JPS649980B2 - - Google Patents
Info
- Publication number
- JPS649980B2 JPS649980B2 JP56029055A JP2905581A JPS649980B2 JP S649980 B2 JPS649980 B2 JP S649980B2 JP 56029055 A JP56029055 A JP 56029055A JP 2905581 A JP2905581 A JP 2905581A JP S649980 B2 JPS649980 B2 JP S649980B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- formula
- group
- pyridine
- reaction
- 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
- -1 sulfonyloxycarboxylic acid Chemical class 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000006188 syrup Substances 0.000 description 8
- 235000020357 syrup Nutrition 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 125000003118 aryl group Chemical class 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- TXHIDIHEXDFONW-UHFFFAOYSA-N benzene;propan-2-one Chemical compound CC(C)=O.C1=CC=CC=C1 TXHIDIHEXDFONW-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- DBXBTMSZEOQQDU-GSVOUGTGSA-N (r)-3-hydroxyisobutyric acid Chemical compound OC[C@@H](C)C(O)=O DBXBTMSZEOQQDU-GSVOUGTGSA-N 0.000 description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 101150065749 Churc1 gene Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 102100038239 Protein Churchill Human genes 0.000 description 2
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 2
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 2
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- VPFSEYPRDWJMEF-SNVBAGLBSA-N methyl (2R)-2-methyl-3-(4-methylphenyl)sulfonyloxypropanoate Chemical compound COC(=O)[C@H](C)COS(=O)(=O)c1ccc(C)cc1 VPFSEYPRDWJMEF-SNVBAGLBSA-N 0.000 description 2
- OOBWXHLDTFKWAB-SNVBAGLBSA-N methyl (2R)-3-benzylsulfonyloxy-2-methylpropanoate Chemical compound C[C@H](COS(=O)(=O)CC1=CC=CC=C1)C(=O)OC OOBWXHLDTFKWAB-SNVBAGLBSA-N 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- OAHKWDDSKCRNFE-UHFFFAOYSA-N phenylmethanesulfonyl chloride Chemical compound ClS(=O)(=O)CC1=CC=CC=C1 OAHKWDDSKCRNFE-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- HOLHYSJJBXSLMV-UHFFFAOYSA-N 2,6-dichlorophenol Chemical compound OC1=C(Cl)C=CC=C1Cl HOLHYSJJBXSLMV-UHFFFAOYSA-N 0.000 description 1
- FEINRNIWVDWBIG-UHFFFAOYSA-N 2-(4-methylphenyl)sulfonyl-1h-imidazole Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C1=NC=CN1 FEINRNIWVDWBIG-UHFFFAOYSA-N 0.000 description 1
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical class [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical class OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- ATCCIZURPPEVIZ-BYPYZUCNSA-N methyl (2s)-3-hydroxy-2-methylpropanoate Chemical compound COC(=O)[C@@H](C)CO ATCCIZURPPEVIZ-BYPYZUCNSA-N 0.000 description 1
- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- ATCCIZURPPEVIZ-SCSAIBSYSA-N roche ester Chemical compound COC(=O)[C@H](C)CO ATCCIZURPPEVIZ-SCSAIBSYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- FRUIYGAEJNTDCA-UHFFFAOYSA-M sodium;4-[(4-oxocyclohexa-2,5-dien-1-ylidene)amino]phenolate Chemical compound [Na+].C1=CC([O-])=CC=C1N=C1C=CC(=O)C=C1 FRUIYGAEJNTDCA-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
本発明は、医薬の合成中間体として有用な新規
光学活性３−有機スルホニルオキシカルボン酸又
はそのエステル及びその製法に関する。さらに詳
しくいえば、本発明は一般式（）
（式中、R1はメチル、エチル、ベンジル又は
ｐ−メチルフエニル基、R2はメチル又はエチル
基、R3は水素又はC1〜C4の低級アルキル基であ
る。）
で表わされる新規光学活性３−有機スルホニル
オキシカルボン酸又はそのエステル及びその製法
に関するものである。
前記一般式（）で表わされるカルボン酸又は
そのエステルは、文献未記載の新規化合物であ
り、医薬の合成中間体として重要なものである。
例えば式
で表わされるＬ−プロリン誘導体（カプトプリ
ル）は、経口投与が可能な高血圧治療薬として有
望視される化合物であるが、この化合物はＬ−プ
ロリンと、一般式（）でR2がメチル基である
Ｄ型光学活性体との反応成積体かた容易に誘導で
きる。
本発明の新規光学活性３−有機スルホニルオキ
シカルボン酸又はそのエステルとしては、例えば
次のものが挙げられる。
(1) ３−メシルオキシ−２（Ｒ）−メチルプロピオ
ン酸
(2) ３−メシルオキシ−２（Ｒ）−メチルプロピオ
ン酸メチル
(3) ３−ベンジルスルホニルオキシ−２（Ｒ）−メ
チルプロピオン酸
(4) ベンジルスルホニルオキシ−２（Ｓ）−メチル
プロピオン酸
(5) ３−ベンジルスルホニルオキシ−２（Ｒ）−メ
チルプロピオン酸メチル
(6) ３−トシルオキシ−２（Ｒ）−メチルプロピオ
ン酸メチル
(7) ３−トシルオキシ−２（Ｒ）−エチルプロピオ
ン酸メチル
(8) ３−トシルオキシ−２（Ｓ）−メチルプロピオ
ン酸エチル
本発明化合物は、カルボン酸の微生物による３
−ヒドロキシル化（本出願人による特願昭54−
144252等参照）によつて容易にえられる式（）
（式中のR2，R3は前記と同じ）
で示される光学活性３−ヒドロキシ−２−アル
キルプロピオン酸又はそのエステル〔C.T.グー
ジエ（Goodhue）、J.R.シエーフアー
（Schaeffer）、バイオテクノロジー・アンド・バ
イオエンジニアリング，13巻，203頁（1971年）
参照〕と、式（）
（式中、R1は前記と同じ。Ｘはクロル又はＮ
−イミダゾリル基である）
で表わされる有機スルホニル化合物を、塩基の
存在下で反応させることによつて容易に得ること
ができる。塩基としては、有機塩基、例えばトリ
エチルアミン、ピリジン、４−（Ｎ，Ｎ−ジメチ
ルアミノ）−ピリジン、イミダゾール、ジイソプ
ロピルエチルアミン、2.6−ルチジン、Ｎ，Ｎ−
ジメチルアニリン又はＮ，Ｎ−ジエチルアニリ
ン、あるいは水素化ナトリウム又は水素化カリウ
ムなどが使用できる。また、４−（Ｎ，Ｎ−ジメ
チルアミノ）−ピリジンを触媒量用いて、化合物
（）に対して等モル以上、好ましくは1.0−1.5
倍モルの有機塩基、例えばトリエチルアミン又は
ピリジンを使用すると、酢酸エチルや塩化メチレ
ン等の有機溶媒を利用した反応を実施することが
できる。この時の４−（Ｎ，Ｎ−ジメチルアミノ）
−ピリジンの触媒量とは、化合物（）に対して
0.01−10モル％、好ましくは0.05−5.0モル％を意
味する。化合物（）のＸがＮ−イミダゾリル基
である場合には、塩基として水素化ナトリウム又
は水素化カリウムが好ましく用いられる。
化合物（）のR3のC1〜C4の低級アルキル基
としては、メチル、エチル、プロピル、ブチル、
ｔ−ブチル基などを含むが、これらは、R3が水
素である化合物（を対応するアルコール中で、
例えば三弗化硼素エーテレート（BF3・Et2O）
触媒存在下に加熱する方法で容易にえられるエス
テルと、化合物（）との反応で合成される。
化合物（）と化合物（）との反応は、氷冷
下で十分に進行するので特に加熱する必要はな
く、光学純度を保持するために、通常−20゜〜20
℃で実施する。反応時間は10分−24時間と、反応
試剤や反応基質の反応性によつて異なるが、薄層
クロマトグラフイー（TLC）あるいはNMRスペ
クトルの測定等によつて、反応の完結点を知るこ
とができる。
以下、実施例によつて本発明を具体的に説明す
る。
実施例 １
３−メシルオキシ−２（Ｒ）−メチルプロピオン
酸の合成
３−ヒドロキシ−２（Ｒ）−メチルプロピオン酸
（〔α〕25 D−17.6゜，Ｃ＝１，MeOH）（5.3ｇ）をピ
リジン（50ml）に溶解し、氷−食塩浴で−20℃に
冷却しつつ、メシルクロリド（６ml）を１時間で
滴加した。−20゜〜−10℃で１時間撹拌したのち、
氷−食塩浴を外して更に１時間撹拌を行ない、次
いで硫酸（30ｇ）と氷水（200ml）の混合液をゆ
つくり加えて液性をPH１とした。生成物を酢酸エ
チル（100ml×２）で抽出、飽和食塩水（25ml×
４）で洗浄の後、無水硫酸ナトリウムで乾燥し
た。過後、有機溶剤を減圧下に留去して淡黄色
のシロツプ（6.18ｇ）をえた。このシロツプをベ
ンゼン−ヘキサンから再結晶精製して白色結晶
5.5ｇ（5.8％）をえた。
m.p.89〜92℃
〔α〕25 D−84.8゜（C5.0，MeOH）
NMR（90MHz，CDCl3）δppm，1.32（3H，ｄ，
CH3），2.95（1H，ｍ，CH），3.05（3H，Ｓ，−
SCH3），4.30（2H，ｍ，CH2），10.24（1H，Ｓ，
COOH）
νKBr naxcm-11690，1320，1160TLC（ベンゼル−ア
セトン＝２：１，ｖ／ｖ）
Rf＝0.2〔I2，２，６−ジクロロフエノール，イ
ンドフエノールナトリウム塩0.1％エタノール溶
液（以下、IPと略記）〕
実施例 ２
３−ベンジルスルホニルオキシ−２（Ｒ）−メチ
ルプロピオン酸の合成
３−ヒドロキシ−２（Ｒ）−メチルプロピオン酸
（1.04ｇ）を酢酸エチル（10ml）に溶解し、ピリ
ジン（0.9ｇ）と４−（Ｎ，Ｎ−ジメチルアミノ）
−ピリジン（４mg）を加えて氷冷下、ベンジルス
ルホニルクロリド（1.9ｇ）の酢酸エチル溶液
（10ml）を一度に加えて30分撹拌の後、更に室温
で５時間撹拌をすると反応が完結した。以下実施
例１と同様の後処理を行ない。３−ベンジルスル
ホニルオキシ−２（Ｒ）−メチルプロピオン酸2.6
ｇの白色固体をえた。これをヘキサン−アセトン
から再結晶して2.45ｇ（90％）の白色結晶をえ
た。
m.p.116〜117℃
〔α〕25 D−8.3゜（C1.04，MeOH）
NMR（90MHz，アセトン−d6）δppm，1.20
（3H，ｄ，CH3），2.87（1H，ｍ，CH），4.32
（2H，ｍ，OCH2），4.57（2H，Ｓ，PhCH2），
7.43（5H，Ｓ，Ph），9.2〜10.7（1H，ｂ，COOH）
νKBr naxcm-11695，1345，1165，990TLC（EtOAc−
EtOH−H2O＝５：１：１，ｖ／ｖ）Rf＝0.65
（I2，IP）
実施例 ３
３−トシルオキシ−２（Ｒ）−メチルプロピオン
酸メチルの合成
３−ヒドロキシ−２（Ｒ）−メチルプロピオン酸
をメタノール中、BF3・Et2O触媒存在下に加熱
還流する方法で容易にえられる３−ヒドロキシ−
２（Ｒ）−メチルプロピオン酸メチルエステル
（〔α〕25 D−25.2゜，Ｃ＝４，MeOH）（23.6ｇ）をピ
リジン（100ml）に溶解し、氷冷下、トシルクロ
リドの結晶（41.8ｇ）を一度に加えて撹拌を行な
うと、完全な透明溶液から徐々にピリジン塩酸塩
が白色固体として析出した。１時間後に氷浴を外
し、室温下に更に15時間反応させて後、ピリジン
塩酸塩を別し、液に氷冷下50％硫酸を加えて
液性をPH２としてから酢酸エチル（250ml×２）
で抽出した。有機層を食塩水、重そう水、食塩水
の順で洗つた後、無水硫酸マグネシウムで乾燥
し、有機溶剤を減圧下に留去すると無色粘調シロ
ツプ状の３−トシルオキシ−２（Ｒ）−メチルプロ
ピオン酸メチル、48ｇ（90％）がえられた。
〔α〕25 D−10.6゜（C1.18，MeOH）
NMR（90MHz，CDCl3）δppm，1.18（3H，ｄ，
（CH3），2.47（3H，Ｓ，
The present invention relates to a novel optically active 3-organosulfonyloxycarboxylic acid or an ester thereof useful as a synthetic intermediate for pharmaceuticals, and a method for producing the same. More specifically, the present invention relates to the general formula () Novel optical activity represented by This invention relates to 3-organosulfonyloxycarboxylic acid or its ester and its production method. The carboxylic acid represented by the general formula () or its ester is a novel compound that has not been described in any literature, and is important as a synthetic intermediate for pharmaceuticals.
For example, the expression The L - proline derivative (captopril) represented by is a compound that is seen as a promising antihypertensive drug that can be administered orally. A reaction product with the D-type optically active substance can be easily induced. Examples of the novel optically active 3-organosulfonyloxycarboxylic acid or ester thereof of the present invention include the following. (1) 3-Mesyloxy-2(R)-methylpropionic acid (2) Methyl 3-mesyloxy-2(R)-methylpropionic acid (3) 3-benzylsulfonyloxy-2(R)-methylpropionic acid (4 ) Benzylsulfonyloxy-2(S)-methylpropionic acid (5) Methyl 3-benzylsulfonyloxy-2(R)-methylpropionate (6) Methyl 3-tosyloxy-2(R)-methylpropionate (7) Methyl 3-tosyloxy-2(R)-ethylpropionate (8) Ethyl 3-tosyloxy-2(S)-methylpropionate The compounds of the present invention are
-Hydroxylation (patent application filed in 1982 by the applicant)
144252 etc.) can be easily obtained by the formula () (In the formula, R 2 and R 3 are the same as above) Optically active 3-hydroxy-2-alkylpropionic acid or its ester [CT Goodhue, JR Schaeffer, Biotechnology & Bio Engineering, vol. 13, p. 203 (1971)
Reference] and expression () (In the formula, R 1 is the same as above. X is chlor or N
An organic sulfonyl compound represented by -imidazolyl group can be easily obtained by reacting it in the presence of a base. Bases include organic bases such as triethylamine, pyridine, 4-(N,N-dimethylamino)-pyridine, imidazole, diisopropylethylamine, 2,6-lutidine, N,N-
Dimethylaniline or N,N-diethylaniline, sodium hydride or potassium hydride, etc. can be used. In addition, 4-(N,N-dimethylamino)-pyridine is used in a catalytic amount to give an equimole or more, preferably 1.0-1.5 molar amount to the compound ().
When twice the molar amount of an organic base, such as triethylamine or pyridine, is used, the reaction can be carried out using an organic solvent such as ethyl acetate or methylene chloride. 4-(N,N-dimethylamino) at this time
-The catalytic amount of pyridine is relative to the compound ().
It means 0.01-10 mol%, preferably 0.05-5.0 mol%. When X in compound () is an N-imidazolyl group, sodium hydride or potassium hydride is preferably used as the base. Examples of the C 1 to C 4 lower alkyl group of R 3 in the compound () include methyl, ethyl, propyl, butyl,
t-butyl group, etc., but these are compounds in which R 3 is hydrogen (in the corresponding alcohol,
For example, boron trifluoride etherate (BF 3 Et 2 O)
It is synthesized by the reaction of compound () with an ester that can be easily obtained by heating in the presence of a catalyst. The reaction between compound () and compound () proceeds satisfactorily under ice-cooling, so there is no need for particular heating, and in order to maintain optical purity, the temperature is usually -20° to 20°C.
Perform at °C. The reaction time varies from 10 minutes to 24 hours, depending on the reactivity of the reaction reagent and reaction substrate, but the completion point of the reaction can be determined by thin layer chromatography (TLC) or NMR spectrum measurement. can. Hereinafter, the present invention will be specifically explained with reference to Examples. Example 1 Synthesis of 3-mesyloxy-2(R)-methylpropionic acid 3-hydroxy-2(R)-methylpropionic acid ([α] 25 D -17.6°, C=1, MeOH) (5.3 g) Mesyl chloride (6 ml) was added dropwise over 1 hour, dissolved in pyridine (50 ml) and cooled to -20°C in an ice-salt bath. After stirring for 1 hour at -20° to -10°C,
The ice-salt bath was removed and the mixture was stirred for an additional hour, and then a mixed solution of sulfuric acid (30 g) and ice water (200 ml) was slowly added to adjust the pH to 1. The product was extracted with ethyl acetate (100ml x 2) and saturated brine (25ml x
After washing with 4), it was dried with anhydrous sodium sulfate. After evaporation, the organic solvent was distilled off under reduced pressure to obtain a pale yellow syrup (6.18 g). This syrup was purified by recrystallization from benzene-hexane to produce white crystals.
5.5g (5.8%) was obtained. mp89～92℃ [α] 25 D −84.8° (C5.0, MeOH) NMR (90MHz, CDCl 3 ) δppm, 1.32 (3H, d,
CH 3 ), 2.95 (1H, m, CH), 3.05 (3H, S, -
SCH 3 ), 4.30 (2H, m, CH 2 ), 10.24 (1H, S,
COOH) ν KBr nax cm -1 1690, 1320, 1160 TLC (benzel-acetone = 2:1, v/v) Rf = 0.2 [I 2 , 2, 6-dichlorophenol, indophenol sodium salt 0.1% ethanol solution (below) , abbreviated as IP)] Example 2 Synthesis of 3-benzylsulfonyloxy-2(R)-methylpropionic acid 3-hydroxy-2(R)-methylpropionic acid (1.04 g) was dissolved in ethyl acetate (10 ml). , pyridine (0.9 g) and 4-(N,N-dimethylamino)
- Pyridine (4 mg) was added, and under ice-cooling, a solution of benzylsulfonyl chloride (1.9 g) in ethyl acetate (10 ml) was added all at once, and the mixture was stirred for 30 minutes and then further stirred at room temperature for 5 hours to complete the reaction. Thereafter, the same post-processing as in Example 1 was performed. 3-Benzylsulfonyloxy-2(R)-methylpropionic acid 2.6
g of white solid was obtained. This was recrystallized from hexane-acetone to give 2.45 g (90%) of white crystals. mp116～117℃ [α] 25 D −8.3° (C1.04, MeOH) NMR (90MHz, acetone − d 6 ) δppm, 1.20
(3H, d, CH 3 ), 2.87 (1H, m, CH), 4.32
(2H, m, OCH 2 ), 4.57 (2H, S, PhCH 2 ),
7.43 (5H, S, Ph), 9.2~10.7 (1H, b, COOH) ν KBr nax cm -1 1695, 1345, 1165, 990TLC (EtOAc−
EtOH− H2O =5:1:1, v/v) Rf=0.65
(I 2 , IP) Example 3 Synthesis of methyl 3-tosyloxy-2(R)-methylpropionate 3-Hydroxy-2(R)-methylpropionic acid was synthesized in methanol in the presence of a BF 3 ·Et 2 O catalyst. 3-Hydroxy- which can be easily obtained by heating under reflux
2(R)-Methylpropionic acid methyl ester ([α] 25 D -25.2°, C=4, MeOH) (23.6 g) was dissolved in pyridine (100 ml), and tosyl chloride crystals (41.8 g) were dissolved under ice cooling. ) was added all at once and stirred, and pyridine hydrochloride gradually precipitated out as a white solid from a completely transparent solution. After 1 hour, the ice bath was removed, and the reaction was allowed to continue at room temperature for another 15 hours, after which the pyridine hydrochloride was separated, and 50% sulfuric acid was added to the solution under ice cooling to adjust the pH to 2, followed by ethyl acetate (250 ml x 2).
Extracted with. The organic layer was washed with brine, aqueous sodium chloride, and brine in that order, dried over anhydrous magnesium sulfate, and the organic solvent was distilled off under reduced pressure to obtain 3-tosyloxy-2(R)- in the form of a colorless viscous syrup. 48 g (90%) of methyl methylpropionate was obtained. [α] 25 D −10.6° (C1.18, MeOH) NMR (90MHz, CDCl 3 ) δppm, 1.18 (3H, d,
(CH 3 ), 2.47 (3H, S,
【式】），
2.83（1H，ｍ，CH），3.65（3H，Ｓ，OCH3），
4.13（2H，ｍ，CH2），7.33（2H，ｄ，芳香核），
7.78（2H，ｄ，芳香核）
νneat naxcm-11750，1370，1190，1180，980TLC（ベ
ンゼン−アセトン＝９：１，ｖ／ｖ）
Rf＝0.45（UV，I2）
実施例 ４
３−トシルオキシ−２（Ｒ）−メチルプロピオン
酸メチルの合成
３−ヒドロキシ−２（Ｒ）−メチルプロピオン酸
（〔α〕25 D−1.7゜，Ｃ＝５，MeOH）をメタノール中
BF3・Et2O触媒存在下に加熱還流してえられる、
３−ヒドロキシ−２（Ｒ）−メチルプロピオン酸メ
チル（b.p.97℃／24mmHg，〔α〕25 D−3.39゜，Ｃ＝
10，MeOH）（0.6ｇ）を酢酸エチル（10ml）に溶
解し、ピリジン（0.93ｇ）と４−（Ｎ，Ｎ−ジメ
チルアミノ）−ピリジン（６mg）を加えて、室温
下トシルクロリド（850mg）を一度に加え16時間
撹拌した。水（20ml）を加え、酢酸エチル（40
ml）を更に加えて抽出、2NHCl，飽和重そう水、
食塩水の順に洗浄の後、無水硫酸ナトリウムで乾
燥した。以下、実施例３と同様に処理して無色の
シロツプ（1.03ｇ，80％）をえた。
〔α〕25 D−5.8゜（C2.4，MeOH）
NMR（90MHz，CDCl3）δppm，0.87（3H，ｔ，
CH2CH3），1.57（2H，ｑ，CH2CH3），2.45（3H，
Ｓ[Formula]), 2.83 (1H, m, CH), 3.65 (3H, S, OCH 3 ),
4.13 (2H, m, CH 2 ), 7.33 (2H, d, aromatic nucleus),
7.78 (2H, d, aromatic nucleus) ν neat nax cm -1 1750, 1370, 1190, 1180, 980TLC (benzene-acetone = 9:1, v/v) Rf = 0.45 (UV, I 2 ) Example 4 3 Synthesis of methyl -tosyloxy-2(R)-methylpropionate 3-Hydroxy-2(R)-methylpropionic acid ([α] 25 D -1.7°, C=5, MeOH) in methanol
Obtained by heating under reflux in the presence of BF 3・Et 2 O catalyst,
Methyl 3-hydroxy-2(R)-methylpropionate (bp97℃/24mmHg, [α] 25 D -3.39゜, C=
10, MeOH) (0.6 g) was dissolved in ethyl acetate (10 ml), pyridine (0.93 g) and 4-(N,N-dimethylamino)-pyridine (6 mg) were added, and tosyl chloride (850 mg) was dissolved at room temperature. were added all at once and stirred for 16 hours. Add water (20ml) and add ethyl acetate (40ml).
ml) for extraction, 2NHCl, saturated deuterated water,
After sequentially washing with saline, it was dried over anhydrous sodium sulfate. Thereafter, the same treatment as in Example 3 was carried out to obtain a colorless syrup (1.03 g, 80%). [α] 25 D −5.8° (C2.4, MeOH) NMR (90MHz, CDCl 3 ) δppm, 0.87 (3H, t,
CH 2 CH 3 ), 1.57 (2H, q, CH 2 CH 3 ), 2.45 (3H,
S
【式】）2.68（1H，ｍ，CH），
3.65（3H，Ｓ，OCH3），4.15（2H，ｍ，OCH2），
7.32，7.77（各2H，ｄ，芳香核）
νneat naxcm-11740，1360，1175TLC（ベンゼン−ア
セトン＝２：１，ｖ／ｖ）Rf＝0.75（UV，I2）
実施例 ５
３−トシルオキシ−２（Ｒ）−メチルプロピオン
酸メチルの合成
３−ヒドロキシ−２（Ｒ）−メチルプロピオン酸
をエタノール中、BF3・Et2O触媒の存在下に加
熱還流してえられる、３−ヒドロキシ−２（Ｒ）−
メチルプロピオン酸エチル（b.p.85〜87℃／18mm
Hg，〔α〕25 D−21.7゜，Ｃ＝４，MeOH）（1.95ｇ）
を用いて、実施例４と同様の反応、後処理を行な
い無色の油状物質2.5ｇをえた。このものはNMR
スペクトルから、なお不純物を含んでいたので、
シリカゲル（50ｇ）を用いたカラムクロマトグラ
フイー（ベンゼン−ヘキサン＝１：１，ｖ／ｖ及
びベンゼン−酢酸エチル＝９：１，ｖ／ｖ）で精
製し、無色のシロツプ（1.72ｇ，41％）をえた。
〔α〕25 D−7.7゜（Ｃ＝2.0，MeOH）NMR（90M
Hz，CDCl3）δppm，1.20（3H，ｄ，CHCH3），
1.25（3H，ｔ，CH2CH3），2.48（3H，Ｓ，
[Formula]) 2.68 (1H, m, CH), 3.65 (3H, S, OCH 3 ), 4.15 (2H, m, OCH 2 ),
7.32, 7.77 (2H, d, aromatic nucleus each) ν neat nax cm -1 1740, 1360, 1175TLC (benzene-acetone = 2:1, v/v) Rf = 0.75 (UV, I 2 ) Example 5 3- Synthesis of methyl tosyloxy-2(R)-methylpropionate 3-hydroxy-2(R)-methylpropionic acid is obtained by heating and refluxing 3-hydroxy-2(R)-methylpropionic acid in the presence of a BF3 ·Et2O catalyst. (R)-
Ethyl methylpropionate (bp85-87℃/18mm
Hg, [α] 25 D −21.7°, C=4, MeOH) (1.95 g)
The same reaction and post-treatment as in Example 4 were carried out using 2.5 g of a colorless oily substance. This one is NMR
From the spectrum, it still contained impurities, so
It was purified by column chromatography (benzene-hexane = 1:1, v/v and benzene-ethyl acetate = 9:1, v/v) using silica gel (50 g), and a colorless syrup (1.72 g, 41% ) was obtained. [α] 25 D −7.7゜(C=2.0, MeOH) NMR (90M
Hz, CDCl 3 ) δppm, 1.20 (3H, d, CHCH 3 ),
1.25 (3H, t, CH 2 CH 3 ), 2.48 (3H, S,
【式】），2.83（1H，ｍ，CH），4.13
（2H，ｑ，CH2CH3），4.17（2H，ｍ，OCH2），
7.35，7.80（各2H，ｄ，芳香核）
νneat naxcm-11735，1360，1190，1180，980TLC（ヘ
キサン−ジエチルエーテル＝１：１，ｖ／ｖ）
Rf＝0.25（UV，I2）
実施例 ６
３−ベンジルスルホニルオキシ−２（Ｒ）−メチ
ルプロピオン酸メチルの合成
３−ヒドロキシ−２（Ｒ）−メチルプロピオン酸
メチル（1.2ｇ）を酢酸エチル（７ml）に溶解し、
ピリジン（0.9ｇ）と４−（Ｎ，Ｎ−ジメチルアミ
ノ）−ピリジン（４mg）を加えた後、氷冷下ベン
ジルスルホニルクロリド（1.9ｇ）の酢酸エチル
溶液（７ml）を５分間で加え１時間撹拌した。氷
浴を外して更に16時間撹拌した後、実施例４と同
様の抽出、後処理をして無色のシロツプ（2.57
ｇ，94.5％）をえた。
〔α〕25 D−12.8゜（C2.26，MeOH）NMR（90M
Hz，CDCl3）δppm，120（3H，ｄ，CH3），2.80
（1H，ｍ，CH），3.72（3H，Ｓ，OCH3），4.20
（2H，ｍ，OCH2），4.42（2H，Ｓ，[Formula]), 2.83 (1H, m, CH), 4.13 (2H, q, CH 2 CH 3 ), 4.17 (2H, m, OCH 2 ),
7.35, 7.80 (2H, d, aromatic nucleus each) ν neat nax cm -1 1735, 1360, 1190, 1180, 980TLC (hexane-diethyl ether = 1:1, v/v)
Rf=0.25 (UV, I2 ) Example 6 Synthesis of methyl 3-benzylsulfonyloxy-2(R)-methylpropionate Methyl 3-hydroxy-2(R)-methylpropionate (1.2 g) was mixed with ethyl acetate ( 7 ml),
After adding pyridine (0.9 g) and 4-(N,N-dimethylamino)-pyridine (4 mg), a solution of benzylsulfonyl chloride (1.9 g) in ethyl acetate (7 ml) was added over 5 minutes under ice cooling for 1 hour. Stirred. After removing the ice bath and stirring for an additional 16 hours, extraction and post-treatment were carried out in the same manner as in Example 4 to obtain a colorless syrup (2.57
g, 94.5%). [α] 25 D −12.8゜(C2.26, MeOH) NMR (90M
Hz, CDCl 3 ) δppm, 120 (3H, d, CH 3 ), 2.80
(1H, m, CH), 3.72 (3H, S, OCH 3 ), 4.20
(2H, m, OCH 2 ), 4.42 (2H, S,
【式】），
7.40（5H，Ｓ，芳香核）
νneat naxcm-11730，1355，1200，1170，970TLC（ベ
ンゼン−酢酸エチル＝９：１，ｖ／ｖ）Rf＝0.42
（UV，I2）
実施例 ７
３−エタンスルホニルオキシ−２（Ｒ）−メチル
プロピオン酸メチルの合成
３−ヒドロキシ−２（Ｒ）−メチルプロピオン酸
メチル（2.4ｇ）を塩化メチレン（50ml）に溶解
し、トリエチルアミン（2.5ｇ）を加えて−10℃
に冷却しつつ、エタンスルホニルクロリド（2.7
ｇ）をゆつくり滴下した。−10℃で10分撹拌する
と、反応は完結した。氷水25mlを加え、塩化メチ
レン層を分液し、2NHCl，重そう水、食塩水、
水の順序で洗浄した後、無水硫酸ナトリウムで乾
燥した。塩化メチレンを減圧下に留去して淡黄色
オイル（4.0ｇ，95％）をえた。
〔α〕25 D−16.3゜（Ｃ＝2.08，MeOH）NMR（90M
Hz，CDCl3）δppm，1.27（3H，ｄ，CHCH3），
1.41（3H，ｔ，CH2CH3），2.87（1H，ｍ，CH），
3.16（2H，ｑ，CH2CH3），3.78（3H，Ｓ，
OCH3），4.30（2H，ｍ，OCH2）
νneat naxcm-11760，1370，1180，1100TLC（ベンゼ
ン−アセトン＝２：１，ｖ／ｖ）Rf＝0.64（UV，
I2）
実施例 ８
３−トシルオキシ−２（Ｓ）−メチルプロピオン
酸メチルの合成
３−ヒドロキシ−２（Ｓ）−メチルプロピオン酸
（〔α〕25 D＋17.8゜，Ｃ＝１，MeOH）をメタノー
ル中、BF2・Et2O触媒存在下に加熱還流してえ
られる、３−ヒドロキシ−２（Ｓ）−メチルプロピ
オン酸メチル（〔α〕25 D＋25.0゜，Ｃ＝４，MeOH）
を用いて、実施例３と同様の反応、後処理を行な
い、無色のシロツプをえた。
〔α〕25 D＋10.5゜（C1.0，MeOH）
実施例 ９
３−トシルオキシ−２（Ｒ）−メチルプロピオン
酸メチルの合成
３−ヒドロキシ−２（Ｒ）−メチルプロピオン酸
（1.04ｇ）を１，２−ジメトキシエタン（10ml）
に溶解し、水素化ナトリウム（50％鉱油コーテイ
ング，530mg）を加えて窒素気流下に０℃で30分
間撹拌した。この反応液にトシルイミダゾール
（226mg）を一度に加えて更に０℃で１時間撹拌し
た後、氷浴を外して４時間撹拌すると反応が完結
した。0.05Mリン酸緩衝液（PH６，50ml）を加え
た後、生成物を酢酸エチル（50ml×２）で抽出、
以下は実施例７と同様の方法で、無色のシロツプ
（2.4ｇ，88％）をえた。[Formula]), 7.40 (5H, S, aromatic nucleus) ν neat nax cm -1 1730, 1355, 1200, 1170, 970TLC (benzene-ethyl acetate = 9:1, v/v) Rf = 0.42
(UV, I 2 ) Example 7 Synthesis of methyl 3-ethanesulfonyloxy-2(R)-methylpropionate Methyl 3-hydroxy-2(R)-methylpropionate (2.4 g) was dissolved in methylene chloride (50 ml). Dissolve, add triethylamine (2.5g) and cool at -10°C.
Ethanesulfonyl chloride (2.7
g) was slowly added dropwise. The reaction was completed after stirring at −10° C. for 10 minutes. Add 25 ml of ice water, separate the methylene chloride layer, and add 2NHCl, dehydrated water, saline solution,
After sequentially washing with water, it was dried over anhydrous sodium sulfate. Methylene chloride was distilled off under reduced pressure to give a pale yellow oil (4.0 g, 95%). [α] 25 D −16.3゜(C=2.08, MeOH) NMR (90M
Hz, CDCl 3 ) δppm, 1.27 (3H, d, CHCH 3 ),
1.41 (3H, t, CH 2 CH 3 ), 2.87 (1H, m, CH),
3.16 (2H, q, CH 2 CH 3 ), 3.78 (3H, S,
OCH 3 ), 4.30 (2H, m, OCH 2 ) ν neat nax cm -1 1760, 1370, 1180, 1100TLC (benzene-acetone = 2:1, v/v) Rf = 0.64 (UV,
I 2 ) Example 8 Synthesis of methyl 3-tosyloxy-2(S)-methylpropionate 3-hydroxy-2(S)-methylpropionic acid ([α] 25 D +17.8°, C=1, MeOH) Methyl 3-hydroxy-2(S)-methylpropionate ([α] 25 D +25.0°, C=4, MeOH, obtained by heating and refluxing in methanol in the presence of a BF 2 · Et 2 O catalyst )
The same reaction and post-treatment as in Example 3 were carried out using the same method as in Example 3 to obtain a colorless syrup. [α] 25 D +10.5° (C1.0, MeOH) Example 9 Synthesis of methyl 3-tosyloxy-2(R)-methylpropionate 3-hydroxy-2(R)-methylpropionic acid (1.04 g) 1,2-dimethoxyethane (10ml)
Sodium hydride (50% mineral oil coating, 530 mg) was added, and the mixture was stirred at 0° C. for 30 minutes under a nitrogen stream. Tosylimidazole (226 mg) was added at once to this reaction solution, and the mixture was further stirred at 0° C. for 1 hour, then the ice bath was removed and the mixture was stirred for 4 hours to complete the reaction. After adding 0.05M phosphate buffer (PH6, 50ml), the product was extracted with ethyl acetate (50ml x 2),
A colorless syrup (2.4 g, 88%) was obtained in the same manner as in Example 7.
Claims (1)
ｐ−メチルフエニル基、R2はメチル又はエチル
基、R3は水素又はC1〜C4の低級アルキル基であ
る。） で表わされる光学活性３−有機スルホニルオキシ
カルボン酸又はそのエステル。 ２ R1及びR2がメチル基、R3が水素である特許
請求の範囲第１項記載の化合物。 ３ R1がベンジル基、R2がメチル基、R3が水素
である特許請求の範囲第１項記載の化合物。 ４ R1がベンジル基、R2及びR3がメチル基であ
る特許請求の範囲第１項記載の化合物。 ５ R1がｐ−メチルフエニル基、R2及びR3がメ
チル基である特許請求の範囲第１項記載の化合
物。 ６ 式 （式中、R2はメチル又はエチル基、R3は水素
又はC1〜C4の低級アルキル基である。） で表わされる光学活性３−ヒドロキシ−２−アル
キルプロピオン酸又はそのエステルと、一般式 （式中、R1はメチル、エチル、ベンジル又は
ｐ−メチルフエニル基、Ｘはクロル又はＮ−イミ
ダゾリル基である。） で表わされる有機スルホニル化合物を、塩基の
存在下で反応させることを特徴とする、一般式 （式中のR1，R2，R3は前記と同じ） で表わされる光学活性３−有機スルホニルオキシ
カルボン酸又はそのエステルの製法。 ７ 有機塩基の存在下で反応させる特許請求の範
囲第６項記載の製法。 ８ 有機塩基がトリエチルアミンである特許請求
の範囲第７項記載の製法。 ９ 有機塩基がピリジンである特許請求の範囲第
７項記載の製法。 １０ 触媒量の４−（Ｎ，Ｎ−ジメチルアミノ）−
ピリジンの共存下に反応を行なう特許請求の範囲
第７項記載の製法。 １１ 塩基が水素化ナトリウム又は水素化カリウ
ムである特許請求の範囲第６項記載の製法。[Claims] 1. General formula (In the formula, R 1 is a methyl, ethyl, benzyl or p-methylphenyl group, R 2 is a methyl or ethyl group, and R 3 is hydrogen or a C 1 to C 4 lower alkyl group.) -Organic sulfonyloxycarboxylic acid or ester thereof. 2. The compound according to claim 1, wherein R 1 and R 2 are methyl groups, and R 3 is hydrogen. 3. The compound according to claim 1, wherein R 1 is a benzyl group, R 2 is a methyl group, and R 3 is hydrogen. 4. The compound according to claim 1 , wherein R 1 is a benzyl group, and R 2 and R 3 are methyl groups. 5. The compound according to claim 1, wherein R 1 is a p-methylphenyl group, and R 2 and R 3 are methyl groups. 6 formula (In the formula, R2 is a methyl or ethyl group, R3 is hydrogen or a C1 to C4 lower alkyl group.) Optically active 3-hydroxy-2-alkylpropionic acid or its ester represented by formula (In the formula, R 1 is a methyl, ethyl, benzyl or p-methylphenyl group, and X is a chloro or N-imidazolyl group.) , general formula (In the formula, R 1 , R 2 , and R 3 are the same as above.) A method for producing an optically active 3-organosulfonyloxycarboxylic acid or an ester thereof. 7. The production method according to claim 6, wherein the reaction is carried out in the presence of an organic base. 8. The method according to claim 7, wherein the organic base is triethylamine. 9. The production method according to claim 7, wherein the organic base is pyridine. 10 catalytic amount of 4-(N,N-dimethylamino)-
8. The method according to claim 7, wherein the reaction is carried out in the presence of pyridine. 11. The production method according to claim 6, wherein the base is sodium hydride or potassium hydride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56029055A JPS57142960A (en) | 1981-02-28 | 1981-02-28 | Novel optically active 3-organosulfonyloxycarboxylic acid or its ester, and their preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56029055A JPS57142960A (en) | 1981-02-28 | 1981-02-28 | Novel optically active 3-organosulfonyloxycarboxylic acid or its ester, and their preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57142960A JPS57142960A (en) | 1982-09-03 |
| JPS649980B2 true JPS649980B2 (en) | 1989-02-21 |
Family
ID=12265682
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56029055A Granted JPS57142960A (en) | 1981-02-28 | 1981-02-28 | Novel optically active 3-organosulfonyloxycarboxylic acid or its ester, and their preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57142960A (en) |
-
1981
- 1981-02-28 JP JP56029055A patent/JPS57142960A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57142960A (en) | 1982-09-03 |
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