JPS6146460B2 - - Google Patents
Info
- Publication number
- JPS6146460B2 JPS6146460B2 JP53028035A JP2803578A JPS6146460B2 JP S6146460 B2 JPS6146460 B2 JP S6146460B2 JP 53028035 A JP53028035 A JP 53028035A JP 2803578 A JP2803578 A JP 2803578A JP S6146460 B2 JPS6146460 B2 JP S6146460B2
- Authority
- JP
- Japan
- Prior art keywords
- ppm
- succinic acid
- optical purity
- ethanol
- formula
- 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
- 239000010948 rhodium Substances 0.000 claims description 16
- 229910052703 rhodium Inorganic materials 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 8
- WXUAQHNMJWJLTG-UHFFFAOYSA-N 2-methylbutanedioic acid Chemical class OC(=O)C(C)CC(O)=O WXUAQHNMJWJLTG-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 238000011914 asymmetric synthesis Methods 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 230000003287 optical effect Effects 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 6
- LVHBHZANLOWSRM-UHFFFAOYSA-N itaconic acid Chemical class OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 6
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- WXUAQHNMJWJLTG-VKHMYHEASA-N (S)-methylsuccinic acid Chemical compound OC(=O)[C@@H](C)CC(O)=O WXUAQHNMJWJLTG-VKHMYHEASA-N 0.000 description 3
- PRBHEGAFLDMLAL-UHFFFAOYSA-N 1,5-Hexadiene Natural products CC=CCC=C PRBHEGAFLDMLAL-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- PYGSKMBEVAICCR-UHFFFAOYSA-N hexa-1,5-diene Chemical compound C=CCCC=C PYGSKMBEVAICCR-UHFFFAOYSA-N 0.000 description 3
- -1 methylpyrrolidine bisphosphine-rhodium Chemical compound 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- VYXHVRARDIDEHS-QGTKBVGQSA-N (1z,5z)-cycloocta-1,5-diene Chemical compound C\1C\C=C/CC\C=C/1 VYXHVRARDIDEHS-QGTKBVGQSA-N 0.000 description 2
- RVHOBHMAPRVOLO-BYPYZUCNSA-N (2s)-2-ethylbutanedioic acid Chemical compound CC[C@H](C(O)=O)CC(O)=O RVHOBHMAPRVOLO-BYPYZUCNSA-N 0.000 description 2
- WXUAQHNMJWJLTG-GSVOUGTGSA-N (R)-methylsuccinic acid Chemical compound OC(=O)[C@H](C)CC(O)=O WXUAQHNMJWJLTG-GSVOUGTGSA-N 0.000 description 2
- KYILORDWJFEQBS-UHFFFAOYSA-N 2-benzylidenebutanedioic acid Chemical compound OC(=O)CC(C(O)=O)=CC1=CC=CC=C1 KYILORDWJFEQBS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229910020366 ClO 4 Inorganic materials 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GTOFKXZQQDSVFH-VIFPVBQESA-N (r)-2-benzylsuccinate Chemical compound OC(=O)C[C@@H](C(O)=O)CC1=CC=CC=C1 GTOFKXZQQDSVFH-VIFPVBQESA-N 0.000 description 1
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 1
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 1
- NRSMWHGLCNBZSO-UHFFFAOYSA-N 2-ethylidenebutanedioic acid Chemical compound CC=C(C(O)=O)CC(O)=O NRSMWHGLCNBZSO-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QOXHILHNCWCKHN-UHFFFAOYSA-N [2-(diphenylphosphanylmethyl)pyrrolidin-1-yl]-diphenylphosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CC1CCCN1P(C=1C=CC=CC=1)C1=CC=CC=C1 QOXHILHNCWCKHN-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
本発明は、光学活性炭素を有する種々な天然物
または医薬品などの生理活性物質を合成する際に
有用な反応中間体の一つである光学活性なα−メ
チルコハク酸誘導体を得るために安価なイタコン
酸誘導体を原料とし、不斉水素化触媒（2S・
4S）又は（2R・4R）−Ｎ−アシル−４−ジフエ
ニルホスフイノ−２−ジフエニルホスフイノメチ
ル−ピロリジン（以下Ｎ−アシル−PPMと略
す）とロジウムの錯化合物の共存下で水素添加反
応を行ない、容易に高収率で且つ高い不斉化率で
光学活性なα−メチル−コハク酸誘導体を不斉合
成する方法に関する。
天然の有機化合物は不斉炭素を有する場合、ほ
とんど光学活性体の型で存在しており、その生理
活性も対掌体と顕著な差を示すのが通常である。
これらの理由からしても天然の不斉炭素原子を持
つ化合物と同じ物質を触媒的に不斉合成する研究
も近年盛んに行なわれている。
本発明者は先にジヤーナル・オブ・アメリカ
ン・ケミカル・ソサイアテイ、第98巻、第8265頁
（1976年）において不斉水素化触媒としてメチル
ピロリジンビスホスフイン−ロジウム錯化合物を
公表したが、この錯化合物のピロリジン核の
The present invention aims to obtain an optically active α-methylsuccinic acid derivative, which is one of the reaction intermediates useful in the synthesis of various natural products having optically active carbon or physiologically active substances such as pharmaceuticals. Asymmetric hydrogenation catalyst (2S・
4S) or (2R・4R)-N-acyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine (hereinafter abbreviated as N-acyl-PPM) and hydrogenation in the coexistence of a complex compound of rhodium. The present invention relates to a method for easily asymmetrically synthesizing optically active α-methyl-succinic acid derivatives in high yield and high asymmetric rate by carrying out a reaction. When a natural organic compound has an asymmetric carbon, it mostly exists in the form of an optically active form, and its physiological activity usually shows a marked difference from that of its enantiomer.
For these reasons, research has been actively conducted in recent years on the catalytic asymmetric synthesis of the same substances as naturally occurring compounds with asymmetric carbon atoms. The present inventor previously published a methylpyrrolidine bisphosphine-rhodium complex compound as an asymmetric hydrogenation catalyst in the Journal of the American Chemical Society, Vol. 98, p. 8265 (1976). of the pyrrolidine nucleus of the compound
【式】のＨをアシル基で置換した（2S・
4S）又は（2R・4R）−Ｎ−アシル−PPM−ロジ
ウム錯化合物を触媒として用い、イタコン酸誘導
体を水素添加することにより容易に光学活性なα
−メチル−コハク酸誘導体を不斉合成することに
成功した。
本発明の一体系を記述するならば、
〔Ｒは水素又はC1〜C6の低級アルキル基又はアリ
ール基、R1はtert−ブトキシカルボニル基、ベン
ゾイル基、ピコリル基、ニコチル基、イソニコチ
ル基、トリフロロアセチル基、２−テノイル基、
１−ナフトイル基、フロイル基、ペンタフロロベ
ンゾイル基の様な電子吸引性の大きいアシル基〕
の反応式の如く、中性種ロジウムとして〔Rh
（１・５−ヘキサジエン）Cl〕2〔〕0.025ミリモ
ルまたはカチオン種ロジウムとして〔Rh（１・
５−シクロオクタジエン）Ｌ*〕+ClO4 -〔〕
（Ｌ*は不斉配位子Ｎ−アシル−PPMを表わす）
0.013ミリモルを有機溶媒（メタノール、メタノ
ール−ベンゼン混液、エタノールなど）20mlに溶
解し、次いでＮ−アシル−PPM〔〕0.06ミリモ
ルまたは0.03ミリモルを加えて、Ｎ−アシル−
PPM−ロジウム錯化合物を形成させた後、イタ
コン酸誘導体〔〕５ミリモルを加えて溶解し、
常圧もしくは加圧下で０℃乃至100℃の温度、好
ましくは20〜30℃で５乃至50時間を要して水素添
加を行なう。反応終了後溶媒を留去し、残渣を適
宜処理して反応生成物から不斉配位子〔〕及び
ロジウムを分離し、反応生成物α−メチル−コハ
ク酸誘導体〔〕を得る。この時得られるα−メ
チル−コハク酸誘導体〔〕の不斉化率は70〜90
％である。
本発明は光学活性な天然物または医薬品を合成
するための光学活性な中間体を得るのに極めて有
用な方法である。すなわち、（2S・4S）−Ｎ−ア
シル−PPM又は（2R・4R）−Ｎ−アシル−PPM
を使い分けることにより、α−置換コハク酸の
（Ｓ）−（−）−配位の光学活性体が極めて多く出来
たり（Ｒ）−（＋）−配位の光学活性が極めて多く
出来たりするのである。
次に実施例を挙げて本発明方法を更に具体的に
説明するが、本発明はもとよりこれらに限定され
るものではない。
実施例 １
メタノール10ml中に中性種ロジウムとして
〔Rh（１・５−ヘキサジエン）Cl〕211mg（0.025ミ
リモル）及び（2S・4S）−Ｎ−ベンゾイル−４−
ジフエニルホスフイノ−２−ジフエニルホスフイ
ノメチル−ピロリジン（以下Ｎ−ベンゾイル−
PPMと略す）33.5mg（0.06ミリモル）を加えて溶
解し、Ｎ−ベンゾイル−PPM−ロジウム錯化合
物を形成させてからイタコン酸650mg（５ミリモ
ル）を加えて溶解した後、この混合液を加圧撹拌
装置に入れ50気圧の加圧下で20℃で水素添加反応
を行なう。20時間後に反応を中止しメタノールを
減圧留去する。残渣に0.5N苛性ソーダ水溶液を
５ml加えて反応生成物を溶解させ、不溶性のＮ−
ベンゾイル−PPM及びロジウムの部分を吸引
去した後、アルカリ性の水層部に塩酸を加えてPH
1.0としエーテル20mlで抽出を行ないエーテルを
減圧留去すると（Ｓ）−（−）−α−メチル−コハ
ク酸〔〕が結晶として得られる。収量647mg
（収率98％）、〔α〕２０ Ｄ−14.1゜（Ｃ＝１、エタノ
ー
ル）で光学純度は83.5％である。
同様の操作により不斉配位子として次の様な
（2S・4S）−Ｎ−アシル−PPMを用いた場合の生
成物〔〕の収率、施光度、光学純度を記載す
る。（2S・4S）−Ｎ−tert−ブトキシカルボニル−
PPMを用いると〔〕は99％の収率で得られ、
〔α〕２０ Ｄ−12.0゜（Ｃ＝１、エタノール）で光学純
度は71.1％であつた。
（2S・4S）−Ｎ−ピコリル−PPMを用いると
〔〕は98％の収率で得られ、〔α〕２０ Ｄ−11.8゜
（Ｃ＝１、エタノール）で光学純度は70.5％であ
つた。
（2S・4S）−Ｎ−ニコチル−PPMを用いると
〔〕は99％で得られ、〔α〕２０ Ｄ−11.9゜（Ｃ＝
１、エタノール）で光学純度は70.5％であつた。
（2S・4S）−Ｎ−イソニコチル−PPMを用いる
と〔〕は98％で得られ、〔α〕２０ Ｄ−12.1゜（Ｃ＝
１、エタノール）で光学純度は72.0％であつた。
（2S・4S）−Ｎ−トリフロロアセチル−PPMを
用いると〔〕は99％で得られ、〔α〕２０ Ｄ−15.4゜
（Ｃ＝１、エタノール）で光学純度は91.2％であ
つた。
（2S・4S）−Ｎ−（２−テノイル）−PPMを用い
ると〔〕は97％で得られ、〔α〕２０ Ｄ−14.5゜（Ｃ
＝１、エタノール）で光学純度は85.9％であつ
た。
（2S・4S）−Ｎ−（１−ナフトイル）−PPMを用
いると〔〕は96％で得られ、〔α〕２０ Ｄ−13.8゜
（Ｃ＝１、エタノール）で光学純度は81.7％であ
つた。
（2S・4S）−Ｎ−フロイル−PPMを用いると
〔〕は97％で得られ、〔α〕２０ Ｄ−14.4゜（Ｃ＝
１、エタノール）で光学純度は85.3％であつた。
（2S・4S）−Ｎ−ベンタフロロベンゾイル−
PPMを用いると〔〕は98％で得られ、〔α〕２０ Ｄ−
15.1゜（Ｃ＝１、エタノール）で光学純度は89.4
％であつた。
更に不斉配位子の光学対掌体である（2R・
4R）−Ｎ−ベンゾイル−PPMを用いて同様の操作
を行なつたところ（Ｒ）−（＋）−α−メチル−コ
ハク酸〔〕は99％の収率で得られ、〔α〕２０ Ｄ＋
14.8゜（Ｃ＝１、エタノール）で光学純度は87.6
％であつた。
又、（2R・4R）−Ｎ−トリフロロアセチル−
PPMを用いると（Ｒ）−（＋）−α−メチル−コハ
ク酸〔〕は98％の収率で得られ、〔α〕２０ Ｄ＋15.0
゜（Ｃ＝１、エタノール）で光学純度は88.8％で
あつた。
実施例 ２
実施例１の中性種ロジウム〔Rh（１・５−ヘ
キサジエン）Cl〕211mg（0.025ミリモル）の代わ
りにカチオン種ロジウム錯体を用いるのにRh
（１・５−シクロオクタジエン）（アセチルアセト
ネート）15.6mg（0.05ミリモル）をメタノール10
mlに溶解し、70％HClO47.2mgとＮ−ベンゾイル
−PPM28mg（0.05ミリモル）を加えて溶解し
〔Rh（1.5−シクロオクタジエン）（Ｎ−ベンゾイ
ル−PPM）〕+ClO4 -を形成させた後、イタコン酸
650mg（５ミリモル）を加えて溶解し、実施例１
と同様に反応操作を行ない、同様に後処理して光
学活性な（Ｓ）−（−）−α−メチル−コハク酸
〔〕642mg（収率97％）を得た。〔α〕２０ Ｄ−14.5
゜
（Ｃ＝１、エタノール）で光学純度は85.9％であ
つた。
実施例 ３
実施例２の反応混合液の中にトリエチルアミン
5.0mg（0.05ミリモル）を添加した以外は実施例
２と全く同様に行なつて、光学活性な（Ｓ）−
（−）−α−メチル−コハク酸〔〕650mg（収率
98.2％）を得た。〔α〕２０ Ｄ−15.4゜（Ｃ＝１、エタ
ノール）で光学純度は91.2％であつた。
実施例 ４
実施例１の中でイタコン酸650mg（５ミリモ
ル）の代わりにベンジリデン−コハク酸
Optical activity can be easily achieved by hydrogenating itaconic acid derivatives using a (2S/4S) or (2R/4R)-N-acyl-PPM-rhodium complex compound in which H in [Formula] is substituted with an acyl group as a catalyst. α
We succeeded in asymmetrically synthesizing -methyl-succinic acid derivatives. To describe the entire system of the present invention, [R is hydrogen or a C1 to C6 lower alkyl group or aryl group, R1 is a tert-butoxycarbonyl group, benzoyl group, picolyl group, nicotyl group, isonicotyl group, trifluoroacetyl group, 2-thenoyl group,
[Rh
(1,5-hexadiene)Cl] 2 []0.025 mmol or as the cationic species rhodium [Rh(1.
5-cyclooctadiene) L * ] + ClO 4 - []
(L * represents the asymmetric ligand N-acyl-PPM)
Dissolve 0.013 mmol in 20 ml of an organic solvent (methanol, methanol-benzene mixture, ethanol, etc.), then add 0.06 mmol or 0.03 mmol of N-acyl-PPM [] to obtain N-acyl-PPM.
After forming the PPM-rhodium complex compound, 5 mmol of itaconic acid derivative [] was added and dissolved.
Hydrogenation is carried out at a temperature of 0° C. to 100° C., preferably 20° C. to 30° C., for 5 to 50 hours under normal pressure or increased pressure. After completion of the reaction, the solvent is distilled off, and the residue is treated appropriately to separate the asymmetric ligand [] and rhodium from the reaction product to obtain the reaction product α-methyl-succinic acid derivative []. The asymmetry rate of the α-methyl-succinic acid derivative [] obtained at this time is 70 to 90
%. The present invention is an extremely useful method for obtaining optically active intermediates for synthesizing optically active natural products or pharmaceuticals. That is, (2S・4S)-N-acyl-PPM or (2R・4R)-N-acyl-PPM
By properly using α-substituted succinic acid, an extremely large number of (S)-(-)-coordinated optically active forms or an extremely large number of (R)-(+)-coordinated optically active forms can be created. be. Next, the method of the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these. Example 1 11 mg (0.025 mmol) of rhodium as the neutral species [Rh(1,5-hexadiene)Cl] 2 and (2S·4S)-N-benzoyl-4- in 10 ml of methanol.
diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine (hereinafter referred to as N-benzoyl-
After adding and dissolving 33.5 mg (0.06 mmol) of PPM (abbreviated as PPM) to form an N-benzoyl-PPM-rhodium complex, adding and dissolving 650 mg (5 mmol) of itaconic acid, this mixture was pressurized. The mixture is placed in a stirrer and a hydrogenation reaction is carried out at 20°C under a pressure of 50 atm. After 20 hours, the reaction was stopped and methanol was distilled off under reduced pressure. Add 5 ml of 0.5N caustic soda aqueous solution to the residue to dissolve the reaction product, and remove the insoluble N-
After suctioning off the benzoyl-PPM and rhodium parts, hydrochloric acid was added to the alkaline water layer to adjust the pH.
Extract with 20 ml of ether and distill off the ether under reduced pressure to obtain (S)-(-)-α-methyl-succinic acid [] as crystals. Yield 647mg
(Yield: 98%), [α] 20 D −14.1° (C=1, ethanol), and optical purity is 83.5%. The yield, degree of light absorption, and optical purity of the product [] when the following (2S·4S)-N-acyl-PPM was used as the asymmetric ligand by the same operation are described. (2S・4S)-N-tert-butoxycarbonyl-
Using PPM, [] can be obtained in 99% yield,
[α] 20 D −12.0° (C=1, ethanol), and the optical purity was 71.1%. When (2S・4S)-N-picolyl-PPM was used, [] was obtained in a yield of 98%, and the optical purity was 70.5% at [α] 20 D -11.8° (C=1, ethanol). . When (2S・4S)-N-nicotyl-PPM is used, [] is obtained in 99%, [α] 20 D -11.9° (C=
1, ethanol) and the optical purity was 70.5%. When (2S・4S)-N-isonicotyl-PPM was used, [] was obtained in 98%, [α] 20 D -12.1° (C=
1, ethanol) and the optical purity was 72.0%. When (2S·4S)-N-trifluoroacetyl-PPM was used, [] was obtained in 99%, and the optical purity was 91.2% at [α] 20 D -15.4° (C=1, ethanol). When (2S・4S)-N-(2-thenoyl)-PPM was used, [] was obtained in 97%, and [α] 20 D -14.5° (C
= 1, ethanol) and the optical purity was 85.9%. When (2S・4S)-N-(1-naphthoyl)-PPM was used, [] was obtained in 96%, and [α] was obtained at 20 D -13.8° (C=1, ethanol) with an optical purity of 81.7%. Ta. When (2S・4S)-N-furoyl-PPM is used, [] is obtained in 97%, [α] 20 D -14.4° (C=
1, ethanol) and the optical purity was 85.3%. (2S・4S)-N-bentafluorobenzoyl-
Using PPM, [] is obtained in 98%, [α] 20 D −
Optical purity is 89.4 at 15.1° (C=1, ethanol)
It was %. Furthermore, it is the optical antipode of the asymmetric ligand (2R・
When the same operation was carried out using 4R)-N-benzoyl-PPM, (R)-(+)-α-methyl-succinic acid [] was obtained with a yield of 99%, and [α] 20 D +
Optical purity is 87.6 at 14.8° (C=1, ethanol)
It was %. Also, (2R・4R)-N-trifluoroacetyl-
Using PPM, (R)-(+)-α-methyl-succinic acid [ ] was obtained with a yield of 98%, [α] 20 D +15.0
(C=1, ethanol) and the optical purity was 88.8%. Example 2 Using a cationic species rhodium complex instead of the neutral species rhodium [Rh(1,5-hexadiene)Cl] 2 11 mg (0.025 mmol) in Example 1, Rh
(1,5-cyclooctadiene) (acetylacetonate) 15.6 mg (0.05 mmol) in methanol 10
ml, add 7.2 mg of 70% HClO 4 and 28 mg (0.05 mmol) of N-benzoyl-PPM to form [Rh(1.5-cyclooctadiene) (N-benzoyl-PPM)] + ClO 4 - . After that, itaconic acid
Add 650 mg (5 mmol) and dissolve, Example 1
The reaction procedure was carried out in the same manner as above, and the same post-treatment was carried out to obtain 642 mg (yield 97%) of optically active (S)-(-)-α-methyl-succinic acid []. [α] 20 D -14.5
(C=1, ethanol) and the optical purity was 85.9%. Example 3 Triethylamine in the reaction mixture of Example 2
The optically active (S)-
(-)-α-methyl-succinic acid [] 650 mg (yield
98.2%). [α] 20 D −15.4° (C=1, ethanol), and the optical purity was 91.2%. Example 4 Benzylidene-succinic acid was substituted for 650 mg (5 mmol) of itaconic acid in Example 1.
【式】1.03ｇ（５ミリ
モル）を加えた以外は実施例１と全く同様操作の
反応を行ない同様の後処理を行なう事によつて光
学活性な（Ｓ）−（−）−α−ベンジル−コハク酸
1.01ｇ（収率98％）を得た。〔α〕２５ Ｄ−24.3゜（Ｃ
＝２、酢酸エチル）で光学純度は90％であつた。
実施例 ５
実施例１の中でイタコン酸の代わりにエチリデ
ン−コハク酸[Formula] By carrying out the reaction in exactly the same manner as in Example 1 except for adding 1.03 g (5 mmol) and performing the same post-treatment, optically active (S)-(-)-α-benzyl- Succinic acid
1.01 g (yield 98%) was obtained. [α] 25 D -24.3゜(C
= 2, ethyl acetate) and the optical purity was 90%. Example 5 Ethylidene-succinic acid was used instead of itaconic acid in Example 1.
【式】720mg
を加えた他は実施例１と全く同様の操作と反応を
行ない同様の後処理を行なう事によつて、光学活
性な（Ｓ）−（−）−α−エチル−コハク酸705mg
（収率98％）を得た。〔α〕２５ Ｄ−15.6゜（Ｃ＝２、
アセトン）で光学純度は75％であつた。[Formula] 705mg of optically active (S)-(-)-α-ethyl-succinic acid was obtained by carrying out the same operations and reactions as in Example 1 except for adding 720mg of optically active (S)-(-)-α-ethyl-succinic acid.
(yield 98%). [α] 25 D -15.6° (C=2,
acetone) and the optical purity was 75%.
Claims (1)
アシル−４−ジフエニルホスフイノ−２−ジフエ
ニルホスフイノメチルピロリジンとロジウム錯化
合物の存在下、式〔〕 〔Ｒは水素又はC1〜C6のアルキル基又はアリール
基〕 で表わされる化合物を水素添加することを特徴と
する式〔〕 〔Ｒは式〔〕と同じ〕 で表わされる光学活性なα−メチル−コハク酸誘
導体の不斉合成法。[Claims] Linear formula [] or expression []′ [In the formula, R 1 is an acyl group] (2S・4S) or (2R・4R)-N-
In the presence of acyl-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine and a rhodium complex compound, the formula [] [R is hydrogen or a C1 to C6 alkyl group or aryl group] A formula characterized by hydrogenation of a compound represented by [] [R is the same as the formula []] An asymmetric synthesis method for an optically active α-methyl-succinic acid derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2803578A JPS54122219A (en) | 1978-03-10 | 1978-03-10 | Asymmetric synthesis of optical active alphaamethyl succinic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2803578A JPS54122219A (en) | 1978-03-10 | 1978-03-10 | Asymmetric synthesis of optical active alphaamethyl succinic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS54122219A JPS54122219A (en) | 1979-09-21 |
| JPS6146460B2 true JPS6146460B2 (en) | 1986-10-14 |
Family
ID=12237471
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2803578A Granted JPS54122219A (en) | 1978-03-10 | 1978-03-10 | Asymmetric synthesis of optical active alphaamethyl succinic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS54122219A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01165455U (en) * | 1988-05-10 | 1989-11-20 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS54128511A (en) * | 1978-03-27 | 1979-10-05 | Sagami Chem Res Center | Preparation of optically active methyl succinic acid |
-
1978
- 1978-03-10 JP JP2803578A patent/JPS54122219A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01165455U (en) * | 1988-05-10 | 1989-11-20 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS54122219A (en) | 1979-09-21 |
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