JPH0338279B2 - - Google Patents
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- Publication number
- JPH0338279B2 JPH0338279B2 JP22056383A JP22056383A JPH0338279B2 JP H0338279 B2 JPH0338279 B2 JP H0338279B2 JP 22056383 A JP22056383 A JP 22056383A JP 22056383 A JP22056383 A JP 22056383A JP H0338279 B2 JPH0338279 B2 JP H0338279B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- carbon atoms
- propyl
- amino
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 34
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 150000001413 amino acids Chemical class 0.000 claims description 3
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- -1 vinylphosphinic acid ester Chemical class 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- DREPONDJUKIQLX-UHFFFAOYSA-N 1-[ethenyl(ethoxy)phosphoryl]oxyethane Chemical compound CCOP(=O)(C=C)OCC DREPONDJUKIQLX-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000006501 nitrophenyl group Chemical group 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VZRRCQOUNSHSGB-BRDIYROLSA-N (1r,4r,5r)-4-hydroxy-4,6,6-trimethylbicyclo[3.1.1]heptan-3-one Chemical compound C1[C@@H]2C(C)(C)[C@H]1CC(=O)[C@@]2(O)C VZRRCQOUNSHSGB-BRDIYROLSA-N 0.000 description 1
- VZRRCQOUNSHSGB-BYULHYEWSA-N (1s,4s,5s)-4-hydroxy-4,6,6-trimethylbicyclo[3.1.1]heptan-3-one Chemical compound C1[C@H]2C(C)(C)[C@@H]1CC(=O)[C@]2(O)C VZRRCQOUNSHSGB-BYULHYEWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000002333 glycines Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- UPRXAOPZPSAYHF-UHFFFAOYSA-N lithium;cyclohexyl(propan-2-yl)azanide Chemical compound CC(C)N([Li])C1CCCCC1 UPRXAOPZPSAYHF-UHFFFAOYSA-N 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- ZMJJCODMIXQWCQ-UHFFFAOYSA-N potassium;di(propan-2-yl)azanide Chemical compound [K+].CC(C)[N-]C(C)C ZMJJCODMIXQWCQ-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Description
【発明の詳細な説明】
本発明は、グルタミン酸の拮抗物資として有用
である〔S.G.Cull−Candy et.al.，Nature，262，
408（1976）〕、光学活性な〔（３−アミノ−３−カ
ルボキシ）−プロピル−１〕ホスホン酸の新規な
製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention is useful as an antagonist of glutamate [SGCull-Candy et.al., Nature, 262 ,
408 (1976)], relates to a novel method for producing optically active [(3-amino-3-carboxy)-propyl-1]phosphonic acid.
従来、光学活性な〔（３−アミノ−３−カルボ
キシ）−プロピル−１〕ホスホン酸の製造にあた
つては、そのDL−体を光学分割する方法
〔BrainResearch235，378，（1982）〕が知られて
いるが、この方法ではコストが高く、工業的に大
量に製造することが困難であつた。 Conventionally, in the production of optically active [(3-amino-3-carboxy)-propyl-1]phosphonic acid, a method of optically resolving its DL-form [BrainResearch 235 , 378, (1982)] has been used. Although known, this method is expensive and difficult to industrially produce in large quantities.
本発明者らは、かかる欠点を解消すべく、鋭意
研究を重ねた結果、安価なグリシン又は、グリシ
ンのエステルと光学活性なケトン体から得られる
シツフ塩基（下記一般式（）−１又は（）−
２）を、塩基の存在下、ビニルホスフイン酸エス
テル（下記一般式（）とマイケル付加反応させ
ることにより、不整合成に成功し、その結果、選
択的に光学活性な〔（３−アミノ−３−カルボキ
シ）−プロピル−１〕ホスホン酸の合成が可能な
優れた製造法を見い出すに至つた。 In order to eliminate such drawbacks, the present inventors have conducted intensive research and found that Schiff bases (formula ()-1 or ()) obtained from inexpensive glycine or glycine esters and optically active ketone bodies −
2) was subjected to a Michael addition reaction with vinylphosphinic acid ester (the following general formula ()) in the presence of a base, resulting in the asymmetric synthesis of selectively optically active [(3-amino- We have now discovered an excellent manufacturing method that enables the synthesis of 3-carboxy)-propyl-1]phosphonic acid.
すなわち、本発明は、
次式（）−１：
又は、次式（）−２：
（式中、R1は炭素数１〜５の直鎖状もしくは分
岐状のアルキル基、アリール基又はアラルキル基
を表し；＊で示した三個の不整炭素の絶対配置
は、式（）−１の場合はいずれもＳであり、式
（）−２の場合はいずれもＲである）
で示される化合物と、
次式（）：
（式中、R2及びR3は同一でも異なつていてもよ
く、それぞれ、炭素数１〜５の直鎖状もしくは分
岐状のアルキル基、アリール基又はアラルキル基
を表す）
で示される化合物とを、塩基の存在下で反応せし
め、次いで、生成した化合物を加水分解すること
を特徴とする、次式（）：
（上式のアミノ酸は、前記（）−１を使用した
場合はＬ−体であり、前記（）−２を使用した
場合はＤ−体である）
で示される〔（３−アミノ−３−カルボキシ）−プ
ロピル−１〕ホスホン酸の製造法に関するもので
ある。 That is, the present invention provides the following formula ()-1: Or the following formula ()-2: (In the formula, R 1 represents a linear or branched alkyl group, aryl group, or aralkyl group having 1 to 5 carbon atoms; the absolute configuration of the three asymmetric carbons indicated by * is the formula ()-1 In the case of , it is S in all cases, and in the case of formula ()-2, it is R in both cases) and the compound represented by the following formula (): (In the formula, R 2 and R 3 may be the same or different and each represents a linear or branched alkyl group, aryl group, or aralkyl group having 1 to 5 carbon atoms) is reacted in the presence of a base, and the resulting compound is then hydrolyzed, according to the following formula (): (The amino acid of the above formula is the L-form when the above-mentioned ()-1 is used, and the D-form when the above-mentioned ()-2 is used) [(3-amino-3- The present invention relates to a method for producing carboxy)-propyl-1]phosphonic acid.
以下、本発明を更に詳細に説明する。 The present invention will be explained in more detail below.
前記一般式（）−１及び（）−２中、R1で
表わされる炭素数１〜５の直鎖状もしくは分岐状
のアルキル基としては、例えば、メチル、エチ
ル、プロピル、ブチル、tert−プチルが挙げら
れ；アリール基としては、例えば、フエニル、ク
ロルフエニル、ニトロフエニル、メトキシフエニ
ルが挙げられ；アラルキル基としては、例えば、
ベンジルが挙げられる。前記一般式（）中、
R2及びR3で表わされる炭素数１〜５の直鎖状も
しくは分岐状のアルキル基としては、例えば、メ
チル、エチル、プロピル、イソプロピル、ブチ
ル、tert−プチルが挙げられ；アリール基として
は、例えば、フエニル、クロルフエニル、ニトロ
フエニル、メトキシフエニルが挙げられ；アラル
キルとしては、例えば、ベンジルが挙げられる。 In the general formulas ()-1 and ()-2, the linear or branched alkyl group having 1 to 5 carbon atoms represented by R 1 is, for example, methyl, ethyl, propyl, butyl, tert-butyl. Aryl groups include, for example, phenyl, chlorophenyl, nitrophenyl, methoxyphenyl; Aralkyl groups include, for example,
Examples include benzyl. In the general formula (),
Examples of linear or branched alkyl groups having 1 to 5 carbon atoms represented by R 2 and R 3 include methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl; examples of aryl groups include: Examples include phenyl, chlorphenyl, nitrophenyl, methoxyphenyl; examples of aralkyl include benzyl.
一般式（）−１及び（）−２の化合物は、文
献Chem.Pharm.Bull.，26(3)，803−808（1978）に
開示されている方法で製造できる。 Compounds of general formulas ()-1 and ()-2 can be produced by the method disclosed in the literature Chem.Pharm.Bull., 26(3), 803-808 (1978).
一般式（）の化合物については、特願昭57−
13985（昭和57年１月29日出願）に開示されている
方法で製造できる。 Regarding the compound of the general formula (), please refer to the following patent application:
13985 (filed on January 29, 1982).
本反応においては、まず化合物（）−１又は
（）−２と化合物（）とを、塩基の存在下で反
応させる。塩基としては、例えば、ｎ−ブチルリ
チウム、sec−ブチルリチウム、ｔ−ブチルリチ
ウム、リチウムジイソプロピルアミド、リチウム
イソプロピルシクロヘキシルアミド、リチウムジ
（トリメチルシリル）アミド、ナトリウムメチラ
ート、ナトリウムエチラート、ナトリウムハイド
ライド、カリウムｔ−ブトキシド、カリウムジイ
ソブロピルアミド、メチルマグネシウムクロリ
ド、メチルマグネシウムブロミド、メチルマグネ
シウムアイオダイドが用いられる。 In this reaction, first, compound ()-1 or ()-2 and compound () are reacted in the presence of a base. Examples of the base include n-butyllithium, sec-butyllithium, t-butyllithium, lithium diisopropylamide, lithium isopropylcyclohexylamide, lithium di(trimethylsilyl)amide, sodium methylate, sodium ethylate, sodium hydride, potassium t- Butoxide, potassium diisopropylamide, methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide are used.
反応は、通常、有機溶媒中で行われるが、使用
可能な有機溶媒としては、例えば、メタノール、
エタナール、トルエン、ジメトキシエタン、ジメ
チルスルホキシド、テトラヒドロフラン、ジエチ
ルエーテル、ヘキサメチルホスホリルトリアミ
ド、ジオキサンが挙げられる。通常、反応温度は
−100゜〜25℃の範囲で行われ、反応時間は0.5〜
24時間である。化合物（）の使用モル数は、通
常、化合物（）に対して１〜２モルであり、塩
基は、化合物（）の１当量に対して、通常１〜
３当量である。溶媒は、通常用いられる範囲内の
量で使用される。 The reaction is usually carried out in an organic solvent, and usable organic solvents include, for example, methanol,
Examples include ethanal, toluene, dimethoxyethane, dimethyl sulfoxide, tetrahydrofuran, diethyl ether, hexamethylphosphoryltriamide, and dioxane. Usually, the reaction temperature is -100° to 25°C, and the reaction time is 0.5 to 25°C.
It is 24 hours. The number of moles of compound () used is usually 1 to 2 moles relative to compound (), and the amount of base used is usually 1 to 2 moles per equivalent of compound ().
It is 3 equivalents. Solvents are used in amounts within the range commonly used.
かくして、次式（）′−１：
又は、次式（）′−２：
（式中、R1，R2及びR3は前記と同じ意味を有
し；＊で示した三個の不整炭素の絶対配置は、式
（）−１の場合はいずれもＳであり、式（）−
２の場合はいずれもＲである）
で示される中間体が生成する。 Thus, the following equation ()'-1: Or the following formula ()'-2: (In the formula, R 1 , R 2 and R 3 have the same meanings as above; the absolute configuration of the three asymmetric carbons indicated by * is S in each case of formula ()-1, and the formula ()−
In all cases of 2, an intermediate represented by R is produced.
次に、上記化合物（）′−１又は（）′−２
を単離することなく（もちろん、単離する場合も
本発明の技術的範囲内に含まれる）、通常の脱保
護手法（加水分解など）により化合物（）に導
く。すなわち、化合物（）′を含む反応液に、
塩酸、硫酸等の鉱酸を加えて加熱するか、又は反
応液の溶媒を留去後、水−有機溶媒系（有機溶媒
としては、例えば、塩化メチレン、クロロホル
ム、酢酸エチル、トルエン、エーテル等が挙げら
れる。）で有機層を抽出し、さらに抽出液又は抽
出液の濃縮液に鉱酸を加えて、加熱すると、化合
物（）が生成する。鉱酸の使用モル数は、化合
物（）′に対し、大過剰、例えば、30倍モル、
反応温度は通常20〜150℃、反応時間は通常0.5〜
24時間である。なお、化合物（）′をクエン酸
水溶液又は希塩酸で処理すれば、（1S，2S，5S）
−２−ヒドロキシピナン−３−オン又は（1R，
2R，5R）−２−ヒドロキシピナン−３−オンを
回収することもできる。反応終了後、通常の中
和、精製手段により、化合物（）を単離するこ
とができる。生成物をさらに精製する場合は、例
えば強酸性イオン交換樹脂クロマトグラフイーを
用いるか、又は水−アルコール系（アルコールと
しては、例えば、メタノール、エタノール、プロ
ピルアルコール、イソプロピルアルコール、ｎ−
プタノール、tert−ブタノール等が挙げられる）
クロマトグラフイーを用いる。なお、所望であれ
ば、化合物（）をナトリウム塩、カリウム塩、
アンモニウム塩等の塩としてもよく、さらには、
酸付加塩とすることもできる。 Next, the above compound ()'-1 or ()'-2
without isolating (of course, isolation is also included within the technical scope of the present invention), and is led to compound () by ordinary deprotection techniques (such as hydrolysis). That is, to the reaction solution containing the compound ()′,
Add a mineral acid such as hydrochloric acid or sulfuric acid and heat, or distill off the solvent of the reaction solution, and then use a water-organic solvent system (organic solvents include, for example, methylene chloride, chloroform, ethyl acetate, toluene, ether, etc.). When the organic layer is extracted with the following methods, mineral acid is added to the extract or the concentrated solution of the extract, and the mixture is heated, the compound () is produced. The number of moles of the mineral acid used is a large excess, for example, 30 times the mole of the compound ()'.
Reaction temperature is usually 20~150℃, reaction time is usually 0.5~
It is 24 hours. In addition, if compound ()′ is treated with citric acid aqueous solution or dilute hydrochloric acid, (1S, 2S, 5S)
-2-hydroxypinan-3-one or (1R,
2R,5R)-2-hydroxypinan-3-one can also be recovered. After completion of the reaction, compound () can be isolated by conventional neutralization and purification means. If the product is to be further purified, for example by using strongly acidic ion exchange resin chromatography or by using a water-alcohol system (alcohols include, for example, methanol, ethanol, propyl alcohol, isopropyl alcohol, n-
(including butanol, tert-butanol, etc.)
Use chromatography. In addition, if desired, the compound () may be converted into sodium salt, potassium salt,
It may be used as a salt such as ammonium salt, and further,
It can also be used as an acid addition salt.
本発明は、シツフ塩基（）と化合物（）と
を塩基の存在下で反応させ、生成した化合物
（）′−を加水分解することにより、光学活性な
〔（３−アミノ−３−カルボキシ）−プロピル−１〕
ホスホン酸を選択的に合成するものであつて、従
来の化合物（）の光学活性体の製造方法と比べ
ると、安価に、かつ短い工程数で、高収率に、し
かも高選択的に大量に生産できる工業的製造方法
として極めて優れている。 The present invention produces an optically active [(3-amino-3-carboxy)- Propyl-1]
This method selectively synthesizes phosphonic acid, and compared to conventional methods for producing optically active forms of compound (), it can be produced in large quantities at low cost, in a short number of steps, in high yield, and with high selectivity. It is an extremely excellent industrial manufacturing method.
以下、実施例を示して本発明を更に詳細に説明
するが、本発明はこれらの実施例に限定されるこ
とはない。 EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.
実施例 １
〔Ｌ−（３−アミノ−３−カルボキシ）−プロピ
ル−１〕ホスホン酸
窒素気流下、テトラヒドロフラン３mlにカリウ
ムtert−ブトキシド177mgを加えて溶解した後、
この溶液を−78℃に冷却した。この中に化合物
（）（R1：Et，絶対配置Ｓ）200mgを加え、さら
にジエチルビニルホスホネート130mgを加えた。
反応液を−78℃にて１時間撹拌した後、この中に
1NHCl2mlを加え、反応液を減圧濃縮した。得ら
れた残渣に6NHCl4mlを加え、還流下で20時間撹
拌した。反応液を減圧濃縮し、プロピレンオキシ
ド３mlを加え、さらに１時間撹拌した。撹拌終了
後、反応液を濃縮し、得られた粗生成物をイオン
交換樹脂Dowex50W×２（商品名）を用いて精製
すると、目的化合物の結晶性粉末が98mg（収率68
％）得られた。この化合物は、〔α〕D＝＋14.6゜
（C1.0，6NHCl）、融点（m.p）226〜７℃であつ
た。Example 1 [L-(3-amino-3-carboxy)-propyl-1]phosphonic acid After adding and dissolving 177 mg of potassium tert-butoxide in 3 ml of tetrahydrofuran under a nitrogen stream,
The solution was cooled to -78°C. To this was added 200 mg of the compound () (R 1 :Et, absolute configuration S), and further 130 mg of diethyl vinyl phosphonate.
After stirring the reaction solution at -78℃ for 1 hour,
2 ml of 1NHCl was added, and the reaction solution was concentrated under reduced pressure. 4 ml of 6NHCl was added to the obtained residue, and the mixture was stirred under reflux for 20 hours. The reaction solution was concentrated under reduced pressure, 3 ml of propylene oxide was added, and the mixture was further stirred for 1 hour. After stirring, the reaction solution was concentrated and the resulting crude product was purified using ion exchange resin Dowex50W x 2 (trade name) to obtain 98 mg of crystalline powder of the target compound (yield 68
%) obtained. This compound had [α] D =+14.6° (C1.0,6NHCl) and a melting point (mp) of 226-7°C.
実施例 ２
〔Ｄ−（３−アミノ−３−カルボキシ）−プロピ
ル−１〕ホスホン酸
窒素気流下テトラヒドロフラン３mlにカリウム
tert−ブトキシド177mgを加えて溶解した後、こ
の溶解を−78℃に冷却した。この中に化合物
（）（R1：Et，絶対配置Ｒ）200mgを加え、さら
にジエチルビニルホスホネート130mgを加えた。
反応液を−78℃にて１時間撹拌した後、この中に
1NHCl2mlを加え反応液を減圧濃縮した。Example 2 [D-(3-amino-3-carboxy)-propyl-1]phosphonic acid Potassium in 3 ml of tetrahydrofuran under nitrogen stream
After adding and dissolving 177 mg of tert-butoxide, the solution was cooled to -78°C. To this was added 200 mg of the compound () (R 1 :Et, absolute configuration R), and further 130 mg of diethyl vinyl phosphonate.
After stirring the reaction solution at -78℃ for 1 hour,
2 ml of 1NHCl was added and the reaction solution was concentrated under reduced pressure.
以下実施例１と同様に処理し、目的化合物の結
晶性粉末96mg（収率66％）を得た。この化合物は
〔α〕D＝−13.0゜（C1.0，6NHCl）、融点226〜227℃
であつた。 Thereafter, the same treatment as in Example 1 was carried out to obtain 96 mg (yield: 66%) of a crystalline powder of the target compound. This compound has [α] D = -13.0° (C1.0, 6NHCl), melting point 226-227℃
It was hot.
実施例 ３
〔Ｌ−（３−アミノ−３−カルボキシ）−プロピ
ル−１〕ホスホン酸
窒素気流下、テトラヒドロフラン３mlにカリウ
ムtert−ブトキシト177mgを加えて溶解した後、
この溶液を−78℃に冷却した。この中に化合物
（）（R1：tert−ブチル、絶対配置Ｓ）222mgを
加え、さらにジエチルビニルホスホオネート130
mgを加えた。反応液を−78℃にて１時間撹拌した
後、この中に1NHCl2mlを加え、減圧濃縮した。Example 3 [L-(3-amino-3-carboxy)-propyl-1]phosphonic acid After adding and dissolving 177 mg of potassium tert-butoxide in 3 ml of tetrahydrofuran under a nitrogen stream,
The solution was cooled to -78°C. Added 222 mg of the compound () (R 1 : tert-butyl, absolute configuration S) to this, and further added 130 mg of diethyl vinyl phosphoonate.
mg was added. After stirring the reaction solution at -78°C for 1 hour, 2 ml of 1NHCl was added thereto, and the mixture was concentrated under reduced pressure.
以下実施例１と同様に処理し、目的化合物の結
晶性粉末94mg（収率65％）を得た。この化合物は
〔α〕D＝＋14.0゜（C1.0，6NHCl）融点226〜227℃
であつた。 Thereafter, the same treatment as in Example 1 was carried out to obtain 94 mg (yield: 65%) of a crystalline powder of the target compound. This compound has [α] D = +14.0° (C1.0, 6NHCl), melting point 226-227°C
It was hot.
実施例 ４
〔Ｌ−（３−アミノ−３−カルボキシ）−プロピ
ル−１〕ホスホン酸
窒素気流下、テトラヒドロフラン３mlにカリウ
ムtert−ブトキシド117mgを加えて溶解した後、
この溶液を−78℃に冷却した。この中に化合物
（）（R1：ベンジル，絶体配置Ｓ）249mgを加
え、さらにジベンジルビニルホスホネート227mg
を加えた。反応液を−78℃にて１時間撹拌した
後、この中に1NHCl2mlを加え、減圧濃縮した。Example 4 [L-(3-amino-3-carboxy)-propyl-1]phosphonic acid After adding and dissolving 117 mg of potassium tert-butoxide in 3 ml of tetrahydrofuran under a nitrogen stream,
The solution was cooled to -78°C. Added 249 mg of compound () (R 1 : benzyl, absolute configuration S) to this, and further added 227 mg of dibenzyl vinyl phosphonate.
added. After stirring the reaction solution at -78°C for 1 hour, 2 ml of 1NHCl was added thereto, and the mixture was concentrated under reduced pressure.
以下実施例１と同様に処理し、目的化合物の結
晶性粉末91mg（収率63％）を得た。この化合物
は、〔α〕D＝＋13.3゜（C1.0，6NHCl）融点は226〜
227℃であつた。 Thereafter, the same treatment as in Example 1 was carried out to obtain 91 mg (yield: 63%) of a crystalline powder of the target compound. This compound has a melting point of [α] D = +13.3° (C1.0, 6NHCl) of 226~
It was 227℃.
Claims (1)
岐状のアルキル基、アリール基又はアラルキル基
を表し；＊で示した三個の不整炭素の絶対配置は
いずれもＳである） で示される化合物と、 次式（）： （式中、R2及びR3は同一でも異なつていてもよ
く、それぞれ、炭素数１〜５の直鎖状もしくは分
岐状のアルキル基、アリール基又はアラルキル基
を表す） で示される化合物とを、塩基の存在下で反応せし
め、次いで、生成した化合物を加水分解すること
を特徴とする、次式（）−１： （上式のアミノ酸はＬ−体である） で示される〔Ｌ−（３−アミノ−３−カルボキシ）
−プロピル−１〕ホスホン酸の製造法。 ２ 次式（）−２： （式中、R1は炭素数１〜５の直鎖状もしくは分
岐状のアルキル基、アリール基又はアラルキル基
を表し；＊で示した三個の不整炭素の絶対配置は
いずれもＲである） で示される化合物と、 次式（）： （式中、R2及びR3は同一でも異なつていてもよ
く、それぞれ、炭素数１〜５の直鎖状もしくは分
岐状のアルキル基、アリール基又はアラルキル基
を表す） で示される化合物とを、塩基の存在下で反応せし
め、次いで、生成した化合物を加水分解すること
を特徴とする、次式（）−２： （上式のアミノ酸はＤ−体である） で示される〔Ｄ−（３−アミノ−３−カルボキシ）
−プロピル−１〕ホスホン酸の製造法。[Claims] Primary formula ()-1: (In the formula, R 1 represents a linear or branched alkyl group, aryl group, or aralkyl group having 1 to 5 carbon atoms; the absolute configuration of the three asymmetric carbon atoms indicated by * is all S.) A compound represented by and the following formula (): (In the formula, R 2 and R 3 may be the same or different and each represents a linear or branched alkyl group, aryl group, or aralkyl group having 1 to 5 carbon atoms) is reacted in the presence of a base, and then the generated compound is hydrolyzed, the following formula ()-1: (The amino acid in the above formula is L-form) [L-(3-amino-3-carboxy)
-Propyl-1]Production method of phosphonic acid. Quadratic formula ()-2: (In the formula, R 1 represents a linear or branched alkyl group, aryl group, or aralkyl group having 1 to 5 carbon atoms; the absolute configuration of the three asymmetric carbon atoms indicated by * is R.) A compound represented by and the following formula (): (In the formula, R 2 and R 3 may be the same or different and each represents a linear or branched alkyl group, aryl group, or aralkyl group having 1 to 5 carbon atoms) is reacted in the presence of a base, and then the generated compound is hydrolyzed, the following formula ()-2: (The amino acid in the above formula is D-form) [D-(3-amino-3-carboxy)
-Propyl-1]Production method of phosphonic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22056383A JPS60112795A (en) | 1983-11-25 | 1983-11-25 | Preparation of optical active ((3-amino-3-carboxy)-propyl- 1) phosphonic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22056383A JPS60112795A (en) | 1983-11-25 | 1983-11-25 | Preparation of optical active ((3-amino-3-carboxy)-propyl- 1) phosphonic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60112795A JPS60112795A (en) | 1985-06-19 |
| JPH0338279B2 true JPH0338279B2 (en) | 1991-06-10 |
Family
ID=16752948
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP22056383A Granted JPS60112795A (en) | 1983-11-25 | 1983-11-25 | Preparation of optical active ((3-amino-3-carboxy)-propyl- 1) phosphonic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60112795A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11220521B2 (en) * | 2017-04-17 | 2022-01-11 | Nahls Corporation Co., Ltd. | Optically-active 2-amino-phosphonoalkane acid, optically-active 2-amino-phosphonoalkane acid salt, and hydrates of these |
-
1983
- 1983-11-25 JP JP22056383A patent/JPS60112795A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60112795A (en) | 1985-06-19 |
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