ZA200206997B - Asymmetric synthesis of piperazic acid and derivatives thereof. - Google Patents

Asymmetric synthesis of piperazic acid and derivatives thereof. Download PDF

Info

Publication number: ZA200206997B
Authority: ZA; South Africa
Prior art keywords: compound; formula; group; independently selected; protecting group
Prior art date: 2000-05-04

Application number

ZA200206997A

Other languages

English (en)

Inventor

Andrea Robidoux

Siro Serafini

Petra Dieterich

Stephania Leonardi

John Stibbard

Original Assignee

Vertex Pharma

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2000-05-04

Filing date

2002-08-30

Publication date

2003-11-12

2002-08-30 Application filed by Vertex Pharma filed Critical Vertex Pharma

2003-11-12 Publication of ZA200206997B publication Critical patent/ZA200206997B/en

Links

RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 title claims description 28
238000011914 asymmetric synthesis Methods 0.000 title description 6
238000000034 method Methods 0.000 claims description 106
150000001875 compounds Chemical class 0.000 claims description 97
125000006239 protecting group Chemical group 0.000 claims description 47
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 31
238000003786 synthesis reaction Methods 0.000 claims description 27
-1 t-butoxycarbonyl Chemical group 0.000 claims description 27
125000000217 alkyl group Chemical group 0.000 claims description 25
230000015572 biosynthetic process Effects 0.000 claims description 25
229910052739 hydrogen Inorganic materials 0.000 claims description 25
239000000203 mixture Substances 0.000 claims description 25
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 23
UWCWUCKPEYNDNV-LBPRGKRZSA-N 2,6-dimethyl-n-[[(2s)-pyrrolidin-2-yl]methyl]aniline Chemical compound CC1=CC=CC(C)=C1NC[C@H]1NCCC1 UWCWUCKPEYNDNV-LBPRGKRZSA-N 0.000 claims description 21
239000001257 hydrogen Substances 0.000 claims description 20
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
239000002904 solvent Substances 0.000 claims description 18
WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 17
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 15
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
229910001868 water Inorganic materials 0.000 claims description 14
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
125000004122 cyclic group Chemical group 0.000 claims description 12
238000001914 filtration Methods 0.000 claims description 12
125000000623 heterocyclic group Chemical group 0.000 claims description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
125000002619 bicyclic group Chemical group 0.000 claims description 11
239000000725 suspension Substances 0.000 claims description 11
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
125000003118 aryl group Chemical group 0.000 claims description 10
FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical group OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 9
125000004432 carbon atom Chemical group C* 0.000 claims description 8
229910052757 nitrogen Inorganic materials 0.000 claims description 8
239000003960 organic solvent Substances 0.000 claims description 8
239000003444 phase transfer catalyst Substances 0.000 claims description 8
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical group OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 7
239000000706 filtrate Substances 0.000 claims description 7
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
238000001556 precipitation Methods 0.000 claims description 7
239000002516 radical scavenger Substances 0.000 claims description 7
125000000753 cycloalkyl group Chemical group 0.000 claims description 6
125000005842 heteroatom Chemical group 0.000 claims description 6
125000002950 monocyclic group Chemical group 0.000 claims description 6
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 6
229960001270 d- tartaric acid Drugs 0.000 claims description 5
230000002708 enhancing effect Effects 0.000 claims description 5
238000010438 heat treatment Methods 0.000 claims description 5
125000001072 heteroaryl group Chemical group 0.000 claims description 5
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
239000002244 precipitate Substances 0.000 claims description 5
125000006413 ring segment Chemical group 0.000 claims description 5
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
229910052799 carbon Inorganic materials 0.000 claims description 4
229910000104 sodium hydride Inorganic materials 0.000 claims description 4
229910052938 sodium sulfate Inorganic materials 0.000 claims description 4
235000011152 sodium sulphate Nutrition 0.000 claims description 4
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
239000012312 sodium hydride Substances 0.000 claims description 3
JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 0.000 claims description 2
SPXOTSHWBDUUMT-UHFFFAOYSA-M 4-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=C(S([O-])(=O)=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-M 0.000 claims description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
125000002837 carbocyclic group Chemical group 0.000 claims description 2
229910052736 halogen Inorganic materials 0.000 claims description 2
150000002367 halogens Chemical class 0.000 claims description 2
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
125000005543 phthalimide group Chemical group 0.000 claims description 2
229920006395 saturated elastomer Polymers 0.000 claims 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 claims description 2
125000000169 tricyclic heterocycle group Chemical group 0.000 claims description 2
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 2
125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims 2
ULYONBAOIMCNEH-HNNXBMFYSA-N (3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1h-indol-2-one Chemical class COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2NC1=O ULYONBAOIMCNEH-HNNXBMFYSA-N 0.000 claims 1
FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims 1
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
238000006243 chemical reaction Methods 0.000 description 21
150000002148 esters Chemical class 0.000 description 17
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
239000000243 solution Substances 0.000 description 15
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 14
239000002253 acid Substances 0.000 description 14
239000003112 inhibitor Substances 0.000 description 13
239000000543 intermediate Substances 0.000 description 12
238000005804 alkylation reaction Methods 0.000 description 10
238000003756 stirring Methods 0.000 description 10
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
230000003287 optical effect Effects 0.000 description 9
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 8
239000012044 organic layer Substances 0.000 description 8
239000011541 reaction mixture Substances 0.000 description 8
239000003242 anti bacterial agent Substances 0.000 description 7
229940088710 antibiotic agent Drugs 0.000 description 7
239000012267 brine Substances 0.000 description 7
239000003153 chemical reaction reagent Substances 0.000 description 7
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
239000007787 solid Substances 0.000 description 6
WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 5
229960002989 glutamic acid Drugs 0.000 description 5
238000002360 preparation method Methods 0.000 description 5
150000003839 salts Chemical class 0.000 description 5
239000011734 sodium Substances 0.000 description 5
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 4
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 4
QRKPPWPLSQRGSU-UHFFFAOYSA-N diazepine-1-carboxylic acid Chemical compound OC(=O)N1C=CC=CC=N1 QRKPPWPLSQRGSU-UHFFFAOYSA-N 0.000 description 4
239000010410 layer Substances 0.000 description 4
NQQWFVUVBGSGQN-UHFFFAOYSA-N phosphoric acid;piperazine Chemical compound OP(O)(O)=O.C1CNCCN1 NQQWFVUVBGSGQN-UHFFFAOYSA-N 0.000 description 4
NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 4
QVADRSWDTZDDGR-GSVOUGTGSA-N (2r)-5-oxooxolane-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCC(=O)O1 QVADRSWDTZDDGR-GSVOUGTGSA-N 0.000 description 3
FMCAFXHLMUOIGG-JTJHWIPRSA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-JTJHWIPRSA-N 0.000 description 3
BZIBRGSBQKLEDC-BYPYZUCNSA-N (3S)-1,2-diazinane-3-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCNN1 BZIBRGSBQKLEDC-BYPYZUCNSA-N 0.000 description 3
125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
102000011727 Caspases Human genes 0.000 description 3
108010076667 Caspases Proteins 0.000 description 3
229930182847 D-glutamic acid Natural products 0.000 description 3
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
150000007513 acids Chemical class 0.000 description 3
239000003795 chemical substances by application Substances 0.000 description 3
BZIBRGSBQKLEDC-UHFFFAOYSA-N diazinane-3-carboxylic acid Chemical compound OC(=O)C1CCCNN1 BZIBRGSBQKLEDC-UHFFFAOYSA-N 0.000 description 3
238000004128 high performance liquid chromatography Methods 0.000 description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
238000010992 reflux Methods 0.000 description 3
125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
DEPFLWOOVVEOLA-SECBINFHSA-N tert-butyl (2r)-2,5-bis(methylsulfonyl)pentanoate Chemical compound CC(C)(C)OC(=O)[C@H](S(C)(=O)=O)CCCS(C)(=O)=O DEPFLWOOVVEOLA-SECBINFHSA-N 0.000 description 3
229940070710 valerate Drugs 0.000 description 3
FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 description 2
NRBDYQRDIXUSQJ-UHFFFAOYSA-N 2,2-bis(phenylmethoxycarbonyl)piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1(C(=O)OCC=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 NRBDYQRDIXUSQJ-UHFFFAOYSA-N 0.000 description 2
KGLPWQKSKUVKMJ-UHFFFAOYSA-N 2,3-dihydrophthalazine-1,4-dione Chemical compound C1=CC=C2C(=O)NNC(=O)C2=C1 KGLPWQKSKUVKMJ-UHFFFAOYSA-N 0.000 description 2
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 2
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
102100030988 Angiotensin-converting enzyme Human genes 0.000 description 2
FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
102000004190 Enzymes Human genes 0.000 description 2
108090000790 Enzymes Proteins 0.000 description 2
102100028701 General vesicular transport factor p115 Human genes 0.000 description 2
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
101000767151 Homo sapiens General vesicular transport factor p115 Proteins 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
239000011717 all-trans-retinol Substances 0.000 description 2
235000019169 all-trans-retinol Nutrition 0.000 description 2
150000001412 amines Chemical class 0.000 description 2
ZJZOPNINWIGNQW-UHFFFAOYSA-N antibiotic l 156602 Chemical compound O1C(C)C(CC(C)CC)CCC1(O)C(C)(O)C(=O)NC1C(=O)N2NCCCC2C(=O)N(O)C(C)C(=O)NCC(=O)N2NCCCC2C(=O)N(O)C(C)C(=O)OC1C(C)C ZJZOPNINWIGNQW-UHFFFAOYSA-N 0.000 description 2
HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
UEYMRBONTZTXQP-UHFFFAOYSA-N benzyl n-(phenylmethoxycarbonylamino)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NNC(=O)OCC1=CC=CC=C1 UEYMRBONTZTXQP-UHFFFAOYSA-N 0.000 description 2
XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
238000002425 crystallisation Methods 0.000 description 2
230000008025 crystallization Effects 0.000 description 2
238000010511 deprotection reaction Methods 0.000 description 2
150000002009 diols Chemical class 0.000 description 2
238000006073 displacement reaction Methods 0.000 description 2
229940088598 enzyme Drugs 0.000 description 2
235000013922 glutamic acid Nutrition 0.000 description 2
239000004220 glutamic acid Substances 0.000 description 2
238000005984 hydrogenation reaction Methods 0.000 description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
229910052943 magnesium sulfate Inorganic materials 0.000 description 2
235000019341 magnesium sulphate Nutrition 0.000 description 2
230000004048 modification Effects 0.000 description 2
238000012986 modification Methods 0.000 description 2
XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
239000000047 product Substances 0.000 description 2
238000000926 separation method Methods 0.000 description 2
WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
229910000342 sodium bisulfate Inorganic materials 0.000 description 2
229910000029 sodium carbonate Inorganic materials 0.000 description 2
229960001367 tartaric acid Drugs 0.000 description 2
239000011975 tartaric acid Substances 0.000 description 2
235000002906 tartaric acid Nutrition 0.000 description 2
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 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
NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
QIWKCQDJZPRXNS-VIFPVBQESA-N (2s)-2-[(2-carboxybenzoyl)amino]pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)C1=CC=CC=C1C(O)=O QIWKCQDJZPRXNS-VIFPVBQESA-N 0.000 description 1
MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 1
SWYLPIMCJADFNO-QIFPABMSSA-N 101342-90-9 Chemical compound C1CC(C)C(C(/C)=C/C(CC)C(=O)C(\C)=C\C)OC1(O)C(O)(CC)C(=O)NC1C(=O)N2NCCCC2C(=O)N(O)C(COC)C(=O)N(C)C(C)C(=O)N2NCCCC2C(=O)NC(C(C)O)C(=O)OC1C(C)C SWYLPIMCJADFNO-QIFPABMSSA-N 0.000 description 1
229930185601 Aurantimycin Natural products 0.000 description 1
229940126062 Compound A Drugs 0.000 description 1
JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical class CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
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 1
241000124008 Mammalia Species 0.000 description 1
239000012359 Methanesulfonyl chloride Substances 0.000 description 1
238000007126 N-alkylation reaction Methods 0.000 description 1
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
UOFXDKDWFQWWKT-UHFFFAOYSA-N OC(N1CCNCC1)=O.OC(N1CCNCC1)=O.OC(N1CCNCC1)=O.N Chemical compound OC(N1CCNCC1)=O.OC(N1CCNCC1)=O.OC(N1CCNCC1)=O.N UOFXDKDWFQWWKT-UHFFFAOYSA-N 0.000 description 1
108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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
AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 1
238000010521 absorption reaction Methods 0.000 description 1
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
125000002252 acyl group Chemical group 0.000 description 1
229910052784 alkaline earth metal Inorganic materials 0.000 description 1
150000001342 alkaline earth metals Chemical class 0.000 description 1
150000004703 alkoxides Chemical class 0.000 description 1
125000005227 alkyl sulfonate group Chemical group 0.000 description 1
125000005233 alkylalcohol group Chemical group 0.000 description 1
230000029936 alkylation Effects 0.000 description 1
BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
150000001408 amides Chemical class 0.000 description 1
229940024606 amino acid Drugs 0.000 description 1
235000001014 amino acid Nutrition 0.000 description 1
150000001413 amino acids Chemical group 0.000 description 1
238000004458 analytical method Methods 0.000 description 1
239000005557 antagonist Substances 0.000 description 1
230000000259 anti-tumor effect Effects 0.000 description 1
125000005228 aryl sulfonate group Chemical group 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
108010063468 azinothricin Proteins 0.000 description 1
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
RXUBZLMIGSAPEJ-UHFFFAOYSA-N benzyl n-aminocarbamate Chemical compound NNC(=O)OCC1=CC=CC=C1 RXUBZLMIGSAPEJ-UHFFFAOYSA-N 0.000 description 1
150000004657 carbamic acid derivatives Chemical class 0.000 description 1
229910002091 carbon monoxide Inorganic materials 0.000 description 1
150000004649 carbonic acid derivatives Chemical class 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
125000002843 carboxylic acid group Chemical group 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
238000004296 chiral HPLC Methods 0.000 description 1
239000002442 collagenase inhibitor Substances 0.000 description 1
238000004440 column chromatography Methods 0.000 description 1
239000012141 concentrate Substances 0.000 description 1
239000013058 crude material Substances 0.000 description 1
239000012043 crude product Substances 0.000 description 1
VEJZTZFQMSODJC-UHFFFAOYSA-N diazinane-1,3-dicarboxylic acid Chemical compound OC(=O)C1CCCN(C(O)=O)N1 VEJZTZFQMSODJC-UHFFFAOYSA-N 0.000 description 1
DPRXZUJZFGGYDQ-UHFFFAOYSA-N dibenzyl 2-[2-(piperazine-1-carbonyloxy)propan-2-yl]propanedioate Chemical compound C=1C=CC=CC=1COC(=O)C(C(=O)OCC=1C=CC=CC=1)C(C)(C)OC(=O)N1CCNCC1 DPRXZUJZFGGYDQ-UHFFFAOYSA-N 0.000 description 1
SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
238000004821 distillation Methods 0.000 description 1
238000005516 engineering process Methods 0.000 description 1
238000010931 ester hydrolysis Methods 0.000 description 1
238000005886 esterification reaction Methods 0.000 description 1
230000002349 favourable effect Effects 0.000 description 1
150000002222 fluorine compounds Chemical class 0.000 description 1
239000006260 foam Substances 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
150000004679 hydroxides Chemical class 0.000 description 1
229960003444 immunosuppressant agent Drugs 0.000 description 1
230000001861 immunosuppressant effect Effects 0.000 description 1
239000003018 immunosuppressive agent Substances 0.000 description 1
XAAKCCMYRKZRAK-UHFFFAOYSA-N isoquinoline-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=NC=CC2=C1 XAAKCCMYRKZRAK-UHFFFAOYSA-N 0.000 description 1
239000001630 malic acid Substances 0.000 description 1
235000011090 malic acid Nutrition 0.000 description 1
229940099690 malic acid Drugs 0.000 description 1
229960002510 mandelic acid Drugs 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
229910052987 metal hydride Inorganic materials 0.000 description 1
150000004681 metal hydrides Chemical class 0.000 description 1
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
WTLGBIQVBFJEGX-UHFFFAOYSA-N monamycin Chemical compound O=C1C(CC(C)C)N(C)C(=O)C(C2)CCNN2C(=O)C2CCCNN2C(=O)C(C(C)C)OC(=O)C(C(C)C)NC(=O)C2CNC1C2 WTLGBIQVBFJEGX-UHFFFAOYSA-N 0.000 description 1
JJYKJUXBWFATTE-UHFFFAOYSA-N mosher's acid Chemical compound COC(C(O)=O)(C(F)(F)F)C1=CC=CC=C1 JJYKJUXBWFATTE-UHFFFAOYSA-N 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
229930014626 natural product Natural products 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
125000004433 nitrogen atom Chemical group N* 0.000 description 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
239000003336 oxytocin antagonist Substances 0.000 description 1
229940121361 oxytocin antagonists Drugs 0.000 description 1
239000000816 peptidomimetic Chemical group 0.000 description 1
125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
239000011698 potassium fluoride Substances 0.000 description 1
235000003270 potassium fluoride Nutrition 0.000 description 1
239000004304 potassium nitrite Substances 0.000 description 1
235000010289 potassium nitrite Nutrition 0.000 description 1
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
229940002612 prodrug Drugs 0.000 description 1
239000000651 prodrug Substances 0.000 description 1
ZEZKRQQOECKKCQ-NBFOIZRFSA-N prop-2-enyl n-[(3s)-5-oxo-2-phenylmethoxyoxolan-3-yl]carbamate Chemical compound C=CCOC(=O)N[C@H]1CC(=O)OC1OCC1=CC=CC=C1 ZEZKRQQOECKKCQ-NBFOIZRFSA-N 0.000 description 1
238000007363 ring formation reaction Methods 0.000 description 1
125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
239000008259 solid foam Substances 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
239000000126 substance Substances 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
238000010189 synthetic method Methods 0.000 description 1
150000003892 tartrate salts Chemical class 0.000 description 1
GWWLVCDZFMFJAC-UHFFFAOYSA-N tert-butyl diazinane-3-carboxylate Chemical compound CC(C)(C)OC(=O)C1CCCNN1 GWWLVCDZFMFJAC-UHFFFAOYSA-N 0.000 description 1
ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
125000004665 trialkylsilyl group Chemical group 0.000 description 1
125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
238000001665 trituration Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Hydrogenated Pyridines (AREA)
Plural Heterocyclic Compounds (AREA)
Compositions Of Macromolecular Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

ZA200206997A 2000-05-04 2002-08-30 Asymmetric synthesis of piperazic acid and derivatives thereof. ZA200206997B (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US20210400P	2000-05-04	2000-05-04

Publications (1)

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ZA200206997A ZA200206997B (en)	2000-05-04	2002-08-30	Asymmetric synthesis of piperazic acid and derivatives thereof.

Country Status (11)

Country	Link
US (1)	US6632942B2 (fr)
EP (1)	EP1280780B1 (fr)
AT (1)	ATE311370T1 (fr)
AU (2)	AU2001257253B2 (fr)
CA (1)	CA2403304A1 (fr)
DE (1)	DE60115419T2 (fr)
ES (1)	ES2252224T3 (fr)
NZ (1)	NZ520998A (fr)
RU (1)	RU2002135314A (fr)
WO (1)	WO2001083458A2 (fr)
ZA (1)	ZA200206997B (fr)

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FR2853901B1 (fr) *	2003-04-16	2005-06-17	Isochem Sa	Procede de preparation de derives de l'acide hexahydropyridazine-3-carboxylique
WO2005028449A1 (fr) *	2003-06-26	2005-03-31	Honeywell Specialty Chemicals Seelze Gmbh	Procede ameliore de fabrication d'acides hexahydropyridazine-3-carboxyliques 1,2-disubstitues et leurs esters
AU2005247409B2 (en) *	2004-05-15	2011-11-10	Vertex Pharmaceuticals Incorporated	Treating seizures using ICE inhibitors
CA2567080A1 (fr) *	2004-05-27	2005-12-15	Vertex Pharmaceuticals Incorporated	Traitement de maladies a l'aide d'inhibiteurs de l'ice
CN102250014B (zh) *	2010-05-18	2013-11-13	上海奥博生物医药技术有限公司	一种制备手性1-苄氧羰基六氢哒嗪-3-羧酸和手性1,2-二苄氧羰基六氢哒嗪-3-羧酸的方法
CN110343728B (zh) *	2019-06-04	2021-10-08	浙江大学	一种生物转化合成六氢哒嗪-3-羧酸的方法

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US4692438A (en) *	1984-08-24	1987-09-08	Hoffmann-La Roche Inc.	Pyridazo-diazepines, diazocines, and -triazepines having anti-hypertensive activity
DE59310189D1 (de) *	1992-05-18	2001-08-23	Hoffmann La Roche	Asymmetrische Hydrierung

2001
- 2001-04-25 WO PCT/US2001/013330 patent/WO2001083458A2/fr active IP Right Grant
- 2001-04-25 EP EP01930747A patent/EP1280780B1/fr not_active Expired - Lifetime
- 2001-04-25 AU AU2001257253A patent/AU2001257253B2/en not_active Ceased
- 2001-04-25 DE DE60115419T patent/DE60115419T2/de not_active Expired - Lifetime
- 2001-04-25 AU AU5725301A patent/AU5725301A/xx active Pending
- 2001-04-25 ES ES01930747T patent/ES2252224T3/es not_active Expired - Lifetime
- 2001-04-25 AT AT01930747T patent/ATE311370T1/de not_active IP Right Cessation
- 2001-04-25 CA CA002403304A patent/CA2403304A1/fr not_active Abandoned
- 2001-04-25 RU RU2002135314/04A patent/RU2002135314A/ru not_active Application Discontinuation
- 2001-04-25 NZ NZ520998A patent/NZ520998A/en active Application Filing
2002
- 2002-06-14 US US10/168,463 patent/US6632942B2/en not_active Expired - Fee Related
- 2002-08-30 ZA ZA200206997A patent/ZA200206997B/en unknown

Also Published As

Publication number	Publication date
WO2001083458A2 (fr)	2001-11-08
AU2001257253B2 (en)	2006-03-02
DE60115419D1 (de)	2006-01-05
ATE311370T1 (de)	2005-12-15
DE60115419T2 (de)	2006-08-17
WO2001083458A3 (fr)	2002-05-23
EP1280780A2 (fr)	2003-02-05
ES2252224T3 (es)	2006-05-16
AU5725301A (en)	2001-11-12
EP1280780B1 (fr)	2005-11-30
CA2403304A1 (fr)	2001-11-08
US6632942B2 (en)	2003-10-14
RU2002135314A (ru)	2004-05-27
US20030176691A1 (en)	2003-09-18
NZ520998A (en)	2004-11-26

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