JPS63255255A - Production of optically active alpha-methylosin - Google Patents
Production of optically active alpha-methylosinInfo
- Publication number
- JPS63255255A JPS63255255A JP8975087A JP8975087A JPS63255255A JP S63255255 A JPS63255255 A JP S63255255A JP 8975087 A JP8975087 A JP 8975087A JP 8975087 A JP8975087 A JP 8975087A JP S63255255 A JPS63255255 A JP S63255255A
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- apg
- water
- optically
- alpha
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 239000002904 solvent Substances 0.000 claims abstract description 9
- LJMNZJZZESACIJ-UHFFFAOYSA-N 2-amino-3-(4-methoxyphenyl)-2-methylpropanenitrile Chemical compound COC1=CC=C(CC(C)(N)C#N)C=C1 LJMNZJZZESACIJ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract description 3
- 230000003287 optical effect Effects 0.000 claims description 4
- VKDFZMMOLPIWQQ-UHFFFAOYSA-N 2-acetamido-2-phenylacetic acid Chemical compound CC(=O)NC(C(O)=O)C1=CC=CC=C1 VKDFZMMOLPIWQQ-UHFFFAOYSA-N 0.000 claims description 2
- MUZYAEDDOSKNRG-UHFFFAOYSA-N 2-(4-methoxyphenyl)propanenitrile Chemical compound COC1=CC=C(C(C)C#N)C=C1 MUZYAEDDOSKNRG-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 21
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 abstract description 7
- 238000006243 chemical reaction Methods 0.000 abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 abstract description 2
- 239000011707 mineral Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- VKDFZMMOLPIWQQ-VIFPVBQESA-N N-acetyl-L-alpha-phenylglycine Chemical compound CC(=O)N[C@H](C(O)=O)C1=CC=CC=C1 VKDFZMMOLPIWQQ-VIFPVBQESA-N 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VWMVAQHMFFZQGD-UHFFFAOYSA-N 4-hydroxyphenylacetone Chemical compound CC(=O)CC1=CC=C(O)C=C1 VWMVAQHMFFZQGD-UHFFFAOYSA-N 0.000 description 1
- 208000006558 Dental Calculus Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- -1 impropatol Chemical compound 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000010641 nitrile hydrolysis reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は医薬として有用な式（１）で表わされる光学活
性なα−メチロシンの新規製造法に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel method for producing optically active α-methylosine represented by formula (1), which is useful as a pharmaceutical.
光学活性なα−メチロシンを合成する方法としては、（
１）不斉合成による方法（Ｃｈｅｍ、 Ｂｅｒ、 １１
０ 。As a method for synthesizing optically active α-methylosine, (
1) Method by asymmetric synthesis (Chem, Ber, 11
0.
（１９８５）が提案されている。(1985) have been proposed.
前記（１）の方法はその操作が極めて煩雑であり又高価
な光学活性７エネチルアミンを不斉合成い等の欠点があ
り未だ満足すべき製法とは言い難い。The method (1) has drawbacks such as extremely complicated operations and the asymmetric synthesis of expensive optically active 7-enethylamine, so it is still difficult to say that it is a satisfactory production method.
本発明者らは光学活性α−メチロシンの合成について鋭
意研究の結果、従来知られている方法に較べ、容易にし
て簡単な製造方法をここに見い出した。As a result of extensive research into the synthesis of optically active α-methylosine, the present inventors have now discovered a manufacturing method that is easier and simpler than conventionally known methods.
即ち、本発明は式（２）で示されるα−メチル−α−ア
ミノ−β−（４−メトキシフェニル）−プロピオニトリ
ル（以下ｒＡ ＮＪという）の（至）体に溶媒中で光学
活性なアセチルフェニルグリシン（以下ｒＡ Ｐ ＧＪ
という）を作用させることにより光学分割を行ない光学
活性なＡＮを得、次いで得られた光学活性ＡＮを加水分
解することにより式（１）で示される光学活性なα−メ
チロシン
を製造する方法を提供する。That is, the present invention provides an optically active form of α-methyl-α-amino-β-(4-methoxyphenyl)-propionitrile (hereinafter referred to as rANJ) represented by formula (2) in a solvent. Acetyl phenylglycine (rAP GJ)
Provided is a method for producing optically active α-methylosine represented by formula (1) by performing optical resolution to obtain optically active AN, and then hydrolyzing the obtained optically active AN. do.
本発明の方法を反応式で表わすと下記の通りである。The method of the present invention is expressed as a reaction formula as follows.
なお、式（２）で示される（至）−ＡＮは公知のストレ
ッカー法により４−ヒドロキシフェニルアセトンにアン
モニアとシアンカリを作用させて容易に得ることができ
る。Note that (to)-AN represented by formula (2) can be easily obtained by reacting ammonia and cyankali with 4-hydroxyphenylacetone by the known Strecker method.
反応式（１）Ｋ示す光学分割は、まず（至）−ＡＮを適
当な溶媒に溶解しておき、同様に光学活性なＡＰＧを同
種又は異種の溶媒、好ましくはメタノール、エタノール
、イソプロパツールなどのアルコール類に溶解する。次
いで攪拌下Ｋ ＡＰＧ溶液をＡＮ溶液に徐々に加える。In the optical resolution shown by reaction formula (1)K, first, -AN is dissolved in a suitable solvent, and similarly optically active APG is dissolved in the same or different solvent, preferably methanol, ethanol, isopropanol, etc. Soluble in alcohols. Then slowly add the K APG solution to the AN solution while stirring.
このように調製した溶液から難溶性なＡＮ−ＡＰＧ塩を
選択的に晶出し固液を分離する。このよ５にして得られ
た光学活性なＡＮ−ＡＰＧ塩を塩基性物質、好ましくは
アンモニア水で中和し溶媒抽出後、抽出溶媒を留去する
と光学活性なＡＮを得ることができる。From the solution prepared in this manner, the poorly soluble AN-APG salt is selectively crystallized and the solid and liquid are separated. The optically active AN-APG salt obtained in step 5 is neutralized with a basic substance, preferably aqueous ammonia, and after solvent extraction, the extraction solvent is distilled off to obtain optically active AN.
遊離化を行なうことにより高純度の光学活性なＡＮを得
ることができる。High purity optically active AN can be obtained by liberating it.
本発明において用いられる溶媒としてはメタノール、エ
タノール、インプロパツール、アセトン等の親水性溶媒
、ｎ−ヘキサン、ベンゼン、トルエン、酢酸エチル、塩
素系低級炭化水素又はこれらの２種以上の溶媒の混合溶
媒が用いられ会、好ましくは工業的に安価なメタノール
、トルエン等を用いるのが有利である。Solvents used in the present invention include hydrophilic solvents such as methanol, ethanol, impropatol, and acetone, n-hexane, benzene, toluene, ethyl acetate, chlorinated lower hydrocarbons, and mixed solvents of two or more of these solvents. It is advantageous to use methanol, toluene, etc., which are industrially inexpensive.
晶出させるのに種晶を接種しなくてもよいが晶出を効率
的に行なうには難溶性のＡＮ−ＡＰＧ塩を接種するのが
好ましい。Although it is not necessary to inoculate seed crystals for crystallization, it is preferable to inoculate sparingly soluble AN-APG salt in order to perform crystallization efficiently.
出ＡＮＫ対するＡＰＧの仕込モル比は広い範囲に選択し
うるが特に過剰忙用いる必要はなく、好ましくは１．０
〜１．２当量が適当である。The molar ratio of APG to output ANK can be selected within a wide range, but there is no need to use an excessive amount, and it is preferably 1.0.
~1.2 equivalents are suitable.
反応温度及び晶析温度は特に限定しないが使用するＡＮ
の熱安定性を考慮して５°〜４０℃、好ましくは１５〜
２５℃で操作するのが有利である。The reaction temperature and crystallization temperature are not particularly limited, but the AN used
Considering the thermal stability of 5° to 40°C, preferably 15 to 40°C
It is advantageous to operate at 25°C.
次に反応式（Ｉ［）はニトリルの加水分解及び脱メチル
化反応である。光学活性なＡＮから光学活性なα−メチ
ロシンを得る反応は鉱酸、好ましくは４７％臭化水素酸
中又は３５％塩酸と４７％臭化水素酸との混合物中で１
００−１２０゜に加熱するととＫより達成される。Next, reaction formula (I[) is a nitrile hydrolysis and demethylation reaction. The reaction to obtain optically active α-methylosine from optically active AN is carried out in a mineral acid, preferably 47% hydrobromic acid or in a mixture of 35% hydrochloric acid and 47% hydrobromic acid.
This is achieved by heating to 00-120°.
本発明によれば、工業的に容易に入手できる光学活性な
ＡＰＧを用いて光学分割を行ない、容易に光学活性なＡ
Ｎを高純度かつ好収率で得ることができる。更に得られ
たＬ（−３−ＡＮ、は容易に光学活性なＬ−α−メチロ
シンに変換できるので従来法に比べて極めて工業的有利
に製造できる。According to the present invention, optical resolution is performed using optically active APG that is easily available industrially, and optically active APG is easily obtained.
N can be obtained with high purity and good yield. Furthermore, since the obtained L(-3-AN) can be easily converted to optically active L-α-methylosine, it can be produced industrially with great advantage compared to conventional methods.
以下実施例を挙げて本発明を具体的に説明する。The present invention will be specifically explained below with reference to Examples.
実施例１゜
（１） Ｈ−ＡＰＧ２０．３ ｇ （０，１０５モル
）をメタノ−ｋ １２０ ｍｌに溶解し、この中に（ｄ
−ＡＮ２０ｇ（０，１０５モル）をトルエン１５０ｍ１
Ｋ溶解して徐々に加える。このように調製した溶液を２
０〜２３℃で３時間攪拌後、析出結晶を戸別しトルエン
３０ｍ１で洗浄し室温で真空乾燥して（ト）−ＡＮ−（
へ）−ＡＰＧ塩の結晶１４．０９ｇ得た。Example 1゜(1) 20.3 g (0,105 mol) of H-APG was dissolved in 120 ml of methanol-k, and (d
-20g (0,105 mol) of AN in 150ml of toluene
Dissolve K and gradually add. The solution prepared in this way is
After stirring at 0 to 23°C for 3 hours, the precipitated crystals were separated, washed with 30 ml of toluene, and dried under vacuum at room temperature to give (t)-AN-(
14.09 g of crystals of -APG salt were obtained.
〔α〕２０″ ＝−８８，１° （Ｃ＝１．メタノール
）融 点 ＝１１８〜１２０℃ （分解）定量値 Ｎ
＝１１．２３％、計算値 Ｎ＝１０．９５％このように
して得られた結晶１４．０９ｇを１０〜１５℃にて水２
００ ｍｌに懸濁し、２５％アンモニヤ水２８ｍ１で中
和する。遊離した油状物を塩化メチレン３０ｍ１で抽出
する。塩化メチレン層は水１ｏｍｌで洗浄後分取し、塩
化メチレンを留去して（ホ）−ＡＮ６．７２ｇ得た。（
ＮＭＲデーター記載）
〔α）：：、 ＝＋１ｇ、４° （Ｃ＝５、アセトン
）（２） （１）−ｃ−得た［）−ＡＮ ５．１５
ｇ （０，０２７モル） Ｋ ｄ−酒石ｍ４．０６ｇ（
０，０２７モｋ）ｔｔ水５０ｍ１に溶解して加える。こ
のように調整した溶液を２０〜２３℃で２時間攪拌後、
析出結晶を戸別し冷水１０ｍＡ！で洗浄する。得られた
（ト）−ＡＮ−ｄ−酒石酸のウェット結晶を水２００
ｍｌに懸濁し１０〜１５℃で２５％アンモニヤ水１．８
ｍｌで中和する。遊離した油状（−１−）−ＡＮを塩
化メチレン１５ｍＡ！で抽出する。塩化メチレン層を分
取後、４７％臭化水素を加え（ト）−ＡＮを臭化水素酸
塩として抽出する。臭化水素酸層な４時間、１４０°Ｃ
で加熱攪拌する。次ぎに濃縮乾固し残渣に水１００ｍＡ
！を加え、３０％苛性ソーダ水でｐＨ３，５に調整する
。析出する白色結晶を戸別し、水１０ｍＡ’で洗浄後、
真空乾燥してＬ−α−メチロシン４．９６ｇ（収率９５
，２％）得た。[α] 20″ = -88,1° (C = 1. Methanol) Melting point = 118-120°C (Decomposition) Quantitative value N
= 11.23%, calculated value N = 10.95%.
00 ml and neutralized with 28 ml of 25% ammonia water. The liberated oil is extracted with 30 ml of methylene chloride. The methylene chloride layer was washed with 1 oml of water and separated, and the methylene chloride was distilled off to obtain 6.72 g of (e)-AN. (
NMR data description) [α)::, =+1g, 4° (C=5, acetone) (2) (1)-c-obtained [)-AN 5.15
g (0,027 mol) K d-tartar m4.06 g (
0,027 mok) tt Dissolve in 50 ml of water and add. After stirring the solution prepared in this way at 20 to 23°C for 2 hours,
Precipitated crystals are sent door to door with cold water at 10 mA! Wash with The obtained wet crystals of (t)-AN-d-tartaric acid were mixed with 200 g of water.
ml of 25% ammonia water at 10-15°C.
Neutralize with ml. The liberated oily (-1-)-AN was treated with methylene chloride at 15 mA! Extract with After separating the methylene chloride layer, 47% hydrogen bromide was added to extract (t)-AN as a hydrobromide salt. Hydrobromic acid layer for 4 hours at 140°C
Heat and stir. Next, concentrate to dryness and add 100 mA of water to the residue.
! and adjust the pH to 3.5 with 30% caustic soda water. After separating the precipitated white crystals from door to door and washing them with 10 mA' of water,
Vacuum drying yielded 4.96 g of L-α-methylosine (yield: 95
, 2%) was obtained.
〔α−Ｂｓｓ ４−３°（Ｃ＝１、ＩＮ−ＨＣＩ）
融点 ３１０−３１４°Ｃ
文献値（Ｃｈｅｍ、 Ｂｅｒ １旦４ ３５９４−３
６０６）〔α〕５８９４．４° （Ｃ＝１、ＩＮ−ＨＣ
Ｉ）融点 ３１０−３１５゜
実施例２゜
（１） （＋１−ＡＰＧ ２４ｇ （０，１２４モル
）をメタノールＬ４２ｍｌＫ溶解し、この中１ｃｍ−Ａ
Ｎ ２３．６ ｇ（０，１２４モル）を酢酸エチル１６
５ ｍｌに溶解して徐々に加える。このように調製した
溶液を２０〜２３℃で３時間攪拌後、析出結晶を戸別し
酢酸エチル３Ｑｒｎｌで洗浄し室温で真空乾燥して、Ｈ
−ＡＮ−（ト）−ＡＰＧ塩の結晶１３．８ｇ得た。[α-Bss 4-3° (C=1, IN-HCI)
Melting point 310-314°C Literature value (Chem, Ber 1dan4 3594-3
606) [α] 5894.4° (C=1, IN-HC
I) Melting point 310-315° Example 2° (1) (+1-APG 24 g (0,124 mol) was dissolved in 42 ml of methanol L, 1 cm-A
23.6 g (0,124 mol) of N was dissolved in 16 ml of ethyl acetate.
Dissolve in 5 ml and gradually add. After stirring the solution prepared in this way for 3 hours at 20 to 23°C, the precipitated crystals were separated, washed with 3Qrnl of ethyl acetate, dried under vacuum at room temperature, and washed with H
13.8 g of crystals of -AN-(t)-APG salt were obtained.
〔α〕２０″ −＋９３．２° （Ｃ＝１ メタノール
）融 点 ＝１２１−１２２℃ （分解）定量値 Ｎ
＝１１．９５％ 計算値 Ｎ＝９．０５％このように
して得られた結晶１３．８ｇを１０〜１５℃にて水１９
５ｍＡ！に懸濁し、２５％アンモニヤ水７．８ ｒｎｔ
で中和する、遊離した油状物を塩化メチレン３ Ｑ ｍ
ｌで抽出する。塩化メチレン層は水ｔｏｍｘで洗浄後分
取し、塩化メチレンを留去して（ハ）−ＡＮ７．２１ｇ
得た。[α] 20″ -+93.2° (C=1 methanol) Melting point = 121-122°C (decomposition) Quantitative value N
= 11.95% Calculated value N = 9.05% 13.8 g of the crystals thus obtained were mixed with 19 g of water at 10-15°C.
5mA! Suspended in 25% ammonia water 7.8 rnt
Neutralize the liberated oil with 3 Q m of methylene chloride.
Extract with l. The methylene chloride layer was separated after washing with water tomx, and the methylene chloride was distilled off to obtain 7.21 g of (c)-AN.
Obtained.
〔α〕牝、＝−２０．１° （Ｃ−５アセトン）（２）
（１） テ得たＨ−ＡＮ ６．５ ｇ （０，０３
４モ＃）にｐ−酒石酸５．１２ｇ（０，０３４−ｒ＝ル
）を水６３ｍＪに溶・ 解してから加える。このように
調整した溶液を２０〜２３℃で２時間攪拌後析出結晶を
戸別し冷水１０ｍ！で洗浄する。得られた（へ）−ＡＮ
−Ａ−酒石酸のウェット結晶を水２５２ｍ／に懸濁し１
０〜１５℃で２５％アンモニヤ水２．３ ｍｌで中和す
る。遊離した油状（へ）−ＡＮを塩化メチレン１５ｍ１
で抽出する。塩化メチレン層を分取後、４７％臭化水素
酸３９．４ ｆｆ／を加え、（へ）−ＡＮを臭化水素酸
塩として抽出する臭化水素酸層を４時間１４０℃で加熱
攪拌する。次に濃縮乾固し、残渣に水１００ｍＡ’を加
え、３０％苛性ソーダ水でｐＨ３，５忙調整する。析出
する白色結晶を炉別し、水１０ｍ／、；洗浄後真空乾燥
してＤ−α−メチロシン７．０６ｇ（９４，３％）得た
。[α] Female, = -20.1° (C-5 acetone) (2)
(1) The obtained H-AN 6.5 g (0.03
Dissolve 5.12 g (0,034-r=L) of p-tartaric acid in 63 mJ of water and then add to the solution. After stirring the solution prepared in this manner at 20-23°C for 2 hours, the precipitated crystals were separated from each other and poured into 10 m of cold water. Wash with Obtained (to) -AN
-A- Wet crystals of tartaric acid are suspended in 252 m/ml of water and 1
Neutralize with 2.3 ml of 25% ammonia water at 0-15°C. The liberated oil-AN was dissolved in 15 ml of methylene chloride.
Extract with After separating the methylene chloride layer, add 47% hydrobromic acid (39.4 ff/) to extract (he)-AN as a hydrobromide salt. The hydrobromic acid layer is heated and stirred at 140°C for 4 hours. . Next, concentrate to dryness, add 100 mA' of water to the residue, and adjust the pH to 3.5 with 30% caustic soda water. The precipitated white crystals were separated in a furnace, washed with 10 m of water, and then dried in vacuum to obtain 7.06 g (94.3%) of D-α-methylosine.
（ａ）：：、＋ ４．４° （Ｃ＝１、ＩＮ−ＨＣＩ）
融点 ３１０−３１３℃(a)::, +4.4° (C=1, IN-HCI)
Melting point 310-313℃
Claims (1)
フェニル）−プロピオニトリルを溶媒中で光学活性Ｎ−
アセチル−フェニルグリシンを用いて光学分割を行い、
次いで得られた光学活性α−メチル−α−アミノ−β−
（４−メトキシフェニル）−プロピオニトリルを加水分
解することを特徴とする式（１）で表わされる光学活性
α−メチロシンの製造法。 ▲数式、化学式、表等があります▼（１）[Claims] (±)-α-Methyl-α-amino-β-(4-methoxyphenyl)-propionitrile in a solvent with
Optical resolution was performed using acetyl-phenylglycine,
The optically active α-methyl-α-amino-β-
A method for producing optically active α-methylosine represented by formula (1), which comprises hydrolyzing (4-methoxyphenyl)-propionitrile. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8975087A JPS63255255A (en) | 1987-04-14 | 1987-04-14 | Production of optically active alpha-methylosin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8975087A JPS63255255A (en) | 1987-04-14 | 1987-04-14 | Production of optically active alpha-methylosin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63255255A true JPS63255255A (en) | 1988-10-21 |
Family
ID=13979424
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8975087A Pending JPS63255255A (en) | 1987-04-14 | 1987-04-14 | Production of optically active alpha-methylosin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63255255A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110104765A1 (en) * | 2009-10-30 | 2011-05-05 | Aton Pharma, Inc. | Stereoselective synthesis of metyrosine |
-
1987
- 1987-04-14 JP JP8975087A patent/JPS63255255A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110104765A1 (en) * | 2009-10-30 | 2011-05-05 | Aton Pharma, Inc. | Stereoselective synthesis of metyrosine |
| US8841486B2 (en) * | 2009-10-30 | 2014-09-23 | Aton Pharma | Stereoselective synthesis of metyrosine |
| US9452974B2 (en) | 2009-10-30 | 2016-09-27 | Aton Pharma, Inc. | Stereoselective synthesis of metyrosine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPS63255255A (en) | Production of optically active alpha-methylosin | |
| JP2000026418A (en) | New production of derivative of 4-phenyl-1,2,3,6- tetrahydropyridine and intermediate used therefor | |
| KR20020091077A (en) | Novel Process for the Preparation of α-(2-4-Disulfophenyl)-N-tert-Butylnitrone and Pharmaceutically Acceptable Salts Thereof | |
| CN107629039B (en) | The preparation method and intermediate of deuterated acrylamide | |
| JPH03153680A (en) | Biphenyl compound and its preparation | |
| JPH03279348A (en) | Production of 2,4,5-trifluoro-3-alkoxybenzoic acid | |
| JPS6054311B2 (en) | Method for producing 2-isopropylaminopyrimidine | |
| JPS5832872A (en) | Optical resolution of benzothiazepine derivative | |
| JPH08208591A (en) | 2-aminobenzenesulfonic acid derivative and 2-aminobenzenesulfonyl chloride,derivative their production,and their use as synthetic intermediates | |
| JPH0558985A (en) | Production of cyanoguanidine derivative | |
| KR20020091078A (en) | Novel Process for the Preparation of α-(2-4-Disulfophenyl)-N-tert-Butylnitrone and Pharmaceutically Acceptable Salts Thereof | |
| JPH0269469A (en) | Dihydrofuran derivative and production thereof | |
| JPS593476B2 (en) | Optically active chlorpheniramine/acylphenylglycine salt and method for producing the same | |
| JPS61172846A (en) | Method of optical resolution of (+-)-2-chloroprorionic acid | |
| JPH023672A (en) | 2,6-diethylaniline derivative and production thereof | |
| JPS62103088A (en) | Production of 4,5,6,7-tetrahydrothieno(3,2-c)-pyridine or salt thereof | |
| JPS5835136A (en) | Preparation of 6-bromothymol | |
| JPH01313471A (en) | Production of n-sulfamoylamidine compound | |
| JPS58121251A (en) | Preparation of 5-(2-(dialkylamino)ethoxy)carvacrol acetate hydrochloride | |
| BE876900A (en) | PROCESS FOR THE PRODUCTION OF PYRROLIDINE-2-ONES FROM 3-PYRROLINE-2-ONES AND FOR THE PRODUCTION OF 3-PYRROLINE-2-ONES | |
| JPH0374662B2 (en) | ||
| JPH0157104B2 (en) | ||
| JPS6163659A (en) | Preparation of 4-(2,4-dichlorobenzoyl)-1-methyl-5-hydroxypyrazole | |
| JPH0480899B2 (en) | ||
| JPS60166650A (en) | Preparation of acylamino-naphthalene derivative |