MXPA01003683A - NEW PROCESSES FOR PRODUCING&bgr;-ALANINE DERIVATIVE - Google Patents
NEW PROCESSES FOR PRODUCING&bgr;-ALANINE DERIVATIVEInfo
- Publication number
- MXPA01003683A MXPA01003683A MXPA/A/2001/003683A MXPA01003683A MXPA01003683A MX PA01003683 A MXPA01003683 A MX PA01003683A MX PA01003683 A MXPA01003683 A MX PA01003683A MX PA01003683 A MXPA01003683 A MX PA01003683A
- Authority
- MX
- Mexico
- Prior art keywords
- ester
- acid
- alanine
- salt
- piperidyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- 239000011780 sodium chloride Chemical group 0.000 claims abstract description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 150000003839 salts Chemical group 0.000 claims abstract description 33
- 125000002252 acyl group Chemical group 0.000 claims abstract description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 8
- 238000005917 acylation reaction Methods 0.000 claims abstract description 5
- 125000003277 amino group Chemical group 0.000 claims abstract description 5
- -1 4-piperidyl Chemical group 0.000 claims description 170
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000001589 carboacyl group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 150000004684 trihydrates Chemical class 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 34
- 238000003379 elimination reaction Methods 0.000 abstract description 8
- 230000001681 protective Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 229910052739 hydrogen Inorganic materials 0.000 description 86
- 239000000203 mixture Substances 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 125000000217 alkyl group Chemical group 0.000 description 26
- 150000002148 esters Chemical group 0.000 description 24
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 125000004432 carbon atoms Chemical group C* 0.000 description 11
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 9
- 150000002829 nitrogen Chemical group 0.000 description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 9
- 101700067048 CDC13 Proteins 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- UCMIRNVEIXFBKS-UHFFFAOYSA-N β-Alanine Chemical class NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 125000004434 sulfur atoms Chemical group 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 125000005907 alkyl ester group Chemical group 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 125000004430 oxygen atoms Chemical group O* 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 230000002829 reduced Effects 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- LXJOZYKFQPXHMT-MOPGFXCFSA-N (2S)-2-acetamido-3-[[(3R)-1-[3-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]propanoyl]piperidine-3-carbonyl]amino]propanoic acid Chemical compound C1[C@H](C(=O)NC[C@H](NC(=O)C)C(O)=O)CCCN1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1 LXJOZYKFQPXHMT-MOPGFXCFSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 229910052697 platinum Inorganic materials 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- FOXRXVSTFGNURG-VIFPVBQESA-N (2S)-3-amino-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound NC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 FOXRXVSTFGNURG-VIFPVBQESA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N (+)-tartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- FOXRXVSTFGNURG-SECBINFHSA-N (2R)-3-azaniumyl-2-(phenylmethoxycarbonylamino)propanoate Chemical compound [NH3+]C[C@H](C([O-])=O)NC(=O)OCC1=CC=CC=C1 FOXRXVSTFGNURG-SECBINFHSA-N 0.000 description 3
- SSAYTINUCCRGDR-UHFFFAOYSA-N 3-pyridin-4-ylprop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=NC=C1 SSAYTINUCCRGDR-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- LWFWUJCJKPUZLV-UHFFFAOYSA-N N-trimethylsilylacetamide Chemical compound CC(=O)N[Si](C)(C)C LWFWUJCJKPUZLV-UHFFFAOYSA-N 0.000 description 3
- 229960004319 Trichloroacetic Acid Drugs 0.000 description 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N Trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 230000003042 antagnostic Effects 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 3
- 229910052803 cobalt Inorganic materials 0.000 description 3
- 239000010941 cobalt Substances 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- XIWBSOUNZWSFKU-SSDOTTSWSA-N ethyl (3R)-piperidine-3-carboxylate Chemical compound CCOC(=O)[C@@H]1CCCNC1 XIWBSOUNZWSFKU-SSDOTTSWSA-N 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- KLMPZGSRHWHQKF-ZETCQYMHSA-N (2S)-2-acetamido-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(=O)N[C@H](C(O)=O)CNC(=O)OC(C)(C)C KLMPZGSRHWHQKF-ZETCQYMHSA-N 0.000 description 2
- XPPNPKIUPLMABF-CVEARBPZSA-N (2S)-2-acetamido-3-[[(3R)-1-(3-piperidin-4-ylpropanoyl)piperidine-3-carbonyl]amino]propanoic acid Chemical compound C1[C@H](C(=O)NC[C@H](NC(=O)C)C(O)=O)CCCN1C(=O)CCC1CCNCC1 XPPNPKIUPLMABF-CVEARBPZSA-N 0.000 description 2
- WJKGPJRAGHSOLM-LBPRGKRZSA-N (2S)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound CC(C)(C)OC(=O)NC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 WJKGPJRAGHSOLM-LBPRGKRZSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- AMOYMEBHYUTMKJ-UHFFFAOYSA-N 2-(2-phenylethoxy)ethylbenzene Chemical compound C=1C=CC=CC=1CCOCCC1=CC=CC=C1 AMOYMEBHYUTMKJ-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-Methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- 210000001772 Blood Platelets Anatomy 0.000 description 2
- LXJOZYKFQPXHMT-OALUTQOASA-N C1[C@@H](C(=O)NC[C@H](NC(=O)C)C(O)=O)CCCN1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound C1[C@@H](C(=O)NC[C@H](NC(=O)C)C(O)=O)CCCN1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1 LXJOZYKFQPXHMT-OALUTQOASA-N 0.000 description 2
- LXJOZYKFQPXHMT-RTBURBONSA-N C1[C@H](C(=O)NC[C@@H](NC(=O)C)C(O)=O)CCCN1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound C1[C@H](C(=O)NC[C@@H](NC(=O)C)C(O)=O)CCCN1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1 LXJOZYKFQPXHMT-RTBURBONSA-N 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N DABCO Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N Phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N Trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 229920001567 Vinyl ester Polymers 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000007860 aryl ester derivatives Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000008079 hexane Substances 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- OLOFLUKZNNTGBC-PPHPATTJSA-N methyl (2S)-3-amino-2-(phenylmethoxycarbonylamino)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](CN)NC(=O)OCC1=CC=CC=C1 OLOFLUKZNNTGBC-PPHPATTJSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])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 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 125000000628 margaroyl group Chemical group O=C([*])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])C([H])([H])[H] 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])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 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- 125000001402 nonanoyl group Chemical group O=C([*])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 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical compound [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])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 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])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])C([H])([H])C([H])([H])[H] 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 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
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])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 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Abstract
The present invention relates to processes for the preparation of&bgr;-alanine derivative shown by formula (I);wherein R1 is amino protective group, and R2 is acyl group, or a salt thereof, which comprises, subjecting a compound of formula (II);wherein R1 is the same as defined above, and R3 is protected carboxy, or a salt, to elimination reaction of carboxy protective group, and then to acylation reaction of amino group.
Description
NEW PROCESSES TO PRODUCE A DERIVATIVE OF ß-ALANI A
TECHNICAL FIELD The present invention relates to processes for the preparation of a β-alanine derivative. More particularly, it relates to processes for the preparation of a β-alanine derivative which is an antagonist of the glycoprotein Ilb / IIIa, inhibitor of the aggregation of blood platelets and inhibitor of the binding of fibrinogen to blood platelets.
BACKGROUND TECHNIQUE 15 In PCT WO95 / 08536, the processes for producing the β-alanine derivative which is useful as a glycoprotein Ilb / IIIa antagonist and inhibitor of platelet aggregation are described.
DESCRIPTION OF THE INVENTION The object of the present invention is to provide the production process by which the β-alanine derivative, represented by the following formulas [I] and [II], can be produced in a good yield.
yy ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^ > . r? ** i kt »_- 'The present invention provides a process for producing the β-alanine derivative illustrated in Process 1 and 2_ as shown below. Process 1
(ID
or a salt thereof
(I) or a salt of the same 15 Process 2
; D or a salt thereof
reaction of elimination of the protective group of 25 amino (III) or a salt thereof
ugly-asaafcjfe -. * _- ^ _ a_ iá _i__iM_____________ ^ Wffiififea ^ where R1 is an amino protecting group, R2 is an acyl group, and i. R3 is protected carboxy. Among the compounds (I), (II) and (III), some compounds are novel, and some are known. They can be prepared from the known compounds in a conventional manner in this field of the art, or manners similar to those described in the Preparations and / or the Examples mentioned later in the present specification. Suitable salts of the subject compound (I) are conventional pharmaceutically acceptable and non-toxic salts, and include a metal salt such as an alkali metal salt [eg, a sodium salt, potassium salt, etc.], a salt alkaline earth metal [for example a calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [for example trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, salt of dicyclohexylamine, N, N-dibenzylethylenediamine salt, etc.], an organic acid addition salt [for example, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], a salt of
t ^ -fc? fe-t-ci? < = -J- < addition of inorganic acid [eg hydrochloride, hydrobromide, iodide, sulfate, phosphate, etc.], a salt with an amino acid [eg, arginine salt, salt of aspartic acid, salt of glutamic acid, etc.] and the like. In the above and subsequent descriptions of this specification, suitable examples of the various definitions are explained in detail as follows: The term "lower" is intended to mean 1 to 6 carbon atom (s), unless otherwise indicated. another way. The term "upper" is attached to mean a group having from 7 to 20 carbon atoms, unless otherwise indicated. The preferable number of "one or more" in the term "one or more suitable substituent (s)" may be from 1 to 3. The suitable "protected carboxy" may be carboxy protected by a conventional protecting group such as an esterified carboxy group, or a similar one, and the specific examples of the ester moiety in the esterified carboxy group can be groups such as lower alkyl ester [e.g. methyl ester, ethyl ester, ester
»«. *. ^ *, '..t-jts_ propyl, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, isopentyl ester, hexyl ester, isohexyl ester, 1-cyclopropylethyl ester, etc.] which can have suitable substituent (s), for example lower alkanoyloxy-lower alkyl ester [eg acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.], lower alkylsulphonyl-lower alkyl ester [eg 2-mesylethyl ester] , etc.] or mono (or di or tri) halo (lower alkyl) ester [for example 2-iodoethyl ester, 2, 2, 2-trichloroetyl ester, etc.]; Upper alkyl ester [for example heptylester, octyl ester, 3,5-dimethyloctyl ester, 3,7-dimethyloctyl ester, nonyl ester, decyl ester, undecyl ester, dodecyl ester, tridecyl ester, tetradecyl ester, pentadecyl ester, hexadecyl ester, heptadecyl ester, octadecyl ester, nonadecyl ester, adamantyl ester, etc.];
Lower alkenyl ester [for example alkenyl ester of 2 to 6 carbon atoms (for example vinyl ester, allylic ester etc.)]; Lower alkynyl ester [for example alkynyl ester of 2 to 6 carbon atoms (for example ethynyl ester, propynyl ester, etc.)]; Ester Ar (lower alkyl), which may have one or more suitable substituent (s) [for example phenyl ester (lower alkyl), which may have from 1 to 4 lower alkoxy, halogen, nitro, hydroxy, lower alkyl, phenyl, or halo (lower alkyl), (for example, benzyl ester, 4-methoxybenzyl ester, 4-chlorobenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) ester methylic, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, 4-trifluoromethylbenzyl ester, etc.)]; Aryl ester which may have one or more suitable substituent (s) [for example phenyl ester which may have from 1 to 4 lower alkyl, or halogen (for example phenyl ester, 4-chlorophenyl ester, tolyl ester, ester 4-ter
& amp;? b? S ££ -0 * e ** -5 * &t-butylphenyl, xylyl ester, mesityl ester, cumethyl ester, etc.), indanyl ester, etc.]; Cycloalkyloxycarbonyloxy ester (lower alkyl), which may have lower alkyl (for example cyclopentyloxycarbonyloxymethyl ester, cyclohexyloxycarbonyloxymethyl ester, cycloheptyloxycarbonyloxymethyl ester, 1-methylcyclohexyloxycarbonyloxymethyl ester, 1- (or 2) [cyclopentyloxycarbonyloxy] ethyl ester, 1- (or 2) ester [cyclohexyloxycarbonyloxy] ethyl, ester 1- (or 2) [cycloheptyloxycarbonyloxy] ethyl, etc.), etc.]; Ester (5- (lower alkyl) -2-oxo-l, 3-dioxol-4-yl) (lower alkyl) [e.g. ester (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl, ester (5-ethyl-2-oxo-l, 3-dioxol-4-yl) methyl, ester (5-propyl-2-oxo-1,3-dioxol-4-yl) ethyl, ester 1- (or 2 -) (5- methyl-2-oxo-l, 3-dioxol-4-yl) ethyl, ester 1- (or 2) (5-ethyl-2-oxo-l, 3-dioxol-4- il) ethyl, 1- (or 2-) (5-propyl-2-oxo-l, 3-dioxol-4-yl) ethyl ester, etc.]; or similar. Among them, the preferred ones may be the lower alkyl ester, Ar (lower alkyl) ester, aryl ester which may have one or more suitable substituent (s), cycloalkyloxy ester,
carbonyloxy (lower alkyl) or lower alkanoyloxy-lower alkyl ester, and the most preferred may be the methyl ester, ethyl ester, butyl ester, pentyl ester, isopentyl ester, isohexyl ester, benzyl ester, phenethyl ester, phenyl ester, ester indanyl, pivaloyloxymethyl ester, or 1-cyclohexyloxycarbonyloxyethyl ester. A suitable "amino protecting group" can include an acyl group as explained below, a conventional protecting group such as Ar (lower alkyl), which may have from 1 to 3 suitable substituent (s) (for example benzyl) , phenethyl, 1- phenylethyl, benzhydryl, trityl, etc.), [5- (lower alkyl) -2-oxo-l, 3-dioxol-4-yl] (lower alkyl) [for example (5-methyl- 2-oxo-l, 3-dioxol-4-yl) methyl, etc.] or the like; and similar. A suitable "acyl group" and "acyl" may include aliphatic acyl, aromatic acyl, acyl
Arylaliphatic and heterocyclic-aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid, and the like. A suitable example of the "acyl group" can be illustrated as follows:
Aliphatic acyl such as lower or higher alkanoyl (eg formyl) acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropane, hexane, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); Lower or higher alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); Lower or higher alkylsulfonyl (for example methylsulfonyl, ethylsulfonyl, etc.); Lower or higher alkoxysulfonyl (for example methoxysulfonyl, ethoxysulfonyl, etc.); or similar; Aromatic acyl such as aroyl (for example benzoyl, toluoyl, naphthoyl, etc.); Ar (lower alkanoyl) [for example phenyl-alkanoyl of 1 to 6 carbon atoms (for example phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl-alkanoyl of 1 to 6 carbon atoms (for example naphthalethyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; Ar (lower alkenoyl) [for example phenylalkenoyl of 3 to 6 carbon atoms (for example phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl-alkenoyl of 3 to 6 carbon atoms (for example naphthylpropenoyl, naphthylbutenoyl, etc etc.]; Ar (lower alkoxycarbonyl) [for example phenyl-alkoxycarbonyl of 1 to 6 carbon atoms (for example benzyloxycarbonyl, etc.), etc.]; Aryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycarbonyl, etc.); Lower aryloxyalkanoyl (for example phenoxyacetyl, phenoxypropionyl, etc.); Arylcarbamoyl (for example feilcarbamoyl, etc.); Arylthiocarbamoyl (for example phlycythiocarbamoyl, etc.); Arylglyoxyloyl (for example phenylglyoxyloyl, naphthylglyoxyloyl, etc.); Arylsulfonyl which may have from 1 to 4 lower alkyl (for example phenylsulfonyl, p-tolylsulfonyl, etc.); or similar;
^^ ¿^^^^^^. ^^^^ - ^^^^ ^ ^^^.
Hetero-cliquetal acyl such as heterocyclecarbonyl; heterocycle-lower alkanoyl (for example, heterocycloacetyl, -heterocyclopropanoyl, heterocyclobutanoyl, het] | - ^ ecyclopentanoyl, hetero-5-cyclohexanoyl, etc.); Lower heterocycle-alkenoyl (for example heterocyclopropenoyl, heterocyclobutenoyl, heterocyclopentenoyl, heterocyclohexenoyl, etc.); Heterocycloglyxyloyl; or similar; and 10 similar. A "heterocyclic" portion suitable in the terms "heterocyclecarbonyl", "heterocycle-lower alkyl", "heterocycle-lower-alkenoyl", and "heterocycleloglyxyloyl" mentioned above, and "heterocyclic group" means saturated or unsaturated monocyclic or polycyclic heterocyclic group it contains at least one heteroatom such as an oxygen atom, sulfur, nitrogen and the like. Among them, the preferable heterocyclic group may be a heterocyclic group such as: An unsaturated 3 to 8 membered heteromonocyclic group (more preferably 5 or 6 members) containing from 1 to 4 nitrogen atom (s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyridyl,
? ? «AZ. ».. ~ ~ * ^ ~ ** £ ¡* s * 2r ?. i ^^^ ..,. ? t??? ^^ & - ^ ^^^^^^^ A ^ pyzinyl, pyridazinyl, triazolyl, (for example 4H-1, 2,4-triazolyl, 1H-1, 2, 3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (for example 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc .; A saturated 3 to 8 membered heteromonocyclic group (more preferably 5 or 6 membered) containing from 1 to 4 nitrogen atom (s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc .; An unsaturated condensed heterocyclic group containing from 1 to 4 nitrogen atom (s), for example indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, dihydroquinolyl, isoquinolyl, indazolyl,
Quinoxalinyl, dihydroquinoxalinyl, benzotriazolyl, etc.; An unsaturated 3 to 8 membered heteromonocyclic group (more preferably 5 or 6 membered) containing 1 to 2 oxygen atom (s) and 1 to 3
Nitrogen atom (s), for example oxazolyl, isoxazolyl, oxadiazolyl (for example 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1, 2, 5-oxadiazolyl, etc.), etc .; A saturated heteromonocyclic group of 3 to 8
members (more preferably 5 or 6 members) that
it contains from 1 to 2 ato or (s) of oxygen and from 1 to 3 nitrogen atom (s), for example morpholinyl, sydnonyl, etc .; An unsaturated condensed heterocyclic group containing from 1 to 2 oxygen atom (s) and from 1 to 3 nitrogen atom (s), for example benzoxazolyl, benzoxadiazolyl, etc .; An unsaturated heteromonocyclic group of 3 to 8 members (more preferably of 5 or 6 members)
containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), for example thiazolyl, isothiazolyl, thiadiazolyl (for example 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl) , 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, etc.), dihydrothiazinyl, etc .; A saturated 3 to 8 membered heteromonocyclic group (more preferably 5 or 6 membered) containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), for example thiazolidinyl, etc.; 20 An unsaturated heteromonocyclic group of 3 to
8 members (more preferably 5 or 6 members) containing from 1 to 2 sulfur atom (s), for example thienyl, dihydrodithiinyl, dihydroditionyl, etc .; An unsaturated condensed heterocyclic group
containing 1 to 2 sulfur atom (s) and 1 to 3
nitrogen atom (s), for example benzothiazolyl, benzothiadiazolyl, etc .; An unsaturated 3 to 8 membered heteromonocyclic group (more preferably 5 or 6 members) containing an oxygen atom, for example furyl, etc.; An unsaturated 3 to 8 membered heteromonocyclic group (more preferably 5 or 6 membered) containing an oxygen atom and from 1 to 2 sulfur atom (s), for example dihydrooxathiinyl, etc.; An unsaturated condensed heterocyclic group containing from 1 to 2 sulfur atom (s), for example benzothienyl, benzodithiinyl, etc .; An unsaturated condensed heterocyclic group containing an oxygen atom and from 1 to 2 sulfur atom (s), for example benzoxathiinyl, etc .; and similar. The acyl portion mentioned above may have from one to ten, the same or different, suitable substituent (s) such as lower alkyl (for example methyl, ethyl, propyl, etc.); lower alkoxy (for example methoxy, ethoxy, propoxy, etc.); lower alkylthio (for example methylthio, ethylthio, etc.); lower alkylamino (for example, 25 methylamino, ethylamino, propylamino, etc.);
g ^ ^ «fca ^^^^ ^ íl ^^ || ^^ jÉ ^ ^^ j ^^ ** ^« j ^^^ A ^^ Ea ^ K. ^ &jaS- cycle (lower alkyl) "for example cycloalkyl of 3 to 6 carbon atoms (for example cyclopentyl, cyclohexyl, etc.));" - cyclo (lower alkenyl) [for example 5 cycloalkenyl of 3 to 6 carbon atoms (for example cyclohexenyl, cyclohexadienyl , etc.), halogen (for example fluorine, chlorine, bromine, iodine), amino, amino protecting group mentioned above, hydroxy, protected hydroxy mentioned below, cyano, nitro, carboxy, protected carboxy mentioned above, sulfo, sulphamoyl; imino, oxo, amino-lower alkyl (for example aminomethyl, aminoethyl, etc.); carbamoyloxy; hydroxy-lower alkyl (for example hydroxymethyl, 1 or 2-hydroxyethyl, 1 or 2 or 3)
hydroxypropyl, etc.), or the like. A suitable "protected hydroxy" may include acyl mentioned above, phenyl-lower alkyl which may have one or more suitable substituent (s) (for example benzyl, 4-mrtoxybenzyl, trityl,
etc.), trisubstituted silyl (for example tri (lower alkyl) silyl (for example trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like The most preferred example of "protecting group"
amino "can be the lower alkoxycarbonyl or
? Mm * mB * aí. «& .-____._ ^ i ___ ^ = »^ M__f: jria ^^ rtm ^ É? ~ ímáÉ * i? A ***. . ** ±? * & tAta? ij *,? * ÁL *? áÍi Ar (lower alkoxycarbonyl), and the most preferred may be t-butoxycarbonyl or benzyloxycarbonyl. The suitable "acyl group" of R2 can be referred to the "acyl group" mentioned above. Among them, lower alkanoyl may be the most preferred, and acetyl may be the most preferred. The processes of the present invention are explained in detail in the following.
Process 1 The object compound (I) or a salt thereof can be prepared by subjecting a compound (II) or a salt thereof to a removal reaction of the carboxy protecting group, and then the acylation reaction of the amino group.
The elimination reaction of the carboxy protecting group This reaction is carried out according to a conventional method such as hydrolysis, reduction or the like. The hydrolysis is preferably carried out in the presence of a base or an acid, including a Lewis acid.
^ jj ^^ = S ^ ^^^ * M * m * ^ »lt **. * At * M The suitable base may include an inorganic base and an organic base such as an alkali metal [eg lithium, sodium, potassium , etc.], an alkaline earth metal [for example magnesium, calcium, etc.], the hydroxide or carbonate do bicarbonate thereof, trialkylamine [for example trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo- [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, or
similar. Among them, the preferred one can be lithium anhydride. A suitable acid may include an organic acid [eg formic acid, acetic acid, propionic acid, trichloroacetic acid, acid
trifluoroacetic, etc.] and an inorganic acid [for example hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. The elimination using a Lewis acid such
as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like, preferably is carried out in the presence of agents that trap the cation [for example anisole, phenol, etc. ]
The reaction is usually carried out in a solvent such as water, an alcohol [for example methanol, ethanol, etc.], - methylene chloride, tetrahydrofuran, a mixture thereof or
any other solvent that does not adversely influence the reaction. A base or liquid acid can also be used as the solvent. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating. The applicable reduction method for the elimination reaction can include a chemical reduction and a catalytic reduction. The reducing agents suitable for use in chemical reduction are a combination of metal
[For example tin, zinc, iron, etc.] or metal compound [for example chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [for example formic acid, acetic acid, propionic acid, trifluoroacetic acid , p-20-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.]. Suitable catalysts to be used in the catalytic reduction are conventional, such as platinum catalysts [e.g.
platinum, fluffy platinum, platinum black, platinum
colloidal, platinum oxide, platinum wire, etc.], palladium catalysts [eg palladium sponge, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate , etc.], nickel catalysts [eg reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [eg [cobalt reduced, cobalt Raney, etc.], catalysts of
iron [for example reduced iron, Raney iron, etc.], copper catalysts [for example reduced copper, Raney copper, Ulman copper, etc.], and the like. The reduction is usually carried out in a
Conventional solvent which does not adversely influence the reaction, such as water, methanol, ethanol, propanol, 3ST, N-dimethylformamide, or a mixture thereof. Additionally, in the case where the acids mentioned above to be used in the
chemical reduction are in liquid form, they can also be used as a solvent. In addition, a suitable solvent to be used in the catalytic reduction may be the solvent mentioned above, and another conventional solvent such as ether
,. £ 2Mt. ^^,. ^ "^^ ^ A¡, ... ^^ B_iate ^. & ¿^; .. ^ ..-._ diethyl, dioxane, trahydrofuran, etc., or a mixture thereof. The reaction temperature of this reduction is not critical, and the reaction is usually carried out under cooling to heating.
The Acylation Reaction of the Amino Group The acylating agent suitable for use in the present acylation reaction may include the compound of the formula:
R -OH (IV)
(wherein R2 is acyl mentioned above) or its reactive derivative, or a salt thereof. The suitable reactive derivative in the amino group of the compound obtained by the elimination reaction of the carboxy-protective group mentioned above may include an imino-type Schiff base or its tautomeric enamine-type isomer formed by the reaction of the compound obtained by a reaction of removal of the carboxy-protecting group mentioned above with a carbonyl compound such as an aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound obtained
by a removal reaction of the carboxy protecting group mentioned above with a silyl compound such as N, O-bis (tri-phenylsilyl) -acetamide, N-trimethylsilylacetamide or Sikhtylaryl; a derivative formed by the reaction of the compound obtained by a removal reaction of the carboxy-protective group mentioned above with phosphorus trichloride or phosgene, and the like. A suitable reactive derivative of compound 10 (IV) may include an acid halide, an acid anhydride (eg, acetic anhydride, etc.), an activated ester, and the like. Among them, the preferred one may be acid anhydride, and acetic anhydride may be the most preferred. The suitable example 15 can be an acid chloride; acid azide; a mixed anhydride of acid with an acid such as substituted phosphoric acid (eg dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid, ( for example methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (for example, pivalic acid, pentanoic acid,
ü ^ _, ^ _ ^ > > -_ttl ____ M _, »_ jÉ ..J tttt. - * s > . 2 ** a ** »** *» **? ^ M? MÉmi ^ t ^ M? K? L.
isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (for example benzoic acid, etc.); a symmetrical acid anhydride; an amyral, activated with imidazole, 4-substituted imidazole, dimethylpyrazol, triazole or tetrazole; an activated ester (for example cyanomethyl ester, methoxymethyl ester, dimethyl iminomethyl ester [(CH3) 2 + N = CH-], vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenic ester, ester trichlorophenyl, pentachlorophenyl ester, mesylphenol ester, phenylazophenyl ester, phenylthio ester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.); an ester with an N-hydroxy compound (for example N, N-dimethylhydroxylamine, l-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, l-hydroxy-6-chloro- lH-benzotriazole, etc.); and similar. These reactive derivatives can optionally be selected from each other according to the class of the compound obtained by the elimination reaction of the carboxy-protective group mentioned above to be used.
. «M? ^^? The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent that does not adversely affect the reaction, or a mixture thereof. When the compound obtained by the elimination reaction of the carboxy-protecting group mentioned above is used in the form of the free acid or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N'- dicyclohexylcarbodimide; N-cyclohexyl-N '-morpholinoethylcarbodiimide; N-cyclohexyl-N '- (4-diethylamino-cyclohexyl) carbodiimide; N, N'-diisopropylcarbodiimide; N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide; N, N-carbonyl-bis (2-methylimidazole); pentamethylene keten-N-cyclohexylimine; diphenyl-N-cyclohexylimine; Etoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; Isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; triphenylphosphite; Get ouf of
2-ethyl-7-hydroxybenzisoxyzolium; intramolecular salt of 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide; 1- (p-chlorobenzenesulfonyloxy) -6-chloro or l-benzotriazole; the so-called Vilsmeier reagent prepared by the reaction of N, N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc .; or similar. The reaction can also be carried out in the presence of an organic or inorganic base such
as an alkali metal bicarbonate, tri (lower alkyl) amine, pyridine, N- (lower alkyl) -morpholine, N, -di (lower alkyl) benzylamine, or the like. The reaction temperature is not critical, and
The reaction is usually carried out under cooling to heating.
Process 2 The subject compound (III) or a salt thereof can be prepared by subjecting a compound (I) or a salt thereof to a removal reaction of the amino protecting group. This reaction can be carried out in a manner similar to that of Process 1 mentioned in
the above, and therefore the reaction mode and the
* i? - * A _ftfc .- ^ »? *? * ^. The reaction conditions [eg base, acid, catalyst, solvent, reaction temperature, etc.] of this reaction will be referred to for these as explained in Process 1 When the object compound (III) obtained in this way is in salt form, it can be converted to its free form in a conventional manner (eg neutralization, column chromatography, recrystallization, column chromatography with salt removal resin, etc. ). The compounds obtained by Processes 1 and 2_ above can be isolated and purified by a conventional method such as spraying, recrystallization, column chromatography, reprecipitation, or the like. It will be noted that each of the compounds (I), (II) and (III) may include one or more stereoisomers, such as optical isomer (s) and geometric isomer (s) due to atom (s) asymmetric carbon and double (s) bond (s), and all of these isomers and the mixture thereof are included within the scope of this invention. The compounds (I), (II) and (III) or a salt thereof include solvated compounds [by
^^^^ ggjj ^ j ^^ irf? i example inclusion compounds (for "example, hydrate, etc.).] Compounds (I), (II) and (III) or a salt thereof include both, its crystalline form and its non-crystalline form The above invention would make it possible to produce a β-alanine derivative in good yield, and / or obtain a certain stereoisomer thereof having a specific configuration in good yield. The compound (I) or a salt thereof is useful as an intermediate for preparing the compound (III) or a salt thereof, Thus, the production of the compound (I) or a salt thereof in a good yield is useful as the
effective production of the intermediate for the compound (III) or a salt thereof which is useful as an antagonist of the glycoprotein Ilb / IIIa more or less. The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.
Preparation 1 A mixture of 2 (S) -benzyloxycarbonylamino-β-alanine (3.0 g) and p-25-toluenesulfonic acid monohydrate (2.88 g) in benzyl alcohol (15 ml)
it was heated to 120 ° C in a flask equipped with a Dean-Stark equipment. After dissolution, toluene (90 ml) was added thereto, and the mixture was heated to reflux for 3.5 hours. The mixture was cooled to room temperature, and concentrated in vacuo. The residue was redissolved in ethyl acetate, washed with saturated aqueous NaHCO3, water and saline, dried over Na2SO4, and evaporated in vacuo. The product was redissolved in ethyl acetate
(50 mL), and cooled to 0 ° C. To the stirred solution, 4 N HCl in ethyl acetate (2.13 mL) was added dropwise at 0 ° C, then concentrated in vacuo. The oily product was solidified by the addition of a mixture of ethyl acetate and isopropyl ether (1: 1).
The solid was washed with isopropyl ether, and dried in vacuo to give benzyl ester hydrochloride of 2 (S) -benzyloxycarbonylamino-β-alanine (2.75 g). NMR (DMSO-dβ, d): 3.04-3.29 (2 H, m), 4.42-4.53 (1 H, m), 5.02-5.17 (4 H, m), 7.35 (5 H, s), 7.37 (5 H, s),
7.95 (1 H, d, J = 8.4 Hz) MASSES: (m / z): 329 (M + free + 1)
Preparation 2 To a suspension of 2 (S) -25-benzyloxycarbonylamino-β-alanine (2.0 g) in a
mixture of dioxane (14 ml), water (7 ml) and 1 N aqueous NaOH (6.94 ml) was added di-tert-butyl dicarbonate (1.67 g) at 0 ° C. after 10 minutes, the temperature was allowed to reached room temperature, and the mixture was stirred for 5 hours. The reaction mixture was evaporated in vacuo to remove the dioxane, adjusted to pH 3.0 with 20% aqueous KHS0, then extracted with ethyl acetate. The organic layer was washed with water and saline, dried over Na2SO4,
and evaporated in vacuo. The resulting solid was washed with diethyl ether to give N-tert-butoxycarbonyl-2 (S) -benzyloxycarbonylamino-β-alanine (2.28 g). NMR (CDC13, d): 1.42 (9 H, s), 3.44-3.67 (2 H, m),
4.34-4.42 (1 H, m), 5.13 (2 H, s), 7.30-7.36 (5 H, m).
Preparation 3 To a stirred solution of diacetate of
iodobenzene (7.26 g) in a mixture of ethyl acetate (4 ml), acetonitrile (4 ml) and water (22 ml) was added 2 (R) -benzyloxycarbonylamino-succinamic acid (5.0 g) at room temperature. After stirring for 3 hours, the reaction mixture was cooled to 5 ° C,
followed by agitation for 2 hours. The material
Insoluble was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to provide 2 (R) -benzyloxycarbonylamino-β-alanine (4.15 g) as a solid or white. IR (KBr): 3303.5, 3027.7, 2948.6, 21693.2, 1656.5,
1623. 8, 1592.9, 1542.8 cm "1 NMR (D20-TFA, d): 3.35 (1 H, dd, J = 13.4 and 8.7 Hz),
3. 57 (1 H, dd, J = 13.4 and 5.3 Hz), 4.57 (1 H, dd, J =
8. 7 and 5.3 Hz), 5.16 (2 H, s), 7.43 (5 H, s) 10 Masses (m / z): 239 (M + H) + p.f .: 238 ° C (decomposition) [a; 31 6 ° (c 1.0, 1 N aqueous NaOH)
Preparation 4 15 Thionyl chloride was added dropwise
(3.22 ml) to methanol (25 ml) at 40 ° C under a nitrogen atmosphere. After stirring for 30 minutes, 2 (R) -benzyloxycarbonylamino-β-alanine (3 g) was added to the reaction mixture, followed by
warming to room temperature and stirring overnight. The insoluble material was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give methyl ester hydrochloride of 2 (R) -
benzyloxycarbonylamino-β-alanine (3.15 g) as a white solid. IR (KBr): 3365.2, 3317.0, 2950.5, 2885.0, 2850.3,
1733. 7, 1695.1, 1594.8, 1537.0 cm "1 NMR (DMSO-de, d): 3.00-3.24 (2 H, m), 3.68 (3 H, s),
4. 39-4.51 (1 H,), 5.07 (2 H, s), 7.73 (5 H, s),
7. 94 (1 H, d, J = 8.2 Hz9 Masses (m / z): 253 (M + H) + p.f .: 166.0-166.5 ° C [a] D3 ° = 39.2 ° (c = 1.0, MeOH)
The following compounds [Preparation 5 and 6 were obtained according to a manner similar to that of Preparation 4.
Preparation 5 Ethyl ester hydrochloride of 2 (R) -benzyloxycarboni lamino-β-alanine IR (KBr): 3322.7, 2863.8, 1727.9, 1695.1, 1596.8,
1540. 8 cm "1 NMR (DMSO-de, d): 1.18 (3 H, t, J = 7.1 Hz), 3.06 (1
H, dd, J = 13.0 and 9.4 Hz), 3.22 (1 H, dd, J = 13.0 y
4. 7 Hz), 4.13 (2 H, q, J = 7.1 hz), 4.36-4.48 (1 H, m), 5.08 (2 H, s), 7.37 (5 H, s), 7.94 (1 H, d, J =
8. 2 Hz)
^. * ~? »Á £ S ¡* ?? *. ~ * ^.
Mass (m / z): 267 (M + H) + m.p. : 141.0-141.5 ° C [a] 30 = 39.9 ° (c = 1.0, MeOH)
Preparation 6 Hydrochloride of 2 (S) -benzyloxycarbonylamino-β-alanine ethyl ester IR (KBr): 3324.7, 2869.6, 1727.9, 1695.1, 1596.8,
1540. 8 cm "1 10 NMR (DMSO-de, d): 1.18 (3 H, t, J = 7.1 Hz), 3.06 (1
H, dd, J = 13.0 and 9.4 Hz), 3.22 (1 H, dd, J = 13.0 y
4. 7 Hz), 4.13 (2 H, q, J = 7.1 hz), 4.36-4.48 (1 H,), 5.08 (2 H, s), 7.37 (5 H, s), 7.94 (1 H, d, J =
8. 2 Hz) 15 Masses (m / z): 267 (M + H) + p.f. : 141.3-141.8 ° C [a] D30 = -39.9 ° (c = 1.0, MeOH)
Preparation 7 20 To a mixture of (R) -1- [3- (1-tert-butoxycarbonyl-4-piperidyl) propionyl] -3-piperidinecarboxylic acid (20.0 g), methyl ester hydrochloride of 2 (S) -benzyloxycarbonylamino-β-alanine (17.2 g) and 1-hydroxybenzotriazole (8.07 g) in N, N-25 dimethylformamide (200 ml) was added dropwise 1-
ethyl-3- (3-dimethylaminopropyl) carbodiimide (10.9 ml) at 0 ° C. The mixture was stirred at 4 ° C for 15 hours, then poured into ice water (500 ml), and extracted with ethyl acetate. (500 mi x 2). The combined organic layers were washed successively with water, saturated aqueous NaHCO3 and saline, dried over Na2SO4, and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with n-hexane: ethyl acetate (from 1: 1 to ethyl acetate).
Ethyl only) to provide N- [(R) -1- [3- (l-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -benzyloxycarbonylamino- methyl ester β-alanine (30.5 g) as a colorless oil. 15 IR (KBr): 3307, 2933, 1724, 1689, 1535, 1434, 1365, 1272, 1243, 1164 cm "1 NMR (CDC13.D): 0.97-1.38 (2 H, m), 1.46 (9 H, s), 1.53-1.67 (7 H, m), 2.27-2.67 (6 H, m), 3.23-3.39 (3 H, m), 3.69 (3 H, s), 3.54-3.61 (1 H, m) , 4.07-4.14
(4 H, m), 4.64-4.51 (1 H, m), 5.12 (2 H, s), 6.39-6.43 (1 H, m), 7.32-7.35 (5 H, m). Mass (m / z): 503 (M-Boc + 2) +
The following compounds [Preparations 8 to 13] were obtained according to a manner similar to that of Preparation 7.
Preparation 8 N- [(S) -1- [3- (1-tert-Butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidyl-carbonyl] -2 (S) -benzyloxycarbonylamino-β- methyl ester alanine NMR (CDC13.D): 0.98-1.84 (11 H, m), 1.45 (9 H, s), 2.30-2.38 (3 H, m), 2.59-2.71 (2 H, m), 3.32-4.10 ( 8 H,), 3.76 (3 H, s), 4.40-4.50 (1 H, m), 5.09 (1 H, Abq, J = 12.3 Hz), 5.13 (1 H, Abq, J = 12.3 Hz), 7.31 -7.37 (5 H, m). MASS (m / z): 625 (M + Na) +
Preparation 9 N- [(S) -1- [3- (1-tert-Butoxycarboni-4-piperidyl) -propionyl] -3-piperidyl-carbonyl] -2 (R) -benzyloxycarbonylamino-β-alanine methyl ester NMR (CDCl 3, d): 0.97-1.77 (11 H, m), 1.46 (9 H, s), 2.35-2.68 (5 H, m), 3.27-4.21 (8 H, m), 3.70 (3 H, s), 4.47-4.53 (1 H, m), 5.13 (2 H, s), 7.32-7.38 (5 H, m). MASS (m / z): 625 (M + Na) + Preparation 10 Benzyl ester of N- [(R) -1- [3- (1-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidyl- carbonyl] -2 (S) -benzyloxycarbonylamino-β-alanine IR (KBr): 1720, 1710, 1691, 1651 cm "1 NMR (CDC13, d): 0.92-1.15 (2 H, m), 1.25-2.67 (15 H,), 1.46 (9 H, s), 3.12-4.24 (7 H, m), 4.46-4.58 (1 H, m), 5.00-5.18 (4 H, m), 6.40 (1 H, d, J = 9.3 Hz), 7.23-7.37 (10 H, m) MASS (m / z): 701 (M + Na) +
Preparation 11 N- [(R) -1- [3- (1- tert -Butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -benzyloxycarbonylamino-β-alanine IR ethyl ester (KBr): 3309.2, 2977.5, 2935.1, 2859.9, 1726.0, 1689.3, 1652.7, 1535.1 cm "1 NMR (DMSO-de, d): 0.89-1.90 (11 H, m), 1.18 (3 H, t, J = 7.1 hz), 1.38 (9 H, s), 2.20-2.80 (6 H, m), 2.80- 3.60 (3 H, m), 3.65-4.45 (7 H, m), 5.04 (2 H, s), 7.31 (1 H, dd, J = 8.0 and 3.8 Hz), 7.95-8.10 (1 H, m) MASS (m / z): 639 (M + Na) +
Preparation 12 Methyl ester of N- [(R) -1- [3- (1-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (R) -benzyloxycarbonylamino-β- alanine IR (KBr): 3309.2, 2935.1, 2859.9, 1726.0, 1689.3, 1535.1 cm "1 NMR (DMSO-de, d): 0.80-1.90 (11 H, m), 1.38 (9 H, s), 2.20-2.80 (6 H, m), 2.80-4.00 (6 H, m), 3.61 (3 H, s), 4.10-4.45 (2 H, m), 5.04 (2 H, s), 7.36 (5 H, s)
7.64 (1 H, d, J = 8.1 Hz), 7.95-8.15 (1 H, m) MASS (m / z): 603 (M + H) + 625 (M + Na) +
Preparation 13 N- [(R) -1- [3- (1-tert-15-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (R) -benzyloxycarbonylamino-β-alanine ethyl ester IR (KBr): 3309.2, 2977.5, 2935.1, 2859.9, 1726.0, 1689.3, 1654.6, 1535.1 cm'1 NMR (DMSO-de, d): 0.80-1.90 (11 H, m), 1.17 (3 H, t, J
= 7.1 Hz), 1.38 (9 H, s), 2.20-2.80 (6 H, m), 2.80- 3.50 (3 H, m), 3.65-4.45 (7 H, m), 5.04 (2 H, s ), 7.36 (5 H, s) 7.62 (1 H, d, J = 8.1 Hz), 7.95-8.10 (1 H, m) MASS (m / z): 617 (M + H) + 639 (M + Na ) + 25
x ** "» **** - ** - s ^ - **** - **. ^ .ato _._._: .. .. g *. ^? Preparation 14 To a stirred solution of (R) -l- [3- (l-tert-butoxycarbonyl-4-piperidyl) propionyl] -3-piperi-dincarboxylic acid (1.0 g) in tetrahydrofuran (20 ml) was added dropwise isobutyl chloroformate ( 356 μl) and 4-methylmorpholine (300 μl) at -15 ° C under a nitrogen atmosphere to an ice-cooled solution of 2 (S) -benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (783 mg) and N - (trimethylsilyl) acetamide (1.78 g) in tetrahydrofuran
(30 ml) the solution above was added dropwise with stirring under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature, and was stirred for 2 hours, and then partitioned between ethyl acetate and water. The organic layer was separated, washed in succession with water, 5% aqueous KHS04, 5% aqueous NaHC03 and saline, and dried over MgSO4. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel, eluting with n-hexane: ethyl acetate (from 1: 6 to ethyl acetate only) to give N- [(R ) -1- [3- (1-tert-butoxycarbonyl-4-piperidyl) propionyl] -3-piperidylcarbonyl] -2 (S) -benzyloxycarbonylamino-β-alanine (1.36 g) as a
.y ^ i? ^^^^^ i ^^^ j foam, which is the same compound obtained in Preparation 7.
Preparation 15 To a stirred solution of (R) -l- [3- (1-tert-butoxycarbonyl-4-piperidyl) propionyl] -3-piperidinedicarboxylic acid (1.0 g) and N, N-dimethylformamide (210 μl) in dichloromethane (10 mL), oxalyl chloride (240 μL) was added dropwise at 4 ° C under a nitrogen atmosphere. To an ice-cooled solution of 2 (S) -benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (940 mg) and N- (trimethylsilyl) acetamide (2.85 g) in N, N-dimethylformamide (10 ml) was added drop drop the top solution with stirring under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature, and stirred for 2 hours, and then partitioned between a mixture of ethyl acetate and n-hexane and water. The organic layer was separated, washed in succession with water, aqueous 5% NaHC 3 solution and saline, and dried over MgSO 4. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel, eluting with n-hexane: ethyl acetate (from 1: 6 to ethyl acetate only)
to provide N- [(R) -1- [3- (1-tert-butoxycarboni-4-piperidyl) propionyl] -3-piperidylcarbonyl] -2 (S) -benzyloxycarbonylamino-β-alanine methyl ester (. 89 g) as a foam, which is the same compound obtained in Preparation 14.Preparation 16 To a solution of N- (t-butoxycarbonyl) -2 (S) -benzyloxycarbonylamino-β-alanine (6.15 g) in methanol (120 ml) was added 10% Pd / C (50% wet, 1.2 g) . The mixture was stirred vigorously, and hydrogen gas was bubbled through for 1 hour. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in tetrahydrofuran (70 ml) and cooled to 0 ° C with an ice bath. 1N NaOH (36 ml) was added, then acetic anhydride (3.77 ml) was added dropwise with stirring. The mixture was stirred for an additional 1 hour at 0 ° C, then the pH of the mixture was adjusted to 2.5 with 20% aqueous KHS04. The resulting mixture was extracted with ethyl acetate: tetrahydrofuran (200 ml: 100 ml) twice. The combined organic layer was dried over Na 2 SO and evaporated in vacuo. The residue was recrystallized from diethyl ether to give N- (t-butoxycarbonyl) -2 (S) -acetylamino-β-alanine (3.17 g).
IR (KBr): 3370, 3303, 1707, 1689, 1612, 1552, 1513, 1431, 1386, 1369, 1309, 1277, 1254, 1173 cm "1 NMR (DMSO-de, d): 1.37 (9 H, s ), 1.83 (3 H, s), 3.21- 3.27 (2 H, m), 4.18-4.28 (1 H, m), 6.75-6.85 (1 H, 5 m), 7.99 (1 H, d, J = 7.9 Hz) Mass (m / z): 245 (M + H) +.
Preparation 17 To a mixture of N- (t-butoxycarbonyl) -2 (S) -0-acetylamino-β-alanine (3.0 g) in dimethylformamide (60 ml) was added NaHC 3 (2.05 g) at -2 ° C, and a solution of benzyl bromide in dimethylformamide was added
(60 ml) using an addition funnel under stirring.
The mixture was stirred overnight at about 26 ° C, then poured into a mixture of ice-water (300 ml) and hexane-ethyl acetate (8: 2, 500 ml). After the organic layer was separated, the aqueous layer was extracted again with hexane-ethyl acetate (8: 2, 300 ml). The combined organic layers were washed 0 with water (300 ml x 2), saline (300 ml) and dried over Na 2 SO 4, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane: ethyl acetate (8: 2) to give benzyl ester of N- (t-5-butoxycarbonyl) -2 (S) -acetylamino-β-alanine (3.68 g) .
> * *, * ^ ÉU *?? Sl &lL¿k IR (KBr): 3361, 3324, 1739, 1687, 1650, 1536, 1456, 1440, 1392, 1369, 1346, 1319, 1278, 1251, 1203, 1174 cm "1 NMR (CDC13, d): 1.42 (9 H, s), 2.03 (3 H, s), 3.51- 3.56 (2 H, m), 4.60-4.68 (1 H, m), 4.80 (1 H, sa), 5.18 (2 H, s), 7.36 (5 H, similar to singlet) Masses (m / z): 237 (M-Boc + 2H) +.
Preparation 18 To an ice-cooled solution of benzyl ester of N- (t-butoxycarbonyl) -2 (S) -acetylamino-β-alanine (3.44 g) in ethyl acetate (35 ml) was added 4N HCl in ethyl acetate. ethyl (25.5 ml). The mixture was stirred for 2.5 hours at room temperature, then the solvent was decanted. The residue was washed with diethyl ether several times, and dried in vacuo to give benzyl ester hydrochloride of 2 (S) -acetylamino-β-alanine (2.31 g) as a white powder. IR (KBr): 3413, 3245, 1739, 1660, 1612, 1537, 1500, 1454, 1377, 1307, 1220, 1166 cm "1 NMR (DMSO-de, d): 1.89 (3 H, s), 3.03- 3.28 (2 H,), 4.54-4.65 (1 H, m), 5.15 (2 H, s), 7.33-7.39 (5 H, m), 8.25 (3 H, sa), 8.67 (1 H, d, J = 7.7 Hz) Mass (m / z): 237 (M + H) +.
Üm j H i AÚ & Lkj ?? ** ^ Preparation 19 AA a solution of benzyl ester hydrochloride of 2 (S) -acetylamino-β-alanine (1.86 g), N- (t-butoxycarbonyl) -3 (R) -npecpecific acid (1.64 g) and 1-hydroxybenzotriazole (0.97 g) in dimethylformamide (25 ml) was added l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (1.31 g) at 0 ° C. The mixture was stirred for 2 hours at room temperature, then it was poured into ice water: ethyl acetate. The organic layer
Separated was washed with water, saturated aqueous NaHCO3, saline, dried over Na2SO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with CHCl-MeOH (95: 5) to give benzyl ester of N - [(R) -l- (t-15-butoxycarbonyl) -3-piperidyl-carbonyl] -2 (S) -acetylamino-β-alanine (2.84 g). IR (Film): 3300, 2938, 1741, 1666, 1648, 1552, 1533, 1469, 1434, 1367, 1301, 1265, 1241, 1151 cm "1 NMR (CDC13, d): 1.46 (9 H, s), 1.55-1.77 (4 H, m),
2.04 (3 H, s), 2.10-2.22 (1 H, sa), 3.10 (2 H, sa), 3.79 (2 H, sa), 3.64-3.67 (2 H, m), 3.79-3.85 (1 H, sa), 4.62-4.71 (1 H, m), 5.18 and 5.30 (total 2 H, s), 7.26-7.40 (5 H,) Mass (m / z): 348 (M - Boc + 2 H) +. 25
Preparation 20 To an ice-cooled solution of benzyl ester of N- [(R) -1- (t-butoxycarbonyl) -3-piperidylcarbonyl] -2 (S) -acetylamine-alanine (2.7 g) was added HCl 4 N in ethyl acetate (25.5 ml). the mixture was stirred for 2.5 hours at room temperature, then the solvent was removed. The residue was washed with diethyl ether several times, and dried in vacuo to provide benzylester benzyl ester hydrochloride.
N- [(R) -3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine (2.29 g) as a white powder. IR (Film): 3267, 3064, 2958, 1741, 1656, 1543, 1452, 1376 cm "1 NMR (DMSO-d6, d): 1.45-1.87 (4 H, m), 1.91 (3 H, s),
2.62-2.85 (3 H, m), 3.09-3.46 (4 H, m), 4.38-4.42 (1 H, m), 5.01-5.14 (2 H, m), 7.37-7.39 (5 H, m) , 8.37- 8.41 (2 H, m), 8.78 (1 H, sa), 8.98 (1 H, sa) Mass (m / z): 348 (M + H) +.
Example 1 A mixture of N - [(R) -l- [3- (l-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -benzyloxycarbonylamino-β- methyl ester alanine (20 g) and 10% Pd on carbon (50%)
wet) (5 g) in methanol (500 ml) was stirred
Stir vigorously under a hydrogen atmosphere (1033 kg / cm2 [1 atm]) at room temperature. After 2 hours, the undisturbed material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (200 ml), and cooled to 0 ° C. 1 N aqueous LiOH solution (116 ml) was added to the solution in 15 minutes, at 0-3 ° C. after the mixture was stirred for 45 minutes at 0 ° C, acetic anhydride (6.89 ml) was added to the mixture
in 15 minutes at 0-4 ° C. The mixture was stirred for 30 minutes at 0 ° C, then diethyl ether (150 ml) was added. The aqueous layer was separated, and the pH thereof was adjusted to 2.5 with 20% aqueous KHS04, then extracted with ethyl acetate. The extract dried
over Na 2 SO, and concentrated in vacuo to give N - [(R) -l- [3- (1-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -acetylamino- β-alanine (16.3 g) as a colorless oil. 20 IR (KBr): 3303, 2931, 1732, 1664, 1544, 1475, 1436
NMR (CDCl 3, d): 1.07-1.25 (2 H, m), 1.44 (9 H, s),
1. 51-1.76 (7 H,), 1.89-1.95 (2 H,), 2.05 (3 H, s), 2.35-2.39 (3 H, m), 2.61-2.73 (2 H, m), 3.24-3.35
(2 H, m), 3.56-3.84 (3 H, m), 4.06-4.20 (3 H, m), 4.33-4.60 (1 H, m), 7.43-7.51 (2 H, m) Masses (m / z): 519 (M + Na) +.
Example 2 N- [(S) -1- [3- (1-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine was obtained from the ester methyl
N- [(S) -1- [3- (l-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -benzyloxycarbonylamino-β-alanine according to a similar manner to that of Example 1. IR (KBr): 3311, 1738, 1678, 1668, 1655 cm "1 NMR (CDC13.D): 1.00-2.11 (11 H, m), 1.45 (9 H, s), 2.03 (3 H, s), 2.33-240 (3 H, m), 2.60-2.73 (2 H, m),
3. 06-3.26 (2 H, m), 3.48-4.59 (9 H,), 7.52-7.58 (1
H, m), 7.70 (1 H, d, J = 7.0 Hz) Mass (m / z): 497 (M + + 1)
Example 3 N- [(S) -1- [3- (1-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (R) -acetylamino-β-alanine was obtained from the ester N - [(S) -l- [3- (l-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (R) -benzyloxycarbonylamino-β-alanine methyl ester according to a manner similar to that of Example 1. IR (KBr): 3311, 1738, 1720, 1 ^ 6, 1668, 1655 cm "1 NMR (CDC13.D): 1.01-2.06 ^ -1 H, m), 1.45 (9 H , s), 2.06 (3 H, s), 2.12-2.40 (3 H, m), 2.61-2.73 (2 H, m), 3.09-3.86 (6 H, m), 4.00-4.64 (3 H, m ), 7.39-7.43 (1 H, m) Masses (m / z): 497 (M + 1) +.
Example 4 N- [(R) -1- [3- (1-tert-Butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine was obtained from the ester ethyl ester of N- [(R) -1- [3- (l-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -benzyloxycarbonylamino-β-alanine according to a similar to that of Example 1, and it was the same compound obtained in Example 1.
Example 5 N- [(R) -1- [3- (1-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (R) -acetylamino-β-alanine was obtained from the ester N- [(R) -1- [3- (1-tert-Butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (R) -benzyloxycarbonylamino-β-alanine methyl ester according to a similar to that of Example 1. IR (KBr): 3305.4, 2975.6, 2933.2, 2861.8, 1733.7, 1660.4, 1544.7 cm "1 NMR (DMSO-de, d): 0.90-1.95 (11 H, m), 1.38 ( 9 H, s), 1.84 (3 H, s), 2.20-2.80 (5 H,), 2.80-3.60 (4 H, m), 3.70-4.00 (3 H, m), 4.20-4.45 (2 H, m), 7.90-8.10 (2 H, m) Mass (m / z): 495 (M - H) "
Example 6 N- [(R) -1- [3- (1-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (R) -acetylamino-β-alanine was obtained from the ester ethyl ester of N- [(R) -1- [3- (l-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (R) -benzyloxycarbonylamino-β-alanine according to a similar to that of Example 1, and was the same compound obtained in Example 5.
Example 7 A mixture of benzyl ester of N - [(R) -l- [3- (l-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -benzyloxycarbonylamino-β-alanine (540 ml), acetic acid (0.046 ml) and Pd / C at
fri $f 10% (108 mg) in methanol (11 ml) was hydrogen at atmospheric pressure for 1.5 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo. The residue was redissolved in a mixture of dioxane (4.8 ml) and 1 N aqueous NaOH (2.46 ml), cooled to 0 ° C, and acetic anhydride (0.12 ml) was added dropwise. After 5 minutes, the temperature was allowed to reach room temperature. Water and ethyl acetate were added to the
The reaction mixture, and the separated aqueous layer was adjusted to pH 3.0 with 5% aqueous KHS04, extracted with ethyl acetate three times. The combined organic layer was washed with saline, dried over Na2SO4, and evaporated in vacuo to give N-15 [(R) -1- [3- (l-tert-butoxycarbonyl-4-piperidyl) -propionyl] - 3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine (332 mg), which was the same compound obtained in Example 1.
Example 8 To a solution of N- [(R) -1- [3- (1-tert-butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -acetylamino-β- alanine (14.9 g) in ethyl acetate (150 ml) was added dropwise HCl 4
N in ethyl acetate (74.8 ml) for 10 minutes at 0 °
^^ s »^ isMS ^^ ii? ^ & ^? r ^ 4 ^, t > ? ^? rr? a? ^ ^: A ^ _3 and?
C. after the mixture was stirred for 1 hour 20 minutes, a white solid was collected by filtration, and dried in vacuo. The powder was dissolved in water (150 ml), and the solution was neutralized to pH 6.5 with saturated aqueous NaHCO3. The solution was concentrated to about 100 ml, then applied to an ODS column (Disogel-120SPMR, 11), and eluted with 4-6% CH 3 CN / water. The eluent was concentrated in vacuo, and the residue was dissolved at 0.5% in aqueous ethanol (200 ml). After the mixture was stirred at room temperature overnight, and the resulting solid was collected by filtration, and dried in vacuo to provide N- [(R) -1- [3- (4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine (6.85 g) as white crystals. IR (KBr): 3430, 2942, 2861, 1630, 1610, 1475, 1444, 1394 cm "1 NMR (D20, d): 1.37-1.94 (11 H, m), 2.03 (3 H, s), 2.35- 2.54 (3 H, m), 2.85-3.06 (3 H, m), 3.21-3.47 (4 H, m), 3.63-3.74 (1 H, m), 3.89-3.92 1 H, m), 4.15-4.31 (1 H, m), 4.35.4.41 (1 H, m) Mass (m / z): 397 (M + + 1) mp: 233 ° C [] D26 = -11.8 ° (c = 1.0, MeOH)
-flaS »* Analysis for C? 9H32N4? 5 • 2« 20: Calculated: C: 52.76, H: 8.39; N: 12.95 Found: C: 52.42, H: 8. ^ 2 »N: 12.84
Example 9 N- [(S) -1- [3- (4-piperidyl) propionyl] -3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine was obtained from N- [(S) -1 - [3- (l-tert-butoxycarbonyl-4-piperidyl) propionyl] -3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine according to a manner similar to that of Example 8. IR (KBr) : 2947, 2858, 1666, 1628, 1599 cm "1 NMR (D20, d): 1.30-2.30 (11 H, m), 2.03 (3 H, s), 2.35-2.55 (3 H, m), 2.81- 3.05 (3 H, m), 3.12-3.52 (4 H, m), 3.60-3.70 (1 H, m), 3.85-3.97 (1 H, m), 4.13- 4.30 (1 H, m), 4.35- 4.42 (1 H, m) Mass (m / z): 397 (M + 1) + .pf: 131.2-131.7 ° C [a] D27 = + 46.2 ° (c = 1.0, MeOH) Analysis for C? 9H32N 05 • 2.5H20: Calculated: C: 51.69, H: 8.45; N: 12.69 Found: C: 51.25, H: 8.64, N: 12.53 Example 10 N- [(S) -1- [3- (4-piperidyl) propionyl] -3-piperidylcarbonyl] -2 (R.) was obtained "-iacet-ilamino-ß-alanine from N- [(S) ~ g 3- (l-tert-butoxycarbonyl-4-piperidyl) propionyl] -3-piperidylcarbonyl] -2 (R) -acetylamino-β-alanine according to a manner similar to that of Example 8. IR (KBr): 3421, 2941, 2860, 1645, 1637, 1630, 1618 cm "1 NMR (D20, d): 1.37-1.95 (11 H, m) , 2.03 (3 H, s), 2.36-2.54 (3 H, m), 2.80-3.01 (3 H, m), 3.17-3.48 (4 H, m), 3.63-3.75 (1 H, m), 3.81 -3.95 (1 H, m), 4.16- 4.32 (1 H, m), 4.34-4.41 (1 H, m) Masses (m / z): 397 (M + 1) +. p.f. : > 220 ° C [a] D26 = + 12.2 ° (c = 1.0, MeOH) Analysis for C? 9H32N 05 • 2H20: Calculated: C: 52.76, H: 8.39; N: 12.95 Found: C: 52.87, H: 8.99, N: 12.90
Example 11 N- [(R) -1- [3- (4-piperidyl) propionyl] -3-piperidylcarbonyl] -2 (R) -acetylamino-β-alanine was obtained from N- [(R) -1 - [3- (l-tert-butoxycarbonyl-4-piperidyl) propionyl] -3-piperidylcarbonyl] -2 (R) -
fefaS? faith s & acetylamino-β-alanine according to a manner similar to that of Example 8. IR (KBr): 3463.5, 3251.4, # «O89.4, 1666.2, 1627.6, 1598.7, 1542.8 cm" 1 NMR (D20, d): 1.30-2.10 (11 H, m), 2.03 (3 H, s), 2.30-2.65 (3 H, m), 2.80-3.70 (8 H,), 3.80-4.45 (3 H, m) Masses (m / z): 397 (M + H) +, 419 (M + Na) + mp: 124.0-124.5 ° C (10% aqueous isopropanol) [a] D29 = -45.9 ° (c = 1.0, MeOH) Analysis for Ci9H32N4 • 5 • 3H20: Calculated: C: 50.65, H: 8.50, N: 12.44 Found: C: 50.88, H: 8.57, N: 12.49
Example 12 To a solution of benzyl ester hydrochloride of N- [(R) -3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine (231 mg), 3- (4-pyridyl) -2-propenoic acid (82 mg) and 1-hydroxybenzotriazole (81 mg) in dimethylformamide (2 ml) was added dropwise 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.11 ml) at 0 ° C. The mixture was stirred for 2 hours. hours at room temperature, then poured into ice water: ethyl acetate. The separated organic layers were washed successively with water, saturated aqueous NaHC03, saline solution, added on Na2SO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with CHCl3: < Af MeOH (96: 4) to provide benzyl ester of N- [(R) -1- [3- (4-pyridyl) -2-propenoyl] -3-piperidyl-carbonyl] -2 (S) -acetylamino-β - Alanine (263 mg) as a colorless oil. IR (Film): 3376, 3334, 2937, 1739, 1650, 1599, 1550, 1455, 1394, 1301, 1224 cm "1 NMR (CDCI3, d): 1.58-1.87 (4 H, m), 2.02 and 2.06 ( total 3 H, s), 2.15-2.25 (1 H, m), 2.40-2.50 (1 H, m), 3.43-3.76 (4 H, m), 3.91-4.0 (2 H, m), 4.70-4.78 (1 H, m), 5.05-5.19 (2 H, m), 7.08 (1 H, d, J = 15.6 Hz), 7.32-7.38 (7 H, m), 7.54 (1 H, d, J = 15.6 Hz), 8.62-8.65 (2 H, m) Masses (m / z): 479 (M + H) +.
Example 13 A mixture of benzyl ester of N - [(R) -l- [3- (4-pyridyl) -2-propenoyl] -3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine (233 mg) , Pt02 (60 mg) in ethanol (10 ml), 4 N HCl in ethyl acetate (121 ml) and Pt02 (50% wet, 1.2 g) was stirred vigorously under a hydrogen atmosphere (1033 kg / cm2, 1 atm ). After 3.5 hours, the catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in water (10 ml). The solution was adjusted to pH 6.5 with active NaHCO3, then evaporated in vacuo. The residue was purified by chromatography on an ODS column (Disogel-120 SPMR), eluting with 4% CH3CN / water. The eluent was concentrated in vacuo, and lyophilized to provide N- [(R) -1- [3- (4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine (154 mg) as a white powder, which is the compound obtained in Example 8.
Preparation 21 A mixture of 3-piperidinecarboxylic acid ethyl ester (50 g) and L-tartaric acid (48 g) in isopropyl alcohol (1000 ml) and water (5 ml) was stirred at 40 ° C. the solution was cooled and stirred at room temperature. The precipitate was filtered, washed with isopropyl alcohol (50 ml) and dried in vacuo to give the L-tartaric acid salt of the (R) -3-piperidinecarboxylic acid ethyl ester as a white solid. The solid was redissolved in isopropyl alcohol (726 ml) and water 836 ml) at 65 ° C. The solution was cooled and stirred at room temperature. The precipitate was filtered and dried to provide L-tartaric acid salt of the pure ethyl (R) -3-piperidinecarboxylic acid ester (30.3 g). To a solution d @ j | j p. of L-tartaric acid ethyl ester of (R) -3-piperidinecarboxylic acid (30.3 g) in ethyl acetate
(300 mL) and water (60 mL), 12% aqueous sodium hydroxide was added to adjust the pH to 13. The aqueous layer was extracted with ethyl acetate (60 mL) twice, and the combined organic layer was dried with sodium sulfate (8 g). The organic layer was concentrated in vacuo to provide (R) -3-piperidinecarboxylic acid ethyl ester (15.3 g). IR (oil): 2939, 2856, 1731, 1446, 1373 cm "1 NMR (DMSO-de, d): 1.66 (3 H, t), 1.27-1.58 (3 H, m), 1.81-1.89 (1 H , m), 2.26-2.41 (2 H, m), 2.46 (1 H, m), 2.57 (1 H, m), 2.66 (1 H, d), 2.98 (1 H, d), 4.03 (2 H , q) Masses (m / z): 157.
Preparation 22 To a mixture of malonic acid (12 g), pyridine (7.6 g) in ethanol (41 ml) was added dropwise 4-pyridinecarbaldehyde (10.3 g) at 40 ° C. the mixture was stirred at 80 ° C. 5 hours,
, ^ S0 ^ at room temperature. The precipitate was filtered, washed with ethanol and dried in vacuo to give 3- (4-pyridyl) -2-propenoic acid (10.4 g). IR (KBr): 3054, 2359, 1700, 1645, 1607, 1555, 1415, 1341, 1311 cm "1 NMR (DMSO-de, d): 3.33 (1 H, s), 6.78 (1 H, d), 7.52 (1 H, d), 7.66 (2 H, d), 8.62 (2 H, d) Masses (m / z): 150 (M + 1) +.
Preparation 23 A mixture of 3- (4-pyridyl) -2-propenoic acid (10 g), 10% Pd / C (1 g) in acetic acid (40 ml) was hydrogenated (3.0 kg / cm2) at 65 ° C. C for 8 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo. The residue was redissolved in toluene (30 mL) and concentrated in vacuo. The residue was redissolved in water (30 mL) and tetrahydrofuran (50 mL), cooled to 0 ° C, and triethylamine (33 mL) was added dropwise at 5 ° C. Di-carbonate was added to the mixture. -ter-butyl (18.3 g) at 20 ° C, and stirred overnight. The pH was adjusted to 7 with HCl, the organic layer was washed with 10% aqueous citric acid / 40 ml), 5% aqueous sodium chloride (40 ml), dried over magnesium sulfate (5 g), and it was concentrated in vacuo. The residue was redissolved in toluene (20 ml), concentrated in vacuo to 25 ml. The mixture was stirred at 40 ° C for 3 hours, n-heptane (20 ml) was added to the mixture, and it was stirred at 0 ° C overnight. The precipitate was separated and dried to give 3- (l-tert-butoxycarbonyl) -4-piperidyl) propionic acid as a white solid (12.8 g). IR (KBr): 3300, 2937, 1734, 1670, 1479, 1455, 1285, 1173 cm "1 NMR (DMSO-d6, d): 0.9-1.0 (2 H, m), 1.38 (9 H, s), 1.3-1.5 (1 H, m), 1.6 (2 H, m), 2.22 (2 H, t), 2.64 (2 H, m), 3.30 (1 H, s), 3.9 (2 H, m) Masses (m / z): 158 (M + 1 - Boc) +.
Preparation 24 To a mixture of (R) -3-piperidinecarboxylic acid ethyl ester (7.7 g), 3- (l-tert-butoxycarbonyl-4-piperidyl) propionic acid (12.5 g), 1-hydroxybenzotriazole (6.6 g) in l-ethyl-3- (3-dimethylaminopropyl) carbodiimide was added in dimethylformamide.
(7.6 g) at 5 ° C. The mixture was stirred at 25 ° C overnight. Ethyl acetate (96 ml) and water (94 ml) were added to the mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (94 ml) twice. The combined organic layers were washed with 9% aqueous sodium bicarbonate (63 ml), water (63 ml), 20% aqueous sodium chloride (63 ml) and concentrated in vacuo. The residue was dissolved in methanol (164 ml) and added to a solution of lithium hydroxide (3.9 g) in water (110 ml) at 5 ° C. The mixture was stirred overnight, then the pH was adjusted to 2.6. with 3N hydrochloric acid and stirred overnight at 35 ° C. After cooling to 0 ° C, the precipitate was filtered, washed with 30% aqueous methanol and dried in vacuo to give (R) -1 acid. - [3- (1-tert-Butoxycarbonyl-4-piperidyl) propionyl] -3-piperidinecarboxylic acid (13.8 g) as a white solid. IR (KBr): 2931, 2885, 1732, 1688, 1628, 1607, 1471, 1236, 1166 cm "1 NMR (DMSO-de, d): 0.92-1.06 (2 H, m), 1.28-1.51 (3 H , m), 1.38 (9 H, s), 1.51-1.78 (4 H, m), 1.8-2.0 (1 H, m), 2.2-2.4 (4 H, m), 2.5-2.7 (2 H, m ), 2.9-3.1 (1 H,), 3.2-3.8 (1 H, m), 3.7-4.5 (4 H, m) Masses (m / z): 269 (M + 1 - Boc) +.
Example 14 N- [(R) -1- [3- (1-tert-Butoxycarbonyl-4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) -acetylamino-β-alanine (20.0 g) was treated under a 50% RH atmosphere, at 25 ° C for 40 * hours to provide N- [(R) -1- [3- (4-piperidyl) -propionyl] -3-piperidylcarbonyl] -2 (S) trihydrate -acetylamino-ß-alanine (21.6 g), whose stability against moisture was very good. IR (KBr): 2726, 2606, 1658, 1616, 1539, 1328, 1304, 1268, 1232, 1223 cm "1 Diffraction of X-ray powders: (2?) 11.26, 13.39, 18.60, 20.43, 21.16, 22.05
Claims (6)
- CLAIMS 1. A process for preparing a compound of the formula (I): wherein R1 is an amino protecting group, and R2 is an acyl group, or a salt thereof, comprising: subjecting a compound of formula (II): wherein R1 is equal to that defined above, and R3 is protected carboxy, or a salt thereof, to a removal reaction of the carboxy protecting group, and then to an acylation reaction of the amino group.
- 2. A process for preparing a compound of the formula (III): wherein R2 is an acyl group, or a salt thereof, comprising: subjecting a compound of the formula (I) obtained by the process of claim 1, to a removal reaction of the amino protecting group.
- 3. A process according to claim 1 or 2, wherein R 1 is lower alkoxycarbonyl, R 2 is lower alkanoyl, and R 3 is lower alkoxycarbonyl.
- 4. A process according to claim 3, wherein R 1 is tert-butoxycarbonyl, R 2 is acetyl, and R 3 is methoxycarbonyl.
- 5. A compound, which is produced by the process according to claim 1, 2, 3 or 4.
- 6. N- [(R) -1- [3- (4-piperidyl) -propionyl] -3-piperidylcarbonyl trihydrate ] -2 (S) -acetylamino-β-alanine.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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PPPP6465 | 1998-10-12 |
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MXPA01003683A true MXPA01003683A (en) | 2001-12-04 |
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