JP3829266B2 - Optically active amino acid ester, method for producing the same, and method for producing optically active 2-methoxycyclohexanol - Google Patents
Optically active amino acid ester, method for producing the same, and method for producing optically active 2-methoxycyclohexanol Download PDFInfo
- Publication number
- JP3829266B2 JP3829266B2 JP17458597A JP17458597A JP3829266B2 JP 3829266 B2 JP3829266 B2 JP 3829266B2 JP 17458597 A JP17458597 A JP 17458597A JP 17458597 A JP17458597 A JP 17458597A JP 3829266 B2 JP3829266 B2 JP 3829266B2
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- amino acid
- methoxycyclohexanol
- active amino
- acid ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- -1 amino acid ester Chemical class 0.000 title claims description 20
- DCQQZLGQRIVCNH-UHFFFAOYSA-N 2-methoxycyclohexan-1-ol Chemical compound COC1CCCCC1O DCQQZLGQRIVCNH-UHFFFAOYSA-N 0.000 title claims description 16
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 229940024606 amino acid Drugs 0.000 claims description 37
- 235000001014 amino acid Nutrition 0.000 claims description 37
- 150000001413 amino acids Chemical class 0.000 claims description 21
- 230000003287 optical effect Effects 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 238000000926 separation method Methods 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- NPKISZUVEBESJI-AWEZNQCLSA-N N-benzoyl-L-phenylalanine Chemical compound C([C@@H](C(=O)O)NC(=O)C=1C=CC=CC=1)C1=CC=CC=C1 NPKISZUVEBESJI-AWEZNQCLSA-N 0.000 claims description 4
- NPKISZUVEBESJI-UHFFFAOYSA-N Nalpha-benzoyl-L-phenylalanine Natural products C=1C=CC=CC=1C(=O)NC(C(=O)O)CC1=CC=CC=C1 NPKISZUVEBESJI-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- CGRCVIZBNRUWLY-HNNXBMFYSA-N (2s)-2-[(4-methylphenyl)sulfonylamino]-3-phenylpropanoic acid Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CGRCVIZBNRUWLY-HNNXBMFYSA-N 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 150000001298 alcohols Chemical class 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- DCQQZLGQRIVCNH-RNFRBKRXSA-N (1r,2r)-2-methoxycyclohexan-1-ol Chemical compound CO[C@@H]1CCCC[C@H]1O DCQQZLGQRIVCNH-RNFRBKRXSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000011982 enantioselective catalyst Substances 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-UHFFFAOYSA-N 0.000 description 1
- AGPKZVBTJJNPAG-RFZPGFLSSA-N D-Isoleucine Chemical compound CC[C@@H](C)[C@@H](N)C(O)=O AGPKZVBTJJNPAG-RFZPGFLSSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 description 1
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 1
- 229930182832 D-phenylalanine Natural products 0.000 description 1
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 150000007649 L alpha amino acids Chemical class 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- GHDIHPNJQVDFBL-UHFFFAOYSA-N methoxycyclohexane Chemical compound COC1CCCCC1 GHDIHPNJQVDFBL-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003021 phthalic acid derivatives Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 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
- 238000000638 solvent extraction Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
Images
Landscapes
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、医薬や農薬の原料として重要な光学活性アルコール類の製造方法に関するものであり、更に詳しくはラセミアルコール類と光学活性アミノ酸類から得られるアミノ酸エステル類をジアステレオマー分割した後に加水分解する事による光学活性アルコール類の製造法である。
【０００２】
【従来の技術】
従来から光学活性アルコール類の製造法は種々知られている。例えば(1)ラセミアルコールのカルボン酸エステルを酵素で不斉加水分解する方法 （Agric.Biol.Chem., 46,757(1982)）、(2)前駆体のケトン類を酵素で不斉水素化する方法（日化誌、1315（1983)）、(3)前駆体のケトン類を不斉触媒と水素を用いて不斉還元する方法（J.Am.Chem.Soc.,101,3129(1979)）、(4)ラセミアルコールとフタル酸無水物を反応させ、得られたラセミカルボン酸を光学活性α−フェニルエチルアミンで光学分割した後、加水分解して光学活性アルコールを得る方法（EP656344）等が知られている。これらの方法は光学活性アルコール類を製造する優れた方法であるが、それぞれ欠点もある。(1)の方法は高価な酵素を使用すること、また酵素の光学選択性が目的化合物によって大きく異なり、高い光学純度のアルコール類を得る事が難しい場合が多い。(2)では高価な酵素を使用すること、また酵素活性が一般に高くない。(3)では高価な不斉触媒を使用すること、また高い光学純度のアルコール類を得ることが難しい。(4)ではフタル酸誘導体にしてから改めてジアステレオマー塩分割をしなければならず煩雑である、等の欠点がある。
【０００３】
【発明が解決しようとする課題】
本発明は高い光学純度の光学活性の２−メトキシシクロヘキサノールを生産するに当たり、安価で、簡便な工業的製造法を提供することを目的とする。
【０００４】
【課題を解決するための手段】
本発明者らは光学活性アルコール類の製造法を鋭意検討した結果、光学活性アミノ酸類とラセミの２−メトキシシクロヘキサノールから合成されるアミノ酸エステル類をジアステレオマー分割し、次いで加水分解することにより、高い光学純度の光学活性２−メトキシシクロヘキサノールを効率よく製造出来ることを見いだし、本発明を完成させた。即ち、本発明はラセミの２−メトキシシクロヘキサノールと下記一般式（Ｉ）または（ＩＩ）で表される光学活性アミノ酸類と反応させて得られるアミノ酸エステル類をジアステレオマー分割することによる光学活性アミノ酸エステルの製造法、およびその光学活性アミノ酸エステル、更に得られた光学活性アミノ酸エステルを加水分解する事による光学活性２−メトキシシクロヘキサノールの製造方法である。
【化７】
【化８】
【０００５】
【発明の実施の形態】
原料のラセミアルコール類は２−メトキシシクロヘキサノールである（以下これをラセミアルコール類と称する場合もある）。また、ラセミアルコール類とはＲ体とＳ体が等量含まれる混合物だけでなく、Ｓ体、或いはＲ体が５０％以上、９９％以下の混合物も含む。
【０００６】
光学活性アミノ酸類の立体構造は目的に応じてＳ−構造、Ｒ−構造の化合物が使用できる。工業的に大量に、且つ安価に入手できる点から天然型のＬ−α−アミノ酸類が好ましいが、これらに限定されず、非天然型のアミノ酸類でも使用できる。例えば、Ｌ−アラニン、Ｌ−フェニルアラニン、Ｌ−バリン、Ｌ−イソロイシン、Ｌ−ロイシン等の天然型アミノ酸類、Ｄ−アラニン、Ｄ−フェニルアラニン、Ｄ−バリン、Ｄ−イソロイシン、Ｄ−ロイシン等の非天然型アミノ酸等が挙げられる。
【０００７】
本発明においてアミノ酸類は反応性や分割効率を考慮してアミノ基をＮ−置換したアシル誘導体やスルホニル誘導体に変換してから使用する。例えばベンゾイル、トルオイル、クロロベンゾイル等のアリールカルボニル基で修飾したアミノ酸のアシル誘導体が挙げられる。また、ベンゼンスルホニル、トルエンスルホニル、クロロベンゼンスルホニル等のアリールスルホニル基で修飾したアミノ酸のスルホニル誘導体が挙げられる。
【０００８】
光学活性アミノ酸類とラセミアルコール類のエステルは通常の方法で製造できる。例えば光学活性アミノ酸類の酸ハロゲン化物とラセミアルコール類を反応させる方法、光学活性アミノ酸類とラセミアルコール類をエステル化触媒共存下で加熱脱水する方法、光学活性アミノ酸類の酸無水物とラセミアルコール類を反応させる方法等が挙げられる。
【０００９】
かくして製造された光学活性アミノ酸類とラセミアルコール類のエステルをジアステレオマー分割する。光学分割の方法には、それぞれの光学異性体の溶解度差を利用して晶析分離する方法、それぞれの光学異性体をカラム分離する方法、それぞれの光学異性体を擬似移動床を使用して分離する方法等が挙げられ、目的に応じて分割法を選択する事ができる。晶析分離する場合には、晶析溶媒はそれぞれのエステルにより異なるが、一般には水、アルコール類、脂肪族炭化水素類、芳香族炭化水素類、ケトン類、エーテル類、或いはそれらの混合溶媒が使用できる。カラム分割する場合には、カラム充填剤としてシリカゲル、修飾シリカゲル等が使用できる。特に、工業生産をする場合には、カラム分離を擬似移動床で実施するとより効果的である。
【００１０】
ジアステレオマー分割された光学活性アミノ酸エステル類を加水分解することで、目的の光学活性アルコール類を製造できる。エステル類の加水分解は酸、アルカリの何れでも可能であるが、目的化合物のアルコール類がラセミ化を併発しない条件が必須である。例えば硫酸、塩酸等の鉱酸水溶液、或いは水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等のアルカリ水溶液と反応させればよい。その際に、溶媒として水以外にも、メタノール、イソプロパノール、アセトン、トルエン、クロロホルム等の有機溶媒を共存させて加水分解させる事もできる。反応温度はそれぞれの化合物によって加水分解速度が異なる為に一概に云えないが、ラセミ化を併発しない範囲内で加熱してもよく、室温から１００℃が好ましい。かくして得られた光学活性アルコール類を反応液から回収するには、例えば溶媒抽出で光学活性アミノ酸類と分離した後、蒸留する事で光学活性２−メトキシシクロヘキサノールを得ることができる。
【００１１】
【実施例】
以下、実施例及び比較例を挙げて本発明を詳細に説明するが、本発明はこれらに限定されるものではない。尚、ＨＰＬＣでの光学純度分析は、対象化合物により溶離液組成は異なるが、基本的分析条件は以下の通りである。
【００１２】
カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ（ジーエル サイエンス製）、溶離液：０．５％燐酸水溶液／アセトニトリル＝２０〜８０／８０〜２０、流速：２ｍｌ／ｍｉｎ.
実施例１
温度計、滴下ロート、コンデンサー、攪拌機を装着した５００ｍｌの４つ口フラスコにＮ−ベンゾイル−Ｌ−フェニルアラニン２７ｇ（０．１モル）とトルエン３００ｍｌを仕込んだ。次いで、８０〜８５℃で攪拌しながら塩化チオニル１３ｇを３０分間で滴下し、更に１時間攪拌を継続した。反応終了後、減圧濃縮し、未反応の塩化チオニルと塩酸を除去した。濃縮液にトランス−２−メトキシシクロヘキサノール１４．３ｇ（０．１１モル）とトルエン１００ｍｌを加え、８０〜９０℃で２時間反応させた後、減圧濃縮して（１Ｓ）−（Ｎ−ベンゾイル−Ｌ−フェニルアラニルオキシ）−（２Ｓ）−メトキシシクロヘキサンと（１Ｒ）−（Ｎ−ベンゾイル−Ｌ−フェニルアラニルオキシ）−（２Ｒ）−メトキシシクロヘキサンの混合物を得た。濃縮液にメタノール１５０ｍｌを加えて加熱溶解させた後、室温まで冷却して析出物を濾過した。乾燥して１５．２ｇの結晶を得た。組成分析したところ、（１Ｓ）−（Ｎ−ベンゾイル−Ｌ−フェニルアラニルオキシ）−（２Ｓ）−メトキシシクロヘキサンと（１Ｒ）−（Ｎ−ベンゾイル−Ｌ−フェニルアラニルオキシ）−（２Ｒ）−メトキシシクロヘキサンのモル比が４．６／１であった。この結晶を２００ｍｌのメタノールで再結晶して、（１Ｓ）−（Ｎ−ベンゾイル−Ｌ−フェニルアラニルオキシ）−（２Ｓ）−メトキシシクロヘキサンと（１Ｒ）−（Ｎ−ベンゾイル−Ｌ−フェニルアラニルオキシ）−２Ｒ−メトキシシクロヘキサンのモル比が１００／１の結晶を１１．２ｇ得た。この（１Ｓ）−（Ｎ−ベンゾイル−Ｌ−フェニルアラニルオキシ）−（２Ｓ）−メトキシシクロヘキサンのＮＭＲおよびＩＲチャートを図１および図２に示す。ＮＭＲ測定は、日本電子製ＪＭＭＮ−ＥＸ９０を用いて、測定サンプルをＣＤＣｌ3溶液で測定した。ＩＲ測定は、パーキンエルマー社製ＳＹＳＴＥＭ２０００を用いて、ＫＢｒ錠剤法で行なった。
【００１３】
この結晶を１規定水酸化ナトリウム水溶液４４ｍｌとメタノール２０ｍｌに希釈し、４０℃ で２時間反応させて加水分解した。反応液を減圧濃縮して大部分のメタノールを除去した後、２０ｍｌのクロロホルムで３回抽出し、濃縮して（１Ｓ）−ヒドロキシ−（２Ｓ）−メトキシシクロヘキサン３．７ｇを得た。光学純度は９８％ｅｅであった。
【００１４】
また、抽残水層を硫酸で酸性にしたのち、析出結晶を濾過してＮ−ベンゾイル−Ｌ−フェニルアラニンを回収した。このＮ−ベンゾイル−Ｌ−フェニルアラニンは乾燥後、再使用した結果、同様の分割結果を与えた。
【００１６】
実施例２
実施例１と同様の装置にＮ−パラニトロベンゾイル−Ｌ−アラニン２３．８ｇ（０．１モル）、トランス−２−メトキシシクロヘキサノール１４．３ｇ（０．１１モル）、トルエン２００ｍｌを仕込み８０〜８５℃で攪拌した。塩化チオニル１３ｇを１時間で滴下し、更に１時間攪拌した。次いで減圧濃縮し、残査にイソプロパノール１００ｍｌを添加し１時間室温中で攪拌した。析出結晶を濾過し、２規定水酸化ナトリウム水溶液で加水分解して、トランス−２−メトキシシクロヘキサノール５．２ｇ得た。（Ｒ，Ｒ）−体の光学純度は５８％ｅｅであった。
【００１７】
実施例３
実施例１と同様の装置にＮートシル−Ｌ−フェニルアラニン３１．９ｇ（０．１モル）、トランスー２ーメトキシシクロヘキサノール１４．３ｇ（０．１１モル）、トルエン２００ｍｌおよびパラトルエンスルホン酸１ｇを仕込み、５時間加熱環流して反応させた。濃縮後残査を５０ｍｌのイソプロパノールで２回再結晶し、光学純度９９％ｅｅの（１Ｓ）−（Ｎ−トシル−Ｌ−フェニルアラニルオキシ）−（２Ｓ）−メトキシシクロヘキサン１２．５ｇを得た。このＮＭＲおよびＩＲチャートを図３および図４に示す。測定条件は実施例１と同様である。
【００１９】
【発明の効果】
本発明によれば、ラセミの２−メトキシシクロヘキサノールから光学純度の高い光学活性２−メトキシシクロヘキサノールを容易に製造することが出来る。また、回収した光学活性アミノ酸類はリサイクル使用することが出来る。
【図面の簡単な説明】
【図１】実施例１で得た（１Ｓ）−（Ｎ−ベンゾイル−Ｌ−フェニルアラニルオキシ）−（２Ｓ）−メトキシシクロヘキサンのＮＭＲチャートを示す図である。
【図２】実施例１で得た（１Ｓ）−（Ｎ−ベンゾイル−Ｌ−フェニルアラニルオキシ）−（２Ｓ）−メトキシシクロヘキサンのＩＲチャートを示す図である。
【図３】実施例３で得た（１Ｓ）−（Ｎ−トシル−Ｌ−フェニルアラニルオキシ）−（２Ｓ）−メトキシシクロヘキサンのＮＭＲチャートを示す図である。
【図４】実施例３で得た（１Ｓ）−（Ｎ−トシル−Ｌ−フェニルアラニルオキシ）−（２Ｓ）−メトキシシクロヘキサンのＩＲチャートを示す図である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing optically active alcohols that are important as raw materials for pharmaceuticals and agricultural chemicals. More specifically, the present invention relates to hydrolysis after diastereomeric resolution of amino acid esters obtained from racemic alcohols and optically active amino acids. This is a method for producing optically active alcohols.
[0002]
[Prior art]
Conventionally, various methods for producing optically active alcohols are known. For example, (1) Asymmetric hydrolysis of racemic alcohol carboxylates (Agric. Biol. Chem., 46,757 (1982)), (2) Asymmetric hydrogenation of precursor ketones (Nikka Journal, 1315 (1983)), (3) Asymmetric reduction of precursor ketones using an asymmetric catalyst and hydrogen (J. Am. Chem. Soc., 101, 3129 (1979)) (4) A method in which racemic alcohol and phthalic anhydride are reacted and the obtained racemic carboxylic acid is optically resolved with optically active α-phenylethylamine and then hydrolyzed to obtain an optically active alcohol (EP656344) is known. It has been. These methods are excellent methods for producing optically active alcohols, but each has drawbacks. In the method (1), an expensive enzyme is used, and the optical selectivity of the enzyme varies greatly depending on the target compound, and it is often difficult to obtain alcohols with high optical purity. In (2), an expensive enzyme is used, and the enzyme activity is generally not high. In (3), it is difficult to use an expensive asymmetric catalyst and to obtain alcohols with high optical purity. In (4), the diastereomeric salt has to be divided again after making the phthalic acid derivative, which is troublesome.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide an inexpensive and simple industrial production method for producing optically active 2-methoxycyclohexanol having high optical purity.
[0004]
[Means for Solving the Problems]
As a result of intensive studies on the production method of optically active alcohols, the present inventors have obtained a diastereomer resolution of an optically active amino acid and an amino acid ester synthesized from racemic 2-methoxycyclohexanol, followed by hydrolysis. The present inventors have found that optically active 2-methoxycyclohexanol having high optical purity can be efficiently produced, and the present invention has been completed. That is, the present invention provides optical activity by diastereomer resolution of amino acid esters obtained by reacting racemic 2-methoxycyclohexanol with optically active amino acids represented by the following general formula (I) or (II). A method for producing an amino acid ester, an optically active amino acid ester thereof, and a method for producing optically active 2-methoxycyclohexanol by hydrolyzing the obtained optically active amino acid ester.
[Chemical 7]
[Chemical 8]
[0005]
DETAILED DESCRIPTION OF THE INVENTION
The starting racemic alcohol is 2-methoxycyclohexanol (hereinafter sometimes referred to as racemic alcohol) . The racemic alcohols include not only a mixture containing an equal amount of R and S isomers but also a mixture containing 50% or more and 99% or less of S or R isomers.
[0006]
Conformation of optically active amino acids are S- structure according to the purpose, the compound of R- structure can be used. Natural L-α-amino acids are preferred from the viewpoint of being commercially available in large quantities and at a low price, but are not limited to these, and non-natural amino acids can also be used. For example, L- alanine, L- phenylalanine, L- valine, L- isoleucine, natural amino acids L- leucine or the like, D- alanine, D- phenylalanine, D- valine, D- isoleucine, D- leucine, etc. Examples include non-natural amino acids .
[0007]
Amino acids in the present invention is to use after converting the acyl derivatives or sulfonyl derivatives N- substituted amino group in consideration of reactivity and splitting efficiency. Example Ebabe Nzoiru, toluoyl, acyl derivatives of modified amino acids in the arylcarbonyl group such as chloro benzoyl and the like. Further, base Nzensuruhoniru, toluenesulfonyl, a sulfonyl derivative of modified amino acids in the arylsulfonyl group such as chlorobenzene sulfonyl.
[0008]
Esters of optically active amino acids and racemic alcohols can be produced by conventional methods. For example, a method of reacting an acid halide of an optically active amino acid with a racemic alcohol, a method of heating and dehydrating an optically active amino acid and a racemic alcohol in the presence of an esterification catalyst, an acid anhydride of an optically active amino acid and a racemic alcohol And the like.
[0009]
The optically active amino acids and racemic alcohol esters thus prepared are diastereomerically resolved. The optical resolution method includes crystallization separation using the difference in solubility of each optical isomer, column separation of each optical isomer, and separation of each optical isomer using a simulated moving bed. And a division method can be selected according to the purpose. In the case of crystallization separation, the crystallization solvent varies depending on each ester, but generally water, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, ketones, ethers, or a mixed solvent thereof is used. Can be used. When the column is divided, silica gel, modified silica gel or the like can be used as a column filler. In particular, in industrial production, it is more effective to perform column separation in a simulated moving bed.
[0010]
The target optically active alcohol can be produced by hydrolyzing diastereomeric resolved optically active amino acid esters. The ester can be hydrolyzed by either acid or alkali, but it is essential that the alcohol of the target compound does not cause racemization. For example, the reaction may be performed with an aqueous mineral acid solution such as sulfuric acid or hydrochloric acid, or an alkaline aqueous solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium bicarbonate. In that case, it can also hydrolyze by coexisting organic solvents, such as methanol, isopropanol, acetone, toluene, chloroform, other than water as a solvent. The reaction temperature cannot be generally specified because the hydrolysis rate varies depending on each compound. However, the reaction temperature may be heated within a range not causing racemization, and is preferably from room temperature to 100 ° C. In order to recover the optically active alcohol thus obtained from the reaction solution, for example, optically active 2-methoxycyclohexanol can be obtained by distillation after separation from the optically active amino acid by solvent extraction.
[0011]
【Example】
EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated in detail, this invention is not limited to these. Incidentally, the optical purity analysis by HPLC is different in eluent composition depending on the target compound, but the basic analysis conditions are as follows.
[0012]
Column: Inertsil ODS (manufactured by GL Science), eluent: 0.5% phosphoric acid aqueous solution / acetonitrile = 20-80 / 80-20, flow rate: 2 ml / min.
Example 1
A 500 ml four-necked flask equipped with a thermometer, a dropping funnel, a condenser, and a stirrer was charged with 27 g (0.1 mol) of N-benzoyl-L-phenylalanine and 300 ml of toluene. Next, 13 g of thionyl chloride was added dropwise over 30 minutes while stirring at 80 to 85 ° C., and stirring was further continued for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove unreacted thionyl chloride and hydrochloric acid. To the concentrated solution, 14.3 g (0.11 mol) of trans-2-methoxycyclohexanol and 100 ml of toluene were added and reacted at 80 to 90 ° C. for 2 hours, and then concentrated under reduced pressure to give (1S)-(N-benzoyl- A mixture of (L-phenylalanyloxy)-(2S) -methoxycyclohexane and (1R)-(N-benzoyl-L-phenylalanyloxy)-(2R) -methoxycyclohexane was obtained. After 150 ml of methanol was added to the concentrate and dissolved by heating, the solution was cooled to room temperature and the precipitate was filtered. Drying gave 15.2 g of crystals. As a result of composition analysis, (1S)-(N-benzoyl-L-phenylalanyloxy)-(2S) -methoxycyclohexane and (1R)-(N-benzoyl-L-phenylalanyloxy)-(2R)- The molar ratio of methoxycyclohexane was 4.6 / 1. The crystals are recrystallized from 200 ml of methanol to give (1S)-(N-benzoyl-L-phenylalanyloxy)-(2S) -methoxycyclohexane and (1R)-(N-benzoyl-L-phenylalanyl). 11.2 g of a crystal having a molar ratio of (oxy) -2R-methoxycyclohexane of 100/1 was obtained. The NMR and IR charts of this (1S)-(N-benzoyl-L-phenylalanyloxy)-(2S) -methoxycyclohexane are shown in FIG. 1 and FIG. For NMR measurement, JMMN-EX90 manufactured by JEOL Ltd. was used, and the measurement sample was measured with a CDCl3 solution. IR measurement was performed by KBr tablet method using SYSTEM2000 manufactured by PerkinElmer.
[0013]
The crystals were diluted with 44 ml of 1N aqueous sodium hydroxide solution and 20 ml of methanol, and reacted at 40 ° C. for 2 hours for hydrolysis. The reaction solution was concentrated under reduced pressure to remove most of the methanol, then extracted three times with 20 ml of chloroform, and concentrated to obtain 3.7 g of (1S) -hydroxy- (2S) -methoxycyclohexane. The optical purity was 98% ee.
[0014]
Further, the extracted residual water layer was acidified with sulfuric acid, and the precipitated crystals were filtered to recover N-benzoyl-L-phenylalanine. This N-benzoyl-L-phenylalanine was dried and reused, giving similar resolution results.
[0016]
Example 2
The same apparatus as in Example 1 was charged with 23.8 g (0.1 mol) of N-paranitrobenzoyl-L-alanine, 14.3 g (0.11 mol) of trans-2-methoxycyclohexanol, and 200 ml of toluene. Stir at 85 ° C. 13 g of thionyl chloride was added dropwise over 1 hour, and the mixture was further stirred for 1 hour. Subsequently, the mixture was concentrated under reduced pressure, and 100 ml of isopropanol was added to the residue, followed by stirring for 1 hour at room temperature. The precipitated crystals were filtered and hydrolyzed with a 2N aqueous sodium hydroxide solution to obtain 5.2 g of trans-2-methoxycyclohexanol. The optical purity of the (R, R) -isomer was 58% ee.
[0017]
Example 3
In the same apparatus as in Example 1, 31.9 g (0.1 mol) of N-tosyl-L-phenylalanine, 14.3 g (0.11 mol) of trans-2-methoxycyclohexanol, 200 ml of toluene and 1 g of paratoluenesulfonic acid were charged. The reaction was carried out by refluxing with heating for 5 hours. After concentration, the residue was recrystallized twice with 50 ml of isopropanol to obtain 12.5 g of (1S)-(N-tosyl-L-phenylalanyloxy)-(2S) -methoxycyclohexane having an optical purity of 99% ee. . The NMR and IR charts are shown in FIGS. The measurement conditions are the same as in Example 1.
[0019]
【The invention's effect】
According to the present invention, optically active 2-methoxycyclohexanol having high optical purity can be easily produced from racemic 2-methoxycyclohexanol . The recovered optically active amino acids can be recycled.
[Brief description of the drawings]
1 is a diagram showing an NMR chart of (1S)-(N-benzoyl-L-phenylalanyloxy)-(2S) -methoxycyclohexane obtained in Example 1. FIG.
2 is a diagram showing an IR chart of (1S)-(N-benzoyl-L-phenylalanyloxy)-(2S) -methoxycyclohexane obtained in Example 1. FIG.
3 is a diagram showing an NMR chart of (1S)-(N-tosyl-L-phenylalanyloxy)-(2S) -methoxycyclohexane obtained in Example 3. FIG.
4 is an IR chart of (1S)-(N-tosyl-L-phenylalanyloxy)-(2S) -methoxycyclohexane obtained in Example 3. FIG.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17458597A JP3829266B2 (en) | 1996-07-02 | 1997-06-30 | Optically active amino acid ester, method for producing the same, and method for producing optically active 2-methoxycyclohexanol |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8-172711 | 1996-07-02 | ||
| JP17271196 | 1996-07-02 | ||
| JP17458597A JP3829266B2 (en) | 1996-07-02 | 1997-06-30 | Optically active amino acid ester, method for producing the same, and method for producing optically active 2-methoxycyclohexanol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH1072388A JPH1072388A (en) | 1998-03-17 |
| JP3829266B2 true JP3829266B2 (en) | 2006-10-04 |
Family
ID=26494978
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17458597A Expired - Fee Related JP3829266B2 (en) | 1996-07-02 | 1997-06-30 | Optically active amino acid ester, method for producing the same, and method for producing optically active 2-methoxycyclohexanol |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3829266B2 (en) |
-
1997
- 1997-06-30 JP JP17458597A patent/JP3829266B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH1072388A (en) | 1998-03-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2010229157A (en) | Method for preparing r-(-)-carnitine from s-(-)-chlorosuccinic acid or derivative thereof | |
| CN117886708A (en) | Synthesis method of milbelin benzenesulfonate | |
| US6372941B1 (en) | Processes for producing β-halogeno-α-amino-carboxylic acids and phenylcysteine derivatives and intermediates thereof | |
| US4005088A (en) | Process for the chemical separation of racemic modifications of α-aminocarboxylic acid derivatives, and cinchonidine salt intermediates | |
| CN102911107B (en) | The preparation method of S 21403 | |
| US6310242B1 (en) | Process for preparing D-alloisoleucine and intermediates for preparation | |
| JP3829266B2 (en) | Optically active amino acid ester, method for producing the same, and method for producing optically active 2-methoxycyclohexanol | |
| JP4138928B2 (en) | Method for producing D-alloisoleucine and intermediate for production | |
| JP2011098975A (en) | Chiral pure n-(trans-4-isopropyl-cyclohexylcarbonyl)-d-phenylalanine and method for producing crystal structure transformation product thereof | |
| HU204247B (en) | Process for optical resolving raceme compositions of alpha-naphtyl-propionic acid derivatives | |
| US20060135784A1 (en) | Process for producing 3-amino-2-hydroxypropionic acid derivatives | |
| US3796748A (en) | Dehydroabietylammonium d-(-)-2-chloroacetylamino-2-(p-hydroxyphenyl)-acetate | |
| JPS63139179A (en) | Optical resolution of dl-pantolactone | |
| JPH02243663A (en) | Synthesis method of optically active amino acids | |
| JPH10218847A (en) | Production of tartranilic acid | |
| JP3790325B2 (en) | Method for producing N-acetylcysteine derivative | |
| JP4005168B2 (en) | Process for producing optically active 2-aryloxypropionic acid | |
| US5243070A (en) | Process for resolution of racemates of 2,2-dimethylcyclopropanecarboxylic acid | |
| JPH09143173A (en) | Optically active 5,5-diphenyl-2-oxazolidinone derivative | |
| JP4126921B2 (en) | Process for producing optically active β-phenylalanine derivative | |
| JP3888402B2 (en) | Process for producing optically active N-carbobenzoxy-tert-leucine | |
| WO2007055180A1 (en) | Method for producing optically active trans-2-aminocyclohexanol and derivative thereof | |
| JPH05262697A (en) | Diastereomerically pure intermediates and their use in the preparation of (R) or (S) -ketoprofen | |
| JP2877976B2 (en) | Optically active 2,4,4-trimethyl-2-cyclohexen-1-ol and method for producing the same | |
| JP3603151B2 (en) | Method for producing carboxylic acids or derivatives thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20050225 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20050412 |
|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20050602 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20050613 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20050602 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20060328 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060529 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20060627 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20060629 |
|
| R150 | Certificate of patent (=grant) or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20100721 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110721 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120721 Year of fee payment: 6 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120721 Year of fee payment: 6 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130721 Year of fee payment: 7 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130721 Year of fee payment: 7 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140721 Year of fee payment: 8 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |