JPS6055080B2 - tetrapeptide - Google Patents
tetrapeptideInfo
- Publication number
- JPS6055080B2 JPS6055080B2 JP54102381A JP10238179A JPS6055080B2 JP S6055080 B2 JPS6055080 B2 JP S6055080B2 JP 54102381 A JP54102381 A JP 54102381A JP 10238179 A JP10238179 A JP 10238179A JP S6055080 B2 JPS6055080 B2 JP S6055080B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- distilled
- reduced pressure
- under reduced
- added
- 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.)
- Expired
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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
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
【発明の詳細な説明】 本発明は新規なテトラペプチドに関する。[Detailed description of the invention] The present invention relates to novel tetrapeptides.
本発明の化合物は文献未載の新規化合物であり、一般式
Ｈ−Ｔｙｒ−Ｘ−Ｇｌｙ−Ｐｈｅ−ｏｌ（１）〔式中Ｘ
はＧｌｙ又はＡｌａを示す。The compound of the present invention is a new compound that has not been described in any literature, and has the general formula H-Tyr-X-Gly-Phe-ol (1) [in the formula
represents Gly or Ala.
〕で表わされるテトラペプチド及びその塩である。] and its salts.
本発明の化合物はオピエート受容体においてアコニスト
活性作用を有し、鎮静薬、麻酔薬、麻薬拮抗薬及び抗下
痢薬として有用である。また本発明の化合物は低毒性で
あり、上記作用の持続時間も長い。本明細書に於て、ア
ミノ酸に関して略号を使用する場合ＩＵＰＡＣＮＩＵＢ
の規定或いは当該分野における慣用記号に従うものとす
るが、Ｄ、Ｌ又はＤＬ体と明示しない限りこれらすべて
を含むものとする。The compounds of this invention have aconist active action at opiate receptors and are useful as sedatives, anesthetics, narcotic antagonists and anti-diarrheal agents. Furthermore, the compounds of the present invention have low toxicity and the duration of the above action is long. In this specification, when using abbreviations for amino acids, IUPACNIUB
or the common symbols in the field, but unless explicitly stated as D, L, or DL, all of these shall be included.
また−Ｐｈｅ−ｏｌとはフェニルアラニンのＣＯＯＨ基
が還元されてＣＨ２０Ｈ基になつたもの即−ＮＨ−ＣＨ
−℃Ｈ２ＯＨち 肖 を意味する。In addition, -Phe-ol is the product in which the COOH group of phenylalanine is reduced to a CH20H group, i.e. -NH-CH
-℃H2OH means.
、／ 本発明の代表的な化合物を以下に挙げる。,/ Representative compounds of the present invention are listed below.
〇Ｌ−チロシルーグリシルーＬ−フエニルアラニノーノ
レ。〇L-tyrosylglycyl-L-phenylalaninol.
Ｄ−チロシルーグリシルーグリシルーＬ−フエニルア
ラニノールｏ Ｌ−チロシルーＤ−アラニルーグリシル
ーＬーフエニルアラニノールｏ Ｄ−チロシルーＬ−ア
ラニルーグリシルーＤーフエニルアラニノール上記一般
式（１）で表わされる本発明の化合物は通常のペプチド
合成法即ち溶液合成法や固相ペプチド合成法により容易
に製造される。D-Tyrosyl-Glycyl-Glycyl-L-Phenylalaninol o L-Tyrosyl-D-Alanyl-Glycyl-L-Phenylalaninol o D-Tyrosyl-L-Alanyl-Glycyl-D-Phenylalaninol The above general formula ( The compound of the present invention represented by 1) can be easily produced by a conventional peptide synthesis method, that is, a solution synthesis method or a solid phase peptide synthesis method.
斯かるペプチドの合成法としては例えば適当に保護され
且つ活・性化されたアミノ酸同士をＣ−末端より段階的
に結合させる方法、所望のアミノ酸を含む適当な単位の
ペプチドをカップリングさせる方法等を挙げることがで
きる。更に詳しくは本発明の化合物は例えば次のように
して製造される。Methods for synthesizing such peptides include, for example, a method in which appropriately protected and activated amino acids are coupled stepwise from the C-terminus, a method in which an appropriate unit of peptide containing a desired amino acid is coupled, etc. can be mentioned. More specifically, the compound of the present invention is produced, for example, as follows.
即ちまず一般式〔式中Ｒ１はアミノ基の保護基を示す。That is, first, the general formula [wherein R1 represents a protecting group for an amino group] is used.
〕で表わされるチロシン誘導体と一般式〔式中Ｒ２はカ
ルボキシル基の保護基を示す。] and a tyrosine derivative represented by the general formula [wherein R2 represents a carboxyl group protecting group].
Ｘは前記に同じ。〕で表わされるアミノ酸を用い、通常
のペプチド結合生成反応、例えばＤＣＣによる縮合法に
従つて一般式〔式中Ｒｌ，Ｒ２及びＸは前記に同じ。X is the same as above. ] using the amino acid represented by the general formula [where Rl, R2 and
〕で表わされるペプチドが製造される。また一般式
Ｖｖ−ー
％Ｖ′〔式中Ｒ３はアミノ基の保護基、Ｒ４はカ
ルボキシル基の保護基を示す。] is produced. Also general formula
Vv-
%V' [In the formula, R3 represents an amino group-protecting group, and R4 represents a carboxyl group-protecting group.
〕で表わされるジペプチドを水素化硼素ナトリウムで還
元し、次いで脱保護基反応させることにより式で表わさ
れるジペプチドが製造される。] The dipeptide represented by the formula is reduced by sodium borohydride and then subjected to a deprotection reaction to produce the dipeptide represented by the formula.
斯くして製造される一般式（５）のジペプチドと式（６
）のジペプチドとを用い通常のペプチド結合生成反応、
例えばアジド法に従えば一般式〔式中Ｒ１及びＸは前記
に同じ。The dipeptide of general formula (5) produced in this way and the dipeptide of formula (6)
) using a dipeptide, a normal peptide bond formation reaction,
For example, according to the azide method, the general formula [wherein R1 and X are the same as above] is obtained.
〕で表わされるテトラペプチドが製造され、次にこの一
般式（７）のテトラペプチドから通常の脱保護基手段に
より保護基を除去することにより、本発明の化合物が容
易に製造される。斯くして得られる本発明の化合物はペ
プチドを分離するのに通常行われている慣用手段により
容易に単離精製される。The compound of the present invention can be easily produced by producing a tetrapeptide represented by formula (7), and then removing the protecting group from the tetrapeptide of general formula (7) by a conventional deprotecting method. The compound of the present invention thus obtained can be easily isolated and purified by conventional means commonly used to separate peptides.
上記一般式（１）の化合物は医薬的に許容され得る酸と
容易に酸付加塩を形成させることができ、斯かる塩も本
発明化合物に包合される。The compound of general formula (1) above can easily form an acid addition salt with a pharmaceutically acceptable acid, and such salts are also included in the compounds of the present invention.
用いられる塩としては例えは塩化水素、臭化水素等のハ
ロゲ．ン化水素、硫酸、硝酸等の無機酸、シユウ酸、マ
レイン酸、クエン酸、酒石酸、酢酸、ｐ−トルエンスル
ホン酸等の有機酸等を挙げることができる。尚本発明の
化合物には光学異性体及びラセミ体のいずれも包合する
。以下に本発明化合物の製造例を実施例として掲げる。Examples of salts that can be used include halogens such as hydrogen chloride and hydrogen bromide. Examples include inorganic acids such as hydrogen chloride, sulfuric acid and nitric acid, and organic acids such as oxalic acid, maleic acid, citric acid, tartaric acid, acetic acid and p-toluenesulfonic acid. The compounds of the present invention include both optical isomers and racemates. Production examples of the compounds of the present invention are listed below as Examples.
実施例に於ては下記の略語を使用する。ＤＣＣ＝ジシク
ロヘキシルカルボジイミドＤＭＦ＝ジメチルホルムアミ
ド
ＴＦＡ＝トリフルオロ酢酸
またＲｆ値はシリカゲル〔メルク社、キーゼルゲル６０
Ｆ２５，〕上の薄層クロマトグラフィー（ＴＬＣ）にて
、下記混合溶媒を用いて測定したものである。The following abbreviations are used in the examples. DCC = dicyclohexylcarbodiimide DMF = dimethylformamide TFA = trifluoroacetic acid and Rf value is silica gel [Merck & Co., Kieselgel 60
F25,] was measured by thin layer chromatography (TLC) using the following mixed solvent.
ＲｆｌＩクロロホルム−メタノールー水（８： ３：
１）Ｒｆ２・・・ｎ−ブタノールー酢酸一水（３：１：
１）Ｒｆ３・・・クロロホルム−メタノール（１０
：１）Ｒｆ，・・・クロロホルム−メタノール（２０：
１）実施例１Ｌ−チロシルーグリシルーグリシルーＬ−
フエニルアラニノールの製造ｊ第一工程：ｐ−メトキシ
ベンジルオキシカルボニ ルーグリシルーＬ−フ
エニルアラニノ ール（化合物Ａ）ｐ−メトキシ
ベンジルオキシカルボニルーグリシルーＬ−フェニルア
ラニンメチルエステル３ｆ″をメタノール３０ｍ１に溶
解し、氷冷下ＮａＢＨ，２．９ｆＩを除々に加えた。RflI chloroform-methanol-water (8:3:
1) Rf2...n-butanol-acetic acid monohydrate (3:1:
1) Rf3...Chloroform-methanol (10
:1) Rf,...Chloroform-methanol (20:
1) Example 1L-Tyrosyl-glycyl-glycyl-L-
Production of phenylalaninol First step: p-methoxybenzyloxycarbonylglycyl-L-phenylalaninol (compound A) p-methoxybenzyloxycarbonylglycyl-L-phenylalanine methyl ester 3f'' was dissolved in 30 ml of methanol. , NaBH and 2.9 fI were gradually added under ice-cooling.
室温で３時間攪拌した後、３０％酢酸で酸性にし（ＰＨ
４〜５）、溶媒を減圧留去した。残渣を酢酸エチルに溶
解し、１０％クエン酸、５％炭酸水素ナトリウム、飽和
食塩水で順次洗浄した。Ｎａ２ｓＯ４で乾燥後、抽出液
を留去し、残渣を酢酸エチルより再結晶し、ＭｐｌｌＯ
〜１１３Ｃの目的物２．４ｙを得た。Ｒｆｌ：０．７′
５ｓＲｆ，：０．５８
元素分析値（Ｃ２ＯＨ２，Ｏ５Ｎ２として） 理論値（
％）Ｃ６４．５Ｏ；Ｈ６．５Ｏ；Ｎ７．５２分析値（％
）Ｃ６４．６３；Ｈ６．６９；Ｎ７．５５第二工程：ｐ
−メトキシベンジルオキシカルボニ ルーＬ−チ
ロシルーグリシルーグリシ ルーＬ−フエニルア
ラニノール（化合 物Ｂ）ｐ−メトキシベンジル
カルボニルーＬ−チロシルーグリシンヒドラジド（Ｈ．
Ｙａｊｉｍａｅｔａｌ．，Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕ
ｌｌ．，２６，２ｌ３９（１９７８））８３３ｍｇをＤ
ＭＦ２Ｏｍｌに溶解し、冷却下（約−３０℃）１．９Ｎ
ＨＣ１−ＤＩｆ２．８ｍｌ及び亜硝酸イソアミル０．３
ｍ１を加え、約２０分攪拌後トリエチルアミン０．８ｍ
１を加え中和した。After stirring at room temperature for 3 hours, it was acidified with 30% acetic acid (PH
4-5), the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 10% citric acid, 5% sodium hydrogen carbonate, and saturated brine. After drying with Na2sO4, the extract was distilled off, the residue was recrystallized from ethyl acetate, and MpllO
2.4y of the target product of ~113C was obtained. Rfl:0.7'
5sRf,: 0.58 Elemental analysis value (as C2OH2, O5N2) Theoretical value (
%) C64.5O; H6.5O; N7.52 analysis value (%
) C64.63; H6.69; N7.55 Second step: p
-methoxybenzyloxycarbonyl-L-tyrosyl-glycyl-glycine-L-phenylalaninol (Compound B) p-methoxybenzylcarbonyl-L-tyrosyl-glycine hydrazide (H.
Yajimaetal. , Chem. Pharm. Bu
ll. , 26, 2l39 (1978)) 833 mg D
Dissolved in MF2Oml and cooled (approximately -30℃) at 1.9N.
HC1-DIf2.8ml and isoamyl nitrite 0.3
After stirring for about 20 minutes, add 0.8 m of triethylamine.
1 was added to neutralize.
一方化合物Ａ（実施例１の第一工程）７４５ｍ９、アニ
ソール０．６ｍ１をＴＦ′Ａ５ｍｌに溶解し、氷冷下１
時間攪拌後過剰のＴＦ′Ａを減圧留去）し、残渣を数回
石油エーテルで洗浄した。On the other hand, 745 m9 of compound A (first step of Example 1) and 0.6 ml of anisole were dissolved in 5 ml of TF'A, and
After stirring for an hour, excess TF'A was distilled off under reduced pressure), and the residue was washed several times with petroleum ether.
ＮａＯＨペレット上で減圧乾燥した後、ＤＭＦｌ５ｍｌ
に溶解し、トリエチルアミンを加えて中和した。両液を
合し、４℃にて詔時間攪拌後溶媒を減圧留去し、残渣を
酢酸エチルに溶解し、１０％クエン酸、５％炭酸ナトリ
ウム、飽和食塩水で順次洗浄した。Ｎａ２ｓＯ４て乾燥
後、抽出液を減圧留去し、残渣をシリカゲルカラムクロ
マトグラフィー（カラム２．５Ｃｒｆ１ｘあｄ１クロロ
ホルムニメタノールニ１０：１て溶出）により精製し、
Ｍｐｌ８４〜１８８℃の目的物５２０ｍ９を得た。Ｒｆ
ｌ：０．５ｅＩＳＲｆ３：０．１９
元素分析値（Ｃ３ｌＨ３６Ｏ８Ｎ４として）理論値（％
）Ｃ６２．８２；Ｈ６．ｌ２；Ｎ９．４５分析値（％）
Ｃ６２．３６；Ｈ６．３９；Ｎ９．ｌ７第三工程：Ｌ−
チロシルーグリシルーグリシルー Ｌ−フエニルア
ラニノール（化合物 Ｃ）
化合物Ｂ（実施例１の第二工程）１２７Ｔｎ９、アニソ
ール０．０６ｍ１をＴＦＡ３ｍｌに溶解し、氷冷下１時
間攪拌した後過剰のＴＦＡを減圧留去し、残渣にエーテ
ルを加え析出した結晶を枦取した。After vacuum drying on NaOH pellets, 5 ml of DMF1
and neutralized by adding triethylamine. Both solutions were combined and stirred at 4°C for a period of time, then the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and washed successively with 10% citric acid, 5% sodium carbonate, and saturated brine. After drying over Na2sO4, the extract was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (column eluted with 2.5Crf1xad1chloroformimethanol-210:1).
520 m9 of the target product with a Mpl of 84 to 188°C was obtained. Rf
l:0.5eISRf3:0.19 Elemental analysis value (as C3lH36O8N4) Theoretical value (%
) C62.82; H6. l2; N9.45 analysis value (%)
C62.36; H6.39; N9. l7 Third step: L-
Tyrosyl-glycyl-glycyl-L-phenylalaninol (Compound C) Compound B (Second Step of Example 1) 127Tn9 and 0.06 ml of anisole were dissolved in 3 ml of TFA, stirred for 1 hour under ice cooling, and then excess TFA was dissolved. was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals were collected.
３０％酢酸に溶解し、アンパーライトＩＲＡ−４００（
アセテートフォーム）約２ｙを加え室温で３０分攪拌し
た。Dissolved in 30% acetic acid, Amperlite IRA-400 (
About 2y of acetate foam) was added and stirred at room temperature for 30 minutes.
溶媒を減圧留去し、残渣に数回メタノールを加え減圧留
去した。エーテルを加え析出した結晶を枦取し、化合物
Ｃ６Ｏｍ９を得た。Ｒｆｌ：０．２２、Ｒｆ２：０．５
０
元素分析値（Ｃ２２Ｈ２８へＮ４・ＣＨ３ＣＯ２Ｈ・３
１２Ｈ２０として）理論値（％）Ｃ５５．９ｌ；Ｈ６．
８４：ＮｌＯ．８７分析値（％）Ｃ５５．６ｌ；Ｈ６．
６８；ＮｌＯ．５６実施例２Ｌ−チロシルーＤ−アラニ
ルーグリシルーＬ一フエニルアラニノール第一工程：Ｎ
−ｐ−メトキシベンジルオキシカル ボニルーＬ−
チロシルーＤ−アラニン メチルエステル（化合物
Ｄ）ｐ−メトキシベンジルオキシカルボニルーＬ−チロ
シン３４．５ｆＩの酢酸エチル２００ｍ１溶液に氷冷下
ＤＣＣ２Ｏ．６Ｖを加え、２紛後Ｄ−アラニンメチルエ
・ステル（Ｄ−アラニンメチルエステル塩酸塩１４．０
ｆをトリエチルアミン１４ｍ１で中和して得た）のＤＭ
Ｆ８Ｏｍｌ溶液を加えた。The solvent was distilled off under reduced pressure, and methanol was added to the residue several times and the mixture was distilled off under reduced pressure. Ether was added and the precipitated crystals were collected to obtain compound C6Om9. Rfl: 0.22, Rf2: 0.5
0 Elemental analysis value (N4・CH3CO2H・3 to C22H28
12H20) Theoretical value (%) C55.9l; H6.
84:NlO. 87 Analysis value (%) C55.6l; H6.
68;NlO. 56 Example 2 L-Tyrosyl-D-Alanyl-Glycyl-L-Phenylalaninol First step: N
-p-methoxybenzyloxycarbonyl L-
Tyrosyl-D-alanine methyl ester (Compound D) A solution of 34.5 fI of p-methoxybenzyloxycarbonyl-L-tyrosine in 200 ml of ethyl acetate was added with DCC2O. under ice cooling. 6V was added, and after 2 powders D-alanine methyl ester (D-alanine methyl ester hydrochloride 14.0
DM of ) obtained by neutralizing f with 14 ml of triethylamine
Added F80ml solution.
２＠間後析出した尿素誘導体を枦別し、枦液を減圧留去
し、残渣を酢酸エチルに溶解し、１０％クエン酸、５％
炭酸ナトリウム、飽和食塩水で順次洗浄した。After 2 hours, the precipitated urea derivative was separated, the urea solution was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, 10% citric acid, 5%
It was washed successively with sodium carbonate and saturated saline.
Ｎａ２ｓＯ，乾燥後、抽出液を減圧留去し、残渣をエー
テルて洗浄し、粗生成物３２．５ｙを得た。さらに精製
することなく次の行程に供した。第二工程：Ｎ−ｐ−メ
トキシベンジルオキシカル ボニルーＬ−チロシ
ルーＤ−アラニル ヒドラジド（化合物Ｅ）化合
物Ｄ（実施例２の第一工程）２０ｙのメタノール３００
ｍｔ溶液にＨ２ＮＮＨ２・Ｈ２Ｏｌ２ｍｌを加え一晩放
置し析出した結晶を淵取した。After drying with Na2sO, the extract was distilled off under reduced pressure, and the residue was washed with ether to obtain 32.5y of a crude product. It was used in the next step without further purification. Second step: N-p-methoxybenzyloxycarbonyl-L-tyrosyl-D-alanyl hydrazide (compound E) compound D (first step of Example 2) 20y of methanol 300
2 ml of H2NNH2.H2Ol was added to the mt solution and allowed to stand overnight, and the precipitated crystals were collected.
エタノールで十分洗浄し、Ｍｐｌ９Ｏ−１９５℃の目的
物１７ｙを得た。Ｒｆｌ：０．５３元素分析値（Ｃ２ｌ
Ｈ２６Ｏ６Ｎ４・１′洪０として） 理論値（％）Ｃ５
７．３９；Ｈ６．ｌ９；Ｎｌ２．７５分析値（％）Ｃ５
７．６８；Ｈ６．ｌ２；Ｎｌ２．６ｌ第三工程：Ｎ−ｐ
−メトキシベンジルオキシカル ボニルーＬ−チ
ロシルーＤ−アラニル ーグリシルーＬ−フエニ
ルアラニノー ル（化合物Ｆ）化合物Ｅ（実施例
２の第二工程）８６１ｍ９をＤＭＦ２Ｏｍｌに溶解し、
冷却下（約−３０℃）、１．９ＮＨＣ１−ＤＩｆ２．８
ｍｌ及び亜硝酸イソアミル０．３ｍ１を加え、約２０分
攪拌後トリエチルアミン０．８ｍ１を加え中和した。After sufficient washing with ethanol, target product 17y having a temperature of Mpl9O-195°C was obtained. Rfl: 0.53 elemental analysis value (C2l
H26O6N4・1'Hong0) Theoretical value (%) C5
7.39; H6. l9; Nl2.75 analysis value (%) C5
7.68;H6. l2; Nl2.6l Third step: N-p
-Methoxybenzyloxycarbonyl-L-tyrosyl-D-alanyl-glycyl-L-phenylalaninol (Compound F) Compound E (Second Step of Example 2) 861 m9 was dissolved in DMF2Oml,
Under cooling (approximately -30°C), 1.9NHC1-DIf2.8
ml and 0.3 ml of isoamyl nitrite were added, and after stirring for about 20 minutes, 0.8 ml of triethylamine was added to neutralize.
一方化合物Ａ（実施例１の第一工程）７４５ｍ９、アニ
ソール０．６ｍ１をＴＦＡ５ｍｌに溶解し、氷冷下１時
間攪拌後過剰のＴＦ′Ａを減圧留去し、残渣を数回石油
エーテルで洗浄した。ＮａＯＨペレット上で減圧乾燥し
た後、ＤＭＦｌＯｍｔに溶解しトリエチルアミンを加え
て中和した。両液を合し、４℃にて酩時間攪拌後溶媒を
減圧留去し、残渣を酢酸エチルに溶解し、１０％クエン
酸、５％炭酸ナトリウム、飽和食塩水で順次洗浄した。
・Ｎａ２ｓＯ４で乾燥後、抽出液を減圧留去し、残渣を
メタノ−ルー酢酸エチルより再結晶し、Ｍｐｌ９４−１
９７００Ｃの目的物４３０ｍｇを得た。Ｒｆｌ：０．５
８元素分析値（Ｃ，２Ｈ３８Ｏ８Ｎ４として）ｊ 理
論値（％）Ｃ６３．３５；Ｈ６．３ｌ；Ｎ９．２４分析
値（％）Ｃ６２．９ｌ；Ｈ６．４７；Ｎ８．９ｌ第四工
程：Ｌ−チロシルーＤ−アラニルーグリシ ルー
Ｌ−フエニルアラニノール（化合 物Ｇ）化合物
Ｆ（実施例２第三工程）、アニソール０．１ｍ１をＴＦ
′Ａ３ｍｌに溶解し、氷冷下１時間攪拌した後、過剰の
ＴＦＡを減圧留去し、残渣にエーテルを加え析出した結
晶を炉留した。On the other hand, 745 ml of compound A (first step of Example 1) and 0.6 ml of anisole were dissolved in 5 ml of TFA, and after stirring for 1 hour under ice cooling, excess TF'A was distilled off under reduced pressure, and the residue was washed several times with petroleum ether. did. After drying under reduced pressure on NaOH pellets, it was dissolved in DMFiOmt and neutralized by adding triethylamine. Both solutions were combined and stirred at 4°C for an hour, then the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and washed successively with 10% citric acid, 5% sodium carbonate, and saturated brine.
・After drying with Na2sO4, the extract was distilled off under reduced pressure, and the residue was recrystallized from methanol-ethyl acetate.
430 mg of the target product of 9700C was obtained. Rfl:0.5
8 element analysis value (as C, 2H38O8N4) j Theoretical value (%) C63.35; H6.3l; N9.24 Analysis value (%) C62.9l; H6.47; N8.9l Fourth step: L-tyrosyl D-alanyl-glycyl-L-phenylalaninol (compound G), compound F (third step of Example 2), and 0.1 ml of anisole were added to TF.
After the solution was dissolved in 3 ml of A and stirred for 1 hour under ice cooling, excess TFA was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals were distilled in a furnace.
ＮａＯＨペレット上で減圧乾燥した後、３０％酢酸に溶
解し、アンパーライトＩＲＡ−４００（アセテートフォ
ーム）約２ｙを加え、室温で３扮攪拌した。溶媒を減圧
留去し、残渣に数回メタノールを加え減圧留去した。エ
ーテルを加え析出した結晶を枦取し、化合物Ｇｌ３６７
ｌ！９を得た。Ｒｆｌ：０．２６
元素分析値（Ｃ２３Ｈ３。After drying under reduced pressure on NaOH pellets, it was dissolved in 30% acetic acid, about 2 y of Amperlite IRA-400 (acetate foam) was added, and the mixture was stirred at room temperature three times. The solvent was distilled off under reduced pressure, and methanol was added to the residue several times and the mixture was distilled off under reduced pressure. Ether was added, the precipitated crystals were collected, and compound Gl367 was obtained.
l! I got a 9. Rfl: 0.26 Elemental analysis value (C23H3.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP54102381A JPS6055080B2 (en) | 1979-08-10 | 1979-08-10 | tetrapeptide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP54102381A JPS6055080B2 (en) | 1979-08-10 | 1979-08-10 | tetrapeptide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5626856A JPS5626856A (en) | 1981-03-16 |
| JPS6055080B2 true JPS6055080B2 (en) | 1985-12-03 |
Family
ID=14325867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP54102381A Expired JPS6055080B2 (en) | 1979-08-10 | 1979-08-10 | tetrapeptide |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6055080B2 (en) |
-
1979
- 1979-08-10 JP JP54102381A patent/JPS6055080B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5626856A (en) | 1981-03-16 |
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