JPH0515701B2 - - Google Patents
Info
- Publication number
- JPH0515701B2 JPH0515701B2 JP12150485A JP12150485A JPH0515701B2 JP H0515701 B2 JPH0515701 B2 JP H0515701B2 JP 12150485 A JP12150485 A JP 12150485A JP 12150485 A JP12150485 A JP 12150485A JP H0515701 B2 JPH0515701 B2 JP H0515701B2
- Authority
- JP
- Japan
- Prior art keywords
- amino
- dimethoxyphenyl
- methyl
- propionitrile
- acid
- 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 - Lifetime
Links
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 16
- 229960001270 d- tartaric acid Drugs 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 12
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 12
- 235000010755 mineral Nutrition 0.000 claims description 12
- 239000011707 mineral Substances 0.000 claims description 12
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 8
- OEWDSMNBHDNSTP-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-2-methylpropanenitrile Chemical compound COC1=CC=C(C(C)(C)C#N)C=C1OC OEWDSMNBHDNSTP-UHFFFAOYSA-N 0.000 claims description 6
- 229940095064 tartrate Drugs 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 230000003472 neutralizing effect Effects 0.000 claims description 4
- QYPVUSRSPJQLAY-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)-2-methylpropanenitrile Chemical compound COC1=CC=C(CC(C)C#N)C=C1OC QYPVUSRSPJQLAY-UHFFFAOYSA-N 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Chemical class 0.000 description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 4
- -1 (dimethoxyphenyl)-2-methylpropionitrile Chemical compound 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 229960002510 mandelic acid Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010520 demethylation reaction Methods 0.000 description 3
- 239000012456 homogeneous solution Substances 0.000 description 3
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-M D-tartrate(1-) Chemical compound OC(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- VWZUIIYOJGQRBR-UHFFFAOYSA-N 2-(3,4-dihydroxyanilino)-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)NC1=CC=C(O)C(O)=C1 VWZUIIYOJGQRBR-UHFFFAOYSA-N 0.000 description 1
- GEFHJACVQBNFFP-UHFFFAOYSA-N 2-amino-3-(3,4-dimethoxyphenyl)-2-methylpropanenitrile Chemical compound COC1=CC=C(CC(C)(N)C#N)C=C1OC GEFHJACVQBNFFP-UHFFFAOYSA-N 0.000 description 1
- PGQTYXFMSZUGOW-UHFFFAOYSA-N 2-methyl-2-phenylpropanenitrile Chemical compound N#CC(C)(C)C1=CC=CC=C1 PGQTYXFMSZUGOW-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-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
- 235000004279 alanine Nutrition 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- HELHAJAZNSDZJO-OTWIGTIJSA-L disodium;(2s,3s)-2,3-dihydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O HELHAJAZNSDZJO-OTWIGTIJSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000012254 magnesium hydroxide Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
産業上の利用分野
本発明は光学活性な２−アミノ−３−（３，４
−ジメトキシフエニル）−２−メチル−プロピオ
ニトリルの製造法に関する。更に詳しくは光学分
割法を利用したＬ−２−アミノ−３−（３，４−
ジメトキシフエニル）−２−メチルプロピオニト
リルの製造法に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention provides optically active 2-amino-3-(3,4
-dimethoxyphenyl)-2-methyl-propionitrile. More specifically, L-2-amino-3-(3,4-
The present invention relates to a method for producing (dimethoxyphenyl)-2-methylpropionitrile.
従来の技術
Ｌ−２−アミノ−３−（３，４−ジメトキシフ
エニル）−２−メチルプロピオニトリルは血圧降
下作用を有するＬ−３−（３，４−ジヒドロキシ
フエニル）−２−メチル−アラニン（Ｌ−α−メ
チルドバ）の原料として重要な化合物である。Prior Art L-2-amino-3-(3,4-dimethoxyphenyl)-2-methylpropionitrile is a compound of L-3-(3,4-dihydroxyphenyl)-2-methyl that has a blood pressure lowering effect. -It is an important compound as a raw material for alanine (L-α-methyldova).
Ｌ−２−アミノ−３−（３，４−ジメトキシフ
エニル）−２−メチルプロピオニトリルの製造法
は特公昭41−2897によつて公知である。即ち特公
昭41−2897においてはDL−２−アミノ−３−
（３，４−ジメトキシフエニル）−２−メチル−プ
ロピオニトリルを水中に懸濁し、ｄ−酒石酸と反
応させて、析出するＤ−２−アミノ−３−（３，
４−ジメトキシフエニル）−２−メチル−プロピ
オニトリルのｄ−酒石酸塩を過により分離（光
学分割）し、次いで液を中和してＬ−２−アミ
ノ−３−（３，４−ジメトキシフエニル）−２−メ
チル−プロピオニトリルを得ている。 A method for producing L-2-amino-3-(3,4-dimethoxyphenyl)-2-methylpropionitrile is known from Japanese Patent Publication No. 41-2897. That is, in Japanese Patent Publication No. 41-2897, DL-2-amino-3-
(3,4-Dimethoxyphenyl)-2-methyl-propionitrile is suspended in water and reacted with d-tartaric acid to precipitate D-2-amino-3-(3,
The d-tartrate of L-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile was separated by filtration (optical resolution), and the solution was then neutralized to form L-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile. phenyl)-2-methyl-propionitrile is obtained.
一方特公昭49−20305、同20306は水懸濁液中で
ｄ−酒石酸を用いて光学分割することの不利を改
良する為に光学分割剤として光学活性マンデル酸
を用いてDL−２−アミノ−３−（３，４−ジメト
キシフエニル）−２−メチル−プロピオニトリル
を光学分割してＬ−２−アミノ−３−（３，４−
ジメトキシフエニル）−２−メチル−プロピオニ
トリルを得る方法を提案している。 On the other hand, in order to improve the disadvantages of optical resolution using d-tartaric acid in an aqueous suspension, Japanese Patent Publications No. 49-20305 and 20306 used optically active mandelic acid as an optical resolving agent to improve DL-2-amino- 3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile was optically resolved to obtain L-2-amino-3-(3,4-
A method for obtaining (dimethoxyphenyl)-2-methyl-propionitrile is proposed.
発明が解決しようとする問題点
特公昭41−2897の方法においては最初から懸濁
状態で分割操作（光学分割）を実施するため原料
であるDL−２−アミノ−３−（３，４−ジメトキ
シフエニル）−２−メチル−プロピオニトリルの
品質（結晶の形状、純度等）によつて析出するＤ
−２−アミノ−３−（３，４−ジメトキシフエニ
ル）−２−メチル−プロピオニトリルの１水素−
ｄ−酒石酸塩結晶にDL−２−アミノ−３−（３，
４−ジメトキシフエニル）−２−メチル−プロピ
オニトリルが混入し、目的物の純度収量が低下す
るという欠点がある。又DL−２−アミノ−３−
（３，４−ジメトキシフエニル）−２−メチルプロ
ピオニトリルは分解しやすい化合物であるので懸
濁状態で長時間を要して光学分割することは望ま
しいことでない。Problems to be Solved by the Invention In the method of Japanese Patent Publication No. 41-2897, since the resolution operation (optical resolution) is carried out in a suspended state from the beginning, the raw material DL-2-amino-3-(3,4-dimethoxy) D that precipitates depending on the quality of (phenyl)-2-methyl-propionitrile (crystal shape, purity, etc.)
-1 hydrogen of -2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile-
DL-2-amino-3-(3,
There is a drawback that 4-dimethoxyphenyl)-2-methyl-propionitrile is mixed in and the purity yield of the target product is reduced. Also DL-2-amino-3-
Since (3,4-dimethoxyphenyl)-2-methylpropionitrile is a compound that easily decomposes, it is not desirable to optically resolve it in a suspended state for a long time.
一方光学活性マンデル酸を用いる方法は光学活
性マンデル酸が高価であるため高い回収率で光学
活性マンデル酸を回収せねばならず工程が煩雑に
なると共にコスト高になる。 On the other hand, in the method using optically active mandelic acid, since optically active mandelic acid is expensive, optically active mandelic acid must be recovered at a high recovery rate, resulting in complicated steps and high costs.
問題点を解決するための手段
本発明者らは前記したような問題点を解決すべ
く鋭意検討の結果本発明に至つたものである。即
ち本発明はDL−２−アミノ−３−（３，４−ジメ
トキシフエニル）−２−メチル−プロピオニトリ
ル、鉱酸からなる水性溶液にｄ−酒石酸を加え次
いでカセイソーダ又はｄ−酒石酸のナトリウム塩
を加えて鉱酸の一部を中和し析出したＤ−２−ア
ミノ−３−（３，４−ジメトキシフエニル）−２−
メチル−プロピオニトリルの１水素−ｄ−酒石酸
塩を除去することを特徴とするＬ−２−アミノ−
３−（３，４−ジメトキシフエニル）−２−メチル
プロピオニトリルの製造法を提供する。Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and have thus arrived at the present invention. That is, in the present invention, d-tartaric acid is added to an aqueous solution consisting of DL-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile and a mineral acid, and then caustic soda or sodium d-tartaric acid is added. D-2-amino-3-(3,4-dimethoxyphenyl)-2- was precipitated by neutralizing a portion of the mineral acid by adding salt.
L-2-amino- characterized by removing monohydrogen-d-tartrate of methyl-propionitrile
A method for producing 3-(3,4-dimethoxyphenyl)-2-methylpropionitrile is provided.
DL−２−アミノ−３−（３，４−ジメトキシフ
エニル）−２−メチル−プロピオニトリル鉱酸及
びｄ−酒石酸からなる均一な水性溶液に中和剤を
加えてＤ−２−アミノ−３−（３，４−ジメトキ
シフエニル）−２−メチル−プロピオニトリの１
水素−ｄ−酒石酸塩（以後１水素−ｄ−酒石酸塩
という）を沈澱せしめるにあたつて中和剤として
カセイソーダ又はｄ−酒石酸のナトリウム塩（モ
ノナトリウム塩又はジナトリウム塩）を使用した
ときのみ良好に１水素−ｄ−酒石酸塩の沈澱が生
成するということは全く予想できなかつたことで
ある。アルカリ剤としてアンモニア水、カセイカ
リ、水酸化カルシウム、水酸化マグネシウムを用
いたときは１水素−ｄ−酒石酸塩の生成が不十分
であり従つてDL−２−アミノ−３−（３，４−ジ
メトキシフエニル）−２−メチル−プロピオニト
リルからのＤ−体の除去が困難で純度のたかいＬ
−２−アミノ−３−（３，４−ジメトキシフエニ
ル）−２−メチル−プロピオニトリルを得ること
が出来なかつた。 D-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile was prepared by adding a neutralizing agent to a homogeneous aqueous solution consisting of mineral acid and d-tartaric acid. 1 of 3-(3,4-dimethoxyphenyl)-2-methyl-propionitri
Only when caustic soda or sodium salt of d-tartaric acid (monosodium salt or disodium salt) is used as a neutralizing agent in precipitating hydrogen-d-tartrate (hereinafter referred to as monohydrogen-d-tartrate). It was totally unexpected that a 1-hydrogen-d-tartrate precipitate would form so well. When aqueous ammonia, caustic potash, calcium hydroxide, or magnesium hydroxide is used as an alkaline agent, the production of 1-hydrogen-d-tartrate is insufficient, and therefore DL-2-amino-3-(3,4-dimethoxy It is difficult to remove the D-isomer from phenyl)-2-methyl-propionitrile and the purity is high.
-2-Amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile could not be obtained.
本発明の製法を詳細に説明する。 The manufacturing method of the present invention will be explained in detail.
溶媒としては、若干の水と混和しうる有機溶媒
を混合することも可能であるが水を単独で用いた
場合が最もよい結果を与える。その使用量はDL
−２−アミノ−３−（３，４−ジメトキシフエニ
ル）−２−アミノ−３−（３，４−ジメトキシフエ
ニル）−２−メチル−プロピオニトリルに対して
重量で３〜18倍、好ましくは５〜12倍である。 Although it is possible to mix some organic solvents that are miscible with water as the solvent, the best results are obtained when water is used alone. Its usage is DL
-2-amino-3-(3,4-dimethoxyphenyl)-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile 3 to 18 times by weight, Preferably it is 5 to 12 times.
鉱酸としては塩酸、硫酸、臭化水素酸等を用い
ることが出来るが塩酸を用いた場合最もよい結果
を与える。その使用量はDL−２−アミノ−３−
（３，４−ジメトキシフエニル）−２−メチル−プ
ロピオニトリルに対して0.8〜2.5倍モル特に好ま
しくは、0.9〜1.6倍である。 As the mineral acid, hydrochloric acid, sulfuric acid, hydrobromic acid, etc. can be used, but the best results are obtained when hydrochloric acid is used. The amount used is DL-2-amino-3-
The molar amount is particularly preferably 0.8 to 2.5 times, preferably 0.9 to 1.6 times, relative to (3,4-dimethoxyphenyl)-2-methyl-propionitrile.
光学分割剤として用いられるｄ−酒石酸塩類と
してはｄ−酒石酸、ｄ−酒石酸の１ナトリウム
塩、２ナトリウム塩又はそれらの混合物が用いら
れその使用量はｄ−酒石酸としてDL−２−アミ
ノ−３−（３，４−ジメトキシフエニル）−２−メ
チル−プロピオニトリルに対して0.8〜２倍モル、
より好ましくは0.9〜1.5倍モルである。 As the d-tartrate salts used as optical resolution agents, d-tartaric acid, monosodium salts, disodium salts of d-tartaric acid, or mixtures thereof are used, and the amount used is DL-2-amino-3- as d-tartaric acid. 0.8 to 2 times mole relative to (3,4-dimethoxyphenyl)-2-methyl-propionitrile,
More preferably, it is 0.9 to 1.5 times the mole.
Ｄ−２−アミノ−３−（３，４−ジメトキシフ
エニル）−２−メチル−プロピオニトリルの１水
素−ｄ−酒石酸塩を析出させるためには使用した
鉱酸に対して0.5〜1.0倍モル好ましくは0.65〜0.9
倍モルのカセイソーダが用いられこの１部又は全
部をｄ−酒石酸の１ナトリウム塩又は２ナトリウ
ム塩でおきかえることができる。 In order to precipitate monohydrogen-d-tartrate of D-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile, the amount is 0.5 to 1.0 times the mineral acid used. Molar preferably 0.65-0.9
Double the molar amount of caustic soda is used, and part or all of this can be replaced with monosodium or disodium salt of d-tartaric acid.
本発明の製造法はDL−２−アミノ−３−（３，
４−ジメトキシフエニル）−２−メチル−プロピ
オニトリル、鉱酸に水を加えて室温（15〜25℃）
近くで溶解し均一な溶液とする。 The production method of the present invention is DL-2-amino-3-(3,
4-Dimethoxyphenyl)-2-methyl-propionitrile, mineral acid and water at room temperature (15-25℃)
Dissolve nearby to form a homogeneous solution.
次いでｄ−酒石酸を加えもし不溶性物が認めら
れたら別等により除去する。 Next, d-tartaric acid is added, and if any insoluble matter is found, it is removed separately.
次に得られた透明な溶液を10〜20℃に調整した
のち所定量のカセイソーダ、ｄ−酒石酸モノナト
リウム、ｄ−酒石酸ジナトリウムを単独で又は併
用して水溶液又はスラリ−状で滴下する。滴下は
0.25〜２時間を要して加えるのがよく滴下終了後
更に０〜10℃で0.5〜２時間攪拌を続ける。生成
したＤ−２−アミノ−３−（３，４−ジメトキシ
フエニル）−２−メチル−プロピオニトリルの１
水素−ｄ−酒石酸塩を過、遠心分離等の手段に
より除去するＬ−２−アミノ−３−（３，４−ジ
メトキシフエニル）−２−メチル−プロピオニト
リルを含んだ溶液がえられる。この溶液にアンモ
ニア水、カセイソーダ水、カセイカリ等のアルカ
リ剤を加えて中和しＬ−２−アミノ−３−（３，
４−ジメトキシフエニル）−２−メチル−プロピ
オニトリルを結晶として析出せしめとり出すこと
も出来るが遊離したＬ−２−アミノ−３−（３，
４−ジメトキシフエニル）−２−メチル−プロピ
オニトリルは不安定であるのでとり出さないで析
出した目的物を塩化メチレン等の有機溶媒で抽出
し更に鉱酸の水溶液で逆抽出して、Ｌ−２−アミ
ノ−３−（３，４−ジメトキシフエニル）−２−メ
チル−プロピオニトリルの鉱酸溶液として保存又
は原料として用いるか又はこの鉱酸溶液を冷却し
てＬ−２−アミノ−３−（３，４−ジメトキシフ
エニル）−２−メチル−プロピオニトリルの鉱酸
塩（結晶）として取するのが好ましい。 Next, the resulting clear solution is adjusted to 10 to 20 DEG C., and then predetermined amounts of caustic soda, monosodium d-tartrate, and disodium d-tartrate are added dropwise in the form of an aqueous solution or slurry, either alone or in combination. The dripping is
It is best to add the mixture over a period of 0.25 to 2 hours, and after the dropwise addition is complete, stirring is continued for an additional 0.5 to 2 hours at 0 to 10°C. 1 of the generated D-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile
A solution containing L-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile is obtained from which hydrogen-d-tartrate is removed by means such as filtration or centrifugation. This solution is neutralized by adding ammonia water, caustic soda water, caustic potash, etc. to L-2-amino-3-(3,
Although it is possible to precipitate and remove L-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile as a crystal,
Since 4-dimethoxyphenyl)-2-methyl-propionitrile is unstable, it is not taken out, but the precipitated target product is extracted with an organic solvent such as methylene chloride, and then back-extracted with an aqueous solution of mineral acid to obtain L. -2-Amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile can be stored as a mineral acid solution or used as a raw material, or this mineral acid solution can be cooled and L-2-amino- Preferably, it is obtained as a mineral acid salt (crystal) of 3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile.
本発明の製法でえられたＬ−２−アミノ−３−
（３，４−ジメトキシフエニル）−２−メチル−プ
ロピオニトリル（又はこの塩酸塩）は加水分解、
脱メチル化の工程を経てＬ−３−（３，４−ジヒ
ドロキシフエニル）−２−メチル−アラニンに誘
導するに十分な純度を有している。 L-2-amino-3- obtained by the production method of the present invention
(3,4-dimethoxyphenyl)-2-methyl-propionitrile (or its hydrochloride) is hydrolyzed,
It has sufficient purity to be converted into L-3-(3,4-dihydroxyphenyl)-2-methyl-alanine through a demethylation step.
実施例 次に本発明を実施例に更に詳細に説明する。Example Next, the present invention will be explained in more detail with reference to Examples.
実施例 １
フラスコに、水470ml、濃塩酸（36％）31.5ｇ
を仕込み、20℃で攪拌しつつ、DL−２−アミノ
−３−（３，４−ジメトキシフエニル）−２−メチ
ル−プロピオニトリル47.8ｇを徐々に仕込んだ。
完全に均一溶液になつてから、ｄ−酒石酸、17.9
ｇを仕込み、溶解させた。別に、23.2ｇのｄ−酒
石酸のジナトリウム塩を30mlの水に溶解しておき
15〜20℃にて前記のDL−２−アミノ−３−（３，
４−ジメトキシフエニル）−２−メチル−プロピ
オニトリルの溶液の中に滴下した。Ｄ−２−アミ
ノ−３−（３，４−ジメトキシフエニル）−２−メ
チル−プロピオニトリルの１水素−ｄ−酒石酸塩
が微細な斜状晶として析出した。35分で滴下を終
了し、この後30分間で５℃まで冷却し、遠心分離
により、結晶を除去した。Example 1 In a flask, 470 ml of water and 31.5 g of concentrated hydrochloric acid (36%)
was charged, and while stirring at 20°C, 47.8 g of DL-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile was gradually added.
After a completely homogeneous solution, d-tartaric acid, 17.9
g was charged and dissolved. Separately, dissolve 23.2 g of disodium salt of d-tartaric acid in 30 ml of water.
The above DL-2-amino-3-(3,
4-dimethoxyphenyl)-2-methyl-propionitrile solution. Monohydrogen-d-tartrate of D-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile was precipitated as fine oblique crystals. The dropwise addition was completed in 35 minutes, and then the mixture was cooled to 5° C. over 30 minutes, and the crystals were removed by centrifugation.
結晶を除去した上澄液に、10℃にて塩化メチレ
ン80mlを加え、強く攪拌しつつ、28％アンモニア
水で中和し、PH6.2とした、塩化メチレン層を分
離し、水層を再度塩化メチレン80mlで抽出した。
塩化メチレン層を合わせ、濃塩酸（36％）164ｇ
で、塩化メチレン層よりＬ−２−アミノ−３−
（３，４−ジメトキシフエニル）−２−メチル−プ
ロピオニトリルを逆抽出した。 80 ml of methylene chloride was added to the supernatant liquid from which the crystals had been removed at 10°C, and while stirring strongly, it was neutralized with 28% ammonia water to reach a pH of 6.2. The methylene chloride layer was separated, and the aqueous layer was again separated. Extracted with 80 ml of methylene chloride.
Combine the methylene chloride layers and add 164 g of concentrated hydrochloric acid (36%).
Then, from the methylene chloride layer, L-2-amino-3-
(3,4-dimethoxyphenyl)-2-methyl-propionitrile was back extracted.
この塩酸層を一部とり液体クロマトグラフで定
量したところ、Ｌ−２−アミノ−３−（３，４−
ジメトキシフエニル）−２−メチル−プロピオニ
トリル22.0ｇが、塩酸塩として含まれている事が
わかつた。これを使用した原料に対して46.0％の
収率に相当する。 When a portion of this hydrochloric acid layer was taken and quantified by liquid chromatography, L-2-amino-3-(3,4-
It was found that 22.0 g of (dimethoxyphenyl)-2-methyl-propionitrile was contained as a hydrochloride. This corresponds to a yield of 46.0% based on the raw material used.
（参考例）
実施例１で得られたＬ−２−アミノ−３−（３，
４−ジメトキシフエニル）−２−メチル−プロピ
オニトリル22.0ｇを含有する塩酸溶液を60〜70℃
で２時間処理し加水分解したあと２時間で105℃
に昇温し、これに47％臭化水素酸25ｇを仕込んで
還流下４時間反応させた。最初に47％臭化水素酸
を仕込んでから４時間後に９ｇ、14時間後に７
ｇ、28時間後に1.5ｇを追加しつつ常圧で還流下
（105〜109℃）35時間反応させ、脱メチル化反応
を終了した。使用した47％臭化水素酸は、計42.5
ｇであつた。反応終了後40〜50mmHgの減圧下、
塩酸を留去して、内容物の合計が60ｇになつた時
濃縮をやめ、ここに水22ｇを加えて、完溶させ
た。これを48％カ性ソーダ17ｇで徐々に中和し、
PHを4.3に調整した。これを５〜10℃に冷却し、
２時間保温して、析出した結晶を過し、若干量
の氷水で洗浄した。(Reference example) L-2-amino-3-(3,
A hydrochloric acid solution containing 22.0 g of 4-dimethoxyphenyl)-2-methyl-propionitrile was heated at 60 to 70°C.
After 2 hours of treatment and hydrolysis, the temperature reached 105℃ for 2 hours.
25 g of 47% hydrobromic acid was charged thereto and reacted under reflux for 4 hours. After initially charging 47% hydrobromic acid, 4 hours later, 9 g, and 14 hours later, 7 g.
g, and 1.5 g was added after 28 hours, and the reaction was carried out under reflux (105 to 109° C.) at normal pressure for 35 hours to complete the demethylation reaction. The 47% hydrobromic acid used was a total of 42.5
It was hot at g. After the reaction, under reduced pressure of 40-50 mmHg,
When the hydrochloric acid was distilled off and the total content reached 60 g, concentration was stopped, and 22 g of water was added thereto to completely dissolve the contents. This was gradually neutralized with 17g of 48% caustic soda.
Adjusted pH to 4.3. Cool this to 5-10℃,
After keeping the temperature for 2 hours, the precipitated crystals were filtered and washed with a small amount of ice water.
デシケータで乾燥すると粗Ｌ−３−（３，４−
ジヒドロキシフエニル）−２−メチルアラニン1.5
水物23.3ｇが得られこれは液体クロマトグラフに
よる分析で88.5％の純度を有していた。純度換算
の収率は使用したＬ−２−アミノ−３−（３，４
−ジメトキシフエニル）−２−メチルプロピオニ
トリルに対して86.6％であつた。この粗生成物を
塩酸塩として水60mlに溶解後１ｇの活性炭で処理
し、液を48％カ性ソーダで中和しPHを４とし
た。10℃まで冷却し、２時間保温した。析出した
結晶を過・水洗・乾燥して、無色のＬ−３−
（３，４−ジヒドロキシフエニル）−２−メチルア
ラニン1.5水物18.0ｇを得た。（精製）日局法によ
るアルミニウム試薬を用いた施光度測定では
〔α〕20 D＝−28.2°（Ｃ＝4.4、塩化アルミニウム試
薬）であつた。（融点311℃（分解））液体クロマ
トグラフイーによる純度は99.2％であつた。 When dried in a desiccator, crude L-3-(3,4-
dihydroxyphenyl)-2-methylalanine 1.5
23.3 g of aqueous product were obtained which had a purity of 88.5% as analyzed by liquid chromatography. The yield in terms of purity is the L-2-amino-3-(3,4
-dimethoxyphenyl)-2-methylpropionitrile was 86.6%. This crude product was dissolved as a hydrochloride in 60 ml of water, treated with 1 g of activated carbon, and the solution was neutralized with 48% caustic soda to a pH of 4. It was cooled to 10°C and kept warm for 2 hours. The precipitated crystals were filtered, washed with water, and dried to give colorless L-3-
18.0 g of (3,4-dihydroxyphenyl)-2-methylalanine 1.5 hydrate was obtained. (Purification) In the photochromic intensity measurement using an aluminum reagent according to the Japanese Pharmacopoeia method, [α] 20 D = -28.2° (C = 4.4, aluminum chloride reagent). (Melting point: 311°C (decomposed)) Purity by liquid chromatography was 99.2%.
実施例 ２
フラスコに水175ml、濃塩酸（36％）13.2ｇを
仕込み20℃で攪拌しつつ、DL−２−アミノ−３
−（３，４−ジメトキシフエニル）−２−メチル−
プロピオニトリル20ｇを徐々に仕込み、更にｄ−
酒石酸15ｇを加え均一な溶液とした。この溶液を
10℃に冷却し、28％カセイソーダ14.3ｇを20分で
滴下した。間もなくＤ−２−アミノ−３−（３，
４−ジメトキシフエニル）−２−メチル−プロピ
オニトリルの１水素−ｄ−酒石酸塩の析出が起つ
た。28％カセイソーダ滴下終了後更に0.5時間５
℃で攪拌後結晶を遠心分離法により除去した。遠
心分離した上澄液に、塩化メチレン40mlを加え、
攪拌しつつ28％アンモニア水でPH6.25に中和し
た。Example 2 175 ml of water and 13.2 g of concentrated hydrochloric acid (36%) were placed in a flask, and while stirring at 20°C, DL-2-amino-3 was added.
-(3,4-dimethoxyphenyl)-2-methyl-
Gradually add 20g of propionitrile, and then add d-
15 g of tartaric acid was added to make a homogeneous solution. This solution
The mixture was cooled to 10°C, and 14.3 g of 28% caustic soda was added dropwise over 20 minutes. Soon D-2-amino-3-(3,
Precipitation of the monohydrogen-d-tartrate of 4-dimethoxyphenyl)-2-methyl-propionitrile occurred. Another 0.5 hours after 28% caustic soda dripping 5
After stirring at °C, the crystals were removed by centrifugation. Add 40ml of methylene chloride to the centrifuged supernatant,
The mixture was neutralized to pH 6.25 with 28% aqueous ammonia while stirring.
塩化メチレン層を静置分液した後、ここに濃塩
酸10.9ｇ水10ｇを加え強く攪拌しつつ０℃まで冷
却した。析出した結晶を別し18％の塩酸８ml、
塩化メチレン８mlで洗浄し、デシケータで乾燥し
た。10.2ｇのＬ−２−アミノ−３−（３，４−ジ
メトキシフエニル）−２−メチル−プロピオニト
リル塩酸塩の１水物が得られ、収率は40.8％であ
つた。 After the methylene chloride layer was allowed to stand still and separated, 10.9 g of concentrated hydrochloric acid and 10 g of water were added thereto, and the mixture was cooled to 0° C. with strong stirring. Separate the precipitated crystals and add 8 ml of 18% hydrochloric acid.
It was washed with 8 ml of methylene chloride and dried in a desiccator. 10.2 g of L-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile hydrochloride monohydrate was obtained, with a yield of 40.8%.
前記「参考例」に準じ、濃塩酸中、臭化水素酸
を加え加水分解脱メチル化し、純度換算収率86.1
％（液体クロマトグラフによる）で粗Ｌ−α−メ
チルバド1.5水物を得た。 According to the above "Reference Example", hydrolytic demethylation was carried out by adding hydrobromic acid in concentrated hydrochloric acid, and the yield was 86.1 in terms of purity.
% (according to liquid chromatography) to obtain crude L-α-methylbado 1.5 hydrate.
「参考例」におけるのと同様に精製し、精製収
率85.3％で無色のＬ−α−メチルドバ1.5水物を
得、これに日局法による施光度測定で〔α〕20 D＝
−28.3°（Ｃ＝4.4、塩化アルミニウム試薬）の結果
を得た。融点は、311℃（分解）であつた。 Purification was carried out in the same manner as in "Reference Example" to obtain colorless L-α-methyldova 1.5 hydrate with a purification yield of 85.3%, which was determined to have [α] 20 D =
A result of -28.3° (C=4.4, aluminum chloride reagent) was obtained. The melting point was 311°C (decomposed).
発明の効果
DL−２−アミノ−３−（３，４−ジメトキシフ
エニル）−２−メチル−プロピオニトリルから簡
単な操作により効率よくＬ−２−アミノ−３−
（３，４−ジメトキシフエニル）−２−メチル−プ
ロピオニトリルをえることが出来るようになつ
た。Effects of the invention L-2-amino-3- is efficiently produced from DL-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile by a simple operation.
(3,4-dimethoxyphenyl)-2-methyl-propionitrile can now be obtained.
Claims (1)
フエニル）−２−メチル−プロピオニトリル、鉱
酸からなる水性溶液にｄ−酒石酸を加え次いでカ
セイソーダ又はｄ−酒石酸のナトリウム塩を加え
て鉱酸の一部を中和し析出したＤ−２−アミノ−
３−（３，４−ジメトキシフエニル）−２−メチル
−プロピオニトリルの１水素−ｄ−酒石酸塩を除
去することを特徴とするＬ−２−アミノ−３−
（３，４−ジメトキシフエニル）−２−メチルプロ
ピオニトリルの製造法。1 Add d-tartaric acid to an aqueous solution consisting of DL-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile and mineral acid, then add caustic soda or sodium salt of d-tartaric acid. D-2-amino- precipitated by neutralizing a part of the mineral acid
L-2-amino-3- characterized by removing monohydrogen-d-tartrate of 3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile
A method for producing (3,4-dimethoxyphenyl)-2-methylpropionitrile.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12150485A JPS61280461A (en) | 1985-06-06 | 1985-06-06 | Production of l-2-amino-3-(3,4-dimethoxyphenyl)-2-methylpropionitrile |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12150485A JPS61280461A (en) | 1985-06-06 | 1985-06-06 | Production of l-2-amino-3-(3,4-dimethoxyphenyl)-2-methylpropionitrile |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61280461A JPS61280461A (en) | 1986-12-11 |
| JPH0515701B2 true JPH0515701B2 (en) | 1993-03-02 |
Family
ID=14812825
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12150485A Granted JPS61280461A (en) | 1985-06-06 | 1985-06-06 | Production of l-2-amino-3-(3,4-dimethoxyphenyl)-2-methylpropionitrile |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61280461A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007284349A (en) * | 2004-07-27 | 2007-11-01 | Ajinomoto Co Inc | Method for producing monatin or salt thereof |
| CN104628600B (en) * | 2013-11-11 | 2016-08-24 | 上海医药工业研究院 | A kind of preparation method of (S)-methyldopa midbody compound |
-
1985
- 1985-06-06 JP JP12150485A patent/JPS61280461A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61280461A (en) | 1986-12-11 |
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