JPWO2015033781A1 - 二置換アミノ酸残基を含むジペプチド誘導体の製造方法 - Google Patents
二置換アミノ酸残基を含むジペプチド誘導体の製造方法 Download PDFInfo
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- 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
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Abstract
Description
[式(1)において、Xはアミノ基の保護基を表し、R1は、α−一置換アミノ酸の側鎖、又は水素原子を表し、該側鎖は保護されていてもよく、
R2は、R1と結合して前記側鎖を形成する基、又は水素原子を表し、
Ra2及びRb2は、それぞれ独立に、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基又は置換基を有していてもよいアラルキル基を表す。]
下記式(2)で示されるN−末端が保護されたα−一置換アミノ酸若しくはグリシン又はそれらの塩と、
[式(2)において、X、R1及びR2は式(1)におけるX、R1及びR2と同様に定義される。]
下記式(3)で示される二置換アミノ酸又はその塩とを、
[式(3)において、Ra2及びRb2は式(1)におけるRa2及びRb2と同様に定義される。]
縮合剤の存在下で縮合させることを含む、製造方法を提供する。
[式(1)において、Xはアミノ基の保護基を表し、R1は、α−一置換アミノ酸の側鎖、又は水素原子を表し、該側鎖は保護されていてもよく、
R2は、R1と結合して前記側鎖を形成する基、又は水素原子を表し、
Ra2及びRb2は、それぞれ独立に、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基又は置換基を有していてもよいアラルキル基を表す。]
下記式(2)で示されるN−末端が保護されたα−一置換アミノ酸若しくはグリシン又はそれらの塩と、
[式(2)において、X、R1及びR2は式(1)におけるX、R1及びR2と同様に定義される。]
下記式(3)で示される二置換アミノ酸又はその塩とを、
[式(3)において、Ra2及びRb2は式(1)におけるRa2及びRb2と同様に定義される。]
縮合剤の存在下で縮合させることを含む。
Fmoc−Gly−OH
Fmoc−Thr(Ot−Bu)−OH
Fmoc−D−Phe−OH
Fmoc−D−Hcy(Tr)−OH
Fmoc−Hcy(Tr)−OH
Fmoc−Arg(Pbf)−OH
Fmoc−Leu−OH
Fmoc−Phe−OH
Ac−(Allyl)Gly−OH
Boc−(Allyl)Gly−OH・DCHA
(S)−α−(4−Pentenyl)Ala−OH
(R)−α−(4−Pentenyl)Ala−OH
(S)−α−(7−Octenyl)Ala−OH
(R)−α−(7−Octenyl)Ala−OH
(S)−α−(Allyl)Ala−OH・H2O
(R)−α−(Allyl)Ala−OH・H2O
(S)−α−(Propargyl)Ala−OH
(R)−α−(Propargyl)Ala−OH
(S)−α−(Ethyl)Ala−OH・H2O
(R)−α−(Ethyl)Ala−OH・H2O
(S)−α−Me−Asp(Ot−Bu)−OH
(R)−α−Me−Asp(Ot−Bu)−OH
(S)−α−Me−Leu−OH
(R)−α−Me−Leu−OH
(S)−α−Me−Phe−OH・H2O
(R)−α−Me−Phe−OH・H2O
(S)−α−Me−Val−OH
(R)−α−Me−Val−OH
(S)−α−Me−o−fluoroPhe−OH
(R)−α−Me−o−fluoroPhe−OH
(S)−α−Me−m−fluoroPhe−OH
(R)−α−Me−m−fluoroPhe−OH
(S)−α−Me−p−fluoroPhe−OH
(R)−α−Me−p−fluoroPhe−OH
(S)−α−Me−2,6−difluoroPhe−OH
(R)−α−Me−2,6−difluoroPhe−OH
(S)−α−Me−p−CF3O−Phe−OH
(R)−α−Me−p−CF3O−Phe−OH
(S)−α−Me−o−bromoPhe−OH・H2O
(R)−α−Me−o−bromoPhe−OH・H2O
(S)−α−Me−m−bromoPhe−OH・H2O
(R)−α−Me−m−bromoPhe−OH・H2O
(S)−α−Me−p−bromoPhe−OH
(R)−α−Me−p−bromoPhe−OH
(S)−α−Me−m−iodoPhe−OH・H2O
(R)−α−Me−m−iodoPhe−OH・H2O
(S)−α−Me−p−iodoPhe−OH
(R)−α−Me−p−iodoPhe−OH
(S)−α−Me−o−nitroPhe−OH・H2O
(R)−α−Me−o−nitroPhe−OH・H2O
(S)−α−Me−m−nitroPhe−OH・H2O
(R)−α−Me−m−nitroPhe−OH・H2O
(S)−α−Me−p−phenylPhe−OH・H2O
Fmoc:9−フルオレニルメトキシカルボニル;
THF:テトラヒドロフラン;
HBTU:ヘキサフルオロリン酸2−(1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウム;
TEA:トリエチルアミン;
MTBE:メチルt−ブチルエーテル;
Hcy:ホモシステイン;
Tr:トリチル;
NMP:N−メチルピペリドン;
HOBt:1−ヒドロキシベンゾトリアゾール;
DIPEA:ジイソプロピルエチルアミン;
TFA:トリフルオロ酢酸;
Pbf:2,2,4,6,7−ペンタメチル−2,2−ジメチルベンゾフラン−5−スルホニル。
Fmoc−Gly−OH、
Fmoc−Gly−(R)−α−(4−Pentenyl)Ala−OH(ジペプチド)、
Fmoc−Gly−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−OH(トリペプチド)、
Fmoc−Gly−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−OH(テトラペプチド)、
Fmoc−Gly−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−OH(ペンタペプチド)、
のそれぞれに相当するピークの面積比は、4.5時間では31:68:1.5:0.065:未検出(反応率69%)、5.5時間では30:68:2.0:0.091:未検出(反応率70%)、7.9時間では27:70:3.2:0.17:未検出(反応率73%)、23時間では24:68:7.6:0.45:0.047(反応率76%)であった。反応率は、Fmoc−Gly−OH、ジペプチド、トリペプチド、テトラペプチド及びペンタペプチドの合計面積に対するFmoc−Gly−OHの面積の割合から計算した。
Fmoc−Gly−(R)−α−(4−Pentenyl)Ala−OH;
融点:130〜133℃(未校正)。
1HNMR(400MHz、CDCl3)δppm:1.2〜1.4(m、2H);1.60(s、3H);1.86(dt、J1=12.8Hz、J2=4.7Hz、1H);1.9〜2.1(m、2H);2.16(dt、J1=12.8Hz、J2=3.6Hz、1H);3.8〜4.0(m、2H);4.21(t、J=7.2Hz、1H);4.39(d、J=7.2Hz、2H);4.9〜5.0(m、2H);5.70(dt、J1=12.0Hz、J2=10.0Hz、1H);5.78(br.s、1H);6.87(br.s、1H);7.30(dt、J1=7.5Hz、J2=0.9Hz、2H);7.39(t、J=7.5Hz、2H);7.58(d、J=7.5Hz、2H);7.75(d、J=7.5Hz、2H)。
HRMSm/z:437.2071(C25H29N2O5([M+H]+)に対する計算値);437.2078(実測値)。
Fmoc−Gly−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−OH;
HRMSm/z:576.3068(C33H42N3O6([M+H]+)に対する計算値);576.3072(実測値)。
Fmoc−Gly−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−OH;
HRMSm/z:715.4065(C41H55N4O7([M+H]+)に対する計算値);715.4063(実測値)。
Fmoc−Gly−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−(R)−α−(4−Pentenyl)Ala−OH;
HRMSm/z:854.5062(C49H67N5O8([M+H]+)に対する計算値);854.5061(実測値)。
融点:61〜81℃(未校正)。
HRMSm/z:577.2078(C33H37FN2O6([M+H]+)に対する計算値);577.2710(実測値)。
Fmoc−Thr(Ot−Bu)−OH、
Fmoc−Thr(Ot−Bu)−α−Me−o−FluoroPhe−OH(ジペプチド)、
Fmoc−Thr(Ot−Bu)−α−Me−o−fluoroPhe−α−Me−o−fluoroPhe−OH(トリペプチド)
のそれぞれに相当するピークの面積比は、22時間では23:76:1.7(反応率77%)、31時間では20:78:1.9(反応率80%)であった。反応率は、Fmoc−Thr(Ot−Bu)−OH、ジペプチド、トリペプチド、テトラペプチド及びペンタペプチドの合計面積に対するFmoc−Thr(Ot−Bu)−OHの面積の割合から計算した。ただし、テトラペプチド及びペンタペプチドのピークは未検出であった。
HRMSm/z:756.3455(C43H48F2N3O7([M+H]+)に対する計算値);756.3455(実測値)。
Fmoc−D−Hcy(Tr)−(S)−α−Me−o−fluoroPhe−OHの合成
25mLの反応容器に、0.28g(0.45mmol)のFmoc−D−Hcy(Tr)−OHと、0.11g(0.56mmol)の(S)−α−Me−o−fluoroPhe−OHとを仕込み、THF(2mL)に懸濁させた。この懸濁液に、0.52g(1.4mmol)のHBTUと、0.20mL(1.4mmol)のTEAを加え、室温下で5.8時間撹拌を行った。上水(2.5mL)と、酢酸エチル(3.5mL)を加え、室温下で撹拌後、静置し分液した。有機層を飽和重層水(4mL)、0.5mol/Lの塩酸(2mL)、上水(6mL)の順で洗浄後、減圧下で濃縮した。残渣に酢酸エチル(1.9mL)を加え、分散、静置後、吸引ろ過をした。白色粉末を乾燥させ、0.21gのFmoc−D−Hcy(Tr)−(S)−α−Me−o−fluoroPhe−OHを得た(収率59%)。
1HNMR(400MHz、CDCl3)δppm:1.3〜1.6(m、1H);1.46(s、3H);1.6〜1.8(m、1H);2.1〜2.3(m、2H);3.23(d、J=14.0Hz、1H);3.32(d、J=14.0Hz、1H);4.0〜4.2(m、2H);4.17(t、J=6.6Hz、1H);4.34(d、J=6.6Hz、2H);5.29(d、J=8.0Hz、1H);6.49(s、1H);6.9〜7.0(m、2H);7.07(t、J=7.0Hz、1H);7.1〜7.5(m、20H);7.57(d、J=7.0Hz、2H);7.74(d、J=7.0Hz、2H)。
Fmoc−Hcy(Tr)−(S)−α−Me−o−fluoroPhe−OHの合成
25mLの反応容器に、0.23g(0.42mmol)のFmoc−Hcy(Tr)−OHと、0.11g(0.51mmol)の(S)−α−Me−o−fluoroPhe−OH・H2Oとを仕込み、THF(2mL)に懸濁させた。この懸濁液に、0.52g(1.4mmol)のHBTUと、0.20mL(1.4mmol)のTEAを加え、室温下で3.2時間撹拌を行った。上水(2.5mL)と、酢酸エチル(4.3mL)を加え、室温下で撹拌後、静置し分液した。有機層を飽和重層水(4mL)、0.5mol/Lの塩酸(2mL)、上水(6mL)の順で洗浄後、減圧下で濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、0.11gのFmoc−Hcy(Tr)−(S)−α−Me−o−fluoroPhe−OHを無色油状物質として得た(収率32%)。
1HNMR(400MHz、CDCl3)δppm:1.48(s、3H);1.5〜1.7(m、1H);1.7〜1.9(m、1H);2.1〜2.4(m、2H);3.28(s、2H);4.0〜4.1(m、1H);4.1〜4.2(m、1H);4.2〜4.3(m、1H);4.3〜4.4(m、1H);5.25(br.s、1H);6.56(br.s、1H);6.9〜7.0(m、2H);7.06(t、J=6.8Hz、1H);7.1〜7.5(m、20H);7.54(d、J=7.0Hz、2H);7.73(d、J=7.0Hz、2H)。
1HNMR(400MHz、CDCl3)δppm:0.9〜1.0(m、1H);1.0〜1.2(m、1H);1.70(t、J=13.3Hz、1H);1.96(dd、J1=13.3Hz、J2=7.0Hz、2H);2.09(t、J=11.0Hz、1H);2.9〜3.1(m、1H);3.0〜3.2(m、1H);4.18(t、J=6.8Hz、1H);4.2〜4.4(m、2H);4.56(br.s、1H);4.8〜5.0(m、2H);5.63(d、J=8.0Hz、1H);5.6〜5.8(m、1H);6.54(br.s、1H);7.2〜7.3(m、5H);7.30(t、J=7.5Hz、2H);7.39(t、J=7.5Hz、2H);7.54(dd、J1=7.5Hz、J2=2.2Hz、2H);7.76(d、J=7.5Hz、2H)。
融点:129〜132℃(未校正)。
融点:102〜147℃(未校正)。
1HNMR(400MHz、CDCl3)δppm:1.35(br.s、2H);1.42(s、6H);1.51(s、3H);1.6〜1.7(m、2H);1.7〜1.8(m、1H);1.8〜1.9(m、3H);1.9〜2.1(m、2H);2.06(s、3H);2.49(s、3H);2.56(s、3H);2.90(s、2H);3.1〜3.3(m、2H);4.0〜4.2(m、1H);4.2〜4.3(m、3H);4.8〜5.0(m、2H);5.69(dt、J1=16.8Hz、J2=6.5Hz、1H);6.42、6.70(br.s、3H);7.20(t、J=7.6Hz、2H);7.43(t、J=7.6Hz、2H);7.55(d、J=7.6Hz、2H);7.71(d、J=7.6Hz、2H)。
1HNMR(400MHz、CDCl3)δppm:0.8〜1.0(m、6H);1.1〜1.3(m、1H);1.2〜1.4(m、1H);1.5〜1.7(m、3H);1.62(s、3H);1.84(dt、J1=12.8Hz、J2=4.0Hz、1H);1.97(dd、J1=12.8Hz、J2=6.4Hz、2H);2.30(dt、J1=12.8Hz、J2=4.0Hz、1H);4.19(t、J=7.0Hz、2H);4.3〜4.5(m、2H);4.48(br.s、1H);4.8〜5.0(m、2H);5.5〜5.7(m、2H);7.21(br.s、1H);7.30(dt、J1=7.4Hz、J2=0.6Hz、2H);7.39(t、J=7.4Hz、2H);7.57(dd、J1=7.4Hz、J2=2.8Hz、2H);7.75(d、J=7.5Hz、2H)。
1HNMR(400MHz、CDCl3)δppm:0.94(br.s、6H);1.2〜1.3(m、1H);1.3〜1.4(m、1H);1.5〜1.7(m、3H);1.62(s、3H);1.82(dt、J1=13.1Hz、J2=4.4Hz、1H);2.0〜2.1(m、2H);2.2〜2.4(m、1H);4.20(t、J=7.1Hz、1H);4.3〜4.4(m、1H);4.42(dd、J1=10.0Hz、J2=7.1Hz、1H);4.55(br.s、1H);4.9〜5.0(m、2H);5.5〜5.6(m、1H);5.72(dt、J1=17.0Hz、J2=6.8Hz、1H);7.21(br.s、1H);7.30(t、J=7.5Hz、2H);7.39(t、J=7.5Hz、2H);7.57(d、J=7.5Hz、2H);7.76(d、J=7.5Hz、2H)。
1HNMR(400MHz、CDCl3)δppm:1.0〜1.1(m、2H);1.21(br.s、4H);1.32(br.s、2H);1.53(s、3H);1.6〜1.8(m、1H);1.9〜2.0(m、2H);2.0〜2.1(m、1H);3.0〜3.1(m、2H);4.15(t、J=7.2Hz、1H);4.2〜4.3(m、1H);4.35(dd、J1=10.2Hz、J2=7.2Hz、1H);4.71(br.s、1H);4.8〜5.0(m、2H);5.7〜5.9(m、2H);6.85(br.s、1H);7.2〜7.3(m、5H);7.28(t、J=7.5Hz、2H);7.39(t、J=7.5Hz、2H);7.5〜7.6(m、2H);7.75(d、J=7.5Hz、2H)。
Fmoc−Thr(Ot−Bu)−OH、
Fmoc−Thr(Ot−Bu)−o−fluoroPhe−OH(ジペプチド)、
Fmoc−Thr(Ot−Bu)−o−fluoroPhe−o−fluoroPhe−OH(トリペプチド)、
Fmoc−Thr(Ot−Bu)−o−fluoroPhe−o−fluoroPhe−o−fluoroPhe−OH(テトラペプチド)、
のそれぞれに相当するピークの面積比は、1.8時間では72:11:12:5.7(反応率29%)、3時間では72:9.9:13:5.3(反応率28%)、4.1時間では71:9.5:12:7.2(反応率29%)であった。反応率は、Fmoc−Thr(Ot−Bu)−OH、ジペプチド、トリペプチド、テトラペプチド及びペンタペプチドの合計面積に対するFmoc−Gly−OHの面積の割合から計算した(ペンタペプチドは未検出)。
Fmoc−Thr(Ot−Bu)−o−fluoroPhe−OH;
HRMSm/z:585.2371(C32H35FN2NaO6([M+Na]+)に対する計算値);585.2371(実測値)。
Fmoc−Thr(Ot−Bu)−o−fluoroPhe−o−fluoroPhe−OH;
HRMSm/z:728.3142(C41H44F2N3O7([M+H]+)に対する計算値);728.3138(実測値)。
Fmoc−Thr(Ot−Bu)−o−fluoroPhe−o−fluoroPhe−o−fluoroPhe−OH;
HRMSm/z:893.3732(C50H52F3N4O8([M+H]+)に対する計算値);893.3729(実測値)。
H−Leu−Arg−(S)−α−(4−Pentenyl)Ala−Phe−NH2;
HRMSm/z:573.3871(C29H49N8O4([M+H]+)に対する計算値);573.3876(実測値)。
H−Leu−(S)−α−(4−Pentenyl)Ala−Phe−NH2;
HRMSm/z:417.2860(C23H37N4O3([M+H]+)に対する計算値);417.2860(実測値)。
MSデータ
HEMSm/z:573.3871(C29H49N8O4([M+H]+)に対する計算値);573.3874(実測値)。
H−Leu−D−Hcy−(S)−α−Me−o−fluoroPhe−Phe−NH2の合成
参考例1と同様の方法で、H−Leu−D−Hcy−(S)−α−Me−o−fluoroPhe−Phe−NH2を合成した。生成物中には目的物の他に、目的物に対し1.0%のH−Leu−(S)−α−Me−o−fluoroPhe−Phe−NH2及び1.2%のH−(S)−α−Me−o−fluoroPhe−Phe−NH2が混入した。
H−Leu−D−Hcy−(S)−α−Me−o−fluoroPhe−Phe−NH2;
HRMSm/z:574.2858(C29H41FN5O4S([M+H]+)に対する計算値);574.2856(実測値)。
H−Leu−(S)−α−Me−o−fluoroPhe−Phe−NH2;
HRMSm/z:457.2609(C25H34FN4O3([M+H]+)に対する計算値);457.2611(実測値)。
H−(S)−α−Me−o−fluoroPhe−Phe−NH2;
HRMSm/z:344.1769(C19H23FN3O2([M+H]+)に対する計算値);344.1761(実測値)。
H−Leu−D−Hcy−(S)−α−Me−o−fluoroPhe−Phe−NH2の合成
Fmoc−D−Hcy(Tr)−OH、(S)−Fmoc−α−Me−o−fluoroPhe−OHの代わりに実施例4で調製したFmoc−D−Hcy(Tr)−(S)−α−Me−o−fluoroPhe−OHを用いて、参考例3と同様の方法でH−Leu−D−Hcy−(S)−α−Me−o−fluoroPhe−Phe−NH2を合成した。目的物中に、H−Leu−(S)−α−Me−o−fluoroPhe−Phe−NH2及びH−(S)−α−Me−o−fluoroPhe−Phe−NH2の混入はなかった。
HRMSm/z:574.2858(C29H41FN5O4S([M+H]+)に対する計算値);574.2862(実測値)。
H−Leu−Leu−(S)−α−(4−Pentenyl)Ala−Phe−NH2;
HRMSm/z:530.3701(C29H48N5O4([M+H]+)に対する計算値);530.3702(実測値)。
H−Leu−(S)−α−(4−Pentenyl)Ala−Phe−NH2;
HRMSm/z:417.2860(C23H36N4O3([M+H]+)に対する計算値);417.2856(実測値)。
HRMSm/z:530.3701(C29H48N5O4([M+H]+)に対する計算値);530.3708(実測値)。
Claims (3)
- 下記式(1)で示されるN−末端が保護されたジペプチド又はその塩の製造方法であって、
[式(1)において、Xはアミノ基の保護基を表し、
R1は、α−一置換アミノ酸の側鎖、又は水素原子を表し、該側鎖は保護されていてもよく、
R2は、R1と結合して前記側鎖を形成する基、又は水素原子を表し、
Ra2及びRb2は、それぞれ独立に、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基又は置換基を有していてもよいアラルキル基を表す。]
下記式(2)で示されるN−末端が保護されたα−一置換アミノ酸若しくはグリシン又はそれらの塩と、
[式(2)において、X、R1及びR2は式(1)におけるX、R1及びR2と同様に定義される。]
下記式(3)で示される二置換アミノ酸又はその塩とを、
[式(3)において、Ra2及びRb2は式(1)におけるRa2及びRb2と同様に定義される。]
縮合剤の存在下で縮合させることを含む、製造方法。 - 前記式(2)で示されるN−末端が保護されたα−一置換アミノ酸若しくはグリシン又はそれらの塩と、前記式(3)で示される二置換アミノ酸又はその塩とを、化学量論量以上の縮合剤の存在下で縮合させる、請求項1に記載の製造方法。
- 前記式(2)で示されるN−末端が保護されたα−一置換アミノ酸若しくはグリシン又はそれらの塩の反応率が70〜80%に達した時点で、前記式(2)で示されるN−末端が保護されたα−一置換アミノ酸若しくはグリシン又はそれらの塩と前記式(3)で示される二置換アミノ酸又はその塩との反応を終了させる、請求項1又は2に記載の製造方法。
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Title |
---|
NEBEL, K. ET AL.: "Stereoselective synthesis of isovaline (IVA) and IVA-containing dipeptides for use in peptide synthe", TETRAHEDRON, vol. Vol. 44, No. 15, JPN6014049478, 1988, pages pp. 4793-6 * |
PAIRA, T. K. ET AL.: "Peptide-Polymer Bioconjugates via Atom Transfer Radical Polymerization and Their Solution Aggregatio", MACROMOLECULES, vol. Vol. 43, No. 9, JPN6014049480, 2010, pages pp. 4050-4061 * |
TANTRY, S. J. ET AL.: "Synthesis of Nα-protected peptide acids by N→C chain extension employing O,N-bis-trimethylsilyl-am", INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY, vol. Vol. 43B, No. 6, JPN6014049479, 2004, pages pp. 1282-1287 * |
VERARDO, G. ET AL.: "α-N-Protected dipeptide acids: a simple and efficient synthesis via the easily accessible mixed anh", JOURNAL OF PEPTIDE SCIENCE, vol. Vol. 19, No. 5, JPN6014049477, March 2013 (2013-03-01), pages pp. 315-324 * |
VRUDHULA, V. M. ET AL.: "Cephalosporin prodrugs of paclitaxel for immunologically specific activation by L-49-sFv-beta-lact", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. Vol. 13, JPN6017048876, 2003, pages pp. 539-542 * |
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