JP2014172856A - Method for producing optically active tetrahydrofuran-2-carboxylic acid - Google Patents
Method for producing optically active tetrahydrofuran-2-carboxylic acid Download PDFInfo
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- JP2014172856A JP2014172856A JP2013046400A JP2013046400A JP2014172856A JP 2014172856 A JP2014172856 A JP 2014172856A JP 2013046400 A JP2013046400 A JP 2013046400A JP 2013046400 A JP2013046400 A JP 2013046400A JP 2014172856 A JP2014172856 A JP 2014172856A
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- tetrahydrofuran
- carboxylic acid
- optically active
- purity
- aromatic amine
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 13
- UJJLJRQIPMGXEZ-UHFFFAOYSA-N tetrahydro-2-furoic acid Chemical compound OC(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-N 0.000 title abstract description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000002904 solvent Substances 0.000 claims abstract description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 27
- UJJLJRQIPMGXEZ-BYPYZUCNSA-N (2s)-oxolane-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCO1 UJJLJRQIPMGXEZ-BYPYZUCNSA-N 0.000 claims abstract description 23
- 150000004982 aromatic amines Chemical class 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 11
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 11
- 150000002430 hydrocarbons Chemical class 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 9
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- UJJLJRQIPMGXEZ-SCSAIBSYSA-N tetrahydrofuran-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCCO1 UJJLJRQIPMGXEZ-SCSAIBSYSA-N 0.000 claims description 19
- 238000000605 extraction Methods 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- -1 aromatic amine salt Chemical class 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 abstract description 26
- 150000003839 salts Chemical class 0.000 abstract description 12
- 239000002253 acid Substances 0.000 abstract description 3
- 239000004210 ether based solvent Substances 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000005406 washing Methods 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 238000004821 distillation Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 150000003939 benzylamines Chemical class 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000010409 thin film Substances 0.000 description 3
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 238000005882 aldol condensation reaction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- SOZMSEPDYJGBEK-ZCFIWIBFSA-N (1r)-1-(4-bromophenyl)ethanamine Chemical compound C[C@@H](N)C1=CC=C(Br)C=C1 SOZMSEPDYJGBEK-ZCFIWIBFSA-N 0.000 description 1
- PINPOEWMCLFRRB-ZCFIWIBFSA-N (1r)-1-(4-chlorophenyl)ethanamine Chemical compound C[C@@H](N)C1=CC=C(Cl)C=C1 PINPOEWMCLFRRB-ZCFIWIBFSA-N 0.000 description 1
- QGCLEUGNYRXBMZ-ZCFIWIBFSA-N (1r)-1-(4-fluorophenyl)ethanamine Chemical compound C[C@@H](N)C1=CC=C(F)C=C1 QGCLEUGNYRXBMZ-ZCFIWIBFSA-N 0.000 description 1
- HLCLTOJXMUXWQW-ZCFIWIBFSA-N (1r)-1-(4-iodophenyl)ethanamine Chemical compound C[C@@H](N)C1=CC=C(I)C=C1 HLCLTOJXMUXWQW-ZCFIWIBFSA-N 0.000 description 1
- SOZMSEPDYJGBEK-LURJTMIESA-N (1s)-1-(4-bromophenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(Br)C=C1 SOZMSEPDYJGBEK-LURJTMIESA-N 0.000 description 1
- PINPOEWMCLFRRB-LURJTMIESA-N (1s)-1-(4-chlorophenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(Cl)C=C1 PINPOEWMCLFRRB-LURJTMIESA-N 0.000 description 1
- QGCLEUGNYRXBMZ-LURJTMIESA-N (1s)-1-(4-fluorophenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(F)C=C1 QGCLEUGNYRXBMZ-LURJTMIESA-N 0.000 description 1
- HLCLTOJXMUXWQW-LURJTMIESA-N (1s)-1-(4-iodophenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(I)C=C1 HLCLTOJXMUXWQW-LURJTMIESA-N 0.000 description 1
- XJEHTASYOBAEDB-VOTSOKGWSA-N (e)-5-methylhept-4-en-3-one Chemical compound CC\C(C)=C\C(=O)CC XJEHTASYOBAEDB-VOTSOKGWSA-N 0.000 description 1
- WCGMLWCUUJVXJQ-QPJJXVBHSA-N (e)-5-methylhept-5-en-3-one Chemical compound CCC(=O)C\C(C)=C\C WCGMLWCUUJVXJQ-QPJJXVBHSA-N 0.000 description 1
- OYLCUJRJCUXQBQ-UHFFFAOYSA-N 1-hepten-3-one Chemical compound CCCCC(=O)C=C OYLCUJRJCUXQBQ-UHFFFAOYSA-N 0.000 description 1
- AAUHUDBDDBJONC-UHFFFAOYSA-N 3-methylhept-3-ene Chemical compound CCCC=C(C)CC AAUHUDBDDBJONC-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
Abstract
Description
本発明は医薬中間体原料として重要な光学活性テトラヒドロフラン−２−カルボン酸の工業的製造方法に関するものである。 The present invention relates to an industrial process for producing optically active tetrahydrofuran-2-carboxylic acid which is important as a raw material for pharmaceutical intermediates.
光学活性テトラヒドロフラン−２−カルボン酸は、医薬等産業上有用な化合物として知られており、例えば、β−ラクタム抗生物質の中間体原料として使用されていることが報告されている（特許文献１参照）。 Optically active tetrahydrofuran-2-carboxylic acid is known as an industrially useful compound such as pharmaceuticals, and for example, it has been reported that it is used as an intermediate material for β-lactam antibiotics (see Patent Document 1). ).
光学活性テトラヒドロフラン−２−カルボン酸を製造する方法としては、例えば、
（１）ラセミ体のテトラヒドロフラン−２−カルボン酸を光学活性芳香族アミンまたは光学活性アミノ酸アミドを用いて光学分割して光学活性テトラヒドロフラン−２−カルボン酸を製造する方法（特許文献２参照）、
（２）ラセミ体のテトラヒドロフラン−２−カルボン酸を（Ｒ）−フェニルエチルアミンで光学分割して（Ｓ）−テトラヒドロフラン−２−カルボン酸を製造する方法（特許文献３参照）、
（３）低純度の光学活性を有する（Ｒ）−テトラヒドロフラン−２−カルボン酸をアキラルアミンであるジシクロヘキシルアミンを用いて光学精製して高純度の光学活性を有するテトラヒドロフラン−２−カルボン酸を製造する方法（特許文献４参照）などが知られている。
As a method for producing optically active tetrahydrofuran-2-carboxylic acid, for example,
(1) A method for producing optically active tetrahydrofuran-2-carboxylic acid by optical resolution of racemic tetrahydrofuran-2-carboxylic acid using optically active aromatic amine or optically active amino acid amide (see Patent Document 2),
(2) A method of producing (S) -tetrahydrofuran-2-carboxylic acid by optical resolution of racemic tetrahydrofuran-2-carboxylic acid with (R) -phenylethylamine (see Patent Document 3),
(3) (R) -tetrahydrofuran-2-carboxylic acid having low purity optical activity is optically purified using dicyclohexylamine which is an achiral amine to produce tetrahydrofuran-2-carboxylic acid having high purity optical activity. A method (see Patent Document 4) is known.
しかしながら、上記（１）の方法は、高価な光学分割剤を使用している点、その光学分割剤が不安定なため、回収利用時に光学純度低下を避けるのに煩雑な精製工程を必要とする点、光学分割後に解塩処理し、目的物を抽出する際、環境負荷の大きいジクロロメタンを使用する点、また上記（２）の方法は、工程中に光学分割剤である（Ｒ）−フェニルエチルアミンを由来とする不純物としてアセトフェノンを副生し、これが製品中に残存してしまう点、また上記（３）の方法は、高価な光学精製剤を使用しているにもかかわらず、光学精製工程の収率が非常に低い点、光学分割後に解塩処理し、目的物を抽出する際に使用するメチルエチルケトン由来で蒸留でも除去しきれない％オーダーの不純物が副生してしまう点とそれぞれ問題を有している。 However, the method (1) uses an expensive optical resolving agent, and the optical resolving agent is unstable, so that a complicated purification step is required to avoid a decrease in optical purity during recovery. On the other hand, when extracting a target substance by performing salt removal after optical resolution, dichloromethane having a large environmental load is used, and the method of (2) described above is (R) -phenylethylamine which is an optical resolution agent in the process. As a result, acetophenone is by-produced as an impurity derived from the above and remains in the product, and the method (3) described above is an optical purification step in spite of using an expensive optical purification agent. The yield is very low, and there is a problem that impurities on the order of%, which are derived from methyl ethyl ketone used for extracting the target product after salt separation after optical resolution and cannot be removed even by distillation, are by-produced. Shi There.
光学活性テトラヒドロフラン−２−カルボン酸を医薬原料として用いる場合、高純度の光学活性を有することが強く求められている。高い生産性で効率的な高光学活性テトラヒドロフラン−２−カルボン酸の製造法の創出が望まれてきた。 When optically active tetrahydrofuran-2-carboxylic acid is used as a pharmaceutical raw material, it is strongly required to have high purity optical activity. It has been desired to create a process for producing highly optically active tetrahydrofuran-2-carboxylic acid with high productivity and efficiency.
本発明の目的は、医薬原料として重要な高光学活性テトラヒドロフラン−２−カルボン酸を、安価で入手容易な原料を使用して工業的に適した製造方法を提供することを課題とする。 An object of the present invention is to provide an industrially suitable production method for highly optically active tetrahydrofuran-2-carboxylic acid, which is important as a pharmaceutical raw material, using raw materials that are inexpensive and readily available.
本発明者等は、前記課題を解決するために鋭意検討を重ねた結果、本発明を見出すに至った。即ち、本発明は、次の３工程、
（第一工程）一般式
As a result of intensive studies in order to solve the above problems, the present inventors have found the present invention. That is, the present invention includes the following three steps:
(First step) General formula
（式中、Ｒ１は水素原子あるいはハロゲノ基を示し、Ｒ２は水素原子あるいはメチル基を示し、＊は当該炭素原子が光学活性中心であることを示す）で表される（Ｒ）−または（Ｓ）−テトラヒドロフラン−２−カルボン酸と芳香族アミンとの塩を水中にて無機金属塩基で塩交換したのち、炭化水素系溶媒及び／またはエーテル系溶媒で芳香族アミンを除去して、（Ｒ）−または（Ｓ）−テトラヒドロフラン−２−カルボン酸を含有する水層を得る工程、
（第二工程）第一工程で得た水層に無機酸を添加してｐＨを酸性にしてから、テトラヒドロフランで抽出する工程、
（第三工程）第二工程で得た抽出液を濃縮、及び蒸留する工程、
を含む、一般式
(Wherein R1 represents a hydrogen atom or a halogeno group, R2 represents a hydrogen atom or a methyl group, and * represents that the carbon atom is an optically active center) (R)-or (S ) -Tetrahydrofuran-2-carboxylic acid and aromatic amine salt are exchanged with an inorganic metal base in water, and then the aromatic amine is removed with a hydrocarbon solvent and / or an ether solvent, and (R) Obtaining an aqueous layer containing-or (S) -tetrahydrofuran-2-carboxylic acid;
(Second step) A step of adding an inorganic acid to the aqueous layer obtained in the first step to make the pH acidic, followed by extraction with tetrahydrofuran,
(Third step) Concentrating and distilling the extract obtained in the second step,
Including general formula
（式中、＊は当該炭素原子が光学活性中心であることを示す）で表される高純度（Ｒ）−または（Ｓ）−テトラヒドロフラン−２−カルボン酸の製造方法である。 (Wherein, * indicates that the carbon atom is an optically active center) is a method for producing high purity (R)-or (S) -tetrahydrofuran-2-carboxylic acid.
本発明により、医薬原料として重要な高純度テトラヒドロフラン−２−カルボン酸を安価で入手容易な原料から、高い生産性で効率的な工業的に適した方法で製造することが可能である。 According to the present invention, high-purity tetrahydrofuran-2-carboxylic acid important as a pharmaceutical raw material can be produced from an inexpensive and readily available raw material by a highly productive and efficient industrially suitable method.
本発明により製造された光学活性テトラヒドロフラン−２−カルボン酸は、化学純度や光学純度が高く、医薬原料として用いることができる。 The optically active tetrahydrofuran-2-carboxylic acid produced according to the present invention has high chemical purity and optical purity and can be used as a pharmaceutical raw material.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明は、次の３工程、
（第一工程）一般式
The present invention includes the following three steps:
(First step) General formula
（式中、Ｒ１は水素原子あるいはハロゲノ基を示し、Ｒ２は水素原子あるいはメチル基を示し、＊は当該炭素原子が光学活性中心であることを示す）で表される（Ｒ）−または（Ｓ）−テトラヒドロフラン−２−カルボン酸と芳香族アミンとの塩を水中にて無機金属塩基で塩交換したのち、炭化水素系溶媒及び／またはエーテル系溶媒で芳香族アミンを除去して、（Ｒ）−または（Ｓ）−テトラヒドロフラン−２−カルボン酸を含有する水層を得る工程、
（第二工程）第一工程で得た水層に無機酸を添加してｐＨを酸性にしてから、テトラヒドロフランで抽出する工程、
（第三工程）第一工程で得た抽出液を濃縮、及び蒸留する工程、
を含む、一般式
(Wherein R1 represents a hydrogen atom or a halogeno group, R2 represents a hydrogen atom or a methyl group, and * represents that the carbon atom is an optically active center) (R)-or (S ) -Tetrahydrofuran-2-carboxylic acid and aromatic amine salt are exchanged with an inorganic metal base in water, and then the aromatic amine is removed with a hydrocarbon solvent and / or an ether solvent, and (R) Obtaining an aqueous layer containing-or (S) -tetrahydrofuran-2-carboxylic acid;
(Second step) A step of adding an inorganic acid to the aqueous layer obtained in the first step to make the pH acidic, followed by extraction with tetrahydrofuran,
(Third step) A step of concentrating and distilling the extract obtained in the first step,
Including general formula
（式中、＊は当該炭素原子が光学活性中心であることを示す）で表される高純度（Ｒ）−または（Ｓ）−テトラヒドロフラン−２−カルボン酸の製造方法である。 (Wherein, * indicates that the carbon atom is an optically active center) is a method for producing high purity (R)-or (S) -tetrahydrofuran-2-carboxylic acid.
第一工程は、一般式 The first step is a general formula
表される光学活性テトラヒドロフラン−２−カルボン酸と芳香族アミンとの塩を使用する。Ｒ１は水素原子あるいはハロゲノ基を示し、好ましくは、フルオロ基、クロロ基、ブロモ基、ヨード基、より好ましくは、クロロ基、ブロモ基である。Ｒ２は水素原子あるいはメチル基を示し、＊は当該炭素原子が光学活性中心であることを示す。 The represented salt of optically active tetrahydrofuran-2-carboxylic acid and aromatic amine is used. R1 represents a hydrogen atom or a halogeno group, preferably a fluoro group, a chloro group, a bromo group or an iodo group, more preferably a chloro group or a bromo group. R2 represents a hydrogen atom or a methyl group, and * represents that the carbon atom is an optically active center.
本発明で使用される芳香族アミンは、例えば、ベンジルアミン、（Ｒ）−（＋）−１−フェニルエチルアミン、（Ｓ）−（−）−１−フェニルエチルアミン、（Ｒ）−（＋）−１−（４−フルオロフェニル）エチルアミン、（Ｓ）−（−）−１−（４−フルオロフェニル）エチルアミン、（Ｒ）−（＋）−１−（４−クロロフェニル）エチルアミン、（Ｓ）−（−）−１−（４−クロロロフェニル）エチルアミン、（Ｒ）−（＋）−１−（４−ブロモフェニル）エチルアミン、（Ｓ）−（−）−１−（４−ブロモフェニル）エチルアミン、（Ｒ）−（＋）−１−（４−ヨードフェニル）エチルアミン、（Ｓ）−（−）−１−（４−ヨードフェニル）エチルアミンなどが挙げられるが、好ましくは、ベンジルアミン、（Ｒ）−（＋）−１−フェニルエチルアミン、（Ｓ）−（−）−１−フェニルエチルアミン、さらに好ましくはベンジルアミンである。 The aromatic amine used in the present invention is, for example, benzylamine, (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine, (R)-(+) — 1- (4-fluorophenyl) ethylamine, (S)-(−)-1- (4-fluorophenyl) ethylamine, (R)-(+)-1- (4-chlorophenyl) ethylamine, (S)-( -)-1- (4-chlorophenyl) ethylamine, (R)-(+)-1- (4-bromophenyl) ethylamine, (S)-(-)-1- (4-bromophenyl) ethylamine, (R)-(+)-1- (4-iodophenyl) ethylamine, (S)-(−)-1- (4-iodophenyl) ethylamine, and the like can be mentioned, and benzylamine, (R) is preferable. -(+)-1-Fe Ruechiruamin, (S) - (-) - 1- phenylethylamine, further preferably benzylamine.
第一工程で使用する無機金属塩基は、例えば、水酸化ナトリウム、水酸化カリウム等の金属水酸化物、炭酸水素ナトリウム、炭酸水素カリウム等の金属炭酸水素塩、炭酸ナトリウム、炭酸カリウム等の金属炭酸塩等が挙げられるが、好ましくは水酸化ナトリウム、水酸化カリウムである。これら無機金属塩基は単独で用いてもよいし、２種以上を混合して用いてもよい。無機金属塩基の使用量は、光学活性テトラヒドロフラン−２−カルボン酸に対して、好ましくは０．８〜１．２モル倍、さらに好ましくは１．０〜１．１モル倍である。 Examples of the inorganic metal base used in the first step include metal hydroxides such as sodium hydroxide and potassium hydroxide, metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and metal carbonates such as sodium carbonate and potassium carbonate. Examples of the salt include sodium hydroxide and potassium hydroxide. These inorganic metal bases may be used alone or in combination of two or more. The amount of the inorganic metal base to be used is preferably 0.8 to 1.2 mol times, more preferably 1.0 to 1.1 mol times with respect to the optically active tetrahydrofuran-2-carboxylic acid.
第一工程では、炭化水素系溶媒及び／またはエーテル系溶媒で芳香族アミンを除去する。炭化水素系溶媒及び／またはエーテル系溶媒により、芳香族アミンを洗浄除去することが好ましい。 In the first step, the aromatic amine is removed with a hydrocarbon solvent and / or an ether solvent. The aromatic amine is preferably removed by washing with a hydrocarbon solvent and / or an ether solvent.
第一工程で使用する炭化水素系溶媒は、例えば、トルエン、ベンゼン、ｐ−キシレン、ヘキサン、ヘプタン等が挙げられるが、芳香族アミンの除去効率が高い点からトルエン、ｐ−キシレン等の芳香族炭化水素系溶媒が好ましく、より好ましくはトルエンである。炭化水素系溶媒の使用量や洗浄回数は特に制限されない。 Examples of the hydrocarbon solvent used in the first step include toluene, benzene, p-xylene, hexane, heptane and the like, but aromatics such as toluene and p-xylene are used because of high removal efficiency of aromatic amines. A hydrocarbon solvent is preferable, and toluene is more preferable. The amount of hydrocarbon solvent used and the number of washings are not particularly limited.
第一工程で使用するエーテル系溶媒は、例えば、ジエチルエーテル、テトラヒドロフラン、メチルｔｅｒｔ−ブチルエーテル、シクロペンチルメチルエーテル等が挙げられるが、芳香族アミンの除去効率が高い点から、テトラヒドロフラン、メチルｔｅｒｔ−ブチルエーテルが好ましく、より好ましくはテトラヒドロフランである。エーテル系溶媒の使用量や洗浄回数は特に制限されない。 Examples of the ether solvent used in the first step include diethyl ether, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, etc. From the viewpoint of high removal efficiency of aromatic amines, tetrahydrofuran and methyl tert-butyl ether are used. Tetrahydrofuran is more preferable. The amount of ether solvent used and the number of washings are not particularly limited.
本発明の第一工程では、炭化水素系溶媒中の微量不純物を洗浄除去することを目的として、炭化水素系溶媒での洗浄後に、エーテル系溶媒で洗浄することもできる。エーテル系溶媒としては、例えば、テトラヒドロフラン、メチルｔｅｒｔ−ブチルエーテル、シクロペンチルメチルエーテル等が挙げられるが、好ましくはテトラヒドロフランである。エーテル系溶媒の使用量や洗浄回数は特に制限されない。 In the first step of the present invention, for the purpose of washing and removing trace impurities in the hydrocarbon solvent, it can be washed with an ether solvent after washing with the hydrocarbon solvent. Examples of ether solvents include tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, and the like, with tetrahydrofuran being preferred. The amount of ether solvent used and the number of washings are not particularly limited.
塩交換の温度は、好ましくは、２０〜４０℃であり、反応時間は、好ましくは、１時間以上である。 The salt exchange temperature is preferably 20 to 40 ° C., and the reaction time is preferably 1 hour or more.
第一工程における芳香族アミンの除去率は、好ましくは、９９％以上であり、より好ましくは、９９．５％以上である。 The aromatic amine removal rate in the first step is preferably 99% or more, and more preferably 99.5% or more.
第二工程では、第一工程で得た水層に無機酸を添加してｐＨを酸性にしてから、テトラヒドロフランで抽出する。第二工程は、第一工程で得た水層に無機酸を添加し、解塩してからテトラヒドロフランで光学活性テトラヒドロフラン−２−カルボン酸を抽出することを主たる目的としている。 In the second step, an inorganic acid is added to the aqueous layer obtained in the first step to make the pH acidic, followed by extraction with tetrahydrofuran. The main purpose of the second step is to add an inorganic acid to the aqueous layer obtained in the first step, salt the solution, and then extract the optically active tetrahydrofuran-2-carboxylic acid with tetrahydrofuran.
第二工程で使用する無機酸は、例えば、硫酸、塩酸、硝酸、リン酸等が挙げられるが、好ましくは硫酸である。これら無機酸は単独で用いてもよいし、２種以上を混合して用いてもよい。無機酸の使用量は、光学活性テトラヒドロフラン−２−カルボン酸に対して、好ましくは０．８〜１．２モル倍、さらに好ましくは０．９〜１．１モル倍である。 Examples of the inorganic acid used in the second step include sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid, and sulfuric acid is preferable. These inorganic acids may be used alone or in combination of two or more. The amount of the inorganic acid to be used is preferably 0.8 to 1.2 mol times, more preferably 0.9 to 1.1 mol times with respect to the optically active tetrahydrofuran-2-carboxylic acid.
第二工程におけるｐＨは、好ましくは、１．８〜２．５であり、より好ましくは、１．９〜２．１である。 The pH in the second step is preferably 1.8 to 2.5, more preferably 1.9 to 2.1.
第二工程で使用する抽出溶媒は、テトラヒドロフランである。公知例（特開平９−１４３１０１）ではジクロロメタンを使用しているが、本溶媒は環境への負荷が大きいため工業的に適した溶媒とは言えない。また、公知例（特開２００２−１７１９９４）ではメチルエチルケトンを使用しているが、本溶媒は濃縮中に分子間アルドール縮合反応が併発し、副生するメチルエチルケトンの二量体（５−メチル−５−ヘプテン−３−オン、及び５−メチル−４−ヘプテン−３−オン）が蒸留操作でも除去されず、不純物として製品中に１〜２％程度残存してしまう。さらに、本発明の特徴であるベンジルアミンを使用する場合、ベンジルアミン由来の不純物であるベンズアルデヒドが濃縮中にメチルエチルケトンとＣｌａｉｓｅｎ−Ｓｃｈｍｉｄｔ縮合反応が併発し、縮合体が副生してしまうおそれがあるので、本発明で使用する抽出溶媒としては適していない。一方、テトラヒドロフランを使用した場合、製品中に残存するような不純物の副生は見られず、高純度の光学活性テトラヒドロフラン−２−カルボン酸の製造に適している。 The extraction solvent used in the second step is tetrahydrofuran. In a known example (Japanese Patent Laid-Open No. 9-143101), dichloromethane is used, but this solvent is not an industrially suitable solvent because it has a large environmental load. In addition, methyl ethyl ketone is used in the publicly known example (Japanese Patent Laid-Open No. 2002-171994), but this solvent undergoes an intermolecular aldol condensation reaction during concentration, resulting in a by-product methyl ethyl ketone dimer (5-methyl-5-5). Hepten-3-one and 5-methyl-4-hepten-3-one) are not removed by distillation operation, and remain in the product as about 1 to 2% as impurities. Furthermore, when benzylamine, which is a feature of the present invention, is used, benzaldehyde, which is an impurity derived from benzylamine, may concomitantly generate methyl ethyl ketone and Claisen-Schmidt condensation reaction during concentration, resulting in the formation of a condensate. The extraction solvent used in the present invention is not suitable. On the other hand, when tetrahydrofuran is used, no by-product of impurities remaining in the product is observed, which is suitable for the production of high-purity optically active tetrahydrofuran-2-carboxylic acid.
第二工程で使用するテトラヒドロフランの使用量は、光学活性テトラヒドロフラン−２−カルボン酸に対して０．５〜２．０重量倍あり、より好ましくは、０．５〜１．０重量倍である。 The amount of tetrahydrofuran used in the second step is 0.5 to 2.0 times by weight with respect to the optically active tetrahydrofuran-2-carboxylic acid, and more preferably 0.5 to 1.0 times by weight.
第三工程では、第二工程で得た抽出液を濃縮、及び蒸留する。第三工程は、好ましくは、第二工程で得た抽出液を濃縮してテトラヒドロフランを留去し、さらに蒸留することで高純度の光学活性を有するテトラヒドロフラン−２−カルボン酸を得る。第三工程により得られたテトラヒドロフラン−２−カルボン酸は、高純度であり、そのまま、製品化することができる。 In the third step, the extract obtained in the second step is concentrated and distilled. In the third step, preferably, the extract obtained in the second step is concentrated to distill off the tetrahydrofuran, and further distilled to obtain tetrahydrofuran-2-carboxylic acid having high purity optical activity. Tetrahydrofuran-2-carboxylic acid obtained by the third step has high purity and can be commercialized as it is.
蒸留の方法は、熱による光学純度の低下を抑制するため、薄膜蒸留が好ましく用いられる。蒸留温度は、低温の方が好ましく、通常、減圧下で実施される。 As the distillation method, thin film distillation is preferably used in order to suppress a decrease in optical purity due to heat. The distillation temperature is preferably lower, and is usually carried out under reduced pressure.
第三工程により得られたテトラヒドロフラン−２−カルボン酸の化学純度は、通例、９９．０％以上であり、好ましくは、９９．２〜１００％である。また、第三工程により得られたテトラヒドロフラン−２−カルボン酸の光学純度は、通例、９９．０％ｅ．ｅ以上であり、好ましくは、９９．２〜１００％ｅ．ｅである。 The chemical purity of the tetrahydrofuran-2-carboxylic acid obtained by the third step is usually 99.0% or more, preferably 99.2 to 100%. Further, the optical purity of the tetrahydrofuran-2-carboxylic acid obtained in the third step is usually 99.0% e.e. e, preferably 99.2 to 100% e.e. e.
以下実施例により本発明を説明する。 The following examples illustrate the invention.
実施例中の化学純度、光学純度は以下に示す方法で測定した。 The chemical purity and optical purity in the examples were measured by the following methods.
＜化学純度分析法＞
高速液体クロマトグラフィー（ＨＰＬＣ）分析条件
カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ−３ ４．６ｍｍφ×１５０ｍｍ，０．２５μｍ（ＧＬ Ｓｃｉｅｎｃｅｓ）
移動相： Ａ液：２０ｍＭリン酸緩衝液（ｐＨ２．１）、Ｂ液：アセトニトリル
グラジエント：Ａ／Ｂ＝８０／２０（３分）→２５分→５０／５０（１０分）→２分→８０／２０（５分）
流速： １ｍＬ／分
カラム温度：４０℃
検出器：ＵＶ（２３０ｎｍ）
保持時間：３．１分（テトラヒドロフラン−２−カルボン酸） 。
<Chemical purity analysis method>
High-performance liquid chromatography (HPLC) analysis conditions Column: Inertsil ODS-3 4.6 mmφ × 150 mm, 0.25 μm (GL Sciences)
Mobile phase: A solution: 20 mM phosphate buffer (pH 2.1), B solution: acetonitrile Gradient: A / B = 80/20 (3 minutes) → 25 minutes → 50/50 (10 minutes) → 2 minutes → 80 / 20 (5 minutes)
Flow rate: 1 mL / min Column temperature: 40 ° C
Detector: UV (230 nm)
Retention time: 3.1 minutes (tetrahydrofuran-2-carboxylic acid).
＜光学純度分析法＞
高速液体クロマトグラフィー（ＨＰＬＣ）分析条件
カラム：ＳＵＭＩＣＨＩＲＡＬ ＯＡ−６０００ ４．６ｍｍφ×２５０ｍｍ，５μｍ（住化分析センター）
移動相：２ｍＭ硫酸銅（II）水溶液／アセトニトリル＝９０／１０（ｖ／ｖ）
流速：１．０ｍＬ／分
カラム温度：４０℃
検出器：ＵＶ（２５４ｎｍ）
保持時間：５．４分（（Ｒ）−テトラヒドロフラン−２−カルボン酸）
７．９分（（Ｓ）−テトラヒドロフラン−２−カルボン酸）。
<Optical purity analysis method>
Analysis conditions for high performance liquid chromatography (HPLC) Column: SUMICHILAR OA-6000 4.6 mmφ × 250 mm, 5 μm (Sumitomo Chemical Analysis Center)
Mobile phase: 2 mM copper (II) sulfate aqueous solution / acetonitrile = 90/10 (v / v)
Flow rate: 1.0 mL / min Column temperature: 40 ° C
Detector: UV (254 nm)
Retention time: 5.4 minutes ((R) -tetrahydrofuran-2-carboxylic acid)
7.9 minutes ((S) -tetrahydrofuran-2-carboxylic acid).
参考例１ （Ｒ）−テトラヒドロフラン−２−カルボン酸・ベンジルアミン塩の製造
温度計、コンデンサー及び撹拌機の付いた２Ｌ四つ口フラスコに、（Ｒ）−および（Ｓ）−テトラヒドロフラン−２−カルボン酸の混合物２００ｇ（１．７２モル，９６．２％ｅ．ｅ．（Ｒ））、２−プロパノール７００ｇを加え、６５℃まで昇温した。６０〜７０℃でベンジルアミン２０３ｇ（１．９０モル）を滴下し、完溶後、６５℃まで降温してから種晶を添加し、同温度付近で１時間熟成した。その後、２０℃まで緩やかに冷却し、同温度付近で１時間熟成してから析出結晶をろ過し、減圧乾燥後、（Ｒ）−テトラヒドロフラン−２−カルボン酸・ベンジルアミン塩３３７．２ｇを得た。その塩の光学純度は、９９．５％ｅ．ｅ．であり、仕込みテトラヒドロフラン−２−カルボン酸のＲ体に対する取得塩中のＲ体収率は、８９．６％であった。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δｐｐｍ： ７．４３−７．２７（ｍ，５Ｈ），４．０２（ｍ，１Ｈ），３．８９（ｓ，２Ｈ），３．７５（ｍ，１Ｈ），３．６４（ｍ，１Ｈ），１．９８（ｍ，１Ｈ），１．７３（ｍ，３Ｈ）
１３Ｃ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δｐｐｍ：１７６．４，１３７．１，１２８．４，１２７．７，７８．３，６７．５，４２．９，３０．０，２５．０
ｍ．ｐ．：１３４−１３５℃。
Reference Example 1 Production of (R) -tetrahydrofuran-2-carboxylic acid / benzylamine salt To a 2 L four-necked flask equipped with a thermometer, a condenser and a stirrer, (R)-and (S) -tetrahydrofuran-2-carboxylic acid were added. 200 g of an acid mixture (1.72 mol, 96.2% ee (R)) and 700 g of 2-propanol were added, and the temperature was raised to 65 ° C. At 60 to 70 ° C., 203 g (1.90 mol) of benzylamine was added dropwise. After complete dissolution, the temperature was lowered to 65 ° C., seed crystals were added, and the mixture was aged for 1 hour at around the same temperature. Thereafter, the mixture was slowly cooled to 20 ° C. and aged at around the same temperature for 1 hour, and then the precipitated crystals were filtered and dried under reduced pressure to obtain 337.2 g of (R) -tetrahydrofuran-2-carboxylic acid / benzylamine salt. . The optical purity of the salt is 99.5% e.e. e. The yield of R isomer in the obtained salt relative to the R isomer of the tetrahydrofuran-2-carboxylic acid charged was 89.6%.
1 H-NMR (DMSO-d 6 , 400 MHz) δ ppm: 7.43-7.27 (m, 5H), 4.02 (m, 1H), 3.89 (s, 2H), 3.75 (m , 1H), 3.64 (m, 1H), 1.98 (m, 1H), 1.73 (m, 3H)
13 C-NMR (DMSO-d 6 , 400 MHz) δ ppm: 176.4, 137.1, 128.4, 127.7, 78.3, 67.5, 42.9, 30.0, 25.0
m. p. : 134-135 ° C.
実施例１
（第一工程）
温度計、コンデンサー及び撹拌機の付いた２Ｌ四つ口フラスコに、参考例１で得た（Ｒ）−テトラヒドロフラン−２−カルボン酸・ベンジルアミン塩３３７．２ｇ、水２７２．６ｇ、３２％苛性ソーダ水１９２．５ｇ（１．５４モル）を加え、完溶させた。次いでトルエン１７５ｇを加え、ベンジルアミンをトルエン層側に抽出除去した。ベンジルアミンが除去されたことを確認した後、テトラヒドロフラン１７５ｇを加え、静置後、テトラヒドロフラン層を分液除去し、洗浄後水層６８８．８ｇを得た。
Example 1
(First step)
In a 2 L four-necked flask equipped with a thermometer, a condenser and a stirrer, (R) -tetrahydrofuran-2-carboxylic acid / benzylamine salt 337.2 g obtained in Reference Example 1, water 272.6 g, 32% sodium hydroxide aqueous solution 192.5 g (1.54 mol) was added and completely dissolved. Subsequently, 175 g of toluene was added, and benzylamine was extracted and removed to the toluene layer side. After confirming that benzylamine was removed, 175 g of tetrahydrofuran was added, and after standing, the tetrahydrofuran layer was separated and removed, and 688.8 g of an aqueous layer was obtained after washing.
（第二工程）
温度計、コンデンサー及び撹拌機の付いた２Ｌ四つ口フラスコに、第一工程で得られた洗浄後水層６８８．８ｇを加え、３５℃〜４５℃で９８％硫酸７５．５ｇを滴下し、同温度範囲で１時間熟成してから分液した。水層にさらにテトラヒドロフラン各８７．７ｇを加え、二次、三次抽出をおこなった。抽出率は、８７．７％であった。
(Second step)
To a 2 L four-necked flask equipped with a thermometer, a condenser and a stirrer, 688.8 g of the water layer after washing obtained in the first step was added, and 75.5 g of 98% sulfuric acid was dropped at 35 ° C. to 45 ° C. Liquid separation was carried out after aging for 1 hour in the same temperature range. Further, 87.7 g of each tetrahydrofuran was added to the aqueous layer, followed by secondary and tertiary extraction. The extraction rate was 87.7%.
（第三工程）
温度計、コンデンサー及び撹拌機の付いた２Ｌ四つ口フラスコに、抽出後のテトラヒドロフラン層を合わせた液５７０．８ｇを加え、溶媒を濃縮留去し、析出した無機塩を除くため濾過を実施した。最後に、減圧下、薄膜蒸留（熱媒温度：１３０℃）により（Ｒ）−テトラヒドロフラン−２−カルボン酸１５４．８ｇを得た。化学純度：９９．３％、光学純度：９９．５％ｅ．ｅ．であり、総合収率：７７．４％であった。
(Third process)
To a 2 L four-necked flask equipped with a thermometer, a condenser and a stirrer was added 570.8 g of the combined tetrahydrofuran layer after extraction, the solvent was concentrated and distilled, and filtration was performed to remove the precipitated inorganic salt. . Finally, 154.8 g of (R) -tetrahydrofuran-2-carboxylic acid was obtained by thin film distillation (heating medium temperature: 130 ° C.) under reduced pressure. Chemical purity: 99.3%, optical purity: 99.5% e.e. e. The overall yield was 77.4%.
参考例２ （Ｓ）−テトラヒドロフラン−２−カルボン酸・ベンジルアミン塩の製造
温度計、コンデンサー及び撹拌機の付いた２Ｌ四つ口フラスコに、（Ｒ）−および（Ｓ）−テトラヒドロフラン−２−カルボン酸の混合物２００ｇ（１．７２モル，９５．７％ｅ．ｅ．（Ｓ））、２−プロパノール７００ｇを加え、６５℃まで昇温した。６０〜７０℃でベンジルアミン２０３ｇ（１．９０モル）を滴下し、完溶後、６５℃まで降温してから種晶を添加し、同温度付近で１時間熟成した。その後、２０℃まで緩やかに冷却し、同温度付近で１時間熟成してから析出結晶をろ過し、減圧乾燥後、（Ｓ）−テトラヒドロフラン−２−カルボン酸・ベンジルアミン塩３３２．２ｇを得た。その塩の光学純度は、９９．５％ｅ．ｅ．であり、仕込みテトラヒドロフラン−２−カルボン酸のＳ体に対する取得塩中のＳ体収率は、８８．３％であった。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δｐｐｍ： ７．４３−７．２７（ｍ，５Ｈ），４．０２（ｍ，１Ｈ），３．８９（ｓ，２Ｈ），３．７５（ｍ，１Ｈ），３．６４（ｍ，１Ｈ），１．９８（ｍ，１Ｈ），１．７３（ｍ，３Ｈ）
１３Ｃ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δｐｐｍ：１７６．４，１３７．１，１２８．４，１２７．７，７８．３，６７．５，４２．９，３０．０，２５．０
ｍ．ｐ．：１３４−１３５℃。
Reference Example 2 Production of (S) -tetrahydrofuran-2-carboxylic acid / benzylamine salt A 2 L four-necked flask equipped with a thermometer, a condenser and a stirrer was charged with (R)-and (S) -tetrahydrofuran-2-carboxylic acid. 200 g (1.72 mol, 95.7% ee (S)) of an acid mixture and 700 g of 2-propanol were added, and the temperature was raised to 65 ° C. At 60 to 70 ° C., 203 g (1.90 mol) of benzylamine was added dropwise. After complete dissolution, the temperature was lowered to 65 ° C., seed crystals were added, and the mixture was aged for 1 hour at around the same temperature. Thereafter, the mixture was slowly cooled to 20 ° C. and aged at around the same temperature for 1 hour. The precipitated crystals were filtered and dried under reduced pressure to obtain 332.2 g of (S) -tetrahydrofuran-2-carboxylic acid / benzylamine salt. . The optical purity of the salt is 99.5% e.e. e. The S form yield in the obtained salt relative to the S form of the prepared tetrahydrofuran-2-carboxylic acid was 88.3%.
1 H-NMR (DMSO-d 6 , 400 MHz) δ ppm: 7.43-7.27 (m, 5H), 4.02 (m, 1H), 3.89 (s, 2H), 3.75 (m , 1H), 3.64 (m, 1H), 1.98 (m, 1H), 1.73 (m, 3H)
13 C-NMR (DMSO-d 6 , 400 MHz) δ ppm: 176.4, 137.1, 128.4, 127.7, 78.3, 67.5, 42.9, 30.0, 25.0
m. p. : 134-135 ° C.
実施例２
（第一工程）
温度計、コンデンサー及び撹拌機の付いた２Ｌ四つ口フラスコに、参考例２で得た（Ｓ）−テトラヒドロフラン−２−カルボン酸・ベンジルアミン塩３３２．２ｇ、水２６８．６ｇ、３２％苛性ソーダ水１８９．７ｇ（１．５２モル）を加え、完溶させた。次いでトルエン１７３ｇを加え、ベンジルアミンをトルエン層側に抽出除去した。ベンジルアミンが除去されたことを確認した後、テトラヒドロフラン１７３ｇを加え、静置後、テトラヒドロフラン層を分液除去し、洗浄後水層６７８．７ｇを得た。
Example 2
(First step)
In a 2 L four-necked flask equipped with a thermometer, a condenser and a stirrer, 332.2 g of (S) -tetrahydrofuran-2-carboxylic acid / benzylamine salt obtained in Reference Example 2, 268.6 g of water, 32% caustic soda water 189.7 g (1.52 mol) was added and dissolved completely. Subsequently, 173 g of toluene was added, and benzylamine was extracted and removed to the toluene layer side. After confirming that benzylamine was removed, 173 g of tetrahydrofuran was added, and after standing, the tetrahydrofuran layer was separated and removed to obtain 678.7 g of an aqueous layer after washing.
（第二工程）
温度計、コンデンサー及び撹拌機の付いた２Ｌ四つ口フラスコに、第一工程で得られた洗浄後水層６７８．７ｇを加え、３５℃〜４５℃で９８％硫酸７４．４ｇを滴下し、同温度範囲で１時間熟成してから分液した。水層にさらにテトラヒドロフラン各８６．４ｇを加え、二次、三次抽出をおこなった。抽出率は、８７．７％であった。
(Second step)
To a 2 L four-necked flask equipped with a thermometer, a condenser and a stirrer was added 678.7 g of the aqueous layer after washing obtained in the first step, and 74.4 g of 98% sulfuric acid was added dropwise at 35 to 45 ° C. Liquid separation was carried out after aging for 1 hour in the same temperature range. Further, 86.4 g each of tetrahydrofuran was added to the aqueous layer, followed by secondary and tertiary extraction. The extraction rate was 87.7%.
（第三工程）
温度計、コンデンサー及び撹拌機の付いた２Ｌ四つ口フラスコに、抽出後のテトラヒドロフラン層を合わせた液５１７．５ｇを加え、溶媒を濃縮留去し、析出した無機塩を除くため濾過を実施した。最後に、減圧下、薄膜蒸留（熱媒温度：１３０℃）により（Ｓ）−テトラヒドロフラン−２−カルボン酸１５２．５ｇを得た。化学純度：９９．４％、光学純度：９９．５％ｅ．ｅ．であり、総合収率：７６．３％であった。
(Third process)
To a 2 L four-necked flask equipped with a thermometer, a condenser, and a stirrer, 517.5 g of the combined tetrahydrofuran layer was added, the solvent was concentrated and distilled, and filtration was performed to remove the precipitated inorganic salt. . Finally, 152.5 g of (S) -tetrahydrofuran-2-carboxylic acid was obtained by thin film distillation (heating medium temperature: 130 ° C.) under reduced pressure. Chemical purity: 99.4%, optical purity: 99.5% e.e. e. The overall yield was 76.3%.
実施例３
実施例１の第一工程において、洗浄溶媒をトルエンからｐ−キシレンに変えた以外は実施例１と同様の操作をおこなった。得られた（Ｒ）−テトラヒドロフラン−２−カルボン酸１５３．６ｇは、化学純度：９９．２％、光学純度：９９．５％ｅ．ｅ．であり、総合収率：７６．８％であった。
Example 3
In the first step of Example 1, the same operation as in Example 1 was performed except that the washing solvent was changed from toluene to p-xylene. The obtained (R) -tetrahydrofuran-2-carboxylic acid 153.6 g has a chemical purity of 99.2% and an optical purity of 99.5% e.e. e. The overall yield was 76.8%.
比較例１
実施例１の第三工程において、抽出溶媒をテトラヒドロフランからメチルエチルケトンに変えた以外は実施例１と同様の操作をおこなった。得られた（Ｒ）−テトラヒドロフラン−２−カルボン酸１５５．２ｇは、化学純度：９６．３％（５−メチル−５−ヘプテン−３−オン：１．５％、５−メチル−４−ヘプテン−３−オン：０．５％を含む）、光学純度：９９．５％ｅ．ｅ．であり、総合収率：７７．６％であった。実施例１〜３の場合、化学純度が９９．２％以上であったが、比較例１では、化学純度が９６．３％であり、低かった。
Comparative Example 1
In the third step of Example 1, the same operation as in Example 1 was performed except that the extraction solvent was changed from tetrahydrofuran to methyl ethyl ketone. The obtained (R) -tetrahydrofuran-2-carboxylic acid (155.2 g) had a chemical purity of 96.3% (5-methyl-5-hepten-3-one: 1.5%, 5-methyl-4-heptene). -3-one: 0.5% included), optical purity: 99.5% e.e. e. The overall yield was 77.6%. In Examples 1 to 3, the chemical purity was 99.2% or higher, but in Comparative Example 1, the chemical purity was 96.3%, which was low.
比較例２
実施例１の第二工程において、抽出溶媒をテトラヒドロフランからメチルｔｅｒｔ−ブチルエーテルに変えた。抽出率は、５９．８％であり、低かった。
Comparative Example 2
In the second step of Example 1, the extraction solvent was changed from tetrahydrofuran to methyl tert-butyl ether. The extraction rate was 59.8%, which was low.
比較例３
実施例１の第二工程において、抽出溶媒をテトラヒドロフランからシクロペンチルメチルエーテルに変えた。抽出率は、２７．３％であり、かなり低かった。
Comparative Example 3
In the second step of Example 1, the extraction solvent was changed from tetrahydrofuran to cyclopentyl methyl ether. The extraction rate was 27.3%, which was quite low.
比較例４
実施例１の第二工程において、抽出溶媒をテトラヒドロフランからトルエンに変えた。抽出率は、１．７％であり、著しく低かった。
Comparative Example 4
In the second step of Example 1, the extraction solvent was changed from tetrahydrofuran to toluene. The extraction rate was 1.7%, which was extremely low.
Claims (3)
（第一工程）一般式
（第二工程）第一工程で得た水層に無機酸を添加してｐＨを酸性にしてから、テトラヒドロフランで抽出する工程、
（第三工程）第二工程で得た抽出液を濃縮、及び蒸留する工程、
を含む、一般式
(First step) General formula
(Second step) A step of adding an inorganic acid to the aqueous layer obtained in the first step to make the pH acidic, followed by extraction with tetrahydrofuran,
(Third step) Concentrating and distilling the extract obtained in the second step,
Including general formula
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| JPH01216983A (en) * | 1988-02-26 | 1989-08-30 | Hiroyuki Nohira | Method for optical resolution of (+-)-tetrahydrofuran-2-carboxylic acid |
| JPH037272A (en) * | 1989-02-07 | 1991-01-14 | Suntory Ltd | Production of optically active tetrahydro-2-furoic acid |
| JPH0859517A (en) * | 1994-06-15 | 1996-03-05 | Toray Ind Inc | Optical resolution agent and production of optically active tetrahydrofuran-carboxylic acid using the same |
| JPH0971576A (en) * | 1995-09-06 | 1997-03-18 | Toray Ind Inc | Production of carboxylic acid or its ester |
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| JP2002171994A (en) * | 2000-09-27 | 2002-06-18 | Nagase & Co Ltd | Method for producing optically active tetrahydrofuran-2-carboxylic acid or its antipode ester |
| CN101429180A (en) * | 2007-11-09 | 2009-05-13 | 雅本化学（苏州）有限公司 | Process for producing S-tetrahydrochysene furoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01216983A (en) * | 1988-02-26 | 1989-08-30 | Hiroyuki Nohira | Method for optical resolution of (+-)-tetrahydrofuran-2-carboxylic acid |
| JPH037272A (en) * | 1989-02-07 | 1991-01-14 | Suntory Ltd | Production of optically active tetrahydro-2-furoic acid |
| JPH0859517A (en) * | 1994-06-15 | 1996-03-05 | Toray Ind Inc | Optical resolution agent and production of optically active tetrahydrofuran-carboxylic acid using the same |
| JPH0971576A (en) * | 1995-09-06 | 1997-03-18 | Toray Ind Inc | Production of carboxylic acid or its ester |
| JPH09143101A (en) * | 1995-11-24 | 1997-06-03 | Toray Ind Inc | Production of optically active carboxylic acid |
| JP2002171994A (en) * | 2000-09-27 | 2002-06-18 | Nagase & Co Ltd | Method for producing optically active tetrahydrofuran-2-carboxylic acid or its antipode ester |
| CN101429180A (en) * | 2007-11-09 | 2009-05-13 | 雅本化学（苏州）有限公司 | Process for producing S-tetrahydrochysene furoic acid |
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| CN112979591A (en) * | 2021-03-01 | 2021-06-18 | 安徽金轩科技有限公司 | Oxidation extraction process for recycling dichloromethane in preparation of furan ammonium salt |
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