MXPA00001039A - A process for the preparation of cyclopropylacetylene - Google Patents
A process for the preparation of cyclopropylacetyleneInfo
- Publication number
- MXPA00001039A MXPA00001039A MXPA/A/2000/001039A MXPA00001039A MXPA00001039A MX PA00001039 A MXPA00001039 A MX PA00001039A MX PA00001039 A MXPA00001039 A MX PA00001039A MX PA00001039 A MXPA00001039 A MX PA00001039A
- Authority
- MX
- Mexico
- Prior art keywords
- contacting
- lithium
- halo
- cyclopropylethylene
- cyclopropylacetylene
- Prior art date
Links
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title description 26
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 65
- OTZXZTJDUFZCNC-ONEGZZNKSA-N (E)-3-cyclopropylprop-2-enoic acid Chemical compound OC(=O)\C=C\C1CC1 OTZXZTJDUFZCNC-ONEGZZNKSA-N 0.000 claims abstract description 28
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 23
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 22
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 claims abstract description 17
- 230000002194 synthesizing Effects 0.000 claims abstract description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 39
- 239000002585 base Substances 0.000 claims description 37
- 239000003795 chemical substances by application Substances 0.000 claims description 37
- 239000003054 catalyst Substances 0.000 claims description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 30
- -1 sodium alkoxide Chemical class 0.000 claims description 25
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-Bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 23
- 230000002140 halogenating Effects 0.000 claims description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 20
- 229910052751 metal Inorganic materials 0.000 claims description 17
- 239000002184 metal Substances 0.000 claims description 17
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 13
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- 229940113083 morpholine Drugs 0.000 claims description 12
- XIXADJRWDQXREU-UHFFFAOYSA-M Lithium acetate Chemical group [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims description 11
- 229940071257 Lithium acetate Drugs 0.000 claims description 11
- HUCVOHYBFXVBRW-UHFFFAOYSA-M Caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 10
- IMNIMPAHZVJRPE-UHFFFAOYSA-N DABCO Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Chemical group ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 10
- ODZPKZBBUMBTMG-UHFFFAOYSA-N Sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- QTMDXZNDVAMKGV-UHFFFAOYSA-L Copper(II) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 8
- UEGPKNKPLBYCNK-UHFFFAOYSA-L Magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 claims description 8
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 8
- 229960000314 Zinc Acetate Drugs 0.000 claims description 8
- DJWUNCQRNNEAKC-UHFFFAOYSA-L Zinc acetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O DJWUNCQRNNEAKC-UHFFFAOYSA-L 0.000 claims description 8
- 239000011654 magnesium acetate Substances 0.000 claims description 8
- 235000011285 magnesium acetate Nutrition 0.000 claims description 8
- 229940069446 magnesium acetate Drugs 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000004246 zinc acetate Substances 0.000 claims description 8
- VSGNNIFQASZAOI-UHFFFAOYSA-L Calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 7
- 239000001639 calcium acetate Substances 0.000 claims description 7
- 235000011092 calcium acetate Nutrition 0.000 claims description 7
- 229960005147 calcium acetate Drugs 0.000 claims description 7
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- 235000013904 zinc acetate Nutrition 0.000 claims description 7
- BUWXUSLQPDDDSD-UHFFFAOYSA-N 2-methyl-2-(2-methylbutan-2-yloxy)butane Chemical compound CCC(C)(C)OC(C)(C)CC BUWXUSLQPDDDSD-UHFFFAOYSA-N 0.000 claims description 6
- DVSDBMFJEQPWNO-UHFFFAOYSA-N Methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 6
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 claims description 5
- OKDQKPLMQBXTNH-UHFFFAOYSA-N N,N-dimethyl-2H-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 claims description 5
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000001187 sodium carbonate Substances 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 claims description 4
- 229960005235 Piperonyl Butoxide Drugs 0.000 claims description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 4
- 239000001184 potassium carbonate Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- OREAFAJWWJHCOT-UHFFFAOYSA-L 2,2-dimethylpropanedioate Chemical compound [O-]C(=O)C(C)(C)C([O-])=O OREAFAJWWJHCOT-UHFFFAOYSA-L 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N Diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims description 3
- GXHFUVWIGNLZSC-UHFFFAOYSA-N Meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 claims description 3
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 claims description 3
- TVFDJXOCXUVLDH-UHFFFAOYSA-N Cesium Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052792 caesium Inorganic materials 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- UPQZOUHVTJNGFK-UHFFFAOYSA-N diethyl 2-methylpropanedioate Chemical compound CCOC(=O)C(C)C(=O)OCC UPQZOUHVTJNGFK-UHFFFAOYSA-N 0.000 claims 1
- AYBLPISRXMEMBV-UHFFFAOYSA-N dimethyl 2,2-diethylpropanedioate Chemical compound COC(=O)C(CC)(CC)C(=O)OC AYBLPISRXMEMBV-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 28
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 14
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 239000000463 material Substances 0.000 abstract description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N Efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- QDJSZVRLBGARTP-UHFFFAOYSA-N 2-cyclopropylprop-2-enoic acid Chemical compound OC(=O)C(=C)C1CC1 QDJSZVRLBGARTP-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 102000015084 HIV Reverse Transcriptase Human genes 0.000 description 10
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 239000003125 aqueous solvent Substances 0.000 description 7
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000007792 addition Methods 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 238000005658 halogenation reaction Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4H-1,2-benzoxazin-3-one Chemical class C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 102000016615 EC 2.7.7.49 Human genes 0.000 description 4
- 108010092799 EC 2.7.7.49 Proteins 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N Anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000008079 hexane Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- 230000029812 viral genome replication Effects 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-Trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-Dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 210000001124 Body Fluids Anatomy 0.000 description 2
- 229940117389 Dichlorobenzene Drugs 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N Diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N Methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N Nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N Phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M Tetra-n-butylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000000977 initiatory Effects 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical class [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- HVCFCNAITDHQFX-UHFFFAOYSA-N 1-cyclopropylethanone Chemical compound CC(=O)C1CC1 HVCFCNAITDHQFX-UHFFFAOYSA-N 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- MSIDGEINKGACAX-UHFFFAOYSA-N 2-bromoethenylcyclopropane Chemical compound BrC=CC1CC1 MSIDGEINKGACAX-UHFFFAOYSA-N 0.000 description 1
- PBVZQAXFSQKDKK-UHFFFAOYSA-M 3-methoxy-3-oxopropanoate Chemical compound COC(=O)CC([O-])=O PBVZQAXFSQKDKK-UHFFFAOYSA-M 0.000 description 1
- URUBCNBOMBFTHK-UHFFFAOYSA-M 3-oxo-3-pentan-3-yloxypropanoate Chemical group CCC(CC)OC(=O)CC([O-])=O URUBCNBOMBFTHK-UHFFFAOYSA-M 0.000 description 1
- 229940022663 Acetate Drugs 0.000 description 1
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 1
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- YNQLUTRBYVCPMQ-UHFFFAOYSA-N ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates generally to novel methods for the synthesis of cyclopropylacetylene which is an essential reagent in the asymmetric synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1,4-dihydro- 2H-3,1-benzoxazin-2-one;a useful human immunodeficiency virus (HIV) reverse transcriptase inhibitor. In the process, cyclopropane carboxaldehyde is condensed with malonic acid to form 3-cyclopropylacrylic acid;3-cyclopropylacrylic acid is halogenated to form (E, Z)-1-halo- 2-cyclopropylethylene;and (E, Z)-1-halo-2-cyclopropylethylene is dehydrohalogenated to form cyclopropyl acetylene. This improvement provides for high conversion of inexpensive, readily available staring materials into cyclopropylacetylene, high overall yields and can be conducted on an industrial scale.
Description
PROCESS FOR THE PREPARATION OF CICLOPROPILACE ILENO
FIELD OF THE INVENTION
The present invention relates generally to novel methods for the synthesis of cyclopropylacetylene which is an essential reagent in the asymmetric synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoroethyl-1,4-dihydro-2H-3 , l-benzoxazin-2-one; an inhibitor of human immunodeficiency virus (HIV) reverse transcriptase.
BACKGROUND OF THE INVENTION
Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the RNA genome. Reverse transcriptase, therefore, is a clinically relevant goal for the chemotherapy of retroviral infections. since the inhibition of the virally encoded reverse transcriptase can interrupt the viral replication.
REF .: 32059 A variety of compounds are effective in the treatment of human immunodeficiency virus (HIV), which is the retrovirus that causes the progressive destruction of the human immune system with the resulting initiation of AIDS. Effective treatment through the inhibition of HIV reverse transcriptase is known both from nucleoside-based inhibitors, such as azidothymidine, and non-nucleoside-based inhibitors. It has been found that benzoxazinones are useful inhibitors based on non-nucleosides of HIV reverse transcriptase. (S) -6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1, -dihydro-2H-3, 1-benzoxazin-2-one of the formula (VI):
(VI) is not only a highly potent reverse transcriptase inhibitor, but is also effective against the resistance of HIV reverse transcriptase. Due to the importance of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3, l-benzoxazin-2-one, a reverse transcriptase inhibitor, processes need to be developed economic and efficient synthetics for its production. Cyclopropylacetylene "is an important reagent in the synthesis of compound (VI) Thompson et al., Tetrahedron Lets ters 1995 36, 937-940 describes the asymmetric synthesis of an enantiomeric benzoxazinone by the addition of highly enantioselective acetylide followed by cyclization with a condensing agent to form the benzoxazinone shown later.As a cyclopropylacetylene reactant is synthesized in a 65% yield by 5-chloropentino cyclization with n-but-lithium at 0 ° -80 ° C in cyclohexane followed by chloride arrest. The process generates a low yield of cyclopropylacety which is not feasible for the large commercial process of a difficult reagent of anejaj.
Thompson et al, PCT International Patent Application Number WO 9622955 Al discloses an improved cyclopropylacetylene system useful in the synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3, l-benzoxazin-2-one. The application WO 0922955 Al describes methods that continue to be inefficient in the total synthesis on a scale of one kilogram for which this invention makes significant improvements. The chemical literature shows the majority of cyclopropylacetylene preparations involving the conversion of cyclopropylmethyl ketone to cyclopropylacetylene via the following chemical scheme. The method will produce cyclopropylacetylene on a small scale < 1 kilogram, but it is not capable of bulk production, in this way an alternative is developed.
The above methods for the synthesis of cyclopropylacetylene use toxic reagent combinations, difficult to handle, relatively expensive materials, incomplete conversions and low yields that lead to total synthesis to be inefficient and a yield of cyclopropylacetylene of lower purity. In this way, it is desirable to discover new synthetic routes for cyclopropylacetylene on a large scale which improve these limitations and provide high yields of desired cyclopropylacetylene.The present invention describes novel compounds and a novel scale process for the preparation of cyclopropylacetylene. The improvements on the previously described preparations of cyclopropylacetylene are the low economic price and availability of the starting materials; the convenience and high yields for chemistry; and the ability to crystallize and store without degrading the first intermediate, 3-cyclopropylacrylic acid. The invention provides novel chemistry for the production of cyclopropylacetylene from cyclopropane carboxaldehyde. The process provides a high yield (> 90%) for the convenient reaction of cyclopropane carboxaldehyde with malonic acid to give the 3-cyclopropylacrylic acid. Subsequent transformation of 3-cyclopropylacrylic acid to cyclopropylvinyl halide occurs in high yields using convenient reaction conditions. The final preparation of cyclopropyl acetylene by dehydrohalogenation from the cyclopropylvinyl halide proceeds in high yields and with suitable purities such that the cyclopropylacetylene produced can be stored or used as a solution in an inert solvent.
None of the references cited in the above describes the methods of the present invention for the synthesis of cyclopropylacetylene.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to an improved process suitable for the large-scale preparation of cyclopropylacetylene. In the process, the cyclopropane carboxaldehyde is condensed with malonic acid to form 3-cyclopropylacrylic acid; acid
! jr;? rptt7p1acr? r > is falcgaia ±) to form (E, Z) -l-ha3j3-2-cp 1oprcpi letri lax >; and dehydrogenated in (E, Z) -l-halo-2-cyclopropylethylene to form cyclopropylacetylene. This improvement provides high conversion of inexpensive starting materials, readily available in cyclopropylacetylene, high total yields can be realized on an industrial scale.
DETAILED DESCRIPTION OF THE INVENTION
In a first embodiment, the present invention provides a process for the preparation of cyclopropylacetylene comprising: (1) contacting the cyclopropane carboxaldehyde with malonic acid, or a malonic acid substitute in the presence of a base catalyst to form an acid 3- cyclopropylacrylic; (2) contacting 3-cyclopropylacrylic acid with a metal catalyst and a halogenating agent to form (E, Z) -l-halo-2-cyclopropylethylene; and (3) contacting (E, Z) -l-halo-2-cyclopropylethylene with a strong base to form cyclopropylacetylene. In a preferred embodiment, the present invention provides a process for the preparation of cyclopropylacetylene wherein the malonic acid substitution of 2,2-dimethyl-1,3-dioxan-4,6-dione, dimethyl malonate, malonate of diethyl, and monomethyl malonate. In another preferred embodiment, the present invention provides a process for the preparation of cyclopropylacetylene wherein the base catalyst of pyridine, pyrrolidine, piperidine, morpholine, N-methylmorpholine, 1,4-diazabicyclo [2.2.2] octane, N, is selected. N-dimethylaminopyridine, N, N-diethylaniline, quinoline, N, N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium alkoxide, lithium alkoxide and potassium alkoxide, where the ethoxide, ethoxide, butoxide, t-butoxide and t-amyloxide are selected. In another preferred embodiment, the present invention provides a process for the preparation of cyclopropylacetylene wherein the metal catalyst is selected from lithium acetate, magnesium acetate, zinc acetate, calcium acetate, copper iodide and copper bromide. In another preferred embodiment, the present invention provides a process for the preparation of cyclopropyl acetylene wherein the halogenation agent is selected from N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide. In a further preferred embodiment, the present invention provides a process for the preparation of cyclopropylacetylene comprising: (1) contacting cyclopropane carboxaldehyde with malonic acid in the presence of a base catalyst selected from: pyridine, pyrrolidine, piperidine, morpholine,
N-methylmorpholine, 1,4-diazabicyclo [2.2.2] octane, N, N-dimethylaminopyridine, N, -diethylaniline, quinoline, N, N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide , sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium alkoxide, lithium alkoxide and potassium alkoxide, wherein the alkoxide is selected from methoxide, ethoxide, butoxide, t-butoxide and t-amyloxide; to form 3-cyclopropylacrylic acid; (2) contacting 3-cyclopropylacrylic acid with a metal catalyst selected from: lithium acetate, magnesium acetate, zinc acetate, calcium acetate, copper iodide, and copper bromide; and a halogenating agent to form (E, Z) -l-halo-2-cyclopropylethylene; and (3) contacting (E, Z) -l-halo-2-cyclopropylethylene with methyl lithium, potassium t-butoxide, potassium hydroxide, or sodium amide to form cyclopropyl acetylene. In yet a further preferred embodiment, the present invention provides a process for the preparation of cyclopropyl-acetylene comprising: (1) contacting the cyclopropane carboxaldehyde with malonic acid in the presence of a base catalyst selected from: pyridine, pyrrolidine, piperidine, morpholine, or a combination thereof; to form 3-cyclopropylacrylic acid; (2) contacting 3-cyclopropylacrylic acid with a meta catalyst, selected from: lithium acetate, magnesium acetate, zinc acetate, calcium acetate, copper iodide, and copper bromide; and a halogenating agent to form (E, Z) -l-halo-2-cyclopropylethylene; and (3) contacting (E, Z) -l-halo-2-cyclopropylethylene with potassium t-butoxide, potassium hydroxide or sodium amide to form cyclopropylacetylene. In yet a further preferred embodiment, the present invention provides a process for the preparation of cyclopropyl-acetylene comprising: (1) contacting cyclopropane carba aldehyde with malonic acid in the presence of a base catalyst selected from: pyridine, pyrrolidine, piperidine , morpholine, or a combination thereof; to form 3-cyclopropylacrylic acid; (2) contacting 3-cyclopropylacrylic acid with lithium acetate and a halogenating agent to form (E, Z) -l-halo-2-cyclopropyl-ethylene; and (3) contacting (E, Z) -l-halo-2-cyclopropylethylene with methyl lithium, potassium t-butoxide, potassium hydroxide, or sodium amide to form cyclopropylacetylene. In a more preferred embodiment, the halogenating agent is N-bromosuccinimide. In a second embodiment, the present invention provides a process for the preparation of cyclopropylacetylene comprising step (2) contacting 3-cyclopropylacrylic acid with a metal catalyst and a halogenating agent in the presence of a phase transfer agent to form (E, Z) -l-halo-2-cyclopropylethylene. In a third embodiment, the present invention provides a process for the preparation of cyclopropylacetylene comprising in step (3) contacting (E, Z) -l-halo-2-cyclopropylethylene with a strong base in the presence of an agent of phase transfer to form cyclopropylacetylene. In a fourth embodiment, the present invention provides a compound of the formula C3H5CH = CHBr. In a fifth embodiment, the present invention provides a compound of the formula C3H5CH = CHC1. The processes of the present invention are useful for the preparation of cyclopropylacetylene, an essential intermediate in the synthesis of (S) -β-chloro-4-cyclopropylethynyl-4- trifluoromethyl 1-1, 4-dihydro-2H-3, 1- benzoxazin-2-one, which is useful as a reverse transcriptase inhibitor of human immunodeficiency virus (HIV) and compounds that are useful intermediates in the synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1 , 4-dihydro-2H-3, l-benzoxazin-2-one. Such HIV reverse transcriptase inhibitors are useful for the inhibition of HIV and the treatment of HIV infection. Such HIV reverse transcriptase inhibitors are useful for the inhibition of HIV in an ex vivo sample that contains HIV or is expected to be exposed to HIV. Thus, such HIV reverse transcriptase inhibitors can be used to inhibit HIV present in the body fluid sample (e.g., body fluid or semen samples), which contains or is suspected to contain or be exposed to HIV. Such HIV reverse transcriptase inhibitors are also useful as standards or reference compounds for use in tests or assays to determine the ability of an agent to inhibit viral replication and / or HIV reverse transcriptase, for example in a pharmaceutical research program . In this manner, such HIV reverse transcriptase inhibitors can be used as a control or reference compound in such assays and as a quality control standard. The reactions of the synthetic methods claimed herein are carried out in suitable solvents which can be easily selected by one skilled in the art of organic synthesis, the suitable solvents generally being any solvent which is substantially unreactive with the starting materials (reagents) , the intermediates, or products at the temperatures at which the reactions are carried out, ie, temperatures that may be in the range of the freezing temperature of the solvent to the boiling temperature of the solvent, unless the purpose of the solvent is stop the reaction. A given reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents can be selected for a particular reaction step independent of any other reaction step. Suitable halogenated solvents include chlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichlorobenzene, dichloroethane and trichloroethane. Suitable ether solvents include: tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, or t-butyl methyl ether. Suitable or aromatic hydrocarbon solvents include: benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-xylene, o-xylene, p-xylene, octane, indane, nonane, naphthalene and mesitylene. As used herein, the term "base catalyst" refers to any agent that catalyzes the condensation of malonic acid with the carbonyl of cyclopropyl carboxaldehyde in this manner effecting the formation of the cyclopropylacrylic acid. Examples of base catalysts include, but are not limited to, alkylamines and aromatic amines such as: pyridine, pyrrolidine, piperidine, morpholine, N-methylmorpholine, 1,4-diazabicyclo [2.2.2] octane (DABCO), N, N- diethylaniline, N, N-dimethylaminopyridine, quinoline and N, N-diisopropylethylamine, as well as sodium, potassium, lithium or cesium hydroxide; sodium carbonate, "potassium, lithium or cesium; and alkoxide bases such as sodium, lithium or potassium methoxides, ethoxides, butoxides, t-butoxides and t-amyloxides." As used herein, the term "metal catalyst" "refers to any agent that catalyzes the decarboxylation and subsequent halogenation of the cyclopropylacrylic acid by a halogenating agent in step (2) to effect the formation of a (E, Z) mixture of l-halo-2-cyclopropylethylene. Metal catalysts include, but are not limited to, sodium carbamate, potassium carbamate, lithium carbamate, copper bromide and metal acetates, including but not limited to, lithium acetate, magnesium acetate, zinc acetate and acetate As used herein, the term "halogenating agent" refers to any agent that under the conditions of step (2) effects halogenation of the cyclopropylacrylic acid in the presence of a base catalyst to effect the formation of a mixture (E, Z) of l-halo-2-cyclopropylethylene. Examples of halogenating agents include, but are not limited to, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, Br2, Cl2, triphenylphosphine dibromide, and triphenylphosphine dichloride. As used herein, the term "strong base" refers to any base the presence of which in the reaction facilitates the synthesis of cyclopropylacetylene from l-halo-2-cyclop.propylethylene. Suitable bases can be selected by one skilled in the art of organic synthesis. Suitable bases include, but are not limited to, inorganic bases such as alkali metal, alkaline earth metal and ammonium hydroxides and alkoxides. Suitable bases also include, but are not limited to, metal amides and alkyl lithiums. Examples of suitable strong bases are lithium diisopropylamide, sodium amide, sodium methoxide, potassium t-butoxide, sodium butoxide, sodium potassium t-amyloxide, potassium hydroxide, sodium hydroxide, methyl-lithium, butyl- lithium, hexyl lithium, phenyllithium and tertiary alkylammonium hydroxides. The present invention is contemplated to be practiced at least on a multigram scale, kilogram scale, multikilogram scale or industrial scale. The multigram scale as used herein, is preferably the scale wherein at least one starting material of 10 grams or more is present, more preferably at least 50 grams more, even more preferably at least 100 grams. or more. The multikilogram scale, as used herein, is proposed to mean the scale where more than one kilogram of at least one starting material is used. The industrial scale as used herein is proposed to be understood as a scale on which it is different from a laboratory scale and which is sufficient to supply sufficient product either for clinical testing or distribution to consumers.
Synthesis
It is an object of the present invention to provide an improved process for the synthesis of cyclopropylacetylene which is useful in the synthesis of benzoxazinones which are useful as inhibitors of HIV reverse transcriptase. The methods of the present invention to form as an example and without limitation, can be further understood by reference to Scheme 1. Scheme 1 details the general synthetic method for cyclopropylacetylene synthesis initiating cyclopropane carboxaldehyde and malonic acid. Alternatively, one skilled in the art of organic synthesis can react a malonic acid substitute, as described below, by malonic acid in the Step, (1). Similarly, alternative halogenating agents for halosuccinimide are described below. »
Scheme 1. Stage 1: COOH < COOH
COOH based on reflux
Step 2: solvent, 2 (mixture of E-Z) metal catalyst X = C1, 2a X »Br, 2b X« I, 2c Stage 3: H base, -HX-^, > = H 3 CPA Stage 1. Condensation: Preparation of cyclopropylacrylic acid.
This step is carried out by reacting cyclopropane carboxaldehyde in a suitable non-aqueous solvent at a suitable temperature with malonic acid in the presence of a suitable base catalyst to form cyclopropylacrylic acid. For general guidance, cyclopropane carboxaldehyde is contacted with about 1 to about 2 molar equivalents of malonic acid, stirred and heated, if necessary to dissolve the reagents, additionally contacted with about 0.1 to about 5.0 molar equivalents of a suitable base catalyst and heated to a temperature sufficient to form cyclopropylacrylic acid. During the formation of the cyclopropylacrylic acid, water is generated as a product and can be eliminated by standard methods in the art. Cyclopropylacrylic acid can be separated from the reaction as a stable solid by standard methods of development known to one skilled in the art of organic synthesis. Examples of standard development are shown in Examples 1 and 2.
Suitable non-aqueous solvents are any hydrocarbon, ether, halogenated hydrocarbon, or aromatic solvents in which it is soluble, and cyclopropane carboxaldehyde and which, combined with the base used, of some solubility for malonic acid. These may include, but are not limited to, pentane, hexane, heptane, toluene, xylenes, benzene, mesitylenes, t-butyl methyl ether, dialkyl ethers (ethyl, butyl), diphenylether, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, acetonitrile. , dichlorobenzene, dichloroethane, and trichloroethane. Preferred non-aqueous solvents are heptane, toluene and pyridine. The suitable temperature for the condensation reaction is the room temperature at the reflux temperature of the non-aqueous solvent, a condition easily determined by one skilled in the art of organic synthesis. It is preferred to run the reaction at a reflux temperature. Preferred base catalysts are alkylamines and aromatic amines, especially pyridine, pyrrolidine, piperidine and morpholine or a combination thereof. More preferred are piperidine or morpholine in combination with pyridine.
In an alternative for malonic acid, a "malonic acid substitute" can be used. As used herein, examples of a malonic acid substitute, such as 2,2-dimethyl-l, 3-dioxane-4,6-dione or mono- or malonic acid esters, such as dimethyl malonate or Diethyl or malonate, ie monomethyl, can also be used. In the case of 2,2-dimethyl-1,3-dioxane-4,6-dione, very mild bases such as sodium acetate can be used to effect condensation. Additional malonic acid substitutes such as cyanoethanoic acid, mono (C 1 -C 6) alkyl malonate or di (Ci-Cβ) alkyl malonate can also be used to effect the condensation. As used in the present "alkyl" it is proposed to include both saturated straight or branched chain aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "C.Calkyl" means alkyl having from 1 to 6 carbon atoms, - that is, methyl, ethyl, propyl, butyl, pentyl, hexyl and branched isomers thereof. Additionally, it is understood by an expert in the technique of organic synthesis that the use of a malonic acid substitute in the stage
(1) may result in the formation of a protected cyclopropylacrylic acid such as the cyclopropylacrylate ester. It is understood that such product is easily converted by acid or base hydrolysis, methods known to one skilled in the art, to form the desired product, cyclopropylacrylic acid. It is understood that one skilled in the art can determine the preferred reaction time of Step 1 as temperature dependent, base catalyst and non-aqueous solvent. Generally, the reaction time is about 1 to about 48 hours.The preferred reaction time is about 1 to about 12 hours.
Step 2. Halogenation: Preparation of (E, Z) -1-halo-2-cyclopropylethylene.
This step comprises the halogenation of cyclopropylacrylic acid by a halogenating agent in the presence of a metal catalyst. For general guidance, cyclopropylacic acid is dissolved and about 0.01 to about 0.5 molar equivalents, preferably 0.05 to 0.2 molar equivalents, more preferably 0.05 to 0.15 molar equivalents, more preferably about 0.1 molar equivalent of a metal catalyst in a suitable solvent after which about 1.0 to about 1.3 molar equivalents of a halogenating agent are added. The reaction is stirred for a sufficient amount of time, preferably, about 2 minutes at about 48 hours, more preferably about 30 minutes at about 3 hours, depending on the catalyst, to form an E, Z mixture of 1-halo 2-cyclopropylethylene. The (E, Z) -1-halo-2-cyclopropylethylene can be separated from the reaction as a stable liquid by distillation or by stopping with water followed by standard methods of development. An example of standard development is shown in Example 3. The preferred metal catalysts for step (2) are lithium acetate, magnesium acetate, zinc acetate, calcium acetate, copper iodide, and copper bromide. Most preferred is lithium acetate. Preferred halogenating agents for step (2) are N-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide; N-chlorosuccinimide and N-bromosuccinimide are more preferred; N-bromosuccinimide is more preferred. The preferred solvents for step (2J) are aqueous acetonitrile and aqueous acetone, the most preferred one being aqueous acetonitrile, 97: 3 acetonitrile: water.In an aqueous solvent system the amount of water required is a sufficient amount of water to dissolve the water. Furthermore, it is optional that the reaction of step (2) can be run in the presence of a phase transfer agent.The suitable phase transfer agents include Aliquat®336, ethers of tetraalkylammonium chloride and halide Tetraoctylammonium chloride and tetrabutylammonium bromide are examples of suitable tetraalkylammonium halides Alternatively, step (2) may be carried out in organic solvents, for example, saturated hydrocarbons, aromatic hydrocarbons, and ethers, presence of a phase transfer agent The preferred organic solvents are anisole, xylene and acetonitrile.
Stage 3: Elimination: Preparation of cyclopropylacetylene.
This step comprises the removal of hydrogen halide from l-halo-2-cyclopropylethylene to form cyclopropylacetylene. For general guidance, a reaction vessel is charged, fixed with a medium to monitor and control the reaction temperature, with a suitable non-aqueous solvent and about 1 to about 3 equivalents of a strong base, depending on the base . It is preferred to use about 2 equivalents of a strong base. While stirring, 1-halo-2-cyclopropylethylene is added in a proportion that the internal temperature does not exceed the boiling point of the cyclopropylacetylene; preferably about 35 ° C. After the addition, the reaction is stirred for about 10 minutes to about 24 hours, preferably about 10 minutes. at about 4 hours, from. more preferably about one hour at room temperature to form cyclopropylacetylene. One skilled in the art can determine an adequate stir time for the conditions and reagents. The reaction is stopped with water or a mild acid, such as acetic acid. The cyclopropylacetylene can then be isolated by distillation, vacuum distillation or atmospheric distillation. Vacuum distillation is preferred if the solvent has a high boiling point, for example dimethyl sulfoxide.
Atmospheric distillation can be used if the solvent has a low boiling point. The nonaqueous solvents for step (3) are 'liquid ammonia, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidinone, dimethylformamide, dioxane, diethyl ether, diphenyl ether, dibutyl ether, anisole, chlorobenzene, toluene, xylene (s), mesitylene, dodecane and several mixed long chain alkanes. A preferred solvent is dimethyl sulfoxide It is understood that the solvents suitable for step (3) do not react with the strong base added in step (3) The preferred l-halo-2-cyclopropylethylenes are 1-bromo-2 -cyclopropilet iléne and l-chloro-2-cyclopropylethylene. ~~
The strong bases for step (3) are sodium amide, sodium methoxide, potassium t-butoxide, lithium diisopropylamide, sodium butoxide, potassium sodium t-amyloxide, potassium hydroxide, sodium hydroxide, methyl- lithium, butyl lithium, hexyl lithium, phenyllithium and tertiary alkylammonium hydroxides. Preferred bases are sodium amide, potassium hydroxide and potassium t-butoxide; more preferred is sodium amide and potassium t-butoxide; and even more preferred is potassium t-butoxide. Additionally, it is optional that the reaction of "step (3) can be run in the presence of a phase transfer agent." Suitable phase transfer agents include Aliquat®336, crown ethers, and tetrabutylammonium bromide. that the following examples are illustrative of the present invention These examples are presented to exemplify the invention and are not constructed to limit the scope of the invention.
Example 1 Preparation of 3-cyclopropylacrylic acid (1):
Cyclopropane carboxaldehyde (100 g, 1.43 moles, 1 equivalent), malonic acid (297 g, 2.85 moles, 2 equivalents) and pyridine (565 g, 7.15 moles, 5 equivalents) are stirred together in a suitable reaction vessel equipped with a reflux condenser and a stirring medium. The suspension is stirred vigorously with heating at about 50 ° C, during which time the malonic acid gradually dissolves. The piperidine (15 ml, 15 mmol, 1 mol%) is then added and the reaction mixture is heated to 80-85 ° C (internal temperature). After maintaining at this temperature for about 1.5 hours, the reaction mixture is heated to reflux (about 115 ° C) for three hours. The reaction mixture is then cooled to 0 ° C, and 500 ml of cold water is added, followed by the slow addition of 680 ml of concentrated, aqueous hydrochloric acid solution, with vigorous stirring. A mass of pale yellow crystals form gradually, and are filtered off and washed several times with cold water. This first sowing of product is dried at a constant weight to produce 68 g (43%) of 3-cyclopropylacrylic acid. The mother liquors are extracted with ethyl acetate (3 x 400 ml) and the combined organic layers are concentrated under vacuum to obtain a second seeding of 28 g (17%) of the product. The remaining mother liquors are then concentrated and filtered once more to obtain 21 g (13%) of the product. This represents a total yield of 112 g (70%). The desired product has a melting point range of 63-65 ° C (uncorrected) and gives satisfactory 1 H NMR and mass spectra.
Example 2 Preparation of 3-cyclopropylacrylisoic acid (1)
Treat a solution of cyclopropane carboxaldehyde (7.0 g, 100 mmol) in 50 ml of toluene with 11.5 g (110 mmol) of malonic acid. The stirred suspension is treated with 0.87 g (10 mmol, 10 mol%) of morpholine, followed by 3.95 g (50 mmol, 50 mol%) of pyridine. The mixture is then heated to reflux with a supply made for the removal of water. Water is observed to separate from the reaction mixture for about one hour, during which time slightly more than the theoretical amount of water is removed (2 ml). The reaction mixture is now a clear solution, pale yellow. The reaction is allowed to cool to room temperature, washed with 50 ml of 10% aqueous hydrochloric acid solution, and washed twice with 50 ml portions of water. The toluene solution is concentrated to about a quarter volume, diluted with 40 ml of n-heptane, and stirred with cooling to about 5 ° C. It is observed that the product is precipitated from the solution as fine pale yellow needles. The product is collected by filtration and dried at a constant weight. The yield is approximately 8.5 g (76%). A second seeding of the product (1.7 g) can be obtained by evaporating the mother liquors to dryness under reduced pressure, followed by trituration of the resulting residue with cold n-heptane (0 ° C) for a total yield of 10.2 g (91%). . ,
Example 3 Preparation of (E, Z) -l-bromo-2-cyclopentylethylene (2b)
The cyclopropylacrylic acid obtained in step 1 is dissolved (30 g, 268 mmol, 1 equivalent, made by Example 1) and lithium acetate dihydrate
(273 g, 26.8 mmol, 0.1 equivalent) in 300 mL of acetonitrile and water (9 mL). The solution is stirred at room temperature for about five minutes, and then treated with N-bromosuccinimide.
(57.2 g, 321 mmol, 1.2 equivalents). The reaction mixture is stirred at room temperature for 45 minutes and then quenched with 100 ml of H20 and extracted with hexanes (3 x 300 ml). The combined organic layers are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The desired product is obtained as a mixture of stereochemically isomeric isomers as determined by NMR analysis and GC (colorless liquid, 32 g, 82% yield, boiling point 45 ° C / ~ 20 mm Hg).
Example 4 Preparation of cyclopropylacetylene:
A suitable reaction flask equipped with a stirring medium and a means for monitoring the temperature are charged with DMSO (20 ml) and potassium tert-butoxide (2.24 g, 20 mmol) to give a pale yellow solution. Cyclopropyl vinyl bromide 2b (1.47 g, 10 mmol) is added in such proportion that the internal temperature does not exceed 35 ° C. The reaction is complete after stirring at room temperature for an additional 30 minutes after the addition is complete. The reaction mixture is then treated with H20 (approximately 20 mmol, approximately 0.4 ml). Pure cyclopropylacetylene is obtained by direct vacuum distillation from the reaction mixture in about 80% yield.
Example 5 Preparation of 3-cyclopropylacrylic acid (1)
A 3-liter round four-necked flask equipped with a mechanical stirrer, an internal thermocouple and a Dean-Stark apparatus with a reflux condenser is connected to a nitrogen inlet and an oil bubbler with a solution of cyclopropyl carboxaldehyde (92%, 300 g (326 g), 4.28 moles, 1 equivalent) in heptane (1.07 liters). To this stirred solution is added malonic acid (534.1 g, 5.14 moles, 1.2 equivalents) in one portion followed by pyridine (173 ml, 2.14 moles, 0.5 equivalents). The solution is stirred vigorously. at 30 ° C (can be heated up to 35 ° C to maintain malonic acid solution) for 15 minutes (to avoid clumping) and a catalytic amount of piperidine (42.33 ml, 0.1 equivalents, 0.428 moles) is carefully added. After the addition is complete, the mixture is heated to 75 ° C until it starts refluxing. After two hours of reflux, the internal temperature is increased to 95 ° C to maintain a constant reflux for another two hours. The water collected from the Dean-Stark trap is 73 ml. The reaction is monitored by 1 H NMR indicating that there is no aldehyde after this period of time. The reaction mixture is then cooled to 0 ° C, and an aqueous solution of HCl (670 ml, 0.8 equivalents) is added slowly to keep the internal temperature below 10 ° C. A pale yellow fine precipitate forms slowly. The heterogeneous mixture is stirred at 0 ° C for 2 hours and then filtered through a 3000 ml porous glass buchner funnel. The solid paste is washed with a dilute aqueous solution of HCl (1 x 0.5 N, 500 ml), and water (2 x 500 ml). The off-white solid is dried under the air flow at room temperature overnight to yield 453 g (94%) of cyclopropylacrylic acid. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (14)
- Having described the invention as above, the claim contained in the following claims is claimed as property: 1. A process for the synthesis of cyclopropylacetylene, the process is characterized in that it comprises: (i) contacting the cyclopropane carboxaldehyde with malonic acid, or a Malonic acid substitute in the presence of a base catalyst to form 3-cyclopropylacrylic acid. (ii) contacting the 3-cyclopropylacrylic acid with a metal catalyst and a halogenating agent to form (E, Z) -l-halo-2-cyclopropylethylene; and (iii) contacting (E, Z) -l-halo-2-cyclopropylethylene with a strong base to form cyclopropylacetylene.
- 2. The process according to claim 1, characterized in that the substitute of. Malonic acid is selected from 2,2-dimethyl-1,3-dioxane-4,6-dione. dimethyl malonate, diethyl malonate, and monomethyl malonate.
- 3. The process according to claim 1, characterized in that the base catalyst is selected from pyridine, pyrrolidine, piperidine, morpholine, N-methylmorpholine, 1/4-diazabicyclo [2.2.2] octane, N, N-dimethylaminopyridine, N , N-diethylaniline, quinoline, N, N-diisopropylethylamine, sodium hydroxide, potassium hydroxide-, lithium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium alkoxide, lithium alkoxide and potassium alkoxide, where the methoxide, ethoxide, butoxide, t-butoxide and t-amyloxide are selected.
- 4. The process according to claim 1, characterized in that the metal catalyst is selected from lithium acetate, magnesium acetate, zinc acetate, calcium acetate, copper iodide and copper bromide.
- 5. The process according to claim 1, characterized in that the halogenating agent is selected from N-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide.
- 6. The process according to claim 1, characterized in that it comprises: (i) contacting the cyclopropane carboxaldehyde with malonic acid in the presence of a base catalyst selected from: pyridine, pyrrolidine, piperidine, morpholine, N-methylmorpholine, 1,4-diazabicyclo [2.2.2] octane, N, N-dimethylaminopyridine, N, N-diethylamine, quinoline, N, N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, carbonate of cesium, sodium alkoxide, lithium alkoxide and potassium alkoxide, wherein the methoxide, ethoxide, butoxide, t-butoxide and t-amyloxide are selected; to form 3-cyclopropylacrylic acid; (ii) contacting the 3-cyclopropylacrylic acid with a metal catalyst selected from: lithium acetate, magnesium acetate, zinc acetate, calcium acetate, copper iodide and copper bromide; and a halogenating agent to form (E, Z) -l-halo-2-cyclopropylethylene; and (iii) contacting (E, Z) -l-halo-2-cyclopropylethylene with methyl lithium, potassium t-butoxide, potassium hydroxide, or sodium amide to form cyclopropylacetylene.
- 7. The process according to claim 6, characterized in that it comprises: (i) contacting the cyclopropane carboxaldehyde with malonic acid in the presence of a base catalyst selected from: pyridine, pyrrolidine, piperidine, morpholine, or a combination thereof; to form 3-cyclopropylacrylic acid; (ii) contacting the 3-cyclopropylacrylic acid with a metal catalyst selected from: lithium acetate, magnesium acetate, zinc acetate, calcium acetate, copper iodide and copper bromide; and a halogenating agent to form (E, Z) -l-halo-2-cyclopropylethylene; and (iii) contacting (E, Z) -l-halo-2-cyclopropylethylene with potassium t-butoxide, potassium hydroxide or sodium amide to form cyclopropylacetylene.
- 8. The compliance process. with claim 6, characterized in that it comprises: (i) contacting the cyclopropane carboxaldehyde with malonic acid in the presence of a base catalyst selected from: pyridine, pyrrolidine, piperidine, morpholine, or a combination thereof; to form 3-cyclopropylacrylic acid; (ii) contacting 3-cyclopropylacrylic acid with lithium acetate and a halogenating agent to form (E, Z) -l-halo-2-cyclopro-yl-ethylene; and (iii) contacting (E, Z) -l-halo-2-cyclopropylethylene with methyl-lithium, potassium t-butoxide, potassium hydroxide or sodium amide to form cyclopropylacetylene.
- 9. The process according to claim 1, characterized in that it further comprises in step (2) contacting the 3-cyclopropylacrylic acid with a metal catalyst and a halogenating agent in the presence of a phase transfer agent to form (E, Z) -l-halo-2-cyclopropylethylene.
- 10. The process according to claim 1, characterized in that it further comprises step (3) by contacting (E, Z) -l-halo-2-cyclopropylethylene with a strong base in the presence of a phase transfer agent for form cyclopropylacetylene.
- 11. The process according to claim 6, characterized in that the halogenating agent is N-bromosuccinimide.
- 12. The process according to claim 7, characterized in that the halogenating agent is N-bromosuccinimide.
- 13. The process according to claim 8, characterized in that the halogenating agent is N-bromosuccinimide.
- 14. The compound of the formula C3HsCH = CHBr
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/054,402 | 1997-07-31 |
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MXPA00001039A true MXPA00001039A (en) | 2001-05-07 |
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