KR930004511B1 - Optical division method of α-haloalkanoic acid racemic mixture - Google Patents

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Description

Optical division method of α-haloalkanoic acid racemic mixture

The present invention relates to a new optical splitting method of the α-haloalkanoic acid racemic mixture of the following general formula (I).

In the general formula (I), R is a C _1-10 alkyl group or C _5-12 aryl group and X represents a chlorine atom or bromine atom or iodine atom. Optically pure α-haloalkanoic acids are important intermediates for the synthesis of pharmaceutical pesticides and natural products. In particular, (S) -α-halopropionic acid is of great industrial importance as an intermediate of many phenoxypropionic acid herbicides such as (R) -Diclofop-methyl (Hoechst) and (R) -fluszifop-butyl (ICI).

Optically pure [alpha] -haloalkanoic acid can be used to divide these compounds using optically active organic bases such as (+)-cinconine, (-)-cinconidine, brucin and the like [H. J. nestler, Z. Naturforsch. B; Anorg, Chem. Org. Chem. 35B (3) (1980) 366; J. Crosby, Eur. Pat. Appl. 163435 (1985); C.A. 105 (1985) 114607 v], α-amino acids, α-hydroxy acids and the like obtained by chemical conversion. Recently, a method of dividing each optical isomer from a racemic mixture using an enzyme such as lipase has been published. [A.M. Klibanov, US-Pat, 4,601,987; A.M. Klibanov, J. Am. Chem, Soc., 1984 106, 2687.

However, these known methods are not only difficult to separate, but also have low yields and cannot be used for large scale production. The present invention is isolated by a very simple chromatographic operation using an optically active oxazolidinone derivative of the following general formula (II) as a chiral derivating agent, which can be simply synthesized from optically active β-aminoalcohols obtained from natural products. It is a method to obtain a large amount of optically pure α-haloalkanoic acids easier and economically by generating a pair of diastereo isomers that can be made.

In General Formula (II), R ¹ is a C _1-10 allyl group or C _6-12 aryl group.

The separation method of the ceramic mixtures of general formula (I) according to the present invention can be represented by the following reaction scheme.

The present invention is described in detail as follows.

Characterization of the method for cleaving the α-haloalkanoic acid racemic mixture according to the present invention is characterized by the reaction of the racemic mixture of the α-haloalkanoic acid derivative of formula (III) with the optically active compound of formula (II) The diastereo isomers of are produced and then their different physical properties are used to separate them and to obtain the respective isomers of optically pure α-haloalkanoic acid from them.

Compounds of formula (III) are obtained by reacting compounds of formula (I) with thionylcrolide, phosphorus tribromide, oxalylchlori and the like.

Optically active oxazolidinone compounds of the general formula (II) used in the present invention include (S) -valinol, (1R, 2S) -norephedrine, (1S, 2R) -norephedrine, (S) -phenyl Β-amino alcohols having optical activity easily obtained from natural products such as glycineol, (S) -alanineol, (S) -phenylalanineol, (S) -leucineol, and (S) -tert-leucineol, etc. It is obtained by reacting with diethyl carbonate and the like, the yield is almost 90% or more in quantitative terms. More details on these synthesis methods can be found in J. Am. Chem. Soc. 73 (1951) 4199, and the like.

Compounds of formula (II) are reacted with the same equivalents of n-butyllithium or sodium hydride to obtain alkali metal salts of compounds of formula (II), which are then obtained to obtain compounds of formula (III) of the same equivalents. Yield is almost quantitative. Suitable reaction temperatures at this time are between -20 ° C and 20 ° C. Compounds of formula (IV) are mixtures of two diastereomeric isomers which are readily separated by conventional column chromatography methods. In this case, when R is alkyl, the diastereo isomer ratio (R _f ) is very large, ranging from 2 to 3, and these diastereoisomers are completely separated by simple chromatography, whereas R is an aryl group. In general, the development ratio of each diastereoisomer was less than 1.5. As the developing solvent, ethyl acetate and hexane were most preferably used in a mixture of 4: 1 to 10: 1.

(R²가 수소원자인 경우),

(R²가 수소원자가 아닌 경우)의 첫머리 글자는 α-할로알카노익산 부위의 것이고 두번째 글자는 또는 글자들은 광학활성옥사졸리디논기에 관한 것이다. 또한, 이때 광학활성 옥사졸리디논 부위의 RS 또는 SR 등의 표시는 각각 치환체 R¹과 R²가 있는 비대칭 탄소의 절대구조를 뜻한다.In the diastereo isomer of the general formula (IV), each pair of symbols

(When R ² is a hydrogen atom),

The first letter of the letter (when R ² is not a hydrogen atom) is the α-haloalkanoic acid moiety and the second letter or the letter relates to the optically active oxazolidinone group. In this case, RS or SR of the optically active oxazolidinone moiety means an absolute structure of an asymmetric carbon having substituents R ¹ and R ² , respectively.

Compound (IV) is separated into diastereo isomers and each of the isomers is reacted at -20 ° C-0 ° C in the presence of an alkali metal alkoxide and tetrahydrofuran solvent to obtain a general formula having an optical purity of 99.5% or more. Obtain the ester mixture of IV). In particular, the oxazolidinone compound of the general formula (II) used as the chiral derivative is not completely degraded or racemized and is almost completely recovered. This is one of the great advantages of the present invention. As already described above, alkyl- (S) -2-halopropionate is an intermediate that is particularly dominant in the synthesis of (R) -phenoxypropionic acid derivative herbicides.

The optically pure ester compound of formula (V) thus obtained is hydrolyzed or hydrogenated in the case of benzyl ester in the presence of a palladium catalyst to give optically pure (more than 99.5% of optical purity) α-haloalkanoic acid of formula (I). Can be obtained.

As described above, the method of dividing the α-haloalkanoic acid racemic mixture according to the present invention is a very economical and excellent method that can separate each isomer in almost quantitative yield by a simple method unlike the existing methods. .

The invention is illustrated in detail by the following several representative examples. Unless otherwise noted, the following reactions proceed under nitrogen atmosphere.

Example 1

N- [2-bromopropionyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

108.5 ml of n-butyllithium (2.5 M THF solution) was dissolved in 450 ml of tetrahydrofuran in 48.13 g of (4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone at -10 ° C. Add at temperature and stir for 30 minutes at this temperature. The reaction solution is added to a solution in which 28.4 ml of (+)-2-bromo propionyl bromide is dissolved in 150 ml of anhydrous tetrahydrofuran at -10 ° C.

The reaction mixture is stirred for about 30 minutes and then poured into 150 ml of an aqueous solution of ammonium chloride. The organic layer was extracted with ethyl acetate and the combined organic layers were dried over anhydrous forget-me-not, and the solvent was removed under reduced pressure. A mixture of diastereo isomers of oxazolidinones is obtained. The diastereoisomeric mixture thus synthesized is separated into individual isomers through column chromatography (developing solvent: n-hexane: ethyl acetate = 7: 1).

i) first developing solute: N-[(2S) -2-bromopropionyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR (CDCl ₃ ) δ: 0.94 (d, J = 6.6 HzH, 3H, -N-CH (CH ₃ )-), 1.86 (d, J = 6.7 Hz, 3H, CH ₃ -CH (Br)-), 4.77 ('p', 1H, -N-CH (CH ₃ -CH-), 5.75 (q, J = 7Hz, 1H, CH ₃ -CH (Br)-), 5.76 (d, J = 7Hz, 1H, -CH (C ₆ H ₅ ) -O-), 7.2-7.6 (m, 5H, C ₆ H ₅ )

mp: 90 ℃

ii) second developing solute: N-[(2R) -2-bromopropionyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR (CDCl ₃ ) δ: 0.91 (d, J = 6.6 Hz, 3H, -N-CH (CH ₃ )-), 1.86 (d, J = 6.7 Hz, CH ₃ -CH (Br)-), 4.84 ( 'p', 1H, -N-CH (CH ₃ ) -CH-), 5.68 (q, J = 7Hz, 1H, CH ₃ -CH (Br)-), 5.74 (d, J = 7Hz, 1H,- CH (C ₆ H ₅ ) -O-), 7.2-7.6 (m, 5H, -C ₆ H ₅ )

mp: 98 ℃

Example 2

N- [2-chloropropionyl)-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

The experimental method was the same as in Example 1, and the yield was almost political.

i) First developing solute: N-[(2R) -2-chloropropionyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR (CDCl ₃ ) δ: 0.9 (d, J = 8Hz, 3H, -N-CH (CH ₃ )-), 1.6 (d, J = 6Hz, 3H, CH ₃ -CH (Cl)-), 4.80 ( 'p', 1H, -N-CH (CH ₃ ) -CH-), 5.62 (q, J = 7Hz, 1H, CH ₃ -CH (Cl)-), 5.77 (d, J = 7Hz, 1H,- CH (C ₆ H ₅ ) -O-), 7.4 (m, 5H, C ₆ H _5- )

mp: 95 ℃

ii) second developing solute: N-[(2R) -2-chloropropionyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR (CDCl ₃ ) δ: 0.91 (d, J = 8 Hz, 3H-N-CH (CH ₃ )-), 1.6 (d, J = 6Hz, 3H, CH ₃ -CH (Cl)-), 4.83 (' p ', 1H, -N-CH (CH ₃ ) -CH-), 5.52 (q, J = 7 Hz, 1H, CH ₃ -CH (Cl)-), 5.70 (d, J = 7 Hz, 1H, -CH (C ₆ H ₅ ) -O-), 7.4 (m, 5H, C ₆ H _5- )

Example 3

N- [2-bromobutyryl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

The experimental method was the same as in Example 1, and the yield was almost political.

i) first developing solute: N-[(2-bromobutyryl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR (CDCl ₃ ) δ: 0.90 (d, J = 7Hz, 3H, -N-CH (CH ₃ )-), 1.06 (m, J = 7Hz, 3H, CH ₃ -CH _2- ), 1.8-2.35 ( m, 2H, CH ₃ -CH ₂ -CH (Br)-(d, J = 7Hz, 3H, CH ₃ -CH (Br)-), 4.81 ('p', 1H, -N-CH (CH ₃ ) -CH-), 5.61 (q, J = 7 Hz, 1H, CH ₂ -CH (Br)-), 5.77 (d, J = 7 Hz, 1H, -CH (C ₆ H ₅ ) -O-), 7.1- 7.6 (m, 5H, -C ₆ H ₅ )

mp: 73 ℃

ii) second developing solute: N-[(2R) -2-bromobutyryl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR (CDCl ₃ ) δ: 0.95 (d, J = 7 Hz, 3H, -N-CH (CH ₃ )-), 1.1 (t, J = 7 Hz, 3H, CH ₃ -CH _2- ), 2.11 (m, 2H, CH ₃ -CH ₂ -CH (Br)-), 4.83 (m, 1H, -N-CH (CH ₃ ) -CH-), 5.54 (t, J = 7 Hz, 1H, -CH ₂ -CH ( Br)-), 5.70 (d, J = 7 Hz, 1H, -CH (C ₆ H ₅ ) -O-), 7.2-7.5 (br, s, 5H, -C ₆ H ₅ )

mp: 94 ℃

Example 4

N- [2-bromo-3-methylbutyryl]-(4R, 5S) -4-methyl-5-phenyl-oxazolidinone

The experimental method was the same as in Example 1, and the yield was almost political.

i) First developing solute: N-[(2S) -2-bromo-3-methylbutyryl] 3- (4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR (CDCl ₃ ) δ: 0.92 (d, J = 7HzH, 3H, -N-CH (CH ₃ )-), 1.05 (d, J = 7Hz, 3H, CH ₃ ) ₂ CH), 1.15 (d, J = 7 Hz, 3H, (CH ₃ ) ₂ CH-), 2.35 (sym.m.1H, (CH ₃ ) ₂ CH-), 4.82 ('p', 1H, -N-CH (CH ₃ ) -CH- ), 5.56 (d, J = 7Hz, 1H, (CH ₃ ) ₂ CH-CH (Br)-), 5.75 (d, J = 7Hz, 1H, -CH (C ₆ H ₅ ) -O-), 7.2 -7.6 (m, 5H, -C ₆ H ₅ )

ii) second developing solute: N-[(2R) -2-bromo-3-methylbutyryl]-(4R, 5S) -4-methyl-5-phenyl-5-oxazolidinone

NMR (CDCl ₃ ) δ: 0.92 (d, J = 6Hz, 3H, -N-CH (CH ₃ )-), 1.06 (d, J = 7Hz, 3H, (CH ₃ ) ₂ CH-), 1.18 (d , J = 7Hz, 3H, (CH ₃ ) ₂ CH-), 2.37 (sym.m, 1H, (CH ₃ ) ₂ CH-), 4.84 ('q', 1H, -N-CH (CH ₃ )- CH), 5.49 (d, J = 7 Hz8.8 1H, 1 (CH ₃ ) ₂ CH (Br)-), 5.71 (d, J = 7.4,1H, -CH (C ₂ H ₅ ) -O-), 7.2-7.6 (m, 5H, -C ₆ H ₅ )

mp: 79 ℃

Example 5

N- [2-bromohexanoyl]-(4R, 5S) -4-methyl-5-phenyl-oxazolidinone

The experimental method was the same as in Example 1, and the yield was almost energetic.

i) First developing solute: N-[(2S) -2-bromohexanoyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR (CDCl ₃ ) δ: 0.9 (m, 6H, CH ₃ -CH _2- , N-CH (CH ₃ )-), 1.4 (m, 4H, CH ₃ -CH ₂ -CH _2- ), 2.1 (m , 2H, -CH ₂ -CH (Br)-), 4.80 ('p', J = 7Hz, 1H, -N-CH (CH ₃ ) -CH-), 5.65 (t, 8Hz, 1H, -CH ₂ -CH (Br)-), 5.75 (d, J = 8 Hz, 1H, -CH (C ₆ H ₅ ) -O-), 7.2-7.6 (m, 5H-C ₆ H ₅ )

mp: 111 ℃

ii) second developing solute: N-[(2R) -2-bromohexanoyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

NMR (60MHz, CDCl ₃ ) δ: 0.9 (m, 6H, CH ₃ -CH ₂ -CH ₃ -CH-), 1.4 (m, 4H, CH ₃ -CH ₂ -CH _2- ), 2.1 (m, 2H , -CH ₂ -CH (Br)-), 4.84 ('p', 1H, -N-CH (CH ₃ -CH-), 5.62 (t, J = 7.4Hz, 1H, -CH ₂ -CH (Br )-), 5.71 (d, J = 7.7 Hz, 1H, -CH (C ₆ H ₅ ) -O-), 7.2-7.6 (m, 5H, -C ₆ H ₅ )

mp: 89 ℃

Example 6

N- [bromophenylacetyl]-(4R, 5S) -methyl-5-phenyl-2-oxazolidinone

The experimental method was the same as in Example 1, and the yield was almost political.

i) First developing solute: N-[(2S) -bromophenylacetyl]-(4R, 5S) -methyl-5-phenyl-2-oxazolidinone

NMR (CDCl ₃ ) δ: 0.9 (d, J = 9Hz, 3H, -N-CH (CH ₃ )-), 4.85 ('p', 1H, -N-CH (CH ₃ ) -CH-), 5.75 (d, J = 7Hz, 1H, -CH (C ₆ H ₅ ) -O-), 6.93 (s, 1H, C ₆ H ₅ CH (Br)-), 7.8 (m, 10H, 2 C ₆ H ₅ -)

mp: 161 ℃

ii) first developing solute: N-[(2R) -bromophenylacetyl]-(4R, 5S) -methyl-5-phenyl-2-oxazolidinone

NMR (CDCl ₃ ) δ: 0.9 (d, J = 9Hz, 3H, -N-CH (CH ₃ )-), 4.9 (m, 1H, -N-CH (CH ₃ ) -CH-), 5.8 (d , J = 7Hz, 1H, -CH (C ₆ H ₅ ) -O-), 6.9 (s, 1H, C ₆ H ₅ CH (Br)-), 7.8 (m, 10H, 2 C ₆ H ₅ )

Example 7

N- [2-bromo-4-phenylbutyryl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone

The experimental method was the same as in Example 1, and the yield was almost political.

i) First developing solute: N-[(2S) -bromo-4-phenylbutyryl]-(4R, 5S) -methyl-5-phenyl-2-oxazolidinone

NMR (200MHz, CDCl ₃ ) δ 0.94 (d, J = 7Hz, 3H, CH ₃ -CH-N), 2.0-3.0 (d, 4H, -CH ₂ CH _2- ), 4.8 ('p', 1H, CH ₃ -CH (N) -CH), 5.7 (d, J = 7Hz, 1H, CH ₃ -CH-Br), 5.8 (d, J = 7Hz, 1H, -CH (O) -C ₆ H ₅ ) , 7.0-7.4 (m, 10H, 2 C ₆ H _5- )

ii) second developing solute: N-[(2R) -bromo-4-phenylbutyryl]-(4R, 5S) -methyl-5-phenyl-2-oxazolidinone

NMR (200MHz, CDCl ₃ ) δ: 0.94 (d, J = 7Hz, 3H, CH ₃ -CH-N), 2.0-3.0 (m, 4H, -CH ₂ CH _2- ), 4.8 ('p', 1H , CH ₃ -CH (N) -CH), 5.7 (d, J = 7Hz, 1H, CH ₃ -CH-Br), 5.8 (d, J = 7Hz, 1H, -CH (O) -C ₆ H ₅ ), 7.0-7.4 (m, 10H, 2-C ₆ H ₅ )

Example 8

Benzyl- (2R) -2-bromopropionate

44.5 g (0.1425 mol) of N-[(2R) -2-bromopropy was obtained by reacting lithium benzylate obtained by reacting 15.5 g (0.1431 mol) of benzyl alcohol with 57 ml (2.5 M tetrahydrofuran solution) of butyllithium. Onyl]-(4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone is slowly added to a solution of 350 ml of tetrahydrofuran at -10 ° C. After stirring for 1 hour, the reaction mixture was poured into an aqueous ammonium chloride solution to neutralize and the organics were extracted with ethyl acetate. The organic layer is dried over anhydrous forget-me-not, the solvent is removed, and the product is evaporated under reduced pressure.

Yield: 99% or more

bP: 85 ℃ / 0.4mmHg

NMR (CDCl ₃ ) δ: 1.8 (d, J = 7Hz, 3H, CH ₃ -CH (Br)-), 4.4 (q, J = 7Hz, 1H, CH ₃ -CH (Br)-), 5.2 (s , 2H, -CH ₂ -C ₆ H ₅ ), 7.4 (s, 5H, -C ₆ H ₅ )

Example 9

Butyl- (2S) -2-bromopropionate

Experimental method is the same as in Example 9.

Yield: 92%

bp: 86-7 ℃ / 15mmHg

[α] _d = 18.9 °

Example 10

(2S) -2-bromopropionic acid

4.9 g (0.02 mol) of benzyl- (2S) -2-bromopropionate was dissolved in 100 ml of ethyl alcohol, followed by addition of 500 mg of 10% palladium activated carbon in a hydrogen reduction reactor (hydrogen pressure 30 psi) 2- The reaction is stirred for 4 hours. After completion of the reaction, palladium activated carbon was filtered off, and ethyl alcohol was distilled off to obtain 2.9 g of propionic acid.

Yield: 95% or more

bp: 72-80 ℃ / 0.3-0.4mmHg

[α] _x = -26.6 ° C. (cq, CHCl ₃ ) (ee = 99.9%)

Claims (1)

The metal salt of the compound of formula (II) is reacted with the compound of formula (III) to generate a pair of diastereoisomers of formula (IV), and these isomers are separated by column chromatography and separated by column chromatography. Of the α-haloalkanoic acid racemic mixture which esterifies each of the optical isomers of the compound of formula (IV) to obtain an optically pure compound of formula (V) and reduces the compound of formula (V). Powder method.

In the above formula, R is a C _1-10 alkyl group or C _0-12 aryl group, X is a chlorine atom or bromine atom or iodine atom, R ¹ is a C _1-10 alkyl group or C _6-12 aryl group, R ² is a hydrogen atom or a C _1-10 alkyl group or C _6-12 aryl group, and R 'is an ester residue.