JPH07165684A - Phenethylamine derivative and its production - Google Patents
Phenethylamine derivative and its productionInfo
- Publication number
- JPH07165684A JPH07165684A JP6170524A JP17052494A JPH07165684A JP H07165684 A JPH07165684 A JP H07165684A JP 6170524 A JP6170524 A JP 6170524A JP 17052494 A JP17052494 A JP 17052494A JP H07165684 A JPH07165684 A JP H07165684A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- phenethylamine
- bis
- derivative
- dopamine
- 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.)
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Classifications
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- 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、医薬化合物の合成中間
体として有用なフェネチルアミン誘導体の結晶性塩及び
その製法に関する。TECHNICAL FIELD The present invention relates to a crystalline salt of a phenethylamine derivative useful as a synthetic intermediate for pharmaceutical compounds and a process for producing the same.
【０００２】[0002]
【従来の技術】Ｎ−（Ｎ−アセチルメチオニル）−Ｏ，
Ｏ’−ビス（エトキシカルボニル）ドーパミン（以下、
ドーパミン誘導体という）は、優れた腎血流増加作用を
有する有用な医薬化合物であり、従来、該化合物の製法
としては、例えば、Ｎ−アセチルメチオニンをその反応
性誘導体とし、これに３，４−ビス（エトキシカルボニ
ルオキシ）フェネチルアミンのｐ−トシル酸塩を反応さ
せる方法が知られている（特開昭５５−７２４２号）。2. Description of the Related Art N- (N-acetylmethionyl) -O,
O′-bis (ethoxycarbonyl) dopamine (hereinafter,
(Referred to as dopamine derivative) is a useful pharmaceutical compound having an excellent effect of increasing renal blood flow. Conventionally, as a method for producing the compound, for example, N-acetylmethionine has been used as its reactive derivative and 3,4- A method for reacting a p-tosylate salt of bis (ethoxycarbonyloxy) phenethylamine is known (JP-A-55-7242).
【０００３】[0003]
【発明が解決しようとする課題】しかしながら上記既知
方法は、Ｎ−アセチルメチオニンの活性化工程と、続く
縮合工程との溶媒を変えなければならないため、最終目
的物であるドーパミン誘導体のＮ−アセチルメチオニン
からの収率が低い等の難点があった。However, in the above-mentioned known method, the solvent for the activation step of N-acetylmethionine and the subsequent condensation step must be changed, so that the final target, N-acetylmethionine of the dopamine derivative is obtained. However, there are some problems such as low yield.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、種々研究
を重ねた結果、３，４−ビス（エトキシカルボニルオキ
シ）フェネチルアミンが結晶性良好なシュウ酸塩・１／
２水和物を形成することを見出すと共に、この結晶性シ
ュウ酸塩・１／２水和物を用いれば、簡便な操作でかつ
収率よく、最終目的物であるドーパミン誘導体を取得し
うることを見出し、本発明を完成するに至った。As a result of various studies, the present inventors have found that 3,4-bis (ethoxycarbonyloxy) phenethylamine is an oxalate.
In addition to finding that a dihydrate is formed, the use of this crystalline oxalate / hemihydrate makes it possible to obtain a dopamine derivative which is a final target product with a simple operation and a good yield. The present invention has been completed and the present invention has been completed.
【０００５】即ち、本発明は、優れた腎血流増加作用を
有するドーパミン誘導体の合成中間体として有用な３，
４−ビス（エトキシカルボニルオキシ）フェネチルアミ
ン・シュウ酸塩・１／２水和物及びその製法に関する。That is, the present invention is useful as a synthetic intermediate for a dopamine derivative having an excellent effect of increasing renal blood flow.
The present invention relates to 4-bis (ethoxycarbonyloxy) phenethylamine / oxalate / hemihydrate and a method for producing the same.
【０００６】本発明の３，４−ビス（エトキシカルボニ
ルオキシ）フェネチルアミン・シュウ酸塩・１／２水和
物は、一般式〔Ｉ〕The 3,4-bis (ethoxycarbonyloxy) phenethylamine oxalate hemihydrate of the present invention has the general formula [I]
【０００７】[0007]
【化２】 [Chemical 2]
【０００８】(式中、Ｚは酸で除去しうるアミノ基の保
護基を表す。）で示される化合物を、シュウ酸・水和物
で処理し、析出結晶を採取することにより取得すること
ができる。(In the formula, Z represents an amino-protecting group which can be removed by an acid.) A compound represented by the formula: can be obtained by treating the compound with oxalic acid hydrate and collecting the precipitated crystals. it can.
【０００９】本発明において、酸で除去しうるアミノ基
の保護基（Ｚ）としては、例えば、１−メチル−３−オ
キソ−１−ブテニル基、（２−エトキシカルボニル−１
−メチル）ビニル基等があげられる。In the present invention, examples of the protecting group (Z) for an amino group which can be removed with an acid include 1-methyl-3-oxo-1-butenyl group and (2-ethoxycarbonyl-1).
-Methyl) vinyl group and the like.
【００１０】化合物〔Ｉ〕のシュウ酸・水和物による処
理は、適当な溶媒中で加熱攪拌することにより好適に実
施することができる。溶媒としては、例えば、テトラヒ
ドロフラン、酢酸エチル、クロロホルム等を適宜使用で
きる。本処理は、例えば５０℃〜６０℃で実施するのが
好ましい。The treatment of the compound [I] with oxalic acid hydrate can be suitably carried out by heating and stirring in a suitable solvent. As the solvent, for example, tetrahydrofuran, ethyl acetate, chloroform or the like can be appropriately used. This treatment is preferably carried out, for example, at 50 ° C to 60 ° C.
【００１１】上記処理により、アミノ基の保護基（Ｚ）
が除去されると共に、生成物は反応液を冷却することに
よりシュウ酸塩・１／２水和物として析出するので、こ
れを採取することにより、目的とする３，４−ビス（エ
トキシカルボニルオキシ）フェネチルアミン・シュウ酸
塩・１／２水和物を得ることができる。By the above treatment, the amino-protecting group (Z)
Is removed and the product is precipitated as an oxalate hemihydrate by cooling the reaction solution. By collecting this, the desired 3,4-bis (ethoxycarbonyloxy) ) Phenethylamine oxalate hemihydrate can be obtained.
【００１２】かくして得られた３，４−ビス（エトキシ
カルボニルオキシ）フェネチルアミン・シュウ酸塩・１
／２水和物は、Ｎ−アセチルメチオニンの反応性誘導体
（例えば、Ｎ−ヒドロキシコハク酸イミドとのエステル
等の活性エステル等）と、適当な溶媒（例えば、テトラ
ヒドロフラン等）中、塩基（例えば、Ｎ−メチルモルホ
リン等）の存在下で反応させることにより、優れた腎血
流増加作用を有する一般式〔ＩＩ〕3,4-Bis (ethoxycarbonyloxy) phenethylamine oxalate.1 thus obtained
/ 2 hydrate is a reactive derivative of N-acetylmethionine (eg, active ester such as ester with N-hydroxysuccinimide) and a base (eg, tetrahydrofuran) in a suitable solvent (eg, tetrahydrofuran). By reacting in the presence of (N-methylmorpholine, etc.), a general formula [II] having an excellent effect of increasing renal blood flow.
【００１３】[0013]
【化３】 [Chemical 3]
【００１４】で示されるドーパミン誘導体とすることが
できる。A dopamine derivative represented by
【００１５】なお、Ｎ−アセチルメチオニンの反応性誘
導体を、例えばＮ−アセチルメチオニンの活性化により
調製する場合、この活性化工程と該縮合反応を同一溶媒
系（例えば、テトラヒドロフラン）で連続的に実施する
ことができる。When a reactive derivative of N-acetylmethionine is prepared, for example, by activating N-acetylmethionine, this activation step and the condensation reaction are continuously carried out in the same solvent system (eg, tetrahydrofuran). can do.
【００１６】上記方法において、化合物〔ＩＩ〕並びに
Ｎ−アセチルメチオニンの反応性誘導体には、２種の光
学異性体が存在するが、これらのうち、Ｌ配位である化
合物がとりわけ好ましい。In the above method, the compound [II] and the reactive derivative of N-acetylmethionine have two types of optical isomers, and among them, the L-coordinate compound is particularly preferable.
【００１７】尚、本発明の原料化合物〔Ｉ〕は、例え
ば、ドーパミンのアミノ基に、常法により、保護基を導
入した後、該生成物とクロロ炭酸エチルを、脱酸剤の存
在下に縮合反応させて製造することができる。In the starting compound [I] of the present invention, for example, after introducing a protecting group into the amino group of dopamine by a conventional method, the product and ethyl chlorocarbonate are added in the presence of a deoxidizing agent. It can be produced by a condensation reaction.
【００１８】[0018]
実施例 （１）ドーパミン塩酸塩９４．８ｇを水４７０ｍｌに溶
解し、活性炭６ｇ及び水酸化ナトリウム０．４ｇを加え
て脱色後、活性炭をろ去する。ろ液にアセチルアセトン
５５．１ｇを加え５０〜５５℃とした後、水酸化ナトリ
ウム水溶液（水酸化ナトリウム２０．６ｇを水９５ｍｌ
に溶解）を滴下する。反応液を１５℃に冷却後、析出晶
をろ取し、洗浄、乾燥することによりＮ−（１−メチル
−３−オキソ−１−ブテニル）−３，４−ジヒドロキシ
フェネチルアミン１１４．９ｇを得る。収率９７．７％ ｍ．ｐ．１１８−１２０℃。Example (1) 94.8 g of dopamine hydrochloride is dissolved in 470 ml of water, 6 g of activated carbon and 0.4 g of sodium hydroxide are added to decolorize, and the activated carbon is filtered off. 55.1 g of acetylacetone was added to the filtrate and the temperature was adjusted to 50 to 55 ° C., and then an aqueous sodium hydroxide solution (20.6 g of sodium hydroxide was added to 95 ml of water).
Dissolved in) is added dropwise. After cooling the reaction solution to 15 ° C., the precipitated crystals are collected by filtration, washed and dried to obtain 114.9 g of N- (1-methyl-3-oxo-1-butenyl) -3,4-dihydroxyphenethylamine. Yield 97.7% m. p. 118-120 ° C.
【００１９】（２）Ｎ−（１−メチル−３−オキソ−１
−ブテニル）−３，４−ジヒドロキシフェネチルアミン
４７．１ｇ及びクロロホルム２５０ｍｌの混合物に、１
５〜２０℃にてトリエチルアミン４４．５ｇを滴下し、
次いで同温にてクロロ炭酸エチル４６．４ｇを滴下す
る。該混液を８０分間撹拌後、反応液を、洗浄、乾燥
し、溶媒を減圧留去する。得られる油状物〔Ｎ−（１−
メチル−３−オキソ−１−ブテニル）−３，４−ビス
（エトキシカルボニルオキシ）フェネチルアミン〕をテ
トラヒドロフラン２０５ｍｌに溶解し、シュウ酸・二水
和物５０．４ｇを加えて５０℃で３０分間撹拌する。反
応液を冷却し、析出晶をろ取後乾燥させることにより、
３，４−ビス（エトキシカルボニルオキシ）フェネチル
アミン・シュウ酸塩・１／２水和物６７．６ｇを結晶と
して得る。 収率８５．３％ ｍ．ｐ．１０２−１０４℃ 水含量（カールフィッシャー法） 測定値：２．３１％ 理論値：２．２７％ 元素分析（Ｃ14Ｈ19ＮＯ6 ・Ｃ2 Ｈ2 Ｏ4 ・１／２Ｈ2
Ｏとして) 測定値：Ｃ，４８．４１％；Ｈ，５．３６％；Ｎ，３．
３５％ 理論値：Ｃ，４８．４８％；Ｈ，５．５９％；Ｎ，３．
５３％1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6 ）δ：１．２８（６Ｈ，
ｔ，Ｊ＝７．１Ｈｚ），２．８８−２．９６（２Ｈ，
ｍ），３．０３−３．１０（２Ｈ，ｍ），４．２５（４
Ｈ，ｑ，Ｊ＝７．１Ｈｚ），７．２４（１Ｈ，ｄｄ，Ｊ
＝２．０ ａｎｄ８．４Ｈｚ），７．３３（１Ｈ，ｄ，
Ｊ＝２．０Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝８．４Ｈ
ｚ），５．５−８．３（５Ｈ，Ｂｒ） ＩＲνmax KBr （ｃｍ-1）：３０００，１７７０，１６
００，１２６０（第１図参照）。(2) N- (1-methyl-3-oxo-1)
-Butenyl) -3,4-dihydroxyphenethylamine in a mixture of 47.1 g and chloroform 250 ml.
44.5 g of triethylamine was added dropwise at 5 to 20 ° C,
Then, 46.4 g of ethyl chlorocarbonate is added dropwise at the same temperature. After stirring the mixed solution for 80 minutes, the reaction solution is washed and dried, and the solvent is distilled off under reduced pressure. The obtained oily substance [N- (1-
Methyl-3-oxo-1-butenyl) -3,4-bis (ethoxycarbonyloxy) phenethylamine] is dissolved in 205 ml of tetrahydrofuran, 50.4 g of oxalic acid dihydrate is added, and the mixture is stirred at 50 ° C. for 30 minutes. . The reaction solution is cooled, and the precipitated crystals are collected by filtration and dried,
67.6 g of 3,4-bis (ethoxycarbonyloxy) phenethylamine oxalate hemihydrate is obtained as crystals. Yield 85.3% m.p. p. 102-104 ° C. Water content (Karl Fischer method) found: 2.31% Calculated: 2.27% Elemental analysis (C 14 H 19 NO 6 · C 2 H 2 O 4 · 1 / 2H 2
Measured: C, 48.41%; H, 5.36%; N, 3.
35% Theoretical value: C, 48.48%; H, 5.59%; N, 3.
53% 1 H-NMR (DMSO-d 6 ) δ: 1.28 (6H,
t, J = 7.1 Hz), 2.88-2.96 (2H,
m), 3.03-3.10 (2H, m), 4.25 (4
H, q, J = 7.1 Hz), 7.24 (1H, dd, J
= 2.0 and 8.4 Hz), 7.33 (1H, d,
J = 2.0 Hz), 7.36 (1H, d, J = 8.4H)
z), 5.5-8.3 (5H, Br) IRv max KBr (cm -1 ): 3000, 1770, 16
00, 1260 (see FIG. 1).
【００２０】上記生成物を、ＣｕＫα1 （λ＝１．５４
５０Å) 放射線を用いた粉末Ｘ線回折に付したところ、
第１表に示すｄ−値及び線強度（Ｉ）を示した。線強度
（Ｉ）は目視により測定し、ｓｔ＝強、ｍ＝中、ｗ＝弱
で評価した。The above product was converted into CuKα 1 (λ = 1.54)
50Å) When subjected to powder X-ray diffraction using radiation,
The d-value and the line intensity (I) shown in Table 1 are shown. The line intensity (I) was visually measured, and evaluated by st = strong, m = medium, and w = weak.
【００２１】[0021]
【表１】 [Table 1]
【００２２】[0022]
【表２】 [Table 2]
【００２３】参考例 Ｎ−アセチル−Ｌ−メチオニン２０．０ｇ、Ｎ−ヒドロ
キシコハク酸イミド１２．０ｇ及びテトラヒドロフラン
３００ｍｌの混合物に、−１０〜−１５℃でジシクロヘ
キシルカルボジイミド２１．６ｇを加え、同温にて２０
時間攪拌する。Reference Example To a mixture of 20.0 g of N-acetyl-L-methionine, 12.0 g of N-hydroxysuccinimide and 300 ml of tetrahydrofuran was added 21.6 g of dicyclohexylcarbodiimide at -10 to -15 ° C, and the mixture was kept at the same temperature. 20
Stir for hours.
【００２４】該反応液に、３，４−ビス（エトキシカル
ボニルオキシ）フェネチルアミン・シュウ酸塩・１／２
水和物３７．７ｇを加え、Ｎ−メチルモルホリン１９．
２ｇを滴下した後、−１０〜−１５℃で２０時間攪拌す
る。反応液をろ過し、ろ液に酢酸エチルを加え、洗浄、
乾燥後、溶媒を留去する。残渣を酢酸エチルに溶解し、
不溶物をろ去した後、溶媒を留去する。油状残渣にイソ
プロピルアルコール−ｎ−ヘキサンを加え、析出晶をろ
取後、エタノール−水から再結晶させることによりＮ−
（Ｎ−アセチル−Ｌ−メチオニル）−３，４−ビス（エ
トキシカルボニルオキシ）フェネチルアミン３６．２ｇ
を得る。収率８１．０％ ｍ．ｐ．１０６℃ ＩＲνmax nujol （ｃｍ-1）：３２９０，１７６０，１
６３０，１２８０ 比旋光度〔α〕D 20−１６．２°（ｃ＝５, エタノー
ル) 。In the reaction liquid, 3,4-bis (ethoxycarbonyloxy) phenethylamine.oxalate.1 / 2
37.7 g of hydrate was added, and N-methylmorpholine 19.
After dropping 2 g, the mixture was stirred at -10 to -15 ° C for 20 hours. The reaction solution is filtered, ethyl acetate is added to the filtrate, and the mixture is washed,
After drying, the solvent is distilled off. Dissolve the residue in ethyl acetate,
After the insoluble matter is filtered off, the solvent is distilled off. Isopropyl alcohol-n-hexane was added to the oily residue, and the precipitated crystals were collected by filtration and recrystallized from ethanol-water to give N-.
(N-Acetyl-L-methionyl) -3,4-bis (ethoxycarbonyloxy) phenethylamine 36.2 g
To get Yield 81.0% m.p. p. 106 ° C. IRν max nujol (cm −1 ): 3290, 1760, 1
630,1280 Specific rotation [α] D 20 -16.2 ° (c = 5 , ethanol).
【００２５】[0025]
【発明の効果】本発明の３，４−ビス（エトキシカルボ
ニルオキシ）フェネチルアミン・シュウ酸塩・１／２水
和物は、結晶性が良好で、高純度の結晶として容易に取
得することができるという特長を有する。かかる本発明
の水和物を優れた腎血流増加作用を有するドーパミン誘
導体〔ＩＩ〕を製造する際に、合成中間体として用いれ
ば、３，４−ビス（エトキシカルボニルオキシ）フェネ
チルアミンの塩酸塩やｐ−トシル酸塩等を用いる前記従
来法に較べて、ドーパミン誘導体〔ＩＩ〕を高純度で製
造することができるという特長を有する。The 3,4-bis (ethoxycarbonyloxy) phenethylamine oxalate hemihydrate of the present invention has good crystallinity and can be easily obtained as high-purity crystals. It has the feature. When the hydrate of the present invention is used as a synthetic intermediate in the production of a dopamine derivative [II] having an excellent effect of increasing renal blood flow, 3,4-bis (ethoxycarbonyloxy) phenethylamine hydrochloride or Compared with the above-mentioned conventional method using p-tosylate or the like, it has a feature that the dopamine derivative [II] can be produced with high purity.
【００２６】また、本発明の水和物をドーパミン誘導体
〔ＩＩ〕を製造する際に、合成中間体として用いれば、
原料化合物であるＮ−アセチルメチオニンの反応性誘導
体の調製と、それに続く本発明の水和物との縮合反応
を、同一溶媒中で連続的に実施することができるという
特長を有するため、前記従来法に比較し、操作性が格段
に向上するとともに、Ｎ−アセチルメチオニンの反応性
誘導体の単離・精製による損失を防ぎ、Ｎ−アセチルメ
チオニンから最終目的物であるドーパミン誘導体〔Ｉ
Ｉ〕の収率を格段に高めることができる。When the hydrate of the present invention is used as a synthetic intermediate in the production of dopamine derivative [II],
The preparation of a reactive derivative of N-acetylmethionine, which is a raw material compound, and the subsequent condensation reaction with the hydrate of the present invention can be carried out continuously in the same solvent. Compared with the method, the operability is remarkably improved, the loss due to the isolation and purification of the reactive derivative of N-acetylmethionine is prevented, and the final target dopamine derivative [I
The yield of I] can be remarkably increased.
【図１】 実施例で得た化合物のＩＲスペクトルであ
る。FIG. 1 is an IR spectrum of the compound obtained in Example.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 池田 康治 京都府京都市山科区東野狐藪町７−８パー クテラス山科501号 (72)発明者 西本 茂 大阪府箕面市粟生外院１丁目16番Ｂ−110 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Koji Ikeda No. 501 Park Terrace Yamashina, 7-8 Higashino Kitabu-cho, Yamashina-ku, Kyoto City, Kyoto Prefecture (72) Inventor Shigeru Nishimoto 1-16B, Awa Gaien, Minoh City, Osaka Prefecture −110
Claims (2)
キシ）フェネチルアミン・シュウ酸塩・１／２水和物。1. 3,4-Bis (ethoxycarbonyloxy) phenethylamine oxalate hemihydrate.
す。）で示される化合物をシュウ酸・水和物で処理し、
析出結晶を採取することを特徴とする３，４−ビス（エ
トキシカルボニルオキシ）フェネチルアミン・シュウ酸
塩・１／２水和物の製法。2. A compound represented by the general formula [I]: (In the formula, Z represents a protecting group of an amino group which can be removed with an acid.) The compound represented by the following formula is treated with oxalic acid hydrate,
A method for producing 3,4-bis (ethoxycarbonyloxy) phenethylamine / oxalate / hemihydrate, which comprises collecting precipitated crystals.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6170524A JP2526811B2 (en) | 1994-07-22 | 1994-07-22 | Phenethylamine derivative and method for producing the same |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6170524A JP2526811B2 (en) | 1994-07-22 | 1994-07-22 | Phenethylamine derivative and method for producing the same |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2229687A Division JPH078853B2 (en) | 1990-08-30 | 1990-08-30 | Method for producing dopamine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07165684A true JPH07165684A (en) | 1995-06-27 |
| JP2526811B2 JP2526811B2 (en) | 1996-08-21 |
Family
ID=15906541
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| Application Number | Title | Priority Date | Filing Date |
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| JP (1) | JP2526811B2 (en) |
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1994
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|---|---|
| JP2526811B2 (en) | 1996-08-21 |
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