TW201623213A - Method of preparing (1R,2S)-2-(3,4-difluorophenyl)cyclopropy lamine - Google Patents
Method of preparing (1R,2S)-2-(3,4-difluorophenyl)cyclopropy lamine Download PDFInfo
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- TW201623213A TW201623213A TW103144112A TW103144112A TW201623213A TW 201623213 A TW201623213 A TW 201623213A TW 103144112 A TW103144112 A TW 103144112A TW 103144112 A TW103144112 A TW 103144112A TW 201623213 A TW201623213 A TW 201623213A
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- QVUBIQNXHRPJKK-IMTBSYHQSA-N (1r,2s)-2-(3,4-difluorophenyl)cyclopropan-1-amine Chemical compound N[C@@H]1C[C@H]1C1=CC=C(F)C(F)=C1 QVUBIQNXHRPJKK-IMTBSYHQSA-N 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 60
- -1 boron hydride compound Chemical class 0.000 claims abstract description 34
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 15
- 229910010277 boron hydride Inorganic materials 0.000 claims abstract description 9
- 238000006731 degradation reaction Methods 0.000 claims abstract description 5
- 239000000460 chlorine Substances 0.000 claims abstract description 4
- 238000006722 reduction reaction Methods 0.000 claims abstract description 4
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 146
- 150000001875 compounds Chemical class 0.000 claims description 122
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 96
- 239000012044 organic layer Substances 0.000 claims description 73
- 239000002585 base Substances 0.000 claims description 62
- 239000010410 layer Substances 0.000 claims description 55
- 230000035484 reaction time Effects 0.000 claims description 53
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 230000009471 action Effects 0.000 claims description 30
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 30
- 239000000047 product Substances 0.000 claims description 28
- 239000000126 substance Substances 0.000 claims description 25
- 239000012295 chemical reaction liquid Substances 0.000 claims description 24
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-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
- 238000003756 stirring Methods 0.000 claims description 18
- 229940126062 Compound A Drugs 0.000 claims description 17
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 239000003446 ligand Substances 0.000 claims description 14
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 13
- 238000006467 substitution reaction Methods 0.000 claims description 13
- XDLNRRRJZOJTRW-UHFFFAOYSA-N thiohypochlorous acid Chemical compound ClS XDLNRRRJZOJTRW-UHFFFAOYSA-N 0.000 claims description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 239000012298 atmosphere Substances 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- YAXGXEOYWAIEER-UHFFFAOYSA-N acetic acid;triethylphosphane Chemical compound CC([O-])=O.CC[PH+](CC)CC YAXGXEOYWAIEER-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 235000011181 potassium carbonates Nutrition 0.000 claims description 9
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 9
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 8
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 7
- 239000012267 brine Substances 0.000 claims description 7
- 239000011575 calcium Substances 0.000 claims description 7
- 229910052791 calcium Inorganic materials 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 6
- 229940011051 isopropyl acetate Drugs 0.000 claims description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- ZQBSPSZMRYBLLZ-UHFFFAOYSA-N CC(CCCCCCCCCCl)(C)C Chemical compound CC(CCCCCCCCCCl)(C)C ZQBSPSZMRYBLLZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000010941 cobalt Chemical group 0.000 claims description 3
- 229910017052 cobalt Inorganic materials 0.000 claims description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical group [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 229910052759 nickel Chemical group 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 3
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 238000007098 aminolysis reaction Methods 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- MOOAHMCRPCTRLV-UHFFFAOYSA-N boron sodium Chemical compound [B].[Na] MOOAHMCRPCTRLV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 3
- ZTEHOZMYMCEYRM-UHFFFAOYSA-N 1-chlorodecane Chemical compound CCCCCCCCCCCl ZTEHOZMYMCEYRM-UHFFFAOYSA-N 0.000 claims 2
- CJEAKKMNOSJYMY-UHFFFAOYSA-N 2-chloro-2-methylundecane Chemical compound CCCCCCCCCC(C)(C)Cl CJEAKKMNOSJYMY-UHFFFAOYSA-N 0.000 claims 1
- VDDRQJHPSHDTGX-UHFFFAOYSA-N 3-tert-butyl-2-chloro-2-methylundecane Chemical compound C(C)(C)(C)C(C(C)(C)Cl)CCCCCCCC VDDRQJHPSHDTGX-UHFFFAOYSA-N 0.000 claims 1
- 238000007167 Hofmann rearrangement reaction Methods 0.000 claims 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- XLKNMWIXNFVJRR-UHFFFAOYSA-N boron potassium Chemical compound [B].[K] XLKNMWIXNFVJRR-UHFFFAOYSA-N 0.000 claims 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- UNJRFWWCCAHSRB-MRVPVSSYSA-N (2s)-2-(3,4-difluorophenyl)oxirane Chemical compound C1=C(F)C(F)=CC=C1[C@@H]1OC1 UNJRFWWCCAHSRB-MRVPVSSYSA-N 0.000 abstract description 5
- UNJRFWWCCAHSRB-UHFFFAOYSA-N 2-(3,4-difluorophenyl)oxirane Chemical compound C1=C(F)C(F)=CC=C1C1OC1 UNJRFWWCCAHSRB-UHFFFAOYSA-N 0.000 abstract 2
- 238000005915 ammonolysis reaction Methods 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 5
- 229960002528 ticagrelor Drugs 0.000 description 5
- IFMWWVGVDOTBNN-UHFFFAOYSA-N 2-chloro-2,3,3-trimethylbutane Chemical compound CC(C)(C)C(C)(C)Cl IFMWWVGVDOTBNN-UHFFFAOYSA-N 0.000 description 4
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000013517 stratification Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- NBRKLOOSMBRFMH-UHFFFAOYSA-N tert-butyl chloride Chemical compound CC(C)(C)Cl NBRKLOOSMBRFMH-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000005465 B01AC22 - Prasugrel Substances 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 2
- 229960004197 prasugrel Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- PCUXPUYQAAGWLP-UHFFFAOYSA-N 1-cyclohexadecyl-1,8-diazacyclohexadecane Chemical group N1(CCCCCCNCCCCCCCC1)C1CCCCCCCCCCCCCCC1 PCUXPUYQAAGWLP-UHFFFAOYSA-N 0.000 description 1
- RRIQVLZDOZPJTH-UHFFFAOYSA-N 3,5-di-tert-butyl-2-hydroxybenzaldehyde Chemical compound CC(C)(C)C1=CC(C=O)=C(O)C(C(C)(C)C)=C1 RRIQVLZDOZPJTH-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 description 1
- VGEHJDZULQEXFX-UHFFFAOYSA-N O.O.O.O.[Co].[Co] Chemical compound O.O.O.O.[Co].[Co] VGEHJDZULQEXFX-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229910001429 cobalt ion Inorganic materials 0.000 description 1
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 description 1
- ZBYYWKJVSFHYJL-UHFFFAOYSA-L cobalt(2+);diacetate;tetrahydrate Chemical compound O.O.O.O.[Co+2].CC([O-])=O.CC([O-])=O ZBYYWKJVSFHYJL-UHFFFAOYSA-L 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000004698 iron complex Chemical class 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- XOPUORAQCYGJPT-UHFFFAOYSA-N methanesulfonic acid;hydrochloride Chemical compound Cl.CS(O)(=O)=O XOPUORAQCYGJPT-UHFFFAOYSA-N 0.000 description 1
- 229910001453 nickel ion Inorganic materials 0.000 description 1
- BQPGQJRHFPPZHM-UHFFFAOYSA-L nickel(2+);carbonate;tetrahydrate Chemical compound O.O.O.O.[Ni+2].[O-]C([O-])=O BQPGQJRHFPPZHM-UHFFFAOYSA-L 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- KAVSMINTEBGDTI-UHFFFAOYSA-N pyridine;thiophene Chemical compound C=1C=CSC=1.C1=CC=NC=C1 KAVSMINTEBGDTI-UHFFFAOYSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 239000002699 waste 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
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
本發明是有關一種製備(1R,2S)-2-(3,4-二氟苯基)環丙胺的方法，屬於藥物化學技術領域。 The invention relates to a method for preparing (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine, belonging to the technical field of medicinal chemistry.
替卡格雷(ticagrelor)是一種新型的小分子抗凝血藥，具有選擇性的作用效果，歐盟和美國食品藥品管理局(FDA)分別於2010年12月和2011年7月批准上市銷售。目前，包括歐盟、美國、巴西、加拿大、澳大利亞及俄羅斯等40多個國家批准替卡格雷用於治療急性冠狀動脈綜合征(acutecoronarysyndrome，ACS)。臨床試驗證實，與氯吡格雷、普拉格雷等噻吩吡啶類抗凝血藥不同，替卡格雷能可逆性地作用於二磷酸腺苷(adenosinediphosphate，ADP)受體亞型P2Y12，明顯抑制ADP引起的血小板聚集，且口服起效快，有助於改善ACS患者的症狀，降低ACS臨床治療中形成血栓的風險，尤其適用於需要進行冠狀動脈旁 路移植術(coronaryarterybypassgraft，CABG)的患者，克服氯吡格雷和普拉格雷的不足。 Ticagrelor is a new type of small molecule anticoagulant with selective effects. The European Union and the US Food and Drug Administration (FDA) approved the sale in December 2010 and July 2011, respectively. Currently, more than 40 countries including the European Union, the United States, Brazil, Canada, Australia and Russia have approved ticagrelor for the treatment of acute coronary syndrome (ACS). Clinical trials have confirmed that, unlike thiophene pyridine, prasugrel and other thienopyridine anticoagulants, ticagrelor can reversibly act on adenosine diphosphate (ADP) receptor subtype P2Y12, significantly inhibiting ADP Platelet aggregation, and rapid oral administration, can help improve the symptoms of ACS patients, reduce the risk of thrombosis in ACS clinical treatment, especially for the need for coronary artery bypass Patients with pathology (coronaryarterybypassgraft, CABG) overcome the deficiencies of clopidogrel and prasugrel.
(1R,2S)-2-(3,4-二氟苯基)環丙胺是合成替卡格雷的一個關鍵中間體。 (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine is a key intermediate for the synthesis of ticagrelor.
現有技術中，合成(1R,2S)-2-(3,4-二氟苯基)環丙胺的方法主要為兩種：一是通過合成消旋體的2-(3,4-二氟苯基)環丙胺，然後通過拆分得到(1R,2S)-2-(3,4-二氟苯基)環丙胺；這樣會損失一半的原料，造成很大的浪費，而且合成的效率也很低。二是通過合成手性的(S)-(3,4-二氟苯基)環氧乙烷，以此為原料來合成(1R,2S)-2-(3,4-二氟苯基)環丙胺；但目前公佈的合成手性環氧化合物的試劑比較昂貴，最終成本還是很高。 In the prior art, there are mainly two methods for synthesizing (1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamine: one is by synthesizing racemic 2-(3,4-difluorobenzene) () Cyclopropylamine, then by resolution to give (1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamine; this will lose half of the raw materials, causing a great waste, and the synthesis efficiency is also very low. The second is to synthesize (1R,2S)-2-(3,4-difluorophenyl) by synthesizing a chiral (S)-(3,4-difluorophenyl)oxirane. Cyclopropylamine; however, the currently published reagents for the synthesis of chiral epoxy compounds are relatively expensive and the final cost is still high.
因此，需要研發更多製備(1R,2S)-2-(3,4-二氟苯基)環丙胺的方法，以降低其合成成本，從而降低替卡格雷的製備成本。 Therefore, there is a need to develop more methods for preparing (1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamine to reduce the cost of synthesis, thereby reducing the cost of preparation of ticagrelor.
本發明的目的是提供一種製備(1R,2S)-2-(3,4-二氟苯基)環丙胺的方法。此方法包含：(1)使1,2-二氟苯與醯氯在三氯化鋁的作用下進行傅克反應，以形成化合物A，其中醯氯的化學結構式為，其中R為氫、有取代或無取代之烷基或有取
代或無取代之芳香基，化合物A的化學結構式為
根據本發明一實施例，催化劑包含金屬手性配 體，其化學結構式為，其中M為鐵、 鈷或鎳，A為氫、鹵素、烷基或酯基()。 According to an embodiment of the invention, the catalyst comprises a metal chiral ligand, the chemical structural formula of which is Wherein M is iron, cobalt or nickel and A is hydrogen, halogen, alkyl or ester group ( ).
根據本發明一實施例，步驟(1)中，1,2-二氟苯、三氯化鋁與醯氯的莫耳比為1：(1~10)：(1~10)，反應溫度為0~40℃，反應時間為3~30小時；步驟(2)中，化合物A與硼氫化合物的莫耳比為1：(0.2~2)，反應溫度為0~50℃，反應時間為0.5~10小時；步驟(3)中，反應溫度為0~40℃，反應時間為1~12小時；步驟(4)中，產物C、金屬手性配體與水的莫耳比為1：(0.01~0.1)：(0.4~0.8)，反 應溫度10~60℃，反應時間12~60小時；步驟(5)中，化合物D、叔丁醇化合物與磷醯基乙酸三乙酯的莫耳比為1：(1~3)：(1~2)，反應溫度40~110℃，反應時間1~30小時；步驟(6)中，化合物F、醇鈉與甲酸甲酯的莫耳比為1：(0.5~2)：(0.5~2)，反應溫度為40~65℃，氣氛的壓力為0~10托，反應時間為10~80小時；步驟(7)中，化合物G在鹼的作用下進行霍夫曼降解反應，鹼包含氫氧化鈉與次氯酸鈉，化合物G、氫氧化鈉與次氯酸鈉的莫耳比為1：(1~5)：(2~8)，反應溫度為40~65℃，反應時間為1~80小時。 According to an embodiment of the present invention, in the step (1), the molar ratio of 1,2-difluorobenzene, aluminum trichloride and ruthenium chloride is 1: (1~10): (1~10), and the reaction temperature is 0~40°C, the reaction time is 3~30 hours; in step (2), the molar ratio of compound A to borohydride is 1: (0.2~2), the reaction temperature is 0~50°C, and the reaction time is 0.5. ~10 hours; in step (3), the reaction temperature is 0-40 ° C, the reaction time is 1 to 12 hours; in step (4), the molar ratio of product C, metal chiral ligand to water is 1: ( 0.01~0.1): (0.4~0.8), anti The temperature should be 10~60 ° C, the reaction time is 12~60 hours; in step (5), the molar ratio of compound D, t-butanol compound and triethyl phosphonium acetate is 1: (1~3): (1 ~2), the reaction temperature is 40~110 °C, the reaction time is 1~30 hours; in step (6), the molar ratio of compound F, sodium alkoxide and methyl formate is 1: (0.5~2): (0.5~2) The reaction temperature is 40 to 65 ° C, the pressure of the atmosphere is 0 to 10 Torr, and the reaction time is 10 to 80 hours. In the step (7), the compound G is subjected to a Hofmann degradation reaction under the action of a base, and the base contains hydrogen. The molar ratio of sodium oxide and sodium hypochlorite, compound G, sodium hydroxide and sodium hypochlorite is 1: (1~5): (2~8), the reaction temperature is 40~65 °C, and the reaction time is 1~80 hours.
根據本發明一實施例，步驟(1)中，1,2-二氟苯、三氯化鋁與醯氯的莫耳比為1：1.2：1.2，反應溫度為回流溫度，反應時間為10小時；步驟(2)中，化合物A與硼氫化合物的莫耳比為1：0.25，反應溫度為10℃，反應時間為2小時；步驟(3)中，反應溫度為25℃，反應時間為8小時；步驟(4)中，產物C、金屬手性配體與水的莫耳比為1：0.025：0.5，反應溫度為25℃，反應時間為48小時；步驟(5)中，化合物D、叔丁醇化合物與磷醯基乙酸三乙酯的莫耳比為1：1.5：1.5，反應溫度為80℃，反應時間為11小時；步驟(6)中，化合物F、醇鈉與甲酸甲酯的莫耳比為1：0.75：1，反應溫度為40℃，氣氛的壓力為2托，反應時間為48小時；步驟(7)中，化合物G、氫氧化鈉與次氯酸鈉的莫耳比為1：5：2，反應溫度為40℃，反應時間為8小時。 According to an embodiment of the present invention, in the step (1), the molar ratio of 1,2-difluorobenzene, aluminum trichloride and ruthenium chloride is 1:1.2:1.2, the reaction temperature is reflux temperature, and the reaction time is 10 hours. In the step (2), the molar ratio of the compound A to the boron hydride compound is 1:0.25, the reaction temperature is 10 ° C, and the reaction time is 2 hours; in the step (3), the reaction temperature is 25 ° C, and the reaction time is 8 Hour; in step (4), the molar ratio of product C, metal chiral ligand to water is 1:0.025:0.5, the reaction temperature is 25 ° C, and the reaction time is 48 hours; in step (5), compound D, The molar ratio of the tert-butanol compound to triethyl phosphonium acetate is 1:1.5:1.5, the reaction temperature is 80 ° C, and the reaction time is 11 hours; in the step (6), the compound F, the sodium alkoxide and the methyl formate are used. The molar ratio is 1:0.75:1, the reaction temperature is 40 ° C, the pressure of the atmosphere is 2 Torr, and the reaction time is 48 hours; in the step (7), the molar ratio of the compound G, sodium hydroxide and sodium hypochlorite is 1 : 5:2, the reaction temperature was 40 ° C, and the reaction time was 8 hours.
根據本發明一實施例，步驟(1)中，使1,2-二氟苯與醯氯在三氯化鋁的作用下，於一溶劑中及氮氣下進行傅 克反應，溶劑為二氯甲烷、二氯乙烷或其組合；步驟(2)中，使化合物A與硼氫化合物於一溶劑中進行還原反應，硼氫化合物為鈉硼氫、鉀硼氫或其組合，溶劑為醇；步驟(3)中，使產物B於一溶劑中且在鹼的作用下進行閉環反應，溶劑為二氯甲烷、二氯乙烷或其組合，鹼為無機鹼、有機鹼或其組合，無機鹼為氫氧化鉀、氫氧化鈉或其組合，有機鹼為氨水、三乙胺、三丁胺、1,8-二氮雜二環十一碳-7-烯、吡啶、咪唑或其組合；步驟(5)中，使化合物D與磷醯基乙酸三乙酯在一溶劑中及叔丁醇化合物的作用下進行酯化反應，溶劑為苯、甲苯、二甲苯或其組合，叔丁醇化合物為叔丁醇鈉、叔丁醇鉀或其組合；步驟(6)中，使化合物F與甲酸甲酯在氣氛及醇中及在醇鈉的作用下進行氨解反應，醇為甲醇、乙醇或其組合，醇鈉為甲醇鈉、乙醇鈉或其組合。 According to an embodiment of the present invention, in the step (1), the 1,2-difluorobenzene and the ruthenium chloride are subjected to the action of aluminum trichloride in a solvent and under nitrogen. a reaction, the solvent is dichloromethane, dichloroethane or a combination thereof; in the step (2), the compound A and the boron hydride compound are subjected to a reduction reaction in a solvent, and the boron hydride compound is sodium boron hydride, potassium borohydride or In combination, the solvent is an alcohol; in the step (3), the product B is subjected to a ring closure reaction in a solvent and under the action of a base, the solvent is dichloromethane, dichloroethane or a combination thereof, and the alkali is an inorganic base or an organic The base or a combination thereof, the inorganic base is potassium hydroxide, sodium hydroxide or a combination thereof, and the organic base is ammonia water, triethylamine, tributylamine, 1,8-diazabicycloundec-7-ene, pyridine , imidazole or a combination thereof; in the step (5), the esterification reaction of the compound D with triethyl phosphonium acetate in a solvent and a tert-butanol compound, the solvent is benzene, toluene, xylene or In combination, the tert-butanol compound is sodium t-butoxide, potassium t-butoxide or a combination thereof; in the step (6), the compound F and the methyl formate are subjected to an aminolysis reaction under the action of an atmosphere and an alcohol and under the action of sodium alkoxide. The alcohol is methanol, ethanol or a combination thereof, and the sodium alkoxide is sodium methoxide, sodium ethoxide or a combination thereof.
根據本發明一實施例，步驟(2)中，醇為甲醇；步驟(3)中，鹼為三乙胺。 According to an embodiment of the present invention, in the step (2), the alcohol is methanol; and in the step (3), the base is triethylamine.
根據本發明一實施例，其中步驟(1)包含：反應結束後，冷卻反應液；將反應液倒入冰水中攪拌至分層；將分層之水層用二氯甲烷萃取，再合併有機層；依序用水洗、飽和碳酸氫鈉洗及水洗有機層；以硫酸鎂乾燥有機層；以及過濾及濃縮有機層，以得到化合物A；步驟(2)包含：反應結束後，冷卻反應液；依序加入二氯甲烷及滴加NH4Cl水溶液至反應液中，攪拌至分層；將分層之水層用二氯甲烷萃取，再合併有機層；以飽和氯化 鈉水溶液乾燥有機層；以及過濾及濃縮有機層，以得到產物B；步驟(3)包含：反應結束後，冷卻反應液並分層；將分層之水層用二氯甲烷萃取，再合併有機層；以及水洗、乾燥及濃縮有機層，以得到產物C；步驟(4)包含：反應結束後，加入正己烷和水至反應液中，再攪拌及過濾至分層；將分層之水層用正己烷萃取，再合併有機層；以及水洗、乾燥及濃縮有機層，以得到化合物D；步驟(4)更包含：將分層之水層用正己烷萃取之後，再合併水層；加入氯化鈉至水層中，再用乙酸乙酯萃取，再合併有機層；以及用飽和氯化鈉水溶液洗、乾燥及濃縮有機層，以得到化合物E；步驟(5)包含：反應結束後，冷卻反應液；加入水至反應液中靜置至分層；將分層之水層用甲苯萃取，再合併有機層；以及水洗及減壓濃縮有機層，以得到化合物F；步驟(6)包含：反應結束後，冷卻反應液；加入水至反應液中再過濾，以得到一濾餅；依序用甲醇與水之混合物洗、水洗及二異丙醚洗濾餅；以及真空乾燥濾餅，以得到化合物G；步驟(7)包含：反應結束後，冷卻反應液；加入乙酸異丙酯至反應液中靜置至分層；將分層之水層用乙酸異丙酯萃取，再合併有機層；以及水洗及濃縮有機層，以得到(1R,2S)-2-(3,4-二氟苯基)環丙胺。 According to an embodiment of the invention, the step (1) comprises: after the reaction is finished, cooling the reaction liquid; pouring the reaction liquid into ice water and stirring until stratification; extracting the layered water layer with dichloromethane, and merging the organic layer The organic layer is washed with water, saturated with sodium hydrogencarbonate and washed with water; the organic layer is dried with magnesium sulfate; and the organic layer is filtered and concentrated to obtain compound A; step (2) comprises: after the reaction is finished, the reaction liquid is cooled; sequence and dichloromethane was added dropwise NH 4 Cl solution to the reaction mixture, stirred until delamination; the aqueous layer was extracted with dichloromethane stratification, then the organic layers combined; the organic layer was dried with saturated aqueous sodium chloride solution; and Filtration and concentration of the organic layer to obtain product B; step (3) comprises: after the reaction is completed, the reaction liquid is cooled and layered; the layered aqueous layer is extracted with dichloromethane, and the organic layer is combined; and washed, dried and The organic layer is concentrated to obtain product C; step (4) comprises: after the reaction is completed, n-hexane and water are added to the reaction liquid, and then stirred and filtered to separate the layers; the layered aqueous layer is extracted with n-hexane, and then combined. Organic layer; Washing, drying and concentrating the organic layer to obtain compound D; step (4) further comprises: extracting the layered aqueous layer with n-hexane, and then combining the aqueous layer; adding sodium chloride to the aqueous layer, and then using acetic acid The ester is extracted, and the organic layer is further combined; and the organic layer is washed with a saturated aqueous solution of sodium chloride, dried and concentrated to obtain compound E; step (5) comprises: after the reaction is finished, the reaction solution is cooled; and water is added to the reaction solution for standing. To the layering; the layered aqueous layer is extracted with toluene, and the organic layer is further combined; and the organic layer is concentrated by water washing and under reduced pressure to obtain a compound F; the step (6) comprises: after the reaction is finished, the reaction liquid is cooled; The reaction solution is further filtered to obtain a filter cake; the mixture is washed with a mixture of methanol and water, washed with water and diisopropyl ether; and the filter cake is dried under vacuum to obtain compound G; step (7) comprises: reaction After completion, the reaction solution is cooled; isopropyl acetate is added to the reaction solution to stand until the layer is separated; the layered aqueous layer is extracted with isopropyl acetate, and the organic layer is further combined; and the organic layer is washed with water and concentrated to obtain ( 1R,2S)-2-(3,4-difluorophenyl) Propylamine.
根據本發明一實施例，製備(1R,2S)-2-(3,4-二氟苯基)環丙胺的方法更包含：(i)使化合物E與三甲基氯矽烷進行取代反應，以形成化 合物H，化合物H的化學結構式為 (ii)使化合物H與磺醯氯化合物進行取代反應，以形成 化合物J，化合物J的化學結構式為，其中R' 為甲磺醯基或對甲苯磺醯基；以及 (iii)使化合物J進行閉環反應，以形成化合物D，其中步驟(i)在鹼的作用下進行取代反應，鹼包含三乙胺、三丁胺、1,8-二氮雜二環十一碳-7-烯、吡啶、咪唑或其組合；步驟(ii)在鹼的作用下進行取代反應，鹼包含三乙胺、三丁胺、1,8-二氮雜二環十一碳-7-烯、吡啶、咪唑或其組合；步驟(iii)在鹼的作用下進行閉環反應，鹼為氫氧化鉀、氫氧化鈉、碳酸鉀、碳酸鈉、碳酸氫鉀、碳酸氫鈉或其組合。 According to an embodiment of the invention, the method for preparing (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine further comprises: (i) subjecting compound E to trimethylchloromethane for substitution reaction, Forming compound H, the chemical structural formula of compound H is (ii) subjecting compound H to a sulfonium chloride compound to carry out a substitution reaction to form compound J, and the chemical structural formula of compound J is Wherein R ' is methanesulfonyl or p-toluenesulfonyl; and (iii) ring-closing reaction of compound J to form compound D, wherein step (i) is subjected to a substitution reaction under the action of a base, and the base comprises triethyl An amine, tributylamine, 1,8-diazabicycloundec-7-ene, pyridine, imidazole or a combination thereof; step (ii) is subjected to a substitution reaction under the action of a base, the base comprising triethylamine, three Butylamine, 1,8-diazabicycloundec-7-ene, pyridine, imidazole or a combination thereof; step (iii) is subjected to a ring closure reaction under the action of a base, the base is potassium hydroxide, sodium hydroxide, Potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate or a combination thereof.
根據本發明一實施例，步驟(i)中，使化合物E與三甲基氯矽烷於一溶劑中進行取代反應，溶劑為二氯甲烷、二氯乙烷或其組合；步驟(iii)中，使化合物J在醇中及鹼的作用下進行閉環反應，鹼為碳酸鉀、碳酸鈉或其組合。 According to an embodiment of the present invention, in the step (i), the compound E and the trimethylchloromethane are subjected to a substitution reaction in a solvent, the solvent is dichloromethane, dichloroethane or a combination thereof; in the step (iii), The compound J is subjected to a ring closure reaction in an alcohol and a base, and the base is potassium carbonate, sodium carbonate or a combination thereof.
根據本發明一實施例，步驟(i)中，化合物E、鹼與三甲基氯矽烷的莫耳比為1：(1~1.5)：(1~2)，反應溫 度為0~30℃，反應時間為1~12小時；步驟(ii)中，化合物H、鹼與磺醯氯化合物的莫耳比為1：(1~1.2)：(1~1.5)，反應溫度為0~35℃，反應時間為1~8小時；步驟(iii)中，化合物J與鹼的莫耳比為1：(1~10)，反應溫度為0~50℃，反應時間為1~8小時。 According to an embodiment of the present invention, in the step (i), the molar ratio of the compound E, the base and the trimethylchlorodecane is 1: (1 to 1.5): (1 to 2), and the reaction temperature is The degree is 0~30 ° C, the reaction time is 1~12 hours; in step (ii), the molar ratio of the compound H, the base and the sulfonium chloride compound is 1: (1~1.2): (1~1.5), the reaction The temperature is 0~35°C, the reaction time is 1~8 hours; in step (iii), the molar ratio of compound J to alkali is 1: (1~10), the reaction temperature is 0~50°C, and the reaction time is 1 ~8 hours.
根據本發明一實施例，步驟(i)中，化合物E、鹼與三甲基氯矽烷的莫耳比為1：1.2：1.0，反應溫度為0℃，反應時間為1小時；步驟(ii)中，化合物H、鹼與磺醯氯化合物的莫耳比為1：1.0：1.0，反應溫度為0℃，反應時間為6小時；步驟(iii)中，化合物J與鹼的莫耳比為1：3，反應溫度為0℃，反應時間為2小時。 According to an embodiment of the present invention, in the step (i), the molar ratio of the compound E, the base and the trimethylchlorodecane is 1:1.2:1.0, the reaction temperature is 0 ° C, and the reaction time is 1 hour; step (ii) Wherein, the molar ratio of the compound H, the base and the sulfonium chloride compound is 1:1.0:1.0, the reaction temperature is 0 ° C, and the reaction time is 6 hours; in the step (iii), the molar ratio of the compound J to the base is 1 : 3, the reaction temperature was 0 ° C, and the reaction time was 2 hours.
根據本發明一實施例，步驟(ii)包含：反應結束後，加水至反應液中，攪拌至分層；將分層之水層用二氯甲烷萃取，再合併有機層；以及水洗及乾燥旋蒸有機層，以得到化合物J；步驟(iii)包含：反應結束後，過濾反應液，以得到濾液；濃縮濾液，再加入水和乙酸乙酯至分層；將分層之水層用乙酸乙酯萃取，再合併有機層；用鹽水洗、乾燥及濃縮有機層；加入鈣氫至有機層中；以及減壓蒸餾有機層，以得到化合物D。 According to an embodiment of the present invention, the step (ii) comprises: after the reaction is completed, adding water to the reaction liquid, stirring to separate the layers; extracting the layered aqueous layer with dichloromethane, and further combining the organic layers; and washing and drying The organic layer is evaporated to obtain the compound J; the step (iii) comprises: after the reaction is completed, the reaction solution is filtered to obtain a filtrate; the filtrate is concentrated, and water and ethyl acetate are added to the layer; the layered aqueous layer is treated with ethyl acetate The ester is extracted, and the organic layer is further combined; the organic layer is washed with brine, dried and concentrated; calcium hydrogen is added to the organic layer; and the organic layer is distilled under reduced pressure to give compound D.
根據本發明一實施例，製備(1R,2S)-2-(3,4-二氟苯基)環丙胺的方法更包含：
(iv)使化合物E與叔丁基二甲基氯矽烷進行取代反應，以形成化合物K，化合物K的化學結構式為
根據本發明一實施例，步驟(iv)中，使化合物E與叔丁基二甲基氯矽烷於一溶劑中進行取代反應，溶劑為二氯甲烷、二氯乙烷或其組合；步驟(vii)中，使化合物M在醇中及鹼的作用下進行閉環反應，鹼為碳酸鉀、碳酸鈉或其組合。 According to an embodiment of the present invention, in the step (iv), the compound E and the tert-butyldimethylchloromethane are subjected to a substitution reaction in a solvent, the solvent is dichloromethane, dichloroethane or a combination thereof; the step (vii) In the compound, the compound M is subjected to a ring closure reaction under the action of an alcohol and a base, and the base is potassium carbonate, sodium carbonate or a combination thereof.
根據本發明一實施例，步驟(iv)中，化合物E、鹼與叔丁基二甲基氯矽烷的莫耳比為1：(1~1.5)：(1~2)，反應溫度為0~30℃，反應時間為1~12小時；步驟(v)中，化合物K、鹼與磺醯氯化合物的莫耳比為1：(1~1.2)：(1~1.5)，反應溫度為0~35℃，反應時間為1~8小時；步驟(vi)中，使化合物L與四丁基氟化胺於四氫呋喃中在室溫下反應；步驟(vii)中，化合物M與鹼的莫耳比為1：(1~10)，反應溫度為0~50℃，反應時間為1~8小時。 According to an embodiment of the present invention, in the step (iv), the molar ratio of the compound E, the base and the tert-butyldimethylchloromethane is 1: (1 to 1.5): (1 to 2), and the reaction temperature is 0~. At 30 ° C, the reaction time is 1 to 12 hours; in step (v), the molar ratio of the compound K, the base and the sulfonium chloride compound is 1: (1 to 1.2): (1 to 1.5), and the reaction temperature is 0~ 35 ° C, the reaction time is 1 to 8 hours; in step (vi), the compound L is reacted with tetrabutylammonium fluoride in tetrahydrofuran at room temperature; in step (vii), the molar ratio of the compound M to the base It is 1: (1~10), the reaction temperature is 0~50 °C, and the reaction time is 1~8 hours.
根據本發明一實施例，步驟(iv)中，化合物E、鹼與叔丁基二甲基氯矽烷的莫耳比為1：1.2：1.0，反應溫度為0℃，反應時間為6小時；步驟(v)中，化合物K、鹼與磺醯氯化合物的莫耳比為1：1.0：1.0，反應溫度為0℃，反應時間為6小時；步驟(vii)中，化合物M與鹼的莫耳比為1：3，反應溫度為0℃，反應時間為2小時。 According to an embodiment of the present invention, in the step (iv), the molar ratio of the compound E, the base and the tert-butyldimethylchloromethane is 1:1.2:1.0, the reaction temperature is 0 ° C, and the reaction time is 6 hours; In (v), the molar ratio of the compound K, the base and the sulfonium chloride compound is 1:1.0:1.0, the reaction temperature is 0 ° C, and the reaction time is 6 hours; in the step (vii), the molar of the compound M and the base The ratio was 1:3, the reaction temperature was 0 ° C, and the reaction time was 2 hours.
根據本發明一實施例，步驟(v)包含：反應結束後，加水至反應液中，攪拌至分層；將分層之水層用二氯甲烷萃取，再合併有機層；以及水洗及乾燥旋蒸有機層，以得到化合物L； 步驟(vi)包含：反應結束後，加水至反應液中，攪拌至分層；將分層之水層用二氯甲烷萃取，再合併有機層；以及水洗及乾燥旋蒸有機層，以得到化合物M；步驟(vii)包含：反應結束後，過濾反應液，以得到濾液；濃縮濾液，再加入水和乙酸乙酯至分層；將分層之水層用乙酸乙酯萃取，再合併有機層；用鹽水洗、乾燥及濃縮有機層；加入鈣氫至有機層中；以及減壓蒸餾有機層，以得到化合物D。 According to an embodiment of the present invention, the step (v) comprises: after the reaction is completed, adding water to the reaction liquid, stirring to stratification; extracting the layered aqueous layer with dichloromethane, and further combining the organic layer; and washing and drying Evaporating the organic layer to obtain compound L; Step (vi) comprises: after the reaction is completed, adding water to the reaction liquid, stirring to separate the layers; extracting the layered aqueous layer with dichloromethane, and combining the organic layer; and washing and drying the organic layer to obtain a compound M; Step (vii) comprises: after the reaction is completed, the reaction solution is filtered to obtain a filtrate; the filtrate is concentrated, and water and ethyl acetate are added to the layer; the layered aqueous layer is extracted with ethyl acetate, and the organic layer is combined. Washing, drying and concentrating the organic layer with brine; adding calcium hydrogen to the organic layer; and distilling the organic layer under reduced pressure to give Compound D.
下面結合附圖、實施例對本發明作進一步描述。 The present invention will be further described below in conjunction with the accompanying drawings and embodiments.
實施例一：化合物A的製備
向反應瓶中加入二氯甲烷450ml及三氯化鋁133.5g(1mol)，進行攪拌。在氮氣保護下，向反應液中滴加氯乙醯氯113g(1mol)，滴加時間不少於10分鐘。滴加結 束，將反應液加熱到回流反應。回流反應30分鐘後，在回流下滴加1,2-二氟苯97g(0.85mol)，滴加時間不少於2小時。滴加結束後繼續回流反應1小時。反應結束，將反應液冷卻到20℃，再將反應液慢慢倒入500g冰水中，繼續攪拌30分鐘。待分層後，水層用二氯甲烷萃取。合併有機層用水洗，飽和碳酸氫鈉洗，水洗。有機層用過量的硫酸鎂乾燥，過濾，濃縮去除二氯甲烷。得到化合物A 158g，收率98%；1H-NMR：δ(ppm)：5.2(2H,s)；7.6(1H,dd),7.8(1H,m),8.0(1H,dd)。 450 ml of dichloromethane and 133.5 g (1 mol) of aluminum trichloride were added to the reaction flask, followed by stirring. Under a nitrogen atmosphere, 113 g (1 mol) of chloroacetic chloride was added dropwise to the reaction solution, and the dropwise addition time was not less than 10 minutes. At the end of the dropwise addition, the reaction solution was heated to reflux. After refluxing for 30 minutes, 97 g (0.85 mol) of 1,2-difluorobenzene was added dropwise under reflux, and the dropwise addition time was not less than 2 hours. After the completion of the dropwise addition, the reflux reaction was continued for 1 hour. After completion of the reaction, the reaction solution was cooled to 20 ° C, and the reaction solution was slowly poured into 500 g of ice water, and stirring was continued for 30 minutes. After layering, the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, saturated sodium bicarbonate and washed with water. The organic layer was dried over an excess of magnesium sulfate, filtered and concentrated to dichloromethane. To give Compound A 158g, yield 98%; 1 H-NMR: δ (ppm): 5.2 (2H, s); 7.6 (1H, dd), 7.8 (1H, m), 8.0 (1H, dd).
實施例二：產物B的製備 Example 2: Preparation of Product B
向反應瓶中加入甲醇50ml及化合物A 7.6g(0.04mol)。在攪拌的條件下，將反應液冷卻到0℃。慢慢向反應液中加入硼氫化鈉0.378g(0.01mol)，加入的過程中溫度小於5℃。硼氫化鈉加入後，將反應液的溫度升到室溫反應。反應結束後，將反應液冷卻到0℃，加入二氯甲烷，向反應液中滴加10%NH4Cl水溶液75ml。滴加結束後，攪拌30分鐘。分層。水層用二氯甲烷萃取。合併有機層，用鹽水洗。有機層乾燥，過濾。濃縮有機層，得到產物B 7.42g，收率96%；1H-NMR：δ(ppm)：3.9(2H,dd)；5.3(2H,dd)；7.3-7.5(3H,m)。 50 ml of methanol and 7.6 g (0.04 mol) of Compound A were added to the reaction flask. The reaction solution was cooled to 0 ° C under stirring. 0.378 g (0.01 mol) of sodium borohydride was slowly added to the reaction liquid, and the temperature during the addition was less than 5 °C. After the sodium borohydride was added, the temperature of the reaction solution was raised to room temperature to react. After completion of the reaction, the reaction solution was cooled to 0 ° C, dichloromethane was added, and 75 ml of a 10% aqueous NH 4 Cl solution was added dropwise to the reaction mixture. After the completion of the dropwise addition, the mixture was stirred for 30 minutes. Layered. The aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with brine. The organic layer was dried and filtered. The organic layer was concentrated to give the product B, 7.42 g,yield: 96%; 1 H-NMR: δ (ppm): 3.9 (2H, dd); 5.3 (2H, dd); 7.3-7.5 (3H, m).
實施例三：產物C的製備 Example 3: Preparation of Product C
向反應瓶中加入10%氫氧化鈉水溶液10.5g(0.02625mol)、產物B 4.813g(0.025mol)及二氯甲烷(DCM)50ml。在攪拌的條件，室溫反應。反應結束後，冷卻到室溫，分層。水層用二氯甲烷萃取；合併有機層，水洗。乾燥，濃縮有機層，得到產物C 3.8g，收率97.4%；1H-NMR：δ 2.71-2.73(1H,dd)；3.13-3.15(1H,m)；3.82-3.83(1H,m)；7.01-7.27(3H,m)。 To the reaction flask were added 10.5 g (0.02625 mol) of 10% aqueous sodium hydroxide solution, 4.813 g (0.025 mol) of product B, and 50 ml of dichloromethane (DCM). The reaction was carried out at room temperature under stirring conditions. After the reaction was completed, it was cooled to room temperature and layered. The aqueous layer was extracted with dichloromethane; the organic layers were combined and washed with water. Drying, concentrating the organic layer to give the product C 3.8 g, yield 97.4%; 1 H-NMR: δ 2.71-2.73 (1H, dd); 3.13 - 3.15 (1H, m); 3.82-3.83 (1H, m); 7.01-7.27 (3H, m).
實施例四：催化劑的製備 Example 4: Preparation of catalyst
向反應瓶中加入(s,s)-環己二胺22.96g(0.2mol)，無水乙醇1000ml，攪拌溶解。再將化合物I 94.35g(0.4mol)加入到反應液中。將反應液加熱到回流反 應，反應時間約2小時。反應結束後，冷卻到室溫。向反應液中滴加水500ml，攪拌。過濾，濾餅用少量95%乙醇25ml洗，過濾乾燥。得到化合物Ⅱ 106g，收率97%；1H-NMR：δ 1.24(9H,s)；1.41(9H,s)；1.45(1H,m)；1.8-1.65(1H,m)；2.0-1.8(2H,m)；3.32(1H,m)；6.98(1H,d)；7.30(1H,d)；8.3(1H,s)；13.72(1H,s)。 To the reaction flask, 22.96 g (0.2 mol) of (s,s)-cyclohexanediamine and 1000 ml of absolute ethanol were added, and the mixture was stirred and dissolved. Further, 94.35 g (0.4 mol) of the compound I was added to the reaction liquid. The reaction solution was heated to reflux for about 2 hours. After the reaction was completed, it was cooled to room temperature. 500 ml of water was added dropwise to the reaction mixture, followed by stirring. After filtration, the filter cake was washed with a small amount of 95% ethanol 25 ml, and dried by filtration. Obtained Compound II 106g, yield 97%; 1 H-NMR: δ 1.24 (9H, s); 1.41 (9H, s); 1.45 (1H, m); 1.8-1.65 (1H, m); 2.0-1.8 ( 2H, m); 3.32 (1H, m); 6.98 (1H, d); 7.30 (1H, d); 8.3 (1H, s); 13.72 (1H, s).
向反應瓶中加入化合物Ⅱ 106g(0.194mol)及乙醇1500ml，加熱溶解。再向反應液中加入四水合醋酸鈷92.2g(0.485mol)。將反應液加熱到回流反應，反應時間約2小時。冷卻反應液至5℃，加入水750ml，攪拌2小時。過濾，得到深棕色固體。旋蒸，80度乾燥得鈷配體催化劑化合物Ⅲ 109g，收率85%。 To the reaction flask, 106 g (0.194 mol) of compound II and 1500 ml of ethanol were added, and the mixture was dissolved by heating. Further, 92.2 g (0.485 mol) of cobalt acetate tetrahydrate was added to the reaction liquid. The reaction solution was heated to reflux for about 2 hours. The reaction solution was cooled to 5 ° C, 750 ml of water was added, and stirred for 2 hours. Filtration gave a dark brown solid. It was rotary-steamed and dried at 80 ° to obtain 109 g of a cobalt ligand catalyst compound III in a yield of 85%.
將四水合醋酸鈷改為三氯化鐵或四水合碳酸鎳，以同樣的方法，可以得到鐵配體催化劑或鎳配體催化 劑，例如或，但 不限於此。 By changing cobalt cobalt tetrahydrate to ferric chloride or nickel carbonate tetrahydrate, an iron ligand catalyst or a nickel ligand catalyst can be obtained in the same manner, for example. or , but not limited to this.
實施例五：化合物D和E的製備 Example 5: Preparation of Compounds D and E
向反應瓶中加入產物C 101g(0.6474mol)、化合物Ⅲ 10.7g(0.0169mol)及水5.83(0.3237mol)。將反應液在室溫下進行反應。反應60小時後，加入正己烷150ml和水150ml。強力攪拌2小時，過濾。濾液分層，水層用正己烷萃取。 Product C 101 g (0.6474 mol), compound III 10.7 g (0.0169 mol) and water 5.83 (0.3237 mol) were added to the reaction flask. The reaction solution was allowed to react at room temperature. After reacting for 60 hours, 150 ml of n-hexane and 150 ml of water were added. Stir vigorously for 2 hours and filter. The filtrate was separated and the aqueous layer was extracted with n-hexane.
合併有機層，水洗，乾燥，濃縮得化合物D的粗品45g。加入鈣氫2g，水沖泵減壓蒸餾，得化合物D 30g，光學純度98.3%，[α]D15=-4.2°(EtOH)收率30%；1H-NMR：δ 2.71-2.73(1H,dd)；3.13-3.15(1H,m)；3.82-3.83(1H,m)；7.01-7.27(3H,m)。 The organic layer was combined, washed with water, dried and evaporated, then, 2 g of calcium hydrogen was added, and the water was pumped under reduced pressure to obtain a compound D 30 g, an optical purity of 98.3%, [α] D15 = -4.2 ° (EtOH) yield 30%; 1 H-NMR: δ 2.71-2.73 (1H, Dd); 3.13 - 3.15 (1H, m); 3.82-3.83 (1H, m); 7.01-7.27 (3H, m).
合併水層，向水層中加入鹽，再用乙酸乙酯萃取。合併乙酸乙酯，用鹽水洗，乾燥，濃縮得化合物E 65g,[α]D15=-20°(EtOH)。1H-NMR：δ 2.2-2.3(1H,s)；2.71-2.73(1H,s)；3.5-3.9(2H,m)；4.7(1H,d)；7.01-7.27(3H,m)。 The aqueous layers were combined, and a salt was added to the aqueous layer and then ethyl acetate. Ethyl acetate was combined, washed with brine, dried and evaporated to ethylamine. 1H-NMR: δ 2.2-2.3 (1H, s); 2.71-2.73 (1H, s); 3.5-3.9 (2H, m); 4.7 (1H, d); 7.01-7.27 (3H, m).
實施例六：化合物D和E的製備 Example 6: Preparation of Compounds D and E
向反應瓶中加入產物C 101g(0.6474mol)、鐵配合物催化劑10g及水5.83(0.3237mol)。將反應液在室溫下進行反應。反應65小時後，加入正己烷250ml和水150ml。強力攪拌2小時，過濾。濾液分層，水層用正己烷萃取。 Product C 101 g (0.6474 mol), iron complex catalyst 10 g and water 5.83 (0.3237 mol) were added to the reaction flask. The reaction solution was allowed to react at room temperature. After reacting for 65 hours, 250 ml of n-hexane and 150 ml of water were added. Stir vigorously for 2 hours and filter. The filtrate was separated and the aqueous layer was extracted with n-hexane.
合併戊烷，水洗，乾燥，濃縮得化合物D的粗品50g。加入鈣氫2g，水沖泵減壓蒸餾，得化合物D 45g，光學純度80%。 The pentane was combined, washed with water, dried and concentrated to give 50 g of Compound D. 2 g of calcium hydrogen was added, and the water was pumped under reduced pressure to obtain 45 g of compound D, and the optical purity was 80%.
合併水層，向水層中加入鹽，再用乙酸乙酯萃取。合併乙酸乙酯，用鹽水洗，乾燥，濃縮得化合物E 70g。 The aqueous layers were combined, and a salt was added to the aqueous layer and then ethyl acetate. The combined ethyl acetate was washed with brine, dried and evaporated
實施例七：化合物H的製備 Example 7: Preparation of Compound H
向反應瓶中加化合物E 55.9g(0.32126mol)、二氯甲烷560ml及三乙胺66.52g(0.6586mol)，攪拌。將反應液冷卻到-5℃，慢慢向反應液三甲基氯矽烷34.89g(0. 32126mol)，滴加過程中保持溫度小於-5℃。滴加結束，將反應液保持0℃反應1小時，得到化合物H。反應液可直接進行下步反應(請參照實施例八)。 Compound E 55.9 g (0.32126 mol), dichloromethane 560 ml, and triethylamine 66.52 g (0.6586 mol) were added to the reaction flask, followed by stirring. The reaction solution was cooled to -5 ° C, and slowly to the reaction liquid trimethylchloromethane 34.89 g (0. 32126 mol), keeping the temperature below -5 °C during the dropwise addition. After completion of the dropwise addition, the reaction solution was kept at 0 ° C for 1 hour to obtain a compound H. The reaction solution can be directly subjected to the next reaction (refer to Example 8).
實施例八：化合物J的製備 Example 8: Preparation of Compound J
向上述反應液滴滴加甲磺醯氯36.785g(0.32126mol)，滴加過程中保持溫度小於5℃。滴加結束，將反應液保持小於5℃反應。反應結束後向反應液中加入水，攪拌30分鐘，分層。水層用二氯甲烷萃取。合併有機層水洗，乾燥旋蒸得到化合物J 102g；1H-NMR：δ 0.08-0.13(9H,m)；2.80-3.00(3H,d)；3.7-3.9(2H,m)；5.48-5.52(1H,m)；7.01-7.27(3H,m)。 To the above reaction liquid droplets, 36.785 g (0.32126 mol) of methanesulfonate chloride was added dropwise, and the temperature was kept below 5 ° C during the dropwise addition. At the end of the dropwise addition, the reaction solution was kept at a temperature of less than 5 °C. After the completion of the reaction, water was added to the reaction mixture, and the mixture was stirred for 30 minutes and layered. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and dried to dryness to give compound J 102 g; 1 H-NMR: δ 0.08-0.13 (9H, m); 2.80-3.00 (3H, d); 3.7-3.9 (2H, m); 5.48-5.52 ( 1H, m); 7.01-7.27 (3H, m).
實施例九：化合物D的製備 Example 9: Preparation of Compound D
將化合物J 102g溶於甲醇1000ml中，加入碳酸鉀132.4g攪拌反應2小時。終止反應後過濾，濾液濃縮，加入水和乙酸乙酯分層。水層乙酸乙酯萃取。合併乙酸乙酯，用 鹽水洗。有機層乾燥，濃縮得42g。加入鈣氫2g，水沖泵減壓蒸餾，得化合物D 15g，光學純度97.9%。1H-NMR：δ 2.71-2.73(1H,dd)；3.13-3.15(1H,m)；3.82-3.83(1H,m)；7.01-7.27(3H,m)。 102 g of the compound J was dissolved in 1000 ml of methanol, and 132.4 g of potassium carbonate was added thereto, and the mixture was stirred for 2 hours. After the reaction was terminated, it was filtered, and the filtrate was concentrated. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate was washed with brine. The organic layer was dried and concentrated to give 42 g. 2 g of calcium hydrogen was added, and the water was pumped under reduced pressure to obtain 15 g of compound D, and the optical purity was 97.9%. 1 H-NMR: δ 2.71-2.73 (1H, dd); 3.13 - 3.15 (1H, m); 3.82-3.83 (1H, m); 7.01-7.27 (3H, m).
實施例十：化合物F的製備 Example 10: Preparation of Compound F
向反應瓶投甲苯243.0g、叔丁醇鈉32.22g(0.34mol)及磷醯基乙酸三乙酯78.06g(0.35mol)，攪拌溶解形成反應液；然後將反應液加熱到70℃；將化合物D 41.83g(0.268mol)溶於甲苯100g中，然後將該溶液滴加到反應液中，滴加過程中保持反應液溫度60-80℃。滴加結束後，將反應液的溫度升到80℃反應，反應時間約11小時。反應結束後，冷卻到室溫，加入水，分層。水層用甲苯萃取，合併有機層，水洗，減壓濃縮有機層，得到化合物F 48.5g，收率80%；1H-NMR：δ1.22-1.26(1H,m)；1.26-1.30(3H,t)；1.57-1.62(1H,m)；1.82-1.8(1H,m)；2.45-2.50(1H,m)；4.14-4.20(2H,q)；6.82-6.91(2H,m)；7.02-7.09(1H,m)。 To the reaction flask, 243.0 g of toluene, 32.22 g (0.34 mol) of sodium t-butoxide and 78.06 g (0.35 mol) of triethyl phosphonium acetate were stirred and dissolved to form a reaction liquid; then the reaction liquid was heated to 70 ° C; D 41.83 g (0.268 mol) was dissolved in 100 g of toluene, and the solution was added dropwise to the reaction liquid, and the temperature of the reaction liquid was maintained at 60 to 80 ° C during the dropwise addition. After the completion of the dropwise addition, the temperature of the reaction liquid was raised to 80 ° C to react, and the reaction time was about 11 hours. After the reaction was completed, it was cooled to room temperature, water was added, and the layers were separated. The aqueous layer was extracted with toluene, the organic layers were combined, washed with water, the organic layer was concentrated under reduced pressure, to give compound F 48.5g, yield 80%; 1 H-NMR: δ1.22-1.26 (1H, m); 1.26-1.30 (3H , t); 1.57-1.62 (1H, m); 1.82-1.8 (1H, m); 2.45-2.50 (1H, m); 4.14-4.20 (2H, q); 6.82-6.91 (2H, m); 7.02 -7.09 (1H, m).
實施例十一：化合物G的製備 Example 11: Preparation of Compound G
在室溫下，向反應瓶中投化合物F 22.6g(0.1mol)、甲醇67ml(3V)、甲酸甲酯6g(0.1mol)及甲醇鈉40.5(0.075mol)，形成反應液。將反應液密封後，加熱到60℃。再向反應液中通2個大氣壓的氨氣。將反應液保持60℃，壓力為2個大氣壓反應4小時。反應結束後，冷卻，反應器減壓，倒出，加入水134g(6V)，加熱到60℃，攪拌1小時。冷卻到室溫，攪拌，過濾，甲醇/水=1V/1V 40ml洗，水30ml洗，二異丙醚(bp：68.5℃)30ml洗。濾餅於50℃，真空乾燥，化合物G 15.8g，收率80%。1H-NMR：δ1.21-1.27(1H,m)；1.56-1.64(3H,m)；2.47-2.49(1H,m)；5.45(1H,br)；5.63(1H,br)；6.83-6.90(2H,m)；7.03-7.10(1H,m)。 To the reaction flask, Compound F 22.6 g (0.1 mol), methanol 67 ml (3 V), methyl formate 6 g (0.1 mol) and sodium methoxide 40.5 (0.075 mol) were added to the reaction mixture to form a reaction mixture. After the reaction solution was sealed, it was heated to 60 °C. Further, two atmospheres of ammonia gas were passed through the reaction solution. The reaction solution was kept at 60 ° C and the pressure was 2 atmospheres for 4 hours. After completion of the reaction, the mixture was cooled, the reactor was depressurized, poured out, and 134 g (6 V) of water was added thereto, and the mixture was heated to 60 ° C and stirred for 1 hour. After cooling to room temperature, stirring, filtration, methanol/water = 1 V / 1 V 40 ml, water 30 ml wash, diisopropyl ether (bp: 68.5 ° C) 30 ml wash. The filter cake was dried in vacuo at 50 ° C, compound G 15.8 g, yield 80%. 1 H-NMR: δ 1.21-1.27 (1H, m); 1.56-1.64 (3H, m); 2.47-2.49 (1H, m); 5.45 (1H, br); 5.63 (1H, br); 6.90 (2H, m); 7.03-7.10 (1H, m).
實施例十二：(1R,2S)-2-(3,4-二氟苯基)環丙胺的製備 Example 12: Preparation of (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine
在反應瓶中投30%NaOH水溶液54.77g(0.41mol)及化合物G 9g(0.0457mol)，進行攪拌；向反應液中滴加12%NaClO水溶液71g(0.1005mol)，滴加 過程中溫度保持在30℃；滴加結束後，在30℃反應14小時，在40℃反應2小時；反應結束，冷卻到室溫。乙酸異丙酯(bp：89℃)加入到反應液中，分層，水層乙酸異丙酯萃取；合併有機層，水洗，濃縮得到(1R,2S)-2-(3,4-二氟苯基)環丙胺6.57g，收率85%。1H-NMR：δ0.88-0.93(1H,m)；1.03-1.08(1H,m)；1.7(2H,s)；1.79-1.84(1H,m)；2.47-2.51(1H,m)；6.72-6.79(2H,m)；7.00-7.02(1H,m)。 In the reaction flask, 54.77 g (0.41 mol) of a 30% aqueous NaOH solution and 9 g (0.0457 mol) of a compound G were added and stirred; 71 g (0.1005 mol) of a 12% aqueous solution of NaClO was added dropwise to the reaction solution, and the temperature was maintained during the dropwise addition. After 30 ° C, the reaction was carried out at 30 ° C for 14 hours and at 40 ° C for 2 hours; the reaction was completed and cooled to room temperature. Isopropyl acetate (bp: 89 ° C) was added to the reaction solution, and the layers were separated, and the aqueous layer was extracted with isopropyl acetate. The organic layer was combined, washed with water and concentrated to give (1R, 2S)-2-(3,4-difluoro Phenyl) cyclopropylamine 6.57 g, yield 85%. 1 H-NMR: δ 0.88-0.93 (1H, m); 1.03-1.08 (1H, m); 1.7 (2H, s); 1.79-1.84 (1H, m); 2.47-2.51 (1H, m); 6.72-6.79 (2H, m); 7.00-7.02 (1H, m).
值得注意的是，在霍夫曼降解反應中，本發明優選氫氧化鈉與次氯酸鈉作為鹼的來源，以其水溶液為反應體系。此外，由化合物H製備化合物J，或者由化合物K製備化合物L的時候，可以將磺醯氯化合物直接加入到已經反應完成的化合物H或者化合物K的反應體系中，繼續反應即可，而可以節省鹼及溶劑；當然，在其他實施例中，也可將化合物H或者化合物K提純後再配置新的反應體系。 It is to be noted that in the Hofmann degradation reaction, sodium hydroxide and sodium hypochlorite are preferred as the source of the base, and an aqueous solution thereof is used as the reaction system. Further, when the compound J is prepared from the compound H or the compound L is prepared from the compound K, the sulfonium chloride compound can be directly added to the reaction system of the compound H or the compound K which has been reacted, and the reaction can be continued, thereby saving Base and solvent; Of course, in other embodiments, compound H or compound K may be purified and then a new reaction system may be disposed.
重要的是，在本發明中，催化劑為金屬手性配體，用(s,s)-環己二胺與3,5-二叔丁基水楊醛縮合合成手性配體，該手性配體與鈷離子、鐵離子或者鎳離子等金屬離子絡合形成不同活性金屬手性配體。本發明提供之金屬手性配體的催化效果極佳，此外可回收反覆使用，可明顯降低成本。 Importantly, in the present invention, the catalyst is a metal chiral ligand, and a chiral ligand is synthesized by condensation of (s,s)-cyclohexanediamine with 3,5-di-tert-butylsalicylaldehyde. The ligand complexes with metal ions such as cobalt ions, iron ions or nickel ions to form different active metal chiral ligands. The metal chiral ligand provided by the invention has excellent catalytic effect, and can be recycled and reused, which can significantly reduce the cost.
綜合上述，本發明與現有技術相比具有下列優點： In summary, the present invention has the following advantages over the prior art:
(1)操作簡單，同時避免了手性氧化還原時使用昂貴試劑。 (1) Simple operation while avoiding the use of expensive reagents for chiral redox.
(2)利用動力學拆分得到(S)-3,4-二氟苯基環氧乙烷，其原料成本低，且催化劑可反覆使用。 (2) The (S)-3,4-difluorophenyloxirane is obtained by kinetic resolution, the raw material cost is low, and the catalyst can be used repeatedly.
(3)拆分產生的R-構型副產物二醇(即上述化合物E)可進行構型轉化，重新得到(s)-3,4-二氟苯基環氧乙烷(即上述化合物D)，可明顯降低中間體的成本。 (3) The R-configuration by-product diol (ie, the above compound E) produced by the resolution can be subjected to configuration conversion, and (s)-3,4-difluorophenyloxirane (i.e., the above compound D) is recovered. ), can significantly reduce the cost of intermediates.
雖然本發明已以實施方式揭露如上，然其並非用以限定本發明，任何熟習此技藝者，在不脫離本發明之精神和範圍內，當可作各種之更動與潤飾，因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。 Although the present invention has been disclosed in the above embodiments, it is not intended to limit the present invention, and the present invention can be modified and modified without departing from the spirit and scope of the present invention. The scope is subject to the definition of the scope of the patent application attached.
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| CN107417739B (en) * | 2017-06-08 | 2019-11-15 | 中国科学院长春应用化学研究所 | A kind of Schiff base iron compound, its preparation method and its application as catalyst |
| CN107892693A (en) * | 2017-11-14 | 2018-04-10 | 安徽诺全药业有限公司 | A kind of preparation method of ticagrelor |
| CN107814692A (en) * | 2017-11-14 | 2018-03-20 | 安徽诺全药业有限公司 | A kind of ticagrelor key intermediate and preparation method thereof |
| CN108912010B (en) * | 2018-08-01 | 2021-04-06 | 中国科学院长春应用化学研究所 | Schiff base manganese compound, and preparation method and application thereof |
| CN112479895A (en) * | 2019-09-11 | 2021-03-12 | 凯特立斯（深圳）科技有限公司 | Synthetic method of tranylcypromine intermediate |
| CN111233673B (en) * | 2020-02-26 | 2022-08-16 | 苏州元兴生物医药有限公司 | Preparation method of chiral aromatic cyclopropylamine and salt thereof and intermediate used in preparation method |
| CN111269148B (en) * | 2020-04-08 | 2022-02-08 | 台州职业技术学院 | Preparation method of Sacubitril intermediate |
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