JPS60199869A - Esterification - Google Patents

Abstract

PURPOSE:The reaction of an acid adduct of epsilon-guanidinocaproic acid with bis(p- alkoxycarbonylphenyl)sulfite gives a compound which is used as a medicine, because it has antikallikrein activity, in high yield and high purity. CONSTITUTION:A compound of formula I (R is lower alkyl) is allowed to react with an acid adduct of epsilon-guanidinocaproic acid to give an acid adduct of a compound of formula II. The reaction is carried out in an inert solvent such as dimethylformamide at 0-60 deg.C, preferably 15-30 deg.C, for 10-30hr, preferably in the presence of an organic base such as pyridine. The compound of formula I is obtained by allowing a thionyl halide to react with p-hydroxybenzoic ester in the presence of an acid acceptor such as TEA. The compound of formula IIis formed in the reaction mixture in the form of acid adduct. This salt is desirably isolated in the form of a carbonate using aqueous sodium bicarbonate in high yield.

Description

【発明の詳細な説明】 本発明は抗カリクレイン作用を有し、医薬として有用な
一般式（１） （１） （式中、Ｒは低級アルキル基を表わす）で示される化合
物の酸付加塩の新規な製造方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention provides acid addition salts of compounds represented by the general formula (1) (1) (wherein R represents a lower alkyl group) that have anti-kallikrein effects and are useful as pharmaceuticals. This invention relates to a new manufacturing method.

従来この種の化合物の製法としては、例えば酸ハロゲン
化物と７エノール類の反応による酸クロライド法（特公
昭４９−２１０７）、あるいはＮ　−Ｎ’−ジシクロへ
キシルカルボジイミドの存在下、カルボン酸類と７エノ
ール類との反応による縮合法（特公昭５７−５４８２８
）などが知られている。Conventional methods for producing this type of compound include, for example, the acid chloride method (Japanese Patent Publication No. 49-2107), in which an acid halide is reacted with a 7-enol, or the reaction of a carboxylic acid with a 7-enol in the presence of N-N'-dicyclohexylcarbodiimide. Condensation method by reaction with enols (Japanese Patent Publication No. 57-54828
) etc. are known.

しかし、酸クロライド法は副反応の危険や悪臭発生の難
点がある。However, the acid chloride method has drawbacks such as the risk of side reactions and the generation of bad odors.

また、前記縮合法は試薬のＮ　−Ｎ’−ジシクロへキシ
ルカルボジイミドが有毒かつ高価であり、生成物に含有
するジシクロへキシルフレアを分離しなければならない
という欠点がある。そのために酸クロライド法あるいは
縮合法は工業上必ずしも満足しうるものではなかった。Furthermore, the condensation method has disadvantages in that the reagent N-N'-dicyclohexylcarbodiimide is toxic and expensive, and dicyclohexyl flare contained in the product must be separated. Therefore, the acid chloride method or the condensation method has not always been industrially satisfactory.

本発明者らはこれらの問題を解決するため種々研究した
結果、ε−グアニジノカプロン酸の酸付加塩に一般式（
ＩＩ） （ＩＩ） （式中、Ｒは低級アルキル基を表わす）で示される化合
物を作用させることにより、一般式（１） （１） （式中、Ｒは前記と同じ意味を表わす）で示される化合
物の酸付加塩を有利に製造しうろことを見出した。As a result of various studies to solve these problems, the present inventors developed an acid addition salt of ε-guanidinocaproic acid with the general formula (
II) By reacting with a compound represented by (II) (wherein R represents a lower alkyl group), a compound represented by the general formula (1) (1) (wherein R represents the same meaning as above) is obtained. It has now been discovered that acid addition salts of the compounds can be advantageously prepared.

本発明方法によれば、簡単かつ経済的な手段で一般式（
１）の酸付加塩が高収率及び良好な純度で得られる。According to the method of the present invention, the general formula (
The acid addition salt of 1) is obtained in high yield and good purity.

反応は、ジメチルホルムアミド、ジメチルアセトアミド
、ジメチルスルホキサイドなど反応に関与しない溶媒中
、０”−／＋Ｏ１ｌ：好ましくは１５°−５０℃で１０
〜３０時間攪拌することにより容易に行われる。好まし
くはピリジン、トリエチルアミンなどの有機塩基の存在
下行われる。The reaction is carried out in a solvent that does not participate in the reaction, such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc., at 0"-/+O1l: preferably 15°-50°C for 10
This is easily accomplished by stirring for ~30 hours. It is preferably carried out in the presence of an organic base such as pyridine or triethylamine.

ε−グアニジツカグロン酸と酸付加塩を形成する酸とし
ては塩酸、臭化水素酸、硫酸、トルエンスルホン酸、メ
タンスルホン酸などがあげられる。Examples of acids that form acid addition salts with ε-guanidizukagulonic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, toluenesulfonic acid, and methanesulfonic acid.

本発明方法において用いられる一般式（ＩＩ）で示され
る化合物は、ｐ−ヒドロキシ安息香酸エステルにハロゲ
ン化チオニルを脱酸剤の存在下洗反応させることにより
容易に得られる。The compound represented by the general formula (II) used in the method of the present invention can be easily obtained by washing p-hydroxybenzoic acid ester with thionyl halide in the presence of a deoxidizing agent.

この反応において用いられる脱酸剤は、反応の進行につ
れて副生ずるハロゲン化水素を捕捉、不活性化するもの
であり、トリエチルアミン、トリブチルアミン、ジメチ
ルアニリンなどの三級アミン類が特に好ましい。反応は
エーテル、ベンゼン、トルエン、キシレンなどの溶媒中
、０℃〜室温で２〜１０時間攪拌することにより容易に
行われる。The deoxidizing agent used in this reaction is one that captures and inactivates hydrogen halide produced as a by-product as the reaction progresses, and tertiary amines such as triethylamine, tributylamine, and dimethylaniline are particularly preferred. The reaction is easily carried out in a solvent such as ether, benzene, toluene, xylene, etc. by stirring at 0° C. to room temperature for 2 to 10 hours.

本発明方法を工業的に実施する場合、ｐ−ヒドロキシ安
息香酸から一般式（Ｕ）で示される化合物を製造し、こ
れを単離することなくそのままε−グアニジノカプロン
酸の酸付加塩を反応させて、一般式（１）で示される目
的化合物を製造することもできる。When the method of the present invention is carried out industrially, a compound represented by the general formula (U) is produced from p-hydroxybenzoic acid, and the compound is directly reacted with an acid addition salt of ε-guanidinocaproic acid without being isolated. In this way, the target compound represented by the general formula (1) can also be produced.

本発明の目的化合物ＣＩ）は反応液中で酸付加塩の形で
生成する。この塩を収率よく単離、精製するために重炭
酸ナトリウム水溶液にて一度、炭酸塩として取り出すこ
とが望ましい〇 一般式〔■〕で示される化合物は必要により薬理学的に
許容され得る酸付加塩にたやすく変換することができる
。このような酸としては例えば塩酸、臭化水素酸、メタ
ンスルホン酸、トルエンスルホン酸、フマル酸、酒石酸
などがあげられる。The object compound CI) of the present invention is produced in the form of an acid addition salt in the reaction solution. In order to isolate and purify this salt with good yield, it is desirable to remove it as a carbonate once in an aqueous sodium bicarbonate solution. If necessary, the compound represented by the general formula [■] can be added with a pharmacologically acceptable acid. It can be easily converted to salt. Examples of such acids include hydrochloric acid, hydrobromic acid, methanesulfonic acid, toluenesulfonic acid, fumaric acid, and tartaric acid.

次に実施例をあげて本発明を説明する。Next, the present invention will be explained with reference to Examples.

実施例 見 ６−ゲアニジノカプロン酸塩ｅ塩１．０５　？、ビス（
ｐ−エトキシカルボニルフェニル）スルファイト２１？
、及び乾燥ジメチルホルムアミド３−の混合物を攪拌し
、これに乾燥ピリジン１．５ｄを加え室温で２０時間攪
拌した。Example 6-geanidinocaproate e salt 1.05 ? ,Screw(
p-ethoxycarbonylphenyl) sulfite 21?
, and dry dimethylformamide 3- was stirred, 1.5 d of dry pyridine was added thereto, and the mixture was stirred at room temperature for 20 hours.

減圧上溶媒を留去し、残留物にイソプロピルエーテル２
０−を加え約５分間攪拌した。イソプロピルエーテルを
デカンテーシ薔ンにより除去し、残渣にインプロピルニ
ーテール２０ゴ及び水１０ｍ１を加えて攪拌した。水層
を分取し、有機層を水３−で抽出した。水層を合わせ、
これに水冷下飽和重曹水１ｏ−を加え２０分間攪拌した
。生成した沈澱物をＦ取し、水、イングロビルエーテル
の順に洗浄１−１乾燥することにより白色粉末１．８９
を得た。The solvent was distilled off under reduced pressure, and the residue was diluted with isopropyl ether 2.
0- was added and stirred for about 5 minutes. The isopropyl ether was removed using a decant, and 20 g of inpropyl ether and 10 ml of water were added to the residue and stirred. The aqueous layer was separated, and the organic layer was extracted with water. Combine the water layers,
To this was added 1 o of saturated sodium bicarbonate solution while cooling with water, and the mixture was stirred for 20 minutes. The generated precipitate was collected by F, washed with water and inglobil ether in that order 1-1, and dried to obtain a white powder of 1.89%
I got it.

得られた粉末１ｖをとり、これをアセトン２０ｍ１に懸
濁させた。この懸濁液にメタンスルホン酸０−２５９を
加え溶液とした。この溶液にエーテル４０ゴを加え、生
成した結晶を沢取し、エーテルで洗浄した後乾燥させて
ｍｐ９１〜９３℃の無色針状晶として目的化合物１．０
２を得た（８３チ）Ｏ ＫＢｒ　−１。1 vol of the obtained powder was taken and suspended in 20 ml of acetone. Methanesulfonic acid 0-259 was added to this suspension to form a solution. Add 40 grams of ether to this solution, collect the generated crystals, wash with ether, and dry to obtain the target compound as colorless needle crystals with a mp of 91 to 93°C.
Obtained 2 (83 pieces) O KBr -1.

工Ｒｖ　ｃｍ　、　３５０［）”３２００（ＮＨ）ａｘ １７５５、１７１０（Ｃ＝Ｏ） １６７０．１６３０（グアニジウム塩）１２００、１０
５０（８０２） １０５０（８０２）Ｎδ：　１．３６（３Ｈ，ｔ、Ｊ＝
８Ｈｚ、−Ｃ！旦り１．３Ｏ−ＺＯＯ（６Ｈ，ｍ、−（
ＣＨ２）３−）２．６３（２Ｈ，ｔ、Ｊ＝７Ｈｚ、−０
Ｈ２０００）２．７８（３Ｈ，ｅ　、　０Ｈ３ＳＯ３Ｈ
）３、ＯＯ−五３０（２Ｈ，ｍ、　−Ｃ！Ｈ２ＮＨす４
．３２（２Ｈ，ｑ、Ｊ＝８Ｈｚ、−０９０Ｈ３）７．０
４−ａ０８（４Ｈ，ｍ、芳香族水素）参考例 ｐ−ハイドロキシ安息香酸エチル１４６Ｆ及び乾燥エー
テル１００−を氷冷しながら攪拌した。これにチオニル
クロライド６ｔを加えた。この混合物にトリエチルアミ
ン１０．１２を含有する乾燥エーテル溶液２０−を１５
分を要して滴下した。反応混合物を室温にて一夜放置し
た後不溶物を戸去し、エーテルで洗浄した。ｐ液と洗液
を合わせた後溶媒を留去することＫより淡かっ色油秋物
としてビス（ｐ−エトキシカルボニルフェニル〕スルフ
ァイト１９ｆを得た。Engineering Rv cm, 350 [)” 3200 (NH) ax 1755, 1710 (C=O) 1670.1630 (guanidium salt) 1200, 10
50 (802) 1050 (802) Nδ: 1.36 (3H, t, J=
8Hz, -C! 1.3O-ZOO(6H,m,-(
CH2)3-)2.63(2H,t,J=7Hz,-0
H2000) 2.78 (3H,e, 0H3SO3H
)3,OO-530(2H,m, -C!H2NHsu4
．． 32 (2H, q, J=8Hz, -090H3)7.0
4-a08 (4H, m, aromatic hydrogen) Reference Example Ethyl p-hydroxybenzoate 146F and dry ether 100- were stirred while cooling with ice. To this was added 6 tons of thionyl chloride. To this mixture was added 15 ml of a dry ether solution containing 10.12 ml of triethylamine.
It took several minutes to drip. After the reaction mixture was left at room temperature overnight, insoluble materials were removed and washed with ether. After combining the p solution and the washing solution, the solvent was distilled off to obtain bis(p-ethoxycarbonylphenyl)sulfite 19f as a pale brown oil.

ＩＲｖＮａｏｌｍ−’：　１７１５（Ｃ＝Ｏ）ａｘ １２７０（Ｓ＝Ｏ） ＮＭＲ（（！ＤＯ１３）δ：　１．８０（３Ｈ，ｔ、Ｊ
＝８Ｈ２，町０Ｈ２−）４．８０（２Ｈ，ｑ、Ｊ＝８Ｈ
ｚ、ＯＨ，５０Ｈ２−）７．１０〜Ｆ３．２０（４Ｈ，
ｍ、芳香族水素）以　上０ 出願人　日本ケミファ株式会社IRvNaolm-': 1715(C=O)ax 1270(S=O) NMR((!DO13)δ: 1.80(3H,t,J
= 8H2, town 0H2-) 4.80 (2H, q, J = 8H
z, OH, 50H2-)7.10~F3.20(4H,
m, aromatic hydrogen) or more 0 Applicant Nippon Chemifa Co., Ltd.

Claims (1)

【特許請求の範囲】 ε−グアニジノカプロン酸の酸付加塩に一般式 （式中、Ｒは低級アルキル基を表わす）で示される化合
物を作用させることを特徴とする一般式 （式中、Ｒは前記と同じ意味を表わす）で示される化合
物の酸付加塩の製造方法。[Claims] A general formula (wherein R represents a lower alkyl group) characterized in that an acid addition salt of ε-guanidinocaproic acid is reacted with a compound represented by the general formula (wherein R represents a lower alkyl group). A method for producing an acid addition salt of a compound represented by (having the same meaning as above).