JPS6261584B2 - - Google Patents
Info
- Publication number
- JPS6261584B2 JPS6261584B2 JP15004781A JP15004781A JPS6261584B2 JP S6261584 B2 JPS6261584 B2 JP S6261584B2 JP 15004781 A JP15004781 A JP 15004781A JP 15004781 A JP15004781 A JP 15004781A JP S6261584 B2 JPS6261584 B2 JP S6261584B2
- Authority
- JP
- Japan
- Prior art keywords
- hydroxyphenylglycine
- optically active
- pes
- hpg
- phenylethanesulfonate
- 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
Links
- COFMBBYARPOGBA-UHFFFAOYSA-N 1-phenylethanesulfonic acid Chemical compound OS(=O)(=O)C(C)C1=CC=CC=C1 COFMBBYARPOGBA-UHFFFAOYSA-N 0.000 claims description 37
- LJCWONGJFPCTTL-UHFFFAOYSA-N 4-hydroxyphenylglycine Chemical compound OC(=O)C(N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-UHFFFAOYSA-N 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 9
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 claims description 8
- 239000003125 aqueous solvent Substances 0.000 claims description 7
- LJCWONGJFPCTTL-ZETCQYMHSA-N L-4-hydroxyphenylglycine Chemical compound OC(=O)[C@@H](N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-ZETCQYMHSA-N 0.000 claims description 6
- -1 p-hydroxyphenyl Chemical group 0.000 claims description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 2
- 239000004471 Glycine Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 150000003839 salts Chemical class 0.000 description 17
- 239000003795 chemical substances by application Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- 239000013078 crystal Substances 0.000 description 9
- 230000003287 optical effect Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- KKLMJYDGZSAIQX-UHFFFAOYSA-N 2-(n-hydroxyanilino)acetic acid Chemical compound OC(=O)CN(O)C1=CC=CC=C1 KKLMJYDGZSAIQX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical class [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 3
- CRRUGYDDEMGVDY-UHFFFAOYSA-N 1-bromoethylbenzene Chemical compound CC(Br)C1=CC=CC=C1 CRRUGYDDEMGVDY-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical compound [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 1
- IAVPGZZRAJUOGE-UHFFFAOYSA-N [n'-(2-hydroxy-2-phenylethyl)carbamimidoyl]azanium;carbonate Chemical compound [O-]C([O-])=O.NC([NH3+])=NCC(O)C1=CC=CC=C1.NC([NH3+])=NCC(O)C1=CC=CC=C1 IAVPGZZRAJUOGE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は新規ｐ−ヒドロキシフエニルグリシ
ン・α−フエニルエタンスルホン酸塩およびその
光学分割法に関する。
光学活性ｐ−ヒドロキシフエニルグリシンのう
ち、Ｄ−ｐ−ヒドロキシフエニルグリシンは半合
成ペニシリンや半合成セフアロスポリンの原料化
合物として有用な物質であり、又、Ｌ−ｐ−ヒド
ロキシフエニルグリシンは近年虚血性心臓疾患、
心機能不全或いは糖尿病などの治療に用いうる
（特開昭52−41432号）。しかしながらｐ−ヒドロ
キシフエニルグリシンは天然には存在せず、また
合成されたｐ−ヒドロキシフエニルグリシンは
DL一体であるためその光学分割が必要である。
従来、化学的光学分割法としては例えばDL−ｐ
−ヒドロキシフエニルグリシンをＮ−ベンジルオ
キシカルボニル誘導体、Ｎ−クロロアセチル誘導
体、Ｎ−ベンゾイル誘導体に変換し、これら誘導
体をキニン、デヒドロアビエチルアミン、光学活
性α−フエネチルアミンなどで分割する方法（J.
Chem.Soc（Ｃ），1920〜1922（1971），；特開昭
49−56946号、特開昭50−69039号）が知られてい
る。しかしながら、これらの方法ではいずれも
DL−ｐ−ヒドロキシフエニルグリシンを一旦ア
シル誘導体に変換しなければならない上、分割剤
も高価であり、また光学分割後脱アシル化の工程
を必要とするがその際ラセミ化を伴う危険性があ
る。又、DL−ｐ−ヒドロキシフエニルグリシン
をｄ−３−ブロムカンフアー−10−スルホン酸塩
として分割する方法（特開昭51−32541号）又は
ｄ−３−ブロムカンフア−８−スルホン酸塩とし
て分割する方法（特公昭55−45069号）が知られ
ているが、前者は結晶として得られるのがＬ体塩
のみであり高純度のＤ体塩を得る適切な方法とは
いい難く、又、後者についても分割剤が天然物に
由来する高価なものであり、化学的にも充分安定
とは言い難い。他方（±）−α−フエニルエタン
スルホン酸は（±）−フエネチルアルコールをブ
ロム化したのちスルホン化して得られる強酸性化
合物であるが、これを光学分割する方法としては
わずかにストリキニンを用いる方法（J.Chem.
Soc.，1159（1927））が知られているにすぎな
い。
本発明者らはかかる状況に鑑み鋭意研究を重ね
た結果、(1)ｐ−ヒドロキシフエニルグリシンとα
−フエニルエタンスルホン酸とは水性溶媒中で塩
を形成すること；(2)しかもその一方に光学活性体
を用いれば、形成される２種ジアステレオマーの
内Ｄ−ｐ−ヒドロキシフエニルグリシン・（＋）−
α−フエニルエタンスルホン酸塩又はＬ−ｐ−ヒ
ドロキシフエニルグリシン・（−）−α−フエニル
エタンスルホン酸塩が難溶性塩として、また他方
のジアステレオマーが常に易溶性塩として得られ
ること；(3)そのためｐ−ヒドロキシフエニルグリ
シンとα−フエニルエタンスルホン酸塩とはそれ
ぞれその一方のラセミ体の光学分割に他方の光学
活性体を分割剤として利用することができ、これ
によつて工業的有利に光学活性ｐ−ヒドロキシフ
エニルグリシン及び光学活性α−フエニルエタン
スルホン酸を製造し得ることを見出した。
かかる知見に基く本発明はｐ−ヒドロキシフエ
ニルグリシン及びα−フエニルエタンスルホン酸
から選ばれるいずれか一方の光学活性体を分割剤
とし、他方の化合物のラセミ体を光学分割するこ
とを特徴とするｐ−ヒドロキシフエニルグリシン
又はα−フエニルエタンスルホン酸の光学分割法
である。
本発明によれば、水性溶媒中でDL−ｐ−ヒド
ロキシフエニルグリシンに光学活性α−フエニル
エタンスルホン酸を分割剤として作用させるか、
或いは（±）−α−フエニルエタンスルホン酸に
光学活性ｐ−ヒドロキシフエニルグリシンを分割
剤として作用せしめ、生成する塩〔即ち、DL−
ｐ−ヒドロキシフエニルグリシン・光学活性α−
フエニルエタンスルホン酸塩又は光学活性ｐ−ヒ
ドロキシフエニルグリシン・（±）−α−フエニル
エタンスルホン酸塩〕の２種ジアステレオマーの
溶解度差を利用してその難溶性ジアステレオマー
たる一方の光学活性ｐ−ヒドロキシフエニルグリ
シン・光学活性α−フエニルエタンスルホン酸塩
〔即ち，Ｄ−ｐ−ヒドロキシフエニルグリシン・
（±）−α−フエニルエタンスルホン酸塩はＬ−ｐ
−ヒドロキシフエニルグリシン・（−）−α−フエ
ニルエタンスルホン酸塩〕を分離・採取し、必要
とあればこの塩を更に脱塩処理することにより光
学活性ｐ−ヒドロキシフエニルグリシン、光学活
性α−フエニルエタンスルホン酸又はそれらの塩
を製することができる。
分割剤たる光学活性ｐ−ヒドロキシフエニルグ
リシンとしてはそのＤ体及びＬ体、また分割剤た
る光学活性α−フエニルエタンスルホン酸として
はその（＋）体及び（−）体のいずれをも用いる
ことができる。例えば適当な水性溶媒中DL−ｐ
−ヒドロキシフエニルグリシンに（＋）−α−フ
エニルエタンスルホン酸を作用させれば溶液中で
はＤ−ｐ−ヒドロキシフエニグリシン・（＋）−α
−フエニルエタンスルホン酸塩（以下、Ｄ−
HPG・（＋）−PESと称する）とＬ−ｐ−ヒドロ
キシフエニルグリシン・（＋）−α−フエニルエタ
ンスルホン酸塩（以下、Ｌ−HPG・（＋）−PES
と称する）との２種ジアステレオマーが生成する
が、これら両ジアステレオマーのうちＤ−
HPG・（＋）−PESが該水性溶媒中で難溶性塩で
ありＬ−HPG・（＋）−PESは易溶性塩であるた
め、Ｄ−HPG・（＋）−PESのみが晶出する。こ
の場合分割剤として（−）−PESを用いても全く
同様に光学分割することができ、難溶性ジアステ
レオマーとしてＬ−HPG・（−）−PESが得ら
れ、易溶性塩としてＤ−HPG・（−）−PESが得
られる。
一方、（±）−α−フエニルエタンスルホン酸を
光学分割するに際して、その分割剤としてＬ−ｐ
−ヒドロキシフエニルグリシンを作用させる場合
には、Ｌ−HPG・（±）−PESとＬ−HPG・（−）
−PESの２種のジアステレオマーが生成するが、
Ｌ−HPG・（−）−PESが難溶性ジアステレオマ
ーであり、Ｌ−HPG・（＋）−PESが易溶性ジア
ステレオマーであるため、Ｌ−HPG・（−）−
PESが晶析し、Ｌ−HPG・（＋）−PESは液中に溶
存する。これに対し、分割剤としてＤ−ｐ−ヒド
ロキシフエニルグリシンを用いた場合にはＤ−
HPG・（＋）−PESが難溶性、Ｄ−HPG・（−）−
PESが易溶性のジアステレオマーとして生成する
ため、Ｄ−HPG・（＋）−PESのみを晶出させる
ことが可能となる。
被分割物質或いは分割剤たるｐ−ヒドロキシフ
エニルグリシンとしてはその遊離型に限らず、塩
酸塩、硫酸塩の如き鉱酸塩、シユウ酸塩、スルホ
ン酸の如き有機酸塩であつても用いることができ
る。同様にα−フエニルエタンスルホン酸も遊離
型であつても、ナトリウム塩、カリウム塩の如き
アルカリ金属塩、カルシウム塩、マグネシウム塩
の如きアルカリ土類金属塩の他、例えばアンモニ
ウム塩であつても用いることができる。更に被分
割物質たるｐ−ヒドロキシフエニルグリシン又は
α−フエニルエタンスルホン酸は化学合成により
得られるＤ体、Ｌ体の等量混合物の他、一方の光
学活性体を過剰に含む、いわゆる低純度の光学活
性体であつても用いることができる。
本発明は実施するに際し分割剤たるｐ−ヒドロ
キシフエニルグリシン又はα−フエニルエタンス
ルホン酸は上記被分割物質に対し約0.5以上、と
りわけ約0.8〜1.1モル比となるよう用いるのが適
当である。
造塩反応に用いる水性溶媒としては例えば水；
メタノール、エタノールの如き低級アルカノー
ル；アセトン；酢酸、プロピオン酸の如き脂肪
酸、或いはこれらの混合物を好適に用いることが
できるが、とりわけ水が好ましい。
造塩反応は例えば上記溶媒中で、DL−ｐ−ヒ
ドロキシフエニルグリシンと光学活性α−フエニ
ルエタンスルホン酸又は光学活性ｐ−ヒドロキシ
フエニルグリシンと（±）−α−フエニルエタン
スルホン酸を室温乃至加温下にかく拌することに
より実施できる。また、生成するジアステレオマ
ーのうち難溶性塩たるＤ−HPG・（＋）−PES又
はＬ−HPG・（−）−PESの晶析操作は該反応液
を冷却するか、濃縮するか或いは有機溶媒を添加
することにより容易に行なうことができ、該塩を
高純度の結晶として析出せしめることができる。
析出した難溶性塩は通常の固液分離の方法例え
ばろ過、遠心分離等の方法により分離取得するこ
とができる。
上記により取得される難溶性ジアステレオマー
は必要とあらば更に洗浄、再結晶などの処理をす
ることができる。
尚、本発明で得られる各種ジアステレオマーは
いずれも光学的に純粋なｐ−ヒドロキシフエニル
グリシン１モルとα−フエニルエタンスルホン酸
１モルとからなる塩であつて新規化合物である。
その主な物性は下記第１表の通りである。
The present invention relates to a novel p-hydroxyphenylglycine/α-phenylethanesulfonate and a method for optical resolution thereof. Among optically active p-hydroxyphenylglycine, D-p-hydroxyphenylglycine is a useful substance as a raw material compound for semi-synthetic penicillin and semi-synthetic cephalosporin, and L-p-hydroxyphenylglycine has recently been bloody heart disease,
It can be used to treat cardiac dysfunction or diabetes (Japanese Patent Application Laid-open No. 41432/1983). However, p-hydroxyphenylglycine does not exist naturally, and the synthesized p-hydroxyphenylglycine
Since the DL is integrated, optical division is necessary.
Conventionally, as a chemical optical resolution method, for example, DL-p
- A method of converting hydroxyphenylglycine into N-benzyloxycarbonyl derivatives, N-chloroacetyl derivatives, and N-benzoyl derivatives, and resolving these derivatives with quinine, dehydroabiethylamine, optically active α-phenethylamine, etc. (J.
Chem.Soc (C), 1920-1922 (1971),; Tokukai Sho
No. 49-56946, Japanese Patent Application Laid-open No. 50-69039) are known. However, all of these methods
DL-p-hydroxyphenylglycine must be converted into an acyl derivative, the resolving agent is expensive, and a deacylation step is required after optical resolution, but there is a risk of racemization. be. Also, a method of dividing DL-p-hydroxyphenylglycine as d-3-bromocamphor-10-sulfonate (Japanese Patent Application Laid-open No. 32541/1989) or as d-3-bromocamphor-8-sulfonate A splitting method (Japanese Patent Publication No. 55-45069) is known, but the former yields only the L-form salt as crystals and is not an appropriate method for obtaining highly pure D-form salt. Regarding the latter, the resolving agent is derived from natural products and is expensive, and it is difficult to say that it is chemically stable enough. On the other hand, (±)-α-phenylethanesulfonic acid is a strongly acidic compound obtained by brominating (±)-phenethyl alcohol and then sulfonating it. Method used (J.Chem.
Soc., 1159 (1927)) is only known. In view of this situation, the present inventors have conducted intensive research and found that (1) p-hydroxyphenylglycine and α
- Phenylethanesulfonic acid forms a salt in an aqueous solvent; (2) If an optically active substance is used as one of the salts, one of the two diastereomers formed is D-p-hydroxyphenylglycine.・(+)−
α-Phenylethanesulfonate or L-p-hydroxyphenylglycine (-)-α-phenylethanesulfonate is obtained as a sparingly soluble salt, and the other diastereomer is always obtained as a readily soluble salt. (3) Therefore, the optically active form of p-hydroxyphenylglycine and α-phenylethanesulfonate can be used as a resolving agent for the optical resolution of the racemic form of the other; Thus, it has been found that optically active p-hydroxyphenylglycine and optically active α-phenylethanesulfonic acid can be produced industrially advantageously. Based on this knowledge, the present invention is characterized in that the racemic form of the other compound is optically resolved using an optically active substance selected from p-hydroxyphenylglycine and α-phenylethanesulfonic acid as a resolving agent. This is an optical resolution method for p-hydroxyphenylglycine or α-phenylethanesulfonic acid. According to the present invention, optically active α-phenylethanesulfonic acid is allowed to act as a resolving agent on DL-p-hydroxyphenylglycine in an aqueous solvent, or
Alternatively, optically active p-hydroxyphenylglycine is allowed to act on (±)-α-phenylethanesulfonic acid as a resolving agent to form a salt [i.e., DL-
p-hydroxyphenylglycine/optically active α-
Phenylethane sulfonate or optically active p-hydroxyphenylglycine/(±)-α-phenylethane sulfonate]. Optically active p-hydroxyphenylglycine and optically active α-phenylethanesulfonate [i.e., D-p-hydroxyphenylglycine]
(±)-α-phenylethanesulfonate is L-p
-Hydroxyphenylglycine (-)-α-phenylethanesulfonate] is separated and collected, and if necessary, this salt is further desalted to produce optically active p-hydroxyphenylglycine and optically active p-hydroxyphenylglycine. α-phenylethanesulfonic acid or salts thereof can be produced. As optically active p-hydroxyphenylglycine as a resolving agent, both the D and L forms are used, and as optically active α-phenylethanesulfonic acid as a resolving agent, both its (+) and (-) forms are used. be able to. For example, DL-p in a suitable aqueous solvent
- When (+)-α-phenylethanesulfonic acid is applied to hydroxyphenylglycine, D-p-hydroxyphenylglycine・(+)-α
-phenylethanesulfonate (hereinafter referred to as D-
HPG・(+)-PES) and L-p-hydroxyphenylglycine・(+)-α-phenylethanesulfonate (hereinafter referred to as L-HPG・(+)-PES)
D-
Since HPG·(+)-PES is a poorly soluble salt in the aqueous solvent and L-HPG·(+)-PES is an easily soluble salt, only D-HPG·(+)-PES crystallizes. In this case, even if (-)-PES is used as the resolving agent, optical resolution can be achieved in exactly the same way, L-HPG・(-)-PES is obtained as a poorly soluble diastereomer, and D-HPG is obtained as a readily soluble salt.・(-)-PES is obtained. On the other hand, when optically resolving (±)-α-phenylethanesulfonic acid, L-p is used as a resolving agent.
- When acting with hydroxyphenylglycine, L-HPG・(±)-PES and L-HPG・(−)
- Two diastereomers of PES are produced,
Since L-HPG・(-)-PES is a poorly soluble diastereomer and L-HPG・(+)-PES is a readily soluble diastereomer, L-HPG・(-)-
PES crystallizes, and L-HPG·(+)-PES is dissolved in the liquid. On the other hand, when D-p-hydroxyphenylglycine is used as a resolving agent, D-
HPG・(+)−PES is poorly soluble, D−HPG・(−)−
Since PES is produced as a readily soluble diastereomer, it is possible to crystallize only D-HPG·(+)-PES. p-hydroxyphenylglycine, which is the substance to be split or the splitting agent, can be used not only in its free form, but also in mineral acid salts such as hydrochloride and sulfate, and organic acid salts such as oxalate and sulfonic acid. Can be done. Similarly, α-phenylethanesulfonic acid may be in free form, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and even ammonium salts. Can be used. Furthermore, the substance to be resolved, p-hydroxyphenylglycine or α-phenylethanesulfonic acid, is not only a mixture of equal amounts of D-form and L-form obtained by chemical synthesis, but also a so-called low-purity product containing an excess of one of the optically active forms. It is also possible to use an optically active substance. In carrying out the present invention, it is appropriate to use p-hydroxyphenylglycine or α-phenylethanesulfonic acid as a resolving agent in a molar ratio of about 0.5 or more, especially about 0.8 to 1.1 to the substance to be separated. . Examples of the aqueous solvent used in the salt-forming reaction include water;
Lower alkanols such as methanol and ethanol; acetone; fatty acids such as acetic acid and propionic acid; or mixtures thereof can be suitably used; water is particularly preferred. For example, the salt formation reaction is performed by combining DL-p-hydroxyphenylglycine and optically active α-phenylethanesulfonic acid or optically active p-hydroxyphenylglycine and (±)-α-phenylethanesulfonic acid in the above-mentioned solvent. This can be carried out by stirring at room temperature or under heating. In addition, the crystallization operation of D-HPG・(+)-PES or L-HPG・(−)-PES, which are poorly soluble salts among the diastereomers produced, is performed by cooling the reaction solution, concentrating it, or using an organic This can be easily carried out by adding a solvent, and the salt can be precipitated as highly pure crystals. The precipitated poorly soluble salt can be separated and obtained by conventional solid-liquid separation methods such as filtration and centrifugation. The poorly soluble diastereomer obtained in the above manner can be further subjected to treatments such as washing and recrystallization, if necessary. Each of the various diastereomers obtained in the present invention is a salt consisting of 1 mol of optically pure p-hydroxyphenylglycine and 1 mol of α-phenylethanesulfonic acid, and is a new compound.
Its main physical properties are shown in Table 1 below.
【表】
かくして得られたＤ−HPG・（＋）−PES又は
Ｌ−HPG・（−）−PESはイオン交換樹脂処理、
或いはアルカリ処理の如き常法によつて容易に光
学活性ｐ−ヒドロキシフエニルグリシンと光学活
性α−フエニルエタンスルホン酸に分離すること
ができる。例えばＤ−HPG・（＋）−PESの水溶
液をアルカリでｐ−ヒドロキシフエニルグリシン
の等電点に調整すればＤ−ｐ−ヒドロキシフエニ
ルグリシンと（＋）−α−フエニルエタンスルホ
ン酸に分離し、Ｄ−ｐ−ヒドロキシフエニルグリ
シンのみが結晶として析出する。同様にＬ−
HPG・（−）−PESからはＬ−ｐ−ヒドロキシフ
エニルグリシンのみが結晶として析出する。析出
した結晶はろ過等により固液分離すればＤ−又は
Ｌ−ｐ−ヒドロキシフエニルグリシンを得ること
ができる。又母液中には光学的に純粋なα−フエ
ニルエタンスルホン酸アルカリ塩が溶存している
のでこれを中和することにより光学活性α−フエ
ニルエタンスルホン酸を溶液状態で得ることがで
きる。
以上の通り、本発明によれば、DL−ｐ−ヒド
ロキシフエニルグリシンの光学分割に際し、分割
剤としてα−フエニルエタンスルホン酸の（＋）
体又は（−）体を適宜用いることにより所望の光
学活性ｐ−ヒドロキシフエニルグリシンを常に難
溶性ジアステレオマーとして選択的に晶析させる
ことができるという利点が得られる。又、（±）−
α−フエニルエタンスルホン酸の光学分割に際し
ても、分割剤たるｐ−ヒドロキシフエニルグリシ
ンのＤ体又はＬ体を適宜選択して使用するだけで
所望の光学活性フエニルエタンスルホン酸を難溶
性ジアステレオマーとして晶析せしめることがで
きる。
しかもいずれの場合も造塩反応・晶析操作は水
性溶媒中で実施でき操作が極めて簡単であるとい
う利点もあわせ得られる。
加えて、上記の如くすぐれた分割剤である光学
活性α−フエニルエタンスルホン酸は従来、試薬
としての入手も困難であつたが、本発明方法によ
り容易に製造できるので工業的規模においても大
量に供給可能となりその意義は大きい。
尚、本発明の一方の原料物質である（±）−α
−フエニルエタンスルホン酸は〔J.Chem.Soc.，
1159（1927）〕記載の方法に準じ、（±）−α−フ
エネチルアルコールをブロム化し、得られる
（±）−α−フエネチルブロミドをスルホン化して
製することができる。
以下、実施例により本発明をさらに詳細に説明
する。
実施例 １
（±）−PES19.0ｇを含す水溶液450ｇにＬ−
HPG16.7ｇを加えて加熱溶解し、ついで徐冷し室
温で２時間かつ拌する。析出晶をろ取し少量の冷
水で洗浄することにより（−）−PES・Ｌ−
HPG16.2ｇを得た。
〔α〕２５ Ｄ＋79.0゜（Ｃ＝１，メタノール）
実施例 ２
(1) （±）−PES・NH4125ｇ、Ｄ−HPG102.8ｇ
および濃硫酸33.2ｇを水2.2に加熱溶解す
る。ついで室温で２時間かつ拌した。析出晶を
ろ取し水洗・乾燥することにより（＋）−
PES・Ｄ−HPG95.1ｇを得た。
〔α〕２５ Ｄ−79.2゜（Ｃ＝１，メタノール）
(2) (1)で得られた（＋）−PES・Ｄ−HPG29.0ｇ
にメタノール87mlを加えかく拌下に水酸化ナト
リウム水溶液を加えてPH６に調整する。室温下
に２時間かつ拌しろ過することによりＤ−
HPG13.0ｇを得た。
〔α〕２５ Ｄ−155.0゜（Ｃ＝１，Ｎ−HCl）
母液を濃縮してメタノールを留去し水を加えて
IR−120（H+）を充填したカラムに通導しカラム
は水で洗浄する。流出液及び洗液を合せ濃縮する
ことにより（＋）−α−フエニルエタンスルホン
酸の10％溶液150ｇを得た。
実施例 ３
（±）−α−フエニルエチルブロミド55.5ｇに
亜硫酸アンモニウムを作用させて調製した（±）
−PESの反応混合物（150ｇ）にＤ−HPG27.6
ｇ、濃塩酸45.3mlおよび水300mlを加え加熱溶解
し、ついで20℃で２時間かつ拌する。析出晶をろ
取し水洗乾燥することにより（＋）−PES・Ｄ−
HPG23.3ｇを得た。
〔α〕２５ Ｄ−79.4℃（Ｃ＝１，メタノール）
実施例 ４
DL−HPG20ｇおよび濃塩酸11mlを水300mlに溶
解し、これに（＋）−PES・NH424.3ｇを水200ml
に溶解した溶液を徐々に加え室温で２時間かく拌
した。析出晶をろ取し水洗乾燥することにより
（＋）−PES・Ｄ−HPG19.7ｇを得た。
〔α〕２５ Ｄ−75.8゜（Ｃ＝１，メタノール）[Table] The thus obtained D-HPG/(+)-PES or L-HPG/(-)-PES was treated with an ion exchange resin,
Alternatively, it can be easily separated into optically active p-hydroxyphenylglycine and optically active α-phenylethanesulfonic acid by a conventional method such as alkali treatment. For example, if an aqueous solution of D-HPG/(+)-PES is adjusted to the isoelectric point of p-hydroxyphenylglycine with an alkali, it becomes D-p-hydroxyphenylglycine and (+)-α-phenylethanesulfonic acid. The mixture is separated, and only D-p-hydroxyphenylglycine is precipitated as crystals. Similarly, L-
Only L-p-hydroxyphenylglycine is precipitated as crystals from HPG.(-)-PES. If the precipitated crystals are subjected to solid-liquid separation by filtration or the like, D- or L-p-hydroxyphenylglycine can be obtained. Furthermore, since an optically pure alkali salt of α-phenylethanesulfonic acid is dissolved in the mother liquor, optically active α-phenylethanesulfonic acid can be obtained in a solution state by neutralizing this. As described above, according to the present invention, in the optical resolution of DL-p-hydroxyphenylglycine, the (+)
By appropriately using the isomer or the (-) isomer, there is an advantage that the desired optically active p-hydroxyphenylglycine can always be selectively crystallized as a poorly soluble diastereomer. Also, (±)−
When optically resolving α-phenylethanesulfonic acid, the desired optically active phenylethanesulfonic acid can be obtained by simply selecting and using the D-form or L-form of p-hydroxyphenylglycine as a resolving agent. It can be crystallized as a stereomer. Moreover, in either case, the salt-forming reaction and crystallization operation can be carried out in an aqueous solvent, and the operation is extremely simple. In addition, as mentioned above, optically active α-phenylethanesulfonic acid, which is an excellent resolving agent, has traditionally been difficult to obtain as a reagent, but since it can be easily produced by the method of the present invention, it can be produced in large quantities even on an industrial scale. This is of great significance. Note that (±)-α, which is one of the raw materials of the present invention
-Phenylethanesulfonic acid is [J.Chem.Soc.,
1159 (1927)], by brominating (±)-α-phenethyl alcohol and sulfonating the obtained (±)-α-phenethyl bromide. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 (±)- Add L- to 450 g of an aqueous solution containing 19.0 g of PES.
Add 16.7 g of HPG and dissolve by heating, then slowly cool and stir at room temperature for 2 hours. By filtering the precipitated crystals and washing with a small amount of cold water, (-)-PES・L-
Obtained 16.2 g of HPG. [α] 25 D +79.0° (C=1, methanol) Example 2 (1) (±)-PES・NH 4 125 g, D-HPG 102.8 g
Heat and dissolve 33.2 g of concentrated sulfuric acid in 2.2 g of water. The mixture was then stirred at room temperature for 2 hours. By filtering the precipitated crystals, washing with water, and drying, (+)−
95.1 g of PES・D-HPG was obtained. [α] 25 D -79.2° (C=1, methanol) (2) (+)-PES・D-HPG obtained in (1) 29.0 g
Add 87 ml of methanol to the solution, and while stirring, add an aqueous sodium hydroxide solution to adjust the pH to 6. D- by stirring for 2 hours at room temperature and filtering.
13.0g of HPG was obtained. [α] 25 D -155.0゜(C=1,N-HCl) Concentrate the mother liquor to remove methanol and add water.
The flow is passed through a column filled with IR-120 (H + ), and the column is washed with water. The effluent and washing liquid were combined and concentrated to obtain 150 g of a 10% solution of (+)-α-phenylethanesulfonic acid. Example 3 Prepared by reacting ammonium sulfite with 55.5 g of (±)-α-phenylethyl bromide (±)
- D-HPG27.6 in the reaction mixture (150 g) of PES
g, 45.3 ml of concentrated hydrochloric acid and 300 ml of water were added and dissolved by heating, followed by stirring at 20°C for 2 hours. By filtering the precipitated crystals, washing with water and drying, (+)-PES・D-
23.3g of HPG was obtained. [α] 25 D -79.4℃ (C=1, methanol) Example 4 20g of DL-HPG and 11ml of concentrated hydrochloric acid were dissolved in 300ml of water, and 24.3g of (+)-PES・NH 4 was added to 200ml of water.
A solution dissolved in was gradually added and stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed with water, and dried to obtain 19.7 g of (+)-PES.D-HPG. [α] 25 D -75.8° (C=1, methanol)
Claims (1)
ニルエタンスルホン酸塩。 ２ DL−ｐ−ヒドロキシフエニルグリシン・光
学活性α−フエニルエタンスルホン酸塩である特
許請求の範囲第１項記載の化合物。 ３ 光学活性ｐ−ヒドロキシフエニルグリシン・
（±）−α−フエニルエタンスルホン酸塩である特
許請求の範囲第１項記載の化合物。 ４ Ｄ−ｐ−ヒドロキシフエニルグリシン・
（＋）−α−フエニルエタンスルホン酸塩である特
許請求の範囲第１項記載の化合物。 ５ Ｌ−ｐ−ヒドロキシフエニルグリシン・
（−）−α−フエニルエタンスルホン酸塩である特
許請求の範囲第１項記載の化合物。 ６ ｐ−ヒドロキシフエニルグリシン及びα−フ
エニルエタンスルホン酸から選ばれるいずれか一
方の化合物の光学活性体と他方の化合物のラセミ
体を水性溶媒中で反応させ生成する２種ジアステ
レオマーの溶解度差を利用してその難溶性ジアス
テレオマーたる一方の光学活性ｐ−ヒドロキシフ
エニルグリシン・光学活性α−フエニルエタンス
ルホン酸塩を分離・採取することを特徴とする光
学活性ｐ−ヒドロキシフエニルグリシン・光学活
性α−フエニルエタンスルホン酸塩の製造法。[Claims] 1 p-Hydroxyphenylglycine/α-phenylethanesulfonate. 2. The compound according to claim 1, which is DL-p-hydroxyphenylglycine/optically active α-phenylethanesulfonate. 3 Optically active p-hydroxyphenylglycine
The compound according to claim 1, which is (±)-α-phenylethanesulfonate. 4 D-p-hydroxyphenylglycine
The compound according to claim 1, which is (+)-α-phenylethanesulfonate. 5 L-p-hydroxyphenylglycine
The compound according to claim 1, which is (-)-α-phenylethanesulfonate. 6 Solubility of two diastereomers produced by reacting an optically active form of one of the compounds selected from p-hydroxyphenylglycine and α-phenylethanesulfonic acid with a racemic form of the other compound in an aqueous solvent Optically active p-hydroxyphenyl, which is characterized by separating and collecting one of the poorly soluble diastereomers, optically active p-hydroxyphenylglycine and optically active α-phenylethanesulfonate, by utilizing the difference. A method for producing glycine/optically active α-phenylethanesulfonate.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15004781A JPS5852253A (en) | 1981-09-21 | 1981-09-21 | P-hydroxyphenylglycine-alpha-phenylethanesulfonic acid salt and its optical resolution |
| US06/416,338 US4415504A (en) | 1981-09-21 | 1982-09-09 | p-Hydroxyphenylglycine.α-phenylethanesulfonate, process for production thereof and utilization thereof in resolution of p-hydroxyphenylglycine |
| EP82108709A EP0075318B1 (en) | 1981-09-21 | 1982-09-21 | P-hydroxyphenylglycine alpha-phenylethanesulfonate, process for production thereof and utilization thereof in resolution of p-hydroxyphenylglycine |
| DE8282108709T DE3265433D1 (en) | 1981-09-21 | 1982-09-21 | P-hydroxyphenylglycine alpha-phenylethanesulfonate, process for production thereof and utilization thereof in resolution of p-hydroxyphenylglycine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15004781A JPS5852253A (en) | 1981-09-21 | 1981-09-21 | P-hydroxyphenylglycine-alpha-phenylethanesulfonic acid salt and its optical resolution |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5852253A JPS5852253A (en) | 1983-03-28 |
| JPS6261584B2 true JPS6261584B2 (en) | 1987-12-22 |
Family
ID=15488341
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15004781A Granted JPS5852253A (en) | 1981-09-21 | 1981-09-21 | P-hydroxyphenylglycine-alpha-phenylethanesulfonic acid salt and its optical resolution |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5852253A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0467856B1 (en) * | 1990-07-19 | 1997-03-19 | Nippon Zoki Pharmaceutical Co. Ltd. | Aminoalkanesulfonic acid derivatives and pharmaceutical compositions for use in preventing or treating heart diseases |
| EP3174855B1 (en) * | 2014-07-31 | 2023-05-10 | Medivation Technologies LLC | Coformer salts of (2s,3s)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1h-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate and methods of preparing them |
-
1981
- 1981-09-21 JP JP15004781A patent/JPS5852253A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5852253A (en) | 1983-03-28 |
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