JP2015507015A - 4−アミノ−5−ビフェニル−4−イル−2−ヒドロキシメチル−2−メチル−ペンタン酸化合物を調製する方法 - Google Patents
4−アミノ−5−ビフェニル−4−イル−2−ヒドロキシメチル−2−メチル−ペンタン酸化合物を調製する方法 Download PDFInfo
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- JP2015507015A JP2015507015A JP2014557777A JP2014557777A JP2015507015A JP 2015507015 A JP2015507015 A JP 2015507015A JP 2014557777 A JP2014557777 A JP 2014557777A JP 2014557777 A JP2014557777 A JP 2014557777A JP 2015507015 A JP2015507015 A JP 2015507015A
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- Prior art keywords
- compound
- alkyl
- alkylene
- halo
- ether
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000000034 method Methods 0.000 title claims abstract description 48
- -1 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compound Chemical class 0.000 title claims description 142
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 79
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- 125000005843 halogen group Chemical group 0.000 claims description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 29
- 125000006239 protecting group Chemical group 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 25
- 125000002947 alkylene group Chemical group 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 229910052757 nitrogen Chemical group 0.000 claims description 16
- 238000010511 deprotection reaction Methods 0.000 claims description 15
- 125000006241 alcohol protecting group Chemical group 0.000 claims description 14
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical group CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
- 150000003852 triazoles Chemical group 0.000 claims description 7
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 150000003536 tetrazoles Chemical group 0.000 claims description 6
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 6
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 6
- GPAAEZIXSQCCES-UHFFFAOYSA-N 1-methoxy-2-(2-methoxyethoxymethoxymethoxy)ethane Chemical compound COCCOCOCOCCOC GPAAEZIXSQCCES-UHFFFAOYSA-N 0.000 claims description 5
- SDTORDSXCYSNTD-UHFFFAOYSA-N 1-methoxy-4-[(4-methoxyphenyl)methoxymethyl]benzene Chemical compound C1=CC(OC)=CC=C1COCC1=CC=C(OC)C=C1 SDTORDSXCYSNTD-UHFFFAOYSA-N 0.000 claims description 5
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- CPZBTYRIGVOOMI-UHFFFAOYSA-N methylsulfanyl(methylsulfanylmethoxy)methane Chemical compound CSCOCSC CPZBTYRIGVOOMI-UHFFFAOYSA-N 0.000 claims description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical group C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 4
- PRQUBDQDCAULSW-UHFFFAOYSA-N 2-(2h-triazol-4-yl)pyridine Chemical group N1N=NC(C=2N=CC=CC=2)=C1 PRQUBDQDCAULSW-UHFFFAOYSA-N 0.000 claims description 4
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical group C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical group C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012964 benzotriazole Chemical group 0.000 claims description 4
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical group C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 230000003213 activating effect Effects 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 5
- NBUJDNBAOFXVDE-ZBLYBZFDSA-N (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (2s,4r)-2-(hydroxymethyl)-2-methyl-5-(4-phenylphenyl)-4-(2h-triazole-4-carbonylamino)pentanoate Chemical compound O1C(=O)OC(COC(=O)[C@](C)(CO)C[C@@H](CC=2C=CC(=CC=2)C=2C=CC=CC=2)NC(=O)C=2N=NNC=2)=C1C NBUJDNBAOFXVDE-ZBLYBZFDSA-N 0.000 abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000003153 chemical reaction reagent Substances 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 239000003701 inert diluent Substances 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 239000002002 slurry Substances 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- 0 Cc1cc(*)c2nc(*)[n]c2c1 Chemical compound Cc1cc(*)c2nc(*)[n]c2c1 0.000 description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 7
- 239000002178 crystalline material Substances 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 4
- 229910052770 Uranium Inorganic materials 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- PGCMUKPXOQRPAL-NUFPYNSWSA-N (2s,4r)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-2-(oxan-2-yloxymethyl)-5-(4-phenylphenyl)pentanoic acid Chemical compound C([C@@H](NC(=O)OC(C)(C)C)C[C@@](C)(COC1OCCCC1)C(O)=O)C(C=C1)=CC=C1C1=CC=CC=C1 PGCMUKPXOQRPAL-NUFPYNSWSA-N 0.000 description 2
- HYPSOYIJOAOUSD-VQIMIIECSA-N (3r,5r)-3-methyl-2-oxo-5-[(4-phenylphenyl)methyl]pyrrolidine-3-carboxylic acid Chemical compound N1C(=O)[C@](C)(C(O)=O)C[C@H]1CC1=CC=C(C=2C=CC=CC=2)C=C1 HYPSOYIJOAOUSD-VQIMIIECSA-N 0.000 description 2
- BINWGTXNILJCRF-MJGOQNOKSA-N (3s,5r)-3-(hydroxymethyl)-3-methyl-5-[(4-phenylphenyl)methyl]pyrrolidin-2-one Chemical compound N1C(=O)[C@](C)(CO)C[C@H]1CC1=CC=C(C=2C=CC=CC=2)C=C1 BINWGTXNILJCRF-MJGOQNOKSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- JQIZHNLEFQMDCQ-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridazine Chemical compound C1CC=CNN1 JQIZHNLEFQMDCQ-UHFFFAOYSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
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- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000004040 pyrrolidinones Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- NUMQCACRALPSHD-UHFFFAOYSA-N tert-butyl ethyl ether Chemical compound CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D317/34—Oxygen atoms
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- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Description
発明の分野
本発明は、ネプリライシン阻害活性を有する化合物を調製するのに有用である、4−アミノ−5−ビフェニル−4−イル−2−ヒドロキシメチル−2−メチル−ペンタン酸化合物を調製するための方法および中間体に関する。
本発明の譲受人に譲渡されたFleuryらの米国特許出願公開第2012/0213806号は、ネプリライシン阻害剤としての活性を有する化合物を開示しており、その開示は本明細書に参照により組み込まれている。一実施形態では、この出願は、(2S,4R)−5−ビフェニル−4−イル−2−ヒドロキシメチル−2−メチル−4−[(3H−[1,2,3]トリアゾール−4−カルボニル)−アミノ]−ペンタン酸5−メチル−2−オキソ−[1,3]ジオキソール−4−イルメチルエステルおよびその互変異性体(2S,4R)−5−ビフェニル−4−イル−2−ヒドロキシメチル−2−メチル−4−[(1H−[1,2,3]トリアゾール−4−カルボニル)−アミノ]−ペンタン酸5−メチル−2−オキソ−[1,3]ジオキソール−4−イルメチルエステルなどの化合物を開示している。
これらの公開および出願において開示されている化合物は、通常ジアステレオマーとして純粋な出発物質を必要とし、1つまたは複数の中間体をクロマトグラフィーで精製する技法により調製される。このような精製ステップを必要としない方法を開発することにいくつかの利点が存在する。本発明は、その必要性に対処する。
本発明は、式IVの化合物
本発明は、式IVの化合物:
H;
−C1〜8アルキル、例えば、−CH3、−CH2CH3、−(CH2)2CH3、−CH(CH3)2、−CH2CH(CH3)2、−(CH2)3CH3、−(CH2)4CH3、−(CH2)2CH(CH3)2、−(CH2)5CH3、および−(CH2)6CH3;
−C1〜3アルキレン−C6〜10アリール、例えば、ベンジル;
−[(CH2)2O]1〜3CH3、例えば、−(CH2)2OCH3および−[(CH2)2O]2CH3;
−C1〜6アルキレン−OC(O)R10、例えば、−CH2OC(O)CH3、−CH2OC(O)CH2CH3、−CH2OC(O)(CH2)2CH3、−CH2CH(CH3)OC(O)CH2CH3、−CH2OC(O)OCH3、−CH2OC(O)OCH2CH3、−CH(CH3)OC(O)OCH2CH3、−CH(CH3)OC(O)O−CH(CH3)2、−CH2OC(O)O−シクロプロピル、−CH(CH3)−OC(O)−O−シクロヘキシル、−CH2OC(O)O−シクロペンチル、−CH2OC(O)−CH[CH(CH3)2]−NH2、および−CH2OC(O)−CH[CH(CH3)2]−NHC(O)OCH3;
−C1〜6アルキレン−NR11R12、例えば、−(CH2)2−N(CH3)2、
−C1〜6アルキル、例えば、−CH3および−CH2CH3;
−O−C1〜6アルキル、例えば、−OCH3、−O−CH2CH3、および−O−CH(CH3)2;
−O−C3〜7シクロアルキル、例えば、−O−シクロプロピル、−O−シクロヘキシル、および−O−シクロペンチル;
−CH[CH(CH3)2]−NH2;ならびに
−CH[CH(CH3)2]−NHC(O)O−C1〜6アルキルから選択される。
H;
ハロ、例えば、クロロおよびフルオロ;
−C0〜5アルキレン−OH、例えば、−OH、−CH2OH、−CH(OH)CH3、および−C(CH3)2−OH;
−C1〜6アルキル、例えば、−CH3、−(CH2)2CH3、−CH(CH3)2、および−(CH2)3−CH3;
−C3〜7シクロアルキル、例えば、シクロプロピルおよびシクロヘキシル;
−C0〜2アルキレン−O−C1〜6アルキル、例えば、−OCH3、−OCH2CH3、−CH2−OCH3、および−(CH2)2−OCH3;
−C(O)C1〜6アルキル、例えば、−C(O)CH3;
−C0〜1アルキレン−COOH、例えば、−COOHおよび−CH2−COOH;
−C(O)NR20R21、例えば、−C(O)NH2、−C(O)NHCH3、−C(O)N(CH3)2、−C(O)NH−(CH2)2CH3、−C(O)NH−(CH2)2−OH、−C(O)NH−シクロプロピル、−C(O)N(CH3)−CH2CH(CH3)2、および−C(O)N(CH3)[(CH2)2OCH3];
−NHC(O)−フェニレン−OCH3、例えば、−NHC(O)−2−メトキシフェニル;
=O;
ハロ、−OH、および−OCH3から独立して選択される1つまたは2つの基で場合によって置換されているフェニル、例えば、フェニル、2−クロロフェニル、2−フルオロフェニル、2−ヒドロキシフェニル、2−メトキシフェニル、3−クロロフェニル、3−フルオロフェニル、3−メトキシフェニル、4−クロロフェニル、4−フルオロフェニル、4−メトキシフェニル、2,5−ジメトキシフェニル、2,4−ジクロロフェニル、2−メトキシ、5−フルオロフェニル、および3,4−ジクロロフェニル;
ピリジニル;および
ピラジニル
から選択される。
H;
−OH;
−C1〜6アルキル、例えば、−CH3;
−C1〜2アルキレン−COOH、例えば、−CH2COOHおよび−(CH2)2−COOH;
−CH2OC(O)CH(R30)NH2、例えば、−CH2OC(O)CH[CH(CH3)2]NH2;
−CH[CH(CH3)2]−NHC(O)O−C1〜6アルキル;
ピリジニル;および
ハロおよび−OCH3から選択される1つまたは複数の基で場合によって置換されているフェニルまたはベンジル(例えば、4−クロロフェニル、3−メトキシフェニル、2,4−ジクロロフェニル、3,4−ジクロロフェニル、2−クロロ,5−フルオロフェニル、4−クロロフェニル、2,6−ジフルオロ,4−クロロフェニル、2−クロロベンジル、3−クロロベンジル、4−クロロベンジル、3−メトキシベンジル、2−クロロ,5−フルオロベンジル、3−クロロ,5−フルオロベンジル、2−フルオロ,4−クロロベンジル、3−クロロ,4−フルオロベンジル、2,6−ジフルオロ,s3−クロロベンジル、2,6−ジフルオロ,4−クロロベンジル、および2,3,5,6−テトラフルオロ,4−メトキシベンジル)から選択される。
本発明の化合物および方法を記載する場合、他に指摘されていない限り、以下の用語は以下の意味を有する。加えて、本明細書で使用される場合、使用する状況が明らかに他を指示していない限り、単数の形態「1つの(a)」、「1つの(an)」および「その(the)」は、対応する複数の形態を含む。「含む(comprising)」、「含む(including)」および「有する」という用語は、包含的であることを意図し、列挙した要素以外に追加の要素が存在し得ることを意味する。本明細書中で使用されている、成分の量、特性、例えば、分子量など、反応条件などを表現するすべての数は、すべての場合において、他に指摘されていない限り、「約」という用語により修飾されているものであると理解されたい。したがって、本明細書中で記述されている数は、本発明で得ようとしている所望の特性に応じて異なり得る近似値である。少なくとも、かつ均等論の原理の特許請求の範囲への適用を制限しようとする試みとしてではなく、各数は、報告された有効数字を考慮して、および通常の丸め技法を適用することによって、少なくとも解釈されるべきである。
本発明の方法における使用に対して適切な不活性希釈剤は、例示として、これらに限定されずに、有機希釈剤、例えば、酢酸、テトラヒドロフラン(THF)、アセトニトリル(MeCN)、N,N−ジメチルホルムアミド(DMF)、N,N−ジメチルアセトアミド、N−メチルピロリジノン、ジメチルスルホキシド(DMSO)、トルエン、ジクロロメタン(DCM)、アセトン、酢酸エチル、酢酸イソプロピル、メチルt−ブチルエーテル、クロロホルム(CHCl3)、四塩化炭素(CCl4)、1,4−ジオキサン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、エチレングリコールなどが挙げられる。水性希釈剤もまた使用することができ、水ならびに塩基性および酸性の水性希釈剤が挙げられる。前述の希釈剤のうちのいずれかの組合せもまた想定される。
塩基で除去される塩基不安定性N−α−アミノ酸保護基、例えば、9−フルオレニルメトキシカルボニル(Fmoc)およびベンゾイル(Bz)など;
酸で除去される保護基、例えば、t−ブトキシカルボニル(Boc)、β−トリメチルシリルエチルオキシカルボニル(TEOC)、t−アミルオキシカルボニル(Aoc)、アダマンチル−オキシカルボニル(Adoc)、1−メチルシクロブチルオキシカルボニル(Mcb)、2−(p−ビフェニリル)プロピル−2−オキシカルボニル(Bpoc)、2−(p−フェニルアゾフェニル)プロピル−2−オキシカルボニル(Azoc)、2,2−ジメチル−3,5−ジメチルオキシベンジルオキシカルボニル(Ddz)、2−フェニルプロピル−2−オキシカルボニル(Poc)、ベンジルオキシカルボニル(Cbz)、2−フランメチルオキシカルボニル(Foc)、p−メトキシベンジルカルボニル(Moz)、o−ニトロフェニルスルフェニル(Nps)、トシル(Ts)、トリチル、トリフェニルメチル(Tr)、およびシリルエーテル(例えば、トリメチルシリル(TMS)、t−ブチルジメチルシリル(TBS)、トリ−イソ−プロピルシリルオキシメチル(TOM)、およびトリイソプロピルシリル(TIPS)エーテル)など;
水素化分解で除去される保護基、例えば、ジチアスクシノイル(Dts)、ベンジル(Bn)、Cbz、p−メトキシベンジル(PMB)、3,4−ジメトキシベンジル(DMPM)、およびMozなど;
求核試薬で除去される保護基、例えば、2−(t−ブチルスルホニル)−2−プロペニルオキシカルボニル(Bspoc)、ベンゾチオフェンスルホン−2−メトキシカルボニル(Bsmoc)、およびNpsなど;ならびに
カルボン酸から誘導される保護基、例えば、ホルミル、アセチル、およびトリフルオロアセチルなどであり、これらは、酸、塩基、または求核試薬で除去される。
酸で除去される保護基、例えば、アセチル(Ac)、ベンゾイル(Bz)、β−メトキシエトキシメチルエーテル(MEM)、p−メトキシベンジルエーテル(PMB)、メチルチオメチルエーテル、ピバロイル(Piv)、テトラヒドロピラニル(THP)、トリチルまたはトリフェニルメチル(Tr)、およびシリルエーテル(例えば、トリメチルシリル(TMS)、t−ブチルジメチルシリル(TBS)、トリ−イソ−プロピルシリルオキシメチル(TOM)、およびトリイソプロピルシリル(TIPS)エーテル)など;
塩基で除去される保護基、例えば、Ac、Bz、およびPivなど;
水素化分解で除去される保護基、例えば、ベンジル(Bn)、PMB、およびTrなど;
酸化で除去される保護基、例えば、PMBなど;ならびに
フッ化物イオン(例えば、NaF、フッ化テトラ−n−ブチルアンモニウム、HF−ピリジン、またはHF−トリエチルアミン)で除去される保護基、例えば、シリルエーテルなど。
本発明は、式Iの化合物:
本発明は、式IIの化合物:
式IIaの化合物:TはHであり、UはHであり、a、b、R4、およびR5は、式IIの化合物に対して定義されている通りである;
式IIbの化合物:TはP2であり、UはHであり、a、b、R4、およびR5は、式IIの化合物に対して定義されている通りである;
式IIcの化合物:TはP2であり、UはP3であり、a、b、R4、およびR5は、式IIの化合物に対して定義されている通りである;ならびに
本発明は、式IIIの化合物:
式IIIaの化合物:TはP2であり、UはP3であり、a、b、R1、R4、およびR5は式IIIの化合物に対して定義されている通りである;
式IIIbの化合物:TはHであり、UはHであり、a、b、R1、R4、およびR5は式IIIの化合物に対して定義されている通りである;
式IIIcの化合物:TはP2であり、UはHであり、a、b、R1、R4、およびR5は式IIIの化合物に対して定義されている通りである;ならびに
式IIIdの化合物:TはHであり、UはP3であり、a、b、R1、R4、およびR5は式IIIの化合物に対して定義されている通りである。
AcOH 酢酸
CPME シクロペンチルメチルエーテル
DCM ジクロロメタンまたは塩化メチレン
DIPEA N,N−ジイソプロピルエチルアミン
DMAP 4−ジメチルアミノピリジン
DMF N,N−ジメチルホルムアミド
EDCI N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド
EtOAc 酢酸エチル
HCTU (2−(6−クロロ−1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルアミニウムヘキサフルオロホスフェート)
MeCN アセトニトリル
MeOH メタノール
MeTHF 2−メチルテトラヒドロフラン
NaHMDS ナトリウムヘキサメチルジシラジド
NMM N−メチルモルホリン
TFA トリフルオロ酢酸
THF テトラヒドロフラン。
(2S,4R)−5−ビフェニル−4−イル−2−ヒドロキシメチル−2−メチル−4−[(1H−[1,2,3]トリアゾール−4−カルボニル)−アミノ]−ペンタン酸5−メチル−2−オキソ−[1,3]ジオキソール−4−イルメチルエステル
Claims (30)
- 前記エーテル溶媒が2−メチルテトラヒドロフランである、請求項1に記載の方法。
- 前記エーテル溶媒がシクロペンチルメチルエーテルをさらに含む、請求項2に記載の方法。
- 酸性脱保護が、3M HClを用いて行われる、請求項4に記載の方法。
- P1が、アセチル、アダマンチル−オキシカルボニル、t−アミルオキシカルボニル、ベンゾチオフェンスルホン−2−メトキシカルボニル、ベンゾイル、ベンジル、ベンジルオキシカルボニル、2−(p−ビフェニリル)プロピル−2−オキシカルボニル、t−ブトキシカルボニル、2−(t−ブチルスルホニル)−2−プロペニルオキシカルボニル、3,4−ジメトキシベンジル、2,2−ジメチル−3,5−ジメチルオキシベンジルオキシカルボニル、ジチアスクシノイル、ホルミル、9−フルオレニルメトキシカルボニル、2−フランメチルオキシカルボニル、p−メトキシベンジル、p−メトキシベンジルカルボニル、1−メチルシクロブチルオキシカルボニル、o−ニトロフェニルスルフェニル、2−フェニルプロピル−2−オキシカルボニル、2−(p−フェニルアゾフェニル)プロピル−2−オキシカルボニル、シリルエーテル、トシル、トリフルオロアセチル、β−トリメチルシリルエチルオキシカルボニル、トリフェニルメチル、およびトリチルから選択される、請求項4に記載の方法。
- P1がt−ブトキシカルボニルである、請求項6に記載の方法。
- ステップ(a)が、第三級アミン塩基の存在下でクロロギ酸イソブチルを用いて行われる、請求項8に記載の方法。
- 前記第三級アミン塩基がN−メチルモルホリンである、請求項9に記載の方法。
- 前記還元剤がテトラヒドロホウ酸ナトリウムである、請求項8に記載の方法。
- P2が、アセチル、ベンゾイル、ベンジル、p−メトキシベンジルエーテル、β−メトキシエトキシメチルエーテル、メチルチオメチルエーテル、ピバロイル、シリルエーテル、テトラヒドロピラニル、トリフェニルメチル、およびトリチルから選択される、請求項12に記載の化合物。
- TがHまたはテトラヒドロピラニルである、請求項13に記載の化合物。
- P3がアセチル、アダマンチル−オキシカルボニル、t−アミルオキシカルボニル、ベンゾチオフェンスルホン−2−メトキシカルボニル、ベンゾイル、ベンジル、ベンジルオキシカルボニル、2−(p−ビフェニリル)プロピル−2−オキシカルボニル、t−ブトキシカルボニル、2−(t−ブチルスルホニル)−2−プロペニルオキシカルボニル、3,4−ジメトキシベンジル、2,2−ジメチル−3,5−ジメチルオキシベンジルオキシカルボニル、ジチアスクシノイル、ホルミル、9−フルオレニルメトキシカルボニル、2−フランメチルオキシカルボニル、p−メトキシベンジル、p−メトキシベンジルカルボニル、1−メチルシクロブチルオキシカルボニル、o−ニトロフェニルスルフェニル、2−フェニルプロピル−2−オキシカルボニル、2−(p−フェニルアゾフェニル)プロピル−2−オキシカルボニル、シリルエーテル、トシル、トリフルオロアセチル、β−トリメチルシリルエチルオキシカルボニル、トリフェニルメチル、およびトリチルから選択される、請求項12に記載の化合物。
- UがHまたはt−ブトキシカルボニルである、請求項15に記載の化合物。
- 式III’の化合物:
R1は、H、−C1〜8アルキル、−C1〜3アルキレン−C6〜10アリール、−[(CH2)2O]1〜3CH3、−C1〜6アルキレン−OC(O)R10、−C1〜6アルキレン−NR11R12、−C1〜6アルキレン−C(O)R13、−C0〜6アルキレンモルホリニル、−C1〜6アルキレン−SO2−C1〜6アルキル、
R10は、−C1〜6アルキル、−O−C1〜6アルキル、−O−C3〜7シクロアルキル、−CH[CH(CH3)2]−NH2、および−CH[CH(CH3)2]−NHC(O)O−C1〜6アルキルから選択され;R11およびR12は−C1〜6アルキルであるか、または−(CH2)3〜6−、−C(O)−(CH2)3−、または−(CH2)2O(CH2)2−として一緒になり;R13は、−O−C1〜6アルキル、−O−ベンジル、および−NR11R12から選択され;
aは0または1であり;R4は、ハロ、−CH3、−CF3、および−CNから選択され;
bは0であるか、または1〜3の整数であり;各R5は、ハロ、−OH、−CH3、−OCH3、および−CF3から独立して選択され;
P2はアルコール保護基であり;
UはHまたはP3であり、P3はアミノ保護基であり;
R1の中の各アルキル基は、1〜8個のフッ素原子で場合によって置換されている)
またはその塩。 - P2が、アセチル、ベンゾイル、ベンジル、p−メトキシベンジルエーテル、β−メトキシエトキシメチルエーテル、メチルチオメチルエーテル、ピバロイル、シリルエーテル、テトラヒドロピラニル、トリフェニルメチル、およびトリチルから選択される、請求項17に記載の化合物。
- P2がテトラヒドロピラニルである、請求項18に記載の化合物。
- P3がアセチル、アダマンチル−オキシカルボニル、t−アミルオキシカルボニル、ベンゾチオフェンスルホン−2−メトキシカルボニル、ベンゾイル、ベンジル、ベンジルオキシカルボニル、2−(p−ビフェニリル)プロピル−2−オキシカルボニル、t−ブトキシカルボニル、2−(t−ブチルスルホニル)−2−プロペニルオキシカルボニル、3,4−ジメトキシベンジル、2,2−ジメチル−3,5−ジメチルオキシベンジルオキシカルボニル、ジチアスクシノイル、ホルミル、9−フルオレニルメトキシカルボニル、2−フランメチルオキシカルボニル、p−メトキシベンジル、p−メトキシベンジルカルボニル、1−メチルシクロブチルオキシカルボニル、o−ニトロフェニルスルフェニル、2−フェニルプロピル−2−オキシカルボニル、2−(p−フェニルアゾフェニル)プロピル−2−オキシカルボニル、シリルエーテル、トシル、トリフルオロアセチル、β−トリメチルシリルエチルオキシカルボニル、トリフェニルメチル、およびトリチルから選択される、請求項17に記載の化合物。
- UがHまたはt−ブトキシカルボニルである、請求項20に記載の化合物。
- 式IVの化合物:
R1は、H、−C1〜8アルキル、−C1〜3アルキレン−C6〜10アリール、−[(CH2)2O]1〜3CH3、−C1〜6アルキレン−OC(O)R10、−C1〜6アルキレン−NR11R12、−C1〜6アルキレン−C(O)R13、−C0〜6アルキレンモルホリニル、−C1〜6アルキレン−SO2−C1〜6アルキル、
R10は、−C1〜6アルキル、−O−C1〜6アルキル、−O−C3〜7シクロアルキル、−CH[CH(CH3)2]−NH2、および−CH[CH(CH3)2]−NHC(O)O−C1〜6アルキルから選択され;R11およびR12は−C1〜6アルキルであるか、または−(CH2)3〜6−、−C(O)−(CH2)3−、または−(CH2)2O(CH2)2−として一緒になり;R13は、−O−C1〜6アルキル、−O−ベンジル、および−NR11R12から選択され;
Xは、ピラゾール、イミダゾール、トリアゾール、ベンゾトリアゾール、テトラゾール、オキサゾール、イソオキサゾール、チアゾール、ピリミジン、ピリダジン、ベンゾイミダゾール、ピラン、およびピリジルトリアゾールから選択され;
R2は存在しないか、またはH;ハロ;−C0〜5アルキレン−OH;−C1〜6アルキル;−C3〜7シクロアルキル;−C0〜2アルキレン−O−C1〜6アルキル;−C(O)C1〜6アルキル;−C0〜1アルキレン−COOH;−C(O)NR20R21;−NHC(O)−フェニレン−OCH3;=O;ハロ、−OH、および−OCH3から独立して選択される1つまたは2つの基で場合によって置換されているフェニル;ピリジニル;ならびにピラジニルから選択され;R20はHまたは−C1〜6アルキルであり;R21は、H、−C1〜6アルキル、−(CH2)2OH、−(CH2)2OCH3、−(CH2)2SO2NH2、および−C0〜1アルキレン−C3〜7シクロアルキルから選択されるか;またはR20およびR21は一緒になって、ハロまたは−OHで場合によって置換されており、環内に酸素原子を場合によって含有する、飽和または部分不飽和の−C3〜5ヘテロ環を形成し;R2は、存在する場合、炭素原子に結合しており;
R3は、H;−OH;−C1〜6アルキル;−C1〜2アルキレン−COOH;−CH2OC(O)CH(R30)NH2;−CH[CH(CH3)2]−NHC(O)O−C1〜6アルキル;ピリジニル;ならびにハロおよび−OCH3から選択される1つまたは複数の基で場合によって置換されているフェニルまたはベンジルから選択され;R30はH、−CH(CH3)2、フェニル、およびベンジルから選択され;R3は、炭素または窒素原子に結合しており;R3が窒素原子に結合している場合、R3はP4であることができ、P4はアミノ保護基であり;
aは0または1であり;R4は、ハロ、−CH3、−CF3、および−CNから選択され;
bは0であるか、または1〜3の整数であり;各R5は、ハロ、−OH、−CH3、−OCH3、および−CF3から独立して選択され;
P2はアルコール保護基であり;
R1、R2、およびR3の中の各アルキル基は、1〜8個のフッ素原子で場合によって置換されている)
またはその互変異性体もしくは塩。 - Xがトリアゾールである、請求項23に記載の化合物。
- R2がHである、請求項23に記載の化合物。
- P4が、アセチル、アダマンチル−オキシカルボニル、t−アミルオキシカルボニル、ベンゾチオフェンスルホン−2−メトキシカルボニル、ベンゾイル、ベンジル、ベンジルオキシカルボニル、2−(p−ビフェニリル)プロピル−2−オキシカルボニル、t−ブトキシカルボニル、2−(t−ブチルスルホニル)−2−プロペニルオキシカルボニル、3,4−ジメトキシベンジル、2,2−ジメチル−3,5−ジメチルオキシベンジルオキシカルボニル、ジチアスクシノイル、ホルミル、9−フルオレニルメトキシカルボニル、2−フランメチルオキシカルボニル、p−メトキシベンジル、p−メトキシベンジルカルボニル、1−メチルシクロブチルオキシカルボニル、o−ニトロフェニルスルフェニル、2−フェニルプロピル−2−オキシカルボニル、2−(p−フェニルアゾフェニル)プロピル−2−オキシカルボニル、シリルエーテル、トシル、トリフルオロアセチル、β−トリメチルシリルエチルオキシカルボニル、トリフェニルメチル、およびトリチルから選択される、請求項23に記載の化合物。
- R3がP4であり、P4がトリチルである、請求項27に記載の化合物。
- P2が、アセチル、ベンゾイル、ベンジル、p−メトキシベンジルエーテル、β−メトキシエトキシメチルエーテル、メチルチオメチルエーテル、ピバロイル、シリルエーテル、テトラヒドロピラニル、トリフェニルメチル、およびトリチルから選択される、請求項23に記載の化合物。
- P2がテトラヒドロピラニルである、請求項29に記載の化合物。
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JP2015524476A (ja) * | 2012-08-08 | 2015-08-24 | セラヴァンス バイオファーマ アール&ディー アイピー, エルエルシー | ネプリライシン阻害剤 |
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WO2012112742A1 (en) | 2011-02-17 | 2012-08-23 | Theravance, Inc. | Substituted aminobutyric derivatives as neprilysin inhibitors |
AR089955A1 (es) | 2012-02-15 | 2014-10-01 | Theravance Inc | Proceso para preparar compuestos de acido 4-amino-5-bifenil-4-il-2-hidroximetil-2-metil-pentanoico |
USD968626S1 (en) | 2020-08-07 | 2022-11-01 | Recensmedical, Inc. | Medical cooling device |
USD977633S1 (en) | 2020-08-07 | 2023-02-07 | Recensmedical, Inc. | Cradle for a medical cooling device |
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JP2015524476A (ja) * | 2012-08-08 | 2015-08-24 | セラヴァンス バイオファーマ アール&ディー アイピー, エルエルシー | ネプリライシン阻害剤 |
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