JPH075576B2 - Process for producing optically active amino compounds - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing an intermediate in producing an optically active oxazolidinone derivative. This derivative is a useful compound as a raw material of an optically active β blocker useful as a therapeutic drug for antiarrhythmia, hypotension and cataract.

(Problems to be Solved by Prior Art and Invention) Conventional formula (4) (Wherein R ¹ represents hydrogen, a C ₁ -C ₁₂ alkyl group or an aralkyl group, and * represents an asymmetric carbon), and the optically active oxazolidinone derivative represented by the following reaction pathway (I) Method (A) (Chem.Pharm.Bull. , 29, 3593 (1981). Yoshinori Tsuda, etc.) via optically active glyceraldehyde and racemic microbial asymmetric hydrolysis (B)
(JP-A-60-36471), a method (C) (JP-A-60-67470) via a 3-amino-1,2-oxypropane derivative is known.

However, in (A), the optically active glyceraldehyde as a raw material must be synthesized from D-mannitol in multiple stages, and since it is easy to racemize, it is difficult to handle.
In (B), there is a problem that the substrate concentration cannot be increased so much that separation from unreacted ester having the opposite configuration is necessary, and in (C), a 3-amino-1,2-oxypropane derivative is synthesized. It requires several steps of reactions accompanied by side reactions, and has a drawback that the 3-amino-1,2-oxypropane derivative itself is unstable and difficult to handle.

(Means for Solving the Problems) As a result of extensive studies to find a method for producing an optically active oxazolidinone derivative which is an alternative to the above method, the present inventor followed the following reaction route (II) to obtain an optical purity from the optically active benzyl glycidyl ether (O). It was found that an optically active oxazolidinone derivative (4) having a high activity can be easily obtained.

The present invention provides a method for producing the intermediate obtained in this reaction route.

That is, the present invention has the general formula (3) (Wherein ph represents a phenyl group, R ¹ represents hydrogen, a C ₁ -C ₁₂ alkyl group, an aryl group or an aralkyl group, and * represents an asymmetric carbon). In producing the oxazolidin-2-ol derivative, the compound represented by the general formula (2) (In the formula, ph, R ¹ and * are the same as above. R ² represents a lower alkyl group.) Optically active 1- (N-alkoxycarbonyl) amino-3-benzyloxypropane-2
− 140-2 in the presence of a base in a high boiling polar solvent
This is a method characterized by reacting by heating at a temperature of 00 ° C.

Examples of R ¹ of the derivative (3) represented by the general formula (3) include hydrogen, a linear or branched alkyl group having 1 to 12 carbon atoms, an aryl group or an aralkyl group. Specifically, hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl; phenyl, 2- (3,4 -Dimethoxyphenyl) ethyl,
R-1-methyl-3-phenylpropyl and the like can be mentioned.

The derivative (3) of the present invention has the general formula (2) (In the formula, ph, R ¹ and * are the same as above. R ² represents a lower alkyl group.) Optically active 1- (N-alkoxycarbonyl) amino-3-benzyloxypropane-2
-Ol derivative (2) in a high boiling polar solvent in the presence of a base
It can be obtained by heating and reacting at a temperature of 140 to 200 ° C.

A method for synthesizing the derivative (3) of the present invention from the derivative (2) starting from the compound (O) according to the reaction route (II) will be described below.

a) Synthesis of optically active benzyl glycidyl ether (O) or optically active 1-benzyloxy-3-chloro-propan-2-ol The benzyl glycidyl ether (O) used as a raw material here is required to have high optical purity. However, this is an optically active 1-benzyloxy-3-chloro-propane-2 obtained by reacting epichlorohydrin having an optical purity of 98% ee or more with benzyl alcohol in the presence of a Lewis acid catalyst such as a trifluoroboron ether complex. It can be obtained by treating oars with caustic soda or the like.

b) Synthesis of Optically Active 1-Amino-3-benzyloxypropan-2-ol Derivative (1) The reaction between optically active benzyl glycidyl ether (O) and amine is the optically active 1-amino-produced when the amount of amine is small. Since the optically active benzyl glycidyl ether further reacts with the 3-benzyloxypropan-2-ol derivative (1), it is necessary to react with 5-fold equivalent or more, more preferably 10-fold equivalent or more of amine. When the amine has a low boiling point such as isopropylamine, it is preferable to raise the boiling point by mixing a solvent such as water, methanol or ethanol.

The optically active 1-amino-3-benzyloxypropan-2-ol derivative (1) is obtained by reacting the optically active 1-benzyloxy-3-chloropropan-2-ol with an amine equivalent or more under heating and reflux. It can also be obtained. In this case, the product is the optically active 1-amino-3-
Since it is a hydrochloride of benzyloxypropan-2-ol, a free amine can be obtained by post-treatment by adding 1 to 5 mol of a base such as sodium carbonate or potassium carbonate during or after the reaction.

c) Synthesis of optically active 1- (N-alkoxycarbonyl) amino-3-benzyloxypropan-2-ol derivative (2) Optically active 1-amino-3-benzyloxypropane-2
-The reaction of the ol derivative (1) with the alkyl chlorocarbonate is for suppressing the oxycarbonylation to the secondary hydroxyl group-
It is desirable to gradually add alkyl chlorocarbonate in the range of 25 ° C to room temperature. As the chlorocarbonic acid alkyl ester, an alkyl ester such as methyl, ethyl or benzyl can be used. Quantitatively, 1.0 to 1.4 equivalents are desirable.

The base as the acid acceptor can be used in an amount of 1 to 10 times equivalent,
Carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, barium carbonate, magnesium carbonate and sodium hydrogen carbonate are preferred. As the solvent, polar solvents such as acetone, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, N, N-dimethylformaldehyde, dimethyl sulfoxide, ethanol and methanol can be used. Water can also be added to dissolve the carbonate salt used as the base.

d) Production of optically active oxazolidin-2-one derivative (3) Optically active 1- (N-alkoxycarbonyl) amino-3-benzyloxypropan-2-ol derivative represented by the above general formula (2) used in the present invention Examples of R ^{1 in} (2) are the same as above. Examples of R ² include a lower alkyl group, that is, a C _{1 to} C ₄ linear or branched alkyl group or a C _{7 to} C ₁₀ phenyl-substituted alkyl group. Specific examples thereof include an alkyl group such as methyl, ethyl, propyl, isopropyl and butyl, and a phenyl substituted alkyl group such as benzyl, phenylethyl, phenylpropyl and phenylbutyl.

The ring-closing reaction from the derivative (2) to the optically active oxazolidin-2-one derivative (3) is performed by using a high boiling point polar solvent such as N, N-dimethylformaldehyde, N, N-dimethylacetaldehyde, diethylene glycol diethyl ether, and N-methylpyrrolidone. It can be achieved by heating under reflux in the presence of a base such as sodium carbonate or potassium carbonate.

The derivative (3) of the present invention can be converted to the derivative (4) according to the reaction pathway (II). The following will be described in order.

e) Optically active 5-hydroxymethyloxazolidine-2
Synthesis of 4-one derivative (4) The obtained optically active 5-benzyloxymethyloxazolidin-2-one derivative (3) is an optically active 5-hydroxymethyloxazolidin-2-one derivative obtained by hydrogenolysis with a palladium catalyst according to a conventional method. It can be converted to (4). This hydrogenolysis absorbs a theoretical amount of hydrogen in a polar solvent such as methanol, ethanol, acetone, ethyl acetate or acetic acid using a palladium catalyst supported on 0.2 to 10 w / w% activated carbon under a hydrogen pressure of 1 to 5 atm. Can be achieved by reacting up to.

(Effects of the Invention) According to the present invention, as compared with the conventional method, the target substance can be easily obtained in a high yield by a simple reaction route without causing racemization, and the reaction can be performed without side reaction. Can be made.

Specific examples will be described below with reference to examples.

Example The following compound (O) was used to form a derivative (3) by the method of the present invention.
An example in which the derivative (4) is obtained via 1) Synthesis of derivative (1) R-(-)-benzyl glycidyl ether (96% ee) 4
5 g of 9.2 g in 140 g of isopropylamine and 140 g of methanol
After heating and refluxing for an hour, it was confirmed by gas chromatography that the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain S-(−)-1-benzyloxy-3-isopropylaminopropane-2. -Obtained 59.5 g of all.

Yield 89% bp 126-127 ° C / 0.9 Torr ▲ [α] ²³ _D ▼ -8.31 ° (C = 1.06, methanol) NMR (CDCl ₃ ) δ: 1.07 (6H, J = 7.0Hz, CH ₃ ) 2.55〜 2.70 (1H, m, CH) 2.72 to 2.88 (2H, m, CH ₂ ) 3.08 (2H, brs, CH ₂ ) 3.47,3.49 (1H, brs, NH, OH) 3.90 (1H, m, CH) 4.54 (2H, s, CH ₂ ) 7.32 (5H, s, Ph) The optical purity of this product was measured using Chiralcel OD and hexane: 2
-Propanol 50: 2 (v / v), 1.5 ml / min, λmax 256 nm analysis, R-form, S eluting at retention time (Rt) of 8.8 and 10.6 min, respectively
From the body ratio, it was found to be 96% ee.

Also, R-(-)-1-benzyloxy-3-chloropropan-2-ol (96% ee) 18.55 g was heated under reflux in 30 g of isopropylamine and 30 g of methanol for 5 hours, 7.5 g of potassium carbonate was added and further for 2 hours. The mixture was heated under reflux with stirring, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was distilled under reduced pressure to obtain 16.4 g of S-(−)-1-benzyloxy-3-isopropylaminopropan-2-ol. It was Yield 79% 2)
Synthesis of derivative (2) 30.0 g of S-(-)-1-benzyloxy-3-isopropylaminopropan-2-ol was dissolved in 28 g of acetone and 20 g of water, and a solution of 10.19 g of potassium carbonate and 15 g of water was added thereto. In addition, 16.09 g of ethyl chlorocarbonate was added dropwise under stirring so as to keep the reaction solution temperature at 10 ° C. or lower by cooling with an ice water bath. After dropping, the mixture was further stirred for 1 hour at 10 ° C. or lower, then ethyl acetate was added for extraction, and S-(−)-1-benzyloxy-3-
39.8 g of (N-ethoxycarbonyl) isopropylaminopropan-2-ol was obtained in almost quantitative yield.

▲ [α] ²³ _D ▼ −9.96 ° (C = 1.09, Methanol) IR (neat) 3452,1696cm ⁻¹ NMR (CDCl ₃ ) δ: 1.15 (6H, J = 7.0Hz, CH ₃ ) 1.29 (3H, t , J = 7.0Hz, CH ₃ ) 3.30 (2H, brs, CH ₂ ) 3.48 (2H, brs, CH ₂ ) 3.92 (1H, m, CH) 4.15 (2H, q, J = 7.0Hz, CH ₂ ) 4.07 〜4.25 (1H, m, CH) 4.2〜4.5 (1H, brs, OH) 4.56 (2H, s, CH ₂ ) 7.34 (5H, s, Ph) The optical purity of this product is chiral cell OD, hexane: 2
-Propanol 500: 3 (v / v), 1.5 ml / min, H at λmax 256 nm
PLC analysis revealed that the Rt was 95.8% ee from the ratio of S-form and R-form eluting at 38 and 43 minutes, respectively.

3) Preparation of derivative (3) S-(-)-1-benzyloxy-3- (N-ethoxycarbonyl) isopropylaminopropan-2-ol
35 g of the mixture was refluxed and stirred in 20 g of sodium carbonate and 50 ml of N, N-dimethylformaldehyde for 2 days, the completion of the reaction was confirmed by IR spectrum, inorganic salts were removed by filtration, and the solvent was distilled off under reduced pressure to remove S- ( +)-5-Benzyloxymethyl-3-isopropyloxazolidin-2-one 29.4 g was obtained in a nearly quantitative yield.

▲ [α] ²³ _D ▼ + 36.23 ° (C = 1.06, Methanol) IR (neat) 1746,1256,1050cm ^-1 NMR (CDCl ₃ ) δ: 1.14 (6H, d, J = 6.8Hz, CH ₃ ) 3.33 (1H, dd, J = 6.0,8.8Hz, CH) 3.51 (1H, t, J = 8.8Hz, CH) 3.61 (2H, d, J = 6.0Hz, CH ₂ ) 4.08 (1H, sept, J = 6.8Hz, CH) 4.50 to 4.68 (1H, m, CH) 4.57 (2H, s, CH ₂ ) 7.32 (5H, s, Ph) The optical purity of this product was measured using Chiralcel OD and hexane: 2
-Propanol 50: 2 (v / v), 1.5 ml / min, HP at λmax 256 nm
LC analysis was performed. It was found that the Rt was 95.7% ee from the ratio of R-isomer and S-isomer which eluted at 36 and 48 minutes, respectively.

Synthesis Example Synthesis of derivative (4) S-(+)-5-benzyloxymethyl-3-isopropyloxazolidin-2-one 26.67 g of Pb catalyst supported on 5% activated carbon, 2.06 g of acetic acid, 10 g of acetic acid, 3 kg / 100 ml of methanol. cm
^The reaction was carried out under a hydrogen pressure of ² until no more hydrogen was absorbed.
After completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off under reduced pressure, ethyl acetate was added, the mixture was neutralized with a saturated NaHCO ₃ aqueous solution, the solvent was distilled off, and recrystallized from ether to give S-(+)-5. -Hydroxymethyl-3-isopropyloxazolidin-2-one
Obtained 15.20 g. Yield 96.8% mp55 to 56 ° C ▲ [α] ²¹ _D ▼ + 57.2 ° (C = 1.18, CHCl ₃ ) (lit.mp 55 to 56 ° C, ▲ [α] ²¹ _D ▼ + 57.1 ° (C = 1.17) ,
CHCl ₃ ), Chem.Pharm.Bull., 29 (12), 3593 (1981) NMR (CDCl ₃ ) δ: 1.18 (6H, d, J = 6.8Hz, CH ₃ ) 3.43 (1H, dd, J = 8.8) , 6.6Hz, CH) 3.52 (1H, t, J = 8.8Hz, CH) 3.65 (1H, dd, J = -12.5,4.2Hz, CH) 3.86 (1H, brdd, J = -12.5,3.3Hz, CH ) 4.08 (1H, sept, J = 6.8Hz, CH) 4.59 (1H, m, CH)

Claims (1)

[Claims] 1. General formula (3) (Wherein ph represents a phenyl group, R ¹ represents hydrogen, a C ₁ -C ₁₂ alkyl group, an aryl group or an aralkyl group, and * represents an asymmetric carbon). In producing the oxazolidin-2-ol derivative, the compound represented by the general formula (2) (In the formula, ph, R ¹ and * are the same as above. R ² represents a lower alkyl group.) Optically active 1- (N-alkoxycarbonyl) amino-3-benzyloxypropane-2
− 140-2 in the presence of a base in a high boiling polar solvent
A process for producing an optically active 5-benzyloxymethyloxazolidin-2-ol derivative, which comprises reacting by heating at a temperature of 00 ° C.