KR0145799B1 - A process for preparing an optically pure monovalent amine - Google Patents

Abstract

The present invention relates to a method for optically purely preparing the R or S isomer of monovalent amine represented by the following structural formula (1), which is a synthetic intermediate of a compound that inhibits human immunodeficiency virus protease.

Wherein R ¹ represents a D or L amino acid residue, a lower alkyl group or an aryl group which is optionally substituted with an aryl group, and * represents a subsidiary carbon atom.

Description

Method for preparing optically pure monovalent amine

The present invention relates to a method for producing optically pure R or S isomers of monovalent amines represented by the following structural formula (I), which are synthetic intermediates of compounds that inhibit human immunodeficiency virus protease.

Wherein R ¹ represents a D or L amino acid residue, a lower alkyl group or an aryl group which may be substituted or unsubstituted,

* Represents a subtitle carbon atom.

The term lower alkyl group as used herein means a straight or branched chain alkyl group having 1 to 6 carbon atoms, preferably methyl, ethyl, propyl, isobutyl and t-butyl.

The term aryl group means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical, for example a phenyl group, benzyl group, phenylethyl group, phenylpropyl group or phenylbutyl group and preferably means phenyl group.

Preferred examples of amino acid residues are residues of phenylalanine, homophenylalanine, valine, threonine, isoleucine or leucine.

Since the compound represented by the following structural formula (A) shows a strong inhibitory effect on HIV protease, it can be used very effectively as a therapeutic agent for AIDS (see Korean Patent Application No. 92-23089, 93). -10811, 93-21298 and 93-21300.

In the above formula,

R ¹ and * have the same meaning as above.

In this case, the inhibitory activity of the compound (A) against the HIV protease is greatly dependent on the optical properties of the functionalized amine radical located at the C-terminus. That is, the compound (A) has the activity when the R or S isomers exist in the mirror image around the asymmetric carbon of the functionalized amine radical according to the kind of the substituent R ¹ , and the optically pure functionalized amine radical is present. It is more than two times as compared to the racemic mixture, and the activity is particularly excellent when the structure (ga ') has a configuration opposite to the epoxide portion.

In the above formula,

R ¹ and * have the same meaning as above.

Therefore, there is a need to prepare optically pure monovalent amines represented by the above-mentioned structural formula (I) used as functionalized amine radicals located at the C-terminus of the structural formula (A), and thus optically pure monovalent amines. For example, by applying a method already known in the art as illustrated in Scheme 1 below, a ceramic compound may be prepared first and then separated into respective R or S isomers.

In the above formula,

R ¹ and * have the same meaning as above:

X is Cl or Br.

That is, isobutyronitrile (1) is reacted with a Grignard reagent to reduce the generated imine derivative (2) with sodium borohydride to form a racemic amine of the formula (I '), and the racemic amine is Nt-. After amidation with butoxycarbonyl phenylalanine (3), the amino protecting group is removed.

The amide compound (4) from which the protecting group has been removed is separated into optically pure R and S amine isomers by Cyrilka gel column chromatography, and finally, the phenylalanine residue introduced for isomer separation is removed to obtain the desired structural formula (Ia) or (Ib). The amine of) can be obtained optically pure.

However, it is pointed out that this method is not only complicated in the overall process, but in particular, it is very difficult to separate R and S isomers from racemic amide compound (4) and the yield is very low.

Accordingly, the present inventors have studied the method of preparing the optically pure amine of the above formula (I) more simply, and as a result, the monovalent value of the above formula (I) from the L or D amino acids corresponding to the optical properties of the desired amine. It has been found that amines can be prepared directly in pure R or S isomeric form to complete the present invention.

It is an object of the present invention to provide a method for producing optically pure monovalent amines of formula (I) which are synthetic intermediates of HIV protease inhibitors.

Accordingly, the present invention comprises the steps of (a) amidating a L or D amino acid protected with benzyloxycarbonyl of the general formula (V) with N, O-dimethylhydroxyl amine; (b) reacting the amide compound (IV) obtained in step (a) with methylmagnesium bromide and Grignard; (c) olefinizing the methyl ketone of formula (III) obtained in step (b) by vitig reaction with methyltriphenylphosphonium bromide; And (d) hydrogenating the olefin of formula (II) obtained in step (c) under a palladium carbon catalyst, thereby optically corresponding to the amino acid used as starting material for the amine compound of formula (I). Provides a process for the preparation in the form of pure R or S isomers:

In the above formula, R ¹ has the same meaning as above, and Cbz represents a benzyloxycarbonyl group.

Representative bangbab produced in general formula (I) of the present invention is as follows.

In the above formula, R ¹ has the same meaning as above, and Cbz represents a benzyloxycarbonyl group.

In the above Reaction Schemes 2-1 and 2-2, it is particularly important to carry out the Vitig reaction of reaction step (c) in the presence of a base and to maintain the reaction temperature at -20 ° C in order to prevent racemization. As the base used at this time, potassium bis (trimethylsilyl) amide is most preferred.

On the other hand, the hydrogenation reaction of the reaction step (d) is carried out by blowing hydrogen gas of 1 atm under a 10% piladium carbon catalyst, the olefin compound of formula (II) by the reaction is a double bond saturation (saturation) and At the same time the aminoprotecting group benzyloxycarbonyl group is removed.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated more concretely based on a comparative example and an Example. However, the following examples are only intended to help understanding the manufacturing method according to the present invention, but the scope of the present invention is not limited thereto.

Example 1

Preparation of 2-amino-3-methyl-1-phenylbutane hydrochloride

To 13.8 g (0.2 mol) of isobutyronitrile diluted with 50 ml of anhydrous tetrahydrofuran (THF) was added 110 ml (0.22 mol) of 2.0 M benzyl magnesium chloride at room temperature, and the mixture was refluxed for 1 hour and cooled to room temperature. . To the solution was added 200 ml of methanol and 11.4 g (0.3 mol) of NaBH ₄ , followed by stirring at room temperature for 1 hour. After completion of the reaction by adding 1N hydrochloric acid, the solvent was distilled off under reduced pressure, and the pH was adjusted to about 11 by adding 1N NaOH solution to the residue. After adding chloroform to this aqueous solution, the organic layer was separated, dried over anhydrous Na ₂ SO ₄ , and methanolic hydrochloric acid was added to the residue, followed by column chromatography (eluent-dichloromethane: methanol = 10: 1) to give the title compound. 37.5 g (94% yield) was obtained.

Example 2

Preparation of L- (N-t-butoxycarbonyl) -phenylalaninyl-2- (1-phenyl-3-methyl-butyl) imide

1.5 equivalents of 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxy benzotriazole (HOBT) in 26.5 g (0.1 mol) of Nt-butoxycarbonylphenylalanine, respectively ) Was added, and 130 ml of dimethylformamide (DMF) and 15 ml of triethylamine were dissolved. 20 g (0.1 mol) of the compound produced in Example 1 was added at 0 ° C. and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in ethyl acetate (500 ml) and washed with 1N hydrochloric acid (500 ml) and saturated NaHCO ₃ solution (500 ml). The organic layer was dried over anhydrous MgSO ₄ and the solvent was removed by distillation under reduced pressure to obtain 37.7 g (yield 92%) of the title compound.

Example 3

Preparation of L-phenylalaninyl-2- (1-phenyl-3-methyl-butyl) amide

20.5 g (0.05 mol) of the title compound of Example 2 was dissolved in 30 ml of dichloromethane and 15 ml of trifluoroacetic acid, stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. 2N NaOH was added to the residue, the pH was adjusted to about 11, extracted with ethyl acetate, and the solvent was removed by distillation under reduced pressure. Two isomers were separated by column chromatography with ethyl acetate. For Rf = 0.50 and 0.45, 1.6 g (40%) and 1.21 g (30%) were obtained respectively.

Example 4

Preparation of 2-amino-3-methyl-1-phenylbutane

1.46 g (4.7 mmol) of each product of Example 3 were dissolved in 50 mL of anhydrous dichloromethane, respectively, and 0.66 mL (5.5 mmol) of phenyl isothiocyanate was added at room temperature, and the mixture was refluxed for 2 hours. After cooling to room temperature, 10 ml of trifluoroacetic acid was added thereto, refluxed at 60 ° C. for 40 minutes, and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 mL of water, washed with ether, adjusted to pH of about 11 with NaOH, and extracted with chloroform to give each product in 82-85% yield.

Example 5

Preparation of L-N-benzyloxycarbonyl-N'-methoxy-N'-methyl-phenylalanine amide

N-benzyloxycarbonyl-L-phenylalanine (25 g, 84 mmol) and N-methylmorpholine (18.4 mL, 167 mmol) were dissolved in 500 mL of dichloromethane and isobutyl chloroformate (10.8) at -15 ° C. Ml, 84 mmol) was added. After 15 minutes, 1.1 equivalents of N, O-dimethylhydroxylamine was added at the same temperature, followed by stirring at the same temperature for 1 hour and at room temperature for 3 hours. The resulting solution was washed with saturated brine solution (2 × 500 mL) and the organic layer was dried over anhydrous MgSO ₄ and passed through celite. The organic solvent was removed from the filtrate by distillation under reduced pressure to obtain 26.7 g (yield 93%) of product.

Example 6

Preparation of (S) -3-[(N-benzyloxycarbonyl) amino] -1-methyl-4-phenyl-2-butanone

6.84 g (0.02 mol) of each product of Example 5 was dissolved in 60 ml of THF, and 30 ml (0.09 mol) of 3M methyl magnesium bromide ether solution was added at 0 ° C., and stirred at room temperature for 3 hours. Water was added at 0 ° C. to terminate the reaction and the solvent was removed by distillation under reduced pressure. 300 ml of ether was diluted with the residue and washed with ammonium chloride solution (3 × 20 ml). After drying over anhydrous MgSO ₄ , distillation under reduced pressure and then column chromatography (hexane: ethyl acetate = 8: 2) gave 5.11 g (86% yield) of the product.

Example 7

Preparation of (S) -3-[(N-benzyloxycarbonyl) amino] -2-methyl-4-phenyl-1-butene

8.57 g (0.024 mol) of methyltriphenylphosphonium bromide was dissolved in 60 ml anhydrous toluene, 44 ml (0.022 mol) of 0.5 M potassium bis (trimethylsilyl) amide toluene solution was added at -20 ° C, and then 1 hour at the same temperature. Stirred. 5.94 g (0.02 mole) of the product of Example 6 was dissolved in 50 ml of anhydrous toluene and then added to the solution at −20 ° C. over 10 minutes and then stirred at the same temperature for 1 hour. Water was added to terminate the reaction and the solvent was removed by distillation under reduced pressure. 200 ml of dichloromethane was added to the residue, followed by dilution and washing with 1N hydrochloric acid. The organic solvent was dried over anhydrous MgSO ₄ , distilled off under reduced pressure, and then subjected to column chromatography (hexane: ethyl acetate = 9: 1) to give 5.25 g (yield 89%) of the product.

Example 8

Preparation of (S) -2-amino-3-methyl-1-phenyl butane

2.95 g (0.01 mol) of the product of Example 7 was dissolved in 30 ml methanol, and then 200 g of 10% Pd / C was added and stirred for 4 hours under 1 atmosphere of hydrogen. After passing through celite to remove inorganics, the organic solvent was distilled under reduced pressure to obtain 1.63 g of a product quantitatively.

Example 9

Compounds obtained by performing the same method as in Examples 5 to 8 with different kinds of amino acids as starting materials are shown in Table 1 below.

Claims (4)

(a) amidating an L or D-type amino acid protected with benzyloxycarbonyl of formula (V) with N, 0-dimethylhydroxyl amine; (b) reacting the amide compound (IV) obtained in step (a) with methylmagnesium bromide and Grignard; (c) olefinizing the methyl ketone of formula (III) obtained in step (b) by vitig reaction with methyltriphenylphosphonium bromide; And (d) hydrogenating the olefin of formula (II) obtained in step (c) under a palladium carbon catalyst, thereby optically corresponding to the amino acid used as starting material for the amine compound of formula (I). To prepare in the form of pure R or S isomers: In which R ¹ represents a D or L amino acid residue or represents a lower alkyl group or an aryl group which is optionally substituted with an aryl group; Cbz stands for benzyloxycarbonyl. The method according to claim 1, wherein the substituent R ¹ of the compound of general formula (I) is selected from the group consisting of phenyl group, benzyl group, phenylethyl group, phenylpropyl group and phenylbutyl group. The process according to claim 1 or 2, wherein the bitig reaction of reaction step (c) is carried out at −20 ° C. in the presence of potassium bis (trimethylsilyl) amide. The process according to claim 1 or 2, wherein the hydrogenation reaction of the reaction step (d) is carried out by blowing hydrogen gas at 1 atmosphere under a 10% palladium carbon catalyst.