JPWO2018159628A1 - アミノ酸型アシルボランおよびその製造方法 - Google Patents
アミノ酸型アシルボランおよびその製造方法 Download PDFInfo
- Publication number
- JPWO2018159628A1 JPWO2018159628A1 JP2019503031A JP2019503031A JPWO2018159628A1 JP WO2018159628 A1 JPWO2018159628 A1 JP WO2018159628A1 JP 2019503031 A JP2019503031 A JP 2019503031A JP 2019503031 A JP2019503031 A JP 2019503031A JP WO2018159628 A1 JPWO2018159628 A1 JP WO2018159628A1
- Authority
- JP
- Japan
- Prior art keywords
- group
- hydrogen atom
- acylborane
- compound
- substituent
- 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
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 18
- 150000001413 amino acids Chemical class 0.000 title description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 30
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 28
- 125000006239 protecting group Chemical group 0.000 claims abstract description 27
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 24
- 125000003118 aryl group Chemical group 0.000 claims abstract description 19
- 125000001424 substituent group Chemical group 0.000 claims abstract description 19
- 229910052799 carbon Chemical group 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- -1 acyl borane Chemical compound 0.000 claims description 59
- 238000000034 method Methods 0.000 claims description 30
- 229910000085 borane Inorganic materials 0.000 claims description 13
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052796 boron Inorganic materials 0.000 claims description 10
- RWMJRMPOKXSHHI-UHFFFAOYSA-N ethenylboron Chemical compound [B]C=C RWMJRMPOKXSHHI-UHFFFAOYSA-N 0.000 claims description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 7
- 238000005949 ozonolysis reaction Methods 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 241001139947 Mida Species 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 150000003862 amino acid derivatives Chemical class 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
- 150000001875 compounds Chemical class 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- 239000000243 solution Substances 0.000 description 22
- 235000002597 Solanum melongena Nutrition 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 13
- 229940024606 amino acid Drugs 0.000 description 13
- 239000007789 gas Substances 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- XWSGEVNYFYKXCP-UHFFFAOYSA-N 2-[carboxymethyl(methyl)amino]acetic acid Chemical compound OC(=O)CN(C)CC(O)=O XWSGEVNYFYKXCP-UHFFFAOYSA-N 0.000 description 10
- 125000000524 functional group Chemical group 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- 125000003277 amino group Chemical group 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 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 description 5
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 0 BC([C@](COC(*)(*)*)N*)=O Chemical compound BC([C@](COC(*)(*)*)N*)=O 0.000 description 4
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 229940125758 compound 15 Drugs 0.000 description 4
- 229940126208 compound 22 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940125810 compound 20 Drugs 0.000 description 3
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- LSMWOQFDLBIYPM-UHFFFAOYSA-N 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-2h-imidazol-1-ium-2-ide Chemical compound CC1=CC(C)=CC(C)=C1N1[C-]=[N+](C=2C(=CC(C)=CC=2C)C)CC1 LSMWOQFDLBIYPM-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- FHNINJWBTRXEBC-UHFFFAOYSA-N Sudan III Chemical compound OC1=CC=C2C=CC=CC2=C1N=NC(C=C1)=CC=C1N=NC1=CC=CC=C1 FHNINJWBTRXEBC-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- IVHKZGYFKJRXBD-UHFFFAOYSA-N amino carbamate Chemical compound NOC(N)=O IVHKZGYFKJRXBD-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
- 238000005885 boration reaction Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229940099373 sudan iii Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 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 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 108010075254 C-Peptide Proteins 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- OOWVWFNGLWFJNE-UHFFFAOYSA-M [Cu]Cl.[C]1N(C2CCCCC2)C=CN1C1CCCCC1 Chemical compound [Cu]Cl.[C]1N(C2CCCCC2)C=CN1C1CCCCC1 OOWVWFNGLWFJNE-UHFFFAOYSA-M 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005107 alkyl diaryl silyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- BCJCJALHNXSXKE-UHFFFAOYSA-N azado Chemical compound C1C(C2)CC3CC1N([O])C2C3 BCJCJALHNXSXKE-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- WJKJXKRHMUXQSL-UHFFFAOYSA-N benzyl glycinate 4-methylbenzenesulfonate salt Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.NCC(=O)OCC1=CC=CC=C1 WJKJXKRHMUXQSL-UHFFFAOYSA-N 0.000 description 1
- QSNONXQMKXTNQH-UHFFFAOYSA-N benzyl n-(2-oxoethyl)carbamate Chemical compound O=CCNC(=O)OCC1=CC=CC=C1 QSNONXQMKXTNQH-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000005105 dialkylarylsilyl group Chemical group 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 150000002374 hemiaminals Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 125000005027 hydroxyaryl group Chemical group 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical compound NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- CPQCSJYYDADLCZ-UHFFFAOYSA-N n-methylhydroxylamine Chemical group CNO CPQCSJYYDADLCZ-UHFFFAOYSA-N 0.000 description 1
- NTNWKDHZTDQSST-UHFFFAOYSA-N naphthalene-1,2-diamine Chemical group C1=CC=CC2=C(N)C(N)=CC=C21 NTNWKDHZTDQSST-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- AMWSEGBTTPQUKW-ZETCQYMHSA-N tert-butyl n-[(2s)-but-3-yn-2-yl]carbamate Chemical compound C#C[C@H](C)NC(=O)OC(C)(C)C AMWSEGBTTPQUKW-ZETCQYMHSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000005106 triarylsilyl group Chemical group 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Potassium(3-((tert-butoxycarbonyl)amino)prop-1-en-2-yl)trifluoroborate (化合物2)の合成
収量 19.1 g、収率67%
tert-Butyl(2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)allyl)carbamate (化合物3)の合成
収量 16.9 g、収率84%
1H NMR (396 MHz, CD3CN, δ): 1.40 (s, 9H), 2.82 (s, 3H), 3.65 (dt, J = 1.8, 6.3 Hz, 2H), 3.83(d, J = 17.2 Hz, 2H), 3.97 (d, J = 16.8 Hz, 2H), 5.39 (s, 1H), 5.45 (brs, 1H),5.54 (s, 1H).
13C NMR (99 MHz, CD3CN, δ): 28.7 (CH3), 44.6 (CH2), 47.6 (CH3),62.7 (CH2), 79.3 (C), 123.1 (CH2), 145.2 (br, B-C), 157.0(C), 169.4 (C).
11B NMR (127 MHz, CD3CN, δ): 11.19 (s).
HRMS-ESI (m/z): [M+Na]+ calcd for C13H21O6N2 10BNa,334.14212; found: 334.14221.
tert-Butyl(2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)-2-oxoethyl) carbamate (化合物4)の合成
収量 820 mg、収率87%、純度90%
1H NMR (396 MHz, acetone-d6,δ): 1.40 (s, 9H), 3.09 (s, 3H), 4.14-4.18 (m, 4H), 4.38(d, J = 17.2 Hz, 2H), 5.89 (brs, 1H).
13C NMR (99 MHz, acetone-d6,δ): 28.9 (CH3), 47.8 (CH3), 55.5(CH2), 63.4 (CH2), 79.3 (C), 156.9 (C), 169.1 (C). The carbon directly attached to the boron atom was not detected, likely due to quadropolar relaxation.
11B NMR (127 MHz, acetone-d6,δ): 5.38 (s).
HRMS-ESI (m/z): [M+Na]+ calcd for C12H19O7N2 10BNa,336.12138; found: 336.12209.
Potassium ((tert-butoxycarbonyl)glycyl)trifluoroborate (化合物5)の合成
収量 470 mg、収率71%
tert-butyl(S)-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-yl)carbamate (化合物7)の合成
収量 675 mg、収率91%
1H NMR (401 MHz, CDCl3, δ): 1.22 (d, J = 6.4 Hz, 3H), 1.27 (s, 12H), 1.44 (s, 9H), 4.32 (brs,1H), 5.02 (brd, J = 7.2 Hz, 1H), 5.72 (s, 1H), 5.79 (s, 1H).
13C NMR (99 MHz, acetone-d6,δ): 22.9 (CH3), 29.0 (CH3), 47.6(CH3), 50.3 (CH), 62.7 (CH2), 63.0 (CH2), 79.0(C), 122.1 (CH2), 153.1 (br, B-C), 156.5 (C), 169.3 (C), 169.8 (C).
HRMS-EI (m/z): [M-CH3]+ calcd for C14H25O4N1 10B,281.19129; found: 281.19103.
tert-Butyl(2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)allyl)carbamate (化合物8)の合成
収量 398 mg、収率48%
1H NMR (401 MHz, CD3CN, δ): 1.16 (d, J = 6.8 Hz, 3H), 1.37 (s, 9H), 2.83 (s, 3H), 3.79 (d, J =17.2 Hz, 2H), 3.89-4.08 (m, 5H), 5.38 (d, J = 2.0 Hz, 1H), 5.60 (brs, 1H), 5.65(s, 1H).
13C NMR (100 MHz, CD3CN, δ): 45.0 (CH2),47.6 (CH3), 48.2 (CH), 62.7 (CH2), 66.9 (CH2),121.0 (CH), 123.3 (CH2), 126.2 (CH), 128.1 (CH), 128.7 (CH), 142.2 (C)145.2 (C) 157.4 (C) 169.4 (C). The carbon directly attached to the boron atom was not detected, likely due to quadropolar relaxation.
11B NMR (127 MHz, CD3CN, δ): 10.99 (s).
HRMS-ESI (m/z): [M+Na]+ calcd for C14H23O6N2 10BNa,348.15777; found: 348.15828.
tert-Butyl(S)-(1-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)-1-oxopropan-2-yl)carbamate(化合物9)の合成
収量 316 mg、収率 90%、純度 95%
1H NMR (396 MHz, CD3CN, δ): 1.22 (d, J = 6.4 Hz, 3H), 1.39 (s, 9H), 2.83 (s, 3H), 3.91 (dd, J= 6.1, 17.0 Hz, 3H), 4.04 (dd, J = 2.0, 17.0 Hz, 1H), 4.43 (quint, J = 77.2 Hz,1H), 5.54 (brs, 1H).
13C NMR (99 MHz, acetone-d6,δ): 15.6 (CH3), 28.9 (CH3), 47.9(CH3), 58.8 (CH), 63.4 (CH2), 63.4 (CH2), 79.4(C), 156.6 (C), 168.8 (C), 169.4 (C).
11B NMR (127 MHz, acetone-d6,δ): 5.50 (s).
HRMS-ESI (m/z): [M+Na]+ calcd for C13H21O7N2 10BNa,350.13703; found: 350.13671.
化合物10(アミノ酸型アシルボラン)を用いた化学ライゲーション
収量 36.9 mg、収率45%
化合物11(アミノ酸型アシルボラン)を用いたKATライゲーション
収率: 51%
(9H-Fluoren-9-yl)methyl [2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)allyl] carbamate (化合物13)の合成
得られた固体 (1.24 g)とFmoc-OSu (N-[(9H-Fluoren-9-ylmethoxy)carbonyloxy]succinimide) (1.68 g, 5.0 mmol)を100 mLの二径ナスフラスコに加えた後に、窒素雰囲気下でdioxane (33 mL) を加えて0℃に冷やした。DIPEA (N,N−ジイソプロピルエチルアミン) (1.74 mL, 10 mmol)を加え、反応液を室温まで昇温し20時間撹拌した。反応物をNH4Cl水溶液と酢酸エチルを用いて抽出、得られた有機溶媒をbrineで洗った後MgSO4で乾燥した。有機溶媒を濾過し、減圧下濃縮した後、シリカゲルカラムクロマトグラフィーにより化合物13を単離した。
収量 1.65 g、収率 76% (2 steps)
1H NMR (392 MHz, CD3CN, δ): 2.81 (s, 3H), 3.71 (d, J = 5.8 Hz, 2H), 3.81 (d, J = 17.0 Hz, 2H), 3.96 (d, J = 17.1 Hz, 2H), 4.23 (t, J = 6.7 Hz, 1H), 4.34 (d, J = 7.2 Hz, 2H), 5.38 (s, 1H), 5.51 (s, 1H), 5.85 (brs, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7.67 (d, J = 7.2 Hz, 2H) 7.84 (d, J = 7.6 Hz, 2H).
13C NMR (99 MHz, CD3CN, δ): 45.0 (CH2), 47.6 (CH3), 48.2 (CH), 62.7 (CH2), 66.9 (CH2), 121.0 (CH), 123.2 (CH2), 126.2 (CH), 128.1 (CH), 128.7 (CH), 142.2 (C), 145.3 (C), 157.4 (C), 169.4 (C). The carbon directly attached to the boron atom was not detected, likely due to quadropolar relaxation.
HRMS-ESI (m/z): [M+Na]+ calcd for C23H33O6N2 10BNa, 456.15777; found, 456.15848.
(9H-Fluoren-9-yl)methyl [2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)-2-oxoethyl] carbamate (化合物14)の合成
収量 85.1 mg、収率 65%
1H NMR (396 MHz, acetone-d6, δ): 3.10 (s, 3H), 4.17 (d, J = 17.2 Hz, 2H), 4.23-4.35 (m, 5H), 4.39 (d, J = 16.7 Hz, 2H), 6.51 (brt, J = 4.8 Hz, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7.74 (d, J = 7.7 Hz, 2H), 7.87 (d, J = 7.7 Hz, 2H).
13C NMR (99 MHz, acetone-d6, δ): 47.5 (CH3), 47.9 (CH), 55.4 (CH2), 63.1 (CH2), 67.2 (CH2), 120.8 (CH), 126.2 (CH), 128.0 (CH), 128.5 (CH), 142.1 (C), 145.1 (C), 157.3 (C), 168.9 (C). The carbon directly attached to the boron atom was not detected, likely due to quadropolar relaxation.
11B NMR (127 MHz, acetone-d6, δ): 5.35 (s).
HRMS-ESI (m/z): [M+Na]+ calcd for C22H21O7N2 10BNa, 458.13703; found, 458.13718.
Potassium ({[(9H-fluoren-9-yl)methoxy]carbonyl}glycyl)trifluoroborate (化合物15)の合成
収量 328.6 mg, 収率 85%
1H NMR (396 MHz, DMSO-d6, δ): 3.83 (d, J = 5.9 Hz, 3H), 4.12-4.21 (m, 2H), 6.80 (t, J = 5.4 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.73 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 7.7 Hz, 2H).
13C NMR (100 MHz, DMSO-d6, δ): 46.7 (CH), 52.5 (CH2), 65.6 (CH2), 120.1 (CH), 125.4 (CH), 127.1 (CH), 127.7 (CH), 140.7 (C), 144.0 (C), 156.2 (C).
11B NMR (127 MHz, DMSO-d6): -1.58 (s).
HRMS-ESI: [M-K]- calculated for C17H14O3N10BF3, 347.10606; found, 347.10653.
(9H-fluoren-9-yl)methyl(S)-(2-{[3-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)but- 3-en-2-yl]amino}-2-oxoethyl)carbamate (化合物16)の合成
得られた固体 (673.8 mg, 2.70 mmol)、Fmoc-Gly-OH (1.6055 g, 5.4 mmol)、EDC (1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド) (0.7764 g, 4.1 mmol)とHOBt (1-ヒドロキシベンゾトリアゾール)(0.6202 g, 4.6 mmol)を100 mLの二径ナスフラスコに加えた後に、窒素雰囲気下でDMF (21 mL)を加えて0℃に冷やした。DIPEA (0.56 mL, 3.2 mmol)を加え、反応液を室温まで昇温し17時間撹拌した。反応物をNH4Cl水溶液と酢酸エチルを用いて抽出、得られた有機溶媒をbrineで洗った後MgSO4で乾燥した。有機溶媒を濾過し、減圧下濃縮した後、シリカゲルカラムクロマトグラフィーにより化合物16を単離した。
収量 833.8 mg、収率 64% (2 steps)
1H NMR (392 MHz, CD3CN, δ): 1.20 (d, J = 6.7 Hz, 3H), 2.82 (s, 3H), 3.66 (d, J = 6.3 Hz, 2H), 3.79 (d, J = 17.0 Hz, 1H), 3.91 (s, 1H), 3.96 (d, J = 1.8 Hz, 2H), 4.23-4.36 (m, 4H), 5.37 (d, J = 1.8 Hz, 1H), 5.63 (s, 1H), 5.94 (brt, J = 5.6 Hz, 1H), 6.76 (brd, J = 6.7 Hz, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.67 (d, J = 7.2 Hz, 2H), 7.84 (d, J = 7.6 Hz, 2H).
13C NMR (99 MHz, CD3CN, δ): 22.2 (CH3), 44.8 (CH2), 47.7 (CH3), 47.9 (CH), 48.9 (CH), 62.5 (CH2), 62.8 (CH2), 67.3 (CH2), 121.0 (CH), 122.9 (CH2), 126.2 (CH), 128.1 (CH), 128.7 (CH), 142.1 (C), 145.1 (C), 157.6 (C), 169.3 (C), 169.4 (C), 169.7 (C).
11B NMR (127 MHz, CD3CN): 11.03 (s).
HRMS-ESI: [M+Na]+ calculated for C26H28O7N3 10BNa, 527.19488; found, 527.19522.
[α]D 24.0 +25.3 (c 1.0 in CH3CN, 99% ee).
The ee value was determined by HPLC analysis. Daicel CHIRALPAK(登録商標) OD-3, 2-PrOH/Hexane = 100/0, 0.5 mL/min, 40 ℃, (R)-isomer: tR = 49.65 min., (S)-isomer: tR = 44.72 min.
(9H-Fluoren-9-yl)methyl (S)-(2-{[1-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)-1-oxopropan-2-yl]a mino}-2-oxoethyl)carbamate (化合物17)の合成
収量 702.4 mg、収率 76% (純度95%)
1H NMR (396 MHz, DMSO-d6, δ): 1.15 (d, J = 7.2 Hz, 3H), 2.79 (s, 3H), 3.57-3.70 (m, 2H), 4.05 (dd, J = 4.9, 17.2 Hz, 2H), 4.20-4.40 (m, 5H), 4.61 (quint, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.53 (t, J = 6.1 Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.89 (d, J = 7.1 Hz, 2H), 8.02 (d, J = 6.3 Hz, 1H).
13C NMR (100 MHz, DMSO-d6, δ): 14.5 (CH3), 43.1 (CH2), 46.7 (CH), 47.0 (CH3), 56.1 (CH), 62.1 (CH2), 65.8 (CH2), 120.2 (CH), 125.3 (CH), 127.2 (CH), 127.7 (CH), 140.8 (C), 143.9 (C), 156.5 (C), 168.7 (C), 168.8 (C), 169.2 (C).
11B NMR (127 MHz, DMSO-d6, δ): 4.77 (s).
HRMS-ESI: [M+Na]+ calculated for C25H26O8N3 10BNa, 529.17415; found, 529.17476.
[α]D 23.9 +28.3 (c 1.0 in CH3CN).
Potassium ({[(9H-fluoren-9-yl)methoxy]carbonyl}glycyl-L-alanyl)trifluoroborate (化合物18)の合成
収量 346.5 mg、収率 64%
1H NMR (396 MHz, acetone-d6, δ): 1.23 (d, J = 7.1 Hz, 3H), 3.82-3.88 (m, 2H), 4.23-4.34 (m, 3H), 4.59 (quint, J = 6.8 Hz, 1H), 6.89 (brt, J = 4.8 Hz, 1H), 7.31-7.35 (m, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.74 (d, J = 7.1 Hz, 2H), 7.86 (d, J = 7.1 Hz, 2H).
13C NMR (99 MHz, CD3CN, δ): 16.3 (CH3), 44.8 (CH2), 47.8 (CH), 56.5 (CH), 67.4 (CH2), 120.9 (CH), 126.1 (CH), 128.0 (CH), 128.6 (CH), 142.0 (C), 144.97 (C), 145.00 (C), 157.6 (C), 169.4 (C).
11B NMR (127 MHz, acetone-d6): 0.00 (s).
HRMS-ESI: [M-K]- calculated for C20H19O4N2 10BF3, 418.14318; found, 418.14391.
[α]D 24.5 +17.5 (c 1.0 in MeOH).
化合物15を用いた化学ライゲーションによるジペプチド(化合物19)の合成
収量 67.2 mg、収率 50%
1H NMR (392 MHz, CDCl3, δ): 3.93 (d, J = 5.0 Hz, 2H), 4.10 (d, J = 5.0 Hz, 2H), 4.23 (t, J = 6.8 Hz, 1H), 4.45 (d, J = 6.8 Hz, 2H), 5.19 (s, 2H), 5.38 (brs, 1H), 6.41 (brs, 1H), 7.26-7.42 (m, 9H), 7.59 (d, J = 7.2 Hz, 2H), 7.76 (d, J = 7.3 Hz, 2H).
13C NMR (100 MHz, CDCl3, δ): 41.2 (CH2), 44.2 (CH2), 47.0 (CH), 67.1 (CH2), 67.2 (CH2), 119.9 (CH), 125.0 (CH), 127.0 (CH), 127.7 (CH), 128.3 (CH), 128.5 (CH), 128.6 (CH), 134.9 (C), 141.2 (C), 143.6 (C), 156.6 (C), 169.4 (C), 169.6 (C).
HRMS-ESI: [M+Na]+ calculated for C26H24O5N2Na, 467.15774; found, 467.15823.
化合物18を用いた化学ライゲーションによるテトラペプチド(化合物20)の合成
収量 111.6 mg、収率 61% (containing small amount of chlorinated product)
1H NMR (392 MHz, CDCl3, δ): 1.41 (d, J = 6.7 Hz, 3H), 1.98-2.23 (m, 4H), 3.44-3.67 (m, 2H), 3.92 (s, 2H), 4.05 (s, 2H), 4.23 (t, J = 7.2 Hz, 1H), 4.41 (d, J = 7.2 Hz, 2H), 4.56-4.61 (m, 2H), 5.13 (d, J = 12.1 Hz, 1H), 5.18 (d, J = 12.5 Hz, 1H), 5.63 (brs, 1H), 6.73 (brs, 1H), 6.94 (brs, 1H), 7.29-7.42 (m, 9H), 7.60 (d, J = 7.2 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H).
13C NMR (99 MHz, CDCl3, δ): 18.5 (CH3), 24.4 (CH2), 28.8 (CH2), 41.8 (CH2), 44.1 (CH2), 45.9 (CH2), 46.9 (CH), 48.7 (CH), 58.9 (CH), 66.8 (CH2), 67.0 (CH2), 119.7 (CH), 125.1 (CH), 126.9 (CH), 127.5 (CH), 127.9 (CH), 128.2 (CH), 128.4 (CH), 135.3 (C), 141.0 (C), 143.7 (C), 156.6 (C), 166.9 (C), 169.1 (C), 171.5 (C), 172.5 (C).
HRMS-ESI: [M+Na]+ calculated for C34H36O7N4Na, 635.24762; found, 635.24799.
[α]D 24.0 -45.0 (c 1.0 in CH3CN).
化合物20の不純物からの精製は逆相HPLCを用いて以下の条件で行った。Simadzu Prominence HPLC with PDA detector; Mighysil RP-18 GP Aqua column (250 mm L × 4.6 mm ID, 5 μm, Kanto Chemical Co., Inc.); flow rate, 1 mL min-1; temperature, 30℃; mobile phase A, water + 0.05% TFA, mobile phase B, acetonitrile + 0.05% TFA; gradient conditions, 40% B, 0-30 min; 40%-100% B, 30-40 min; 100% B, 40-50 min; detection, 254 nm; injection volume, 25 μL (1mg/mL in acetonitrile/H2O (1:1), 5 cycles).
Daiel CHIRALPAK(登録商標) IC-3, MeOH/CHCl3 = 100/0, 0.5 mL/min, 40 ℃, (L,L)-isomer: tR = 8.59 min., (D,L)-isomer: tR = 12.13 min.
α-アミノアルデヒド (化合物21)のホウ素化によるα-ヒドロキシトリフルオロボレート (化合物22)の合成
収量 279.6 mg, 収率 52%
1H NMR (396 MHz, CD3CN, δ): 1.88 (brd, J = 4.1 Hz, 1H), 2.80-2.82 (m, 1H), 2.99-3.05 (m, 1H), 3.15-3.21 (m, 1H), 5.03 (s, 2H), 5.50 (brs, 1H), 7.29-7.43 (m, 5H).
11B NMR (127 MHz, CD3CN, δ): 3.14 (brs).
α-ヒドロキシトリフルオロボレート (化合物22) の酸化によるアミノ酸型アシルボロン(化合物23)の合成
収量 95.7 mg, 収率 64%
1H NMR (396 MHz, CD3CN, δ): 3.97-4.21 (m, 2H), 5.72 (brs, 1H), 7.29-7.37 (m, 5H).
11B NMR (127 MHz, CD3CN, δ): -1.03 (q, J = 49 Hz).
Claims (6)
- 下記一般式(1)で表されるアシルボラン。
- R1が保護基であり、R2が水素原子であり、R3が水素原子又は置換基を有していてもよいアルキル基であり、R4が−B(MIDA)基又は−BF3K基である、請求項1に記載のアシルボラン。
- R1が保護基であり、R2が水素原子であり、R3が水素原子又は置換基を有していてもよいアルキル基であり、R5およびR6が水素原子である、請求項3に記載の製造方法。
- R1が保護基であり、R2が水素原子であり、R3が水素原子又は置換基を有していてもよいアルキル基である、請求項5に記載の製造方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017037087 | 2017-02-28 | ||
JP2017037087 | 2017-02-28 | ||
PCT/JP2018/007313 WO2018159628A1 (ja) | 2017-02-28 | 2018-02-27 | アミノ酸型アシルボランおよびその製造方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2018159628A1 true JPWO2018159628A1 (ja) | 2019-12-26 |
JP7244921B2 JP7244921B2 (ja) | 2023-03-23 |
Family
ID=63370930
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019503031A Active JP7244921B2 (ja) | 2017-02-28 | 2018-02-27 | アミノ酸型アシルボランおよびその製造方法 |
Country Status (2)
Country | Link |
---|---|
JP (1) | JP7244921B2 (ja) |
WO (1) | WO2018159628A1 (ja) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003033506A1 (fr) * | 2001-10-12 | 2003-04-24 | Kyorin Pharmaceutical Co., Ltd. | Derive d'acide d'aminoborane et medicament inhibiteur de proteasomes le contenant |
CN103387601A (zh) * | 2012-05-11 | 2013-11-13 | 南开大学 | 抗登革热病毒(denv)杂环肽类化合物及其制备方法和用途 |
CN103421083A (zh) * | 2012-05-16 | 2013-12-04 | 南开大学 | 具有1,2,3-三氮唑结构的抗登革热病毒杂环肽类化合物及其制备方法和用途 |
-
2018
- 2018-02-27 JP JP2019503031A patent/JP7244921B2/ja active Active
- 2018-02-27 WO PCT/JP2018/007313 patent/WO2018159628A1/ja active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003033506A1 (fr) * | 2001-10-12 | 2003-04-24 | Kyorin Pharmaceutical Co., Ltd. | Derive d'acide d'aminoborane et medicament inhibiteur de proteasomes le contenant |
CN103387601A (zh) * | 2012-05-11 | 2013-11-13 | 南开大学 | 抗登革热病毒(denv)杂环肽类化合物及其制备方法和用途 |
CN103421083A (zh) * | 2012-05-16 | 2013-12-04 | 南开大学 | 具有1,2,3-三氮唑结构的抗登革热病毒杂环肽类化合物及其制备方法和用途 |
Non-Patent Citations (9)
Title |
---|
"CAS REGISTRY No.1052719-31-9", DATABASE REGISTRY, [ONLINE], JPN7022004816, 25 September 2008 (2008-09-25), ISSN: 0004897858 * |
"CAS REGISTRY No.1060709-30-9", DATABASE REGISTRY, [ONLINE], JPN7022004817, 13 October 2008 (2008-10-13), ISSN: 0004897857 * |
"CAS REGISTRY No.1061578-46-8", DATABASE REGISTRY, [ONLINE], JPN7022004815, 15 October 2008 (2008-10-15), ISSN: 0004897856 * |
"CAS REGISTRY No.1061608-85-2", DATABASE REGISTRY, [ONLINE], JPN7022004814, 15 October 2008 (2008-10-15), ISSN: 0004897855 * |
"CAS REGISTRY No.1061623-30-0", DATABASE REGISTRY, [ONLINE], JPN7022004813, 15 October 2008 (2008-10-15), ISSN: 0004897854 * |
MAZUNIN, DMITRY. ET AL.: "Potassium Acyltrifluoroborate(KAT) Ligations are Orthogonal to Thiol-Michael and SPAAC Reactions: Co", HELVETICA CHIMICA ACTA, vol. 100, no. 2, JPN6018017919, 16 December 2016 (2016-12-16), ISSN: 0004897861 * |
MURAR, CLAUDIA E. ET AL.: "KAHA Ligations That Form Aspartyl Aldehyde Residues as Synthetic Handles for Protein Modification an", J. AM. CHEM. SOC., vol. 136, no. 52, JPN6018017917, 2014, pages 18140 - 18148, XP055543138, ISSN: 0004897860, DOI: 10.1021/ja511231f * |
TAGUCHI, JUMPEI. ET AL.: "Synthesis of Acylborons by Ozonolysis of Alkenylboronates: Preparation of an Enantioenriched Amino A", ANGEWANDTE CHEMIE, INTERNATIONAL EDITION, vol. 56, no. 44, JPN6018017921, 14 September 2017 (2017-09-14), pages 13847 - 13851, XP072097149, ISSN: 0004897862, DOI: 10.1002/anie.201707933 * |
TSENG,CLAIRE C. ET AL.: "Characterization of the Surfactin Synthetase C-Terminal Thioesterase Domain as a Cyclic Depsipeptide", BIOCHEMISTRY, vol. 41, no. 45, JPN6018010730, 2002, pages 13350 - 13359, XP002304806, ISSN: 0004897859, DOI: 10.1021/bi026592a * |
Also Published As
Publication number | Publication date |
---|---|
WO2018159628A1 (ja) | 2018-09-07 |
JP7244921B2 (ja) | 2023-03-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6193960B2 (ja) | ボロン酸エステルおよびボロン酸化合物の合成 | |
KR102122575B1 (ko) | 아마톡신 빌딩 블록 및 아마톡신류의 합성 방법 | |
CN1073946A (zh) | 制备脯氨酸硼酸酯的方法 | |
JP2015518821A (ja) | リシン−グルタミン酸ジペプチド誘導体 | |
JP7242924B2 (ja) | 銅およびニッケル触媒による脱炭酸ホウ素化反応 | |
Hanessian et al. | Novel access to (3 R)-and (3 S)-3-hydroxy-L-aspartic acids,(4 S)-4-hydroxy-L-glutamic acid, and related amino acids | |
JP2023052381A (ja) | 液相ペプチド合成のための方法およびその保護戦略 | |
CN114096554A (zh) | 肽及其制造方法 | |
Alcón et al. | Enantioselective synthesis of unsaturated amino acids using p-methoxybenzylamine as an ammonia equivalent | |
JPH0832716B2 (ja) | アミノ酸からペプチドを合成する方法 | |
CN112585116B (zh) | (2s,3r,4r)-4,5-二羟基异亮氨酸及衍生物的合成 | |
JP7244921B2 (ja) | アミノ酸型アシルボランおよびその製造方法 | |
CN109232712B (zh) | 一种用于抗体药物偶联物的中间体的制备方法 | |
Chiarello et al. | Routes to the Tripeptide Unit of Geodiamoude-A | |
EP0444068A1 (en) | Trialkysilyl esters of amino acids and their use in the synthesis of peptides | |
An et al. | Solution-phase-peptide synthesis without purification of column chromatography and recrystallization by protecting amino acid esters with phosphinyl chloride | |
WO2020162393A1 (ja) | ペプチド化合物の製造方法 | |
JP2002532466A (ja) | α−ヒドロキシ−β−アミノ酸およびアミド誘導体の合成のための方法 | |
Reginato et al. | A stereoselective approach to the synthesis of γ-silylated amino acids | |
AU2016202747B2 (en) | Synthesis of boronic ester and acid compounds | |
Olma et al. | An efficient synthesis of optically active 3-amino-3-alkyl-2-oxetanones | |
JP5097104B2 (ja) | 新規イソジペプチド | |
CN113166057A (zh) | (s)-6-羟基色氨酸及其衍生物的合成 | |
Goodman et al. | The stereocontrolled synthesis of orthogonally protected (R)-α-methyltryptophan | |
JP6579390B2 (ja) | ペプチドの製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190709 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210216 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220405 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220603 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20221018 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221213 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230214 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230303 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7244921 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |