JPH0215050A - Production of optically active (s)-(-)-3-alkylamino-1-aryloxypropan-2-ol - Google Patents
Production of optically active (s)-(-)-3-alkylamino-1-aryloxypropan-2-olInfo
- Publication number
- JPH0215050A JPH0215050A JP16257088A JP16257088A JPH0215050A JP H0215050 A JPH0215050 A JP H0215050A JP 16257088 A JP16257088 A JP 16257088A JP 16257088 A JP16257088 A JP 16257088A JP H0215050 A JPH0215050 A JP H0215050A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- alkylamino
- optically active
- expressed
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 125000001041 indolyl group Chemical group 0.000 claims abstract description 7
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002876 beta blocker Substances 0.000 abstract description 7
- 229940097320 beta blocking agent Drugs 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract 3
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 230000000857 drug effect Effects 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002274 desiccant Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- -1 4-indolyl group Chemical group 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- JOGFTFKRKDIQEK-UHFFFAOYSA-N 1-propoxynaphthalene Chemical compound C1=CC=C2C(OCCC)=CC=CC2=C1 JOGFTFKRKDIQEK-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、−数式
％式％
（式中、Ａｒは置換されていてもよいアリール基または
インドリル基、Ｒは低級アルキル基を示す。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention is based on the formula % (wherein Ar is an optionally substituted aryl group or indolyl group, and R is a lower alkyl group).
で表わされる光学活性（Ｓ）−（−）−３−アルキルア
ミノ−１−アリールオキシプロパン−２−オールの製造
法に関する。The present invention relates to a method for producing optically active (S)-(-)-3-alkylamino-1-aryloxypropan-2-ol represented by:
上記−数式〔１〕で表わされる化合物は、β−ブロッカ
−として重要な医薬品である。例えば−数式〔１］にお
いてＡｒが１−ナフチル基または４−インドリル基であ
り、Ｒがイソプロピル基である化合物はプロプラノロー
ルまたはピンドロールの名称で知られている。The compound represented by the above formula [1] is an important pharmaceutical drug as a β-blocker. For example, a compound in which Ar is a 1-naphthyl group or a 4-indolyl group and R is an isopropyl group in formula [1] is known as propranolol or pindolol.
これらβ−ブロッカ−において一般に光学活性の（Ｓ）
−（−）体はセラミ体よりも優れた薬理作用を有してい
ることが知られている。These β-blockers generally have optically active (S)
It is known that the -(-) form has better pharmacological action than the cerami form.
［従来の技術、発明が解決しようとする課題〕光学活性
のβ−ブロッカ−の製造法について、これまでにいくつ
かの提案がなされている（例えば、Ｋ、 Ｋａｎ ｅｔ
ａｌ、、 Ａｇｒｉｃ、 Ｂｉｏｌ、 Ｃｈｅｍ、＋
４９＋２０τ（１９８５） 、特開昭５７−３２２５
４）。[Prior Art and Problems to be Solved by the Invention] Several proposals have been made so far regarding the production method of optically active β-blockers (for example, K, Kan et al.
al,, Agric, Biol, Chem, +
49+20τ (1985), JP-A-57-3225
4).
しかしながら、これらの方法は反応が多段階であったり
、収率が低いという問題点があり、工業的な製法として
は不十分である。However, these methods have problems such as multi-step reactions and low yields, and are therefore unsatisfactory as industrial production methods.
本発明者らは、光学純度の高い光学活性のβ−ブロッカ
−を容易かつ効率的に製造する方法を見出すべく検討を
重ね、本発明に到達した。すなわち、本発明者らは、酵
素を触媒とする生化学的反応に、より高純度の（Ｓ）−
グリセリン誘導体を製造する方法を開発し、さらにこれ
ら誘導体を光学活性のβ−ブロッカ−の製造に利用すべ
く検討し、該β−ブロッカ−等の製造に有用な新規な合
成中間体〔下記−数式〔２〕で表わされる化合物）を得
、本発明を完成するに至ったのである。The present inventors have conducted repeated studies to find a method for easily and efficiently producing an optically active β-blocker with high optical purity, and have arrived at the present invention. That is, the present inventors have discovered that highly purified (S)-
We developed a method for producing glycerin derivatives, and further investigated the use of these derivatives in the production of optically active β-blockers. They obtained the compound represented by [2] and completed the present invention.
本発明は一般式 ： ％式％（２） （式中、Ｐｈはフェニル基、Ｘはハロゲン原子。The present invention is based on the general formula : % formula % (2) (In the formula, Ph is a phenyl group, and X is a halogen atom.
Ｒは低級アルキル基を示す。）で表わされる光学活性化
合物をそのまま、あるいは予めベンジル基を還元して水
素化した後、−数式
％式％：１
（式中、Ａｒは置換されていてもよいアリール基または
インドリル基を示す。）で表わされる化合物と反応させ
、次いでベンジル基を還元して水素化し、あるいは予め
ベンジル基が還元されている場合はそのままで得ること
を特徴とする一般式ＣＨ，−０−Ａｒ
：
Ｈｏ−ｃ ＜ ＨＣ１）
二
ＬＮＨＲ
（式中、Ａｒは置換されていてもよいアリール基または
インドリル基、Ｒは低級アルキル基を示す。R represents a lower alkyl group. ) The optically active compound represented by formula (%): %: 1 (in the formula, Ar represents an optionally substituted aryl group or indolyl group) is used as it is or after hydrogenation by reducing the benzyl group in advance. ), and then the benzyl group is reduced and hydrogenated, or if the benzyl group has been reduced in advance, it is obtained as it is, with the general formula CH, -0-Ar: Ho-c <HC1) 2LNHR (In the formula, Ar represents an optionally substituted aryl group or indolyl group, and R represents a lower alkyl group.
で表わされる光学活性（Ｓ）−（−）−３−アルキルア
ミノ−１−アリールオキシプロパン−２−オールの製造
法に関する。The present invention relates to a method for producing optically active (S)-(-)-3-alkylamino-1-aryloxypropan-2-ol represented by:
上記本発明の方法は下記反応式で示すことが出来る。式
中、Ｐｈはフェニル基、Ｘはハロゲン原子、Ｒは低級ア
ルキル基、Ａｒは置換されていてもよいアリール基また
はインドリル基を示す。The above method of the present invention can be shown by the following reaction formula. In the formula, Ph represents a phenyl group, X represents a halogen atom, R represents a lower alkyl group, and Ar represents an optionally substituted aryl group or indolyl group.
Ｃｌ１ｌ−０−Ａｒ
本発明の方法では、−数式〔２〕で表わされる光学活性
物質、（Ｓ）−（−）−３−アルキルアミノ−２−ベン
ジルオキシ−ニーハロゲノプロパンを出発原料とし、こ
れを−数式〔３〕で表わされる各種β−プロ・ンカーに
対応するフェノール類、例えば１−ナフトールと反応さ
せてエーテル化ぞせしめる。この反応は適当な溶媒、例
えばメタノールに溶解し、アルゴン気流中数時間還流す
ることにより行われる。なお、反応温度は７０’Ｃ〜１
６０°Ｃ１好ましくは８０″Ｃ〜１３０″Ｃが適当であ
る。Cl1l-0-Ar In the method of the present invention, an optically active substance represented by formula [2], (S)-(-)-3-alkylamino-2-benzyloxy-nihalogenopropane, is used as a starting material, and this is etherified by reacting with a phenol corresponding to various β-pro-linkers represented by formula [3], such as 1-naphthol. This reaction is carried out by dissolving in a suitable solvent, such as methanol, and refluxing for several hours under a stream of argon. In addition, the reaction temperature is 70'C~1
A temperature of 60°C, preferably 80"C to 130"C is suitable.
反応終了後、反応物を減圧１１１１１、適当な有機溶媒
、例えばジクロロメタンを加えたのち、精製水２食塩水
で洗浄し、脱水、乾固する。次いで、残渣を例えばシリ
カゲルカラムクロマトグラフィーにより精製することに
よって一般式〔４〕で表わされる（Ｓ）−（−）−３−
アルキルアミノ−ｌ−アリールオキシ−２−ベンジルオ
キシプロパンを単離ジＱる。After completion of the reaction, the reaction product is subjected to a reduced pressure of 111111C, an appropriate organic solvent such as dichloromethane is added thereto, and then washed with purified water and brine, dehydrated, and dried. Then, the residue is purified by, for example, silica gel column chromatography to obtain (S)-(-)-3- represented by the general formula [4].
Alkylamino-l-aryloxy-2-benzyloxypropane is isolated.
次に、上記−数式〔４〕の化合物を適当な溶媒、例えば
エタノールに溶解し、適当な触媒、例えばパラジウム炭
素の存在下、−２０〜５０ ’Ｃ１通常は常温以下の温
度で水素気流中１０〜３０時間接触還元する。Next, the compound of formula [4] above is dissolved in a suitable solvent such as ethanol, and in the presence of a suitable catalyst such as palladium on carbon, the compound is dissolved in a hydrogen stream of -20 to 50'C1, usually at a temperature below room temperature. Catalytic reduce for ~30 hours.
触媒を濾去して得た濾液を濃縮し、その残渣を、例えば
シリカゲルカラムクロマトグラフィーにより精製して前
記−数式（１）で表わされる（Ｓ）（−）−３−アルキ
ルアミノ−１−アリールオキシプロパン−２−オールを
得る。The filtrate obtained by removing the catalyst by filtration is concentrated, and the residue is purified, for example, by silica gel column chromatography to obtain the (S)(-)-3-alkylamino-1-aryl represented by formula (1). Oxypropan-2-ol is obtained.
また、本発明では一般式〔２］で表わされる光学活性物
質、（Ｓ）−（−）−３−アルキルアミノ２−ベンジル
オキシ−１−ハロゲノプロバンヲ出発原料とし、これを
予め前記した方法と同様の接触還元を行い、−数式［５
］で表わされる（Ｓ）（−）−３−アルキルアミノ−１
−ハロゲノプロパン−２−オールを得、次いでこの化合
物を前記と同様に一般式〔３〕で表わされる各種β−プ
ロ・ツカ−に対応するフェノール類と反応させてエーテ
ル化することにより一般式〔１〕で表わされる（Ｓ）（
−）−３−アルキルアミノ−１−アリールオキシプロパ
ン−２−オールを得ることもできる。In addition, in the present invention, an optically active substance represented by the general formula [2], (S)-(-)-3-alkylamino-2-benzyloxy-1-halogenoproban, is used as a starting material, and this is used in the method described above. A similar catalytic reduction is carried out, − Formula [5
](S)(-)-3-alkylamino-1
-halogenopropan-2-ol is obtained, and then this compound is etherified by reacting with phenols corresponding to various β-pro-tubers represented by general formula [3] in the same manner as described above. 1] (S) (
-)-3-Alkylamino-1-aryloxypropan-2-ols can also be obtained.
このようにして得られた（Ｓ）−（−）−３−アルキル
アミノ−１−アリールオキシプロパン−２オールは、目
的に応じて酸付加塩の形にすることが可能であり、例え
ば塩酸、硫酸等の無機酸あるイハ酢酸、プロピオン酸な
どの有機酸を含む［５溶媒、例えばアルコール類から結
晶化させることにより容易に製造することができる。The thus obtained (S)-(-)-3-alkylamino-1-aryloxypropan-2ol can be made into an acid addition salt form depending on the purpose, such as hydrochloric acid, Contains inorganic acids such as sulfuric acid and organic acids such as acetic acid and propionic acid [5] It can be easily produced by crystallization from a solvent such as an alcohol.
〔実施例］
次に、実施例により本発明を説明するが、本発明はこれ
らの実施例により限定されるものではない。[Examples] Next, the present invention will be explained using Examples, but the present invention is not limited to these Examples.
製造例
１）ピリジン１０戚に光学活性な（Ｓ）−（＋）１−〇
−アセチルー２−０−ベンジルグリセリン４．５ｇを溶
かした溶液に、水冷下にｐ−トルエンスルホン酸クロリ
ド４ｇを加え、室温にて１０時間攪拌した。反応終了後
、氷水中に注ぎ、ジクロロメタンで抽出し、ジクロロメ
タン層をＩＮ硫酸および飽和食塩水で洗浄したのち、適
量の無水硫酸マグネシウムで乾燥させた。乾燥剤を濾別
し、濾液を減圧濃縮して得た残渣をシリカゲルカラムク
ロマトグラフィーに付し、イソプロピルエーテル／クロ
ロホルム（１／１０）で溶出した。溶出液を減圧濃縮し
たところ、（Ｒ）−（＋）−３−０アセチル−２−０−
ベンジル−１−０−１−シルグリセリン７．２ｇが得ら
れた。Production Example 1) To a solution of 4.5 g of optically active (S)-(+)1-〇-acetyl-2-0-benzylglycerin dissolved in pyridine 10, 4 g of p-toluenesulfonic acid chloride was added under water cooling. , and stirred at room temperature for 10 hours. After the reaction was completed, the mixture was poured into ice water and extracted with dichloromethane. The dichloromethane layer was washed with IN sulfuric acid and saturated brine, and then dried over an appropriate amount of anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography and eluted with isopropyl ether/chloroform (1/10). When the eluate was concentrated under reduced pressure, (R)-(+)-3-0acetyl-2-0-
7.2 g of benzyl-1-0-1-silglycerin was obtained.
２）水酸化ナトリウム１．２ｇを５０成のエタノールに
溶かした溶液に、水冷下に上記１）で得られた（Ｒ）−
（＋） −３−０−−アセチル−２−旦一ベンジルー１
−０− ）シルグリセリン７．２ｇを加え、１時間攪拌
した。反応終了後、ＩＮ４酸で中和し、減圧下でエタノ
ールを留去して得た残渣にジクロロメタンを加え、水お
よび飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ
た。乾燥剤を濾別し、濾液を減圧濃縮したところ、（Ｒ
）−（＋）−２−〇−ベンジルー１−０−１−シルグリ
セリン６．３ｇが得られた。2) Add (R)- obtained in 1) above to a solution of 1.2 g of sodium hydroxide dissolved in 50% ethanol under water cooling.
(+) -3-0--acetyl-2-danichi benzyl-1
-0-) 7.2 g of silglycerin was added and stirred for 1 hour. After the reaction was completed, dichloromethane was added to the residue obtained by neutralizing with IN4 acid and distilling off ethanol under reduced pressure, washing with water and saturated brine, and drying over magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
6.3 g of )-(+)-2-0-benzyl-1-0-1-silglycerin was obtained.
３）イソプロピルアミン６ｇに上記２）で得られた（Ｒ
）−（＋）−２−旦−ベンジル−１−旦一トシルグリセ
リン６．３ｇを加え、封管中６０°Ｃで６時間加熱した
。イソプロピルアミンを減圧下に留去し、残渣にジクロ
ロメタンを加え、水および飽和食塩水で洗浄後、無水炭
酸カリウムで乾燥させた。乾燥剤を濾別し、濾液を濃縮
して得た残渣をシリカゲルカラムクロマトグラフィーに
付し、エタノール／クロロホルム（１１５）で？守山し
たところ、（Ｓ）−（−）−１−イソプロピルアミノ２
−ベンジルオキシプロパン−３−オール３．４ｇ（前記
１）の出発原料に対して収率約７６％）が得られた。3) Add (R) obtained in 2) above to 6 g of isopropylamine.
)-(+)-2-Dan-benzyl-1-Dan-tosylglycerin (6.3 g) was added, and the mixture was heated at 60° C. for 6 hours in a sealed tube. Isopropylamine was distilled off under reduced pressure, dichloromethane was added to the residue, washed with water and saturated brine, and dried over anhydrous potassium carbonate. The desiccant was removed by filtration, and the filtrate was concentrated. The resulting residue was subjected to silica gel column chromatography and chromatographed with ethanol/chloroform (115). Moriyama found that (S)-(-)-1-isopropylamino 2
3.4 g of -benzyloxypropan-3-ol (yield of about 76% based on the starting material in 1) was obtained.
４）前記３）で得られた（Ｓ）−（−）−１−イソプロ
ピルアミノ−２−ベンジルオキシプロパン３・−オール
２．２ｇに塩化チオニル５．５ｇを加え、６０°Ｃで３
時間攪拌した。減圧下に塩化チオニルを留去し、残渣に
ジクロロメタンを加え、ＩＮ水酸化ナトリウム溶液で洗
浄し、無水炭酸カリウムで乾燥させた。乾燥剤を濾別し
、濾液を減圧濃縮して得られた残渣をシリカゲルカラム
クロマトグラフィーに付し、エタノール／クロロホルム
（１１５）で溶出したところ、（Ｓ）−（−）−１−ク
ロロ２−ベンジルオキシ−３−イソプロピルアミノプロ
パン２．２ｇが得られた。このものの構造式。4) Add 5.5 g of thionyl chloride to 2.2 g of (S)-(-)-1-isopropylamino-2-benzyloxypropane-3-ol obtained in 3) above, and add 3.5 g of thionyl chloride at 60°C.
Stir for hours. Thionyl chloride was distilled off under reduced pressure, dichloromethane was added to the residue, washed with IN sodium hydroxide solution, and dried over anhydrous potassium carbonate. The desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and eluted with ethanol/chloroform (115). 2.2 g of benzyloxy-3-isopropylaminopropane was obtained. Structural formula of this thing.
旋光度および’Ｈ−ＮＭＲの結果を下記に示す。The optical rotation and 'H-NMR results are shown below.
構造式
％式％
旋光度［α］も’ ＝−１７，１（ｃ＝ １．６．クロ
ロホルム溶液’ Ｈ−Ｎ Ｍ Ｒ（９０ＭＨ２，クロロ
ホルム溶液）δ： ｐｐｍ１．０５ （６Ｈ，ｄ、 Ｊ
＝６．３Ｈｚ）−Ｃｌｌ′。”＼Ｃｔｌ ３
２．６５〜３．ＯＯ（３）１９ｍ）−ＣＨＪＨＣ！ｉり
３．１３（ＬＨ，ｓ）＞Ｎ且
３．６０〜３．９５（３１１，ｍ） −０−Ｃｔｌ−
ＣＨｚＣｉ！４．６４（２Ｈ，ＡＢｑ、 Ｊ’１１．
６Ｈｚ） ＰｈＣＩＩｚＯ−７，３４（５１１，ｓ）
Ｃ６！！Ｓ実施例１
１）製造例で得られた光学活性化合物（Ｓ）−（−）−
１−クロロ−２−ベンジルオキシ−３−イソプロピルア
ミノプロパン２．２ｇをエタノール３０戚に溶かし、こ
れに３％（Ｗ／Ｖ）塩酸エタノール溶液１．２ｍｌおよ
び５％パラジウム炭素０．３ｇを加え、水素気流中１０
時間攪拌した。反応終了後、触媒を濾去し、濾液を減圧
濃縮したところ、（Ｓ）（−）−１−クロロ−３−イソ
プロピルアミノ２−プロパツール塩酸塩１．６ｇ（出発
原料に対して収率約８５％）が得られた。このものの構
造式、融点、旋光度および元素分析値を下記に示す。Structural formula % Formula % Optical rotation [α] is also ' = -17,1 (c = 1.6. Chloroform solution' H-NMR (90MH2, chloroform solution) δ: ppm1.05 (6H, d, J
=6.3Hz)-Cll'. "\Ctl 3 2.65~3.OO(3)19m)-CHJHC!i 3.13(LH,s)>N and 3.60~3.95(311,m) -0-Ctl-
CHzCi! 4.64 (2H, ABq, J'11.
6Hz) PhCIIzO-7,34(511,s)
C6! ! S Example 1 1) Optically active compound (S)-(-)- obtained in Production Example
Dissolve 2.2 g of 1-chloro-2-benzyloxy-3-isopropylaminopropane in ethanol 30, add 1.2 ml of 3% (W/V) hydrochloric acid ethanol solution and 0.3 g of 5% palladium on carbon, 10 in hydrogen stream
Stir for hours. After the reaction was completed, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. 1.6 g of (S)(-)-1-chloro-3-isopropylamino 2-propatur hydrochloride (yield: approx. 85%) was obtained. The structural formula, melting point, optical rotation, and elemental analysis values of this product are shown below.
構造式
％式％
２）ナトリウムメチラート０．６ｇを含むメタノールシ
ン容ン夜２０ｍ！に１−ナフトール０．９ｇヲｉｆｌ解
し、上記実施例１の１）で得られた（Ｓ）−（−）クロ
ロ−３−イソプロピルアミノ−２−プロパツール塩酸塩
０．７５ ｇを加え、アルゴン気流中５時間還流した。Structural formula % formula % 2) Methanol containing 0.6g of sodium methylate 20m per night! 0.9 g of 1-naphthol was dissolved in the solution, and 0.75 g of (S)-(-)chloro-3-isopropylamino-2-propatol hydrochloride obtained in 1) of Example 1 was added. The mixture was refluxed for 5 hours in an argon stream.
反応終了後、反応物を減圧濃縮して得られた残渣にジク
ロロメタンを加えたのち、精製水および飽和食塩水で洗
浄し、無水炭酸カリウムで乾燥させた。乾燥剤を濾別し
、濾液を濃縮乾固して得られた残渣を３％（ｗ／ｖ）塩
酸エタノ−エタノール）合液）
ル溶液５ ｍｌに溶かしたのち、減圧下に濃縮乾固した
。得られた結晶をエーテル−エタノールから再結晶した
ところ、（Ｓ）−（−）−３−イソプロピルアミノ−１
−（１−ナフトキシ）−２−プロパツール塩酸塩０．８
０ｇ（収率７０％）が得られた。After the reaction was completed, the reaction product was concentrated under reduced pressure, and dichloromethane was added to the resulting residue, which was then washed with purified water and saturated brine, and dried over anhydrous potassium carbonate. The desiccant was removed by filtration, and the filtrate was concentrated to dryness. The resulting residue was dissolved in 5 ml of a 3% (w/v) hydrochloric acid/ethanol solution, and then concentrated to dryness under reduced pressure. . When the obtained crystals were recrystallized from ether-ethanol, (S)-(-)-3-isopropylamino-1
-(1-naphthoxy)-2-propatur hydrochloride 0.8
0 g (yield 70%) was obtained.
このものの構造式、融点、旋光度９元素分析値および遊
離アミンの’Ｈ−ＮＭＲおよび
１３Ｃ−ＮＭＲの結果を下記に示す。The structural formula, melting point, optical rotation of this product, nine element analysis values, and the 'H-NMR and 13C-NMR results of the free amine are shown below.
構造式
％式％
示性式
計算値
実験値
Ｃｌ６Ｈ２□ＣｌＮ０゜
Ｃ： ６４．９７． Ｈ： ７．５０． Ｎ ： ４
．７４Ｃ： ６４．６９．Ｈ： ７．４７． Ｎ ：
４．７２エタノール？容液）
遊離アミンの’ ＨＮ Ｍ Ｒ（９０ＭＨｚ 、 ＣＤ
Ｃｌ ３）δ： ｐｐｍ２．８０〜２．９６（５１１，
ｍ）−０！ｊ−Ｃｔ（ｚＮ）ｊ−割、３．７３〜４．２
２（３Ｈ，ｍ） ＨＯ−Ｃｆｉ−Ｃ）ｊｚ−０−Ｃ，
ｏｌ１７６．７４〜６．８４（ＬＨ，ｄｄ、 Ｊ＝２
．２． ６．６Ｈｚ）。Structural formula % Formula % Indicative formula Calculated value Experimental value Cl6H2□ClN0°C: 64.97. H: 7.50. N: 4
．． 74C: 64.69. H: 7.47. N:
4.72 ethanol? HNMR (90MHz, CD) of free amine
Cl3) δ: ppm2.80-2.96 (511,
m) -0! j-Ct(zN)j-division, 3.73-4.2
2(3H, m) HO-Cfi-C)jz-0-C,
ol176.74~6.84 (LH, dd, J=2
．． 2. 6.6Hz).
７．２４〜７．５１（４Ｈ，ｍ）、 ７．７６〜７．
８４（ＬＨ，ｍ）。7.24-7.51 (4H, m), 7.76-7.
84 (LH, m).
８．１８Ｊ、３０（ＩＨ，ｍ）ＣＩｏＨ７’ ＣＮ Ｍ
Ｒ（２２，５Ｍｆｌｚ’、 ＣＤＣＩ！、３）δ
： ｐｐｍ２２．８（ｑ）、 ２２．９（ｑ）、
４９．０（ｄ）、 ４９．５（ｔ）、 ６８．５（
ｄ）。8.18J, 30 (IH, m) CIoH7' CN M
R(22,5Mflz', CDCI!, 3)δ
: ppm22.8(q), 22.9(q),
49.0(d), 49.5(t), 68.5(
d).
７０．７（ｔ）、 １０５．０（ｄ）、 １２０．
６（ｄ）、 １２１．８（ｄ）。70.7(t), 105.0(d), 120.
6(d), 121.8(d).
１２５．２（ｄ）、 １２５．６（ｓ）、 １２５
．８（ｄＬ １２６．４（ｄ）。125.2(d), 125.6(s), 125
．． 8 (dL 126.4(d).
１２７．５（ｄ）、 １３４．５（ｓ）、 １５４
．３（ｓ）実施例２
１）ナトリウムメチラート０．３ｇを含むメタノール？
容？夜２０−に１−ナフトール０．９ｇをン容解し、製
造例で得られた光学活性化合物（Ｓ）−（−）−２−ベ
ンジルオキシ−１−クロロ−３−イソプロピルアミノプ
ロパン１．２ｇを加え、アルゴン気流中５時間還流した
。反応終了後、゛減圧濃縮した残渣にジクロロメタンを
加えたのち、精製水および飽和食塩水で洗浄し、無水炭
酸カリウムで乾燥させた。乾燥剤を濾去し、濾液を減圧
濃縮して得られた残渣をシリカゲルカラムクロマトグラ
フィーに付し、エタノール／クロロホルム（１１５）で
ン守山したところ、（Ｓ）−（−）−２−ベンジルオキ
シ−３−イソプロピルアミノ−１−（１−ナフトキシ）
プロパン１．３ｇ（収率７７％）が得られた。このもの
の構造式、旋高度およびＩＨ−ＮＭＲの結果を下記に示
す。127.5(d), 134.5(s), 154
．． 3(s) Example 2 1) Methanol containing 0.3 g of sodium methylate?
Yong? At night, 0.9 g of 1-naphthol was dissolved to obtain 1.2 g of the optically active compound (S)-(-)-2-benzyloxy-1-chloro-3-isopropylaminopropane obtained in Production Example. was added, and the mixture was refluxed for 5 hours in an argon stream. After the reaction was completed, dichloromethane was added to the residue that was concentrated under reduced pressure, washed with purified water and saturated brine, and dried over anhydrous potassium carbonate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography and chromatography with ethanol/chloroform (115) yielded (S)-(-)-2-benzyloxy. -3-isopropylamino-1-(1-naphthoxy)
1.3 g (yield 77%) of propane was obtained. The structural formula, degree of rotation, and IH-NMR results of this product are shown below.
構造式
％式％）
旋光度〔α）：’＝−２，５°（ｃ＝１．４＋クロロホ
ルム溶液）’ ＨＮ Ｍ Ｒ（９０Ｍｌ（ｚ 、 Ｃ
ＤＣｊ２３）δ ： ｐｐｍ１．５９（ＩＨｌｓ）
／Ｎ旦
２．６５〜２．９８（３８，ｍ）−ＣＩＪＨＣｊｉ、３
．９９〜３．３４（３Ｈ，ｍ） −０−Ｃｊ（−ＣＯ
２−０４，７９（２１（、＾Ｂｑ、 Ｊ＝９．５Ｈｚ
） ＰｈＣ３ｊｚ−０６，７５〜６．８５． ７．２５
〜７．５６． ７．７４〜７．８４． ８．１７〜８．
３４（１２１＋、 ｍ） Ｃ＋ ｏＨｔ、 Ｃｂ
！１５２）上記実施例２の１）で得られた（Ｓ）−（−
）−２−ベンジルオキシ−３−イソプロピルアミノ１−
（１−ナフトキシ）プロパン１ｇをエタノール２０／ｄ
に溶解し、これに５％パラジウム炭素０．２ｇを加え、
水素気流中２４時間攪拌した。反応終了後、触媒を濾去
し、濾液を減圧濃縮して得られた残渣をカラムクロマト
グラフィーに付し、エタノール／クロロホルム（１／３
）で？客用したところ、（Ｓ）−（−）−３−イソプロ
ピルアミノ■−（１−ナフトキシ）−２−プロパツール
０．５ｇ（収率６５％）が得られた。このものの１）（
＝ＮＭＲおよび”Ｃ−ＮＭＲスペクトルを測定したとこ
ろ、実施例１の２）で得られたちのｂ全く一致した。ま
た、このものの塩酸塩の旋光度き測定したところ、〔α
〕”＝−２５° （ｃ＝１． エタノク
ールン合液）であった。Structural formula % Formula %) Optical rotation [α): '=-2,5° (c=1.4+chloroform solution)' HN MR (90 Ml (z, C
DCj23) δ: ppm1.59 (IHLs)
/Ndan 2.65-2.98 (38, m)-CIJHCji, 3
．． 99-3.34 (3H, m) -0-Cj(-CO
2-04,79(21(,^Bq, J=9.5Hz
) PhC3jz-06,75-6.85. 7.25
~7.56. 7.74-7.84. 8.17-8.
34 (121+, m) C+ oHt, Cb
! 152) (S)-(- obtained in 1) of Example 2 above
)-2-benzyloxy-3-isopropylamino 1-
(1-naphthoxy)propane 1g to ethanol 20/d
and add 0.2 g of 5% palladium on carbon,
The mixture was stirred for 24 hours in a hydrogen stream. After the reaction, the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography, and ethanol/chloroform (1/3
)in? When used for commercial purposes, 0.5 g (yield: 65%) of (S)-(-)-3-isopropylamino-(1-naphthoxy)-2-propatol was obtained. This thing 1) (
=NMR and "C-NMR spectra were measured, and they were completely consistent with those obtained in 2) of Example 1. Also, when the optical rotation of the hydrochloride of this product was measured, [α
]”=−25° (c=1. ethanocooln mixture).
（発明の効果〕
本発明によれば、光学純度の高い光学活性（Ｓ）−（−
）−３−アルキルアミノ−１−アリールオキシプロパン
−２−オールを効率よく製造することができる。本発明
によって得られる光学活性（Ｓ）（−）−３−アルキル
アミノ−１−アリールオキシプロパン−２−オールは、
一般にラセミ体よりも優れた薬効を示す各種β−ブロッ
カ−の（Ｓ）体として有用であり、今後の利用が大いに
期待される。(Effects of the Invention) According to the present invention, optically active (S)-(-
)-3-alkylamino-1-aryloxypropan-2-ol can be efficiently produced. The optically active (S)(-)-3-alkylamino-1-aryloxypropan-2-ol obtained by the present invention is
It is useful as the (S) form of various β-blockers, which generally exhibits better medicinal efficacy than the racemic form, and its future use is highly anticipated.
特許出願人 サッポロビール株式会社 阿知波 −雄Patent applicant: Sapporo Beer Co., Ltd. Achiha - male
Claims (2)
級アルキル基を示す。）で表わされる光学活性化合物を
そのまま、あるいは予めベンジル基を還元して水素化し
た後、一般式 Ａｒ−ＯＨ〔３〕 （式中、Ａｒは置換されていてもよいアリール基または
インドリル基を示す。）で表わされる化合物と反応させ
、次いでベンジル基を還元して水素化し、あるいは予め
ベンジル基が還元されている場合はそのままで得ること
を特徴とする一般式▲数式、化学式、表等があります▼
〔１〕 （式中、Ａｒは置換されていてもよいアリール基または
インドリル基、Ｒは低級アルキル基を示す。）で表わさ
れる光学活性（Ｓ）−（−）−３−アルキルアミノ−１
−アリールオキシプロパン−２−オールの製造法。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [2] (In the formula, Ph is a phenyl group, X is a halogen atom, and R is a lower alkyl group). Alternatively, after reducing and hydrogenating the benzyl group in advance, it is reacted with a compound represented by the general formula Ar-OH [3] (wherein Ar represents an optionally substituted aryl group or indolyl group), Then, the benzyl group is reduced and hydrogenated, or if the benzyl group has been reduced beforehand, it is obtained as is. There are general formulas▲mathematical formulas, chemical formulas, tables, etc.▼
[1] Optically active (S)-(-)-3-alkylamino-1 represented by (wherein, Ar is an optionally substituted aryl group or indolyl group, and R is a lower alkyl group)
-Production method of aryloxypropan-2-ol.
ソプロピル基である請求項１記載の製造法。(2) The manufacturing method according to claim 1, wherein in the general formula [1], Ar is a naphthyl group and R is an isopropyl group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16257088A JPH0215050A (en) | 1988-07-01 | 1988-07-01 | Production of optically active (s)-(-)-3-alkylamino-1-aryloxypropan-2-ol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16257088A JPH0215050A (en) | 1988-07-01 | 1988-07-01 | Production of optically active (s)-(-)-3-alkylamino-1-aryloxypropan-2-ol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0215050A true JPH0215050A (en) | 1990-01-18 |
Family
ID=15757099
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16257088A Pending JPH0215050A (en) | 1988-07-01 | 1988-07-01 | Production of optically active (s)-(-)-3-alkylamino-1-aryloxypropan-2-ol |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0215050A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4822649B2 (en) * | 2000-08-04 | 2011-11-24 | インヴィスタ テクノロジーズ エスアエルエル | Method for producing 3-hydroxyalkanenitrile and hydroxyaminoalkane |
-
1988
- 1988-07-01 JP JP16257088A patent/JPH0215050A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4822649B2 (en) * | 2000-08-04 | 2011-11-24 | インヴィスタ テクノロジーズ エスアエルエル | Method for producing 3-hydroxyalkanenitrile and hydroxyaminoalkane |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5225585A (en) | Production of fluoxetine and new intermediates | |
| US4833273A (en) | Process for the resolution of 1-aminoindanes | |
| JPH11310556A (en) | Novel process for producing 2-amino-2-(2-(4octylphenyl) ethyl) propane-1,3-diol | |
| JPH0674243B2 (en) | Optically active atenolol salt with high optical purity and process for producing atenolol | |
| US9771317B2 (en) | Process for preparing lacosamide and related compounds | |
| HU229188B1 (en) | Process for the preparation of n-[(s)-1-carboxybutyl]-(s)-alanine esters and their use for synthesizing perindopril | |
| IE54216B1 (en) | Stereospecific synthesis of 5-phenyl-2s-pentanol | |
| JPH0215050A (en) | Production of optically active (s)-(-)-3-alkylamino-1-aryloxypropan-2-ol | |
| JPS638368A (en) | 4-benzyloxy-3-pyrroline-2-one-1-ylacetamide,manufacture and use | |
| US5149870A (en) | Process for the production of 1-(aminomethyl)cyclohexane acetic acid | |
| JPS6148839B2 (en) | ||
| CN113121414B (en) | Synthesis method of trelagliptin intermediate | |
| JP3134786B2 (en) | 2-Azabicyclo [3.3.0] octane derivatives, their production and optical resolution of diols or amino alcohols | |
| EP1163223A1 (en) | Synthesis of 3-amino-3-aryl propanoates | |
| JPH0327345A (en) | Production of phenetylamines | |
| JP2000178253A (en) | Production of optically active pipecolic acid | |
| JPS63270650A (en) | P-(trans-4-aminomethylcyclohexylcarbonyl) phenylpropionic acid | |
| CN115572231A (en) | Synthesis method of bicyclo [1.1.1] pentane-1, 3-diamine salt | |
| JP2716243B2 (en) | N-benzyl-3-hydroxysuccinamic acid and method for producing the same | |
| JP2003137835A (en) | Method for producing (r)-3-hydroxy-3-(2-phenyl)hexanoic acid | |
| JP3544694B2 (en) | Method for producing N-tert-butyl-2-piperazinecarboxamides | |
| JP3144921B2 (en) | Benzyl ester derivative and method for producing the same | |
| JPH0129793B2 (en) | ||
| CN116410211A (en) | Benzofuran compound | |
| JP3144920B2 (en) | α-Acylaminoketone derivatives, production method thereof and use thereof |