CN101146771A - 2-氮杂双环-[3.3.0]辛烷-3-羧酸衍生物的制备方法 - Google Patents
2-氮杂双环-[3.3.0]辛烷-3-羧酸衍生物的制备方法 Download PDFInfo
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- CN101146771A CN101146771A CNA2006800089574A CN200680008957A CN101146771A CN 101146771 A CN101146771 A CN 101146771A CN A2006800089574 A CNA2006800089574 A CN A2006800089574A CN 200680008957 A CN200680008957 A CN 200680008957A CN 101146771 A CN101146771 A CN 101146771A
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- Prior art keywords
- alkyl
- cycloalkyl
- aryl
- azabicyclo
- octane
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- 238000000034 method Methods 0.000 title claims abstract description 30
- 230000008569 process Effects 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- OQHKEWIEKYQINX-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[b]pyrrol-1-ium-2-carboxylate Chemical class C1CCC2NC(C(=O)O)CC21 OQHKEWIEKYQINX-UHFFFAOYSA-N 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 238000005984 hydrogenation reaction Methods 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000001797 benzyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 150000002081 enamines Chemical class 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 8
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- -1 benzyl ester Chemical class 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 150000003254 radicals Chemical class 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical group 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- RRONHWAVOYADJL-HNNXBMFYSA-N (2s)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 RRONHWAVOYADJL-HNNXBMFYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 4
- 229960003401 ramipril Drugs 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- CEIWXEQZZZHLDM-AAEUAGOBSA-N (2s)-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoic acid Chemical compound CCOC(=O)[C@@H](N[C@@H](C)C(O)=O)CCC1=CC=CC=C1 CEIWXEQZZZHLDM-AAEUAGOBSA-N 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- KOFSFYBXUYHNJL-UHFFFAOYSA-N 1-(cyclopenten-1-yl)pyrrolidine Chemical compound C1CCCN1C1=CCCC1 KOFSFYBXUYHNJL-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 240000003864 Ulex europaeus Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- DVDCTYKWRDJBCR-UHFFFAOYSA-N ethyl 2-(phenylmethoxycarbonylamino)prop-2-enoate Chemical compound CCOC(=O)C(=C)NC(=O)OCC1=CC=CC=C1 DVDCTYKWRDJBCR-UHFFFAOYSA-N 0.000 description 2
- 229940117360 ethyl pyruvate Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 150000003334 secondary amides Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 150000003673 urethanes Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- VXVGAVGVIKGFSI-REOHCLBHSA-N (2s)-2-(iodoamino)propanoic acid Chemical compound IN[C@@H](C)C(O)=O VXVGAVGVIKGFSI-REOHCLBHSA-N 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- XNHUZSZMXSLTQL-UHFFFAOYSA-N 1-bromocyclopentene Chemical compound BrC1=CCCC1 XNHUZSZMXSLTQL-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 238000006237 Beckmann rearrangement reaction Methods 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- 238000006957 Michael reaction Methods 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
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- 125000004423 acyloxy group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
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- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
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- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004517 catalytic hydrocracking Methods 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- XSXLCQLOFRENHC-UHFFFAOYSA-N ethyl n-benzylcarbamate Chemical compound CCOC(=O)NCC1=CC=CC=C1 XSXLCQLOFRENHC-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 239000011630 iodine Substances 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- FQGVVDYNRHNTCK-UHFFFAOYSA-N methyl 2-acetamidopropanoate Chemical compound COC(=O)C(C)NC(C)=O FQGVVDYNRHNTCK-UHFFFAOYSA-N 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 125000002347 octyl 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])[H] 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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Abstract
本发明涉及一种通过氢化环化式(II)中间体制备通式(I)的化合物的方法。
Description
技术领域
本发明涉及一种制备通式(I)的化合物的方法。
背景技术
这类化合物是一类非常有价值的用于制备生物活性试剂的中间体。例如,2-氮杂双环-[3.3.0]-辛烷-3-羧酸可用于制备ACE抑制剂Ramipril_(N-(1-(S)-乙氧羰基-3-苯基-丙基)-(S)-丙氨酰基-(S)-cis,endo-2-氮杂双环-[3.3.0]-辛烷-3-S-甲酸)(A.Kleemann,J.Engel,Pharmaceutical Substances,4th Edition,page 1785,Thieme Verlag Stuttgart,2001)。
已经公开了很多制备外消旋2-氮杂双环-[3.3.0]-辛烷-3-羧酸的方法,例如:
阳极氧化N-酰基环戊烷吡咯,随后进行氰化和水解(DE3151690)。
以双环-[3.3.0]-壬烷-2-酮为起始反应物通过贝克曼重排、卤化以及法沃斯基重排(DE 3151690)。
以环戊烯为起始反应物经由有机汞化合物(DE 3300316,R.Henning,H.Urbach,Tetrahdron Letters,24,5343-6(1983))。
以溴代环戊烯和丝氨酸为起始反应物,使用Bu3SnH分子内环化中间体碘丙氨酸(DE 297620,H.Urbach,R.Henning,Heteterocycles 28,957-65(1989))。
通过氢化四氢环戊烷吡咯-2-羧酸(WO86/00896,US4,587,258)。
通过1,3-两极环加成甲亚胺(L.M.Harwood,L.C.Kitchen,Tetrahedron Lett.,34,6603(1993))。
可能的优选方法((A.Kleemann,J.Engel,PharmaceuticalSubstances,4th edition,page1785,Thieme Verlag Stuttgart,2001);EP 79022;V.Teetz,R.Geiger,H.Gaul,TetrahedronLetters,25,4479-82(1984))包括:首先以丝氨酸为起始反应物,经过3步反应制备得到2-乙酰氨基-3-氯丙酸甲酯(DE 19941062)。将所得化合物与吡咯烷基环戊烯反应得到环戊酮基乙酰氨基丙酸甲酯。在强酸的作用下,伴随着酰胺基和酯基的断裂,上步所得化合物环化从而获得双环亚氨酯。随后催化氢化得到外消旋2-氮杂双环-[3.3.0]-辛烷-3-羧酸。反应过程如方案1所示:
方案1:
该方法主要形成cis-endo构象的2-氮杂双环-[3.3.0]-辛烷-3-羧酸,即,得到的主要是RRR-和SSS-化合物的混合物。为了拆分外消旋体,将羧酸转化为酯,优选苄基酯,然后通过与手性酸成盐将其拆分成非对映异构纯的双环。0,0-二酰酒石酸(DE 3345355)、旋光活性的N-酰基-氨基酸(EP115345)以及苦杏仁酸(J.Martens,S.Lübben,Journal f.prakt.Chemie,332,1111-1117(1990))都可作为手性酸。
为了能够选择性地去除最终活性剂Ramipril中的酯基,使用苄基酯进行偶合并且因此这对于外消旋体的拆分也是优选的。
在优选的方法中(Kleemann Engel,V.Teetz,R.Geiger,H.Gaul,Tetrahdron Letters,25,4479-82(1984)),使用N-苄氧羰基-L-苯丙氨酸(Z-L-Phe-OH)进行苄基酯外消旋体的拆分。使SSS-苄基酯与N-(1-(S)-乙氧羰基-3-苯丙基)-(S)-丙氨酸(NEPA)偶合,随后通过氢化除去苄基酯,最终得到Ramipril(方案2)。
方案2:
发明内容
本发明的目的在于提供一种可用的制备通式(I)中间体的改进方法。特别地,重要的是,该方法能够方便地实现工业规模生产,并且从经济以及生态学角度看,其是优越于现有技术的方法。
根据权利要求实现了该目的。权利要求1至4针对一种优选的制备通式(I)的化合物的方法。权利要求4保护通式(II)的新型中间体化合物。权利要求5至7包含一种根据本发明的制备通式(II)的化合物的方法。
在制备通式(I)的化合物或其盐的方法中,
其中,
R1是H、(C1-C8)-烷基、(C6-C18)-芳基、(C7-C19)-芳烷基、(C1-C8)-烷基-(C6-C18)-芳基、(C3-C8)-环烷基、(C1-C8)-烷基-(C3-C8)-环烷基、(C3-C8)-环烷基-(C1-C8)-烷基,
由于在催化剂的存在下氢化一种通式(II)的化合物,
其中,
R1如上所定义,和
R2是可氢解基团,
可以非常方便地获得目标,并获得满意效果。由于通式(II)的化合物中的R2基团为可氢解基团,本领域技术人员能够以惊人的简单方法一步得到通式(I)的化合物,其可以立即进行随后的常规外消旋体拆分而不必进行进一步的复分解步骤或酯化。所以,在现有技术背景下,以如此简便的一个反应步骤实现三个化学步骤(N-保护基团的离去、环化以及氢化)是不可预见的。
在上述基团的变化范围内,本领域技术人员可以视成本/效益比来自由地选择特别有利的基团。当R1基团优选使用H或者(C1-C8)-烷基时,R2可以任选地为环-取代的苄基。优选的R1基团为例如甲基或者乙基。R2可以优选苄基。
对于根据本发明的方法,本领域技术人员可以使用多种适当的有机溶剂。有利的有机溶剂是那些能够充分溶解所用产品且对反应呈惰性的有机溶剂。因此,优选的有机溶剂选自醇如甲醇、乙醇、异丙醇,醚如二异丙基醚、甲基叔丁基醚、二甲氧基乙烷、THF,芳香烃类如甲苯、二甲苯,羧酸酯如乙酸乙酯、乙酸异丙酯、乙酸正丁酯,仲酰胺如DMF、NMP。非常特别的优选使用与基团R1相对应的醇。因此极其优选使用乙醇或者甲醇作为溶剂。
可以采用与专业知识相类似的方式来实施目标方法。作为催化剂,优选使用那些能够分别引起C=C和C=N双键的氢化以及上述基团的氢化裂解的催化剂。合适的催化剂为非均相和均相催化剂,特别是选自钯、铂、铑、镍、钴的催化剂或者在Houben-Weyl,Methoden derOrganischen Chemie[Methods of Organic Chemistry],Volume4/1c,pages 14-480,Thieme Verlag Stuttgart,1974.中提到的用于这种目的的催化剂。
有利地,在0-100℃,优选10-80℃,特别优选20-30℃温度条件下进行氢化。
可以在反应期间根据本领域技术人员认为适当的值来调整氢气压力。该压力优选为1-50bar,优选1-30bar,更优选1-20bar。
可以按照惯例使用元素氢来进行本发明的氢化。然而,原则上,还可以按照本领域技术人员所知的方式(Houben-Weyl,Methoden derOrganischen Chemie,Volume4/1c,pages67-76,Thieme VerlagStuttgart,1974),以转移氢化的形式来进行。
本发明的主题同样在于通式(II)的化合物或者,如果R1=H,通式(II)的化合物的盐
其中
R1是H、(C1-C8)-烷基、(C6-C18)-芳基、(C7-C19)-芳烷基、(C1-C8)-烷基-(C6-C18)-芳基、(C3-C8)-环烷基、(C1-C8)-烷基-(C3-C8)-环烷基、(C3-C8)-环烷基-(C1-C8)-烷基,和
R2是可氢解基团。这里所述的这些化合物是用于制备通式(I)的化合物的优越的中间体。上述关于R1和R2基团的优选方案类似地适用于此。
在最后的具体实施方案中,本发明涉及通式(II)的化合物的制备。用本发明的方法可以优越地制备这些化合物,包括使通式(III)的化合物
其中
R1和R2如上文所定义,
与通式(IV)的烯胺反应
其中
R3和R4可以相互独立地为(C1-C8)-烷基、(C6-C18)-芳基、(C7-C19)-芳烷基、(C1-C8)-烷基-(C6-C18)-芳基、(C3-C8)-环烷基、(C1-C8)-烷基-(C3-C8)-环烷基、(C3-C8)-环烷基-(C1-C8)-烷基或者R3和R4一起形成任选包含杂原子的(C2-C5)亚烷基桥。上面刚刚提到的R1和R2基团的优选方案同样适用于此。R3和R4基团优选方案为R3和R4基团和氮原子一起形成5-或6-元杂环的方案。特别优选R3和R4基团和氮原子一起形成吡咯烷、哌啶或者吗啉基团的通式(IV)的化合物。
有利地,这里提到的本发明的方法在有机溶剂中进行。优选合适的溶剂为:醚,例如二异丙基醚、甲基叔丁基醚、二甲氧基乙烷、THF,芳香烃,例如甲苯、二甲苯,羧酸酯如乙酸乙酯、乙酸异丙酯、乙酸正丁酯,仲酰胺,例如DMF、NMP,氯代烃如氯仿、二氯甲烷。这里特别优选卤代有机溶剂。极其优选使用氯仿或者二氯甲烷。
通式(IV)的化合物和通式(III)的化合物的反应优选在0-100℃之间的温度,优选10-50℃,特别优选在15-30℃之间进行。
根据本发明,通式(I)的化合物的制备过程如下所述。类似于N-酰基衍生物(M.Bergmann,K.Grafe,Hoppe-Seylers ZeitschriftPhysiologische Chem.187,187(1930)),式(III)的尿烷可以由简单易得的式(V)的化合物
和同样简单易得的式(VI)的尿烷来制备。
对于R1和R2基团,上述定义同样适用。这里优选使用丙酮酸乙酯和苄基-尿烷。该反应优选的通过这样一种方式来进行,在该反应中优选通过共沸蒸馏来除去反应产生的水。特别合适的溶剂是甲苯。然而,本领域技术人员熟知用于该情况的更多适当溶剂。
在不需要进一步地提纯的情况下,可以获得具有足以用于随后反应所需纯度的式(III)的化合物。为了避免式(III)的丙烯酸衍生物不期望的聚合,可以加入自由基清除剂,优选为氢醌。可以如迈克尔反应所描述的那样,随后将通式(III)的化合物加入到通式(II)的化合物中以生成通式(IV)的化合物。在随后的氢化中,脱去N-保护基团并且环化化合物最终得到(I)。
与EP 79022中描述的方法相反,该反应不需要加入强酸。在本发明方法中通过催化氢化就地进行N-保护基团的脱去。由此得到式(II)中间体,其游离态(其中R2是H)非常不稳定,会自发地发生环化。不必如同现有技术(EP 79022)所要求的那样使用强酸。
本发明方法另外的优点在于,由于酯基被保留,式(I)的化合物(其中R1不是H)不必直接用旋光活性酸(比如,例如N-苄氧羰基-L-苯基-丙氨酸)进行外消旋体的拆分。如EP 79022中所描写的新的酯化是不必要的。此外,如果进行氢化而不加入酸,将获得式(I)的酯作为游离碱,并且其可以直接地与旋光活性酸反应而不需要进一步提纯。
可以按照已知的方式,将由此获得的根据本发明制备的2-氮杂双环-[3.3.0]-辛烷-3-羧酸的非对映异构的纯的盐拆分为它们的异构体。通过酸性水解可以将由此获得的对映体富集的2-氮杂双环-[3.3.0]-辛烷-3-羧酸酯转变为相应的游离酸。优选进行释放,以使得(S)-cis-endo-2-氮杂双环-[3.3.0]-辛烷-3-羧酸酯溶于酸性pH水中,以及用有机溶剂提取所获得的旋光活性辅助酸并且再循环。然后可以通过加热该酸性水溶液来水解该酯。通过蒸发反应溶液,可以优选地将2-氮杂双环-[3.3.0]-辛烷-3-羧酸以内盐的形式析出,但是优选以盐酸盐形式析出。可以根据已知的方法(参见上面)使(S)-cis-endo-2-氮杂双环-[3.3.0]-辛烷-3-羧酸与N-(1-(S)-乙氧羰基-3-苯丙基)-(S)-丙氨酸(NEPA)反应生成Ramipril_。
因此,目标方法有助于相当大地简化工业规模的生物活性试剂Ramipril_的合成。依照现有技术背景,不能自然而然地预期到这种简化,相反,在反应期间形成的中间体是非常活泼的中间体化合物,其能够参与许多副反应,例如聚合反应。因此,令人惊讶的事实是,尽管有此风险,但是所述的三个化学反应步骤成为一个过程步骤是可能的。
(C1-C8)-烷基是指甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基或者辛基以及所有它们的成键异构体。
(C1-C8)-烷氧基相当于经由氧原子连接至分子的(C1-C8)-烷基。
(C2-C8)-烷氧基烷基是指其中烷基链被至少一个氧官能团间断的基团,这不适用于二个氧原子相互连接的情况。碳原子数是指包含于该基团中的碳原子总数。
(C3-C5)-亚烷基桥是具有三至五个C原子的碳链,该链经被认为由二个不同的C原子连接至分子。
前面段落中描述的基团可以被卤素和/或包含N、O、P、S、Si原子的基团单-取代或者多取代。特别是上述类型的烷基,在它们的链中包含一个或多个上述杂原子或者经由这些杂原子中的一个连接至分子。
(C3-C8)-环烷基理解为环丙基、环丁基、环戊基、环己基或环庚基等。这些基团可以被一个或多个卤素和/或包含N、O、P、S、Si原子的基团取代和/或在环中包含N、O、P、S原子,例如,1-、2-、3-、4-哌啶基、1-、2-、3-吡咯烷基、2-、3-四氢呋喃基、2-、3-、4-吗啉基。
(C3-C8)-环烷基-(C1-C8)-烷基是一种如上所述的环烷基,其经由如上所述的烷基连接至分子。
本发明上下文中的(C1-C8)-酰氧基是一种具有最多8个C原子的如上定义的烷基,其经由COO-官能团连接至分子。
本发明上下文中的(C1-C8)-酰基是指具有最多8个C原子的如上定义的烷基,其经由CO-官能团连接至分子。
(C6-C18)-芳基可理解为具有6至18个C原子的芳族基团。特别地,包括苯基、萘基、蒽基、菲基、或联苯基或者前述的基团稠合至相关分子所形成的体系例如茚基体系,上述基团或体系可以任选地被卤素、(C1-C8)-烷基、(C1-C8)-烷氧基、NH2、NH(C1-C8)-烷基、N((C1-C8)-烷基)2、OH、CF3、NH(C1-C8)-酰基、N((C1-C8)-酰基)2、(C1-C8)-酰基、(C1-C8)-酰氧基取代。
(C7-C19)-芳烷基是经由(C1-C8)-烷基连接至分子的(C6-C18)-芳基。
本发明上下文中的(C3-C18)杂芳基是指含有3至18个C原子的五-、六-或七-元芳环体系,其在环中包含例如氮、氧或硫的杂原子。这样的杂原子尤其是指例如1-、2-、3-呋喃基、1-、2-、3-吡咯基、1-、2-、3-噻吩基、2-、3-、4-吡啶基、2-、3-、4-、5-、6-、7-吲哚基、3-、4-、5-吡唑基、2-、4-、5-咪唑基、吖啶基、喹啉基、菲啶基、2-、4-、5-、6-嘧啶基的基团。这些基团可以被与上述芳基的相同基团取代。
(C4-C19)-杂芳烷基可理解为相应于(C7-C19)-芳烷基的杂-芳香体系。
适当的卤素(Hal)为氟、氯、溴和碘。
N-保护基团可理解为一般是在氨基酸化学作用中为了保护氮原子而通常引入的保护基团。可以特别提到的基团是:甲酰基、乙酰基、Moc、Eoc、邻苯二甲酰基、Boc、Alloc、Z、Fmoc等。
可氢解基团优选地为选自任选环被取代的苄基的N-保护基团。适当的环上的取代基优选地为4-取代的卤素、硝基、烷基或烷氧基衍生物(Houben-Weyl,Methoden der Organischen Chemie,Volume15/1,page 69,Thieme Verlag Stuttgart,1974)。
本发明上下文中的术语对映体富集或对映体过量理解为一种对映异构体在含有它的旋光对映异构体的混合物中所占的比例为>50%并且<100%。采用如下方法计算ee值:
([对映体1]-[对映体2])/([对映体1]+[对映体2])=ee值
本文中出现的化合物的命名包括所有可能的非对映异构体,其还可用来命名各个非对映异构体的两个旋光对映异构体。
在本说明书中提到的参考文献被认为包括在公开的内容中。
具体实施方式
实施例
N-苄氧基羰基-2-氨基丙烯酸乙酯
在2.5L甲苯中加入288g丙酮酸乙酯、250g氨基甲酸苄酯、2.5g p-甲苯磺酸和1g氢醌,在脱水器中回流反应9h。然后使用硅胶过滤反应液,并用500ml甲苯溶液冲洗。用1g氢醌处理所得滤液,然后使用旋转蒸发器最大程度地浓缩滤液。得到376g油状的N-苄氧基羰基-2-氨基丙烯酸乙酯,HPLC测得其纯度约为90%。
1H-NMR(DMSO-D6):1.23(t,3H),4.18(q,2H),5.11(s,2H),5.61(s,1H),5.78(s,1H),7.37(m,5H),8.86(s,1H)。
2-N-苄氧基羰基氨基-3-(2-氧代环戊烷基)-丙酸乙酯
在CH2Cl2中溶解366g N-苄氧基羰基-2-氨基丙烯酸乙酯(浓度大约为90%)和191g环戊烯基吡咯烷(cyclopentenopyrrolidine),所得溶液室温搅拌16h。接着用350mL乙酸和1L水处理所得反应液,剧烈搅拌15min。相分离后,有机相再用180mL乙酸和1L水的混合物萃取,接着用500mL水洗涤。使用硅胶过滤溶液,然后真空条件下完全蒸发溶剂。最终得到463g油状的2-N-苄氧基羰基氨基-3-(2-氧代环戊烷基)-丙酸乙酯。
1H-NMR(DMSO-D6):1.17(m,3H),1.51(m,2H),1.69(m,1H),1.90(m,1H),2.09(m,5H),4.09(m,2H),4.24(m,1H,主要旋转异构体),5.05(s,2H,主要旋转异构体),7.34(m,5H),7.75(d,IH,主要旋转异构体)。
cis-2-氮杂双环-[3.3.0]-辛烷-3-羧酸乙酯
在1000mL乙醇中溶解200g 2-N-苄氧基羰基氨基-3-(2-氧代环戊基)丙酸乙酯,加入5g催化剂(5%Pd在活性C上),接着在5bar条件下氢化。反应4h,HPLC不再检测到反应原料。过滤催化剂,最大程度浓缩滤液。得到103g淡黄色油状cis-2-氮杂双环-[3.3.0]-辛烷-3-羧酸乙酯,其无需进行提纯即可进行进一步反应。根据1H-NMR光谱,cis-endo异构体占78mol%。
1H-NMR(DMSO-D6主要异构体):
1.18(t,3H),1.30(m,1H),1.51(m,6H),2.19(m,1H),2.48(m,1H),3.50(dd,1H),3.53(m,1H),4.07(dq,2H)。
(s)-cis-endo-2-氮杂双环-[3.3.0]-辛烷-3-羧酸乙酯Z-L-苯丙氨酸盐
在84g N-苄氧基羰基-L-苯丙氨酸的200mL乙酸乙酯的热的溶液中加入100g实施例3中制备的cis-2-氮杂双环-[3.3.0]-辛烷-3-羧酸乙酯。在清液中加入1L MTBE。加入晶种后,室温搅拌4h,该悬浊液变粘稠。
过滤,所得产物用100mL MTBE洗涤两次,50℃真空干燥,得到66.4g(s)-cis-endo-2-氮杂双环-[3.3.0]-辛烷-3-羧酸乙酯Z-L-苯丙氨酸盐。
1H-NMR(DMSO-D6):1.18(t,3H),1.33(m,1H),1.37(m,1H),1.54(m,5H),2.21(m,1H),2.94(ddd,2H),3.57(m,2H),4.08(dq,2H),4.15(m,1H),4.97(s,2H),7.27(m,5H),7.46(d,1H)。
(s)-cis-endo-2-氮杂双环-[3.3.0]-辛烷-3-羧酸盐酸盐
在20mL水和40mL MTBE中加入3.0g(s)-cis-endo-2-氮杂双环-[3.3.0]-辛烷-3-羧酸乙酯Z-L-苯丙氨酸盐。所得悬浊液中加入1mL37%浓度的盐酸后,搅拌混合物,直到反应液变澄清为止。分离水相,用40mL MTBE再次萃取。真空条件下粗略汽提有机相,再用14mL 37%浓度的盐酸处理所得溶液,然后在100-105℃加热14h。所得混合物真空蒸发,剩余物用10mL乙酸后处理并再次进行蒸发操作。所得剩余物溶解到10mL乙酸中,然后加入MTBE进行结晶操作。得到0.95g(s)-cis-endo-2-氮杂双环-[3.3.0]-辛烷-3-羧酸盐酸盐。
1H-NMR(DMSO-D6):1.45(m,1H),1.60(m,3H),1.74(m,2H),1.99(m,1H),2.45(m,1H),2.80(m,1H),3.98(m,1H),4.21(dd,1H),8.70(s,broad,1H),10.60(s,broad,1H),13.80(s,broad,1H)。
Claims (7)
2.根据权利要求1的方法,特征在于
R1为H或者(C1-C8)-烷基,
R2为任选环被取代的苄基。
3.根据权利要求1和/或2的方法,特征在于所述氢化在作为溶剂的醇中进行。
6.根据权利要求5的方法,特征在于所述反应在卤代有机溶剂中进行。
7.根据权利要求5和/或6的方法,特征在于所述反应在20-100℃下进行。
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CN102197026A (zh) * | 2008-10-30 | 2011-09-21 | 帝斯曼知识产权资产管理有限公司 | 雷米普利中间体的合成方法 |
CN103086948A (zh) * | 2011-11-02 | 2013-05-08 | 上海朴颐化学科技有限公司 | (s,s,s)-2-氮杂双环[3,3,0]辛烷-3-羧酸的制备方法 |
CN106536541A (zh) * | 2014-06-11 | 2017-03-22 | 赛诺菲-安万特德国有限公司 | 制备雷米普利的方法 |
CN112557574A (zh) * | 2020-12-31 | 2021-03-26 | 成都普康生物科技有限公司 | 一种测定cbz-aeea含量的方法 |
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WO2011087812A1 (en) * | 2009-12-21 | 2011-07-21 | Vanderbilt University | Alkyl 3-((2-amidoethyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate analogs as selective m1 agonists and methods of making and using same |
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US5175306A (en) * | 1983-01-31 | 1992-12-29 | Hoechst Aktiengesellschaft | Process for the resolution of racemates of optically active bicyclic imino-α-carboxylic esters |
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CN102197026A (zh) * | 2008-10-30 | 2011-09-21 | 帝斯曼知识产权资产管理有限公司 | 雷米普利中间体的合成方法 |
CN103086948A (zh) * | 2011-11-02 | 2013-05-08 | 上海朴颐化学科技有限公司 | (s,s,s)-2-氮杂双环[3,3,0]辛烷-3-羧酸的制备方法 |
CN106536541A (zh) * | 2014-06-11 | 2017-03-22 | 赛诺菲-安万特德国有限公司 | 制备雷米普利的方法 |
TWI675023B (zh) * | 2014-06-11 | 2019-10-21 | 德商賽諾菲阿凡提斯德意志有限公司 | 製備雷米普利(ramipril)之方法 |
CN106536541B (zh) * | 2014-06-11 | 2021-01-08 | 赛诺菲-安万特德国有限公司 | 制备雷米普利的方法 |
CN112557574A (zh) * | 2020-12-31 | 2021-03-26 | 成都普康生物科技有限公司 | 一种测定cbz-aeea含量的方法 |
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