JPS604199B2 - Method for producing aniline dipeptide derivatives - Google Patents

Method for producing aniline dipeptide derivatives

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Publication number
JPS604199B2
JPS604199B2 JP49090565A JP9056574A JPS604199B2 JP S604199 B2 JPS604199 B2 JP S604199B2 JP 49090565 A JP49090565 A JP 49090565A JP 9056574 A JP9056574 A JP 9056574A JP S604199 B2 JPS604199 B2 JP S604199B2
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JP
Japan
Prior art keywords
group
acid
formula
hydrogen
reaction
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
Application number
JP49090565A
Other languages
Japanese (ja)
Other versions
JPS5126853A (en
Inventor
健太郎 平井
暉之 石破
和幸 笹倉
裕彦 杉本
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Filing date
Publication date
Application filed by Shionogi and Co Ltd filed Critical Shionogi and Co Ltd
Priority to JP49090565A priority Critical patent/JPS604199B2/en
Priority to ZA00754877A priority patent/ZA754877B/en
Priority to CA000232782A priority patent/CA1181065A/en
Priority to NLAANVRAGE7509258,A priority patent/NL175789C/en
Priority to DK356475A priority patent/DK155088C/en
Priority to CH1020275A priority patent/CH617668A5/de
Priority to MX000859U priority patent/MX3332E/en
Priority to SE7508829A priority patent/SE427030B/en
Priority to AR259900A priority patent/AR213076A1/en
Priority to ES440032A priority patent/ES440032A1/en
Priority to HU75SI1485A priority patent/HU176016B/en
Priority to DE2535171A priority patent/DE2535171C3/en
Priority to AU83734/75A priority patent/AU491928B2/en
Priority to BE158997A priority patent/BE832190A/en
Priority to FR7524559A priority patent/FR2281131A1/en
Priority to DD187724A priority patent/DD119213A5/xx
Priority to GB32916/75A priority patent/GB1511669A/en
Publication of JPS5126853A publication Critical patent/JPS5126853A/ja
Priority to US05/716,266 priority patent/US4076703A/en
Priority to US05/716,267 priority patent/US4076704A/en
Priority to US05/716,265 priority patent/US4076702A/en
Priority to US05/716,268 priority patent/US4076705A/en
Priority to ES455504A priority patent/ES455504A1/en
Priority to ES455506A priority patent/ES455506A1/en
Priority to ES455505A priority patent/ES455505A1/en
Priority to ES455507A priority patent/ES455507A1/en
Priority to US05/775,646 priority patent/US4240957A/en
Priority to AR270154A priority patent/AR219307A1/en
Priority to AR270151A priority patent/AR213453A1/en
Priority to AR270153A priority patent/AR220325A1/en
Priority to AR270152A priority patent/AR215035A1/en
Priority to US05/867,605 priority patent/US4154727A/en
Priority to CH461779A priority patent/CH627438A5/en
Priority to CH461879A priority patent/CH627439A5/en
Priority to CH827079A priority patent/CH627440A5/en
Priority to CA339,232A priority patent/CA1091652A/en
Publication of JPS604199B2 publication Critical patent/JPS604199B2/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1027—Tetrapeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Neurology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

【発明の詳細な説明】 本発明は一般式 ［式中、 Ｒは水素またはアルキル基、 ＲＩは水素、アルキル基またはフェニル基、Ｒ２は水素
またはアルキル基、Ｒ３は水素またはハロゲン、 Ｒ４はハロゲンをそれぞれ表わす。Detailed Description of the Invention The present invention is based on the general formula [wherein R is hydrogen or an alkyl group, RI is hydrogen, an alkyl group or a phenyl group, R2 is hydrogen or an alkyl group, R3 is hydrogen or a halogen, and R4 is a halogen] Represent each.

］で示されるアニリン系ジベプチド誘導体の製造法に関
する。] The present invention relates to a method for producing an aniline dipeptide derivative shown in the following.

上記定義においてアルキル基としてはメチル、エチル、
フ。In the above definition, alkyl groups include methyl, ethyl,
centre.

ロピル、イソプロピル、ブチル、イソブチル、ｓーブチ
ル、ベンチルなど、ハロゲンとしてはフッ素、塩素、臭
素など、アミノ保護基としてはカルボベンゾキシ、メト
キシカルボニル、ｔ−ブトキシカルボニル、０ーニトロ
フヱニルスルフエニル、クロロベンジルオキシカルポニ
ル、トリトチルなどが例示される。Lopyl, isopropyl, butyl, isobutyl, s-butyl, benzyl, etc. Halogens include fluorine, chlorine, bromine, etc. Amino protecting groups include carbobenzoxy, methoxycarbonyl, t-butoxycarbonyl, 0-nitrophenylsulfenyl, Examples include chlorobenzyloxycarponyl and tritotyl.

［式中、Ｒ、Ｒ１、Ｒ２、Ｒ３、Ｒ４およびＺは前記と
同意義を有する。］本発明方法に従ってまず、（ａーア
ミン（０）とべプチド（ｍ）を、または（ｂ｝グリシン
アミド（Ｗ）とアミノ酸（Ｖ）をそれそれべプチド化反
応の常法に従って縮合させる。[In the formula, R, R1, R2, R3, R4 and Z have the same meanings as above. ] According to the method of the present invention, first, (a-amine (0) and peptide (m) or (b) glycinamide (W) and amino acid (V) are each condensed according to a conventional method for veptidation reaction.

べプチド化反応の常法（以下、ベプチド縮合と略す）と
は、アミン（０）またはグリシンアミド（Ｎ）のアミノ
基と対応するべプチド（ｍ）またはアミノ酸（Ｖ）のカ
ルボキシ基とを統合させてべプチド結合（アミン（ロ）
が関与するときはアミド結合を意味する。以下同じ。）
を形成させることを基本とするが、この目的を達成させ
るための付随的処理、例えば、ベプチド縮合に先立って
アミノ酸を反応性誘導体に導く処理、反応に関与すべき
でない活性基（例えば、アミノ基、カルボキシ基）を予
め保護するための処理等を含むものである。ここでべプ
チド（ｍ）またはアミノ酸（Ｖ）を反応性誘導体に導く
ためには、常法に従って、ハロゲン化、無水物化、アジ
ド化、活性ェステル化などが行われる。保護基の導入に
ついてもべプチド縮合における常法に従えばよい。アミ
ノ基について一例を挙げれば、アルカリの存在下に塩化
カルボベンゾキシを反応させれば、ベプチド（ｍ）また
はアミノ酸（Ｖ）のアミ／基を保護させることができる
。本縮合反応は一般に適当な溶媒の存在下に行われ、そ
のような溶媒としては、塩化メチレン、ジメチルホルム
アミド、ジメチルスルホキシド、ヘキサメチルリン酸ト
リアミド、クロロホルム、ジオキサン、テトラヒドロフ
ランまたはこれらの混合物が例示される。The conventional method of veptidation reaction (hereinafter abbreviated as peptide condensation) is the integration of the amino group of amine (0) or glycinamide (N) with the carboxy group of the corresponding peptide (m) or amino acid (V). Let peptide bond (amine (b)
When involved, it means an amide bond. same as below. )
The basic principle is to form , carboxy group). In order to convert the peptide (m) or amino acid (V) into a reactive derivative, halogenation, anhydride formation, azidation, active esterification, etc. are carried out according to conventional methods. The introduction of a protecting group may also be carried out in accordance with a conventional method for peptide condensation. For example, with regard to amino groups, by reacting carbobenzoxy chloride in the presence of an alkali, the amino/group of the peptide (m) or amino acid (V) can be protected. This condensation reaction is generally carried out in the presence of a suitable solvent, and examples of such solvents include methylene chloride, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, chloroform, dioxane, tetrahydrofuran, or mixtures thereof. .

反応温度は通常約一２０〜３０ｏｏ程度であるが適当に
冷却下または加熱下に反応を実施してもよい。次いで、
アミノ保護基を脱離させる目的で縮合ジベプチド（ｌａ
）を保護基脱離反応（ただし、ここで保護基とはアミノ
保護基のほかフタルィミド基の場合を含む）に付して目
的物質（１）に導く。The reaction temperature is usually about 120 to 30 degrees Celsius, but the reaction may be carried out under appropriate cooling or heating. Then,
For the purpose of removing the amino protecting group, fused dipeptide (la
) is subjected to a protecting group elimination reaction (here, the protecting group includes not only an amino protecting group but also a phthalimide group) to lead to the target substance (1).

具体的にはカルボベンゾキシ基で保護されているときに
は臭化水素酸、フッ化水素酸、トリフルオロ酢酸などの
酸と処理するか、接触還元もしくは液体アンモニア／金
属ナトリウムによる還元に付せばよく、トリチル基で保
護されているときには希酢酸を加熱処理すればよい。ま
た一 Ｒ２ Ｎ ｚがフタルィミド基であるときには適当な溶
媒（例えば、アルコール類、ジメチルホルムアミドなど
）中ヒドラジンを室温下または加熱下に反応させるなど
ガブＩＪェル反応に準拠して実施すればよい。Specifically, when it is protected by a carbobenzoxy group, it can be treated with an acid such as hydrobromic acid, hydrofluoric acid, or trifluoroacetic acid, or subjected to catalytic reduction or reduction with liquid ammonia/metallic sodium. , when the compound is protected with a trityl group, dilute acetic acid may be heated. Further, when -R2Nz is a phthalimide group, the reaction may be carried out according to the Gabb-IJell reaction, such as by reacting hydrazine in a suitable solvent (eg, alcohol, dimethylformamide, etc.) at room temperature or under heating.

本発明の目的物質（１）を、製剤化、結晶化、安定性の
向上などの必要のために適当な駿付加塩例えば、塩酸、
硝酸、硫酸、リン酸、チオシアン酸などの無機酸の酸付
加塩あるいは酢酸、修酸、コハク酸、マレィン酸、リン
ゴ酸、フタル酸などの有機酸の酸付加塩に導くこともで
きる。The target substance (1) of the present invention can be converted into a suitable sulfur addition salt for the needs such as formulation, crystallization, and stability improvement, such as hydrochloric acid,
It can also be converted into acid addition salts of inorganic acids such as nitric acid, sulfuric acid, phosphoric acid, and thiocyanic acid, or acid addition salts of organic acids such as acetic acid, oxalic acid, succinic acid, maleic acid, malic acid, and phthalic acid.

かくして得られるジベプチド譲導体（１）またはその酸
付加塩は優れた同精神作用、とくに静穏作用、抗けいれ
ん作用、催眠作用、筋弛緩作用を示し、抗不安剤、抗け
いれん剤、催眠剤などの向精神薬、またはこれらの合成
中間体としても有用である。The thus obtained dipeptide derivative (1) or its acid addition salt exhibits excellent psychoactive effects, especially tranquilizing, anticonvulsant, hypnotic, and muscle relaxing effects, and is useful as an anxiolytic, anticonvulsant, and hypnotic agent. It is also useful as a psychotropic drug or a synthetic intermediate thereof.

さらにこのジベプチド誘導体（１）は家畜類や家禽類の
生長促進剤としての用途も期待できる。例えば２一ｏー
クロロベンゾィル−４ータロロ−Ｎ−メチル一ＮＱーグ
リシジルグリシンアニリドは抗けいれん作用（ベンチレ
ンテトラゾールに対する）ではＥＤ５ｏｏ．６雌／ｋ９
（マウス、経口投与）および馴化作用ではＥＤ則３．０
の９／ｋ９（マウス、経口投与）を示した。以下に本発
明の実施例を示す。Furthermore, this dipeptide derivative (1) can also be expected to be used as a growth promoter for livestock and poultry. For example, 21o-chlorobenzoyl-4-talolo-N-methyl-NQ-glycidylglycine anilide has an ED5oo of anticonvulsant action (relative to bentrenetetrazole). 6 females/k9
(mouse, oral administration) and habituation effect ED rule 3.0
9/k9 (mouse, oral administration). Examples of the present invention are shown below.

実施例 １ （１｝ トリチルグリシルグリシン５夕をへキサメチル
リン酸トリアミド２４の【に溶解した溶液に−８〜一２
℃にて塩化チオニル１．６夕を滴下し、一５℃にて２０
分間燈梓する。Example 1 (1) In a solution of tritylglycylglycine 50% dissolved in 24% hexamethylphosphoric acid triamide, -8 to 12%
1.6 ml of thionyl chloride was added dropwise at -5°C.
Light up for a minute.

これに２ーアミノ−５−クロロベンゾフェノン３．０８
夕を加え、室温下に一夜放置する。反応液を炭酸水素ナ
トリウム水溶液で中和し、クロロホルムで抽出する。有
機層を水洗し、乾燥し、溶媒を留去する。残澄をエーテ
ルにて結晶化し、２−ペンゾイルー４−クロロ−ＮＱ−
（トリチルグリシル）グリシンアニリド１．７夕を得る
。本品を酢酸エチルより再結晶すると融点１８７〜１８
９ｏｏの針状晶を得る。ＵＶ：＾島袋日２３７．５、２
７４（ｓｈ）、３４３の山（ｌｏｇご：４．５１、４．
０３３．５３）。To this, 2-amino-5-chlorobenzophenone 3.08
Add water and leave at room temperature overnight. The reaction solution was neutralized with an aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer is washed with water, dried, and the solvent is distilled off. The residue was crystallized from ether to give 2-penzoyl-4-chloro-NQ-
1.7 ml of (tritylglycyl)glycine anilide is obtained. When this product is recrystallized from ethyl acetate, the melting point is 187-18.
9oo of needle crystals are obtained. UV: ^ Shimabukuro day 237.5, 2
74 (sh), 343 mountains (log: 4.51, 4.
033.53).

（２’ ２ーベンゾイルー４ークロローＮＱ−（トリチ
ルグリシル）グリシンアニリド１．７夕を５０％酢酸２
０地に懸濁させ、水浴上２折分間加熱する。(2' 2-benzoyl-4-chloroNQ-(tritylglycyl)glycineanilide 1.7 ml of 50% acetic acid 2
Suspend in 0.0% and heat on a water bath for 2 minutes.

冷後、析出する結晶を炉去し、炉液を炭酸水素ナトリウ
ム溶液にて中和し、クロロホルムで抽出する。有機層を
水洗し、乾燥し、溶媒を蟹去すると２ーベンゾイル−４
ークロローＮＱーグリシルーグリシンアニリド０．８夕
を得る。本品を酢酸エチルより再結晶すると、融点１３
５〜１３６℃のプリズム晶を得る。ＵＶ：＾岳袋日２４
１、２７５（ｓｈ）、３４０の仏（ｌｏｇご：４．４へ
４．０入３．５５）。After cooling, the precipitated crystals are removed from the furnace, the furnace solution is neutralized with sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with water, dried, and the solvent was removed to give 2-benzoyl-4.
- Chlorol NQ - 0.8 glycyl-glycine anilide is obtained. When this product is recrystallized from ethyl acetate, the melting point is 13.
Obtain prismatic crystals at a temperature of 5 to 136°C. UV: ＾Takebukuro day 24
1,275 (sh), 340 Buddha (log: 4.4 to 4.0 to 3.55).

実施例 ２〜５ 下記の原料物質（ロ）および（ｍ）を使用して、実施例
１と同様に反応を行い、対応する各生成物（ｌａ）（ｌ
ｂ）を得る：〔式中、Ｚ′はアミノ保護基を表わし、Ｒ
、ＲＩおよびＲ２は前記と同意義を有する。Examples 2 to 5 Using the following raw materials (b) and (m), a reaction was carried out in the same manner as in Example 1, and the corresponding products (la) (l
b) is obtained: [wherein Z' represents an amino protecting group and R
, RI and R2 have the same meanings as above.

〕表 １ 表）表中の略号は下記の意味を有する：日（水素），Ｍ
ｅ（メチル基），Ｂｕ（ブチレ基），Ｃｂｚ（ルレボベ
ンゾキシ基），Ｔｒｉ（トリチル基），ｉ‐（ィソー）
，ｍｐ（融点），ａ）（Ｌ体）。[Table 1 Table) Abbreviations in the table have the following meanings: 日(hydrogen), M
e (methyl group), Bu (butylene group), Cbz (lurebobenzoxy group), Tri (trityl group), i- (iso)
, mp (melting point), a) (L form).

実施例 ６｛１｝ カルボベンゾキシ−Ｌ−ロイシルー
グリシン４．０５夕を無水塩化メチレン５０の‘に懸濁
し、これにトリェチルアミン１．７５畝およびクロル炭
酸エチル１．２叫を−１ｏｏ０で加え、同温度で２０分
間櫨拝する。Example 6 {1} 4.05 μl of carbobenzoxy-L-leucylglycine was suspended in 50 μl of anhydrous methylene chloride, and 1.75 μl of triethylamine and 1.2 μl of ethyl chlorocarbonate were added thereto at −10° C. , and pray at the same temperature for 20 minutes.

さらに２ーアミノ−５−クロロベンゾフェノン２．９１
夕を無水塩化メチレン５０私に溶解した溶液を０℃にて
徐々に加えたのち、氷袷下に１時間１５分蝿拝し、室温
下に１時間３０分鷹梓し、一夜還流する。反応液を炭酸
カリウムと氷の混合物にあげ、塩化メチレンで抽出する
。有機層を水洗し、乾燥し、溶媒を蟹去する。残澄を水
３％を含有するシリカゲルにてカラムクロマトグラフィ
ーに付す。ペンゼン溶出部より原料物質２−アミノー５
一クロロベンゾフェノン１．２１夕を回収したのち、ベ
ンゼン：酢酸エチル（９：１）の溶出部から得られる生
成物をエーテルより再結晶すると、融点９８〜１００ｏ
ｏの結晶として２−ペンゾイルー４−クロロ−ＮＱ−（
カルボベンゾキシ−Ｌーロイシル）グリシンアニリド３
．１３夕を得る。ＩＲ：３４２５３３１ふ１７００、１
６１４伽‐１（ＣＨＣ１３）。Furthermore, 2-amino-5-chlorobenzophenone 2.91
A solution prepared by dissolving 50% of water in anhydrous methylene chloride was gradually added at 0° C., and the mixture was heated under ice for 1 hour and 15 minutes, heated to room temperature for 1 hour and 30 minutes, and refluxed overnight. The reaction solution was poured into a mixture of potassium carbonate and ice, and extracted with methylene chloride. The organic layer is washed with water, dried and the solvent is removed. The residue is subjected to column chromatography on silica gel containing 3% water. Raw material 2-amino-5 from the penzene elution part
After recovering 1.21 kg of monochlorobenzophenone, the product obtained from the benzene:ethyl acetate (9:1) eluate was recrystallized from ether.
2-penzoyl-4-chloro-NQ-(
Carbobenzoxy-L-leucyl)glycine anilide 3
．． Get 13 evenings. IR:3425331fu1700,1
614ka-1 (CHC13).

‘２｝ ペンゾイルー４−クロローＮＱ一（カルボベン
ゾキシーＬーロイシル）グリシンアニリド３．１夕を臭
化水素酸２４％を含む酢酸溶液１５の‘に氷冷下溶解し
、室温下に１．虫時間燈梓する。これにエーテルを加え
、反応液を３０分間静贋する。析出物を炉取し、冷水に
熔解し、塩化メチレン：エーテル（１：２）で抽出する
。有機層を分離したのち、水層を炭酸カリウム水溶液で
アルカリ性とし、食塩を飽和させ、クロロホルムで抽出
する。クロロホルム層を水洗し、無水硫酸マグネシウム
で乾燥し、溶媒を留去する。得られる残基をエーテルか
ら再結晶し、融点１４５〜１４７０の結晶として２−ペ
ンゾイルー４ークロローＮＱ一（Ｌ−ロイシル）グリシ
ンアニリド１．６２８夕を得る。ＩＲ：３３２５・１６
８５・１６３９伽‐１（ＣＨＣＩ３）。'2} Penzoyl-4-chloro NQ-(carbobenzoxy L-leucyl)glycine anilide (3.1) was dissolved in 15 parts of an acetic acid solution containing 24% hydrobromic acid under ice cooling, and the mixture was heated to 1.1 at room temperature. Insect Time Light Azusa. Ether was added to this, and the reaction solution was allowed to stand still for 30 minutes. The precipitate was collected by filtration, dissolved in cold water, and extracted with methylene chloride:ether (1:2). After separating the organic layer, the aqueous layer is made alkaline with an aqueous potassium carbonate solution, saturated with common salt, and extracted with chloroform. The chloroform layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The resulting residue is recrystallized from ether to obtain 1.628 g of 2-penzoyl-4-chloroNQ-(L-leucyl)glycineanilide as crystals with a melting point of 145-1470. IR:3325.16
85.1639 Kaya-1 (CHCI3).

〔Ｑ〕き４．５十５０．７±０．９０（ＥのＨ）。Ｍａ
ｓｓ、ｍ／ｅ４０１（Ｍ十）。実施例 ７〜９ 下記の原料物質（ロ）および（ｍ）を使用して、実施例
６と同様に反応を行い、対応する生成物（ｌａ）（ｌｂ
）を得る：〔式中、Ｒ、Ｒ１、Ｒ２およびＺ′は前記と
同意義を有３５する。[Q] 4.5 + 50.7 ± 0.90 (H of E). Ma
ss, m/e401 (M ten). Examples 7 to 9 Using the following raw materials (b) and (m), a reaction was carried out in the same manner as in Example 6 to produce the corresponding products (la) (lb
) is obtained: [wherein R, R1, R2 and Z' have the same meanings as above.

〕表 ２注）表中の略号は下記の意義を有する：Ｐｒ（
プロピル基），Ｐｈ（フェニル基），他は前記と同意義
を有する。] Table 2 Note) Abbreviations in the table have the following meanings: Pr (
(propyl group), Ph (phenyl group), and others have the same meanings as above.

実施例 １０ Ｑ｝ カルボベンゾキシグリシン１．０５夕をへキサメ
チルリン酸トリアミド８柵に溶解した溶液に一４〜一６
℃にて塩化チオニル０．６夕を加え、一６℃にて１０分
間櫨拝する。Example 10
Add 0.6 ml of thionyl chloride at -6°C for 10 minutes.

これに２ーベンゾイルー４ークロログリシンアニリド１
．４４夕を加え、０℃以下にて２時間燭拝したのち、室
温下に一夜放置する。反応液を炭酸水素ナトリウム水溶
液でアルカリ性として、クロロホルムで抽出する。有機
層を水洗し、乾燥し、溶媒を留去する。残澄にエーテル
および水を加えて結晶させると、融点１６３〜Ｉ６４℃
の結晶として２−ペンゾイル−４ークロローＮＱ−（カ
ルポベンゾキシグリシル）グリシンアニリド１．９夕を
得る。■ 上記生成物を実施例６｛２）と同様に処理し
、２−ペンゾイル−４ークロローＮＱーグリシルグリシ
ンアニリドを得る。実施例 １１ ｔｌ）２・５ージクロロー２−メチルアミノベンゾフェ
ノン３．２Ｍをベンゼン８０の上に溶解した溶液に、フ
タリルーグリシルーグリシルクロリド４．Ｍを加えたの
ち、混合液を７０〜８０ｏｏで１時間擬梓する。To this, 2-benzoyl-4-chloroglycine anilide 1
．． After adding 44 hours of heat, let it stand for 2 hours at below 0°C, and then leave it at room temperature overnight. The reaction solution was made alkaline with an aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer is washed with water, dried, and the solvent is distilled off. When the residue is crystallized by adding ether and water, the melting point is 163 to 64℃.
1.9 ml of 2-penzoyl-4-chloroNQ-(carpobenzoxyglycyl)glycine anilide is obtained as crystals. (2) The above product is treated in the same manner as in Example 6 {2) to obtain 2-penzoyl-4-chloroNQ-glycylglycine anilide. Example 11 tl) Phthalyl-glycyl-glycyl chloride 4. After adding M, the mixture is stirred at 70 to 80 oo for 1 hour.

析出する結晶を炉取し、ベンゼンおよびエタノールで順
次洗浄し、乾燥すれば２一ｏークロロベンゾイルー４ー
クロローＮーメチル−ＮＱ−（フタリルーグリシン）グ
リシンアニリド５．６夕を得る。本品をエタノールから
再結晶すれば融点２１７００の結晶となる。‘２’２一
ｏークロロベンゾイルー４ークロローＮ−メチル一ＮＱ
−（フタリルーグリシル）グリシンアニリド８１．０９
をエタノール５０Ｍに懸濁した溶液にヒドラジンヒドラ
ート２０の‘を加えたのち、約３０分間還流する。冷後
、反応液を炉遇して析出したフタリルヒドラジンを除く
。炉液を濃縮したのち、エーテルで洗浄すると２−ｏ−
クロロベソゾイル４ークロローＮーメチル−ＮＱ−グリ
シルグリシンアニリド・一水和物５５．３夕を得る。本
品を希エタノールより再結晶すると融点９５〜１００ｏ
ｏの結晶となる。元素分析 Ｃ，８日，７０３Ｃ’２Ｎ
３・比０として計算値 Ｃ、５２．４４；日、４．６５
：Ｎ、１０．１９；ＣＩ、１７．２０；日２０、４．３
７実験値 Ｃ、５２．５３；日、４．５９；Ｎ、１０．
１９；ＣＩ、１７．１０：日２０、４．５３塩酸塩・１
′が２０ 融点２１４〜２１−０（分解点）Ｃ比Ｓ０３
別塩 融点２２１〜２２３０○へミシトレート 融点１
１４〜１１６ＣＯオキザレート 融点１６７０以下 実施例 １２ 前記実施例６と同機に下記の化合物を得る。The precipitated crystals are collected in a furnace, washed successively with benzene and ethanol, and dried to obtain 21-chlorobenzoyl-4-chloro-N-methyl-NQ-(phthalylglycine) glycine anilide. When this product is recrystallized from ethanol, it becomes crystals with a melting point of 21,700. '2'2-O-chlorobenzoyl-4-chloro-N-methyl-NQ
-(phthalylglycyl)glycineanilide 81.09
After adding 20% of hydrazine hydrate to a solution of suspended in 50M ethanol, the mixture is refluxed for about 30 minutes. After cooling, the reaction solution was heated in a furnace to remove precipitated phthalylhydrazine. After concentrating the furnace solution and washing with ether, 2-o-
55.3 ml of chlorobesoyl 4-chloro N-methyl-NQ-glycylglycine anilide monohydrate are obtained. When this product is recrystallized from dilute ethanol, the melting point is 95-100o.
It becomes a crystal of o. Elemental analysis C, 8th, 703C'2N
3. Calculated value assuming ratio 0 C, 52.44; Day, 4.65
:N, 10.19; CI, 17.20; Day 20, 4.3
7 Experimental value C, 52.53; day, 4.59; N, 10.
19; CI, 17.10: day 20, 4.53 hydrochloride 1
' is 20 Melting point 214~21-0 (decomposition point) C ratio S03
Different salt melting point 221-2230○ Hemisitrate melting point 1
14-116CO oxalate Melting point: 1670 or less Example 12 The following compound was obtained in the same machine as in Example 6 above.

Claims (1)

【特許請求の範囲】 １ 一般式 ▲数式、化学式、表等があります▼ ［式中、 Ｒは水素またはアルキル基、 Ｒ＾１は水素、アルキル基またはフエニル基Ｒ＾２は水
素またはアルキル基、Ｒ＾３は水素またはハロゲン基、 Ｒ＾４はハロゲン、 Ｚはアミノ保護基をそれぞれ表わすか、あるいは▲数式
、化学式、表等があります▼ はフタルイミド基であってもよ い。 ］で示される化合物を保護基脱離反応に付すことを特徴
とする一般式▲数式、化学式、表等があります▼ ［式中、Ｒ、Ｒ＾１、Ｒ＾２、Ｒ＾３およびＲ＾４は前
記と同意義を有する。 ］で示されるアニリン系ジペプチド誘導体の製造法。[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R is hydrogen or an alkyl group, R^1 is hydrogen, an alkyl group or a phenyl group, R^2 is hydrogen or an alkyl group, R^3 may represent hydrogen or a halogen group, R^4 may represent a halogen, Z may represent an amino protecting group, or ▲ may be a numerical formula, chemical formula, table, etc. ▼ may be a phthalimide group. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R, R^1, R^2, R^3 and R^] 4 has the same meaning as above. ] A method for producing an aniline dipeptide derivative.
JP49090565A 1974-08-06 1974-08-06 Method for producing aniline dipeptide derivatives Expired JPS604199B2 (en)

Priority Applications (35)

Application Number Priority Date Filing Date Title
JP49090565A JPS604199B2 (en) 1974-08-06 1974-08-06 Method for producing aniline dipeptide derivatives
ZA00754877A ZA754877B (en) 1974-08-06 1975-07-29 Dipeptide derivatives and their production
CA000232782A CA1181065A (en) 1974-08-06 1975-07-31 Dipeptide derivatives and their production
NLAANVRAGE7509258,A NL175789C (en) 1974-08-06 1975-08-04 PROCESS FOR PREPARING A PHARMACEUTICAL PREPARATION WITH CALMING ACTION AND PROCESS FOR PREPARING MEDICINAL AMINOIC ACID ANILIDES.
SE7508829A SE427030B (en) 1974-08-06 1975-08-05 PROCEDURE FOR PREPARING BENZOPHENON DERIVATIVES WITH ANTICONVULVIC EFFECT
CH1020275A CH617668A5 (en) 1974-08-06 1975-08-05
MX000859U MX3332E (en) 1974-08-06 1975-08-05 PROCEDURE FOR THE PREPARATION OF DIPEPTIDE DERIVATIVES
DK356475A DK155088C (en) 1974-08-06 1975-08-05 METHOD OF ANALOGUE FOR PREPARING BENZOPHENON-SUBSTITUTED DIPEPTIDE DERIVATIVES OR ACID ADDITION SALTS.
AR259900A AR213076A1 (en) 1974-08-06 1975-08-05 PROCEDURE FOR THE PRODUCTION OF DERIVATIVES OF THE SUBSTITUTED GLICILGLICILANILIDE
ES440032A ES440032A1 (en) 1974-08-06 1975-08-05 Dipeptide derivatives and their production
HU75SI1485A HU176016B (en) 1974-08-06 1975-08-05 Process for producing dipeptide derivatives
DE2535171A DE2535171C3 (en) 1974-08-06 1975-08-06 Benzophenone derivatives and drugs containing these compounds
AU83734/75A AU491928B2 (en) 1974-08-06 1975-08-06 Dipeptide derivatives and their production
BE158997A BE832190A (en) 1974-08-06 1975-08-06 DIPEPTIDIC DERIVATIVES AND THEIR PRODUCTION
FR7524559A FR2281131A1 (en) 1974-08-06 1975-08-06 DIPEPTIDE DERIVATIVES AND THEIR PREPARATION
DD187724A DD119213A5 (en) 1974-08-06 1975-08-06
GB32916/75A GB1511669A (en) 1974-08-06 1975-08-06 Dipeptide derivatives and their production
US05/716,266 US4076703A (en) 1974-08-06 1976-08-20 Dipeptide derivatives and their production
US05/716,268 US4076705A (en) 1974-08-06 1976-08-20 Dipeptide derivatives and their production
US05/716,267 US4076704A (en) 1974-08-06 1976-08-20 Dipeptide derivatives and their production
US05/716,265 US4076702A (en) 1974-08-06 1976-08-20 Dipeptide derivatives and their production
ES455504A ES455504A1 (en) 1974-08-06 1977-01-31 Dipeptide derivatives and their production
ES455506A ES455506A1 (en) 1974-08-06 1977-01-31 Dipeptide derivatives and their production
ES455505A ES455505A1 (en) 1974-08-06 1977-01-31 Dipeptide derivatives and their production
ES455507A ES455507A1 (en) 1974-08-06 1977-01-31 Dipeptide derivatives and their production
US05/775,646 US4240957A (en) 1974-08-06 1977-03-07 Dipeptide derivatives and their production
AR270152A AR215035A1 (en) 1974-08-06 1977-11-28 PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF 2-BENZOIL-N-ALKYL (C1-C6) -N-A- (GLICIL) GLYCINANILIDE
AR270154A AR219307A1 (en) 1974-08-06 1977-11-28 PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF 2-BENXOIL-N ALPHA-GLICIL-GLICIL OR N ALPHA-A-FENILALANILGLICILANILIDA
AR270151A AR213453A1 (en) 1974-08-06 1977-11-28 PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF THE SUBSTITUTED GLICILGLICILANILIDE
AR270153A AR220325A1 (en) 1974-08-06 1977-11-28 PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF GLICIL-GLICIL-2-BENZOIL-5-HALOANILIDE AND ITS SALTS
US05/867,605 US4154727A (en) 1974-08-06 1978-01-06 Dipeptide derivatives and their production
CH461779A CH627438A5 (en) 1974-08-06 1979-05-17 METHOD FOR PRODUCING DIPEPTIDE DERIVATIVES.
CH461879A CH627439A5 (en) 1974-08-06 1979-05-17 METHOD FOR PRODUCING DIPEPTIDE DERIVATIVES.
CH827079A CH627440A5 (en) 1974-08-06 1979-09-12 METHOD FOR PRODUCING DIPEPTIDE DERIVATIVES.
CA339,232A CA1091652A (en) 1974-08-06 1979-11-06 Dipeptide derivatives and their production

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP49090565A JPS604199B2 (en) 1974-08-06 1974-08-06 Method for producing aniline dipeptide derivatives

Publications (2)

Publication Number Publication Date
JPS5126853A JPS5126853A (en) 1976-03-05
JPS604199B2 true JPS604199B2 (en) 1985-02-01

Family

ID=14001941

Family Applications (1)

Application Number Title Priority Date Filing Date
JP49090565A Expired JPS604199B2 (en) 1974-08-06 1974-08-06 Method for producing aniline dipeptide derivatives

Country Status (3)

Country Link
JP (1) JPS604199B2 (en)
BE (1) BE832190A (en)
ZA (1) ZA754877B (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109678751A (en) * 2019-01-07 2019-04-26 广州同隽医药科技有限公司 A kind of compound containing diphenyl-methane structure

Also Published As

Publication number Publication date
JPS5126853A (en) 1976-03-05
ZA754877B (en) 1976-07-28
BE832190A (en) 1975-12-01

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