IE56713B1 - Alpha-bromodiethylcarbonate and its use in the preparation of antibiotics - Google Patents
Alpha-bromodiethylcarbonate and its use in the preparation of antibioticsInfo
- Publication number
- IE56713B1 IE56713B1 IE1360/91A IE911360A IE56713B1 IE 56713 B1 IE56713 B1 IE 56713B1 IE 1360/91 A IE1360/91 A IE 1360/91A IE 911360 A IE911360 A IE 911360A IE 56713 B1 IE56713 B1 IE 56713B1
- Authority
- IE
- Ireland
- Prior art keywords
- process according
- formula
- catalyst
- compound
- carried out
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 16
- 239000003242 anti bacterial agent Substances 0.000 title 1
- 229940088710 antibiotic agent Drugs 0.000 title 1
- 238000000034 method Methods 0.000 claims description 71
- 230000008569 process Effects 0.000 claims description 59
- 238000006243 chemical reaction Methods 0.000 claims description 28
- -1 1-ethoxycarbonyl oxyethyl ester Chemical class 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 23
- 239000003054 catalyst Substances 0.000 claims description 21
- 150000002081 enamines Chemical class 0.000 claims description 17
- 238000005886 esterification reaction Methods 0.000 claims description 16
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 10
- 150000001340 alkali metals Chemical class 0.000 claims description 10
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 229960000723 ampicillin Drugs 0.000 claims description 8
- 229910001513 alkali metal bromide Inorganic materials 0.000 claims description 7
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229960003311 ampicillin trihydrate Drugs 0.000 claims description 6
- 230000032050 esterification Effects 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- 229910001516 alkali metal iodide Inorganic materials 0.000 claims description 5
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 5
- 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 claims description 5
- 239000003444 phase transfer catalyst Substances 0.000 claims description 5
- 150000003242 quaternary ammonium salts Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 150000008282 halocarbons Chemical group 0.000 claims description 3
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 claims description 3
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical group S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical class CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 150000004292 cyclic ethers Chemical class 0.000 claims description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-O oxonium Chemical group [OH3+] XLYOFNOQVPJJNP-UHFFFAOYSA-O 0.000 claims description 2
- 150000004714 phosphonium salts Chemical group 0.000 claims description 2
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 150000003512 tertiary amines Chemical group 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000003672 ureas Chemical class 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims 2
- 240000005020 Acaciella glauca Species 0.000 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 230000001131 transforming effect Effects 0.000 claims 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 37
- 239000000203 mixture Substances 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000013019 agitation Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- RKRZYVQFKUXDEZ-UHFFFAOYSA-N 1-bromoethyl ethyl carbonate Chemical compound CCOC(=O)OC(C)Br RKRZYVQFKUXDEZ-UHFFFAOYSA-N 0.000 description 5
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 5
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 5
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- IWVTXAGTHUECPN-ANBBSHPLSA-N bacampicillin hydrochloride Chemical compound [H+].[Cl-].C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OC(C)OC(=O)OCC)=CC=CC=C1 IWVTXAGTHUECPN-ANBBSHPLSA-N 0.000 description 4
- 229960005412 bacampicillin hydrochloride Drugs 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000004508 fractional distillation Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YVRGKFXJZCTTRB-UHFFFAOYSA-N 1-chloroethyl ethyl carbonate Chemical compound CCOC(=O)OC(C)Cl YVRGKFXJZCTTRB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000005967 Finkelstein reaction Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229940113088 dimethylacetamide Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 3
- 229910052753 mercury Inorganic materials 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229960002699 bacampicillin Drugs 0.000 description 2
- PFOLLRNADZZWEX-FFGRCDKISA-N bacampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OC(C)OC(=O)OCC)=CC=CC=C1 PFOLLRNADZZWEX-FFGRCDKISA-N 0.000 description 2
- 150000001649 bromium compounds Chemical class 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- SNDGLCYYBKJSOT-UHFFFAOYSA-N 1,1,3,3-tetrabutylurea Chemical compound CCCCN(CCCC)C(=O)N(CCCC)CCCC SNDGLCYYBKJSOT-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000008431 aliphatic amides Chemical class 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- IYNDLOXRXUOGIU-LQDWTQKMSA-M benzylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-LQDWTQKMSA-M 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- RMGVZKRVHHSUIM-UHFFFAOYSA-L dithionate(2-) Chemical compound [O-]S(=O)(=O)S([O-])(=O)=O RMGVZKRVHHSUIM-UHFFFAOYSA-L 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical group OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 150000003510 tertiary aliphatic amines Chemical class 0.000 description 1
- 150000003513 tertiary aromatic amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
ASTRA LAKEA'EDEL AKTIEBOLAG, A SWEDISH BODY CORPORATE, OF S-I51 85 SODERTALJE, SWEDEN.
SS7 1 3 The present Invention relates to @b=bi?owod i$thyIcarbonate, which with gr The present invention also relates to novel methods for the preparation of «<-bromodiethylcaEbonateo The present application is divided from Patent Application No, 1445/83 which relates to the use of o-iodo and a-chloro diethyl carbonate, in the presence of a quaternary ammonium salt catalyst, in producing the ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, penicillins and cephalosporins.
The isubstanc® a concerned lo an ampieillin ester which is extremely important fro® the therapeutic view since it is well absorbed wh^n administered orally and gives much higher blood levels of ampiclllln than ampiclllln itself« This ester is isolated in the form of a hydrochloride and is known as bacampicillin hydrochloride.
On the basis of previous known processes (cf. Belgian patent No. 772723), bacampicillin hydrochloride can be synthesized by the two following methods: a A) Reaction of potassium benzylpenicillin with a-chlorodiethylcarbonate in organic solvents or in an aqueous solution of 70% dioxane in the presence of sodium bicarbonate. The 1-efhoxycarbonyloxyethyl ester of benzylpenicillin which is obtained is subjected to the reaction of remov io ing phenyl acetic chain, via the iminochloride-irainoether, in order to obtain the 1-efhoxycarbonyloxyethyl ester of the 6-aminopenicillanic acid, which is isolated as the hydrochloride.
By subsequent condensation of the latter intermediate with D-(-)-aphenylglycine, the compound according to formula I is obtained.
B) Esterification reaction of the 6-(D-(-)-a-azido-a-phenylacetamido)pencillanic acid with a*chlorodiethylcarbonate in a polar solvent.
Subsequently, by catalytic hydrogenation of the 1-ethoxycarbonyloxyethy1 ester of the 6-(D(-)-a-azido-a-phenylacetamido)penici11anic acid the compound according to formula 1 is obtained.
As one can see, these methods are rather complex since they involve the use of numerous raw materials and lengthy processing times.
A prime object of this invention is to provide a method of preparing the active substance concerned which Is easier to carry out and industrially more advantageous. A more specific object of this invention is provide a method of preparing bacampicillin using ampicillin as start ing material, with considerable simplification of the said method and obtaining a high degree of purity of the desired product.
The invention also provides the novel compound ^bromodiethylcarbonate and novel methods for the preparation thereof. vt-Bromodiethylcarbonate is used with great advantage as a 5 reactant and leads to particularly high yield and high purity of the final products in an esterification process to produce bacampicillln° It is possible to achieve the said prime object of preparing the 1-ethoxycarbonyloxyethyl ester of the 6-(D (-)-°^amino10 °^phenylacetamido) pencillanic acid having the following formula: n & CO—ft-CH-COO—CH— 0 — COOC-HI 2 5 ch3 by a) reacting ampicillin, preferably in the form of an alkali 15 metal, alkaline earth metal or organic base salt, with a reactive derivative of acetoacetic acid to form the corresponding enamine having the following formula: where: •A R^ represents an alkyl group containing 1 to 4 carbon atoms, a substi* tuted or unsubstituted aryl group or an aralkyl group; 82 represents hydrogen, an alkyl group containing 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or an aryl kyl group; 83 represents an alkyl group containing 1 to 4 carbon atoas, a substi* tuted or unsubstituted aryl group, an arylkyl group, tin alkoxy group containing 1 to 4 carbon atoms» an aryloxy group or an amino group, and Jt represents hydrogen or an alkali metals an alkaline-earth XO metal or an organic base; b) reacting the resulting intermediate of fonnula II with a-bromo diethyl carbonate having the following formulas Rr^CH-O-COQCJk (III) I ch3 to form the corresponding ester having the following fonnula: fi—coo- ch—o-cooc2h5 3 R and R have the (IV) CH where R same significance as above and c) subjecting ester IV to mild hydrolysis in an acid medium, thus obtaining the compound according to formula (I). 2o The esterification reaction between the compounds II and III can be carried out with or without an esterification catalyst present.
The addition of a catalyst at this stage considerably shortens the reaction times and provides higher yields of the product with a greater degree of purityFor this purpose the following substances can be used as catalysts: quaternary wnonium salts, for example tetrabutylammonium bromide, the bromides or Iodides of alkali metals and: cyclic ethers.
The catalyst may be used in an amount which varies from 0.005 to 0.10 5 moles per mole of compound 111 to amounts which are equimolar with the compound III. In a preferred embodiment tetrabutylammonium bromide is used 1n an amount of from 0.01 to 0.10 moles per mole of compound III. 3 Illustrative examples of the radicals R * R and R are: aryl: substituted aryl: phenyl substituted with halogen such as Cl and Br Ths radical X Is selected among groups which are well known 1n she art, for «sample alkali metal: Ha, ft alkaline earth metals: Ca, Hg 5 organic base: organic bases which are known in the synthesis of penicilHas, e.g. tertiary «ionium groups, triethylamine, ethyl pi peri dine and niathylmorpholine. in the preferred embodiment «· the invention, the group protecting the anlno group of the ampicillin is a l-methoxy-carbonyl-propen-2-yl group IO or a l@tf»xy-cflrbonyl’propen-2-y1 group for which the preferred intermediate is the sodium or potassium salt of the N-(-1 -methoxy-carbonylpropen-2-yl) penicillanic acid respectively H-(l-ethoxy-carbonylpropen2-yl penicillanic acid .according to formula 11 ([J - methyl; R2 3 methyl; R » methoxy or ethoxy and X Ha or K).
The intermediate IV is stable in a neutral or alkaline medium, whereas In an acid medium it Is possible to remove the group protecting the amino group simply, quickly and selectively.
The group protecting the amino group of the ampicillin can be selected e.g. from the groups mentioned in the British patent specification 991536, and from other groups which are known in the art.
The o-bromodi ethyl carbonate, compound III, which is a novel compound and as such included in the scope of the invention may be prepared by reacting the corresponding α-chlorodi ethyl carbonate with sodium bromide as is exemplified in Example 1 below.
Hore specifically, therefore, the process method according to a preferred embodiment of this invention, comprises the following stages: θ transformation of ampicillin trihydrate In a polar solvent, for example £MM1methyiforw4!i1deD Into a salt thereof, for example potassium, and subsequent formation of the corresponding enamine (II) by reaction with a derivative of acetoacetic add, for example methyl acetoacetate. - addition of an esterification catalyst, preferably tetrabutylairanonium bromide * addition of α-bromdiethylcarbonate to the reaction mixture to form the 1-ethoxycorbonyloxyethyl ester of the ampicillin in the form of the enamine (IV). - hydrolysis of the protective group with HC1 diluted in an organic solvent, for example n-butyl acetate/woter. - recovery of the bacampicillin hydrochloride by saturation In the aqueous phase, for example with sodium chloride and extraction with a suitable solvent, for example n-butyl acetate. - concentration of the solution at low pressure in n-butyl acetate - in order to crystallize the product to a high level of purity, the product then being isolated by filtration.
Among the main advantages of the process according to the invention, the principal one is that, by this process, it is possible to obtain bacampicillin hydrochloride practically in one operation and with a high degree of purity.
In fact the impurities which are present in the product obtained by the process according to the present invention are negligible as compared with the known processes of the previous state of the art.
Another equally important advantage is that ampicillin trihydrate is used as the starting material, this being a known antibiotic which is Easily obatainable in pure form and at low cost.
The Intermediate (II) can be easily prepared as described for example 1n British patent specification 991586 with a yield of over 95% by reaction of ampicillin trihydrate with methyl or ethyl acetoacetate. to 502 more than the stoichiometric ratio, in the presence of an organic base or an alkali metal carbonate, for example potassium carbonate.
The Intermediate (III can be Isolated and added to the esterification reaction in solid form. Or, without isolation of the intermediate (II), the esterification reaction can be effected in the same solvent in which tlie reaction for the formation of enamine (21) took place.
The reaction for the formation of ampicillin enamine (II) is conducted in an aprotic polar solvent, such as Ν,Ν-dimethylacetamide, N,N-di1O methylformamide, dimethoxyethane, dimethylsulphoxide, tetrahydrofuran or dioxane.
To complete the reaction, it is sufficient to leave the components of the mixture in contact at a temperature between 0°C and 60"C, preferably between 20°C and 30°C, for 2 to 8 hours, preferably 3 hours.
The compound II can be prepared via acylation of 6-aminopenicillanic acid with a corresponding enamine derivative of phenylglycine to the formation of the compound II which thereafter can be esterified directly and converted to bacampicillin with isolation of the compound II.
The esterification reaction after the addition of the o-bromdiethylcar20 bonate fo the said mixture, takes place at a temperature between 15 °C and 80’C, preferably between 4SeC and 55’C, for a period of time from 1 hour to 24 hours, preferably from 5 to 10 hours.
The esterification reaction is suitably carried out in an organic solvent such as methylene chloride or acetone, dimethyl acetamide, di25 methylformamide and dimethylsulfoxide, or in a mixture of organic solvents. If is possible fo use also organic solvent containing water.
The use of esterification catalyst is desirable when acetone is used as solvent for the esterification reaction. in ϊη the easiest and most suitable conditions for industrial purposes, the esterified enamine (IV) is isolated by dilution of the reaction mixture with water and subsequent extraction with a suitable solvent which is immiscible with water, for example n-butyl acetate» The acetate phase is agitated with a dilute solution (0.2 to 0.3K) of HCI until the protective group is completely hydrolysed, which requires a contact time of 2 to 8 hours, preferably 4-5 hours, at ordinary temperatures.
A By addition of sodium chloride, compound (I) separates out from the aqueous phase in the form of the hydrochloride, which is extracted with a suitable solvent, for example n-butyl acetate.
By concentrating the organic phase at low pressure at a temperature of 40°C until a small volume remains, crystallization of the product according to formula (I) takes place.
The crystalline product is isolated by filtration, washing and vacuum drying.
The following examples illustrate aspects of the present invention.
Examples 1, 5, 6, 7, 8 and 9 illustrate processes for preparing<-broroodiethylcarbonate and Examples 2, 3 and 4 illustrate processes using All percentages are by weight unless otherwise stated Example 1 Preparation of cL^broradlethylcarbonaee IO acetone MBr -i- Cl-CH-OCOOC2Hg--™>Br-^H»OCOOC2H5vNaCl ch3 ch3 Sodium bromide (102.9 g) dissolved in aceton (600 ml) was reacted for 2-3 hours at ambient temperature (20-25°C) with ^chlorodiethylcarbonafe (152.6 g) dissolved in 100 ml of acetone. The mixture was then concentrated under vacuum at low temperature, mas. 35°C, until a semi-solid mass was obtained. The reaction mixture was then partitioned with B^O/ethyl ether. The aqueous phase was separated and was then extracted twice #ith 400 oil of ethyl ether.
The combined organic phases containing the c*.-bromdiethylcarbonate were washed with V? 000 ml of H20 1000 nil of 1% sodium metabisulphate aqueous solution 1000 ml of NaCl saturated solution The organic phase was dried over Hg sulphate, and then concentrated under vaccum at low temperature, max. 35°C to give the title product (60%) in the form of a liquid which initially was colourless or slightly yellow-brown.
It was used directly in the esterification step accord4/ig to Example 2 below.
IO Example 2 .08 g (0.181 m) of finely ground anhydrous potassium carbonate are suspended in 200 ml of N,Ν-dimethylacetamide and 32.4 ml (0.3 m) of methyl acetoacetate and 60.4 g (0.15 m) pf ampicillin trihydrate are added.
The mixture is maintained under fast agitation for 5 hours at 20°C 25°C; after this time 46.1 g (0.234 m) of bromdiethylcarbonate, 6 g (0.02 m) of tetrabutyl ammonium bromide and 100 ml of N,N-dimethylacetamide are added.
It is heated under agitation for 10 hours at 40°C - 42°C; the reaction mass is poured into a mixture consisting of 1200 ml of water and 400 ml of n-butyl acetate.
The aqueous phase is collected and extracted with another lui ml of n-butyl acetate.
The reunited organic phases are washed twice with 100 ml of water each time. 150 ml N HC1 and 370 ml of water are added to the organic phase which is subjected to agitation; it is left under agitation at 22°C 23eC for 4 hours.
The aqueous phase is collected and the organic phase is extracted with 100 ml of wat^r.
Tlie reunited aqueous phases are brought to pH 4 with a 10% aqueous solution of Hci^COj6 theh bleaching carbon Is added to them and they are filtered. 300 ml of n-butyl acetate and GO § of sodluei chloride are added to the aqueous filtrate.
The organic phase is separated and the aqueous phase 1s extracted with 200 ml of n-butyl acetate. io The reunited phase 1n n-butyl acetate are concentrated at low pressure at 40°C to a volume of approximately 300 till. The product Is left to crystallise for 15 hours at ¢5%.
It 1s f11teredb washed with n-butyl acetate (100 ml) and ethyl acetate (100 ml,* Kt 1s vacuum dried at 40*C for 24 hours. field: 54.2 g (72%) of the 1-ethoxycarbonyloxyethyl ester of the 6(0(-,-a-amino-o-phenylacetufnido, penicillanlc add with m.p. 160-2°C. (d) and characteristics conforming to the authentic hydrochloride sample.
Example 3 A mixture of 160 ml acetone, 22.6 g (0.075 mol) of the potassium salt of D(-)-N-methoxycarbonylpropen«2-yl-aminophenylacetic acid, 6.9 ml (0.088 mol) ethyl chlorofonaate and 3 drops of N-methyl morpholine. Is stirred for 15 minutes at a temperature of -20 - -30°C- To this reaction mixture a solution of 16.2 g S-aminopenicillanic acid, dissolved in 35 ml water through the gentle addition of 7.6 g (0.075 mol, triethylamine with agitation, is added in one portion, after which the mixture is diluted with 90 ml acetone and chilled to -20°C.
After stirring for 45 minutes, without any additional cooling, 23.4 g (0.117 mol) of α-bromodi ethyl carbonate, 3 g (0.01 mol) of tetrabutylammonium bromide and 250 ml of ft,dimethylformamide are added in that order. The mixture is stirred for 18 hours at 25°C. After that time the reaction mass is poured into a mixture consisting of 600 ml of water and 200 ml of n-butyl acetate and it is agitated until a complete solution is obtained: The aqueous phase is collected and extracted with another 50 ml of n-butyl acetate.
The reunited organic phases are washed twice with 50 ml of water each time. 185 ml of water Is added to the organic phase and 1 N HCl is added dropwise with agitation to a pH of 1.9. The mixture is left under agitation at 22-23°C for 4 hours.
The aqueous phase is collecefed and the organic phase is extracted with 50 ml of wafer. The reunited aqueous phases are brought fo pH 4 with a 10% aqueous solution of fta^COp active carbon is added to them and they are filtered. 150 ml of n-butyl acetate and 40 g of sodium chloride are added fo the aqueous filtrate.
The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. The reunited phases in butyl acetate are concentrated at low pressure at 40°C fo a volume of approximately 150 ml.
The product is left to crystallise for 15 hours at *5eC.
If 1$ filtered, washed with n-butyl acetate (25 ml) and ethyl acetate (25 ml). If is dried under a vacuum of 10 mm Hg at 25eC for 24 hours. yield: 1.17 η of the 1-ethoxycarbonyloxyethy 1 ester of 6-(D(-)~a-amino -α-phenyl acetamldopenlcillanic acid hydrochloride with m.p. 159-16VC and characteristics (Mt. TLC) conforming to an authentic sample.
Example 3a The procedure of example 3 was repeated with the difference that the G-emlnopenlcillanic acid was dissolved In 20 ml water instead of in 35. field: 1-05 g of the ethoxycarbonyloxyethyl ester of §-(D(-)^a-smino-aphenylacetamidopenici 11anic acid hydrochloride as a white crystalline powder with m.p. 148~1510Ce with decomposition^ and characteristics (TLCe IR) conforming to an authentic sample.
Example4 6-25 g (0.045 ra) of finely ground anhydrous potassium carbonate are . suspended in 50 nl of dimethyl sulphoxide and 8.1 ml (0.C75 m) of methyl acetoacetate and 15.1 g (0.0375 ra) of ampicillin trihydrate are added.
The mixture is maintained under fast agitation for 5 hours at 20eC - 25eCs after this time 11.5 g (0.059 m) of broraodiethylcarbonate and 25 ml of dimethyl sulphoxide are added.
It is heated under agitation for 1? hours af 35»37°C; the reaction mass is poured into a mixture consisting of 300 ml of wafer and 100 ml of n-butyl acetate.
The aqueous phase is collected and extracted with another 100 ml of n-butyl acetate.
The reunited organic phases are washed twice with 25 ml of wafer each time. 02.5 ml of water and HHCI (7.0 ml) to a pH of 1.9 are added to the organic phase which is subjected to agitation; it is left under agitation at 220C - 23°C for 2,5 hours.
The novel compound ^bromdiethylcarbonate of the Invention, novel and inventive processes for the preparation thereof and its use in the preparation of the ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid, will now be described and exemplified in more detail.
This aspect of the invention is concerned with improvements in and relating to the preparation of @t-bromodiefhylcarbonate of the formula: Br I CHj-CHoOoCO.O.CjHg (XII) k The alpha-bromo diethylcarbonate of the formula (III) may according to a further aspect of the invention, which is further dealt with later? be used in the synthesis of the alpha(ethoxycarbonyloxy)-ethyl ester of 6-aminopenicillanic acid.
According to the invention two novel and inventive processes, herebelow denoted process A and process B, are provided for the preparation of alpha-bromodiethylcarbonate of the formula III.
A. The first of these processes, process A, comprises the steps of: (a) reacting an aldehyde of the formula ch3cho VI with carbonyl bromide COBr2 VII to give an alpha-brgpo-bromoformate of the formula I CB j-CH. 0. CO θ Br VIII 1? and; (b) reacting the alpha-bromo-bromoformate of formula VIII with an alcohol of the formula to yield the desired alpha-bromo-dlethyl carbonate of the formula III.
Thus, the process A 1n accordance with the invention may be summarised by the reaction scheme: Br Br « 2 5 ι CH3CHO * C0Br2 -rCHj— CH.O.CO.Br.-> CH^-CH.O.CO.O.C^ * HBr The alpha-bromo-bromoformate of the formula VIII Is In it self a new compound and 1s provided as a further feature of the invention. 1q The reaction between the aldehyde, CH^CHO, and carbonyl bromide is most suitably carried out 1n the presence of a catalyst which may be, for example, a tertiary amine (for example a tertiary aliphatic amine, a tertiary mixed alkyl/aryl amine or a tertiary aromatic amine), tertiary phosphine» amide, substituted urea or thiurea, phosphoric acid amide, tertiary oxonium or sulphonium salt, or a quaternary ammonium or phosphonium salt. Preferred examples of catalysts for use in the process A according to the invention include pyridine, dimethylformamide, tetra-n-butyl urea, hexamethyl-phosphorie-tri-amide and benzyltri methyl aimnonium bromide.
The catalyst Is suitably used in an amount of from 0.05 to 0.5, preferably from 0.05 to 0.15« moles of catalyst per mole of aldehyde.
The reaction between the aldehyde and the carbonyl bromide is suitably carried out in the presence of a solvent which may be, for example, an aromatic hydrocarbon such as toluene or a halogenated hydrocarbon such as dlchloromethane, carbon tetrachloride or chlorobenzene. The reaction between the aldehyde and the carbonyl bromide is suitably carried at a temperature of from -40 to 120°Ce preferably 0 - 40eC.
The carbonyl bromide will usually be used 1n molar excess with respect to the aldehyde, suitably in a molar excess of from 10 to 100*, pre30 ferably from 20 to 50£.
The Intermediate alpha-bromo-bromoformate of formula VII! produced in step (a) of the process A of the Invention need not be Isolated prior to reaction with the alcohol CgHgOH and. indeed» If is generally preferred not fo do so. Thus, in accordance with a preferred embodiment of the invention, the reaction mixture obtained from step (a) 1s freed of excess carbonyl bromide, for example by warming under reduced pressore or by purging with nitrogen. The crude alpha-bromo-bromoformate- t containing reaction mixture 1s then reacted with an excess of the alcohol. The reaction may conveniently be effected by heating the mixture under reflux until the evolution of hydrogen bromide ceases or by adding a tertiary base to the mixture and» 1f necessary, warming It. Any residual catalyst from step (a) or its complex with carbonyl bromide does not appear to Interfere with the subsequent reaction and, 1n some cases, appears beneficial.
The resultant crude alpha-bromocarbonete may conveniently be isolated from the reaction mixture by fractional distillation under reduced pressure.
Process A is illustrated in Examples Sand 6, which are given by way of Illustration only. 3. The second process, process 8, of the invention for the preparation of α-bromodiethylcarbonate will now be described. Method 8 is exemplified in Example 7* which is given by way of illustration only.
Process B of the invention is concerned with improvements in and relating to the preparation of a-bromod1ethylcarbonate by a modification of the Finkelstein reaction, that is by reaction of an alkyl chloride or arylalkyl chloride (or a compound containing such a group, with @n alkali metal bromide or alkali metal iodide to replace the chlorine substituent by a bromine or iodine substituent respectively; or by the reaction of an alkyl bromide or arylalkyl bromide (or a compound containing such a group) with an alkali metal Iodide to replace the bromine substituent by an iodine substituent.
The Finkelstein reaction is useful since the resulting Iodides are generally more reactive than the bromides which in turn are sore reactive than the chlorides. In some cases only catalytic amounts of the alkali metal bromide or iodide are necessary and the resulting more reactive species is allowed fo react with the desired substrate regenerating the alkali metal bromide or iodide* thus continuing the reaction.
Not all optionally substituted alkyl chlorides or arylalkyl chlorides undergo the reaction and, in particular, it has been found difficult fo carry out the reaction with alpha-chloro esters and alpha-chlorocarbonates* that is compounds fn which the chlorine atom is attached to a carbon atom which 1ss in turn,, attached to either end of a group -8(0)-0-. An exempt of such an alpha-chlorocarbonate is e-chlorodiethyl carbonate* which is a known isifenaediate in the preparation of the ethoicycarbonyloxyethyl ester of e-amlnopenicillanic acid.
It has now been found* in accordance with’the present invention, that this problem may be overcome by carrying out the reaction using a twophase solvent system* one phase of which is water and the other is a water-immiscible organic solvent* in the presence of a phase transfer catalyst.
According to process 8 of the invention* therefore* there is provided a process for the preparation of o-bromodi ethyl carbonate by reaction of o-chlorodiethylcarbonate with an alkali metal bromide, which process is characterised in that the reaction is carried out in a two-phase solvent system comprising water and a water-1eniscible organic solvent in the presence of a phase transfer catalyst.
Suitable w&ter-inmriscible organic solvents for use in accordance with the invention include halogenated hydrocarbons, for exa^le halogenated paraffins such as dlchloromethane; and aromatic hydrocarbons such as toluene. Suitable phase transfer catalysts include quaternary esuaoniwa salts, for example tetraalkyl mioniura salts such as cetyl trimethyl «tonium bromide and tetra-n-butyl mionium hydrogen sulphate. The alkali metal bromide may* for example, be sodium* potassium* or lithium bromide, lithium bromide being preferred.
Thus, in process B of the Invention, orchlorodiethylcarbonate of the fonnula: S1 1 CH3- CH-0-C-0-CjHj Π is reacted in a two-phase solvent system, one phase of which is water , and the other 1s a wafer-immiscible organic solvent, with an alkali metal bromide of the formula R-Br X in which fonnula R is an alkali metal such as Ha, K and Ll, to the formation of the compound of the fonnula: 3r 0 I s c«3-ch—o—c— 0-CjjHg m As noted above, the preferred alkali metal R is Li so that LiBr is t a preferred reagent of the formula X.
In connection with process B it has been found that lithium bromide may be used with advantage in a conventional Finkelstein reaction (i.e. one employing a single phase organic solvent system), for example fo halogenafe an alpha-chloro-carbonate. This method is exemplified in Example 8.
Accordingly, the present invention also provides, in accordance with a further embodiment thereof, a process for the preparation of o-bromodiethylcarbonate which comprises reacting o«ch1orodiethylcarbonate with lithium bromide.
Suitable solvents for such a process Include lower aliphatic alcohols, lower alphatic ketones, lower aliphatic ethers and lower aliphatic amides of formic acid.
In order that the Invention may he well understood the following examples are given by way of illustration.
A mixture of acetaldehyde (44 gB 1 mole)P carbon tetrachloride (300 wl) * 5 and freshly distilled carbonyl bromide (235 g, 1.25 mole, was cooled to 0°C and maintained at this temperature by external cooling during the addition over a period of 1 hour of pyridine (11.9 g, 0.15 mole).
/ The mixture was allowed to warm up to ambient temperature and then heated to 5O°£ and maintained at this temperature for a period of 3 lo hours during which time a precipitate formed.
Evaporation of the reaction mixture under reduced pressure at 50°C gave a semi solid oily mass which readily dissolved in ethanol (92 g, mole) on warming and heating under reflux. After heating under reflux for a further 2 hours, excess ethanol was removed in vacuo and the 15 residue triturated with water (100 ml, and methylene dichloride (200 ml).
Separation of the organic layer and fractional distillation afforded pure ethyl alpha-bromo-ethyl-carbonate (130 g, 66% yield) having a boiling point of 90-92°C at 45 mms of mercury pressure and identical in all respects with an authentic specimen.
Example 6 A mixture of acetaldehyde (44 g, 1 mole), dlchloromethane (300 ml) and hexamethy1phosphoric-tri-amide (17.9 g0 0.1 mole) was cooled to -10°C and freshly distilled carbonyl bromide (207 gP bi mole) was gradually added over a period of 4 hours during which time the temperature was allowed to rise to 10®C.
The mixture was then heated under gentle reflux (ca. 40*0 for 4 hours.
While still under reflux, ethanol (69 g. 1.5 mole) was carefully added ovsr a period of 1 hour and heating under reflux continued for a i further 1 hour.
Fractional distillation of the resulting mixture afforded pure ethyl alpha-bromoethyl-carbonate directly (114 g„ 58% yield).
The authenticity of the ethyl alpha-bronoethyl carbonate formed was confirmed by analysis and independent synthesis as follows.
Oiefhylcarbonate (118 g, 1.0 mole) was stirred and heated to between 110°C and 120°C and Illuminated by a 150 watt tungsten filament lamp.
Bromine (96 g, 0.6 mole) was added dropwise over a period of 3 to 4 hours and at such a rate that the mixture did not deepen beyond a pale orange colour.
After addition of bromine was complete, the mixture was cooled to ambient temperature and sodium bicarbonate (20 g) added.
Distillation and fractionation of the resulting mixture gave authentic ethyl alpha-bromo-ethyl carbonate (84.2 g. 70% yield) having a boiling point of 87-88®C at 40 rams of mercury pressure.
Example 7 A mixture of lithium bromide (43 g, 0.5 mb ethyl alphachloroethyl carbonate (15.3 g, 0.1 m); water (100 ml), dichloromethane (100 ml) and cetyl trimethyl ammonium bromide (1.5 g) was stirred at ambient temperature for 24 hours. The aqueous layer was removed and replaced Ity a frosh solution of lithium bromide (26 g. 0.3 m) in wafer (40 ml) containing cetyl trisethyl «ionium bromide (1 g). After stirring for a further 24 hours during which time the temperature was raised to 3S°C0 the organic layer was separated, dried and vacuum distilled to afford after repeated fractionation the new compound, ethyl alphe-bromo ettyl carbonate (15.0 g, 76% yield) having a boiling point of 90-92®C at 35 EnftS of mercury pressure.
Found: C 30.7s H 4.8 Br 40.1% Calculated: C 30.5: H 4.6: Br 40.6% The ftHR spectrum exhibited peaks as follows:- (3H9 triplet) *ch9.ch i C* 4 (3He doublet) - CH.CH (2He Quartet) - CH^.CH. (IHp Quartet) " ch.ch3 Example β Lithium bromide (17.4 g, 0.2 m) was dissolved in dimethyl formamide (150 ml) And the mixture cooled to ambient temperature. Ethyl alphachloroethyl carbonate (30.5 g, 0.2 m) was added and the mixture stirred et ambient temperature for 24 hours. The precipitated lithium chloride was filtered off and the filtrate vacuum distilled fo afford after careful re-fractionation, ethyl alpha-bromoethyl carbonate in 76% yield based upon recovered ethyl alphachloroethyl carbonate.
Exaaple 9 Tlie authenticity of the foregoing new compound ethyl slpha-bromoethyl carbonate was confirmed by Independent synthesis as follows:A mixture of diethyl carbonate (35 @n 0.3 m) in carbon tetrachloride (60 ml) and alpha-a&o-isobutyronlfrile (AIBN) (0.1 g) was heated to gentle reflux and di bromodimethyl hydantoin (28.6 g, 0.1 m) was added in small aliquots over a period of 8 hours together with further additions of ΑΪΒΝ (8x0.05 g): care being taken to ensure that free bromine did not accumulate In the reaction mixture. At the end of the reaction the mixture was subjected to vacuum fractional distillation to afford pure ethyl alpha-bromoethyl carbonate (32.3 g, 82% yield) identical in all respects with the product of Examples 7 and 8.
Claims (28)
1. Process for the preparation of the 1-ethoxycarbonyl oxyethyl ester of the 6-(D-(-)-a-amino-Q-phenylacetamido) penicillanic acid with the formula: CH - CO - NH - CH CO - CH C (It I I x “3 - a-CH - COO - CH - 0 - COOCgHg 5 comprising a) reacting ampicillin, or an alkali metal, alkaline earth metal or organic base salt thereof, with a reactive derivative of acetoacetic acid to form the corresponding enamine with the formula: (Π) τ wherein R represents an alkyl group containing 1-4 carbon atoms, a substituted or non-substituted aryl group or an aralkyl group; R 2 represents hydrogen, an alkyl group containing 1-4 carbon atoms, a substituted or non-substituted aryl group or an aralkyl group; 15 represents an alkyl group containing 1-4 carbon atoms, a substituted or non-substituted aryl group, an aralkyl group, an alkoxy e group containing 1-4 carbon atoms, an aryloxy group or an amine group, and X represents hydrogen or an alkali metal, an alkaline earth metal or an organic base: * b) reacting an alkali metal, alkaline earth metal or an organic base salt of formula II with a-bromo*-diethyl carbonate with the formula: Br-^J-O-COO C 2 H 5 (III) 5 to form the corresponding ester with the formula: (IV) wherein R 1 , R 2 and R 3 have the meanings specified above, and c) subjecting ester IV to mild hydrolysis in an acid medium* 10 2. Process according to claim 1, wherein the ampicillin salt is an alkali metal or alkaline earth metal salt obtained by transforming ampicillin trihydrate by a per se known method in a polar solvent. 3. Process according to claim 2 in which the solvent is 15 Ν,Ν-dimethylformamide„ 4. Process according to claim 1, 2 or 3, wherein the formation of the enamine (II) is carried out by reacting the salt of ampicillin with an alkyl acetoacetate in an o aprotic polar solvent at a temperature of 0 C to 60 C and 20 for 2 to 8 hours.
2. ?
3. 5 - Process according to claim 4, wherein the alkyl acetoacetate is methyl or ethyl acetoacetate and is used in an amount 10-50¾ more than the stoichiometric ratio. C. Process according to claim 4 or 5» wherein the aprotic polar solvent is selected from Η,Ώ-dimethylacetamide, £j?,H*-4imethylf ormamide, dimethoxyethane, dimethylsulphoxlde, tetrahydrofuran and dioxane.
4. 7. Process according to any one of claims 4 to 6, wherein the enamine formation is carried out at a temperature of 20*0 to 30”C«
5. 8. Process according to any one of claims 4 to 7, wherein enamine formation is carried out in a time of 3 hours.
6. 9- Process according to any one of the preceding claims, wherein enamine formation is carried out in the presence of an organic base or an alkali metal carbonate or alkaline earth metal carbonate.
7. 10· Process according to any one of the preceding claims, wherein the esterification reaction of the enamine (II) is carried out by addition to the reaction mixture of a-bromodiethyl carbonate, the reaction being carried out at a temperature of 15-80 a C and for a time of 1-24 hours.
8. 11. Process according to any one of the preceding claims, wherein the esterification is carried out in the presence of a catalyst.
9. 12. Process according fo claim 11 wherein the catalyst is selected from quaternary ammonium salts, alkali metal bromides, alkali metal iodides and cyclic ethers.
10. 13. Process according fo claim 12, wherein the catalyst is 5 tetrabutylammonium bromide.
11. 14. Process according to any one of claims 11 fo 13, wherein the catalyst is present in an amount of from 0.005 to 0.10 moles per mole of the compound III,
12. 15. Process according fo claim 14 wherein the catalyst is 10 present in an amount of from 0.01 to 0.10 moles per mole of the compound III,
13. 16. Process according to any one of the preceding claims, wherein the esterification reaction temperature is 45°C to 55°C. 15
14. 17. Process according fo any one of the preceding claims, wherein the esterification reaction is carried out in 5-10 hours.
15. 18. Process according to any one of the preceding claims, wherein the hydrolysis is carried out with dilute 20 hydrochloric acid after isolating ester (IV).
16. 19. A process according fo claim 1 substantially as hereinbefore described with reference fo any one of the Examples.
17. 20. The compound of the formula: 0 11 Br-CH-O-C-O ~C o H e I 2 5 ch 3
18. 21. Λ process for che preparation of the compound of the formula; Br CH 3 -CH-O-C-O- C 2 H 5 III comprising reacting an aldehyde of the formula 5 CH 3 CHO VI with carbonyl bromide COBr 2 VII to form a compound of the formula: Br I CH 3 - CH » OCO - Br VIII 10 followed by reacting the compound VIII with C^H^OH.
19. 22 . A process according to claim 21, carried out in the presence of a catalyst.
20. 23. A process according to claim 22, wherein the catalyst is used in an amount of from 0.05 to 0.5 moles per mole of 15 the compound VI.
21. 24. A process according to claim 23 wherein the amount of catalyst used per mole of the compound VI is 0.05 to 0.15 moles.
22. 25. A process according to claim 22, 23 or 24 wherein the 20 catalyst is a tertiary amine, a tertiary phosphine, an amide, substituted urea or thiourea, a phosphoric acid amide, a tertiary oxonium or sulphonium salt, or a quaternary ammonium or phosphonium salt.
23. 26. A process for the preparation of a compound of the 25 formula: Br 0 I II ch 3 - ch-o-c-o - c 2 h 5 III XX by reacting the compound of the formula: Cl 0 1 11 ch 3 ~ch-o-c~o- c 2 h 5 with an alkali bromide of the formula: R - 9r in which fonnula R is an alkali metal wherein the reaction is carried out in a two-phase solvent system comprising v/ater and a water-immiscible organic solvent in the presence of a phase transfer catalyst.
24. 27„ A process according to claim 26 wherein R is lithium,
25. 28. A process according to claim 27, wherein the organic solvent is a halogenated hydrocarbon or an aromatic hydrocarbon.
26. 29. A process according fo claim 28« wherein the organic solvent is dichlorornethane·
27. 30. A process according to any one of claims 26 to 29, wherein the phase transfer catalyst is a quaternary ammonium salt.
28. 31. A process according to claim 21 or 26 substantially as hereinbefore described with reference fo any one of the Examples-
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT22141/82A IT1190897B (en) | 1982-06-29 | 1982-06-29 | PROCEDURE FOR THE PREPARATION OF THE 1-ETHOXYCARBONYLOXYETHYL ACID ACID 6- (D (-) - ALPHA AMINOALPHA-PHENYLACETAMIDE) -PENICILLANIC |
GB8226751 | 1982-09-20 | ||
GB8228622 | 1982-10-06 | ||
GB8232629 | 1982-11-16 | ||
GB838300331A GB8300331D0 (en) | 1983-01-07 | 1983-01-07 | Preparation of bromo carbonates |
IE1445/83A IE56712B1 (en) | 1982-06-29 | 1983-06-20 | Process for the production of 1-ethoxycarbonyloxyethyl ester of 6-(d-(-)-alpha-amino-alpha-phenylacetamido)penicillanic acid |
Publications (2)
Publication Number | Publication Date |
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IE911360L IE911360L (en) | 1983-12-29 |
IE56713B1 true IE56713B1 (en) | 1991-11-20 |
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ID=27546821
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Application Number | Title | Priority Date | Filing Date |
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IE1360/91A IE56713B1 (en) | 1982-06-29 | 1983-06-20 | Alpha-bromodiethylcarbonate and its use in the preparation of antibiotics |
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IE (1) | IE56713B1 (en) |
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