CN104370755B - Preparation method for optical activity active 3-amino butanol and optical activity 3-amino butyric acid - Google Patents
Preparation method for optical activity active 3-amino butanol and optical activity 3-amino butyric acid Download PDFInfo
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- CN104370755B CN104370755B CN201410488279.2A CN201410488279A CN104370755B CN 104370755 B CN104370755 B CN 104370755B CN 201410488279 A CN201410488279 A CN 201410488279A CN 104370755 B CN104370755 B CN 104370755B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- AGMZSYQMSHMXLT-UHFFFAOYSA-N 3-aminobutan-1-ol Chemical compound CC(N)CCO AGMZSYQMSHMXLT-UHFFFAOYSA-N 0.000 title abstract description 11
- 230000003287 optical Effects 0.000 title abstract description 9
- OQEBBZSWEGYTPG-UHFFFAOYSA-N 3-aminobutanoic acid Chemical compound CC(N)CC(O)=O OQEBBZSWEGYTPG-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 238000006722 reduction reaction Methods 0.000 claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 37
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 19
- 239000002841 Lewis acid Substances 0.000 claims abstract description 11
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 11
- 230000000694 effects Effects 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 239000003054 catalyst Substances 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 22
- 239000010948 rhodium Substances 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 22
- KZMGYPLQYOPHEL-UHFFFAOYSA-N ethoxyethane;trifluoroborane Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 17
- 238000005984 hydrogenation reaction Methods 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 14
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 14
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 13
- 238000009833 condensation Methods 0.000 claims description 12
- 230000005494 condensation Effects 0.000 claims description 12
- 238000006482 condensation reaction Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 239000003638 reducing agent Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- CROBTXVXNQNKKO-UHFFFAOYSA-N borohydride Chemical compound [BH4-] CROBTXVXNQNKKO-UHFFFAOYSA-N 0.000 claims description 8
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 6
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 6
- 229910052703 rhodium Inorganic materials 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 241000894007 species Species 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- WTEOIRVLGSZEPR-UHFFFAOYSA-N Boron trifluoride Chemical group FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- 238000005292 vacuum distillation Methods 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 238000010009 beating Methods 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 3
- 229910052796 boron Inorganic materials 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- NZTNZPDOBQDOSO-UHFFFAOYSA-N lithium;boron(1-) Chemical compound [Li+].[B-] NZTNZPDOBQDOSO-UHFFFAOYSA-N 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- HHUJLKPGQMFFMS-UHFFFAOYSA-N potassium;boron(1-) Chemical compound [B-].[K+] HHUJLKPGQMFFMS-UHFFFAOYSA-N 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 241000276438 Gadus morhua Species 0.000 claims 3
- 235000019516 cod Nutrition 0.000 claims 3
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 claims 3
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 21
- 238000000034 method Methods 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000002699 waste material Substances 0.000 abstract description 5
- 238000006197 hydroboration reaction Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 15
- 230000002194 synthesizing Effects 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 13
- 238000001514 detection method Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminum hydride Chemical compound [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- AGMZSYQMSHMXLT-SCSAIBSYSA-N (3R)-3-aminobutan-1-ol Chemical compound C[C@@H](N)CCO AGMZSYQMSHMXLT-SCSAIBSYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- RHWKPHLQXYSBKR-BMIGLBTASA-N Dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 description 7
- 229960002542 dolutegravir Drugs 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229940014075 Tivicay Drugs 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000007605 air drying Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000007867 post-reaction treatment Methods 0.000 description 4
- 238000003672 processing method Methods 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- XYIBRDXRRQCHLP-UHFFFAOYSA-N Ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000012159 carrier gas Substances 0.000 description 3
- 238000007599 discharging Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- BHHGXPLMPWCGHP-UHFFFAOYSA-N 2-Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N Sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 150000003869 acetamides Chemical class 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- -1 amino-acid ester Chemical class 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- DDKMFOUTRRODRE-UHFFFAOYSA-N chloromethanone Chemical compound Cl[C]=O DDKMFOUTRRODRE-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ZFDIRQKJPRINOQ-HWKANZROSA-N ethyl (E)-but-2-enoate Chemical compound CCOC(=O)\C=C\C ZFDIRQKJPRINOQ-HWKANZROSA-N 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- AGMZSYQMSHMXLT-BYPYZUCNSA-N (3S)-3-aminobutan-1-ol Chemical class C[C@H](N)CCO AGMZSYQMSHMXLT-BYPYZUCNSA-N 0.000 description 1
- OFJRNBWSFXEHSA-UHFFFAOYSA-N 2-(3-amino-1,2-benzoxazol-5-yl)-N-[4-[2-[(dimethylamino)methyl]imidazol-1-yl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound CN(C)CC1=NC=CN1C(C=C1F)=CC=C1NC(=O)C1=CC(C(F)(F)F)=NN1C1=CC=C(ON=C2N)C2=C1 OFJRNBWSFXEHSA-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 229940068561 Atripla Drugs 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N Benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N Ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- 210000003746 Feathers Anatomy 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N Mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229940117803 Phenethylamine Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229950010535 Razaxaban Drugs 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N Sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N Triphenylphosphine oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 229910000090 borane Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N diazomethane Chemical group C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- DMJZZSLVPSMWCS-UHFFFAOYSA-N diborane Chemical compound B1[H]B[H]1 DMJZZSLVPSMWCS-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 1
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000630 rising Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention discloses a preparation method for optical activity active 3-amino butanol and optical activity 3-amino butyric acid. The optical activity active 3-amino butanol preparation method comprises: in a solvent, under effects of a hydroboration reduction agent and a Lewis acid, carrying out a reduction reaction on a compound represented by a formlu 65 to produce a compound represented by a formlu 14. The optical activity active 3-amino butyric acid preparation method comprises: carrying out a hydrolysis reaction on a compound represented by a formlu 64 to produce a compound represented by a formlu 65. According to the present invention, the preparation method has characteristics of cheap and easily-available raw materials, simple operation, short process route, no hazard of raw materials, high yield, little waste production, environment protection, high raw material conversion rate, high product chemical purity and high product optical purity, and the industrialization is easily achieved. The formulas 64, 65 and 14 are defined in the instruction.
Description
Technical field
The present invention is specifically related to the preparation method of a kind of optically active 3- amino butanols and 3- aminobutyric acids.
Background technology
Du Lutewei, Dolutegravir, are developed by GlaxoSmithKline PLC company, the medicine of the AntiHIV1 RT activity that FDA is recently approved
Thing, is shown in structural formula 1, its trade name Tivicay.Official FDA represents that HIV crowd needs to enter the hand-manipulating of needle according to personal considerations
Treatment to property, and the breakthrough of this medicines of Tivicay is have recognised, new selection is provided for patient.
In the research carried out in 2011 to 2012 years, after patient receives the Tivicay treatments of 48 weeks and 96 weeks, have
88% conditions of patients has clear improvement, better than the Atripla of Gilead companies.So at 2 months 2013, FDA announced to add
The evaluation of fast Tivicay, and ratify within 13rd with August in 2013.Thereafter Canada's health department is also on November 4th, 2013
Have approved Du Lutewei.
Tivicay is produced by GlaxoSmithKline PLC, and sold by ViiVHealthcare, both block in U.S. north.
Tivacay is approved can be controlled to HIV regardless of Tivicay whether was received before which to the extensive into crowd of HIV
Treat, or the treatment of other integrase inhibitors；Approval does not use which before being used in the child of more than 12 years old simultaneously yet
The treatment of its intergrase；Which has wide range of applications.
As Du Lutewei is very new, the country does not also see that related development is reported at present.World patent
WO2012018065 has carried out related summary report, two of which to the Du Lutewei routes of other developers to Yuan Yan producers
Typically synthetic route is A methods and B methods, as described below.
A methods：
B methods：
The introducing that chiral functional group be can be seen that from both the above route is all by key compound 14, i.e. (R) -3-
Amino butanol is building.(R) chiral purity of -3- amino butanols determines the purity of follow-up synthetic intermediate, so as to pairing
Very important effect is played into highly purified Du Lutewei.Therefore exploitation is with route synthesis of high purity efficiently, inexpensive
(R) -3- amino butanols be reduce Du Lutewei crude drug costs, promote the committed step of its range of application.
For synthesizing with optically active (R) -3- amino butanols and (S) -3- amino butanols, document report mainly has five
The method of kind：(1) chemical resolution method；(2) chemical derivatization, the reduction of (three) enzyme process, the synthesis of (four) chiral raw material, (five) prepare color
Spectrometry.Simply it is been described by below.
(1) chemical resolution method
In patent US2011/275855, the research worker of BASF AG is reported and splits racemization using mandelic acid 27
3- amino butanols 26 are come the method that synthesizes (R) -3- amino butanols.The method be current report method in most practicality
One of method.As classical disconnecting route, an other isomer is got rid of by the method by splitting, and causes raw material
Waste.General method for splitting is, by (i.e. 28) after target isomer and resolution reagent forming salt, then to use alkali separate out, with having
Machine solvent extraction.Here because (R) -3- amino butanols have very big water solublity, the research worker of BASF is not adopted
The conventional free technique for extracting again, but using 4- (2- hydroxyethyls) morpholine this material 29 both as solvent, and conduct
Alkali is added in 28, is then carried out straight run distillation and is obtained target product.As the compound 29 for mixing in the product is difficult to remove, institute
Product index is set to by purity 98% with which, containing about 1% impurity compound 29.
The method is currently to be capable of one of route of feather weight amplification, but due to 29 presence, product purity is restricted.
(2) chemical derivatization
The research worker of early stage is to be introduced by the induction of chiral reagent for the chiral centre in (R) -3- amino butanols
's.1977, Wojciech J.Stec in J.Org.Chem.1977,42 (9), report in 1650-1652 using chiral benzene
The addition of ethamine and Ethyl crotonate carrys out synthesizing chiral compound 32, but yield also only has 33%.Followed by lithium aluminium hydride reduction also
Original obtains the amino alcohol 33 protected, then obtains target product through palladium carbon hydrogenation.This route yield is low, and using being difficult to industry
Change the lithium aluminium hydride reduction of operation, so being not suitable for amplifying production.
Subsequently, Volkmar Wehner in 2003 et al. are done to above-mentioned route in United States Patent (USP) US2003/73723
2 points of improvement.One is that chiral phenethylamine is changed to the bigger derivant 34 of steric hindrance, and two is that Ethyl crotonate is changed to steric hindrance is bigger
Fructus Crotonis tert-butyl acrylate 35.Purpose is intended to by increasing steric hindrance so that during synthesis compound 36, chiral selectivity increases.Together
When carry out at -78 DEG C to increase selectivity and reacting, and using expensive inflammable butyl lithium.In the reduction of final step,
Reducing agent, and inflammable ether are done as solvent using lithium aluminium hydride and trichlorine rate, these are all unfavorable for amplifying production.
Because above-mentioned final step is Lithium aluminum hydride reduction, product is difficult to purify, so Ronald Albers et al. exist
The order of its last two steps have exchanged by (WO2006/76595) using during above-mentioned route within 2006.Because by palladium dydroxide
Hydro-reduction be placed on finally, it is easy to obtain high-purity product.But the yield of the patent report first step is only 37%.
In order to overcome Volkmar Wehner in 2003 et al. last in the route of United States Patent (USP) US2003/73723 report
The shortcoming of one step, scientist Wataru Kuriyama of Japanese STOL company et al. investigated new ester group hydro-reduction
Catalyst 40, and be successively reported in Advanced Synthesis and Catalysis, 2010, Vol352 (1), 92-96 and
United States Patent (USP) US2010/63294.
Simultaneously in order to easily reduce, the less methyl ester for being easy to and reducing is have selected.But the yield of its first step is also only
33%.What is more important, the catalyst will synthesize through multistep, expensive, and which will reach 0.2 in the consumption of final step
～0.5% mol ratio.This also has many work do from practical application.
The research worker of Japanese STOL also reports its new catalyst 40 simultaneously for the amino-acid ester 44 that Boc is protected
Hydro-reduction.Same problem is that catalyst amount is larger, adds catalyst and is difficult in itself synthesize, it is difficult to realize industrial metaplasia
Produce.
In the report of early stage, also there is the induction of other utilization chipal compounds to introduce chiral centre, such as Celia
In the Tetrahedron Letter of 1992,1992, Vol.33 (20), 2895-2898 reports compound 45 to Andres etc.
With the reaction of acetaldehyde, regrettably its selectivity is poor, and the ratio of 46 two isomers of product is only 80:20, do not reach selection
Property synthesis purpose.
(3) enzyme process reduction
Paseale Besse in 1999 et al. are in Tetrahedron Assymetry, 1999, Vol 10 (11), 2213-
2224 report a new synthetic route.This route is with cheap ethyl acetoacetate 49 as raw material, but whole piece route is related to
And reaction it is complicated, it is tediously long so that holistic cost is higher, be also unfavorable for industrialized production.As second step uses lithium aluminium hydride also
It is former；4th step is Mitsunobu reactions, uses more expensive DEAD, while product is because substantial amounts of triphenylphosphine oxide (is derived from
Mitsunobu reagent triphenylphosphines) it is difficult to purification；5th step is using larger hydrazine hydrate of toxicity etc..These shortcomings are resulted in
This route fails to realize industrialization so far.
(4) chiral raw material synthesis
In order to develop new synthetic route Michal Achmatowicz et al. 2005 in Tetrahedron, 2005,61
(38), 9031-9041 reports the synthetic route with D-alanine as initiation material.Although the route raw material D-alanine 55 is easy
, but some used reagents limit its wide variety of prospect.Such as second step reaction is using dangerously explosive diazonium first
Used as reagent, only this point allows for the route and is difficult to promote alkane, and Azimethylene. here does not have other alternative
Reagent.Latter step also uses more expensive silver benzoate, and these all limit its range of application.
(5) preparative chromatography
Bodil Van Niel of Roche Holding Ag et al. are reported with racemization in world patent WO2014/9447 recently
Method of the 3- aminobutyric acids for raw material.3- aminobutyric acids and Cbz-Cl reactions first obtains the amino acid derivativges 61 protected, its
One group of raceme (S) -61 and (R) -61 are obtained by borane reduction.This group of raceme is again by chiral preparative high-performance liquid chromatographic
Method is separated, and then palladium carbon catalytic hydrogenation obtains target product.The route is carried out using preparative chromatography, is only applicable to experiment
The Fast back-projection algorithm of room scale, it is difficult to realize industrialized production.
The content of the invention
The technical problem to be solved is to overcome optically active 3- amino butanols of the prior art
Preparation method expensive starting materials, raw material are inflammable and explosive, material toxicity is big, cost is too high, purity is relatively low, yield is relatively low, produce waste material
It is more to easily cause wastage of material and be unfavorable for the defects such as industrialized production, and provide a kind of optically active 3- amino butanols and
The preparation method of 3- aminobutyric acids.The present invention preparation method raw material it is cheap and easy to get, simple to operate, process route is short, raw material without
Danger, high income, produce waste material it is few, beneficial to environmental protection, high feed stock conversion, product chemistry purity and optical purity
Height, and it is easily achieved industrialization.
The invention provides a kind of preparation method of compound as shown in Equation 14, which comprises the steps：In solvent,
In the presence of Borohydride reducing agent and lewis acid, the compound as shown in formula 65 is carried out into reduction reaction, generated such as 14 institute of formula
The compound for showing；
Wherein, the carbon of * marks is chiral carbon, and which is S types or R types；And the configuration of the chiral carbon is in described reduction reaction
In do not change.
Wherein, the Borohydride reducing agent in described reduction reaction can be various conventional boron hydrogen in the such reaction in this area
Change reducing agent, one or more in preferred sodium borohydride, potassium borohydride and lithium borohydride.
Lewis acid in described reduction reaction can be various conventional lewis acids in the such reaction in this area, preferably
One or more in anhydrous zinc chloride, anhydrous calcium chloride and anhydrous magnesium chloride.
The solvent of described reduction reaction can be the various solvents of routine in the such reaction in this area, preferably anhydrous tetrahydrochysene furan
Mutter and/or anhydrous methyl tertbutyl ether.
The mass ratio of the volume of the solvent of described reduction reaction and the described compound as shown in formula 65 preferably (8～
14)：1, more preferably (10～12)：1, the unit of the volume of the solvent of described reduction reaction is milliliter, described such as 65 institute of formula
The unit of the quality of the compound for showing for gram.
The mol ratio of the Borohydride reducing agent described in described reduction reaction and the described compound as shown in formula 65
It is preferred that (1.2～2.2)：1, more preferably (1.3～2.2)：1, most preferably (1.8～2.2)：1.
Lewis acid described in described reduction reaction is preferred with the mol ratio of the described compound as shown in formula 65
(0.6～1.05)：1, more preferably (0.95～1.05)：1.
Described reduction reaction preferably comprises following steps：First by described solvent, described Borohydride reducing agent and institute
The lewis acid mix homogeneously stated, and stir 20～50 minutes at 10～35 DEG C, then heat to 50～60 DEG C of stirrings 3～5
Hour, 10～35 DEG C are subsequently cooled to, and are added the described compound as shown in formula 65, and temperature are controlled at 10～40 DEG C, plus
Back flow reaction is to slowly warm up to after complete, you can.
The process of described reduction reaction can be supervised using the traditional test methods (such as TLC or HPLC) in this area
Control, is preferably 24 as reaction end, the time of described reduction reaction when typically disappearing using the compound as shown in formula 65
～30 hours.
After described reduction reaction terminates, it is preferred that also can further include the operation of post processing.Described post processing
Method and condition can be the method and condition of the such post-reaction treatment routine in this area, preferably：After reaction terminates, will reaction
System is cooled to 10～15 DEG C, and (preferred volume is the 0.4～0.6 of the quality of the compound as shown in formula 65 to be slowly added dropwise methanol
Times methanol, methanol volume unit is milliliter, the unit of the quality of the compound as shown in formula 65 for gram) and sodium hydroxide it is water-soluble
Liquid (preferably mass fraction is 35～50% sodium hydrate aqueous solution) simultaneously controls temperature at 10～40 DEG C, 10～35 after adding
Stir 3～5 hours at DEG C, filter, wash (preferably being washed with tetrahydrofuran), filtrate concentration, vacuum distillation, you can.
Preferably, the preparation method of described compound as shown in Equation 14, which still further comprises following steps：Will be as
Compound shown in formula 64 is hydrolyzed reaction, generates the described compound as shown in formula 65；
Wherein, the carbon of * marks is chiral carbon, and which is S types or R types；And the configuration of chiral carbon is in described hydrolysis
Do not change；Described R is C1～C3Alkyl.
Wherein, described C1～C3The preferred methyl of alkyl or ethyl.
Described hydrolysis are preferably carried out under acid condition or alkalescence condition, are more preferably carried out in acid condition.
Described acid condition is preferably carried out in aqueous hydrochloric acid solution.
When described hydrolysis are carried out in aqueous hydrochloric acid solution, hydrogen chloride and such as formula 64 in described aqueous hydrochloric acid solution
The mol ratio of shown compound preferably 4：1～8：1, more preferably 5：1～6：1.
Preferably 90～100 DEG C, more preferably 95～100 DEG C of the temperature of described hydrolysis.
The process of described hydrolysis can be supervised using the traditional test methods (such as TLC or HPLC) in this area
Control, is preferably 10 as reaction end, the time of described hydrolysis when typically disappearing using the compound as shown in formula 64
～12 hours.
After described hydrolysis terminate, it is preferred that also can further include the operation of post processing.Described post processing
Method and condition can be the method and condition of the such post-reaction treatment routine in this area, preferably：After reaction terminates, will reaction
System is concentrated (preferred concentrating under reduced pressure), and acetone is added after being cooled to 30～40 DEG C, and (preferred volume is the change as shown in formula 64
The acetone of 1.8～2.5 times of the quality of compound, the volume unit of acetone is milliliter, the quality of the compound as shown in formula 64
Unit for gram) beating, filter, filter cake acetone drip washing, be dried, be dried gained solid in the condition for maintaining the temperature at 10～50 DEG C
Under organic solvent (preferred tetrahydrofuran) neutralize alkali mix homogeneously, after being cooled to room temperature, filter, washing (preferably use tetrahydrochysene furan
Mutter washing), it is dried (preferred forced air drying, the more preferably forced air drying under conditions of 60 DEG C), you can.
The preferred inorganic base of alkali in " and alkali mix homogeneously " and/or organic base in the operation of described post processing.It is described
The preferred sodium hydroxide of inorganic base, potassium hydroxide, Lithium hydrate, Feldalat NM, Sodium ethylate, in potassium tert-butoxide and sodium tert-butoxide one
Plant or various.The preferred triethylamine of described organic base and/or pyridine." and alkali mix homogeneously " in the operation of described post processing
In alkali and the described compound as shown in formula 64 mol ratio preferably (0.7～1.2)：1, more preferably 1:1.After described
When the alkali in " and alkali mix homogeneously " in the operation of process is sodium hydroxide, described sodium hydroxide is preferably with sodium hydroxide
The form of aqueous solution is added, and is added more preferably in the form of the sodium hydrate aqueous solution that mass fraction is 50%.
Preferably, the preparation method of described compound as shown in Equation 14, which still further comprises following steps：Solvent
In, by the compound as shown in formula 63 in the presence of asymmetric hydrogenation catalyst, hydrogenation is carried out with hydrogen, generate described
The compound as shown in formula 64；
Wherein, the carbon of * marks is chiral carbon, and which is S types or R types；Described R is C1～C3Alkyl.
Wherein, described C1～C3The preferred methyl of alkyl or ethyl.
Described asymmetric hydrogenation catalyst can be the conventional various asymmetric hydrogenation catalyst of the such reaction in this area, excellent
Select the asymmetric hydrogenation catalyst of rhodium and the cooperation species of phosphine formation.When the compound 64 for generating is R configurations, described rhodium with
The preferred Rh of asymmetric hydrogenation catalyst (RcSp-DuanPhos) (COD) BF of the cooperation species that phosphine is formed4、Rh(RcSp-
DuanPhos)(NBD)BF4With one or more in Rh (SSRR-TangPhos) (COD) BF4；When the compound 64 for generating is
During S configurations, the preferred Rh of the asymmetric hydrogenation catalyst (ScRp-DuanPhos) of the cooperation species that described rhodium is formed with phosphine
(COD)BF4And/or Rh (ScRp-DuanPhos) (NBD) BF4。
The solvent of described hydrogenation can be the various conventional solvents of the such reaction in this area, preferred alcohols solvent.Institute
The preferred methanol of alcohols solvent stated and/or ethanol.
Preferably 1～10 atmospheric pressure of the pressure of hydrogen in described hydrogenation, more preferably 1～5 atmospheric pressure, most preferably
1～3 atmospheric pressure.
Described hydrogenation is preferably carried out at 10～35 DEG C, is more preferably carried out at 20～30 DEG C.
The consumption of described asymmetric hydrogenation catalyst can be the various conventional amount useds of the such reacting middle catalyst in this area,
Preferably, the mol ratio preferably 1 of described asymmetric hydrogenation catalyst and the described compound as shown in formula 63:5000～1:
20000, more preferably 1:8000～1:10000.
The volume mass ratio preferably 4 of the solvent of described hydrogenation and the described compound as shown in formula 63:1～6:
1, more preferably 4.5:1～5:1 wherein, and the volume unit of solvent is L, the mass unit of the compound as shown in formula 63 for kilogram.
The process of described hydrogenation can be entered using the traditional test methods (such as GC, TLC or HPLC) in this area
Row monitoring, as reaction end when typically being disappeared using the compound as shown in formula 63, the time of described hydrogenation is preferably
For 20～24 hours.
After described hydrogenation terminates, it is preferred that also can further include the operation of post processing.Described post processing
Method and condition can be the method and condition of the such post-reaction treatment routine in this area, preferably：After reaction terminates, will reaction
System is concentrated, you can.
Preferably, the preparation method of described compound as shown in Equation 14, further comprises following steps：In solvent
In, under condensation catalyst effect, the compound as shown in formula 62 and acetamide are carried out into condensation reaction, generated described
Compound as shown in formula 63；
Wherein, described R is C1～C3Alkyl.
Wherein, described C1～C3The preferred methyl of alkyl or ethyl.
Condensation catalyst in described condensation reaction can be the conventional various catalyst of the such reaction in this area, excellent
Select one or more in p-methyl benzenesulfonic acid, boron trifluoride diethyl etherate and polyphosphoric acids.
The solvent of described condensation reaction can be the conventional various solvents of the such reaction in this area, preferred hexamethylene, toluene,
One or more in normal heptane and benzene.
The mol ratio preferably 1.4 of described acetamide and the described compound as shown in formula 62：1～3.5：1, more preferably
1.4：1～1.5：1.
The mass ratio preferably 4 of the volume of the solvent of described condensation reaction and the compound as shown in formula 62:1～6:1,
The wherein unit of the volume of solvent to rise, the unit of the quality of the compound as shown in formula 62 for kilogram.
When described condensation catalyst is p-methyl benzenesulfonic acid, described p-methyl benzenesulfonic acid is with described such as formula
The mass ratio of the compound shown in 62 preferably 1:20～3:20, more preferably 1:20～7:100.
When described condensation catalyst is boron trifluoride diethyl etherate, boron trifluoride in described boron trifluoride diethyl etherate
Content can be the various customary amounts of the boron trifluoride diethyl etherate used by the condensation reaction of this area.
When described condensation catalyst is boron trifluoride diethyl etherate, described boron trifluoride diethyl etherate is with described such as formula
The mass ratio of the compound shown in 62 preferably 1:25～1:15, more preferably 1:20.
When described condensation catalyst is polyphosphoric acids, the degree of polymerization of described polyphosphoric acids can contract for this area
The various degree of polymerization of the routine of the polyphosphoric acids used in conjunction reaction.
When described condensation catalyst is polyphosphoric acids, described polyphosphoric acids are with described as shown in formula 62
The mass ratio of compound preferably 1:2～1:4.
The process of described condensation reaction can be supervised using the traditional test methods (such as GC or TLC) in this area
Control, the typically mol ratio with the compound as shown in formula 63 with the compound as shown in formula 62 reach 9:As reaction end when 1,
Preferably more than the 24 hours time of described condensation reaction.
After described condensation reaction terminates, it is preferred that also can further include the operation of post processing.Described post processing
Method and condition can be the method and condition of the such post-reaction treatment routine in this area, preferably：After reaction terminates, will reaction
System carries out stratification, and after upper strata is cooled to room temperature, add water layering, takes upper organic layer concentration, filters, dry to filter cake vacuum
It is dry, you can.The quality and the mass ratio preferably 1 of the compound as shown in formula 62 of the described water added water in layering:1.04～
1.5:1。
Present invention also offers a kind of preparation method of the compound as shown in formula 65, which comprises the steps：Will be such as formula
Compound shown in 64 is hydrolyzed reaction, generates the compound as shown in formula 65；
Wherein, the carbon of * marks is chiral carbon, and which is S types or R types；And the configuration of chiral carbon is in described hydrolysis
Do not change；Described R is C1～C3Alkyl.
Wherein, the condition of the method for described hydrolysis is the same as those described above.
In the present invention, the described relevant material of razaxaban as shown in Equation 14, it is preferred that the following institute of its synthetic route
Show：
Wherein, the carbon of * marks is chiral carbon, and which is S types or R types；And the configuration of chiral carbon is in described hydrolysis
Do not change；Described R is C1～C3Alkyl.
On the basis of common sense in the field is met, above-mentioned each optimum condition, can combination in any, obtain final product each preferable reality of the present invention
Example.
Agents useful for same of the present invention and raw material are commercially available.
The present invention positive effect be：The preparation method raw material of optically active 3- amino butanols of the present invention is honest and clean
Valency is easy to get, simple to operate, process route is short, raw material without danger, high income, produce waste material it is few, beneficial to environmental protection, raw material
High conversion rate, product chemistry purity and optical purity are high, and are easily achieved industrialization.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Among applying a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product description is selected.
Wherein used catalyst [Rh ((Rc, Sp)-Duanpos) is (COD)] BF4, [Rh ((Sc, Rp)-Duanpos)
(COD)] (COD) BF4 can be bought from STREM or ALDRICH companies for BF4 and Rh (SSRR-TangPhos).
Embodiment 1：The synthesis (Catalyzed by P-Toluenesulfonic Acid) of 3- acetylamino Ethyl crotonates
52 kilograms of ethyl acetoacetates, 35 kilograms of acetamides and 300L hexamethylene are added in 500 liters of reactors, is fully stirred
Mix.3 kilograms of p-methyl benzenesulfonic acids are subsequently adding, and are to slowly warm up to flow back and by fraction water device water-dividing.When reaction about 24 hours,
Sampling GC detections, when product and raw material ratio reach 9:When 1, stop stirring, stand.It is layered while hot, upper strata is cooled to room temperature, then
50 kilograms of washing layerings of water, upper organic layer concentration are added to separate out up to a large amount of solids, be filtrated to get white crystal, be vacuum dried
Obtain 37.6 kilograms of white solid, yield 55%.Fusing point：64-65℃.Vapor detection purity：98.7%.
1H NMR(300MHz,CDCl3)：δ 1.28 (t, J=7.2Hz, 3H), 2.14 (s, 3H), 2.38 (s, 3H), 4.15
(q, J=7.2Hz, 2H), 4.89 (s, 1H), 11.15 (bs, 1H).
Embodiment 2：The synthesis (boron trifluoride diethyl etherate catalysis) of 3- acetylamino Ethyl crotonates
500 grams of ethyl acetoacetates, 340 grams of acetamides and 3 liters of hexamethylene are added in 5 liters of round-bottomed flasks, is sufficiently stirred for.
25 grams of boron trifluoride diethyl etherate are subsequently adding, and are to slowly warm up to flow back and by fraction water device water-dividing.When reaction about 24 hours, sampling
GC is detected, when product and raw material ratio reach 9:When 1, stop stirring, stand.It is layered while hot, upper strata is cooled to room temperature, is subsequently adding
500 milliliters of washing layerings of water, upper organic layer concentration is until the precipitation of a large amount of solids, is filtrated to get white crystal, is vacuum dried
394 grams of white solid, yield 61%.Fusing point：64.5-65℃.Vapor detection purity：99.1%.
1H NMR(300MHz,CDCl3)：δ 1.28 (t, J=7.2Hz, 3H), 2.14 (s, 3H), 2.38 (s, 3H), 4.15
(q, J=7.2Hz, 2H), 4.89 (s, 1H), 11.15 (bs, 1H).
Embodiment 3：(R) synthesis of -3- acetylminobutyric acids ethyl ester
200 grams of 3- acetylaminos Ethyl crotonates and 800 ml methanols are added in 2L hydrogenation reaction cauldrons, nitrogen displacement 30
Minute；Then by 83 milligrams of Rh (SSRR-TangPhos) (COD) BF under nitrogen protection4In adding reactor.It is carefully added into hydrogen
Gas, maintains 1～5 atmospheric pressure to react 20～24 hours under room temperature；Completely, discharging is concentrated to give oily to gas chromatographic detection raw material reaction
186 grams of thing, yield 92%, ee99.4%.Ee vapor detection conditions：Astec CHIRALDEXTM B-DM
30mx0.32mmx0.12um chromatographic columns.Carrier gas：Nitrogen；Flow velocity：1.5mL/min；Column temperature：110 DEG C of constant temperature；Retention time：R‐3‐
Acetylminobutyric acid ethyl ester 14.7 minutes, S-3- acetylminobutyric acid ethyl esters, 12.8 minutes.
1H NMR(300MHz,CDCl3):δ6.15(brs,1H),4.39-4.31(m,1H),4.21(q,7.2Hz,2H),
2.52 (dd, 2.8,5.3Hz, 2H), 1.96 (s, 3H), 1.27 (t, J=7.2Hz, 3H), 1.23 (d, J=6.6Hz, 3H).
Embodiment 4：(R) synthesis of -3- acetylminobutyric acids ethyl ester
100 kilograms of 3- acetylaminos Ethyl crotonates and 500 liters of methanol are added in 1000L hydrogenation reaction cauldrons, nitrogen is put
Change 60 minutes；Then by 45 grams of Rh (RcSp-DuanPhos) (COD) BF under nitrogen protection4In adding reactor.It is carefully added into hydrogen
Gas, maintains 1-5 atmospheric pressure to react 20～24 hours under room temperature；Completely, discharging is concentrated to give oily to gas chromatographic detection raw material reaction
88 kilograms of thing, yield 87%, ee99.2%.Ee vapor detection conditions：Astec CHIRALDEXTM B-
DM30mx0.32mmx0.12um chromatographic columns.Carrier gas：Nitrogen；Flow velocity：1.5mL/min；Column temperature：110 DEG C of constant temperature；Retention time：R‐
3- acetylminobutyric acids ethyl ester 14.7 minutes, S-3- acetylminobutyric acid ethyl esters, 12.8 minutes.
1H NMR(300MHz,CDCl3):δ6.15(brs,1H),4.39-4.31(m,1H),4.21(q,7.2Hz,2H),
2.52 (dd, 2.8,5.3Hz, 2H), 1.96 (s, 3H), 1.27 (t, J=7.2Hz, 3H), 1.23 (d, J=6.6Hz, 3H).
Embodiment 5：(S) synthesis of -3- acetylminobutyric acids ethyl ester
250 grams of 3- acetylaminos Ethyl crotonates and 1 liter of methanol are added in 2L hydrogenation reaction cauldrons, 30 points of nitrogen displacement
Clock；Then by 135 milligrams of Rh (ScRp-DuanPhos) (COD) BF under nitrogen protection4In adding reactor.It is carefully added into hydrogen,
1～5 atmospheric pressure is maintained to react under room temperature 20～24 hours；Completely, discharging is concentrated to give grease to gas chromatographic detection raw material reaction
232 grams, yield 91%, ee99.2%.Ee vapor detection conditions：Astec CHIRALDEXTM B-DM
30mx0.32mmx0.12um chromatographic columns.Carrier gas：Nitrogen；Flow velocity：1.5mL/min；Column temperature：110 DEG C of constant temperature；Retention time：R‐3‐
Acetylminobutyric acid ethyl ester 14.7 minutes, S-3- acetylminobutyric acid ethyl esters, 12.8 minutes.
1H NMR(300MHz,CDCl3):δ6.15(brs,1H),4.39-4.31(m,1H),4.21(q,7.2Hz,2H),
2.52 (dd, 2.8,5.3Hz, 2H), 1.96 (s, 3H), 1.27 (t, J=7.2Hz, 3H), 1.23 (d, J=6.6Hz, 3H).
Embodiment 6：(R) synthesis of -3- amino butanols
Add what embodiment 4 was obtained in equipped with mechanical agitation, reflux condensing tube, tetra- mouthfuls of reaction bulbs of 20L of thermometer
(R) 1750 grams and 3650 grams water of -3- acetylminobutyric acids ethyl ester, 5500 grams of concentrated hydrochloric acid (mass fraction of hydrogen chloride in concentrated hydrochloric acid
36%), it is heated to 95～100 DEG C to be kept for 12 hours.Water is steamed in decompression, closely does to reactant liquor, adds after being cooled to 30～40 DEG C
3.4L acetone is beaten；Solid is separated out, is filtered, acetone drip washing is dry to obtain about 1200 grams of white solids.By this white solid and 1.5
Stir in the round-bottomed flask for rising 10 liters of anhydrous tetrahydro furan addition, the sodium hydrate aqueous solution of lower 660 gram 50% of the Deca of cooling is simultaneously
Control temperature is at 10～50 DEG C.Completion of dropping obtains milky slurry, is cooled to room temperature, filters, and solid is washed with a small amount of THF
Wash, gained solid forced air drying (60 DEG C) obtains about 1280 grams of white solids.
13L anhydrous tetrahydro furans and 1067 grams of anhydrous zinc chlorides (having a little heat release) are added in the reactor of 50L, carefully
Criticize plus 590 grams of sodium borohydrides (noting heat release and aerogenesis).It is stirred at room temperature 30 minutes, then heats to 50～60 DEG C and stir 3 hours.
After being cooled to room temperature, 1280 grams of white solids of gained above are dividedly in some parts, and temperature are controlled at 10～40 DEG C.After adding, slowly
It is warming up to back flow reaction 24 hours.System becomes the suspended system of grey, is cooled to 10-15 DEG C, be slowly added dropwise 640 ml methanols and
200 gram of 40% sodium hydrate aqueous solution, and temperature is controlled at 10～40 DEG C.After adding, 3～5 hours are stirred at room temperature.Filter, THF
Washing, is filtered dry to obtain colourless liquid；Concentration, vacuum distillation (10～65 DEG C) obtain 495 grams of clear viscous liquids R-3- amino butanols,
Yield 54%.Purity 99.2%, ee99.3%.
Purity gas chromatogram is directly determined.Ee is determined：First by 3- amino butanols in sodium hydrate aqueous solution with benzyloxy
The reaction of carbonyl chlorine generates N-Cbc-3- amino butanols, then uses Liquid Detection.Chromatographic column AD-H；Mobility normal hexane：Isopropanol
(9:1)；Flow velocity, 1 ml/min.Detection wavelength, 210 nanometers.Retention time, S- isomers, 11.1 minutes, R- isomers
12.2 minutes.
1HNMR(300MHz,DMSO,ppm):δ4.48(3H,s),3.47(2H,s),2.96(1H,s),1.47-1.41
(2H,q),1.02-0.99(3H,d)。
Embodiment 7：(S) synthesis of -3- amino butanols
70 grams of S-3- acetylaminos are added in equipped with mechanical agitation, reflux condensing tube, tetra- mouthfuls of reaction bulbs of 1L of thermometer
Ethyl n-butyrate., 150 grams of water, 220 grams of concentrated hydrochloric acid (mass fraction 36% of hydrogen chloride in concentrated hydrochloric acid) are heated to 95～100 DEG C of guarantors
Hold 10 hours.Water is steamed in decompression, closely does to reactant liquor, and 150 milliliters of acetone beating are added after being cooled to 30-40 DEG C；Separate out solid, mistake
Filter, acetone drip washing are dry to obtain about 45 grams of white solids.This white solid and 100 milliliters of anhydrous tetrahydro furans are added into 2 liters of circle
Stir in the flask of bottom, cooling is lower to be added 17 grams of solid sodium methylates and control temperature at 10～50 DEG C.Completion of dropping obtains milky
Slurry, is cooled to room temperature, filters, and solid washed with a small amount of THF, gained solid forced air drying (60 DEG C) obtain about 49 grams it is white
Solid.
600 milliliters of anhydrous tetrahydro furans and 43 grams of anhydrous zinc chlorides (having a little heat release) are added in the reactor of 2L, it is little
The heart batch plus 24 grams of sodium borohydrides (noting heat release and aerogenesis).It is stirred at room temperature 30 minutes, then heats to 50-60 DEG C and stir 3 hours.
After being cooled to room temperature, 49 grams of white solids of gained above are dividedly in some parts, and temperature are controlled at 10～40 DEG C.It is after adding, slow to rise
Temperature was to back flow reaction 24 hours.System becomes the suspended system of grey, is cooled to 10-15 DEG C, is slowly added dropwise 25 ml methanols and 8 grams
40% sodium hydrate aqueous solution, and temperature is controlled at 10～40 DEG C.After adding, 3-5 hours are stirred at room temperature.Filter, THF washings,
It is filtered dry to obtain colourless liquid；Concentration, vacuum distillation (10～65 DEG C) obtain 17 grams of clear viscous liquids R-3- amino butanols, yield
47%.Purity 99.1%, ee99.2%.
Purity gas chromatogram is directly determined.Ee is determined：First by 3- amino butanols in sodium hydrate aqueous solution with benzyloxy
The reaction of carbonyl chlorine generates N-Cbc-3- amino butanols, then uses Liquid Detection.Chromatographic column AD-H；Mobility normal hexane：Isopropanol
(9:1)；Flow velocity, 1 ml/min.Detection wavelength, 210 nanometers.Retention time, S- isomers, 11.1 minutes, R- isomers
12.2 minutes.
1HNMR(300MHz,DMSO,ppm):δ4.48(3H,s),3.47(2H,s),2.96(1H,s),1.47-1.41
(2H,q),1.02-0.99(3H,d)。
Claims (10)
1. a kind of preparation method of compound as shown in Equation 14, it is characterised in which comprises the steps：In solvent, in boron
In the presence of hydro-reduction agent and lewis acid, the compound as shown in formula 65 is carried out into reduction reaction, generated as shown in Equation 14
Compound；Described reduction reaction is comprised the steps of：First by described solvent, described Borohydride reducing agent and described
Lewis acid mix homogeneously, and stir 20～50 minutes at 10～35 DEG C, then heat to 50～60 DEG C and stir 3～5 hours,
10～35 DEG C are subsequently cooled to, the described compound as shown in formula 65 are added, and temperature is controlled at 10～40 DEG C, delay after adding
Slowly it is warming up to back flow reaction, you can；
Wherein, the carbon of * marks is chiral carbon, and which is S types or R types；And the configuration of the chiral carbon in described reduction reaction not
Change；
The preparation method of described compound as shown in Equation 14, which still further comprises following steps：By as shown in formula 64
Compound is hydrolyzed reaction, generates the described compound as shown in formula 65；
Wherein, the carbon of * marks is chiral carbon, and which is S types or R types；And the configuration of chiral carbon is not sent out in described hydrolysis
It is raw to change；Described R is C1～C3Alkyl.
2. preparation method as claimed in claim 1, it is characterised in that the Borohydride reducing agent in described reduction reaction is boron
One or more in sodium hydride, potassium borohydride and lithium borohydride；
And/or, the lewis acid in described reduction reaction is in anhydrous zinc chloride, anhydrous calcium chloride and anhydrous magnesium chloride
Plant or various；
And/or, the solvent of described reduction reaction is anhydrous tetrahydro furan and/or anhydrous methyl tertbutyl ether；
And/or, the volume of the solvent of described reduction reaction and the mass ratio of the described compound as shown in formula 65 for (8～
14)：1, the unit of the volume of the solvent of described reduction reaction is milliliter, the quality of the described compound as shown in formula 65
Unit for gram；
And/or, the Borohydride reducing agent described in described reduction reaction and the described compound as shown in formula 65 mole
Than for (1.2～2.2)：1；
And/or, the lewis acid described in described reduction reaction with the mol ratio of the described compound as shown in formula 65 is
(0.6～1.05)：1.
3. preparation method as claimed in claim 1 or 2, it is characterised in that the volume of the solvent of described reduction reaction and institute
The mass ratio of the compound as shown in formula 65 stated is (10～12)：1；The unit of the volume of the solvent of described reduction reaction is
Milliliter, the unit of the quality of the described compound as shown in formula 65 for gram；
And/or, the Borohydride reducing agent described in described reduction reaction and the described compound as shown in formula 65 mole
Than for (1.3～2.2)：1；
And/or, the lewis acid described in described reduction reaction with the mol ratio of the described compound as shown in formula 65 is
(0.95～1.05)：1；
And/or, after described reduction reaction terminates, further comprise the operation of post processing；The method of described post processing and
Condition is：After reaction terminates, reaction system is cooled to into 10～15 DEG C, methanol and sodium hydrate aqueous solution is slowly added dropwise and is controlled
Temperature is stirred 3～5 hours at 10～35 DEG C after adding at 10～40 DEG C, is filtered, washing, filtrate concentration, vacuum distillation, you can.
4. preparation method as claimed in claim 1, it is characterised in that described C1～C3Alkyl is methyl or ethyl；
And/or, described hydrolysis are carried out under acid condition or alkalescence condition；
And/or, the temperature of described hydrolysis is 90～100 DEG C；
And/or, after described hydrolysis terminate, further comprise the operation of post processing；The method of described post processing and
Condition is：After reaction terminates, reaction system is concentrated, acetone beating is added after being cooled to 30～40 DEG C, is filtered, filter cake is used
Acetone drip washing, is dried, and is dried gained solid equal with alkali mixing in organic solvent under conditions of maintaining the temperature at 10～50 DEG C
It is even, after being cooled to room temperature, to filter, washing is dried, you can.
5. preparation method as claimed in claim 4, it is characterised in that described hydrolysis are carried out in acid condition；
And/or, the temperature of described hydrolysis is 95～100 DEG C；
And/or, after described hydrolysis terminate, when further comprising the operation of post processing, described post-processing operation
In, described concentration is concentrating under reduced pressure；And/or, the volume of described acetone is the 1.8 of the quality of the compound as shown in formula 64
～2.5 times of acetone, the volume unit of acetone is milliliter, the unit of the quality of the compound as shown in formula 64 for gram；And/or,
In " being dried gained solid under conditions of maintaining the temperature at 10～50 DEG C in organic solvent " in the operation of described post processing
Organic solvent be tetrahydrofuran；And/or, the alkali in " and alkali mix homogeneously " in the operation of described post processing is inorganic base
And/or organic base；And/or, the alkali in " and alkali mix homogeneously " in the operation of described post processing is with described such as 64 institute of formula
The mol ratio of the compound for showing is (0.7～1.2)：1.
6. preparation method as claimed in claim 5, it is characterised in that described acid condition is entered in aqueous hydrochloric acid solution
OK；When described hydrolysis are carried out in aqueous hydrochloric acid solution, hydrogen chloride and as shown in formula 64 in described aqueous hydrochloric acid solution
Compound mol ratio be 4：1～8：1.
7. preparation method as claimed in claim 1, it is characterised in that the preparation side of described compound as shown in Equation 14
Method, which still further comprises following steps：In solvent, by the compound as shown in formula 63 asymmetric hydrogenation catalyst effect
Under, hydrogenation is carried out with hydrogen, generate the described compound as shown in formula 64；
Wherein, the carbon of * marks is chiral carbon, and which is S types or R types；Described R is C1～C3Alkyl.
8. preparation method as claimed in claim 7, it is characterised in that wherein, described C1～C3Alkyl is methyl or ethyl；
And/or, described asymmetric hydrogenation catalyst is the asymmetric hydrogenation catalyst of the cooperation species that rhodium is formed with phosphine；Work as life
Into compound 64 be R configurations when, the asymmetric hydrogenation catalyst of the cooperations species that described rhodium is formed with phosphine is Rh (RcSp-
DuanPhos)(COD)BF4、Rh(RcSp-DuanPhos)(NBD)BF4With the one kind in Rh (SSRR-TangPhos) (COD) BF4
Or it is various；When the compound 64 for generating is S configurations, the asymmetric hydrogenation catalyst of the cooperation species that described rhodium is formed with phosphine
For Rh (ScRp-DuanPhos) (COD) BF4And/or Rh (ScRp-DuanPhos) (NBD) BF4；
And/or, the solvent of described hydrogenation is alcohols solvent；
And/or, in described hydrogenation, the pressure of hydrogen is 1～10 atmospheric pressure；
And/or, described hydrogenation is carried out at 10～35 DEG C；
And/or, described asymmetric hydrogenation catalyst and the mol ratio of the described compound as shown in formula 63 are 1:5000～
1:20000；
And/or, the described solvent of hydrogenation and the volume mass ratio of the described compound as shown in formula 63 are 4:1～6:
1, the volume unit of solvent is L, the mass unit of the compound as shown in formula 63 for kilogram.
9. preparation method as claimed in claim 7 or 8, it is characterised in that the preparation of described compound as shown in Equation 14
Method, further comprises following steps：In a solvent, under condensation catalyst effect, by the chemical combination as shown in formula 62
Thing carries out condensation reaction with acetamide, generates the described compound as shown in formula 63；
Wherein, described R is C1～C3Alkyl.
10. preparation method as claimed in claim 9, it is characterised in that described C1～C3Alkyl is methyl or ethyl；
And/or, the condensation catalyst in described condensation reaction is p-methyl benzenesulfonic acid, boron trifluoride diethyl etherate and poly phosphorus
One or more in acid；When described condensation catalyst is p-methyl benzenesulfonic acid, described p-methyl benzenesulfonic acid with
The mass ratio of the described compound as shown in formula 62 is 1:20～3:20；When described condensation catalyst is boron trifluoride
During ether, described boron trifluoride diethyl etherate and the mass ratio of the described compound as shown in formula 62 are 1:25～1:15；Work as institute
When the condensation catalyst stated is polyphosphoric acids, the quality of described polyphosphoric acids and the described compound as shown in formula 62
Than for 1:2～1:4；
And/or, the solvent of described condensation reaction is one or more in hexamethylene, toluene, normal heptane and benzene；
And/or, described acetamide and the mol ratio of the described compound as shown in formula 62 are 1.4：1～3.5：1；
And/or, the volume of the solvent of described condensation reaction is 4 with the mass ratio of the compound as shown in formula 62:1～6:1,
The wherein unit of the volume of solvent to rise, the unit of the quality of the compound as shown in formula 62 for kilogram.
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| CN105001098B (en) * | 2015-07-26 | 2016-09-14 | 嵊州市油脂化工有限公司 | A kind of preparation method of 3 (R)/(S)-amino-n-butyl alcohol |
| CN104961640B (en) * | 2015-07-26 | 2016-09-07 | 嵊州市油脂化工有限公司 | A kind of preparation method of optically pure 3-amino-n-butyl alcohol |
| CN108424370A (en) * | 2017-02-13 | 2018-08-21 | 上海弈柯莱生物医药科技有限公司 | A kind of preparation method of R-3- amino butanols |
| CN106966912B (en) * | 2017-04-01 | 2019-07-02 | 沧州那瑞化学科技有限公司 | (R) preparation method of -3- amino butanol |
| CN108689866B (en) * | 2017-04-06 | 2022-05-10 | 江西博腾药业有限公司 | Synthesis method of (R) -3-aminobutanol |
| CN109576317B (en) | 2017-09-29 | 2023-01-06 | 弈柯莱(台州)药业有限公司 | Method for preparing R-3-aminobutyric acid by enzyme method |
| CN108374027B (en) * | 2018-03-09 | 2019-08-20 | 长兴制药股份有限公司 | A kind of preparation method of R-3- aminobutyric acid |
| CN108586272A (en) * | 2018-06-28 | 2018-09-28 | 浙江昌明药业有限公司 | A kind of preparation method of 3- aminopropanols or 3- alanine derivatives |
| CN110054563A (en) * | 2019-06-10 | 2019-07-26 | 江西隆莱生物制药有限公司 | The Preparation Method And Their Intermediate of butyrolactone compound |
| CN110683960A (en) * | 2019-08-22 | 2020-01-14 | 台州达辰药业有限公司 | Synthesis method of (R) -3-aminobutanol |
| CN113336655A (en) * | 2020-12-30 | 2021-09-03 | 江西迪赛诺制药有限公司 | Preparation method of (R) -3-aminobutanol |
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