JPH0665657B2 - Production of optically active mandelic acid - Google Patents
Production of optically active mandelic acidInfo
- Publication number
- JPH0665657B2 JPH0665657B2 JP59234180A JP23418084A JPH0665657B2 JP H0665657 B2 JPH0665657 B2 JP H0665657B2 JP 59234180 A JP59234180 A JP 59234180A JP 23418084 A JP23418084 A JP 23418084A JP H0665657 B2 JPH0665657 B2 JP H0665657B2
- Authority
- JP
- Japan
- Prior art keywords
- mandelic acid
- optically active
- acid
- phenylalanine
- complex
- 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 - Fee Related
Links
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 title claims description 31
- 229960002510 mandelic acid Drugs 0.000 title claims description 18
- 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 title claims description 17
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 21
- 230000003287 optical effect Effects 0.000 claims description 19
- 230000002378 acidificating effect Effects 0.000 claims description 14
- 238000010494 dissociation reaction Methods 0.000 claims description 13
- 230000005593 dissociations Effects 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 229960005190 phenylalanine Drugs 0.000 description 34
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 21
- 239000013078 crystal Substances 0.000 description 21
- 238000000034 method Methods 0.000 description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 9
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 4
- 229930182832 D-phenylalanine Natural products 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 239000003729 cation exchange resin Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 3
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- -1 DL-mandelic acid diisopropylamine salt Chemical compound 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000003518 caustics Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000019832 sodium triphosphate Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- QIJIUJYANDSEKG-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-amine Chemical class CC(C)(C)CC(C)(C)N QIJIUJYANDSEKG-UHFFFAOYSA-N 0.000 description 1
- QWCKQJZIFLGMSD-UHFFFAOYSA-N 2-Aminobutanoic acid Natural products CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 1
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-UHFFFAOYSA-N 0.000 description 1
- UPWLDSYIAGBPIF-UHFFFAOYSA-N 2-aminobutan-1-ol;2-hydroxy-2-phenylacetic acid Chemical compound CCC(N)CO.OC(=O)C(O)C1=CC=CC=C1 UPWLDSYIAGBPIF-UHFFFAOYSA-N 0.000 description 1
- GAWAYYRQGQZKCR-UHFFFAOYSA-N 2-chloropropionic acid Chemical compound CC(Cl)C(O)=O GAWAYYRQGQZKCR-UHFFFAOYSA-N 0.000 description 1
- WWILHZQYNPQALT-UHFFFAOYSA-N 2-methyl-2-morpholin-4-ylpropanal Chemical compound O=CC(C)(C)N1CCOCC1 WWILHZQYNPQALT-UHFFFAOYSA-N 0.000 description 1
- CFZGIDYCUWFUJR-UHFFFAOYSA-N 3-(dimethylamino)azepan-2-one Chemical compound CN(C)C1CCCCNC1=O CFZGIDYCUWFUJR-UHFFFAOYSA-N 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- QWCKQJZIFLGMSD-GSVOUGTGSA-N D-alpha-aminobutyric acid Chemical compound CC[C@@H](N)C(O)=O QWCKQJZIFLGMSD-GSVOUGTGSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 description 1
- 229940077239 chlorous acid Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 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
- 238000002955 isolation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 229940048084 pyrophosphate Drugs 0.000 description 1
- 229940005657 pyrophosphoric acid Drugs 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-I triphosphate(5-) Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O UNXRWKVEANCORM-UHFFFAOYSA-I 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 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」 本発明は光学活性マンデル酸の製法に関する。更に詳し
くはDL−マンデル酸と光学活性なフエニルアラニンとの
複合体を光学分割して光学活性なマンデル酸を得る方法
に関する。DETAILED DESCRIPTION OF THE INVENTION "Industrial field of application" The present invention relates to a method for producing an optically active mandelic acid. More specifically, it relates to a method of optically resolving a complex of DL-mandelic acid and an optically active phenylalanine to obtain an optically active mandelic acid.
「従来の技術」 光学活性なマンデル酸は医薬品の中間体として重要であ
りDL−マンデル酸の光学分割法等によつて製造される。“Prior Art” Optically active mandelic acid is important as an intermediate for pharmaceuticals and is produced by an optical resolution method of DL-mandelic acid.
即ちDL−マンデル酸の高額分割法としては、特開昭58−
177933に記載の光学活性なα−ジメチルアミノ−ε−カ
プロラクタムを分割剤として使用する方法、特開昭55−
147236に記載の光学活性なα−フエネチルアミンを分割
剤として使用する方法、特開昭53−119844に記載の光学
活性なアミノ酸を分割剤として使用する方法、等が知ら
れている。That is, as a high-value splitting method for DL-mandelic acid, Japanese Patent Laid-Open No. 58-
A method of using the optically active α-dimethylamino-ε-caprolactam described in 177933 as a resolving agent, JP-A-55-
A method using an optically active α-phenethylamine described in 147236 as a resolving agent, a method using an optically active amino acid described in JP-A-53-119844, and the like are known.
また、光学活性な分割剤を使用しない例として特開昭55
−115846に記載のDL−マンデル酸のジイソプロピルアミ
ン塩又は1,1,3,3−テトラメチル・ブチルアミン塩、特
開昭56−123936に記載のDL−マンデル酸のDL−２−アミ
ノブタノール塩等を、優先晶出法による分割し次いで分
解して光学活性なマンデル酸を得る方法等が知られてい
る。In addition, as an example in which an optically active resolving agent is not used, JP-A-55
-115846 DL-mandelic acid diisopropylamine salt or 1,1,3,3-tetramethylbutylamine salt, DL-mandelic acid DL-2-aminobutanol salt described in JP-A-56-123936 There is known a method of obtaining optically active mandelic acid by dividing the compound by preferential crystallization and then decomposing it.
以上の方法のうち優先晶出法による方法は溶媒の容積当
りの得量が少なく、操作が複雑で、工業的に有利な方法
とはいえない。Among the above methods, the method by the preferential crystallization method is not an industrially advantageous method because the amount of the solvent obtained per volume is small and the operation is complicated.
また、光学活性な分割剤を用いる従来のジアステレオマ
ー形成方法においては分割剤が高価であり、分割剤のわ
ずかのロスが製品のコストに大きく影響する等の欠点が
ある。本発明の方法は近年、人工甘味料「アスパルテー
ム」の原料として、安価に製造される様になつたフエニ
ルアラニンの光学活性体を分割剤として用いるものであ
るが、Ｌ−フエニルアラニンを分割剤として、DL−マン
デル酸を光学分割する方法は日本化学雑誌92巻999頁（1
971）により公知である。Further, in the conventional diastereomer forming method using an optically active resolving agent, the resolving agent is expensive, and a slight loss of the resolving agent has a drawback that the product cost is greatly affected. In recent years, the method of the present invention uses, as a resolving agent, an optically active form of phenylalanine, which has come to be manufactured at low cost, as a raw material of an artificial sweetener "aspartame". The method of optically resolving DL-mandelic acid as an agent is described in Vol.
971).
分割剤とし光学活性なフエニルアラニンを用いる方法は
前記のα−フエネチルアミン等のような液体アミンとち
がつて光学分割が終つたのち光学活性なフエニルアラニ
ンが難溶性の複合体結晶として回収される点、あるいは
光学活性なフエニルアラニン及び光学活性なフエニルア
ラニンとDL−マンデル酸との複合体の溶解度が前記のア
ラニン、メチオニン又はα−アミノ酪酸等に比べ小さい
ので分割剤としての光学活性フエニルアラニンのロスが
小さい点等ですぐれている反面光学活性なフエニルアラ
ニンと光学活性なマンデル酸との複合体の水系溶媒に対
する溶解度が十分でないので例えば前記日本化学雑誌に
記載のような方法で光学分割を行つたのでは使用溶媒の
容積当りの得量が低いという欠点がある。The method of using optically active phenylalanine as the resolving agent is different from the above-mentioned liquid amine such as α-phenethylamine and the like, and after the optical resolution is completed, the optically active phenylalanine is recovered as a slightly soluble complex crystal. However, the solubility of the optically active phenylalanine and the complex of the optically active phenylalanine and DL-mandelic acid is smaller than that of the alanine, methionine, α-aminobutyric acid, etc. On the other hand, the loss of phenylalanine is excellent in that it is small, but the solubility of the complex of optically active phenylalanine and optically active mandelic acid in an aqueous solvent is not sufficient. However, there is a drawback that the amount of the solvent used per volume is low if the optical resolution is performed by.
「本発明が解決しようとする問題点」 DL−マンデル酸と光学活性なフエニルアラニンとの複合
体を光学分割して光学活性なマンデル酸をえるにあたつ
て使用溶媒の容積当りの仕込み効率を飛躍的に向上させ
る方法の開発が望まれている。"Problems to be Solved by the Present Invention" When a complex of DL-mandelic acid and optically active phenylalanine is optically resolved to give optically active mandelic acid, the charging efficiency per volume of the solvent used It is desired to develop a method for dramatically improving
「問題点を解決するための手段」 前記したような問題点を解決すべく鋭意努力した結果、
本発明者らはDL−マンデル酸と光学活性なフエニルアラ
ニンと複合体を水又は水と他の溶媒との混合溶媒中、水
中における常温での酸解離指数（pKa）値が0.9〜３の範
囲にある酸性物質の存在下に光学分割し、えられた光学
活性マンデル酸と光学活性フエニルアラニンとの複合体
を分解して光学活性フエニルアラニンを除去することに
よつて光学活性マンデル酸の得量を公知の方法に比べ飛
躍的に向上させることが出来ることを見出し本発明を完
成させた。"Means for solving problems" As a result of diligent efforts to solve the above problems,
The present inventors have prepared a complex of DL-mandelic acid, an optically active phenylalanine, and water in water or a mixed solvent of water and another solvent, and have an acid dissociation index (pKa) value of 0.9 to 3 at room temperature in water. By optically resolving in the presence of an acidic substance in the range and decomposing the obtained complex of optically active mandelic acid and optically active phenylalanine to remove optically active phenylalanine, The present invention has been completed by finding that it is possible to remarkably improve the yield of the method as compared with the known method.
本発明の理論的根拠は必ずしも明白でないが光学活性な
マンデル酸と光学活性なフエニルアラニンとの複合体の
熱時における溶解性が本発明に使用する酸性物質が存在
しない場合に比べて予想外に大きくなることに起因する
ものと考えられる。Although the rationale for the present invention is not always clear, the solubility of the complex of the optically active mandelic acid and the optically active phenylalanine under heat is unexpected as compared with the case where the acidic substance used in the present invention is not present. It is believed that this is due to the fact that
本発明で用いる酸性物質は水中、常温での酸解離指数
（pKa）値が0.9〜３の範囲のものである。pKaが0.9以下
の強酸、同じく３以上の弱酸では使用溶媒の容積当りの
仕込み効率をあげる効価がないか極めて小さい。本発明
で用いられる酸性物質の具体例としてはスルフアミン
酸、硫酸（第２解離）、リン酸（第１解離）ピロリン酸
（第１、第２解離）、トリポリリン酸（第１、第２解
離）、硫酸水素ナトリウム、硫酸水素カリウム、硫酸水
素アンモニウム等の重硫酸塩、ピロリン酸ソーダ、トリ
ポリリン酸ソーダ等のピロリン酸又はトリポリリン酸
塩、亜硫酸（第１解離）、亜塩素酸、クロロ酢酸、シア
ノ酢酸、ジクロロ酢酸、フルオロ酢酸、ブモロ酢酸、ピ
ルビン酸、２−クロロプロピオン酸、マレイン酸、マロ
ン酸等があげられる。なお上記において（ ）内は、本
発明の目的に使用する角酸性物質の解離段階を示す。例
えば、硫酸でな第一段解離は酸性が強すぎるため、第二
段目の解離を利用し、重硫酸塩として用いるか又は、硫
酸の第一解離と造塩する分だけ光学活性なフエニルアラ
ニンを所定量より過剰に用いるようにする。前記の酸性
物質は例えば、硫さとカ性ソーダを系内に加えて重硫酸
ソーダを系内で調製してもよい。これらの酸性物質の使
用量は分解剤として用いる光学活性なフエニルアラニン
の0.01〜３倍モル好ましくは0.05〜２倍モルである。使
用する酸性物質の解離度に応じて最適量が異なるので、
あらかじめ高温時での溶解性、低温時におけるＬ−フエ
ニルアラニン・Ｌ−マンデル酸又はＤ−フエニルアラニ
ン・Ｄ−マンデル酸複合体の析出量を確認の上、前記使
用量の範囲でその最適量を決定するのが望ましい。The acidic substance used in the present invention has an acid dissociation index (pKa) value in the range of 0.9 to 3 at room temperature in water. With a strong acid having a pKa of 0.9 or less, and also with a weak acid of 3 or more, there is little or no effect of increasing the charging efficiency per volume of the solvent used. Specific examples of the acidic substance used in the present invention include sulfamic acid, sulfuric acid (second dissociation), phosphoric acid (first dissociation) pyrophosphoric acid (first and second dissociation), and tripolyphosphoric acid (first and second dissociation). , Bisulfate such as sodium hydrogensulfate, potassium hydrogensulfate, ammonium hydrogensulfate, pyrophosphate or tripolyphosphate such as sodium pyrophosphate, sodium tripolyphosphate, sulfurous acid (first dissociation), chlorous acid, chloroacetic acid, cyanoacetic acid , Dichloroacetic acid, fluoroacetic acid, bumoloacetic acid, pyruvic acid, 2-chloropropionic acid, maleic acid, malonic acid and the like. In addition, in the above, the inside of () shows the dissociation step of the horny acidic substance used for the purpose of the present invention. For example, since the first-step dissociation with sulfuric acid is too acidic, the second-step dissociation is used and used as a bisulfate, or the optically active phenyl is formed as much as the first dissociation of sulfuric acid and salt formation. Try to use alanine in excess of a given amount. The acidic substance may be prepared by adding sodium bisulfate to the system by adding sulfur and caustic soda. The amount of these acidic substances used is 0.01 to 3 times mol, preferably 0.05 to 2 times mol, of the optically active phenylalanine used as a decomposing agent. Since the optimum amount varies depending on the dissociation degree of the acidic substance used,
The solubility at high temperature and the deposition amount of L-phenylalanine / L-mandelic acid or D-phenylalanine / D-mandelic acid complex at low temperature are confirmed in advance, and the optimum amount is within the above range. It is desirable to determine the amount.
分割剤として使用する光学活性なフエニルアラニンとし
てはＤ−フエニルアラニン又はＬ−フエニルアラニンが
用いられ、分割すべきDL−マンデル酸の0.1〜３倍モル
好ましくは0.2〜1.5倍モル量使用する。但し前記したよ
うに例えば酸性物質として硫酸を用いた場合はこの範囲
を超えて使用する事もある。As the optically active phenylalanine used as a resolving agent, D-phenylalanine or L-phenylalanine is used, and 0.1- to 3-fold molar amount, preferably 0.2-1.5-fold molar amount, of DL-mandelic acid to be resolved is used. To do. However, as described above, for example, when sulfuric acid is used as the acidic substance, it may be used beyond this range.
光学分割に用いる溶媒は水が最もよいが、メタノール、
エタノール、イソプロパノール等の低級アルコール、酢
酸、プロピロン酸等の低級脂肪酸DMF、DMSO、ジメチル
イミダゾリジノン等の非プロトン性極性溶媒等と水の混
合溶媒も使用出来る。溶媒の使用量としては、できるだ
け少ない方が望ましいが、最適の実施形態においては分
割すべきDL−マンデル酸の1.5から５重量倍使用する。Water is the best solvent for optical resolution, but methanol,
A mixed solvent of water with a lower alcohol such as ethanol or isopropanol, a lower fatty acid such as acetic acid or propyroic acid, DMF, DMSO, dimethylimidazolidinone or the like and water can also be used. The amount of the solvent used is preferably as small as possible, but in the optimum embodiment, it is used in an amount of 1.5 to 5 times by weight of DL-mandelic acid to be resolved.
分割の操作の一例を示すと、まずDL−マンデル酸、Ｌ−
フエニルアラニン又はＤ−フエニルアラニン、本発明に
おける前記酸性物質、溶媒をフラスコに仕込み、昇温し
てそれらを均一に溶解させる。この温度は通常50℃〜10
0℃が適当である。溶解後冷却して、５〜40℃ぐらいの
温度で析出するＬ−マンデル酸とＬ−フエニルアラニン
又はＤ−マンデル酸とＤ−フエニルアラニンとの複合体
を結晶としてとり出す。尚、冷却の途中で、微量の種晶
を添加し、結晶を析出させた場合、一層光学純度のよい
ものが得られる。また、芒硝、食塩、スルフアミン酸
塩、硫酸アンモニウム等の塩類を加えて分割時複合体の
収量を向上させる事もできる。また場合によつては結晶
を析出させる時に添加された酸性物質の一部または全部
をカ性ソーダ等のカ性アルカリ又はアンモニアで中和し
て光学純度がやや悪い結晶を多くとることもできる。得
られた光学活性複合体から光学活性マンデルの単離は公
知の方法により行うことができる。例えば光学活性マン
デル酸・光学活性フエニルアラニン複合体を苛性アルカ
リ等で中和してアルカリ性にて過し次いで光学活性マ
ンデル酸を含む液を酸で酸性化して光学活性マンデル
酸をえる。その他酸による処理、有機溶剤に抽出法等も
利用できる。An example of the splitting operation is as follows: DL-mandelic acid, L-
Phenylalanine or D-phenylalanine, the acidic substance of the present invention, and a solvent are charged in a flask and heated to uniformly dissolve them. This temperature is usually 50 ℃ ~ 10
0 ° C is suitable. After dissolution, the mixture is cooled and the complex of L-mandelic acid and L-phenylalanine or D-mandelic acid and D-phenylalanine that precipitates at a temperature of about 5 to 40 ° C. is taken out as crystals. If a small amount of seed crystal is added during the cooling to precipitate the crystal, a crystal having a higher optical purity can be obtained. Further, salt such as Glauber's salt, common salt, sulfamate, ammonium sulfate and the like can be added to improve the yield of the complex upon resolution. In some cases, a part or all of the acidic substance added at the time of precipitating crystals can be neutralized with caustic alkali such as caustic soda or ammonia to obtain many crystals with slightly poor optical purity. Isolation of the optically active Mandel from the obtained optically active complex can be performed by a known method. For example, the optically active mandelic acid / optically active phenylalanine complex is neutralized with caustic alkali or the like to make it alkaline, and then the liquid containing the optically active mandelic acid is acidified with an acid to obtain the optically active mandelic acid. In addition, treatment with an acid, extraction method with an organic solvent and the like can be used.
得られた光学活性なマンデル酸はそのままで或いは更に
精製操作を加えてより高純度のＬ−又はＤ−マンデル酸
とした上で医薬品製造の為の原料として用いられる。The obtained optically active mandelic acid is used as it is or after further purification operation to obtain L- or D-mandelic acid of higher purity, which is used as a raw material for drug production.
「実施例」 次に実施例により本発明を具体的に説明する。"Examples" Next, the present invention will be specifically described with reference to Examples.
実施例１ 水450ml、95％硫酸21.4g、Ｌ−フエニルアラニン107.5g
を仕込み、次いでDL−マンデル酸180gを徐々に加え昇温
して均一に溶解させる。約80℃で溶解する。その後徐々
に冷却し、70〜72℃にて、Ｌ−マンデル酸・Ｌ−フエニ
ルアラニン複合体の微粉砕された乾燥結晶（0.1g）を種
晶として添加する。約３時間後35℃まで冷却して析出し
た結晶を遠心分離機で別する。Example 1 450 ml of water, 21.4 g of 95% sulfuric acid, 107.5 g of L-phenylalanine
Then, 180 g of DL-mandelic acid is gradually added to raise the temperature and dissolve uniformly. Melts at about 80 ° C. Then, the mixture is gradually cooled, and at 70 to 72 ° C., finely pulverized dry crystals (0.1 g) of the L-mandelic acid / L-phenylalanine complex are added as seed crystals. After about 3 hours, it is cooled to 35 ° C. and the precipitated crystals are separated by a centrifuge.
110gのＬ−マンデル酸:L−フエニルアラニン（1:1）複
合体が得られた。110 g of L-mandelic acid: L-phenylalanine (1: 1) complex was obtained.
得られた結晶の１部をとり陽イオン交換樹脂を用い複合
体を分解しＬ−マンデル酸を分離した。A part of the obtained crystal was taken and the complex was decomposed using a cation exchange resin to separate L-mandelic acid.
そのＬ−マンデル酸の旋光度は▲〔α〕20 D▼＝＋114.1
゜（Ｃ＝2,水）を示しこれは光学純度73.1％に相当す
る。The optical rotation of L-mandelic acid is ▲ [α] 20 D ▼ ＝ ＋ 114.1
(C = 2, water), which corresponds to an optical purity of 73.1%.
又複合体の結晶105gを水200mlに分散しここに25％カ性
ソーダ水溶液を徐々に滴下して複合体を分解させると同
時にＬ−マンデル酸をそのナトリウム塩として溶解させ
た。これを過しＬ−フエニルアラニンを除き、その
液を硫酸で酸析しＬ−マンデル酸を結晶として得た。乾
燥後の収量は37gであつた。得られたＬ−マンデル酸の
旋光度は▲〔α〕20 D▼＝＋153.5゜（Ｃ＝2,水）を示し
これは光学純度98.4％に相当する。Further, 105 g of the crystal of the complex was dispersed in 200 ml of water, and 25% caustic soda aqueous solution was gradually added thereto to decompose the complex, and at the same time, L-mandelic acid was dissolved as its sodium salt. This was passed to remove L-phenylalanine, and the solution was acid-deposited with sulfuric acid to obtain L-mandelic acid as crystals. The yield after drying was 37 g. The optical rotation of the obtained L-mandelic acid was ▲ [α] 20 D ▼ = + 153.5 ° (C = 2, water), which corresponds to an optical purity of 98.4%.
更に前記においてＬ−マンデル酸・Ｌ−フエニルアラニ
ンの複合体を分離した後の分割液を硫酸で強酸性とし
Ｄ−マンデル酸の種晶を微量加えて30℃迄冷却した。Further, the separated liquid after separating the complex of L-mandelic acid / L-phenylalanine in the above was made strongly acidic with sulfuric acid, and a small amount of seed crystals of D-mandelic acid were added and cooled to 30 ° C.
Ｄ−マンデル酸20.5gがえられその旋光度は▲〔α〕20 D
▼＝−151.6゜（Ｃ＝2,水）であった。20.5 g of D-mandelic acid was obtained and its optical rotation was ▲ [α] 20 D
▼ = -151.6 ° (C = 2, water).
実施例２ 水150ml、DMF 45ml、スルフアミン酸22.0g、カ性ソー
ダ11.5gを加え、ここにＬ−フエニルアラニン37.46g、D
L−マンデル酸60gを加え83℃に昇温して溶解させた。こ
れを冷却し、73℃で、Ｌ−マンデル酸・Ｌ−フエニルア
ラニン複合体の微粉砕結晶0.13gを種晶として添加し
た。３時間で40℃まで冷却し析出した結晶を別した。
結晶を水洗し、乾燥した。Ｌ−マンデル酸・Ｌ−フエニ
ルアラニン複合体52gが得られた。Example 2 150 ml of water, 45 ml of DMF, 22.0 g of sulfamic acid and 11.5 g of caustic soda were added, and L-phenylalanine 37.46 g, D
60 g of L-mandelic acid was added and the temperature was raised to 83 ° C. to dissolve it. This was cooled, and at 73 ° C., 0.13 g of finely pulverized crystal of L-mandelic acid / L-phenylalanine complex was added as a seed crystal. After cooling to 40 ° C. for 3 hours, the precipitated crystal was separated.
The crystals were washed with water and dried. 52 g of L-mandelic acid / L-phenylalanine complex was obtained.
これを実施例１に準じてカ性ソーダを用いて分解し、1
4.3gのＬ−マンデル酸を得た。旋光度は▲〔α〕20 D▼
＝＋152.6゜（Ｃ＝2,水）を示し、これは光学純度97.8
％に相当する。This was decomposed using caustic soda according to Example 1, and 1
4.3 g of L-mandelic acid was obtained. Optical rotation is ▲ [α] 20 D ▼
= + 152.6 ° (C = 2, water), which has an optical purity of 97.8
Equivalent to%.
実施例３ 水450ml、芒硝10.8g、95％硫酸29.5gを加え、重硫酸ソ
ーダを生成させた。ここに、Ｌ−フエニルアラニン102
g、光学純度12.5％のDL−体含有のLM−マンデル酸180g
を仕込んだ。後は実施例１に準じた操作を実施し135.2g
の分割結晶を得た。その１部をとり実施例１と同じ様
に、陽イオン交換樹脂を用い複合体を分解した。得られ
たＬ−マンデル酸の旋光度は、▲〔α〕20 D▼＝＋129.9
゜（Ｃ＝2,水）であり、これは、光学純度83.3％に相当
する。Example 3 450 ml of water, 10.8 g of sodium sulfate and 29.5 g of 95% sulfuric acid were added to produce sodium bisulfate. Here, L-phenylalanine 102
180 g of LM-mandelic acid containing DL-form with optical purity of 12.5%
Was charged. After that, carry out the operation according to Example 1 to obtain 135.2 g.
To obtain divided crystals. A part of the mixture was taken and decomposed in the same manner as in Example 1 using a cation exchange resin. The optical rotation of the obtained L-mandelic acid is ▲ [α] 20 D ▼ = + 129.9
(C = 2, water), which corresponds to an optical purity of 83.3%.
残りの複合体を実施例１の方法に準じて40gのＬ−マン
デル酸をえた。According to the method of Example 1, 40 g of L-mandelic acid was obtained from the remaining complex.
実施例４ 実施例１においてＬ−フエニルアラニンの代わりにＤ−
フエニルアラニンを用いる他は実施例１とほぼ同様の操
作によつてＤ−マンデル酸37.7g、Ｌ−マンデル酸1.8g
を得た。旋光度は各各▲〔α〕20 D▼＝−152.7゜（Ｃ＝
2,水）、▲〔α〕20 D▼＝＋151.5゜（Ｃ＝2,水）であつ
た。Example 4 Instead of L-phenylalanine in Example 1, D-
By substantially the same procedure as in Example 1 except that phenylalanine was used, 37.7 g of D-mandelic acid and 1.8 g of L-mandelic acid were used.
Got The optical rotation is ▲ [α] 20 D ▼ = -152.7 ° (C =
2, water), ▲ [α] 20 D ▼ = + 151.5 ° (C = 2, water).
比較例 日本化学雑誌92巻113頁（1971年）に記載され方法にな
らつて次の試験を行つた。Comparative Example The following tests were conducted according to the method described in Vol. 92, page 113, Japan Chemistry Journal (1971).
DL−マンデル酸20g、Ｌ−フエニルアラニンを13g、300m
lフラスコに取り、水を140ml加えて昇温した。80℃で溶
解させた。（これ以上Ｌ−フエニルアラニンを添加する
と、80〜85℃で完溶させる事ができなかつた。） 溶液を徐々に冷却し、76℃にてＬ−フエニルアラニン・
Ｌ−マンデル酸複合体の種晶を添加した。更に冷却し35
℃にて析出している結晶を別した。複合体の収量は、
18.8gであり、その１部をとつて陽イオン交換樹脂を用
い複合体を分解して得たＬ−マンデル酸は▲〔α〕20 D
▼＝＋88.8゜（Ｃ＝2,水）であり、光学純度は56.9％で
あつた。DL-mandelic acid 20g, L-phenylalanine 13g, 300m
The mixture was placed in a 1-flask, 140 ml of water was added, and the temperature was raised. Melted at 80 ° C. (Addition of more L-phenylalanine did not allow complete dissolution at 80-85 ° C.) The solution was gradually cooled and L-phenylalanine /
Seed crystals of L-mandelic acid complex were added. Cool further 35
Crystals precipitated at ℃ were separated. The yield of the complex is
18.8 g, L-mandelic acid obtained by decomposing the complex with a cation-exchange resin after removing 1 part is ▲ [α] 20 D
▼ = + 88.8 ° (C = 2, water) and the optical purity was 56.9%.
更に実施例１に準じてＬ−マンデル酸を取り出したとこ
ろ3.2gのＬ−マンデル酸が得られた。Further, when L-mandelic acid was taken out according to Example 1, 3.2 g of L-mandelic acid was obtained.
「発明の効果」 DL−マンデル酸と光学活性フエニルアラニンとの複合体
を光学分割し次いで分解して光学活性マンデル酸を得る
にあたつて光学活性マンデル酸の使用溶媒の容積当りの
収量を大幅に向上させることが出来るようになつた。"Effect of the invention" When a complex of DL-mandelic acid and optically active phenylalanine is optically resolved and then decomposed to obtain optically active mandelic acid, the yield of the optically active mandelic acid per volume of the solvent used is determined. It has become possible to greatly improve it.
Claims (1)
値が0.9〜３の範囲にある酸性物質の存在下、水又は水
と他の混合溶媒中でDL−マンデル酸と光学活性なフエニ
ルアラニンの複合体を光学分割しえられた光学活性マン
デル酸と光学活性フエニルアラニンの複合体から該光学
活性フエニルアラニンを除去することを特徴とする光学
活性マンデル酸の製法。1. An acid dissociation index (pKa) in water at room temperature.
Optically active mandelic acid obtained by optical resolution of a complex of DL-mandelic acid and optically active phenylalanine in water or other mixed solvent of water in the presence of an acidic substance having a value in the range of 0.9 to 3. A method for producing an optically active mandelic acid, which comprises removing the optically active phenylalanine from a complex of the optically active phenylalanine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59234180A JPH0665657B2 (en) | 1984-11-08 | 1984-11-08 | Production of optically active mandelic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59234180A JPH0665657B2 (en) | 1984-11-08 | 1984-11-08 | Production of optically active mandelic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61115052A JPS61115052A (en) | 1986-06-02 |
| JPH0665657B2 true JPH0665657B2 (en) | 1994-08-24 |
Family
ID=16966924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59234180A Expired - Fee Related JPH0665657B2 (en) | 1984-11-08 | 1984-11-08 | Production of optically active mandelic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0665657B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ298847B6 (en) * | 1997-09-11 | 2008-02-27 | Pharmacia & Upjohn Company | A method for producing a protease inhibitor |
| HU230004B1 (en) | 2001-06-21 | 2015-04-28 | Sanofi Aventis | Resolution process for (r)-(-)-2-hydroxy-2-(2-chlorophenyl)-acetic acid |
| JP5112658B2 (en) * | 2006-08-11 | 2013-01-09 | 三菱レイヨン株式会社 | Method for producing α-hydroxycarboxylic acid |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59181244A (en) * | 1983-03-29 | 1984-10-15 | Yamakawa Yakuhin Kogyo Kk | Optical resolution of dl-phenylalanine |
-
1984
- 1984-11-08 JP JP59234180A patent/JPH0665657B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61115052A (en) | 1986-06-02 |
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