxide, lithium hydroxide；Described solvent (d) is methanol, ethanol, different
Propyl alcohol, propyl alcohol, the tert-butyl alcohol, butanol, toluene, ether, methyl tertiary butyl ether(MTBE), isopropyl ether, dioxane, tetrahydrofuran, ethylene glycol
At least one of dimethyl ether, diethylene glycol dimethyl ether.
7. preparation method according to claim 1, it is characterised in that：In step (6), described alkali (d) is triethylamine, pyrrole
Pyridine, DMAP, morpholine, caustic alcohol, sodium tert-butoxide, sodium tert-amyl alcohol, sodium carbonate, potassium carbonate, sodium acid carbonate, hydrogenation
At least one of sodium, sodium hydroxide, hydrofining, potassium hydroxide, lithium hydroxide；Described solvent (e) and solvent (f) are tetrahydrochysene
Furans.
8. a kind of preparation method of chiral 3- morpholines formic acid compound, it is characterised in that comprise the steps：
Chirality 3- morpholine first alcohol compounds (I) are made in preparation method first according to any one of claim 1~7, to
Compound (I), alkali (e), the second catalyst, solvent (g) are added in reaction unit, cooling is lower to be added at oxidant, -20~80 DEG C
Reaction 1~24 hour, reaction is filtered after terminating, and solid washing, liquid phase solvent extraction, aqueous phase is adjusted to acidity, solvent extraction,
Organic phase through drying, be concentrated to give target chiral product (II)
R is fluorenylmethyloxycarbonyl, p-toluenesulfonyl, trifluoroacetyl group, trityl, tertbutyloxycarbonyl, benzyloxycarbonyl group, benzyl in formula
Base, acetyl group.
9. preparation method according to claim 8, it is characterised in that：Described oxidant be sodium chlorite, calcium chlorite,
At least one of potassium chlorite, postassium hypochlorite, sodium hypochlorite, calcium hypochlorite；Described alkali (e) is sodium carbonate, potassium carbonate, carbon
At least one of potassium hydrogen phthalate, sodium acid carbonate；The second described catalyst is tetramethyl piperidine nitrogen oxides, KBr, iodate
At least one of potassium；Described solvent (g) is at least one in water, acetone, acetonitrile, tetrahydrofuran, N, N- dimethylformamides
Kind.
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| CN101906097A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | 1,3-dioxane compounds, their synthesis method and their application in medicine |
| JP2011178779A (en) * | 2010-02-04 | 2011-09-15 | Daiichi Sankyo Co Ltd | Imidazopyridin-2-one derivative |
| CN102617503A (en) * | 2011-03-03 | 2012-08-01 | 上海常丰生物医药科技有限公司 | Novel synthetic method of (S)-3-morpholinyl carboxylic acid |
| WO2012120476A1 (en) * | 2011-03-10 | 2012-09-13 | Lupin Limited | Substituted morpholines as modulators for the calcium sensing receptor |
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| CN101906097A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | 1,3-dioxane compounds, their synthesis method and their application in medicine |
| JP2011178779A (en) * | 2010-02-04 | 2011-09-15 | Daiichi Sankyo Co Ltd | Imidazopyridin-2-one derivative |
| CN102617503A (en) * | 2011-03-03 | 2012-08-01 | 上海常丰生物医药科技有限公司 | Novel synthetic method of (S)-3-morpholinyl carboxylic acid |
| WO2012120476A1 (en) * | 2011-03-10 | 2012-09-13 | Lupin Limited | Substituted morpholines as modulators for the calcium sensing receptor |
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