JPH11279154A - Production of alfa,alfa'-diaminoalcohol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently produce an α,α'-aminoalcohol derivative that is useful as an intermediate for HIV protease inhibitor by starting with L-serine and passing via a novel oxazolinone intermediate. SOLUTION: A compound of formula I (R<1> is an alkyl) ms allowed to react with a halomagnesium dialkylamide in the presence of a haloacetic acid and magnesium chloride to form a compound of formula II. The product is reduced with sodium borohyciride or the like, then, the product is treated with a base such as potassium t-butoxide to form a compound of formula III. Further, the product is allowed to react with a compound of formula IV, then with a thiophenol, and the product is protected its amino group to give the objective compound of formula V (R<2> may be substituted with an alkyl, a heteroaryl or an aralkyl).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an α, α'-diamino alcohol, ie, the following formula (8)

[0002]

Embedded image

[3S- (3α, 4aβ, 8aβ)]-
2- [2'-hydroxy-3'-phenylthiomethyl-
4'-aza-5'-oxo-5 '-(2 "-methyl-
3 "-Hydroxyphenyl) pentyl] decahydroisoquinoline-3-Nt-butylcarboxamide. The compounds of formula (8) above are very useful as intermediates for HIV protease inhibitors. Compound.

[0004]

2. Description of the Related Art As a conventional method for producing an α, α′-amino alcohol derivative represented by the above formula (8), for example, the following method is known. 1) A method in which serine is used as a starting material and produced via an azide compound. (International Publication No. WO95 / 09843) 2) A method of producing 2-butene-1,4-diol as a starting material via a chiral amine. (International publication number WO9
7/11937, WO 97/11938)

[0005]

In the above-mentioned method 1), the method 1) requires explosive diazomethane in an intermediate step, or requires a certain low-temperature reaction condition. There are inefficiencies. The method 2) uses a large amount of methylene chloride, the use of which is regulated industrially. There was such a problem.

[0006] In view of the above, an object of the present invention is to provide a method for efficiently producing an α, α'-amino alcohol derivative useful as an intermediate of an HIV protease inhibitor. Another object of the present invention is to provide a novel intermediate compound useful for producing the compound and a method for producing the same.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in accordance with the above-mentioned object, and as a result, as shown in FIG.
Starting from serine, via a novel oxazolidinone intermediate represented by the formula (2), α represented by the formula (7)
The present inventors have found a method for producing an α′-amino alcohol derivative, and have completed the present invention.

[0008]

FIG.

That is, the gist of the present invention is as follows: a) The following formula (1)

[0010]

Embedded image

A compound represented by the formula: wherein R1 represents an alkyl group, is represented by the following formula (2)

[0012]

Embedded image

Wherein X represents a halogen atom. B) Further reduction, the following formula (3)

[0014]

Embedded image

Wherein X is the same as defined above, and c) is further treated with a base to obtain a compound represented by the following formula (4):

[0016]

Embedded image

D) further converting the compound into a compound represented by the following formula (5):

[0018]

Embedded image

By reacting with a compound represented by the following formula (6):

[0020]

Embedded image

E) further reacting with thiophenol, and subsequently protecting the amino group;

[0022]

Embedded image

Wherein R ² is an alkyl group, an aryl group,
Which may be substituted with a heteroaryl group or an aralkyl group].

Hereinafter, the present invention will be described in more detail. Here, R ¹ is an alkyl group, for example, a methyl group, an ethyl group, an isopropyl group, a butyl group and the like. R ² represents an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted aralkyl group.

The "alkyl group" preferably has 1 carbon atom.
To 6 and may be linear or branched, and specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a t-butyl group.
Preferably, they are a methyl group and an ethyl group. The “optionally substituted alkyl group” means that the above alkyl group may be substituted with one or more substituents that do not affect the reaction. Specific examples of the substituent include a hydroxyl group; a halogen atom such as fluorine, chlorine, bromine and iodine; an amino group; a nitro group; and a carbon atom having 1 carbon atom such as a methylamino group, an ethylamino group, a hexylamino group, and a dimethylamino group. To 6 mono or dialkylamino groups; cyano groups and the like. Preferred are a hydroxyl group, a halogen atom, an amino group and the like. In addition, the substitution position and the number of the substituent for the alkyl group are not particularly limited.

Specific examples of the "aryl group" include a phenyl group, a naphthyl group and a biphenyl group, and a phenyl group is preferred. The "optionally substituted aryl group" means that the above aryl group may be substituted with one or more substituents which do not affect the reaction. Examples of the substituent include the substituents represented by the “alkyl group which may be substituted” and the like, and a carbon group having 1 carbon atom such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.
To 6 alkyl groups; vinyl group, allyl group, butenyl group,
An alkenyl group having 2 to 6 carbon atoms such as a pentenyl group and a hexenyl group; and an acyloxy group having 2 to 6 carbon atoms such as an acetyloxy group, a propionyloxy group, a butyryloxy group, a pivaloyloxy group, and a hexanoyloxy group. Preferably, an alkyl group, a hydroxyl group, a halogen atom,
An alkoxy group and an acyloxy group. The substitution position and the number of substituents on the aryl group are not particularly limited, but are preferably 1 to 3 substituents, more preferably 1 to 2 substituents.

The "heteroaryl group" is an aromatic group containing a hetero atom, and examples thereof include a pyridyl group and a furyl group. The “optionally substituted heteroaryl group” is a heteroaryl group which may be substituted with one or more substituents which do not affect the reaction. Examples of the substituent include the substituents represented by the above-mentioned “aryl group which may be substituted”, and the like, preferably an alkyl group, a hydroxyl group,
A halogen atom, a mono- or dialkylamino group, an alkoxy group, and an acyloxy group. The substitution position and the number of substituents on the heteroaryl group are not particularly limited, but are preferably 1 to 3 substituents,
More preferably, it is a 1- to 2-substituted product.

The "aralkyl group" is the above-mentioned alkyl group substituted with the above-mentioned aryl group, and specifically includes a benzyl group, a phenethyl group and a phenylpropyl group.
The “optionally substituted aralkyl group” means that the aralkyl group may be substituted with one or more substituents that do not affect the reaction. Specifically, benzyl group, halogen-substituted benzyl group, alkyl-substituted benzyl group, alkoxy-substituted benzyl group, phenethyl group, halogen-substituted phenethyl group, alkyl-substituted phenethyl group, alkoxy-substituted phenethyl group, phenylpropyl group, halogen-substituted phenylpropyl group, Examples thereof include an alkyl-substituted phenylpropyl group and an alkoxy-substituted phenylpropyl group, and preferred are a benzyl group and a phenethyl group. The substitution position and number of the substituents with respect to the aralkyl group are not particularly limited, but are preferably 1 to 3 substituents.

Step (a): Carburizing Reaction In this step, for example, compound 1 is prepared by adding
Haloacetic acid or a salt thereof or a silyl ester thereof, and a halomagnesium dialkylamide or t-butylmagnesium halide in the presence of magnesium chloride;
In this step, the compound 2 is obtained by performing the reaction at a temperature of 70 ° C, preferably -10 to 40 ° C. Suitable organic solvents include, for example, ether solvents such as diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran, and more preferably tetrahydrofuran.

The halogen of the haloacetic acid is a chlorine atom or a bromine atom, and examples of the salt include sodium chloroacetate, potassium chloroacetate and sodium bromoacetate. As the silyl ester of haloacetic acid, for example,
And trimethylsilyl chloroacetate. As the halomagnesium dialkylamide used in this step,
For example, chloromagnesium diisopropylamide, chloromagnesium pyrrolidide and the like can be mentioned, and these can be obtained by, for example, preparing from n-butylmagnesium chloride and diisopropylamine or pyrrolidine. Examples of the t-butylmagnesium halide include, for example, t-butylmagnesium chloride.

Step (b): Reduction In this step, compound 2 is treated with sodium borohydride in a solvent such as an alcohol, preferably methanol or ethanol, at a temperature of -30 to 70 ° C, preferably -15 to 30 ° C. Simply using lithium aluminum hydride, preferably using sodium borohydride.

Step (c): Ring Closure of Halohydrin Compound 3 is reacted in a solvent such as tetrahydrofuran or methylene chloride in the presence of a base such as potassium t-butoxide or sodium hydride at a temperature of 0 to 70 ° C., preferably It can be easily performed at a temperature of 0 to 30C.

Step (d): Reaction of epoxide with amide (6) Compound 4 and amide 5 are reacted in a solvent such as an alcohol, preferably ethanol, at a reflux temperature, preferably at 20 to 100 ° C.
Particularly, it can be easily performed while heating to 80 ° C.

Step (e): Thioetherification and protection of amino group The thioetherification is carried out by reacting compound 6 in a thiophenol solvent in the presence or absence of a catalyst, for example, lithium chloride or the like, at a reflux temperature, preferably 130 to 130.degree. It can be easily performed while heating to 160 ° C. The resulting amino alcohol may be subjected to operations such as extraction at the time of purification, which may cause a decrease in the recovery rate. Therefore, it is desirable to continuously protect the amino group.

In the step of protecting the amino group, the amino alcohol is acylated with a desired acylating agent in a suitable solvent in the presence of a suitable base, and if necessary, the protecting group on R ² is deprotected. , Compound 7 or an enantiomer thereof.
Suitable reaction temperatures are between 0 and 20 ° C, preferably between 0 and 10 ° C.

Suitable bases include, for example, pyridine,
Lutidine, picoline, triethylamine, diisopropylethylamine, dimethylaminopyridine, DBU, D
Organic bases such as BN; lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate and the like; preferably an inorganic base, more preferably sodium hydrogen carbonate.

The acylating agent may be any as long as it reacts with a primary amino group. Examples thereof include an optionally substituted alkyl carboxylic anhydride such as acetic anhydride and pivalic anhydride; benzoic anhydride Optionally substituted aryl carboxylic acid anhydrides such as toluic anhydride; optionally substituted alkyl carboxylic acid chlorides such as acetyl chloride and pivaloyl chloride; optionally substituted heteroaryl carboxylic acids such as benzoyl chloride and toluyl chloride Acid chlorides; optionally substituted alkyl carboxylic acid anhydrides, optionally substituted aralkyl carboxylic acid chlorides; optionally substituted heteroarylalkyl carboxylic acid chlorides, and the like.
Further, an acid chloride having a protecting group such as 3-acetoxy-2-methylbenzoyl chloride can also be used.

The appropriate solvent is appropriately selected depending on the kind of the base to be used. Examples thereof include alcohol solvents such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol and t-butyl alcohol; Benzene, toluene, hexane,
Hydrocarbon solvents such as xylene; diethyl ether;
Ether solvents such as 2-dimethoxyethane and tetrahydrofuran; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate;
Polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, and water; and mixed solvents thereof, and the like, preferably a two-layer system of an ester solvent and water, and more preferably ethyl acetate. And water.

When a protecting group is present in the acylating agent, the protecting group can be deprotected. The deprotection method varies depending on the type of the protecting group. For example, when 3-acetoxy-2-methylbenzoyl chloride is used as an acylating agent, the acetyl group of the protecting group is treated with a suitable base in a suitable solvent. Can be removed. Suitable reaction temperatures are between 0 and 100 ° C, preferably 20 ° C.
５０50 ° C. Examples of the protecting group to be deprotected include an acetyl group, a pivaloyl group, a benzoyl group, a trichloroacetyl group, a trifluoroacetyl group and the like.

Suitable bases include, for example, organic bases such as amines such as ammonia, methylamine, ethylamine, dimethylamine and diethylamine; lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, and the like. An inorganic base such as potassium carbonate may be mentioned, preferably amines, and more preferably ammonia.

Suitable solvents include, for example, alcohol solvents such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol n-butyl alcohol and t-butyl alcohol; and hydrocarbon solvents such as benzene, toluene, hexane and xylene. Ether solvents such as diethyl ether, 1,2-dimethoxyethane and tetrahydrofuran; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate. A polar solvent such as N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, and water; or a mixed solvent thereof, preferably an alcoholic solvent, and more preferably methanol.

The compound 7 and various intermediate compounds and their enantiomers produced as described above can be separated and purified by known separation and purification means, for example, concentration, extraction, chromatography, and the like.
By appropriately performing means such as recrystallization, it can be collected as an object of any purity. Compound 8 and salts of various isomers thereof can be produced by a known method.

[0043]

EXAMPLES Hereinafter, the present invention will be specifically described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example Production of (S) -4-carbomethoxyoxazolidin-2-one (I)

[0045]

Embedded image

L-serine (1.05 g) was dissolved in a 1 M aqueous sodium hydroxide solution (30 ml). To the solution, 1,4-dioxane containing triphosgene (3.0 g) (20 m
l) was added dropwise and stirred at room temperature for 2 hours. After concentrating the solvent of the reaction mixture and adding methanol (60 ml) to the residue,
Stirred overnight at room temperature. After distilling off methanol and cooling with ice,
An aqueous solution of sodium hydrogen carbonate was added, and the product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to give L-4-carbomethoxyoxazolidine-2-one (0.68 g).

Optical purity was determined by HPLC analysis conditions; Column; 4.6 mφ × Chiral Cell ODH (manufactured by Daicel).
250 mm, solvent: isopropanol / hexane = 1:
1, flow rate: 0.3 ml / min. , Column temperature;
Observation wavelength: 210 nm, it was confirmed that ≧ 99% ee. ¹ H NMR (CDCl ₃ ): 5.65 (br
s, 1H), 4.63 (t, 1H), 4.55 (dd,
1H), 4.42 (dd, 1H), 3.83 (s, 3
H)

Example 1 Preparation of (S) -4- (2-chloroacetyl) -1,3-oxazolidin-2-one (II)

[0049]

Embedded image

In a nitrogen gas atmosphere, (S) -4-carbomethoxyoxazolidin-2-one (8.5 g, 59 mm
ol) sodium monochloroacetate (10.3 g, 88.
4 mmol), magnesium chloride (8.4 g, 88.2).
mol) and tetrahydrofuran (100 ml) was stirred at 40 ° C for 2 hours (referred to as solution A). on the other hand,
Under a nitrogen gas atmosphere, diisopropylamine (27.4 g, 270.8 mmol) was added dropwise to n-butylmagnesium chloride (2 M tetrahydrofuran solution, 118 ml) at 40 ° C. over 30 minutes, and the mixture was further stirred at 40 ° C. for 2 hours. (Referred to as liquid B). Solution A and Solution B at an internal temperature of 10 ° C
After about 30 minutes before and after the addition, the mixture was further stirred at 40 ° C. for 2 hours. Next, the reaction solution was added to a solution of ice-cooled concentrated sulfuric acid (30 g) and water (300 ml), and stirred for 30 minutes to hydrolyze the reaction solution. Extraction was performed three times with ethyl acetate (300 ml), and the organic phase was washed with saturated saline and dried over sodium sulfate. The obtained organic phase was concentrated to obtain a brownish crude product (12.3 g). ¹ H NMR
_{(CDCl 3): 7.08 (brs} , 1H), 4.80
(Dd, 1H), 4.71 (t, 1H), 4.52 (d
d, 1H), 4.26 (s, 2H)

Example 2 Preparation of 4 (S)-(2-chloro-1-hydroxyethyl) -1,3-oxazolidin-2-one (III)

[0052]

Embedded image

The crude product 4 (S)-obtained in Example 2 under ice-cooling
Sodium borohydride (2.3 g) was added to an ethanol solution (100 ml) of (2-chloroacetyl) -1,3-oxazolidin-2-one (12.3 g), and the mixture was stirred under ice cooling for 3 hours. The mixture was treated with a 1M aqueous hydrochloric acid solution (100 ml), ethanol was distilled off, and the mixture was extracted with ethyl acetate. After the extract was concentrated, it was purified by a silica gel column (developing phase: ethyl acetate) and purified by 4 (S)-(2-chloro-1-hydroxyethyl).
-1,3-Oxazolidin-2-one (4.12 g,) was obtained. ¹ H NMR (Acetone-d ₆ ): 6.75 (brs, 1
H), 4.83 (d, 1H), 4.40 (t, 1H),
4.24 (dd, 1H), 4.05 (dd, 1H),
3.61 (m, 2H), 2.85 (brs, 1H)

Example 3 Preparation of 4 (S)-(1,2-epoxy) -1,3-oxazolidin-2-one (IV)

[0055]

Embedded image

Under ice cooling, 4 (S)-(2-chloro-1-hydroxyethyl) -1,3-oxazolidin-2-one (600.
To a solution of 4 mg) in tetrahydrofuran (12 ml) was added potassium t-butoxide (474.4 mg). After stirring for 2 hours, the mixture was treated with a saturated aqueous ammonium chloride solution (5 ml),
Tetrahydrofuran was distilled off under reduced pressure. Thereafter, extraction was performed with ethyl acetate, the organic phase was concentrated, and 4 (S)-(1,2-
Epoxy) -1,3-oxazolidin-2-one (319.
4 mg). _{^{1 HNMR (Acetone-d 6)}} : 6.78
(Brs, 1H), 4.48 (t, 1H), 4.22
(Dd, 1H), 3.89 (m, 1H), 3.12
(M, 1H), 2.69 (dd, 1H), 2.63 (d
d, 1H)

Example 4 [3 (S)-(3α, 4aβ, 8aβ)]-[2-hydroxy-2- (2-oxo-1,3-oxazolan-4-)
Yl) ethyl] decahydroisoquinoline-3-Nt-
Production of butylcarboxamide (V)

[0058]

Embedded image

4 (S)-(1,2-epoxy) -1,3-oxazolidin-2-one (182 mg) in ethanol (3 ml)
[3 (S)-(3α, 4aβ, 8aβ)]-N-
(Tert-Butyl) decahydro-3-isoquinolinecarboxamide (333.7 mg) was added. 2 at 60 ° C
After heating and stirring for an hour, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate) to give Compound V (311.4 mg, 0.847 m
mol). _{^{1 HNMR (Acetone-d 6)}} : 7.28
(Brs, 1H), 7.01 (brs, 1H), 4.3
8 (t, 1H), 4.23 (dd, 1H), 3.69
(M, 1H), 3.60 (m, 1H), 2.91 (m, 1H)
2H), 2.60 (m, 1H), 2.16 (m, 1
H), 1.97-1.32 (m, 23H).

Example 5 [3 (S)-(3α, 4aβ, 8aβ)]-2- [2′-
Hydroxy-3'-phenylthiomethyl-4'-aza-
5'-oxo-5 '-(2 "-methyl-3" -hydroxyphenyl) pentyl] decahydroisoquinoline-3-
Production of Nt-butylcarboxamide (VI)

[0061]

Embedded image

Compound V (115 mg, 0.3 mmol) was added to lithium chloride (10 mg) and thiophenol (100 μm).
1) was added, the system was purged with argon, and heated and stirred at 150 ° C. for 1 hour. Next, the reaction solution was allowed to cool to room temperature, and sodium hydrogen carbonate (63 mg), water (3 ml) and methylene chloride (3 ml) were added, and the mixture was vigorously stirred. Under ice-cooling, 3-acetoxy-2-methylbenzoyl chloride (63.6 mg,
0.3 mmol) was added dropwise, and the mixture was further stirred for 1 hour under ice-cooling. Then, the organic layer was separated and concentrated under reduced pressure. The concentrate was dissolved in methanol (0.5 ml), 28% aqueous ammonia (0.3 ml) was added, and the mixture was stirred for 2 hours. The resulting precipitate is purified by column chromatography of the reaction product,
Compound VI (20.4 mg) was obtained. ¹ H NMR (CDC
_{l 3): 7.45 (m,} 2H), 7.32-7.17
(M, 4H), 7.06 (m, 2H), 6.84 (m,
1H), 5.49 (brs, 1H), 5.37 (m, 1
H), 4.47 (m, 1H), 4.07 (m, 1H),
3.78 (m, 1H), 3.42 (m, 1H), 2.9
1 (m, 1H), 2.61-2.43 (m, 2H),
2.31 (s, 3H), 2.30-2.17 (m, 2
H), 2.02-1.93 (m, 2H), 1.77-
1.11 (m, 12H), 1.07 (s, 9H)

Example 6 [3 (S)-(3α, 4aβ, 8aβ)]-2- [2′-
Hydroxy-3'-phenylthiomethyl-4'-aza-
5′-oxo-5′-phenylpentyl] decahydroisoquinoline-3-Nt-butylcarboxamide (VI
I) Manufacturing

[0064]

Embedded image

Compound V (115 mg) was added to lithium chloride (1
0.2 mg) and thiophenol (100 μl)
After replacing the inside of the system with argon, the mixture was heated and stirred at 150 ° C. for 1 hour. Next, the reaction solution was allowed to cool to room temperature, and sodium hydrogen carbonate (63.0 mg), water (3 ml), and methylene chloride (3 ml).
Was added and stirred vigorously. Benzoyl chloride (42μ
l) was added dropwise, and the mixture was further stirred at room temperature for 18 hours. The reaction product was purified by column chromatography and [3
(S)-(3R *, 4aR *, 3aR *, 2'S *, 3 '
S *)]-2- [2'-Hydroxy-3'-phenylthiomethyl-4'-aza-5'-oxo-5'-phenylpentyl] decahydroisoquinoline-3-N-t-butylcarboxamide ( 23.8 mg). ¹ H NMR
_{(CDCl 3): 7.67 (d} , 1H), 7.49-
7.16 (m, 10H), 5.49 (brs, 1H),
4.47 (m, 1H), 4.07 (m, 1H), 3.8
5 (m, 1H), 3.42 (m, 1H), 2.91
(M, 1H), 2.61-2.43 (m, 2H), 2.
30-2.17 (m, 2H), 1.77-1.11
(M, 12H), 1.07 (s, 9H)

[0066]

Industrial Applicability An α, α'-diaminoalcohol derivative useful as an HIV protease inhibitor can be industrially advantageously produced.

[0067]

[Brief description of the drawings]

FIG. 1 is a reaction diagram for producing α, α ′ diamino alcohol from (S) -4-alkoxycarbonyloxazolidin-2-one (1).

Claims (3)

[Claims] 1. a) The following formula (1): [Wherein R ¹ represents an alkyl group] and a compound represented by the following formula (2): [In the formula, X represents a halogen atom], and b) further reduced to obtain a compound represented by the following formula (3): Wherein X is the same as defined above, and c) is further treated with a base to give a compound of the following formula (4): D) Further, the compound is converted into a compound represented by the following formula (5): By reacting with a compound represented by the following formula (6): E) further reacting with a thiophenol, and subsequently protecting the amino group; [Wherein R ² may be substituted with an alkyl group, an aryl group, a heteroaryl group or an aralkyl group]. 2. The following formula (1): Wherein R ¹ is as defined above, and a haloacetic acid, or a salt thereof, or a silyl ester thereof is reacted with a halomagnesium dialkylamide or t-butylmagnesium halide to give the following formula (2): The method according to claim 1, wherein the compound is converted into a compound represented by the formula: wherein X is the same as defined above. 3. The following formula (2): [Wherein X is the same as defined above], a novel oxazolidinone derivative represented by the formula: