JPH0344381A - Optically active oxazolidinone derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as optically active beta-blockers as a remedy for arrhythmia, hypotension and cataract by subjecting a benzyloxymethyloxazolidin-one derivative to hydrogenolysis in the presence of a palladium catalyst. CONSTITUTION:A 5-benzyloxymethyloxazolidin-2-one derivative expressed by formula I (Ph is phenyl; R<1> is H, 1-12C alkyl, aryl or aralkyl; * indicates asymmetric carbon atom) is subjected to hydrogenolysis in the presence of a palladium catalyst to afford the objective compound expressed by formula II. Furthermore, the compound expressed by formula I as the starting raw material is a new substance and can be obtained by starting from benzyl glycidyl ether provide a new 1-amino-3-benzyloxypropan-2-ol derivative and further passing the resultant derivative through a new 1-(N-alkoxycarbonyl)amino-3- benzyloxypropan-2-ol derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a method for producing optically active oxazolidinone derivatives. This derivative is antiarrhythmic and blood pressure lowering.

This compound is useful as a raw material for optically active β-blockers useful as therapeutic agents for cataracts.

(Prior art and problems to be solved by the invention) Conventionally, general formula (4) (in formula (4), R1 is hydrogen, an alkyl group of 01 to CT2,
or represents an aralkyl group, and * represents an asymmetric carbon. 〉
The optically active oxazolidinone derivative represented by can be obtained by the method (A) via optically active glyceraldehyde shown in the following reaction route (I) (Chem, Pharm, B
Asymmetric ice thawing by microorganisms of ul t, , 29.3593 (1981), Yoshinori Tsuda et al.) and racemates (B)
(Machikai Sho 60-36471, etc.), 3-amino-1,2-
Method (C) via oxypropane derivative (Unexamined Japanese Patent Publication [
1360-67470> etc. are known.

○ However, in (A>), the raw material optically active glyceraldehyde must be synthesized from D-mannitol in multiple steps, and it is difficult to handle because it is easily racemized.
In B), there are problems such as the substrate concentration cannot be made very high and it is necessary to separate the unreacted ester with the opposite configuration, and in (C), a 3-amino-1,2-oxypropane derivative is synthesized. However, it requires several steps of reaction accompanied by side reactions, and furthermore, the 3-amino-1,2-oxypropane derivative itself has the drawback of being an unstable compound and difficult to handle.

(Means for Solving the Problems) As a result of intensive studies to find a method for producing optically active oxazolidinone derivatives in place of the above-mentioned method, the inventors of the present invention determined that optically active benzyl glycidyl ether (0) was It has been found that a highly pure optically active oxazolidinone derivative (4) can be easily obtained.

The present invention provides a derivative (4) obtained according to this reaction route.

That is, the present invention relates to general formula (3) (wherein ph is a phenyl group, R1 is hydrogen, 01 to Crz
represents an alkyl group, aryl group or aralkyl group,
* represents an asymmetric carbon. ) 5-benzyloxymethyloxazolidin-2-one derivative (3) represented by the general formula (4) (where R1 and * are the same as above) is hydrogenolyzed in the presence of a palladium catalyst. ) is a method for producing an optically active oxazolidinone derivative (4).

A method for synthesizing derivative (4) from derivative (3) starting from compound (0) according to reaction route (It>) will be described below.

a> Synthesis of optically active benzyl glycidyl ether (0) or 1-benzyloxy-3-chloro-propan-2-ol benzyl glycidyl ether (0) used as a raw material here
0) is required to have high optical purity, and this is an optically active product obtained by reacting epichlorohydrin with an optical purity of 98% ee or higher with benzyl alcohol in the presence of a Lewis acid catalyst such as a trifluoroboron ether complex. Na1-
It can be obtained by treating benzyloxy-3-chloro-propan-2-ol with caustic soda or the like.

b) Synthesis of 1-amino-3-benzyloxypropan-2-ol derivative (1) The reaction between benzyl glycidyl ether (0) and an amine produces 1-amino-3-benzyloxypropan-2-ol when the amount of amine is small. Since benzyl glycidyl ether further reacts with the 2-ol derivative (1), it is necessary to react with 5 times equivalent or more, more preferably 10 times equivalent or more of ane.Also, the amine has a boiling point such as isopropylamine. If the boiling point is low, it is preferable to mix a solvent such as water, methanol, or ethanol to raise the boiling point.

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

C) Synthesis of 1-(N-alkoxycarbonyl)amino-3-benzyloxypropan-2-ol derivative (2) 1-amino-3-benzyloxypropan-2-ol derivative (1) and alkyl chlorocarbonate The reaction was carried out at 5°C to suppress oxycarbonylation to secondary hydroxyl groups.
It is desirable to gradually add the alkyl chlorocarbonate at temperatures ranging from ~room temperature. Methyl and ethyl chlorocarbonate alkyl esters.

Alkyl esters such as benzyl can be used. In terms of quantity, 1.0 to 1.4 equivalents are desirable.

The base as an acid acceptor can be used in an amount of 1 to 10 times equivalent, and carbonates such as sodium carbonate, potassium carbonate, carbon M1 notium, barium carbonate, magnesium carbonate, and sodium hydrogen carbonate are preferred. Solvents are acetone, dioxane,
Tetrahydrofuran, ethylene glycol dimethyl ether, N,N-dimethyl formaldehyde, dimethyl sulfoxide.

Polar solvents such as ethanol and methanol can be used. Water can also be added to dissolve the carbonate used as base.

d) Synthesis of oxazolidin-2-one derivative (3) The ring-closing reaction to oxazolidin-2-one derivative (3) is performed using N,N-dimethylformaldehyde, N,N-dimethylacetaldehyde. This can be achieved by heating under reflux with sodium carbonate or potassium carbonate in a polar solvent such as diethylene glycol diethyl ether or N-methylpyrrolidone.

The 1-amino-3-benzyloxypropan-2-ol derivative (1), 1-(N-alkoxycarbonyloxypropan-2-ol derivative (2) and 5-benzyloxymethyloxazolidine-2) obtained here -one derivative (
All of 3) are vfr-standardized gold compounds that have not been described in any literature, and are important intermediates in producing the 5-hydroxymethyloxazolidin-2-one derivative (4) with high optical purity described below.

e) Synthesis of 5-hydroxymethyloxazolidin-2-one derivative (4) 5-benzyloxymethyloxazolidin-2-one derivative represented by the general formula (3) used in the present invention <3
Examples of R1 in ) 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, and isopropyl.

n-butyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
Examples include undecyl, dodecyl:phenyl, 2-(3,4-dimethoxyphenyl>ethyl, R-1-methyl-3-phenylpropyl).

This 5-benzyloxymethyloxazolidin-2-one derivative (3) can be easily converted to 5-hydroxymethyloxazolidine-2-one by hydrogenolysis using a palladium catalyst in a conventional manner.
It can be converted into the 2-one derivative (4). That is, this hydrogenolysis is carried out under a hydrogen pressure of 1 to 5 atm, for example, 0.2 to IO.
A high yield can be achieved by carrying out the reaction using a palladium catalyst supported on W/W% activated carbon in a polar solvent such as methanol, ethanol, acetone, ethyl acetate, acetic acid, etc. until the theoretical amount of hydrogen is absorbed.

(Effects of the Invention) According to the present invention, compared to conventional methods, the target substance can be easily obtained in good yield through a simple reaction route without causing racemization, and the reaction can be carried out without side reactions. be able to.

The present invention will be specifically explained below with reference to examples.

(Example) Examples of obtaining derivative (4) from compound (0) by the method of the present invention are shown below in order.

Example 1) Synthesis of derivative (1) R-(-)-benzyl glycidyl ether (96% e
e) 49.2g of isopropylamine 140(],
Heat under reflux in 140 g of methanol for 5 hours, confirm the completion of the reaction using gas chromatography, remove the solvent under reduced pressure, and distill the residue under reduced pressure to obtain S-(-)-1-benzyloxy-3. -isopropylaminopropan-2-ol59. 5 (got J.

Yield 89% bp126-127℃10. 9Torr [α] Xi-8
．． 31” (C=1.06, )NMR
(CDC13) δ: 1.07 (6tl, J=7.0H
z, CH3) 2,55 ~ 2.70 (?H,
m, CH)2,72 ~2.88 (2tl,
m, CH2 )3, ()8 (2H, b
r S, CH2 >3, 47, 3.49 (each l
tl, br s, NH, OH)3,90
(IH, m, CM>4, 54 (2
tl, S, CH2 )7, 32 (5
tl, S, Ph) Optical 811 degree of this is determined using Chiralcel OD, hexane:2-Cl/<Nol5
0:2 (v/v).

Analysis was performed at 1 and 5 ml/mill and λmaX 256 nm, and it was found to be 96% ee from the ratio of the R isomer and the 3 isomer eluting at retention times (Rt > 8.8 and 10.6 minutes, respectively).

In addition, 18.55 g of R-(-)-1-benzyloxy-3-chloropropan-2-ol (96% ee) was heated under reflux for 5 hours in 30 Cl of isopropylamine and 30 ml of methanol, and 7 g of potassium carbonate was added. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was distilled under reduced pressure to give S-(-11-benzyloxy-3-isopropylaminopropane-2-
All 1B. 4 (l) was obtained. Yield 79% 2> derivative (2
) Synthesis of 30.0 g of 5-(-)-1-benzyloxy-3-isopropylaminopropan-2-ol and 289 g of acetone.
．． Dissolved in 20 g of water, add a solution consisting of 10.19 g of potassium carbonate and 15 g of water, cool in an ice-water bath, and stir while keeping the reaction temperature below 10°C. 09 () was dropped.It took 1 hour to receive the drop.
After stirring at 0°C or lower, extract by adding ethyl acetate,
39.80 of 5-(-)-1-benzyloxy-3-(N-ethoxycarbonyl)isopropylaminopropan-2-ol was obtained in an almost quantitative yield.

[α] Xi -9,96° (C=1.09.methanol>IR(neat) 3452.1696cm-1
HMR(CDO23>δ:1.15 (6H.

1.29 (3H.

3.30 (2H.

3.48 (2H.

3.92 (1M.

J=7.0Hz, CH3) t, J=7.0Hz, CH3)br s, C
H2) br s, CH2) m, CH) 4.15 (2H,Q, J=7.0tl
Z, CH2) 4.07~/1.25 (IH, m
, CH) 4.2-4.5 (11, br s, 0
H) 4.56 (2N, S, CH2)
7.34 (5H, S, Ph) The optical purity of this product was determined using Chiralcel OD, hexane = 2-propertool 500:3 (V/V).

1.5d/min, λmax 256nm
Analysis was conducted and the ratio of 8 isomers and R isomers eluting at Rt of 38.43 minutes revealed that the ee was 95.8%.

3) Synthesis of derivative (3) 35 g of S-(-)-1-benzyloxy-3-(N-ethoxycarbonyl)isopropylaminopropan-2-ol was mixed with 20 g of sodium carbonate and 50 g of N,N-dimethylformaldehyde. The completion of the reaction was confirmed by IR spectrum, the inorganic salt was filtered off, and the solvent was distilled off under reduced pressure to give S-(+)-5-benzyloxymethyl-propyloxazolidine-2. -on 29.4
(] was obtained in almost quantitative yield.

[α] Xi +36. 23° (C=1.06, methanol>IR (neat) 1746. 1256.
1050cm-1HMR (CDα3) δ: 1.14 (6N, d.

3, 33 (1N, dd.

3, 51 (IH, t.

3, 61 (2H, d.

4, 08 (IH, Sept.

4,50 ~4.68 (IH, m, CH) 4,5
7 (2H, S, CH2)7, 32
(5H, s, Ph) The optical purity of this product was determined using Chiralcel OD, and hexane = 2-propertool 50:2 (v/v).

1.5d/min, λmax 256nm, PLC
analyzed.

Rt each 36. From the ratio of the R and 8 forms eluting at 48 minutes, it was found that the ee was 95.7%.

4) Preparation of derivative (4) S- (+)-5-benzyloxymethyl-3isopropyloxazolidin-2-one26. 67 (J 5
% activated carbon supported Pd catalyst and 2.06 g of acetic acid iog.

J=6.8tlz, CH3) J=6.0, 8.8Hz, CH) J=8.8Hz, CH) J=6. OHz, CH2) J=6.8Hz, CH) The reaction was carried out under a hydrogen pressure of 3 kCI/rffl in 100 rdl of methanol until no more hydrogen was absorbed. After the reaction, the catalyst was removed by filtration, the solvent was distilled off under reduced pressure, ethyl acetate was added, neutralized with saturated NaHCO: + aqueous solution, the solvent was distilled off, and recrystallized with ether to give S-(10)- 15.20 i;l of 5-hydroxymethyl-3-isopropyloxazolidin-2-one was obtained. Yield 96.8%mp5
5～56℃ [α] +57.2° (C=1.18, CHCi3
)( lit.mp55~56℃, [α] ”fj +
57.1.

(C=1.17, CHCj!3), Chem.
Pharm. Bu'' 512), 3593 (1981)) NMR (CDα3> δ: 1.18 (6H, d.

3, 43 (1) 1, dd.

3, 52 (IH, t.

3,65 (1M, dd.

3, 86 (IH, br dd.

4, 08 (IH, Set) t.

4, 59 (IH, m, CH) J=6.8H
z, CH3) J=8.8, 6.6Hz, CH) J=8.8Hz, CH) J=-12.5, 4.2Hz, CH) J=-12.5
, 3.3Hz, CH) J=6.8Hz, CH)

Claims (1)

[Claims] General formula (3) ▲Mathematical formulas, chemical formulas, tables, etc.▼(3) (In the formula, ph is a phenyl group, R^1 is hydrogen, C_1 to C
_1_2 represents an alkyl group, aryl group or aralkyl group, and * represents an asymmetric carbon. ) is characterized by hydrogenolyzing the 5-benzyloxymethyloxazolidin-2-one derivative represented by (4) in the presence of a palladium catalyst. A method for producing an optically active oxazolidinone derivative represented by the formula (R^1, * is the same as above).