JPH0215094A - Preparation of peptide - Google Patents
Preparation of peptideInfo
- Publication number
- JPH0215094A JPH0215094A JP1086537A JP8653789A JPH0215094A JP H0215094 A JPH0215094 A JP H0215094A JP 1086537 A JP1086537 A JP 1086537A JP 8653789 A JP8653789 A JP 8653789A JP H0215094 A JPH0215094 A JP H0215094A
- Authority
- JP
- Japan
- Prior art keywords
- added
- acid
- water
- group
- solvent
- 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
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title description 2
- 239000002253 acid Substances 0.000 claims abstract description 24
- 125000006239 protecting group Chemical group 0.000 claims abstract description 15
- -1 4-methoxy-2,3,6-trimethylbenzenesulfonyl group Chemical group 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims description 28
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 63
- 150000001413 amino acids Chemical class 0.000 abstract description 18
- DWLYVEYCCPEHLX-UHFFFAOYSA-N 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride Chemical compound COC1=CC(C)=C(S(Cl)(=O)=O)C(C)=C1C DWLYVEYCCPEHLX-UHFFFAOYSA-N 0.000 abstract description 2
- 238000003379 elimination reaction Methods 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract 2
- 230000008030 elimination Effects 0.000 abstract 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- 229910001868 water Inorganic materials 0.000 description 64
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- 238000001914 filtration Methods 0.000 description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 49
- 238000002844 melting Methods 0.000 description 29
- 230000008018 melting Effects 0.000 description 29
- 239000000843 powder Substances 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- 239000013078 crystal Substances 0.000 description 24
- 238000000921 elemental analysis Methods 0.000 description 24
- 238000000034 method Methods 0.000 description 22
- 238000010531 catalytic reduction reaction Methods 0.000 description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 12
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- 238000006243 chemical reaction Methods 0.000 description 8
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- 238000003756 stirring Methods 0.000 description 7
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000010306 acid treatment Methods 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- ZUSSTQCWRDLYJA-UHFFFAOYSA-N n-hydroxy-5-norbornene-2,3-dicarboximide Chemical compound C1=CC2CC1C1C2C(=O)N(O)C1=O ZUSSTQCWRDLYJA-UHFFFAOYSA-N 0.000 description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- OOFAEFCMEHZNGP-UHFFFAOYSA-N 1-n',1-n'-dimethylpropane-1,1-diamine Chemical compound CCC(N)N(C)C OOFAEFCMEHZNGP-UHFFFAOYSA-N 0.000 description 2
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 102000004862 Gastrin releasing peptide Human genes 0.000 description 2
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- 150000008065 acid anhydrides Chemical class 0.000 description 2
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- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
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- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
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- PUBCCFNQJQKCNC-XKNFJVFFSA-N gastrin-releasingpeptide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(C)C)[C@@H](C)O)C(C)C)C1=CNC=N1 PUBCCFNQJQKCNC-XKNFJVFFSA-N 0.000 description 2
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- 238000001035 drying Methods 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- WEVKQMBWAPJFSP-UHFFFAOYSA-N ethyl acetate;2-pyridin-2-ylacetic acid;hydrate Chemical compound O.CCOC(C)=O.OC(=O)CC1=CC=CC=N1 WEVKQMBWAPJFSP-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000011521 glass 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
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002668 lysine derivatives Chemical class 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- VHNBNECUVQXBQA-UHFFFAOYSA-N methylsulfanylbenzene;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CSC1=CC=CC=C1 VHNBNECUVQXBQA-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- JXHZRQHZVYDRGX-UHFFFAOYSA-M sodium;hydrogen sulfate;hydrate Chemical compound [OH-].[Na+].OS(O)(=O)=O JXHZRQHZVYDRGX-UHFFFAOYSA-M 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 239000013076 target substance Substances 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 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
Classifications
-
- 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
Abstract
Description
【発明の詳細な説明】
本発明は、ω−アミ７基または（および）α−゛ｒミノ
八を４へ７トキシー２．３．６−ドリメチルベンゼンス
ルホニルＪＪで１家護したアミノ酸を用いるペプチドの
製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention uses an amino acid in which the ω-ami7 group or (and) α-rminoh8 group is monoprotected with 4 to 7-toxy 2,3,6-drimethylbenzenesulfonyl JJ. This invention relates to a method for producing peptides.
通常、ペプチドをｎ造するに当っては、ω−アミ７ノ１
（メ（まα−”ｒミツ〕人は１１十′：護しておく必要
がある。特に、ジ°／’ミノ酸におけるω−アミ７ノ、
（（たとえば、リジン、オル二手〕、α、γ−ジアミノ
ブチリック°ｒ／ノド、α、β−ジアミノプロピオン酸
）のω−了ミノ１．（の（’ｌ： Ｗ”ｔ ；□（に関
しては、そのα−アミノ（υ１穫基を選択的に１７Ｊ断
する必要があり、とりわ（プ市要である。ｆＣ来、ω−
アミノ基の（７護Ｊ、（とじては、！・リフルオロ酢酸
等の酸に安定で、接触還元によって除去できるカルボベ
ンゾキシ基または接触還元に安定で、酸によって除去で
きる（−ブチルオキシ／Ｊルボニル劫が繁１１１されて
いるか、）Ｑ ７１１なペプチドの合成の場合は、この
両（ｌｉ已護Ｊ、（のみては不十分°Ｃあり、トリフル
オロ酢酸等の酸処理、接触還元の山背に安定であり、か
つ最後に緩和な酸性条１′「Ｃ除去できる保ｎ’ｌＬｋ
か望まれていた。トリフルオロ酢酸等の酸処理、接触還
元の両者に安定な保護基としては、従来、ジイソプロビ
ルオキンカルボニル基、ｐ−メチルベンジルスルホニル
基等が知られているが、両者ともその除去には、フ！１
（水弗化水素等の強酸を用いなければならない。しかし
、無水弗化水素の使用は、工業的利用の面からは望まし
くないものである。また、ペンセンスルホニル型の１呆
護基として、ｐ−トルエンスルホニルノ、（がリジンの
ω−アミノ結の保護基として用いられたこともあるが、
この保護基は、液体アンモニア中すトリウム処理によっ
てのみ除去でき、種々の酸処理に対して極めて安定であ
るという欠点を有する。Usually, when producing a peptide, ω-amino 7-1
(Ma(α-"r Mitsu) people need to protect 110'. In particular, ω-amino7 in di°/'mino acids,
((e.g., lysine, or2), α, γ-diaminobutyric °r/nod, α, β-diaminopropionic acid) It is necessary to selectively cleave 17J of its α-amino (υ1) group, which is particularly important. Since fC, ω-
The amino group (7) is a carbobenzoxy group that is stable to acids such as fluoroacetic acid and can be removed by catalytic reduction, or the carbobenzoxy group that is stable to catalytic reduction and can be removed by acid (-butyloxy/Jrubonyl). In the case of the synthesis of 711 peptides, both of these methods are insufficient (°C, acid treatment with trifluoroacetic acid etc., catalytic reduction). is stable and finally has a mild acidic treatment that can remove carbon.
It was desired. Diisopropyloquine carbonyl group, p-methylbenzylsulfonyl group, etc. are conventionally known as protecting groups that are stable against both acid treatment such as trifluoroacetic acid and catalytic reduction, but both of them are difficult to remove. ,centre! 1
(A strong acid such as aqueous hydrogen fluoride must be used. However, the use of anhydrous hydrogen fluoride is undesirable from the standpoint of industrial use. Also, as a pencenesulfonyl-type monoprotective group, p-Toluenesulfonyl, (has been used as a protecting group for the ω-amino linkage of lysine,
This protecting group has the disadvantage that it can only be removed by treatment with sodium chloride in liquid ammonia and is extremely stable to various acid treatments.
本発明者らは、種々の置換ベンゼンスルホニル型の保護
基を検討した結果、４−メトキシ−２゜３．６−ｌ・リ
メチルベンセンスルホニル基が緩和な酸処理によって、
除去できることを見い出し、さらに６〕１究した結果、
本発明を完成した。As a result of examining various substituted benzenesulfonyl-type protecting groups, the present inventors found that 4-methoxy-2゜3.6-l-limethylbenzenesulfonyl group can be protected by mild acid treatment.
As a result of further research, we found that it could be removed.
The invention has been completed.
すなわら、本発明は、ω−アミノ基または（および）α
−アミノ基を有するペプチドの製造にあたり、ω−アミ
７基または（および）α−アミノ基含有アミノ酸または
ペプチドのω−アミ７基または（および）α−アミ７基
を、４−メトキ／−２゜３、（３−トリメチルベンゼン
スルホニル基でＩ呆５簀し、ペプチド縮合したのら、該
保護基を酸で脱離ｌしめることを特徴とするペプチドの
Φν造法である。That is, the present invention provides an ω-amino group or (and) an α-amino group.
- In the production of a peptide having an amino group, the ω-ami7 group or (and) the α-ami7 group of an amino acid or peptide containing an ω-amino group or 4-methoxy/-2 3. This is a method for producing a peptide Φν, which is characterized in that the protecting group is removed with an acid after the peptide is condensed with a 3-trimethylbenzenesulfonyl group.
本発明で用いられる４−メトキシ−２，３，６トリメチ
ルヘンゼンスルポニル基は、新規な保護基であり、通常
、ハロゲニドの形て使用に供せられ、たとえば祭考例１
の方法で製造される。The 4-methoxy-2,3,6 trimethylhenzenesulponyl group used in the present invention is a novel protecting group and is usually used in the form of a halide, such as Example 1.
manufactured by the method.
本発明において、４−メトキシ−２，３，６−１−ノメ
チルヘンゼンスルホニル基で保護されたω−アミノ基ま
たは（および）α−アミノ基を有するアミノ酸は、たと
えば次の常套手段で製造できる。In the present invention, an amino acid having an ω-amino group or (and) an α-amino group protected with a 4-methoxy-2,3,6-1-nomethylhenzenesulfonyl group can be produced, for example, by the following conventional method. can.
すなわら、４−メトキシ−２，３，６−１リメチルベン
ゼンスルホニルハライド、好ましくはクロライドと、ω
＝”７’ミノ基または（および）α−アミ７基をイｆす
るアミノ酸を反応させることにより製造できる。この反
応は、たとえば約−１０〜＋５０°Ｃの範囲の適宜の温
度で、溶媒（例、水、含水テトラヒドロフラン、含水ジ
オキサン、含水アセトン、含水アセトニトリル、含水ジ
メチルホルムアミド）を使用して実施することができる
。4-methoxy-2,3,6-1-limethylbenzenesulfonyl halide, preferably chloride, and ω
="7'Mino group or (and) α-amino group can be produced by reacting an amino acid which has an α-amino group. This reaction can be carried out in a solvent ( Examples include water, aqueous tetrahydrofuran, aqueous dioxane, aqueous acetone, aqueous acetonitrile, aqueous dimethylformamide).
また、上記の反応において、所望によりその逆層のα−
アミ７基を公知の１呆護基、たとえばカルボベンゾキシ
基、ｐ−ニトロベンジルオキシカルボニル）Ａ、 ｐ−
メトキシベンジルオキシカルボニル基、Ｌ−ブトキ／カ
ルボニル基、し−アミロキシカルボニル基、９−フルオ
レニルメトキシカルボニル基、イソニコチニルオキシカ
ルボニル基、。In the above reaction, if desired, α-
Amino group 7 is replaced with a known protective group, such as carbobenzoxy group, p-nitrobenzyloxycarbonyl)A, p-
methoxybenzyloxycarbonyl group, L-butoxy/carbonyl group, amyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, isonicotinyloxycarbonyl group.
トロフェニルスルフェニルＬ ２−（ｐ−ビフェニル
）イソプロピルオキシカルボニル基などで常角手段で（
′４鳳篠したのち、反応に供してもよい。Trophenylsulfenyl L 2-(p-biphenyl)isopropyloxycarbonyl group, etc.
'4 After heating, it may be subjected to reaction.
次に、」１記の反応において、アミノ酸がα、ω−ジア
ミノ酸である場合、その金属塩、好ましくは１−＋１塩
と、４−メトキシ−２，３，６−ドリメチルベンゼンス
ルポニルハライドを反応させると、ω−アミノｈ〜が」
１記保護、ｌＩＥで１呆護されたα、ω−ジアミノ酸の
金属塩を製造でき、これを常套手段（例、硫化水素また
はＥＤＴΔ、または樹脂、処理）で全屈を除去して遊１
々１Ｆのα−アミ７基およびカルホキ７１１１人をイア
するω−（呈護アミノ酸を専む告できる。Next, in the reaction of item 1, when the amino acid is an α,ω-diamino acid, a metal salt thereof, preferably a 1-+1 salt, and a 4-methoxy-2,3,6-drimethylbenzenesulfonyl When a halide is reacted, ω-amino h~
A metal salt of an α,ω-diamino acid protected by IE can be prepared, and the metal salt of α,ω-diamino acid protected by IE can be removed by conventional means (e.g., treatment with hydrogen sulfide, EDTΔ, or a resin), and the metal salt can be protected by IE.
Each of the 1F α-amino acids and the 7111 α-amino acids can be exclusively identified as ω-(protective amino acids).
か＜シ゛ζ１１１られる４−メトキシ−２，３，６−ト
リメチルベンゼンスルボニル基で１呆Ｍ誓されたωアミ
ツム（またはくおよび）α−アミ７基を有するアミノ酸
の例表しては、一般式
％式％
〔式中、Ｒ，Ｒ，は少なくともいづれか一方は、４−メ
トキシ−２，３，６−１−リメチルベンゼンスルホニル
ノ、（を、池は水素または４−メトキン−２゜３、（３
−トリメチルベンゼンスルボニルＪＵ以外の（−′：護
ツノ−を表わす〕で示されるリジン誘導体が挙げられる
。Examples of amino acids having an α-amino group of 4-methoxy-2,3,6-trimethylbenzenesulfonyl group represented by the general formula % formula % [In the formula, at least one of R and R is 4-methoxy-2,3,6-1-limethylbenzenesulfonyl, (, and hydrogen or 4-methquine-2゜3, (3
Lysine derivatives other than -trimethylbenzenesulfonyl JU (-': represents a protective horn) are mentioned.
このようにし−Ｃ得られる本発明の４−メトキシ２．３
．６−ドリメチルベンゼンスルホニルハで１霜度された
ω−アミ７基または（および）α−アミ７ノ、（をＭす
るアミノ酸は、必要に応じてジシクロヘキシルアミン、
シクロヘキシルアミン、ナトリウムなどの塩と１．だの
ら、該アミノ酸を含有するペプチドの製造に際し極めて
有利に（重用しうる。The 4-methoxy 2.3 of the invention thus obtained -C
．． The amino acid containing ω-amino group or (and) α-amino group added with 6-dimethylbenzenesulfonyl is optionally dicyclohexylamine,
Salts such as cyclohexylamine and sodium 1. Danora can be used extremely advantageously (heavily) in the production of peptides containing the amino acid.
この製造法としては常套手段が採用でき、例えばＭ、
１３ｏｄａｎｓｋｙ及びＭ、 Ａ、 ０ｎｄｅＬｔｉ著
、ペプチド・シンセシス（ＰｅｐＬｉｄｅ ５ｙｎｔ
ｂｅｓｉｓ）、 Ｉｎｔｅｒｓｃｉｅｎｃｅ、 Ｎｅ
ｗ Ｙｏｒｋ＋ ４９ Ｇ ６年； Ｆ、 ’ｔＡ、
Ｆｉｎｎ及びに、 ｌｌｏｒｍａｎｎ著 ザ・プロテイ
ンズ（ＴｈｅＩ’ｒｏＬｅｉｎｓ）、第２巻、 Ｉｌ、
Ｎｅｕｒａｔｈ、 Ｒ，Ｌ、 ｌ１ｉｌｌ 編集、八
ｃａｄｅｍｉｃ Ｐｒｅｓｓ Ｉｎｃ、 Ｎｅｗ Ｙｏ
ｒｋ、 １９７６年、泉屋信夫池著°゛ペプチド合成′
°丸善（体用９７５年などに、７１１１！載された方法
、たとえばアジド法。Conventional methods can be used for this manufacturing method, such as M,
13odansky and M. A. OndeLti, Peptide Synthesis (PepLide 5ynt
besis), Interscience, Ne
w York+ 49 G 6 years; F, 'tA,
Finn and Llormann, The Proteins, Volume 2, Il.
Edited by Neurath, R,L, l1ill, 8 academic Press Inc, New Yo
rk, 1976, Nobuoike Izumiya, ``Peptide Synthesis''
° Maruzen (Taiyo 975, etc., 7111! Methods listed, such as the azide method.
クロライド法、酸無水物法、混酸無水物法、 ＤＣＯ
法、活性エステル法、ウッドワード試薬ｌくを用いる）
ｊ法、カルボジイミダゾール法、酸化還元法。Chloride method, acid anhydride method, mixed acid anhydride method, DCO
method, activated ester method, and Woodward reagent)
j method, carbodiimidazole method, redox method.
１） ＣＣ／ＩＩ ＯＮ 方法なとか挙げられる。1) CC/II ON method is an example.
次に、ペプチド縮合後、本発明の保護基を酸によって脱
離させる。この脱離方法としては、メタンスルフオン酸
法、トリフルオロメタンスルフオン酸法等の公知の酸処
理方法が適用できる。さらに、本発明方法の場合には、
新しい酸処理方法として、少量のメタンスルホン酸を含
有するトリフルオロ八′１酸、またはトリフルオロ酢酸
が有利に使用でき、１１ｒにチオアニソールまたはアニ
ソールのγｊ在下で行なうと脱離反応が非常に有利に進
行する。Next, after peptide condensation, the protecting group of the present invention is removed with an acid. As this desorption method, known acid treatment methods such as methanesulfonic acid method and trifluoromethanesulfonic acid method can be applied. Furthermore, in the case of the method of the present invention,
As a new acid treatment method, trifluoroocta'1 acid containing a small amount of methanesulfonic acid or trifluoroacetic acid can be advantageously used, and the elimination reaction is very favorable when carried out in the presence of thioanisole or γj of anisole on 11r. Proceed to.
特に、４−メトキシ−２，３，６−１−リメチルベンゼ
ンスルホニルへが、ω−アミ７基の保護基として用いら
れた場合は、約０．０５Ｍ−ＩＭ、好ましくは約０．１
Ｍ〜０．５Ｍの低濃度のメタンスルホン酸を含むトリフ
ルオロ酢酸−チオアニソールで、またα−アミ７基の作
護爪として用いられた場合は、１−記の条件以外に、ト
リフルオロ酢酸チオ゛ｒニソールのみによっても除去で
きる。In particular, when 4-methoxy-2,3,6-1-limethylbenzenesulfonyl is used as a protecting group for the ω-ami7 group, about 0.05 M-IM, preferably about 0.1
When using trifluoroacetic acid-thioanisole containing methanesulfonic acid at a low concentration of M to 0.5M, and when used as a protective nail for α-ami7 group, trifluoroacetic acid It can also be removed with thionisole alone.
ところで、一般にＩｖＲ５基を脱離する際し、そのペプ
チド中に、アスパラギンや“ｒスバラギン酸残、！ｌ（
を劇イｒする場合には、サクシンイミド型の副反応が生
ずることがあり、またセリンやスレオニン残基がｒｊ在
するとＮ→Ｏアシル転位が起る。本発明方法の場合、こ
れらのアミノ酸残基を含むペプチドであってもトリフル
オロ酢酸、あるいは希薄なメタンスルホン酸をトリフル
オロ酢酸のような緩和な酸を用いることにより、上記の
ような副反応を抑制することができる。By the way, generally when removing the IvR5 group, asparagine, "rsubaragic acid residue, !l(
In the case of a strong reaction, a succinimide-type side reaction may occur, and if a serine or threonine residue is present, an N→O acyl rearrangement occurs. In the case of the method of the present invention, even if the peptide contains these amino acid residues, the above side reactions can be avoided by using trifluoroacetic acid or diluted methanesulfonic acid with a mild acid such as trifluoroacetic acid. Can be suppressed.
次に、本発明を参考例および実施例をあげて、さらに詳
しく説明する。なお、本明細書においてはアミノ酸、ペ
プチド、保護基、活性基等に関し、１旧）ＡＣ−１ｕｌ
ｌ ｃｏｍｍｉｓｓｉｏｎ ｏｎ １３ｉ
ｏ１ｏｇｉｃａｌＮｏｍｅｎｃｌａＬｕｒｅに基づ（略
号あるいは当該分野における慣用略号で表示する場合が
ある。それらを例示する。′Ｉ’ｒｐ：）リブトファン
；Ｌｙｓ：リジン；１１ｉｓ：ヒスチジン；Δｒｇ：ア
ルギニン；Ｓｅｒ：セリ７ ； Ｇ Ｉｙ：グリノン；
Δｌ ａ ： ’／’ラニン；Ｐｒｏ：ブロＪン・Ｔｈ
ｒ：スレオニン・Ｇ１口：グルタミン；Ｖａｔ：ハリン
：Ｉ、（！Ｕ：ロイシン；ｌｉｅ：イソロイシン；Ｍｅ
Ｌ・メチオニン；ｉ’ｙｒ：チロシン（以上、特に表示
のない場合はアミノ酸はＬ体をさすものとする。Next, the present invention will be described in more detail with reference to reference examples and examples. In addition, in this specification, regarding amino acids, peptides, protecting groups, active groups, etc.,
l commission on 13i
Based on the o1ologicalNomenclaLure (may be represented by an abbreviation or a common abbreviation in the field. Examples are 'I'rp:) Ributophan; Lys: Lysine; 11is: Histidine; Δrg: Arginine; Ser: Seri7; G Iy: Glinone;
Δla: '/'lanin; Pro: Bro J'n Th
r: Threonine/G1: Glutamine; Vat: Harin: I, (!U: Leucine; lie: Isoleucine; Me
L-methionine; i'yr: tyrosine (unless otherwise specified, the amino acids refer to the L-form.
（ｒＪＬ、Ｃ１１’を除＜）；Ｚ：カルボヘンゾキ’／
；ＢＯＣ：Ｌ−ブトキシカルボニル；０ＢｕＬ：ｔ−ブ
チルエステル：１ＩＯＮＢおよびＯＮＢ：Ｎ−ハイドロ
キシ−５−フルホルネンー２．３−：、；カルボキシイ
ミドおよびそのエステル・ＨＯ［３（：Ｎ−／’イドロ
キンベンヅトリアゾール、ＤＣＣ： Ｎ、Ｎ’−ジシク
ロへキシルカルボジイミド； ＤＣＵ ： Ｎ、Ｎ’ジ
シクロへキ／ルウレ゛７”ｌ’ｍｅ：ベンタメチルベン
ゼンスルポニル；Ｍｔｒ：４−メトキシ−２，３゜６−
ドリメチルベンゼンスルホニル；ＣＨΔニジクロヘキシ
ルアミン； Ｄ ＣＨＡ・ジシクロヘキシルアミン；Ｄ
ＭＦニジメチルホルムアミド、 ’ＦＥ八ニへリエチル
アミン。また本明細書に示す薄層クロマトグラフィーの
展開溶媒は、Ｒｆ’：クロロポルム−メタノール−酢酸
（９： ｌ ： ０．５）；＋＜ｒ″：酢酸エチル−ピ
リジン−酢酸−水（６０：２０ ： ６ ： ｌ Ｏ）
； Ｒｒ’： クロｏホルムーメ９／−ルー水（７：
３ ： ０．５）； Ｒｒ’： ｎ−ブタノールピリジ
ン−酢酸−水（３０：２０：６：２４）である。(rJL, excluding C11'<);Z: Karbohenzoki'/
;BOC: L-butoxycarbonyl; 0BuL: t-butyl ester: 1IONB and ONB: N-hydroxy-5-fluorone-2.3-:,;carboximide and its esters HO[3(:N-/'Idroquine Benztriazole, DCC: N,N'-dicyclohexylcarbodiimide; DCU: N,N'dicyclohexyl/urethane: bentamethylbenzenesulponyl; Mtr: 4-methoxy-2,3゜6−
Dolimethylbenzenesulfonyl; CH∆ dicyclohexylamine; D CHA dicyclohexylamine; D
MF dimethylformamide, 'FE dimethylformamide. Further, the developing solvent for thin layer chromatography shown in this specification is Rf': chloroporum-methanol-acetic acid (9: l: 0.5); +<r'': ethyl acetate-pyridine-acetic acid-water (60:20). : 6 : l O)
; Rr': Chloroformume 9/-Ru water (7:
3:0.5); Rr': n-butanolpyridine-acetic acid-water (30:20:6:24).
参考例１
（１） ２．３．５−トリメチルアニソールの合成２．
３，５４９メチルフェノールｌｏｇ、、沃化メチルｉｏ
、４ｄをジメチルスルフオキシド１００−にとかし、水
冷し、これに、６０％油性水素化ナトリウム５．６ｇを
加え、１０時間かきまぜた。これに水を加えたのち、エ
ーテルで抽出し、エーテル層は水洗し、無水流酸ナトリ
ウムで乾燥した。溶媒を留去して、油状物を得た。収ｆ
ｆｉ１２９ｇ（定量的）。Reference Example 1 (1) Synthesis of 2.3.5-trimethylanisole2.
3,549 methylphenol log, methyl iodide io
, 4d was dissolved in dimethyl sulfoxide 100- and cooled with water. 5.6 g of 60% oily sodium hydride was added thereto and stirred for 10 hours. After adding water to this, it was extracted with ether, and the ether layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to give an oil. Collection f
fi129g (quantitative).
（２）４−メトキシ−２，３，６−トリメチルベンゼン
スルフオニルクロリドの合１戊
２．３＋ ５ ’・リメチルアニソール４．５ｇを、
塩化メチレン５００藏にとかし、−５〜−１０°Ｃに冷
ノｊｌｌ したのも、クロルスルフォン酸６ 、 Ｏｔ
ａｌｌ ヲ含む塩化メチレン溶液４００藏を滴下した。(2) 4.5 g of 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride,
Chlorsulfonic acid 6,000 was dissolved in 500 g of methylene chloride and cooled to -5 to -10°C.
400 g of a methylene chloride solution containing all of the above was added dropwise.
その後、室温にまでもどし、５９６炭酸水素ナトリウム
水をａむ水−ににあけた。塩化メチレン層は水洗したの
Ｉ５、無水硫酸マグネシウムで乾燥した。溶媒を留去し
たのち、ｎ−へキサンより結晶として、ろ取した。収！
ｉ！５．０ｇ（６７，０％）融点 ５ Ｇ−５８°Ｃ
元素分析 Ｃ、，１１、，０，Ｓ Ｃ１２として計算値
： Ｃ，／１ｇ、２９： ＩＩ、５．２７； Ｓ、
１２．８９：Ｃ（！、 １４．２６
実験値 Ｃ，４８，４２； ＩＩ、５．２１； Ｓ
、１２．６１；Ｃρ、 １４．２５
参考例２
１ト川、ｙｓ（Ｍｔｒ）０１１ の製ノ青１、ｙｓｉ
ｌｃ４５４ ｇを水３００滅にとかし、約５０００で加
熱した。これにＣｌＩＣＯ３・Ｃｕ（Ｏｌｌ）ｔの粉末
１１６ｇを加え、５時間加熱還流した。不溶物をろ去し
たのら１．！Ｊ（ｌ易でさらにｔし浄した。ろ液を約１
００ｒｎｌにｌ層線し、これにＮａ１ｌＣＯ３９６ｇ
、 ＭＬｒＣ（！８２ｇを劇むアセトン溶液４５（Ｌｕ
を滴下し、１５時間かきまＵ′た。アセトンを減圧留去
し、ｔＪｌ出した結晶をろ取した。これを水５００ ｒ
Ｊに懸濁し、１）旧Δ−２Ｎａ５６ｇを加え、かきまげ
たのち、１７１出する結晶をろ取し、希酢酸より再結晶
した。Thereafter, the temperature was returned to room temperature, and 596 sodium bicarbonate water was poured into a glass of water. The methylene chloride layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, crystals were collected by filtration from n-hexane. Revenue!
i! 5.0g (67,0%) Melting point 5 G-58°C Elemental analysis C,,11,,0,S Calculated value as C12: C,/1g, 29: II, 5.27; S,
12.89:C(!, 14.26 Experimental value C, 48,42; II, 5.21; S
, 12.61; Cρ, 14.25 Reference Example 2 1 Togawa, ys (Mtr) 011 manufactured by 1, ysi
454 g of lc was dissolved in 300 ml of water and heated at about 5,000 ml of water. To this was added 116 g of ClICO3.Cu(Oll)t powder, and the mixture was heated under reflux for 5 hours. After filtering off the insoluble matter, 1. ! The filtrate was further purified with a
Add 1 layer to 00rnl and add 96g of Na1lCO3 to this.
, MLrC (!82g acetone solution 45 (Lu
was added dropwise and stirred for 15 hours. Acetone was distilled off under reduced pressure, and the crystals released at tJl were collected by filtration. Add this to 500 r of water
1) 56 g of old Δ-2Na was added and stirred, and the crystals 171 produced were collected by filtration and recrystallized from dilute acetic acid.
収量 ４３．５ｇ（４０，５％）融点２２４−２２８
°Ｃ
［α］２３＋１． Ｉｏ（ｃ＝０．９２． メタノー
ル）。Yield 43.5g (40.5%) Melting point 224-228
°C [α]23+1. Io (c=0.92.methanol).
［）
Ｒｒ” ０．１８
元素分析 Ｃ３ｅｌ−１ｔｏｏ ｓＮ −３’ 指）’
（ｔ○として計算値：Ｃ，５２，２９； Ｈ，７，４
１； Ｎ、？、６２；Ｓ ８７３
実験値：Ｃ，５２，１８； １１，７．１４； Ｎ
、？、５５；Ｓ、８．７０
参考例３
Ｚ−１、ｙｓ（Ｍｔｒ）ＯＩｌ’ＤＣｉｌへの製造ｌｙ
ｓ（ＭＬｒ）４０．０ ｇをＩＮ−水酸化ナトリウム１
３０ｍ、＆にとかし、水冷した。これにＺ−ＣＩ２２０
．６ｇ、ＩＮ−水酸化ナトリウム１１０旋を滴下したの
ら、そのま＼約４時間かきまぜた。クエン酸を加えて酸
性にしたのち、酢酸エチルで目的物を抽出し水洗、無水
硫酸すトリウムで乾燥した。溶媒を留去したのち、エー
テルにとかし、ＤＣＩＩＡ ２０ ＭＯ，を加えて結晶
としてろ取した。これをＭｅＯＩｌより１１結晶した。[) Rr" 0.18 Elemental analysis C3el-1too sN -3'finger)'
(Calculated value as t○: C, 52, 29; H, 7, 4
1; N,? , 62; S 873 Experimental value: C, 52, 18; 11, 7.14; N
,? , 55; S, 8.70 Reference Example 3 Production to Z-1, ys(Mtr)OIl'DCil
s(MLr) 40.0 g IN-sodium hydroxide 1
30m, and cooled with water. Z-CI220 for this
．． 6g of IN-sodium hydroxide was added dropwise, and the mixture was stirred for about 4 hours. After making the mixture acidic by adding citric acid, the target product was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After evaporating the solvent, it was dissolved in ether, and DCIIA 20 MO was added thereto, and crystals were collected by filtration. This was crystallized 11 times from MeOIl.
収ｆｆ１５３．４ ｇ（７２，０％）
融点 １６４−１６５°Ｃ
［α］２３
」−５
８° （Ｃ＝ ０．８６
ｉｎ Ｍｅｏｌｌ）
Ｒｆ’ Ｏ。 ７２
元素分析 ＣｔＪｌ ３ｔｏ ７Ｎ ！Ｓ ’ Ｃ＋ｄ
（２３Ｎとして計算値： Ｃ，６４，＋６．Ｉ−１，８
，２３； Ｎ、６．２４３ ４．７６
実験値： Ｃ，６３，８０，１＋、８．２８； Ｎ、６
．１３Ｓ、４．７０
参考例４
１１０ｃ Ｉ、ｙｓ（ＭＬｒ）（川 １）ＣＩＩＡ
の製造１、、ｙｓ（Ｍｌｒ） ｌ 、 ｌ Ｏｇをジオ
キサン１ＯｙＪ、水５Ｉｎｌのｌ昆１１ｋにｌ川え、こ
れにトリエチルアミン０．６３１Ｊを加えた。次いで、
Ｂｏａ−０１１Ｏ、８１ｇを加え、−・皮かきまぜ、ジ
オキサンを留去したのしクエン酸水を加えて酸性にした
のら、酌酸エチルで抽出し、無水流酸すトリウド
留去したのら、残留物をエーテルにとかし、ｌ）Ｃ！Ｉ
ＡＯ．６０ｍρを加えて析出する結晶をろ取した。Yield: 153.4 g (72.0%) Melting point: 164-165°C [α]23'-58° (C=0.86 in Meoll) Rf'O. 72 Elemental Analysis CtJl 3to 7N! S'C+d
(Calculated value as 23N: C,64,+6.I-1,8
, 23; N, 6.243 4.76 Experimental value: C, 63, 80, 1+, 8.28; N, 6
．． 13S, 4.70 Reference Example 4 110c I, ys (MLr) (River 1) CIIA
Preparation 1. ys(Mlr) l, lOg was added to 11k of 1OyJ of dioxane and 5Inl of water, and 0.631J of triethylamine was added thereto. Then,
Added 81g of Boa-011O, stirred the skin, distilled off the dioxane, added citric acid water to make it acidic, extracted with ethyl oxate, and distilled off the anhydrous acid solution. Dissolve the residue in ether and l)C! I
A.O. 60 mρ was added and the precipitated crystals were collected by filtration.
収量 １．２６ｇ（６５．６％）、融点 １６９１７
０’ｃ
［α］、 ＋８．６°（Ｃ＝ ０．８８．メタノール
）Ｒ１” ０．７１
元素分析 ＣｚｌＨ３４０７Ｎ ｚｓ ’ Ｃｌｔｆ’
１２３Ｎとして旧算値・Ｃ，６１，９４； Ｉ−１，８
，９８； Ｎ、６．５７３ ５．０１
実験値： Ｃ，６２，＋ｇ； Ｈ，９，２２； Ｎ、６
．５０；Ｓ、５．０７
参考例５
ＭＬｒ−Ｇａｙ−Ｏｌｌの製造
グリシン０．７５ｇを２Ｎ−水酸化すｉ・リウム水５ｈ
、１にとかし水冷した。これにＭｔｒ−（Ｊｊ（２、４
８ｇ ）ノＴ ＩＩ Ｆ溶液（ＩＭりと、２Ｎ−水酸化
ナトリウム水５ｇを滴下したのら、そのま＼約３時間か
きまぜた。クエン酸酸性としたのち、Ｔ ＩＩ Ｆを留
去し、酢酸エチルで抽出し、水洗し、無水硫酸ナトリウ
ムで乾燥した。溶媒を留去すると結晶となるのでこれを
ろ取し、酢酸エチルより再結晶した。Yield 1.26g (65.6%), melting point 16917
0'c [α], +8.6° (C = 0.88.methanol) R1" 0.71 Elemental analysis CzlH3407N zs 'Cltf'
Old calculation value as 123N・C, 61,94; I-1,8
,98; N, 6.573 5.01 Experimental value: C, 62, +g; H, 9,22; N, 6
．． 50; S, 5.07 Reference Example 5 Production of MLr-Gay-Oll 0.75 g of glycine was dissolved in 2N-sulfur hydroxide solution for 5 hours.
, and cooled in water. To this, Mtr-(Jj(2, 4
8g) TIIF solution (IMrito, 5g of 2N sodium hydroxide solution) was added dropwise and stirred for about 3 hours. After acidifying with citric acid, TIIF was distilled off and acetic acid was added. It was extracted with ethyl, washed with water, and dried over anhydrous sodium sulfate. When the solvent was distilled off, crystals formed, which were collected by filtration and recrystallized from ethyl acetate.
収量 ０．８０ｇ（２７，８％）
融点 １４９−４５２°Ｃ，Ｒｆ’ ０．４９元素分
叶 Ｃ、、ＩＩ 、７０５Ｎ Ｓとしてｉｉｌ算（直
： Ｃ，５０，１６： Ｈ５，９７° Ｎ、４．８
８’Ｓ、１１．１６
実験値： Ｃ，５０，２１，Ｈ，６，０？、 Ｎ、４．
７８；Ｓ ＩＩ １４
参考例６
Ｍｌｒ −ｌｌｅ −１ｕｌｌ の’ＪＪｉ’Ｍｅ２
．Ｉ６ｇを水３０蔵に懸濁し、炭酸水素すトリウＡ２．
８０ｇを加えて加熱溶解した。これを水冷したのち、′
「ＩＩ Ｉ” ２０ｄを加え、さらにＭＬｒ−Ｃ１！
（３，７３ｇ ）のｉ゛ＩＩ ［？溶液（１０＋Ｊ）を
加え“Ｃ−ＩＩかきまぜた。′ｒ Ｈｒ；を留去したの
ち、クエン酸酸性としてエーテルで抽出し、無水硫酸す
ｉ・リウムて乾燥した。溶媒を留去したのち、少量のエ
ーテルにとかし、ＣＩ−１Δ １．ｏｄを加えて析出す
る結晶をろ取した。収量 ３．５０ｇ（５２７％）、
融点 ＋８９−１９０°Ｃ
［α］２３ ＋１３．６°（Ｃ＝ １．０６゜Ｒｆ’
０．６４
元素分析 Ｃ＋５ｌ−１、、ＯＳＮ Ｓ −Ｃ，１−１
、、Ｎとして計算値・Ｃ，５９，７０，Ｈ，８，６５；
Ｎ、６．３３；３ ７．２５
実験値：Ｃ，５９，９９；
Ｓ、７．０９
Ｎ、６．２８；
メタノール）
ｔ（，８，４１：
試験例１
アミ７基の保護基としてのＭｌｒ基の酸による切断の検
討
（１） Ｉ、ｙｓ（ＭＬｒ）： Ｌｙｓ（ＭＬｒ）
Ｉ ＯｍｇにＱ、ＩＭ−ＭＳＡ −１’ ＦＡ−チオア
ニソール（９：１）ｌ蔵を加え、室温で１〜２時間放置
したのち、ＴＬＣにて反応の１王子を追跡するとｌｙｓ
（Ｍｔｒ）に相当するスポットが完全に消失し、ニンヒ
ドリンで発色するとＬｙｓに相当するスポットが現われ
た。またＴ Ｆ Ａ処理には安定であった。Yield 0.80g (27.8%) Melting point 149-452°C, Rf' 0.49 elemental content C, II, 705N
: C, 50, 16: H5, 97° N, 4.8
8'S, 11.16 Experimental value: C, 50, 21, H, 6, 0? , N, 4.
78; S II 14 Reference Example 6 'JJi'Me2 of Mlr -lle -1ull
．． Suspend 6g of I in 30ml of water and add 2.2g of hydrogen carbonate.
80g was added and dissolved by heating. After cooling this with water,
“II I” 20d is added, and MLr-C1!
(3,73g) i゛II [? The solution (10+J) was added and stirred with "C-II. 'r Hr;" was distilled off, the solution was acidified with citric acid, extracted with ether, and dried over anhydrous sodium sulfate. After the solvent was distilled off, a small amount was dissolved in ether, 1.od of CI-1Δ was added, and the precipitated crystals were collected by filtration. Yield: 3.50 g (527%),
Melting point +89-190°C [α]23 +13.6° (C = 1.06°Rf'
0.64 Elemental analysis C+5l-1,,OSN S-C,1-1
,, Calculated value as N・C, 59, 70, H, 8, 65;
N, 6.33; 3 7.25 Experimental value: C, 59,99; S, 7.09 N, 6.28; Examination of cleavage of Mlr group with acid (1) I, ys (MLr): Lys (MLr)
When 1 volume of Q, IM-MSA-1' FA-thioanisole (9:1) was added to I Omg, and the mixture was left to stand at room temperature for 1 to 2 hours, the reaction was followed by TLC.
The spot corresponding to (Mtr) completely disappeared, and when colored with ninhydrin, a spot corresponding to Lys appeared. It was also stable to TFA treatment.
（２） Ｍｔｒ−Ｇｌｙ−Ｏｌｌ： Ｍｔｒ−Ｇｌｙ−
Ｏｉｌ ２０ｍｇ１Ｉ：Ｔ ＦＡ−チオアニソール（９
：１ ）０．５ａを加え、室温で２時間放置したのち、
ＴＬＣにて反応の様子を追跡した。その結果、Ｍｔｒ−
ＧｌｙＯＨに相当するスポットが完全に消失し、ニンヒ
ドリンで発色すると、Ｇｌｙに相当するスポットが現わ
れた。また、ＴＦＡ処理に対しては安定であった。(2) Mtr-Gly-Oll: Mtr-Gly-
Oil 20mg1I:T FA-thioanisole (9
:1) After adding 0.5a and leaving it at room temperature for 2 hours,
The reaction was followed by TLC. As a result, Mtr-
The spot corresponding to GlyOH completely disappeared, and when color was developed with ninhydrin, a spot corresponding to Gly appeared. Furthermore, it was stable against TFA treatment.
以上の事実からアミノ基の保、１４基としてのｌｔｒ基
は、緩和な条件で除去できることが明らかになった。From the above facts, it has become clear that the ltr group as the amino group and the 14 group can be removed under mild conditions.
実施例Ｉ
鴎ガストリン・リリージング・ペフ゛チド（ＧＲＰ）の
！！！！造
（１） Ｂｏｏ−Ｌｏｕ−Ｍｅｔ−ＮＨ２の製造Ｂｏ
ｏ−Ｍｅｔ−ＮＨ２（１０，Ｂ ｙ）に４ Ｎ −Ｌ（
ＣＩ／酢酸４０ｙＩｌを加えたのち、振＃）まぜると、
結晶が析出するのでエーテ〃を加えてこれをろ取し、乾
燥した。これをＤ Ｍ Ｆ ２ ’ＯＯｍｌにとかし
、水冷し、Ｔ Ｅ Ａ ７． Ｏ＊ｔを加えて中和し
た。これにＢｏｏ−■、ｅｕ−ＯＮＢ（Ｂｏｏ−Ｌｅｕ
−ＯＨ８，Ｏｆ 、 ＨＯＮＢ ６．８５ｆ。Example I: Gastrin releasing peptide (GRP)! ! ! ! Production (1) Production Bo of Boo-Lou-Met-NH2
o-Met-NH2(10,B y) to 4N-L(
After adding 40yIl of CI/acetic acid, shake #) and mix.
Since crystals were precipitated, ether was added thereto and the crystals were filtered and dried. Dissolve this in DM F2'OOml, cool with water, and TEA7. O*t was added to neutralize. In addition to this, Boo-■, eu-ONB (Boo-Leu
-OH8,Of, HONB 6.85f.
ＤＣＣＴ、８；３！より調製する）を加えて一夜かきま
ぜた。溶媒を留去したのち酢酸エチルにとかし、重曹水
、クエン酸水で洗浄したのち、ΔｊｌＨ水硫酸ナトリウ
ムを用いて乾燥した。溶媒を留去すると結晶が析出する
のでエーテルを加えてこれをろ取し、メタノールーエー
テμよシ再結晶した。DCCT, 8;3! ) and stirred overnight. After distilling off the solvent, it was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and citric acid, and then dried using ΔjlH sodium hydrosulfate. When the solvent was distilled off, crystals were precipitated, and ether was added thereto and the crystals were collected by filtration and recrystallized from methanol-ether μ.
収量 １０．８Ｆ（８６，８％）
一触点 １５２−１５４°Ｃ，（α］Ｄ−８４，２（Ｃ
繻１．Ｏａ 、 ＤＭＦ）、 Ｒｆ ０１６５元
素分析 Ｃ１６Ｈ３，０４Ｎ３Ｓ として計１ｆ値：
ｃ、５ａ、１５； ａ、８．６４； Ｎ、Ｈ，ｔ３
ａｉＳ、 ８．８７
宍Ｍｊｋ値： ｃ、５Ｂ、５６； Ｈ，８，７２１ｍ
、１１．４７；８、８．９２
（２） Ｂｏａ Ｈｌｓ（Ｍｔｒ）ＯＬＩ ＤＣＨＡ
の製造Ｂｏｏ・ｌ１ｉｓ ＯＨ５，１１ｆを水ａ
Ｏａｔ 、アセトンａＯｇｔの混合液にとかし、水冷し
た。これにＴＥＡ５、６ ｒｓｌを加えたのち、Ｍｔｒ
−Ｃ１４，９７ｆのアセトン浴液Ｆ３０ｇｔを加え、２
時間かきまぜた。アセトンを減圧留去したのち、クエン
酸酸性として、酢酸エチルで抽出し、水洗したのち無水
ｆ硫酸ナトリウムを用いて乾燥した。溶媒を留去したの
ち。Yield 10.8F (86.8%) Touch point 152-154°C, (α]D-84,2(C
Satin 1. Oa, DMF), Rf 0165 elemental analysis Total 1f value as C16H3,04N3S:
c, 5a, 15; a, 8.64; N, H, t3
aiS, 8.87 Shishi Mjk value: c, 5B, 56; H, 8,721m
, 11.47; 8, 8.92 (2) Boa Hls (Mtr) OLI DCHA
Production of Boo・l1is OH5,11f with water a
The mixture was dissolved in a mixed solution of Oat and acetone aOgt and cooled with water. After adding TEA5 and 6 rsl to this, Mtr
- Add 30gt of acetone bath solution of C14,97f,
I stirred the time. After acetone was distilled off under reduced pressure, the residue was acidified with citric acid, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After distilling off the solvent.
少量の酢酸エチルにとかし、ＤＣＩ（Ａ ３．６Ｍｔ
を加え、溶媒を留去して冷Ｊｌｆ内で一夜放置した。析
出した結晶に、エーテルを加えて、これをろ取した。収
量 ７．８０ ｆ （６０，１％〕ａ
融点 １８６−１３７’ｃ、（α〕□ ＋１８．８（Ｃ
＝１．０１．メタ／−ＩＬ／）、Ｒｆ’ ０．６８元
素分析 Ｃ３３Ｈ５２０ヮＮ、 Ｓ として計算値：
ｃ、６１．０８； ａ、８．０８； Ｎ、８．６４
＋８、４．９４
実験値： ｃ、６１．１９； ｕ、８．０５； ａ、
８．８９＋３、４．７８
（３） Ｂｏａ Ｈｌｓ（Ｍｔｒ） Ｌｅｕ Ｍｅｔ
ＮＨ２のｙａＢｏｏ Ｌ１３＋１ ＭｅｔＮＨ２１０，
０１に４ Ｎ −１（Ｃユ／酢酸ａｃｍｅを加え、室温
で２０分間放置したのちエーテルを加えて沈澱としてろ
取し乾燥・）ｂ８゜一方、Ｂｏｏ−Ｈｌｓ（Ｍｔｒ）Ｏ
Ｈ−ＤＣＨＡ １６． ＯＷを酢酸エチルに懸濁しＩ
Ｎ−硫酸２７ｍ１を加えて分液し、無水硫酸ナトリウム
を用いて乾燥した。溶媒を留去したのち、アセトニトリ
ル１００ｔｔにとかし、ＨＯＮＢ５、（Ｈ’を加えて水
冷し、ＤＣＣ５，８ｆを加えて、−後反応したのち析出
するＤＣＵをろ去した。先に調製したアミン成分をＤ
Ｍ Ｆ １００ ｇｌにとかし、Ｔ Ｅ Ａ ４．
６ ｗｔで中和したのち、活性エステルを加えて、６時
間かきまぜた。溶媒を留去したのち、酢酸エチルに転溶
し、重Ｗ水、クエン酸水。Dissolve in a small amount of ethyl acetate and add DCI (A 3.6Mt
was added, the solvent was distilled off, and the mixture was left overnight in a cold Jlf. Ether was added to the precipitated crystals, which were collected by filtration. Yield 7.80 f (60.1%)a Melting point 186-137'c, (α]□ +18.8(C
=1.01. Meta/-IL/), Rf' 0.68 Elemental analysis Calculated value as C33H520ヮN, S:
c, 61.08; a, 8.08; N, 8.64
+8, 4.94 Experimental value: c, 61.19; u, 8.05; a,
8.89+3, 4.78 (3) Boa Hls(Mtr) Leu Met
NH2's yaBoo L13+1 MetNH210,
01 to 4 N -1 (Cyu/acetic acid acme was added, left at room temperature for 20 minutes, ether was added and the precipitate was collected by filtration and dried.)b8゜Meanwhile, Boo-Hls(Mtr)O
H-DCHA 16. Suspend OW in ethyl acetate and add I
27 ml of N-sulfuric acid was added to separate the layers, and the mixture was dried using anhydrous sodium sulfate. After the solvent was distilled off, it was dissolved in 100 tt of acetonitrile, HONB5, (H' was added, cooled with water, DCC5,8f was added, and the precipitated DCU was filtered off after the post-reaction. D
Mix in 100 gl of MF, TEA 4.
After neutralizing with 6 wt, active ester was added and stirred for 6 hours. After distilling off the solvent, the mixture was dissolved in ethyl acetate, deuterated water, and citric acid water.
水の順に洗浄し、無水硫酸ナトリウムで乾燥した。The mixture was washed successively with water and dried over anhydrous sodium sulfate.
溶媒を留去したのちエーテルを加えて粉末としてろ取し
た。収量 １５．１ｙ（８６，０％）融点 １２９−１
ａｌ”Ｃ，（α〕ゎ−１８．８（Ｃ＝０．８７．ＤＭＦ
）、Ｒｒｌ ０．６４元素分析 Ｃ３２■５００Ｂ Ｎ
５ Ｂ２として計算値： ｃ、５４．０６＋ ｎ、７
．０９＋ Ｎ、１１．８２＋８、９．０２
実験値： Ｃ，５４，６９＋ Ｈ，？、８９；Ｎ、１
１．９７＋８、８．３９
（４） Ｚ−Ｖａｌ−Ｇｌｙ−ＯＢｕｔの製造Ｚ−Ｇ
ｌｙ−ＯＢｕｔ１２． Ｏｆを）夕／ −ＩＶ中で接触
還元したのち溶媒を留去し、ＤＭＦにとかし水冷した。After distilling off the solvent, ether was added and the powder was collected by filtration. Yield 15.1y (86.0%) Melting point 129-1
al”C, (α〕ゎ-18.8(C=0.87.DMF
), Rrl 0.64 elemental analysis C32■500B N
5 Calculated value as B2: c, 54.06 + n, 7
．． 09+ N, 11.82+8, 9.02 Experimental value: C, 54,69+ H,? ,89;N,1
1.97+8, 8.39 (4) Production of Z-Val-Gly-OBut Z-G
ly-OBut12. After catalytic reduction of Of (1/-IV), the solvent was distilled off, and the residue was dissolved in DMF and cooled with water.
これにＺ−Ｖａｌ−ＯＨ８，８０ｆ 、 ＨＯＮＢ
７．２０ノ、ＤＣＣ８，２４５’を加え、−夜かきまぜ
た。To this, Z-Val-OH8,80f, HONB
7.20 min, added DCC 8,245' and stirred overnight.
Ｖ「出し７ｃＤＣＵをろ去したのち残留物を酢酸エナ〃
にとかし、重曹水、クエン酸水で洗浄したのち、無水（
＃酸ナトリウムで乾燥し孜。溶媒を留去し、残留物に石
油ベンジンを加えて結晶としてろ収したのち、酢酸エチ
ル−石油ベンジンよυ再結晶しり。収ｆｆｉ １１．
１Ｆ（８７，０％）融点 １４１℃、〔α〕２３−２１
． ｔ’ ｃ Ｃ＝１．１６ 。After filtering off the 7 cDCU, the residue was treated with enamel acetate.
After washing with acid, baking soda solution, and citric acid solution, wash with anhydrous (
# Dry with sodium acid. The solvent was distilled off, petroleum benzine was added to the residue, the crystals were collected by filtration, and then recrystallized from ethyl acetate-petroleum benzine. Collectionffi 11.
1F (87,0%) Melting point 141℃, [α] 23-21
．． t' c C=1.16.
ＤＭＦ）、Ｒｆｌ ０．８０
元素分りｉ’ Ｃ１９１１２８０！５ Ｎ２ とし
て計算値： ｃ、６２．６２； ｕ、７．７４； Ｎ
、７．６９火９値： Ｃ，６２，４９，Ｈ，７，６０
； Ｎ、７．７２＋５） Ｚ−Ａｌａ−ＶＩＡＩ−Ｇ
ｌｙ−Ｑ１３ｕ ＣＤＢａ造ｚ−Ｍａｌ−ａｌｙ−ＱＢ
ｕ １０． ＯｊＦ ｔ−メタノ−〃中、接触還元し
たのち、Ｄ Ｍ Ｆ １００ ｍｌにとかし、Ｚ−Ａ
ｌａ−ＯＨ５，７ｆ 、 ＨＯＮＢ ４．１ ｆを加え
、水冷した。これにＤＣＣ６゜２ｙを加えて一夜かきま
ぜる。υ１°出したＤＣＵをろ去し、溶媒を留去すると
、結晶が析出するので、酢酸エチルを加えて結晶をろ取
し、よく洗浄した。DMF), Rfl 0.80 Elemental division i' C1911280!5 Calculated value as N2: c, 62.62; u, 7.74; N
, 7.69 Tue 9 value: C, 62,49, H, 7,60
; N, 7.72+5) Z-Ala-VIAI-G
ly-Q13u CDBa z-Mal-aly-QB
u 10. After catalytic reduction in OjF t-methanol, it was dissolved in 100 ml of DMF, and Z-A
la-OH5.7f and HONB 4.1f were added and cooled with water. Add DCC6°2y to this and stir overnight. When the DCU released by υ1° was removed by filtration and the solvent was distilled off, crystals were precipitated. Ethyl acetate was added thereto, the crystals were collected by filtration, and thoroughly washed.
収量 １０．ｆＭ（９６，４％）
融点 １８４−１８５℃、〔α〕ｚｔ５−７．８Ｄ
（Ｃ−１，０６，ＤＭＦ）、Ｒｆｌ Ｏ，６７元素分
析 ０２２■３３０６ Ｎ３ として、ｔｉ球値：
Ｃ，６０，６７ｉ Ｈ，７，６４ｉ Ｎ、９．６５実
験幀： Ｃ，６０，９１ｉ ＩＩ、７．８６ｉ Ｎ、
９．７７（６］ Ｚ−Ｔｒｐ（Ｍｔｒ）−Ａｌａ−Ｖ
ａｌ−Ｇｌｙ ＯＢｕ の製造Ｚ−Ａｌａ−Ｖａｌ−
Ｇａｙ ０Ｔ３ｕ５． Ｏｆをメタノール中接触還元し
たのち、溶林を留去し、ＤＩＪＦ １００ｉｘｌにと
かした。これにＺ−Ｔｒｐ（Ｍｔｒ）ＯＨ６，ａ ４１
。Yield 10. fM (96,4%) Melting point 184-185℃, [α]zt5-7.8D (C-1,06,DMF), Rfl O,67 Elemental analysis 022■3306 N3, Ti sphere value:
C, 60, 67i H, 7, 64i N, 9.65 Experimental section: C, 60, 91i II, 7.86i N,
9.77(6) Z-Trp(Mtr)-Ala-V
Production of al-Gly OBu Z-Ala-Val-
Gay 0T3u5. After catalytic reduction of Of in methanol, the solvent was distilled off and dissolved in DIJF 100ixl. To this, Z-Trp(Mtr)OH6,a 41
.
ｕｏｕＴ １．８Ｇｆを加えて水冷し、ＤＣＣ２，８５
ｙを加え、−夜かきまぜた。υ「出したＤ ＣＵ ｆ、
ろ去し、溶媒を留去したのち、少量のｎ−ブタノ−〃を
含む酢酸エチルで抽出し、１ｖＬ！！／水で洗浄したの
ち、無水詭酸ナトリウムで乾燥した。、溶媒を留去し、
エーテＮ’２加えて沈叙としてろ収したのち、メタノー
ル−ｖμ酸エチル−エーテルより結晶として、これをろ
取した。Add uouT 1.8Gf and cool with water, DCC2.85
Add y and stir overnight. υ"D CU f,
After filtering it off and distilling off the solvent, it was extracted with ethyl acetate containing a small amount of n-butano. ! / After washing with water, it was dried with anhydrous sodium formate. , distill off the solvent,
After adding ether N'2 and collecting the precipitate by filtration, crystals were collected from methanol-vμ acid ethyl ether by filtration.
収量 ８．８（１（９６，６％〕
融点 １５４−１５５ ’Ｃ、（α）２８−２２．７゜
（Ｃ−０，８８，ＤＭＦＪ、Ｒｒｌ ０．６８元素分Ｕ
ｌ’ Ｃｔ３Ｌｔａ６０、。Ｎ、５ Ｓ として計
算値： Ｃ，６１，８５ｉ ＩＩ、６．７６ｉ Ｎ、
８．ａ９ｉＳ、８．８４
実験値： ｃ、６２．０６； Ｈ，７，０ｔｉ
Ｎ、８．５８＋ｓ、８．５８
ｆ７） Ｄｏｏ Ｈｌｓ（Ｍｔｒ）Ｔｒｐ（Ｍｔ
ｒ）Ａｌａ−Ｖａｌ−ＧｌｙＯｔ３ｕｔの製造
Ｚ−Ｔｒｐ（Ｍｔｒ）−Ａｌａ−Ｖａｌ−Ｇｌｙ ＯＢ
ｕ ８． ＯＩＩをＤＭＦ−メタノール中、接触還元
したのちメタノールを留去した。これにＢｏｏ−１１１
ｓ（ＭｔｒＪＯＨ（Ｂｏ。Yield 8.8 (1 (96,6%) Melting point 154-155'C, (α) 28-22.7° (C-0,88, DMFJ, Rrl 0.68 elemental U
l' Ct3Lta60,. Calculated value as N, 5 S: C, 61, 85i II, 6.76i N,
8. a9iS, 8.84 Experimental value: c, 62.06; H, 7,0ti
N, 8.58+s, 8.58 f7) Doo Hls (Mtr) Trp (Mt
r) Production of Ala-Val-GlyOt3ut Z-Trp(Mtr)-Ala-Val-Gly OB
u8. After catalytic reduction of OII in DMF-methanol, methanol was distilled off. Boo-111 for this
s(MtrJOH(Bo.
Ｈｌｓ（Ｍｔｒ）ＯＨ−ＤＣＩＪＡ ６．２２ ｆより
調製ノ、 ＨＯＮＢ１．９０ｙを加えて水冷したのち、
ＤＣＣ２，１８Ｖを加え、−夜かきまぜた。析出したＤ
ＣＵ 荀ろ去したのち、溶媒を留去し、エーテｌｖ（
＋−加えて沈Ｕとしてろ取した。これをメタノール、酢
酸エチル、エーテルの混合面で洗浄した。Prepared from Hls(Mtr)OH-DCIJA 6.22 f, added HONB1.90y and cooled with water,
Added DCC 2.18V and stirred overnight. Precipitated D
After filtering off the CU, the solvent was distilled off and the ether lv (
+- was added and collected by filtration as precipitate U. This was washed with a mixture of methanol, ethyl acetate, and ether.
収液 １０．２ｆ（９２，５％〕
融点 ２０２−２０４℃、〔αＪ２Ｂ−１６，１’１ン
（Ｃ−１１８，ＤＭＦ４°）、ｎｒｌＯ，６８元素分ｖ
ｒＣ５６Ｈ７７０１４’［ｌ ８２ トシテ計算値：
Ｃ，５８，４６ｉ Ｈ，６，７５ｉ Ｎ、９．７４ｉ
Ｓ、５．５７
実験値： Ｃ，５８，８２Ｓ Ｌ（，６，５４ｉ
Ｎ、９．５８ｉＳ、５．５１
（３） Ｂｏｏ−８ｏｒ−ｌｉｅ（Ｍｔｒ）−Ｔｒｐ
（Ｍｔｒ）−Ａｌａ−Ｖａ）Ｑ１３ｒＱｎの製造
Ｂｏ ｃ−Ｈｌ ｓ （Ｍｔ ｒ ）−Ｔｒ ｐ （Ｍ
ｔｒ ）−Ａｌａ−Ｖａｎ−Ｇｌ ｙＯＢｕ’４、Ｏｆ
ニＴ Ｆ Ａ ａ ０ｚｌｋ加え、室温で５０分間振り
まぜたのち、ＴＦＡを留去し、エーテルを加えて沈床と
してろ取しｉｌｌ、燥した。一方Ｂｏａ−８Ｏｒ−ＯＨ
０，７６ｆ 、 ＨＯＮＢ ０．７２ Ｆをアセトニ
トリＡ／２０ｗ１にとかし、水冷しこれにＤＣＣ：
０．８８ｆ／を加えて４時間かきまぜた。先に調製した
アミン成分をＤ Ｍ Ｆ ５０ ｗｌにとかし、’ｌ’
ＥＡ１．０〆ｌを加えて中和したのち、活性エステルを
加えて、−夜かきまぜた。溶媒を留去したのち、夕凪の
酢酸を加えてさらに水を加えて沈誠としてろ取し乙。こ
れを１１ Ｍ ｋ’−水より再沈でんしり、、収攬 ３
．６０（８５，０％）
融点 １４８−１５２’Ｃ，（αｙ！３−１６．４゜■
〕
（Ｃ−１，０９，ＤＭＦ）
元素分り？ Ｃ，Ｈ，４０□６Ｎ９ ｓ２−２１１２
０として計阜値： Ｃ，５４，２６ｉ Ｈ，６，４６
ｉ Ｎ、ＩＯ，８６ｉ）ｉ、 ５．２７
実験値： ｅ、６４．５８； Ｉ（，６，ａａｉ
Ｎ、１０．８２；Ｓ、５．５１
ｆ？） Ｚ−Ａｒｇ（Ｐｍｅ ）−Ｇｌｙ−ＯＢｕ’
の！８１！造ｚ−Ｑｌ、ｙ ０Ｉ３ｕ １ ａ ９
ｋメタノ−／’ ８００ ｗｌ中、接触還元したのち、
溶媒を留去し残留物をＤＭＦ２００ ａｔにとかした。Recovered liquid 10.2f (92.5%) Melting point 202-204℃, [αJ2B-16,1'1n (C-118, DMF4°), nrlO, 68 elements v
rC56H77014'[l 82 calculated value:
C, 58,46i H, 6,75i N, 9.74i
S, 5.57 Experimental value: C, 58, 82S L(, 6, 54i
N, 9.58iS, 5.51 (3) Boo-8or-lie(Mtr)-Trp
Production of (Mtr)-Ala-Va)Q13rQn Boc-Hls (Mtr)-Tr p (M
tr )-Ala-Van-GlyOBu'4, Of
After adding 2 TFA and shaking at room temperature for 50 minutes, TFA was distilled off, ether was added to form a precipitate, which was collected by filtration, illumination, and drying. On the other hand, Boa-8Or-OH
0.76f, HONB 0.72F was dissolved in acetonitrile A/20w1, cooled with water, and DCC:
0.88f/ was added and stirred for 4 hours. Dissolve the amine component prepared earlier in 50 wl of DMF, 'l'
After neutralizing by adding 1.0 liter of EA, active ester was added and stirred overnight. After distilling off the solvent, add Yunagi's acetic acid, then add water and filter it to make a sediment. This was reprecipitated from 11 M k'-water, and collected. 3
．． 60 (85,0%) Melting point 148-152'C, (αy!3-16.4゜■
] (C-1,09,DMF) Elemental identification? C, H, 40□6N9 s2-2112
Calculated value as 0: C, 54, 26i H, 6, 46
i N,IO,86i)i, 5.27 Experimental value: e,64.58; I(,6,aai
N, 10.82; S, 5.51 f? ) Z-Arg(Pme)-Gly-OBu'
of! 81! z-Ql, y 0I3u 1 a 9
After catalytic reduction in k methanol/'800 wl,
The solvent was distilled off and the residue was dissolved in DMF200at.
これに、Ｚ−Ａｒｇ（Ｐｍｅ ）ＯＨ（Ｚ−ＡｒＨ（Ｐ
ｍｅ）０１１・ＣＩＡ ２０ ｆより調製〕 を加え
、水冷しＨＯＢＴ ５．４ ｆ 、 ＤＣＣ８，２ｆ
ｋ加えて一夜かきまぜた。析出したＤＣＵｉろ去したの
ち、ｌ谷Ｕを留去し、残留物１に酢酸エチルにとかした
。To this, Z-Arg(Pme)OH(Z-ArH(Pme)
me) Prepared from 011・CIA 20 f] and cooled with water, HOBT 5.4 f, DCC8,2 f
k and stirred overnight. After the precipitated DCUi was removed by filtration, Ltani U was distilled off, and the residue 1 was dissolved in ethyl acetate.
これを、ぼｄ水、クエン酸水で洗浄したのち無水ｔｉ＋
ｉｒ酸ナトリウムで乾燥する。溶媒を留去したのち、石
油ベンジンを加えて粉末としてろ収した。After washing this with bod water and citric acid water, anhydrous ti+
Dry with sodium irate. After distilling off the solvent, petroleum benzine was added and the powder was collected by filtration.
収Ｉｎ １９．８ｆ（９５，０％）
ａｔ点 ５５−６０’Ｃ，（αｌｊ’＋０．２（Ｃ−０
，８８，ＤＭＩ’ン、 Ｒｆ ０．６２７Ｉｌｌ：
＊分哲 Ｃ３１［４５０ツＮ５Ｓ として計算値：
ｃ、５８．９３＋ Ｈ，７，１８； Ｎ、１ｔ、ｏ９
ｉ８．５．０８
突験値： ｃ、５８．９６； Ｈ，７，旧−、Ｎ、１
０．６７；８．５．０５
１ｏＩ Ｚ−Ｔｙｒ−Ｐｒｏ−ＱＢｕ’ の製造７
、−Ｐｒｏ ０Ｂｕｔ１５．０１１をメタノール３００
ｇ／にとかし接触還元したのち、溶媒を留去しＤｌ［４
００／にとかした。これに７．−Ｔｙｒ−ＯＨ（Ｚ−Ｔ
ｙｒ−０１（−ＤＣｉ ２０．０９より調製） 、
ＵＯＢＴ ６．７５ ｆを加えて氷冷し、さらにｎｃｃ
ｌｏ、４ｙを加えて、−夜かきまぜた。析出し−ｆ
ｃＤＣＵをろ去し、溶媒を留去したのち、酢酸エチルに
とかし、■留水、クエン酸水で洗浄し、無水硫酸ナトリ
ウムで乾燥し九。溶媒を置去したのち、シリカゲルのカ
ラム（７，５Ｘ９ｆｆｉ）に付し、１％ＭａＯ１１／
りａ ロホルムで溶出し、目的物の分画を集め、１猫し
たのち、石油ベンジンを加えて粉末としてろ取した。Yield In 19.8f (95.0%) at point 55-60'C, (αlj'+0.2(C-0
,88,DMI'n, Rf 0.627Ill:
*Calculated value as Buntetsu C31 [450tsuN5S:
c, 58.93+ H, 7,18; N, 1t, o9
i8.5.08 Accident value: c, 58.96; H, 7, old-, N, 1
0.67; 8.5.05 1oI Production of Z-Tyr-Pro-QBu' 7
,-Pro 0But15.011 in methanol 300
After catalytic reduction, the solvent was distilled off to give Dl[4
I combed it to 00/. 7. -Tyr-OH(Z-T
yr-01 (prepared from -DCi 20.09),
Add UOBT 6.75 f, cool on ice, and add ncc
Add lo, 4y and stir overnight. Precipitation-f
After removing cDCU by filtration and distilling off the solvent, it was dissolved in ethyl acetate, washed with distilled water and citric acid water, and dried over anhydrous sodium sulfate. After removing the solvent, it was applied to a silica gel column (7,5X9ffi) and 1% MaO11/
Elution was carried out with roform, fractions of the target substance were collected, and after one drop, petroleum benzine was added and the powder was collected by filtration.
収量 １５．４ｆ（８２，２％〕
〔α〕シ３９．９°（Ｃ−０，８３、ＩＩＦ） ｎｔ”
０．６２元素分析 Ｃ２６１１３２０６Ｉ痴・’、４
ｕ２０としてｄ１口Ｉｉ： ｃ、６５．Ｃ９； Ｈ，
ｆ３．９７； ｒｉ、５．８７夾ム倹イ＋ａ ：
Ｃ，６５，７０ｉ ｕ、 ６．９３ｉ Ｎ、
５．６６０１） Ｚ−ＩＩｓ−Ｔｙｒ−Ｐｒｏ−ＯＢ
ｕｔ−Ｚ−Ｔｙｒ−Ｐｒｏ−０１３ｕ’ １５．２
ｆ／をメタノール３００ｎｔｌにとかし、融触還元した
のち、１８謀を留去し、残留物をＤ Ｍ Ｆ ２００
ｔｔｔにとかした。これにＺ−１１θＯＩ（８，Ｏｆ
、 １１０１４Ｂ ６．５９を加え水冷したのち、Ｄ
ＣＣ７，４Ｗを加えて一夜かきまぜた。少坦のＮ 、
Ｎ−ジメチ／Ｉ／１０パンジアミンを加えたのち、Ｄ
ＣＵをろ去し、溶媒會減圧で留去した。残留物を酢酸エ
チルにとかしたのち、重留水、クエン酸水で洗浄し、無
水側〔酸ナトリウムで乾燥した。Yield 15.4f (82.2%) [α] 39.9° (C-0.83, IIF) nt”
0.62 elemental analysis C26113206Ichi・', 4
d1 mouth Ii as u20: c, 65. C9; H,
f3.97; ri, 5.87 +a:
C, 65, 70i u, 6.93i N,
5.6601) Z-IIs-Tyr-Pro-OB
ut-Z-Tyr-Pro-013u' 15.2
After f/ was dissolved in 300 ntl of methanol and subjected to catalytic reduction, 18 ml was distilled off, and the residue was dissolved in DMF 200 ntl.
I combed it to ttt. To this, Z-11θOI (8, Of
, 11014B 6.59 was added and cooled with water, then D
I added CC7,4W and stirred it overnight. Shodan's N,
After adding N-dimethy/I/10 pandiamine, D
CU was filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with heavy distilled water and citric acid water, and dried over anhydrous sodium chloride.
溶媒を留去すると結晶が析出するので石油ベンジンを加
えて、これをろ取したのち、メタノール−エーテル−石
油ベンジンより再結晶した。When the solvent was distilled off, crystals were precipitated, so petroleum benzine was added and the crystals were collected by filtration and then recrystallized from methanol-ether-petroleum benzine.
収電 １０．！ｌ１ｌ（６２，５％）
を融点 １７７−１７８″Ｃ２〔α〕２３−３８．ａ■
〕
（Ｃ＝１．ｌ ｌ 、 ］’、）Ｍ上’）、ＲｆｌＯ，
６２元素分ｖｒ０３２Ｈ４３°７Ｎ３として計算値：
ｃ、６６．０７； Ｉｆ、７．４５； Ｎ、７．２２
夾験泣： Ｃ，６６，０７，）１，７．７４．
ｈｌ、７．１９ｕｌ Ｚ−ＩＩｓ−’ｌ°ｙｒ−Ｐｒ
ｏ−０１１の製造Ｚ−１１ｏ−Ｔｙｒ−Ｐｒｏ ＯＢｕ
” ６．Ｏｆ／ Ｋ’ｌ’ Ｆ Ａ ６０ ｗｌを加え
、室温で１時間ふりまぜたのち、置去し、残留物を酢酸
エチルにとかし、水洗したのち無水硫酸ナトリウムで乾
燥した。溶媒を留去したのちエーテルを加えて粉末とし
てろ取した。Power collection 10. ! l1l (62,5%) with melting point 177-178″C2[α]23-38.a■
] (C=1.l l, ]', )M on'), RflO,
Calculated value for 62 elements vr032H43°7N3:
c, 66.07; If, 7.45; N, 7.22
Crying: C, 66, 07,) 1, 7.74.
hl, 7.19ul Z-IIs-'l°yr-Pr
Production of o-011 Z-11o-Tyr-Pro OBu
6. Added 60 wl of Of/K'l' F A and stirred at room temperature for 1 hour, then left to stand. The residue was dissolved in ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off. After evaporation, ether was added and the powder was collected by filtration.
収Ｍ ５．１０ｙ（９４，２％）
融点 ７２−７４℃、〔α都−２５，２（Ｃ−１，０１
，ＤＭｌｉ’ ン 、 Ｒｒ’ ０．４４
元素分析 Ｃ２８Ｈ３５０ワＮ３ として／ｉ）￥ｍ
： Ｃ，６Ｂ、９８； ＩＩ、６，７１
； Ｎ、７．９９実ｌａ値： Ｃ，６ａ、７５ｉ
Ｈ，Ｇ、６７、 Ｎ、７．８４（１３１Ｚ−１１ｅ−
Ｔｙｒ−Ｐｒｏ−Ａｒｇ（Ｐ＋ｎｏ ） Ｇｌｙ ＯＢ
ｕ’の製造
Ｚ−ＡｒｇＣＰｍｅ）−Ｇｌｙ−ＯＢｕｔ７．５８νを
） 夕／ −ｙＬｙ８００耐にとかし、ｌ Ｎ−塩酸Ｌ
Ｑｗｔを加えたのち、接触還元した。溶媒を留去したの
ち残留物をＤＭＦ １００ｇｔにとかし、水冷し−ｒ
’ｌ’ＥＡ２．００譚ｔを加えて中和した。これに、２
−工ＩＦＩ−Ｔｙｒ−Ｐｒｏ−Ｏ１ｌ ５．７８＆
、 ＨＯＢＴ ２．２３ｙ、 ＤＣＣａ、／ＬＣ１を
加えて一夜かきまぜた。析出し７’ｃ １）ＣＵをろ去
したのち、溶媒を留去し、残留物を酪酸エチルにとかし
た。これを甫暫水、クエン酸水で洗浄し、無水硫酸ナト
リウＪ・で乾燥した１、溶媒を留去し、残留物をシリカ
ゲルのカラム（５，５Ｘ１０ＤＨ）に付し、２％ＭｅＯ
Ｈ／クロロホルムで溶出し、目的物の分画を集め儂縮し
たのちエーテ／ｌ／を加えて粉末としてろ収した。Yield M 5.10y (94.2%) Melting point 72-74℃, [α-25,2(C-1,01
, DMli' , Rr' 0.44
Elemental analysis C28H350WN3/i) ¥m
: C, 6B, 98; II, 6, 71
; N, 7.99 Actual la value: C, 6a, 75i
H, G, 67, N, 7.84 (131Z-11e-
Tyr-Pro-Arg (P+no) Gly OB
Production of u'Z-ArgCPme)-Gly-OBut7.58ν) evening/-yLy 800 resistant, lN-hydrochloric acid L
After adding Qwt, catalytic reduction was performed. After distilling off the solvent, the residue was dissolved in 100 gt of DMF, cooled with water, and
It was neutralized by adding 'l'EA 2.00 t. To this, 2
- Engineering IFI-Tyr-Pro-O1l 5.78&
, HOBT 2.23y, DCCa, /LC1 were added and stirred overnight. Precipitation 7'c 1) After CU was filtered off, the solvent was distilled off and the residue was dissolved in ethyl butyrate. This was washed with boiling water and citric acid water, dried over anhydrous sodium sulfate, and the solvent was distilled off.
Elution was carried out with H/chloroform, fractions of the target product were collected and evaporated, and ether/l/ was added thereto to obtain a powder which was collected by filtration.
＋１３（ｆＩｉ７．２０１／ （６２，２％）融点 １
１０−１１２’Ｃ，Ｃα３２” −２８，３’″υ
（Ｃ−１，１９，ＤＭＦＩ、ｎｆ Ｏ，５９元素分析
Ｃ５、Ｈヮ、０□１Ｎ８Ｓ−Ｈ２Ｏとして１１″算泣
： Ｃ，５９，８５； ｕ、’？’、２９ｉ Ｎ、ｔ
ｏ、９ａｉＳ、 ａ、ｔａ
実験Ｉｎ ： Ｃ，６０，１６； ｕ、７．５６；
Ｎ、１０．り５；Ｓ、 ２．９８
Ｈ＋ ＺＴ、ｙｅ（Ｍｔｒ）−ｒｌｎ−Ｔｙｒ−Ｐｒ
ｏ−ＡｒＨｌ（Ｐｍｏ）−ＧｌｙＯヒ１１ｔの製弯
２−工１ｅ−Ｔｙｒ−Ｐｒｏ−Ａｒｇ（Ｐｍｏ）−Ｇｌ
ｙ−ＯＢｕ ７．Ｏｆｌｕｌｌ／−／Ｌ／ａ ６０ｍ
１にとかし、Ｉ Ｎ −Ｎ酸７ ｍｌを加えて接触還元
した。溶媒を留去したのち残留物をＤ Ｍ Ｉ＋′２０
０ ａｌｌにとかし、氷冷し、ＴＥＡ１．０ｄを加えて
中和した。これにＺ−Ｌｙｅ（ｌＪｔｒ）−ＯＬＩ Ｃ
Ｚ−Ｌｙｓ（ｌＪｔｒ）ＯＨ−ＤＣＨＡ ４．７４９よ
り調製〕。+13 (fIi7.201/ (62,2%) Melting point 1
10-112'C, Cα32"-28,3'"υ (C-1,19, DMFI, nf O, 59 elemental analysis C5, Hwa, 11" calculation as 0□1N8S-H2O: C,59, 85; u, '?', 29i N, t
o, 9aiS, a, ta Experiment In: C, 60, 16; u, 7.56;
N, 10. 5; S, 2.98 H+ ZT, ye(Mtr)-rln-Tyr-Pr
Curing of o-ArHl(Pmo)-GlyOhi 11t 2-Process 1e-Tyr-Pro-Arg(Pmo)-Gl
y-OBu 7. Ofull/-/L/a 60m
1 and added 7 ml of IN-N acid for catalytic reduction. After distilling off the solvent, the residue was DM I+'20
0 all, cooled on ice, and neutralized by adding 1.0 d of TEA. To this, Z-Lye(lJtr)-OLI C
Prepared from Z-Lys(lJtr)OH-DCHA 4.749].
［ＯＢＴ １２（１１、：ｏｃｃｔ、ｓｏｐを加えて
、−伎かきまぜた。析出したＤＣＵをろ去し残留物を６
ト酸エチｌしにとかした。これをＪｆＬｗ水、クエン酸
水で洗浄したのち、無水硫酸ナトリウムで乾燥した。[OBT 12(11, :occt, sop was added and stirred. The precipitated DCU was filtered off and the residue was
It was dissolved in ethyl toric acid. This was washed with JfLw water and citric acid water, and then dried over anhydrous sodium sulfate.
ｍ［を留去し、エーテ／１／を加えて粉末としたのち、
ｒｉＩ′酸エチル−エーテルより２回再沈鑵した。After distilling off m[ and adding ether/1/ to make a powder,
It was reprecipitated twice from riI' acid ethyl ether.
！■祉 ８．４０ｆ（８７，５％］
−点 １１６〜１１８ ’Ｃ、Ｃα〕２３−１９．９（
Ｃ＝１．０５．ＤＭＦ）、Ｒｆｌ Ｏ，５９元元素析
Ｃ６６Ｎ９６０１５ Ｎ１０ Ｓ２として計算値：
Ｃ，５９，４４薯ｕ、７．２６； ＩＪ、ｔｏ、５ｏ
ｉＳ、 ４．８１
実験値： Ｃ，５９，１０ｉ １１，７．／１４．
ｒＪ、１０．４６゜Ｓ、 ４．９８
ＱＳ） Ｚ−Ｔｈｒ−Ｌｙｕ（Ｍｔｒ）−１１ｅ−’
ｆ’ｙｒ−Ｐｒｏ−ＡｒＥ（（Ｐ＋ｎｏ）−Ｇｌｙ−Ｏ
ＢｕｔのＭａ
Ｚ −Ｌ ｙａ（ＩＪｔｒ）−１１ｅ−Ｔｙｒ−Ｐｒｏ
−Ａｒｇ（ｐＨ＋（１）−ｒ）ｇｒｏ１３ｕ ７．
５０ ｆ ｋ、メタノ−＃：ｄ６（１＋を中、接触還元
したのち、ｆ４謀を留去し、これを１）Ｍｌ’１０（１
＋／にとかした。これに、Ｚ−Ｔｈｒ−ＯＨ１，４９ｙ
、 ＨｏＮｎ １．５１ｙを加えて水冷したのち、
ＤＣＣｌ、７８Ｆを加えて一夜かきまぜた。少はのＮ、
Ｎ−ジメチル１０パンジアミンを加え、ＤＣＵ’ｉろ去
したのち、溶媒を留去し、残留物を中口のｎ −ブタノ
ールを含む酢酸エチルにとかした。これをｔ４１／水で
洗浄したのち水洗し、無水硫酸ナトリウムで乾燥した。! ■Welfare 8.40f (87.5%) - points 116-118 'C, Cα] 23-19.9 (
C=1.05. DMF), Rfl O, 59 elemental analysis C66N96015 N10 Calculated value as S2:
C, 59, 44 薯u, 7.26; IJ, to, 5o
iS, 4.81 Experimental value: C,59,10i 11,7. /14.
rJ, 10.46°S, 4.98 QS) Z-Thr-Lyu(Mtr)-11e-'
f'yr-Pro-ArE((P+no)-Gly-O
But's Ma Z -L ya (IJtr) -11e-Tyr-Pro
-Arg(pH+(1)-r)gro13u 7.
50 f k, methano-#: After catalytic reduction of d6 (1+), f4 was distilled off, and this was converted into 1) Ml'10 (1
+/I combed it. To this, Z-Thr-OH1,49y
, After adding HoNn 1.51y and cooling with water,
DCCl and 78F were added and stirred overnight. Shohano N,
After adding N-dimethyl 10-panediamine and filtering off the DCU'i, the solvent was distilled off and the residue was dissolved in ethyl acetate containing a medium volume of n-butanol. This was washed with t41/water and then with water, and dried over anhydrous sodium sulfate.
、溶媒を留去し、残留物にエーテルを加えて粉末とした
のち、これをろ取した。The solvent was distilled off, and ether was added to the residue to make a powder, which was then collected by filtration.
収Ｍ ８．０）（９９，２％）
融点 １２２−１２４”ｃ、（α、：ｌｌ −２５，
５（Ｃ＝０．８２．ＤＭＦ）、 Ｉげ１０．５９元素
分析 Ｃヮ。Ｈ１０３０１７’ｌ□Ｓ２として計ｊａ’
ｆｆｉ ： Ｃ，５８，６０＋ Ｈ，７，２４＋ Ｎ
、１０．７４ｉＳ、 ４．４７
東ｈｗｉａ ： Ｃ，５８，６１ｉ １，７．２
９ｉ １７，１０．４７ｉＢ、４．０２
＋１５） Ｂｏａ−Ｌｏｕ−Ｔｈｒ−Ｉ、ｙｎ（Ｍ
ｔｒ）−■ｔＧ−’Ｌ’ｙｒ−Ｐｒｏ−ＡｒＢ（Ｐｍｅ
）−Ｇｌｙ ０Ｂｕｔ＜１）！４造Ｚ−Ｔｈｒ−Ｌｙ
ｓ（Ｍｔｒ）−１１ｏ−Ｔｙｒ−Ｐｒｏ−Ａｒｇ（Ｐｉ
ｃｏ）−Ｇ１３’ＯＢｕ” ７．５ ｙ 、メタノール
７３５０ ｍｌにとかしパフトルエンスルホン酸０．９
９ Ｗを加えて接Ｍｍ元したのちｍμを留去した。これ
をＤＭＩｉ’ｌＯＯ盾ｌにとかし、水冷し、Ｔ Ｋ Ａ
０．７４１１！を加えて中和した。これにＢｏｏ−
Ｌ＋１ｕ−０１１１，８７ｆ／ 、 ＨＯＮＢｌ、４１
ｇ、）ノＣＣ１，６２ｙヶ加えて一夜かき゛まぜた。Ｉ
ＪＣＵをろ去し、溶媒を１１７去したのち、酢酸エチル
にとかし、瓜曹水、クエン酸水で洸浄し、無水（側端ナ
トリウムで乾燥した。ｆ８媒を留去し九のち、エーテ／
ｌ／を加えて粉末としてろ取した５゜収桓 ７．５５ｙ
（９５，４％〕
（Ｃ＝ １．００ 、 ＬｌＭＦ ） 、 Ｒｒｌ
Ｏ，５９元素分析 Ｃ７３”１１６０１Ｂ” １２
Ｓ２ ・１１２０ として計５１値： Ｃ，５７，
２３； ｕ、？、７６； Ｎ、Ｌｏ、９７；Ｓ、４．１
９
実験値： Ｃ，５’ｉ’、５ａｉ Ｈ，ｓ、１２
Ｎ？、ｉｏ、６６ｉＳ、８．９０
４’ｌ） Ｂ（ｒ ＯＡｌａ Ｌｅｕ Ｔｈ
ｒ Ｌｙ Ｂ（Ｍｔｒ） ｌ１ｏ−Ｔ７ｒ −Ｐ
ｒｏ−ＡｒＢ（Ｐｍｅ ）−Ｇｌｙ−０）１の’ＥＪａ
ｔ３ｏａ−Ｌｎｕ、−Ｔｈｒ−’Ｌｙｓ（ＪＪｔｒ）−
１１１Ｊ−Ｙｙｒ−Ｐｒｏ−ＡｒＢ（Ｐｍｏ）−Ｇｌｙ
ＯＢｕ ４’、 ２０ ｆに、ＴＦＡ４０＊ｔを加
え、室温で６０分間ふりませたのち溶媒を留去し、エー
テ）Ｖを加えて粉末としてろ収し、乾燥した。これ２
ｎ Ｍ Ｆ ５０ ｔｅｌにとかし、水冷しＴＥＡｏ、
８０ ｗｔを加えた。これに、Ｂｏｏ−Ａｌａ−ＯＲ
１４（Ｉｌｏ。Yield M 8.0) (99.2%) Melting point 122-124"c, (α,:ll -25,
5 (C=0.82.DMF), Ige10.59 Elemental analysis Cヮ. Total ja' as H103017'l□S2
ffi: C, 58, 60+ H, 7, 24+ N
, 10.74iS, 4.47 East hwia: C, 58, 61i 1, 7.2
9i 17, 10.47iB, 4.02 +15) Boa-Lou-Thr-I, yn(M
tr)-■tG-'L'yr-Pro-ArB(Pme
)-Gly 0But<1)! 4-Z-Thr-Ly
s(Mtr)-11o-Tyr-Pro-Arg(Pi
co)-G13'OBu" 7.5 y, dissolved in 7350 ml of methanol, puffed toluenesulfonic acid 0.9
After adding 9 W and contacting Mm, mμ was distilled off. Comb this with DMIi'lOO shield l, cool it with water, and TKA
0.7411! was added to neutralize it. Boo- to this
L+1u-0111,87f/, HONBl, 41
g,) 1.62 years of CC was added and stirred overnight. I
After removing JCU by filtration and removing 117 of the solvent, it was dissolved in ethyl acetate, washed with melon soda water and citric acid water, and dried over anhydrous sodium chloride.
7.55y
(95.4%) (C=1.00, LlMF), Rrl
O,59 elemental analysis C73"11601B" 12
Total of 51 values as S2 ・1120: C, 57,
23; u,? , 76; N, Lo, 97; S, 4.1
9 Experimental values: C, 5'i', 5ai H, s, 12
N? , io, 66iS, 8.90 4'l) B(r OAla Leu Th
r Ly B(Mtr) l1o-T7r -P
'EJa of ro-ArB(Pme)-Gly-0)1
t3oa-Lnu, -Thr-'Lys(JJtr)-
111J-Yyr-Pro-ArB(Pmo)-Gly
TFA40*t was added to OBu 4', 20 f, and after shaking at room temperature for 60 minutes, the solvent was distilled off, ether) V was added, and a powder was collected by filtration and dried. This 2
n MF 50 tel, cooled with water, TEAo,
80 wt was added. To this, Boo-Ala-OR
14 (Ilo.
−Ａｌａ−ＯＨ０，５２ＩＩ 、 ＨＯＮＢ ０１５
４ｆ、ＤＣＣｏ、６２ｙより調製）を加えて一夜かき壮
ぜた。、少鼠のＮ、Ｎ−ジメチルプロパンジアミンを加
えて＃Ｉ峰を留去したのち、酢酸水を加えて沈澱として
ろ取した。これを含水メタノールで（Ｊ）沈禮した。-Ala-OH0,52II, HONB 015
4f, DCCo, prepared from 62y) and stirred overnight. After adding a small amount of N,N-dimethylpropanediamine and distilling off the #I peak, aqueous acetic acid was added and the precipitate was collected by filtration. This was precipitated with aqueous methanol (J).
収ｈｔ ａ、６（１（８８，１％）
融点 １２８−１ ａ Ｏ’Ｃ、Ｃα］２３−３２．９
゜（Ｃ＝０．９８．ＤＭＥ’）、 Ｒ４’ ０．４
０元素分析 ＣＨＯＮＳ ・２１Ｌ２０として計算ｍ
： Ｃ，５５，２６ｉ １１，７．５４ｉ Ｎ、１
１．６４ｉＳ、４．１０
実験値： （：、５５．０２； ｕ、６．８９；
Ｎ、１１．ａ８＋Ｓ、３．７７
ｎ’ｌ’） Ｚ−８ｏｒ−Ｐｒｏ ０Ｂｕｔｃ１７造
Ｚ−Ｐｒｏ−ＯＢｕ １１．Ｏｆ ’ｆｃメタノー＃
ａ ００ ｗｌｌ／Ｃとかし、接触還元したのちｌｔｉ
媒’を置去し、ＤＭｌｉ’２００１１ｔにとかした。こ
涯にＺ−８ｅｒ−ＯＲ７，２ＩＩ 。Yield ht a, 6 (1 (88,1%) Melting point 128-1 a O'C, Cα] 23-32.9
゜(C=0.98.DME'), R4' 0.4
0 elemental analysis CHONS ・Calculated as 21L20 m
: C, 55, 26i 11, 7.54i N, 1
1.64iS, 4.10 Experimental value: (:, 55.02; u, 6.89;
N, 11. a8+S, 3.77 n'l') Z-8or-Pro 0Butc17 Z-Pro-OBu 11. Of'fc methanol #
After a 00 wll/C combing and catalytic reduction, lti
The medium was removed and dissolved in DMli'20011t. In this case, Z-8er-OR7,2II.
ＨＯＢＴ ４．９ Ｏｆ 、 ＤＣＣ７，５０ｆＹｃ加
えて一夜かきまぜた。析出したＤＣＵをろ去し、溶媒を
置去し、残留物を酢酸エチ〃にとかした。これ分電Ｗ水
、クエン酸水で洗浄したのち、λ（（水硫酸ナトリウム
で乾燥した。溶媒を留去し、石油ベンジンを加えて結晶
としてろ収したのち、酢酸エナルーエーテルより再結晶
した。I added HOBT 4.9 Of, DCC 7.50fYc and stirred it overnight. The precipitated DCU was filtered off, the solvent was removed, and the residue was dissolved in ethyl acetate. After washing with water and citric acid, the solvent was distilled off, petroleum benzine was added, the crystals were collected by filtration, and then recrystallized from acetic acid enal ether. .
収量 ９．５０ ｆ （６７，２％）
ｍ、ａ １２６−１２７．’Ｃ，（αＪ２３−５０．
９（Ｃ−０，９５，ＤＭＦ）、 Ｈｒｌ Ｏ，６５
元素分＃ｒ Ｃ２０Ｈ２８０６Ｎ２として計算値：
Ｃ，６１，２１ｉ Ｈ，７，１９ｉ Ｎ、７．１４実
い値： Ｃ，６１，４６； Ｈ，７，１６；
Ｎ、７．３１α？） Ｚ−Ｑｌｙ−８ｅｒ−Ｐｒｏ−
ＯＢｕ”の製造Ｚ−８ｅｒ−Ｐｒｏ−ＯＢｕｔ１０．
Ｏｆ ｆメタノ−Ａ２Ｂ ００ｔｒｉにとかし、接触還
元したのち溶媒を留去し、ＤＭ Ｆ ａ ００ ｆ！！
ｔにとかした。これにＺ−０１ｙ−０１１５，０６ｆ
、 Ｉ（ＯＮＢ ５．１３ ｆ／を加えて水冷したのち
ＴＪ ＣＣ５，８９！ｉｌを加えて一夜かきまぜた。少
量のＨ、Ｎ−ジメチルプロパンジアミンを加えたのち、
ＤＣＵをろ去し、溶媒を留去した。残留物を酢酸エチル
にとかし、ｍｔ’ｙ水、クエン酸水で洗浄し、５ＨＨｉ
水硫酸ナトリウムで乾燥した。溶媒を留去し、石油ベン
ジンを加えて結晶としてろ取したのち、エーテルで再結
晶した。収量 ７．’７０ＷＣ７２，１％）融点 ９６
−９８℃、〔α〕”” −５３，４（ｅ＝■）
１．０５．ＤＭＦ）、 Ｒｆ Ｏ，６１元素分υｒ
Ｃ２２［３１０ワＮ３として計）Ｊ［： Ｃ，５
８，７８，１！、６．９５． Ｎ、９．８５夾験値：
ｃ、５８．８６； ｕ、７．０４； ｔｖ、９．４６
に’） Ｚ−Ｇｌｙ−Ｇｌｙ−８ｅｒ−Ｐｒｏ−ＯＢ
ｕｔの製１７、−０１ｙ−８ｏｒ−Ｐｒｏ−ＣＩＢｕｔ
７． Ｏｆ ｋメタノール２００ ｗｅにとかし、接触
還元したのち、溶媒を留去し、残留物をＤＭＦ １０
０〜ｔにとかした。これにＺ−Ｇｌｙ−ｏｎ ａ 、ｏ
ｙ 、 Ｉ（ＯＮＢ ａ、 ｔ ｏ ｙ ＋加えて水
冷したのちＤＣＣ３，６０ｆを加えて一夜かきまセタ。Yield 9.50 f (67,2%) m, a 126-127. 'C, (αJ23-50.
9 (C-0,95,DMF), Hrl O,65
Calculated value as element #r C20H2806N2:
C,61,21i H,7,19i N,7.14 Actual value: C,61,46; H,7,16;
N, 7.31α? ) Z-Qly-8er-Pro-
Production of "OBu" Z-8er-Pro-OBut10.
After catalytic reduction, the solvent was distilled off and DM Fa 00 f! !
Combed to t. To this Z-01y-0115,06f
, I (ONB 5.13 f/) was added and cooled with water, then TJ CC 5,89!il was added and stirred overnight. After adding a small amount of H,N-dimethylpropanediamine,
DCU was filtered off and the solvent was distilled off. The residue was dissolved in ethyl acetate, washed with mt'y water and citric acid water, and 5HHi
Dry with sodium hydroxide sulfate. The solvent was distilled off, petroleum benzine was added, the crystals were collected by filtration, and then recrystallized from ether. Yield 7. '70WC72,1%) Melting point 96
-98℃, [α]”” -53,4 (e=■) 1.05. DMF), Rf O, 61 elements υr
C22 [Total as 310W N3) J[: C, 5
8,78,1! , 6.95. N, 9.85 experimental value:
c, 58.86; u, 7.04; tv, 9.46
ni') Z-Gly-Gly-8er-Pro-OB
ut made 17, -01y-8or-Pro-CIBut
7. After dissolving in methanol 200 ml and performing catalytic reduction, the solvent was distilled off and the residue was dissolved in DMF 10 ml.
It was combed from 0 to t. Z-Gly-on a, o to this
y, I (ONBa, t o y +), cooled with water, added DCC3.60f and stirred overnight.
少量のＮ、Ｎ−ジメチルプロパンジアミンを加えたのち
、ＤＣＵをろ去し、溶媒１に置去し尺。After adding a small amount of N,N-dimethylpropanediamine, the DCU was filtered off and placed in Solvent 1.
残留物を酢酸エチｙにとかし、飽和ｔｉ塩水で洗浄した
のち、無水硫酸ナトリウムでＩＩｌ、燥した。溶媒を留
去しエーテルを加えて結晶としたのちろ収し酢酸エチル
で再結晶した。The residue was dissolved in ethyl acetate, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off and ether was added to form crystals, which were collected and recrystallized from ethyl acetate.
収ｉｔ ５．７（１（７８，５％）
融点 １２９−１８０℃、〔α〕七３−４７．０（Ｃ−
０，８１，ＤＭＦＪ、 Ｒｆｌ Ｑ、４７尤索分析
Ｃ２４Ｈ３４０８Ｎ４としてｄ１゛算値： ｃ、５
６．９０； ｕ、６．７７； Ｎ、１１．０６！＊験値
： Ｃ，５６，７５； Ｈ，６，６ｓｉ Ｎ、１０．
９０３１） Ｚ−（Ｊｌｎ−Ｐｒｏ−ＯＢｕもの装造
Ｚ−Ｐｒｏ−ＯＢｕｔｌ ６．２ ｆをメタノ−／’
３５０ ｗｔにとかし接触還元したのち溶媒を留去し、
ＤＭＦ２００ ｍｌにとかした。これにＺ−Ｇｉｎ−Ｏ
ｌｌ １２．４ ｙ。Yield: 5.7 (1 (78.5%)) Melting point: 129-180°C, [α]73-47.0 (C-
0,81, DMFJ, Rfl Q, 47 likelihood analysis d1゛ calculated value as C24H3408N4: c, 5
6.90; u, 6.77; N, 11.06! *Experimental value: C, 56,75; H, 6,6si N, 10.
9031) Z-(Jln-Pro-OBu equipment Z-Pro-OButl 6.2 f methanol/'
After melting to 350 wt and catalytic reduction, the solvent was distilled off,
It was dissolved in 200 ml of DMF. Z-Gin-O to this
ll 12.4 y.
［ＯＢＴ ７．１ （ｉ ｆを加えて水冷し、ｎｃｃ
ｌＱ、９＆を加えて一夜かきまぜた。析出したＤＣＵを
ろ去し溶媒を留去したのち、酢酸エチμにとかし、重佇
水、クエン酸水で′ｔ３Ｉ１３ ／−％し、無水硫酸ナ
トリウムで乾燥した。溶媒を置去したのち、石Ｍｔ＋ベ
ンジンを加えて結晶としてこれをろ取し、酢酸エチル−
石油ベンジンより再結晶した。[OBT 7.1 (Add if, water cool, ncc
Added lQ, 9 & and stirred overnight. After the precipitated DCU was filtered off and the solvent was distilled off, it was dissolved in ethyl acetate, diluted with citric acid water and citric acid water, and dried over anhydrous sodium sulfate. After removing the solvent, Mt stone + benzine was added, the crystals were collected by filtration, and ethyl acetate-
Recrystallized from petroleum benzene.
収量 １５．８ｙ（８２，５％ン
（Ｃ掌１．０６ 、 ＤＭＥ” ） 、 Ｒｆｌ
Ｏ，６２元素分析 Ｃ２２”３１ ｏ６ Ｎ３として計
算値： Ｃ，６０，９５ｉ Ｊ７．２１ｉ １Ｊ、９
．６９夾−値： ｃ、６０．９５； Ｉ（，７，ａｆ
Ｓｉ Ｎ、９．４１１ｄＪ Ｚ−Ｌｅｕ−Ｇｉｎ−Ｐ
ｒｏ−ＯＢｕｔ（Ｑ！ｌ！！！造Ｚ−Ｇｌｎ−Ｐｒｏ−
ＯＢｕｔ８．ＯＷ 、バラトルエンヌルホン酸３．５
１ｙをメｐ ／ −）ｖａ ｏ ｏ ｔｒｔｖｃとかし
接触還元したのち、溶媒を留去した。残留物をＤＭＦ２
０（１＋ｔにとかしたのち水冷し、ＴＥＡ２．６ｍ／を
加えて中和した。これにＺ−ＬｕｕＯＨ（ＺＬｓｕＯＨ
ＤＣＩＩＡ８．２４９より調製） 、ＬＩＯＮＢ ４．
００？ 、 ＤＣＣ４．６０ｆを加えて一夜かきまぜた
１、少量のＮ 、 １（−ジメチｐ）”ロバンジアミン
を加えたのちＤＣＵをろ去し、溶媒を留去した。残留物
と酢酸エチμにとかし、重曹水、クエン酸水で洗浄し、
無水硫酸ナトリウムでｌｄｌ＋Ｌ、、た。溶媒を留去し
、結晶が析出するので石油ベンジンを加えてこれをろ取
し、酢酸エチル−石油ベンジンで再結晶した。Yield: 15.8y (82.5%), Rfl
O,62 elemental analysis C22”31 o6 Calculated value as N3: C,60,95i J7.21i 1J,9
．． 69 value: c, 60.95; I(,7, af
SiN, 9.411dJ Z-Leu-Gin-P
ro-OBut(Q!l!!!Z-Gln-Pro-
OBut8. OW, valatoluene sulfonic acid 3.5
After catalytic reduction of 1y with mep/-) va o o trtvc, the solvent was distilled off. DMF2 the residue
0 (1+t), cooled with water, and neutralized by adding 2.6 m/ of TEA.To this, Z-LuuOH (ZLsuOH
Prepared from DCIIA8.249), LIONB 4.
00? , 4.60f of DCC was added and stirred overnight. After adding a small amount of N, 1(-dimethyp)"lovandiamine, the DCU was filtered off and the solvent was distilled off. The residue was dissolved in ethyl acetate, Wash with baking soda water and citric acid water,
ldl+L with anhydrous sodium sulfate. The solvent was distilled off, and as crystals precipitated, petroleum benzine was added and the crystals were collected by filtration and recrystallized from ethyl acetate-petroleum benzine.
収量 ７．７０ダ（７６，８％ン
融点 ６２−６４’Ｃ，Ｃα〕ｊ３−５１．７（Ｃ＝ｔ
、１１．ＤＭＦ）、 Ｒｒ” ０．６１元素分析
Ｃ２８■４２０７Ｎ４として計算値： Ｃ，６１，５
２＋ Ｈ，７，７５，Ｎ、１０．２５東験値： Ｃ，
６１，１９ｉ Ｈ，７，７５ｉ ＩＪ、１０．１１ｇ１
） １３ｏｏ−Ｐｒｏ−Ｌｅｕ−Ｇｌｎ−Ｐｒｏ−Ｏ
Ｂｕｔ（ＤｄａＺ−Ｌｅｕ−Ｇｌｎ−Ｐｒｏ−ＯＢｕ”
７． ＯｆをメタノールＢＯＯｍｔにとかし接触還
元したのち溶媒を留去し、残留物をｉ）Ｍ Ｆ １０
０ ｍｌ！にとかした。これにＢｏａ−Ｐｒｏ ＯＨ２
，４２１１、ＩＩＩ）ＮＢ ２．７６１／ ｋ加えて
水冷したのち、Ｄ ＣＣｉ ｌ ７１／を加えて一夜か
き゛まぜた。少量のＮ 、 Ｎ−ジメチルグロバンジア
ミンを加えたのちＤＣＵをろ去し溶媒を留去し、酢酸エ
チルにとかした。これをｔｋ”／水、クエン酸水で洗浄
したのち無水硫酸ナトリウムで乾燥した。Yield 7.70 Da (76.8%) Melting point 62-64'C, Cα] j3-51.7 (C=t
, 11. DMF), Rr” 0.61 elemental analysis
Calculated value as C28■4207N4: C,61,5
2+ H, 7, 75, N, 10.25 East experimental value: C,
61,19i H, 7,75i IJ, 10.11g1
) 13oo-Pro-Leu-Gln-Pro-O
But(DdaZ-Leu-Gln-Pro-OBu”
7. After catalytic reduction of Of in methanol BOOmt, the solvent was distilled off and the residue was converted into i) M F 10
0ml! I grinned. Boa-Pro OH2 for this
, 4211, III) After adding NB 2.761/k and cooling with water, DCCil 71/k was added and stirred overnight. After adding a small amount of N,N-dimethylglobandiamine, DCU was filtered off, the solvent was distilled off, and the mixture was dissolved in ethyl acetate. This was washed with tk''/water and citric acid water, and then dried over anhydrous sodium sulfate.
ｆｄｌＪＸを留去したのち、エーテル−石油ベンジンよ
り粉末としてろ収した。収ｈｋ ６．５０Ｆ（８３，
３％ン
融点 ７４−７６℃、〔α〕’：３−７６．３’（Ｃ＝
１．１ ９ 、 ＤＭＦ ） 、ｎｒ”０．６
０元素分４Ｉ’ｒ Ｃ３０■５１０Ｂ ［５として計
算値： Ｃ，５９，０５ｉ Ｈ，８，４８＋ Ｎ、１
１．４９央験値： Ｃ，５８，８９ｉ Ｈ，８，１２
ｉ Ｎ、１１．０８Ｃ１，４ｊ Ｂｏｏ−Ａｌａ−Ｐ
ｒｏ−Ｌｅｕ−Ｇｌｎ−Ｐｒｏ−０１１の製造Ｂｏｏ−
Ｐｒｏ−Ｌｅｕ−Ｇｌｎ−Ｐｒｏ＝ＯＢｕｔ６．ＯＶに
ＴＦＡＧＯａｌを加え、室温で６０分曲ふりまぜたのち
、ｍ線を留去し、残留物にエーテルを加えて粉末として
ろ取し、乾燥した。これ（Ｉｌ−１１ＭＢ″１００ｇ？
にとかし水冷し、ＴＥＡ２．８（ｌａｙｔを加えたのち
、Ｂｏｃ−Ａｌａ−ＯＮＢ（Ｂｏｏ−Ａｌａ−ＯＨ１，
９５９、ＨＯＮＢ２、ＯＴｆ／ 、Ｔ）ＣＣ２，８ＢＷ
より調製）（ｉｌ−加えて一夜かきまぜた。溶媒を留去
したのち中位の酢酸を加え、次いでエーテルを加えて粉
末としてろ取した。これをクロロホルムにとかし、シリ
カゲルのカラム（５，５Ｘ８α）に付し、５％メタノ−
）Ｖ／クロロホルムで溶出し、目的物の分画を取り、１
１！１縮したのち、エーテルを加えて粉末としてろ取し
た。収量 ４．５０ｆ（７３，２％）
融点 １２４−１２８’ｃ、（α）２３−８２．１（Ｃ
−１，０４，ＤＭＦ）、 Ｒｆ’ ０．１８元素分
析 Ｃ２ＤＩ’４８０９ Ｎ５として計算値： ｃ、
５５．７５； Ｕ、７．’７４ｉ ｎ、１３．４５夾験
値： Ｃ，５５，ａ８ｉ １（，７，６５ｉ Ｎ、１
８．２１Ｃｄ） Ｂｏａ−Ａｌａ−Ｐｒｏ−Ｌｏｕ−
Ｇｌｎ−Ｐｒｏ−Ｇ１３’−Ｇｌｙ−８ｏｒ−Ｐｒｏ−
ＯＢｕもの製造
Ｚ−Ｇｌｙ−Ｇｌｙ−８ｅｒ−Ｐｒｏ−ＯＢｕｔ ２
．２ ａ ｆ ′ｊＦｒ／’ ！ ／−／Ｌ’ｌＱＯｇ
ｔｌｃとかし接触還元したのち、溶媒を留去し、残留物
をＤ Ｍ Ｆ ５０ ｔｔｔｌにとかした。これにＢｏ
ｏ−Ａｌａ−Ｐｒｏ−Ｌｅｕ−Ｇｉｎ−Ｐｒｏ−ＯＨ２
，５Ｏｆ 。After fdlJX was distilled off, the powder was collected by filtration from ether-petroleum benzine. Accommodation hk 6.50F (83,
3% melting point 74-76℃, [α]': 3-76.3' (C=
1.19, DMF), nr”0.6
0 element content 4I'r C30 ■ 510B [Calculated value as 5: C, 59,05i H, 8, 48 + N, 1
1.49 median: C, 58,89i H, 8,12
i N, 11.08C1, 4j Boo-Ala-P
Production of ro-Leu-Gln-Pro-011 Boo-
Pro-Leu-Gln-Pro=OBut6. TFAGOal was added to the OV, and after stirring at room temperature for 60 minutes, the m-line was distilled off, and ether was added to the residue, which was filtered as a powder and dried. This (Il-11MB″100g?
After stirring and cooling with water, add TEA2.8 (layt), then add Boc-Ala-ONB (Boo-Ala-OH1,
959, HONB2, OTf/, T) CC2, 8BW
(prepared from ) (IL) and stirred overnight. After distilling off the solvent, medium acetic acid was added, then ether was added and the powder was collected by filtration. This was dissolved in chloroform and filtered through a silica gel column (5,5×8α). and 5% methanol
) Elute with V/chloroform, take a fraction of the target product, and
After shrinking by 1:1, ether was added and the powder was collected by filtration. Yield 4.50f (73.2%) Melting point 124-128'c, (α) 23-82.1(C
-1,04, DMF), Rf' 0.18 Elemental analysis C2DI'4809 Calculated value as N5: c,
55.75; U, 7. '74i n, 13.45 experimental value: C,55,a8i 1(,7,65i N,1
8.21Cd) Boa-Ala-Pro-Lou-
Gln-Pro-G13'-Gly-8or-Pro-
OBu manufacturing Z-Gly-Gly-8er-Pro-OBut 2
．． 2 a f 'jFr/'! /-/L'lQOg
After catalytic reduction with tlc, the solvent was distilled off and the residue was dissolved in DMF50tttl. Bo to this
o-Ala-Pro-Leu-Gin-Pro-OH2
,5Of.
ＨＯＮＢ ０．９０ ｆｌｆ加えて水冷し、さらＫＴ
）ＣＣｔ、ｏａｙを加えて一夜かきまぜた。析出したＤ
ＣＵをろ去したのちＩ８線を留去し、これを少量のｎ−
ＢｕＯＨを含む酢酸エチルにとかし、飽和食塩水で洗浄
したのち無水硫酸ナトリウムで乾燥し几、。溶媒を留去
したのち、エーテＩＶ−ｆ加えて粉末とじてろ取した。Add HONB 0.90 flf, cool with water, and add KT
) CCt and oay were added and stirred overnight. Precipitated D
After filtering off the CU, the I8 line was distilled off, and a small amount of n-
Dissolve in ethyl acetate containing BuOH, wash with saturated saline, and dry over anhydrous sodium sulfate. After the solvent was distilled off, ether IV-f was added and the powder was collected by filtration.
収は ３．８５ｙ（９８，８％）融点 １００−１０５
’ｃ、（α〕２３−７４．０１〕
（Ｃ−０，９２，ＤＭＦ）、 Ｒｆ ０．１９
元素分析 Ｃ４，Ｈ７４０□４）Ｔｌｏ−Ｈ２Ｃとして
計算値： ｃ、５４．２０； Ｈ，７，６８； １１
，１４．ｏ５夾鹸値： Ｃ，５４，Ｏｌｉ Ｈ，
７，４５； Ｎ、Ｃ３，４４ｆ Ｂｏａ−Ａｌａ
−Ｐｒｏ−Ｌｅｕ−Ｇｌｎ−ｐｒｏ−Ｃ１ｌｙ−Ｇａｙ
−８ｅｒ−ｐｒｏ−０’ｒｌの製造
Ｄｏａ−Ａｌａ−Ｐｒｏ−Ｌｆｌｌｕ−Ｑｌｎ−Ｐｒｏ
Ｇｌｙ Ｇ１３’−８ｆ３ｒ−Ｐｒｏ−ＯＢｕｔ
ｌ、ＯｆｌにＴＦＡＩＯｔｔを加え、室温で１時間ふシ
まぜたのち躊躇を留去し、エーテ／Ｉ／を加えて粉末と
してろ取した。これをＤＭＦ１０ＩＩｇ／にとかじ、水
冷したのちＴｇＡｏ、４６ぽｔ２加え、次にＢＯＱ−０
：” ０．２７１を加えて４１時間かきまぜた。Yield: 3.85y (98.8%) Melting point: 100-105
'c, (α]23-74.01] (C-0,92,DMF), Rf 0.19
Elemental analysis C4, H740□4) Calculated value as Tlo-H2C: c, 54.20; H, 7,68; 11
,14. o5 depletion value: C, 54, Oli H,
7,45; N, C3,44f Boa-Ala
-Pro-Leu-Gln-pro-C1ly-Gay
-8er-pro-0'rl production Doa-Ala-Pro-Lfluu-Qln-Pro
Gly G13'-8f3r-Pro-OBut
TFAIOtt was added to Ofl and Ofl, and the mixture was stirred at room temperature for 1 hour, then the residue was distilled off, and Ete/I/ was added and the mixture was filtered as a powder. Add this to DMF10IIg/, cool with water, add TgAo, 46pot2, then BOQ-0
:” Added 0.271 and stirred for 41 hours.
溶媒を留去したのち、酢酸１．５ ｘｔｔ金加え、エー
テ）Ｖを加えて粉末としてろ収した。これをメタノール
−エーテルより再沈殿した。−。After the solvent was distilled off, 1.5 x tt gold acetic acid was added, and ether) V was added, and the mixture was filtered as a powder. This was reprecipitated from methanol-ether. −.
収量 ０１８７ｇ（９２，４％）
融点 １４１−１４５℃、〔α〕七Ｂ−７２．９゜（Ｃ
−０，９８，ＤＭＦ）、 Ｒｆ Ｏ，２９元素
分υ？ Ｃ４１Ｈ６６０１４Ｎ１０ ・ａ Ｈ２０と
して計）ｉ［、拉： Ｃ，５０，４０ｉ ）Ｉ、７．
４ｔ３ｉ Ｎ、１４．８４夾験値： Ｃ，５０，１
６ｉ Ｉｆ、６．７６ｉ Ｎ、１４．１１に１）
Ｂｏｏ−８ｅｒ−Ｈｌｓ（Ｍｔｒ）−’ｌ”ｒｐ（Ｍ
ｔｒ）−Ａｌａ−Ｖａｌ−Ｇｌｙ−Ｈｌｓ（Ｍｔｒ）−
Ｌｏｕ−Ｍｅｔ−Ｎｌ２ の製造Ｂｏｏ−Ｈ１ｓ（Ｍ
ｔｒ）−Ｌ＠ｕ−Ｍｅｔ Ｎｌ２ ａ、 ９７ ｆ Ｋ
： ＴＥ”Ａ４０ｔｘｌ−ｆ加え、室温で１０分間ふり
まぜたのち、１ 、、３ Ｎ−塩酸４．１１１ｔを加え
て溶媒を留去し、エーテμを加えて粉末としてろ収し、
乾燥した。これをＤＭＦ４０ｇｔにとかし、氷冷し、Ｔ
ＥＡ Ｏ，８６ゴを加え、次いでＢＯ（］−８ｅｒ−Ｈ
１ｓ（Ｍｔｒ）−Ｔｒｐ（Ｍｔｒ）−４１ａ−Ｖａｌ−
Ｇｌｙ−ＯＨ５，５０Ｗ 、■ＯＮＢ １．Ｏｆ／
。Yield 0187g (92.4%) Melting point 141-145℃, [α]7B-72.9゜(C
-0,98,DMF), Rf O, 29 elements υ? C41H66014N10 ・a Total as H20)i[,拉拉：C,50,40i)I,7.
4t3i N, 14.84 Experimental value: C, 50, 1
6i If, 6.76i N, 14.11 1)
Boo-8er-Hls(Mtr)-'l”rp(M
tr)-Ala-Val-Gly-Hls(Mtr)-
Production of Lou-Met-Nl2 Boo-H1s (M
tr)-L@u-Met Nl2 a, 97 f K
: Add 40txl-f of TE"A, stir for 10 minutes at room temperature, add 4.111t of 1,,3N-hydrochloric acid, distill off the solvent, add ether μ and collect by filtration as a powder,
Dry. Dissolve this in DMF40gt, cool on ice, and
Add EA O,86go, then BO(]-8er-H
1s(Mtr)-Trp(Mtr)-41a-Val-
Gly-OH5,50W, ■ONB 1. Of/
.
］）ＣＧ１．１５＆を加え一夜かきまぜた。Ｐｒ出した
ＤＣＵをろ去し、溶媒を留去したのち、水を加えて粉末
としてろ取した。次いでこれを含水エタノールで洗浄し
た。収量 ７．ａ５ＩＣ８８，９％ン融点 １９２−１
９８’Ｃ，（α〕翌−１２，５°（ｃ−１，０５，、Ｄ
ＭＦ）、 Ｒｆ’ ０．５０元素分析 Ｃ８２Ｈ１
□４０２□’１５ Ｓ４として計算値： Ｃ，５５，
５１ｉ Ｈ，６，４８ｉ Ｎ、１１．８４ｉＳ、７．２
８
実験値： Ｃ，５５，６６； ｕ、６．７４Ｂ Ｎ、
１１．８８；Ｓ、６．５５
．２４ １１ｏａ−８８ｒ−Ｈｌｓ−’Ｉ’ｒｐ、
（Ｍｔｒ）二Ａｌａ−Ｖａｌ−Ｇｌｙ−Ｈ１ｓ−Ｌｅｕ
−Ｍｅｔ−Ｎｌ２の製造Ｂｏｏ−８ｏｒ−１（１ｓ（Ｍ
ｔｒ）−Ｔｒｐ（ＭｔｒノーＡｌａ−Ｖａｌ−Ｇｌｙ−
Ｈｌｓ（Ｍｔｒ）−Ｌｅｕ−Ｍｅｔ−Ｎｌ２ ａ、 Ｏ
ｙｆ ＤＭＦ１５ｔＨｌにとかし、ＨＯＢＴ ２．３
０９を加えて３０分間処理したのち、溶媒を留去し、エ
ーテ／Ｌ’を加えて粉末としてろ取ν゛へ１゜
収量 ２．１５ノ（９２，５％）
融点 １９１−１９８″Ｃ，（α〕デー１８．８゜（Ｃ
寓０．９４ 、 ＤＭｒ’） 、 Ｒｔ Ｏ，６４
元素分析 Ｃ６２Ｈ９００１５Ｎ１５ Ｓ２ ” Ｈ２
０として計算値： ｃ、５４．４５； Ｈ，６，７８
Ｂ Ｎ、１５Ｊ６；８、４．６９
実験値： Ｃ，５ａ、９２ｉ １１，６．４ａ； Ｎ
、１５．８０ｉＢ、４．８４
％Ｚ？） Ｂｏａ−Ａｈａ−Ｌｅｕ−Ｔｈｒ−Ｌｙｓ
（Ｍｔｒ）−１１ｅ−Ｔｙｒ −Ｐｒｏ−Ａｒｇ（Ｉ’
＋＋ｕ＋）−Ｇ１３’−８ｏｒ−ｆ（ｉａ−’Ｌ”ｒｐ
（Ｍｔｒ）−Ａｌａ−Ｖａｌ−Ｇｌｙ−Ｈｌ ｓ−Ｌｅ
ｕ−Ｍｅ ｔ−Ｎｌ２の製造Ｂｏａ−８ｅｒ−Ｈ１ｓ−
Ｔｒｐ（Ｍｔｒ）−Ａｌａ−Ｖａｌ−Ｇｌｙ−Ｈｌｓ−
Ｌｕｕ−ＭｅｔＮ＋１２２． ＯｆにＴＦＡ２０ｇ？を
加え、室温で１５分間処理したのち留去し、エーテルを
加えて粉末としてろ取し、乾燥した。これをＤＭＦ５ゴ
にとかし、ＴＥＡ １．２４ｍ１を加えてよくかきま
ぜたのち、エーテルを加えて沈殿させ粉末としてろ取し
た。これをエーテル２０ｍｔにとかし、Ｂｏｏ−Ａｌａ
−Ｌｅｕ−Ｔｈｒ−Ｌｙａ （Ｍｔｒ ）−工１１１−
Ｔｙｒ−Ｐｒｏ −Ａｒｇ（Ｐｍｅ）−Ｇｌ）’−ＯＨ
１，７８ｆ 、 ［１ＭＢ ０．４１１を加えたのち水
冷し、ＤＣＣ０，４７ｆ ’ｆｒ：加えて一夜かきまぜ
た。溶媒を留去したのち、エタノール−酢酸エチ〃を加
えて粉末としてろ取したのち、熱エタノールで洗浄した
。]) Added CG1.15& and stirred overnight. After removing the Pr released DCU by filtration and distilling off the solvent, water was added and the powder was collected by filtration. This was then washed with aqueous ethanol. Yield 7. a5IC88.9% Melting point 192-1
98'C, (α] Next day -12,5° (c-1,05,, D
MF), Rf' 0.50 elemental analysis C82H1
□402□'15 Calculated value as S4: C, 55,
51i H, 6, 48i N, 11.84iS, 7.2
8 Experimental value: C, 55, 66; u, 6.74B N,
11.88; S, 6.55. 24 11oa-88r-Hls-'I'rp,
(Mtr)2Ala-Val-Gly-H1s-Leu
-Production of Met-Nl2Boo-8or-1(1s(M
tr)-Trp(MtrNoAla-Val-Gly-
Hls(Mtr)-Leu-Met-Nl2 a, O
yf Dissolve in DMF15tHl, HOBT 2.3
After adding 09 and treating for 30 minutes, the solvent was distilled off, and ether/L' was added and the powder was collected by filtration. (α] Day 18.8° (C
0.94, DMr'), Rt O,64
Elemental analysis C62H90015N15 S2 ” H2
Calculated value as 0: c, 54.45; H, 6,78
B N, 15J6; 8, 4.69 Experimental value: C, 5a, 92i 11, 6.4a; N
, 15.80iB, 4.84%Z? ) Boa-Aha-Leu-Thr-Lys
(Mtr)-11e-Tyr-Pro-Arg(I'
++u+)-G13'-8or-f(ia-'L"rp
(Mtr)-Ala-Val-Gly-Hl s-Le
Production of u-Me t-Nl2 Boa-8er-H1s-
Trp(Mtr)-Ala-Val-Gly-Hls-
Luu-MetN+122. Of TFA20g? was added, treated at room temperature for 15 minutes, and then distilled off. Ether was added, the powder was collected by filtration, and dried. This was dissolved in 5 DMF, 1.24 ml of TEA was added, and the mixture was stirred well. Ether was added to precipitate the mixture, which was filtered as a powder. Dissolve this in 20 mt of ether and use Boo-Ala.
-Leu-Thr-Lya (Mtr)-Eng.111-
Tyr-Pro-Arg(Pme)-Gl)'-OH
After adding 1,78f, [1MB 0.411, it was cooled with water, DCC0,47f'fr: and stirred overnight. After distilling off the solvent, ethanol-ethyl acetate was added to the powder, which was collected by filtration and washed with hot ethanol.
収ｆｆｉ ａ、ａＯｆ（９９，７％）融点 ２２２−
２２８ ’Ｃ（分解）
（（ｔ ）２３−２２．８°（Ｃ−１，０２，ＤＩＪＰ
）、ｎｒ”０．６７元素分析 Ｃ１２９Ｈ１９３０３１
Ｎ２８３４・８１（２０として計算値： Ｃ，ｓａ、
ａ４ｉ Ｈ，７，２５＋ Ｎ、１ａ、５０；Ｓ、４．４
２
央験！１１ ： Ｃ，５Ｂ、７３５７ １（，６，
９８； Ｎ、１２．９１ｉ８．４．５８
茜 Ｂｏｏ−Ａｌａ−Ｐｒｏ−Ｌｏｕ−Ｇｌｎ−Ｐｒ
ｏ−Ｇｌｙ−Ｇｌｙ−８ｅｒ−Ｐｒｏ−Ａｌａ−Ｌｅｕ
−Ｔｈｒ−Ｌｙｏ（Ｍｔｒ）−Ｉｃｅ−’ｌ’ｙｒ−Ｐ
ｒｏ−Ａｒｇ（Ｐｍｅ ）−Ｇｌｙ−８ｅｒ−１１ｅ（
Ｍｔ、ｒ）−Ｔｒｐ（Ｍしｒ）−Ａｌａ−Ｖａｌ−Ｇｌ
ｙ−Ｈｌｓ−Ｔ、ａｕ−Ｍθｔ−Ｎｌ２の製造Ｂｏｏ−
Ａｌａ−Ｌｅｕ−Ｔｋｓｒ−Ｌ７［！（Ｍｔｒ）−１１
，ｅ−Ｔｙｒ−Ｐｒ。Absorption a, aOf (99,7%) Melting point 222-
228'C (decomposition) ((t)23-22.8°(C-1,02,DIJP
), nr"0.67 elemental analysis C129H193031
N2834・81 (calculated value as 20: C, sa,
a4i H, 7, 25+ N, 1a, 50; S, 4.4
2 Central exam! 11: C,5B,7357 1(,6,
98; N, 12.91i8.4.58 Akane Boo-Ala-Pro-Lou-Gln-Pr
o-Gly-Gly-8er-Pro-Ala-Leu
-Thr-Lyo(Mtr)-Ice-'l'yr-P
ro-Arg(Pme)-Gly-8er-11e(
Mt,r)-Trp(Mshir)-Ala-Val-Gl
Production of y-Hls-T, au-Mθt-Nl2 Boo-
Ala-Leu-Tksr-L7 [! (Mtr)-11
, e-Tyr-Pr.
−Ａｒｇ（Ｐｍｅ）−Ｇｌｙ−８ｅｒ−ｆ（ｉｕ−Ｔｒ
ｐ（Ｍｔｒ） −Ａｌａ−Ｖａｌ−Ｇｌｙ−Ｈｌｓ−Ｌ
ｅｕ−Ｍｅｔ−Ｎｌ２５００ ’９に、ＴＦＡ５１ｔを
加え、ふυまぜたのち留去し、エーテルを加えて粉末と
してろ取した。これ°をＤＭＦ１ｍ／にとかじ、ＴＥＡ
０．２ｍｌを加えてよくかきまぜたのち、エーテル
を加えて粉末としてろ取した。これを、ＤＭＦ５１／に
とかし、Ｂｏｏ−Ａｌａ−Ｐｒｏ−Ｌｎｕ−Ｇｉｎ −
Ｐｒｏ−Ｇｌｙ−Ｇａｙ−８ｅｒ−Ｐｒｏ−ＯＨ２１７
Ｑ 、 ＨＯＩＩＴ５０ｑ／を加えたのち水冷し、ＤＣ
Ｃ１６０Ｍ１ｋ加えて一夜かきまぜた。析出した１）Ｃ
Ｕをろ去したのち、癖謀を留去し、残留物に酢酸エチル
を加えて粉末としてろ取した。これをＤＭＦ−メタノー
ルにとかし、約８０分間加熱したのち、メタノールを留
去し、残留物に酢酸エチ／Ｉ／を加えて粉末としてろ取
した。次いでこれをメタノール−水で洗浄した。収量
４８０呼（７２，２％）融点 ２０ Ｂ −２０８”Ｃ
（分解］〔α〕七Ｂ−８５，２（Ｃ冒０．９ａ、ＤＭＩ
’）。-Arg(Pme)-Gly-8er-f(iu-Tr
p(Mtr)-Ala-Val-Gly-Hls-L
TFA51t was added to eu-Met-Nl2500'9, stirred, and then distilled off. Ether was added and the mixture was filtered as a powder. Transfer this ° to DMF1m/TEA
After adding 0.2 ml and stirring well, ether was added and the powder was collected by filtration. Dissolve this in DMF51/Boo-Ala-Pro-Lnu-Gin -
Pro-Gly-Gay-8er-Pro-OH217
Q, After adding HOIIT50q/, cool with water, and DC
I added C160M1k and stirred it overnight. Precipitated 1)C
After U was filtered off, the filtrate was distilled off, and ethyl acetate was added to the residue, which was filtered as a powder. This was dissolved in DMF-methanol and heated for about 80 minutes, then the methanol was distilled off, and ethyl acetate/I/ was added to the residue, which was filtered as a powder. This was then washed with methanol-water. yield
480 No. (72,2%) Melting point 20 B -208”C
(Decomposition) [α] 7B-85,2 (C 0.9a, DMI
').
Ｒｆ３０．６６
元素分析 Ｃ１６５Ｈ２４９０４２Ｎ３８ Ｓｉ・６
Ｈ２０として計′＃、値： Ｃ，５ａ、９５ｉ Ｈ，
７゜１６； ｕ、１４．４９＋Ｓ、 ８．４９
実験値： Ｃ，５４，０８，Ｈ，６，８７ｉ Ｎ、１
４．１９＋８、８．４８
（３／） Ｈ−Ａｌａ−Ｐｒｏ−Ｌｏｕ−Ｇｌｎ−Ｐｒ
ｏ−Ｇｌｙ−Ｇ１３’−８ｏｒ−Ｐｒｏ−Ａｌａ−Ｌｅ
ｕ−Ｔｈｒ−Ｌｙｓ−工１θ−Ｔｙｒ−Ｐｒｏ−Ａｒｇ
−ｏ１ｙ−８ｅ ｒ−１１１５−Ｔｒｐ−Ａｌａ−Ｖａ
ｌ−Ｇｌｙ−１４１ａ−Ｌｅｕ−Ｍｏ ｔ −ＮＦ２（
島ＧＲＰ）の製造
１３ｏｏ−Ａｌａ−Ｐｒｏ−Ｌｅｕ−Ｇｌｎ−Ｐｒｏ−
Ｇｌｙ−Ｇｌｙ−８ｏｒ−Ｐｒｏ−Ａｌａ−Ｌｅｕ−Ｔ
ｈｒ−Ｌｙｓ（ＭｔｒＪ−工１ｅ−Ｔｙｒ−Ｐｒｏ −
Ａｒｇ（Ｐｎｌｏ）−Ｇｌｙ−８ｅｒ−Ｈ１ｓ＝Ｔｒｐ
（Ｍｔｒ）−Ａｌａ−Ｖａｌ−Ｇｌｙ−Ｈｌｓ−Ｌｅｕ
−Ｍｅｔ ＮＦ２１００”ｆに０．３Ｍメタンスルホン
酸／ＴＦＡ−チオアニソ−／Ｉ／（９：１）８ｔｔｔを
加え、室温で２時間ふＱ′１ぜたのち酢酸アンモニア１
００ｑを加えてＴＢ”Ａを留去し、工−テＡ／’ｉ加え
て粉末としてろ取した。これを少量のＩＮ酢酸水にとか
し、セファデックスＧ−２５のカラム（２，２Ｘ１２０
ｃｍ）に付した。ＩＮ−酢酸で浴出しＩＴＯｗｌ−２７
０ｇ／の分画を取り、凍結乾燥したのち、少量の水にと
かしＡｍｂθｒｌｉ ｔｅＩＲＡ ４１０（１ｘｌＯ
ｍ）のカラムを通したのち、カルボキシメチルセルロー
スのカラム（２，２Ｘ１７Ｑｌ）に付した。水（４００
ｍｌ）−〇、４Ｍ酢酸アンモニア水Ｃ４０Ｃ４０Ｏの線
型勾配法で溶出し、３３５〜８６５ｔｘｌの分１ＩｈＩ
を集めて凍結乾燥した。収量 ２８ｑ（８５％）。Rf30.66 Elemental analysis C165H249042N38 Si・6
Total '# as H20, value: C, 5a, 95i H,
7゜16; u, 14.49+S, 8.49 Experimental value: C, 54,08, H, 6,87i N, 1
4.19+8, 8.48 (3/) H-Ala-Pro-Lou-Gln-Pr
o-Gly-G13'-8or-Pro-Ala-Le
u-Thr-Lys-1θ-Tyr-Pro-Arg
-o1y-8e r-1115-Trp-Ala-Va
l-Gly-141a-Leu-Mo t -NF2 (
13oo-Ala-Pro-Leu-Gln-Pro-
Gly-Gly-8or-Pro-Ala-Leu-T
hr-Lys(MtrJ-Eng.1e-Tyr-Pro-
Arg(Pnlo)-Gly-8er-H1s=Trp
(Mtr)-Ala-Val-Gly-Hls-Leu
-Met NF2100"f was added with 8ttt of 0.3M methanesulfonic acid/TFA-thioaniso-/I/(9:1), and after 2 hours at room temperature, ammonia acetate 1
00q was added to distill off TB''A, and TB''A was added and collected by filtration as a powder. This was dissolved in a small amount of IN acetic acid water, and the column of Sephadex G-25 (2.2 x 120
cm). IN-Acetic acid bathing ITOwl-27
A fraction of 0 g/ml was taken, freeze-dried, and then dissolved in a small amount of water.
After passing through the column (m), it was applied to a carboxymethyl cellulose column (2,2×17Ql). Water (400
ml)-〇, eluted with a linear gradient method of 4M aqueous ammonia acetate C40C40O, 335-865txl of 1IhI
were collected and freeze-dried. Yield 28q (85%).
（ｃｌ ）七２−１０２．２°（ｃ −ｏ、ａ ２ 、
１％ａｌ”ｍ）Ｒｆ４０．Ｇ９
アミノ酸分析ｆｆ（４％チオグリコール酸／６Ｎ塩酸加
水分解） ： Ｌ３’８１．００（１）！ ｆ（ｉａ
ｔ、７ａ（２Ｊ＋ｒｃ
ｉ”ｌｎｒ
ｌｙ
Ｍｅｔ
ｙｒ
１．０４ （１１Ｔｒｐ Ｏ，Ｇ７ （１）Ｂ Ｔ
ｈｒｌ、７７ （２）＋ Ｇｌｕ １．１１（１）ｔ
’Ｐｒ。(cl)72-102.2°(c-o, a2,
1% al”m) Rf40.G9 Amino acid analysis ff (4% thioglycolic acid/6N hydrochloric acid hydrolysis): L3'81.00 (1)! f(ia
t, 7a (2J+rc i”lnr ly Met yr 1.04 (11Trp O,G7 (1) B T
hrl, 77 (2) + Glu 1.11 (1)t
'Pr.
４．２８ （４） ＨＡｈａ ａ、１９（３）ｉ Ｖ
ｌｌｌｌ、０２ （１） ｌ 工１ｅ ０ 、９６
（１） ｌ ’Ｌｅｕ１．００（Ｉ） （平均回収率
７８．７％１．０６ （１） ＋
４．２０ （４） ｓ
１．０６ （１） ！
８．０４（３）ｉ
ノ4.28 (4) HAha a, 19(3)i V
llll, 02 (1) l 工１e 0, 96
(1) l 'Leu1.00 (I) (Average recovery rate 78.7% 1.06 (1) + 4.20 (4) s 1.06 (1) ! 8.04 (3) i ノ
Claims (3)
するペプチドの製造にあたり、ω−アミノ基または（お
よび）α−アミノ基含有アミノ酸またはペプチドのω−
アミノ基または（および）α−アミノ基を、４−メトキ
シ−２，３，６−トリメチルベンゼンスルホニル基で保
護し、ペプチド縮合したのら、該保護基を酸で脱離せし
めることを特徴とするペプチドの製造法。(1) When producing a peptide having an ω-amino group or (and) an α-amino group, the ω-amino acid or peptide containing an ω-amino group or (and) an α-amino group
The amino group or (and) α-amino group is protected with a 4-methoxy-2,3,6-trimethylbenzenesulfonyl group, the peptide is condensed, and then the protecting group is removed with an acid. Method for producing peptides.
ンスルホン酸を用いる特許請求の範囲第（１）項記載の
製造法。(2) The production method according to claim (1), in which trifluoroacetic acid or (and) methanesulfonic acid is used as the acid.
特許請求の範囲第（１）項または第（２）項記載の製造
法。(3) The manufacturing method according to claim (1) or (2), wherein the protecting group is removed in the presence of thioanisole.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1086537A JPH0215094A (en) | 1989-04-05 | 1989-04-05 | Preparation of peptide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1086537A JPH0215094A (en) | 1989-04-05 | 1989-04-05 | Preparation of peptide |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56174125A Division JPS5874648A (en) | 1981-10-29 | 1981-10-29 | Preparation of peptide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0215094A true JPH0215094A (en) | 1990-01-18 |
| JPH0224835B2 JPH0224835B2 (en) | 1990-05-30 |
Family
ID=13889750
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1086537A Granted JPH0215094A (en) | 1989-04-05 | 1989-04-05 | Preparation of peptide |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0215094A (en) |
-
1989
- 1989-04-05 JP JP1086537A patent/JPH0215094A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0224835B2 (en) | 1990-05-30 |
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