JP3444666B2 - Method for producing (2S, 3S) -3-methyl-2-thiopentanoic acid derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention is industrially useful (2S, 3
The present invention relates to a novel method for producing a S) -3-methyl-2-thiopentanoic acid derivative.

[0002]

2. Description of the Related Art In recent years, the role of physiologically active peptides or peptide hormones has come to the fore as an important factor controlling the homeostasis of the living body. For example, in the circulatory system, angiotensin-II (AT-II), vasopressin (VP), etc. were previously known, and atrial natriuretic peptide (ANP) family was discovered after the 1980s. , As well as elucidation of the role of cardiovascular system in pathological conditions, its application to pharmaceuticals has attracted attention. However, many of these bioactive peptides, or their derivatives,
It is said that its application to pharmaceuticals is limited due to its shortcomings such as short half-life of in vivo metabolism and lack of activity upon oral administration. In order to overcome this problem, many compounds having a peptide-like structure that are metabolically stable and effective even in oral administration have been developed.

For example, in Japanese Patent Application No. 5-308577, the compound (A) shown below is converted to neutral endopeptidase (NEP-24.11, hereinafter abbreviated as NEP) which is a degrading enzyme of the ANP family and angiotensin-I conversion. It is a dual inhibitor that simultaneously inhibits the enzyme (hereinafter abbreviated as ACE) and is disclosed as a compound that can be orally administered, has good metabolic stability, and is expected to have extremely excellent efficacy in heart failure and hypertension. There is.

[0004]

[Chemical 33]

[Wherein, R 1 represents a hydrogen atom or an acyl group. R2 means a hydrogen atom or a protective group for a carboxyl group. R3, R4, and R5 each independently represent a hydrogen atom, a lower alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. R
6 and R7 each independently represent a hydrogen atom, a lower alkyl group, an optionally substituted aryl group, or an optionally substituted arylalkyl group. In the synthesis of the compound represented by the general formula (I) which is the object compound of the present invention, the amine compound (IV) and the compound (b), (c) or (d) are usually subjected to an amidation reaction. .

[0006]

[Chemical 34]

[0007]

[Chemical 35]

[0008]

However, all of the above compounds (b), (c) and (d) are expensive and use D-alloisoleucine (B) as a starting material, which is troublesome for large-scale synthesis. There is.

Therefore, in order to synthesize the compound (I) industrially, it was necessary to consider an industrially advantageous new synthetic method with high yield and good operability.

[0010]

In view of the above situation, the present inventors have set out to find an industrially advantageous synthetic method. As a result, they have found that the method shown below achieves the intended purpose, and completed the present invention. That is, L-isoleucine (II)

[0011]

[Chemical 36]

Hydroxylation of α-hydroxycarboxylic acid (III)

[0013]

[Chemical 37]

General formula (I) having a step of obtaining

[0015]

[Chemical 38]

[Wherein R ¹ represents a hydrogen atom or an acyl group. R ² means a hydrogen atom or a protecting group for a carboxyl group. ] (2S, 3S) -3-methyl-2-
A method for producing a thiopentanoic acid derivative, which comprises α-hydroxycarboxylic acid (III)

[0017]

[Chemical Formula 39]

And the general formula (IV)

[0019]

[Chemical 40]

[Wherein R ³ , R ⁴ , and R ⁵ each independently represent a hydrogen atom, a lower alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. . R ⁶ and R ⁷ each independently represent a hydrogen atom, a lower alkyl group, an optionally substituted aryl group, or an optionally substituted arylalkyl group. R ^2a means a protecting group for carboxylic acid. ]
By coupling an amine derivative represented by the general formula (V)

[0021]

[Chemical 41]

A general formula (I) having a step characterized by synthesizing an α-hydroxycarboxylic acid amide derivative represented by

[0023]

[Chemical 42]

[In the formula, R ¹ represents a hydrogen atom or an acyl group. R ² means a hydrogen atom or a protecting group for a carboxyl group. ] (2S, 3S) -3-methyl-2-
A method for producing a thiopentanoic acid derivative, which is represented by the general formula (V)

[0025]

[Chemical 43]

The α-hydroxy carboxylic acid amide derivative represented by the formula (I)

[0027]

[Chemical 44]

[In the formula, R ¹ represents a hydrogen atom or an acyl group. R ² means a hydrogen atom or a protecting group for a carboxyl group. ] (2S, 3S) -3-methyl-2-
A method for producing a (2S, 3S) -3-methyl-2-thiopentanoic acid derivative, which comprises the step of obtaining a thiopentanoic acid derivative.

In the present invention, R ³ , R ⁴ , R ⁵ , R ⁶
And the lower alkyl group in the definition of R ⁷ means a straight-chain or branched alkyl group having 1 to 6 carbon atoms,
For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group, neopentyl group, tert-pentyl group , 1-methylbutyl group, 2-methylbutyl group, 1,2
-Dimethylpropyl group, hexyl group, isohexyl group,
1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 2,3-
Dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,
It means a 2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl group and the like.

In the aryl group which may have a substituent as defined in the definition of R ³ , R ⁴ , R ⁵ , R ⁶ or R ⁷ , aryl means phenyl, 1-naphthyl, 2-naphthyl, anthracenyl. And so on. Further, the substituent in this case, a hydroxyl group, a halogen atom, a lower alkyl group,
It means a lower alkoxy group, an amino group, a nitro group and the like.

In the arylalkyl group which may have a substituent as defined in the definition of R ³ , R ⁴ , R ⁵ , R ⁶ or R ⁷ , aryl means phenyl, 1-naphthyl,
It means 2-naphthyl, anthracenyl and the like. Further, the alkyl in this case has the same meaning as the above lower alkyl group. Further, the substituent means a hydroxyl group, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, a nitro group and the like.

The acyl group in the definition of R ¹ is a group derived from an aliphatic carboxylic acid such as an acetyl group, a propionyl group, an acryloyl group and a propioroyl group, a carbocyclic group such as a toluoyl group, a cinnamoyl group and a naphthoyl group. Examples thereof include a group derived from a formula carboxylic acid, a furoyl group, a thenoyl group, a nicotinoyl group, and a group derived from a heterocyclic carboxylic acid. The carboxyl protecting group in the definition of R ² means a lower alkyl group such as a methyl group and an ethyl group, an acyl group such as acetyl and benzoyl, and the like.

The present invention is different from the conventional production method using D-alloisoleucine as a starting material, and inexpensively supplies L-isoleucine which can be supplied in a large amount by hydroxy to synthesize α-hydroxycarboxylic acid (II), By introducing this into the α-hydroxycarboxylic acid amide derivative represented by the general formula (IV), the (2S, 3S) -3-methyl-2-thiopentanoic acid derivative (I) can be easily obtained. In order to convert the α-hydroxycarboxylic acid amide derivative represented by the general formula (V) into the target compound (2S, 3S) -3-methyl-2-thiopentanoic acid derivative (I), a commonly used method or a usual method is used. The methods used can be combined and proceed. For example, a hydroxyl group of an α-hydroxycarboxylic acid amide derivative is halogenated, and this is acylthiolated to form (2S, 3S) -3-
A methyl-2-thiopentanoic acid derivative (I) can be obtained. In this case, the halogenation may be performed by any method, but a method of introducing a halogen atom in a stereo-inverted manner is preferable from the viewpoint of reducing the number of steps and operability. Further, in the target compound, R ¹ represented by the general formula (Ic) is an acyl group, R ²
In the α-acylthiocarboxylic acid amide derivative in which is a hydrogen atom, the α-halocarboxylic acid amide derivative obtained by the above method may be first hydrolyzed to remove the carboxylic acid protecting group and then acylthiolated. Good.

In order to facilitate the understanding of the present invention,
The preferred embodiments of the present invention will be described in more detail, but the present invention is not limited thereto.

Manufacturing method A

[0036]

[Chemical formula 45]

[0037]

[Chemical formula 46]

First Step This step is a step of obtaining an α-hydroxycarboxylic acid (II) by hydroxylating the amino group of L-isoleucine (I) by a conventional method. The hydroxylation can be carried out by a commonly used method, but preferably L-
It is carried out by reacting isoleucine (I) with a nitrite agent such as sodium nitrite in dilute sulfuric acid, or by reacting with sodium nitrite in acetic acid to form an acetate and then hydrolyzing it.

Second step This step is a step of condensing α-hydroxycarboxylic acid (II) obtained in the first step and amine derivative (III) by a conventional method to obtain hydroxycarboxylic acid amide derivative (IV). is there.
The reaction is carried out by a commonly used method, for example, α-hydroxycarboxylic acid (II) and amine derivative (I
II) is EEDQ (1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), DEC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) Alternatively, by reacting in an inert solvent such as methylene chloride or tetrahydrofuran in the presence of a commonly used condensation reagent such as diethyl cyanophosphonate,
The amide derivative (IV) can be obtained.

Third Step This step is a step of halogenating the hydroxycarboxylic acid amide derivative (IV) by a conventional method to obtain the α-halogencarboxylic acid amide derivative (XV). Any conventionally used method may be used as long as it is a method of sterically inverting halogenation. For example, (i) a method of reacting with a dialkyl azodicarboxylate, triphenylphosphine and zinc bromide or zinc iodide in an organic solvent such as tetrahydrofuran.
(ii) an organic phosphorus compound such as trialkylphosphine, triphenylphosphine, triphenylphosphite, etc., and N-halosuccin in an organic solvent such as acetonitrile, dimethylformamide, or dichloromethane, in the presence or absence of a base such as pyridine. Method of reacting halogen compounds such as imide and bromine / iodine (iii) Sulfonic acid by reacting with tosylic acid chloride or trifluoromethanesulfonic anhydride in the presence of a base such as pyridine and triethylamine in an inert solvent such as dichloromethane After forming the ester, a method of reacting with a halogenating reagent such as lithium halide can be mentioned, and particularly preferably, in an organic solvent such as acetonitrile, dimethylformamide and dichloromethane, in the presence or absence of a base such as pyridine. To Triaki Preferred is a method of reacting an organic phosphorus compound such as phosphine, triphenylphosphine, triphenyl phosphite, etc. and a halogen compound such as N-halosuccinimide, bromine / iodine, and particularly a method using triphenylphosphine and bromine as reagents. .

Fourth Step This step is a step of obtaining an α-acylthiocarboxylic acid amide derivative (XVI) by acylthiolation of the α-halocarboxylic acid amide derivative (XV) obtained in the third step. The reaction is carried out by a conventional method, for example, by reacting an α-halocarboxylic acid amide derivative (XV) with a thiocarboxylic acid salt such as potassium thioacetate or sodium thioacetate in a polar solvent such as acetonitrile or acetone, or potassium carbonate. The α-acylthiocarboxylic acid amide derivative (XVI) can be obtained by reacting with a thiocarboxylic acid such as thioacetic acid or thiobenzoic acid in the presence of a base such as cesium carbonate.

[0042] The fifth step This step is intended compound, or when R ¹ R ¹ and R ² is a hydrogen atom is an acyl group, a step of performing when R ² is hydrogen atom. That is, the α-acylthiocarboxylic acid amide derivative (XVI) obtained in the fourth step is hydrolyzed by a conventional method to give (2S, 3S) -3-
It is a step of obtaining a methyl-2-thiopentanoic acid derivative (XVII). It can be hydrolyzed by ordinary hydrolysis, that is, in a dilute aqueous alkaline solution such as sodium hydroxide or lithium hydroxide or a dilute aqueous mineral acid solution. The target compound was obtained when R ¹ was an acyl group (2S, 3
Using the S) -3-methyl-2-thiopentanoic acid derivative (XVII), proceed to the sixth step below.

Sixth Step This step is a step carried out when the target compound has R ¹ as an acyl group. That is, obtained in the fifth step (2S, 3
S) -3-Methyl-2-thiopentanoic acid derivative (XVII) is acylated by a conventional method to obtain an α-acylthiocarboxylic acid amide derivative (XVIII). The reaction is carried out by a commonly used method, for example, an acid anhydride such as acetic anhydride, an acylating agent such as an acid halide and an α-mercaptocarboxylic acid amide derivative (XVII), acetonitrile,
By reacting in a non-aqueous solvent such as tetrahydrofuran or dichloromethane, or by treating in an aqueous solvent in the presence of a base such as potassium hydrogen carbonate, sodium hydrogen carbonate or triethylamine or cobalt chloride, α-acyl thiocarboxylic acid Amide derivative
(XVIII) can be obtained. After the hydroxylation of L-isoleucine and the condensation of the amine derivative (III) with the production method A to obtain the hydroxycarboxylic acid amide derivative (IV), the target compound can also be obtained by the following method.

Manufacturing method B

[0045]

[Chemical 47]

First Step This step is a step of hydrolyzing the α-halocarboxylic acid amide derivative (XV) obtained in the third step of the production method A by a conventional method to obtain a carboxylic acid compound (XX). By normal hydrolysis,
That is, it can be hydrolyzed in a dilute aqueous alkali solution such as sodium hydroxide or lithium hydroxide or a dilute mineral acid aqueous solution.

Second Step This step is a step of obtaining an α-acylthiocarboxylic acid amide derivative (XVI) by acylthiolation of the α-halocarboxylic acid amide derivative (XX) obtained in the first step. Although the reaction is carried out by a conventional method, for example, by reacting the α-halocarboxylic acid amide derivative (XX) with a thiocarboxylic acid salt such as potassium thioacetate and sodium thioacetate in a polar solvent such as acetonitrile, dimethylsulfoxide and acetone, Alternatively, the α-acylthiocarboxylic acid amide derivative (XVIII) can be obtained by reacting with a thiocarboxylic acid such as thioacetic acid or thiobenzoic acid in the presence of a base such as potassium carbonate or cesium carbonate.

Next, examples will be given to facilitate understanding of the present invention, but it goes without saying that the present invention is not limited thereto. Example 1 (2S, 3S) -2-Hydroxy-3-methylpentanoic acid

[0049]

[Chemical 48]

A mixture of 100 g (0.762 mmol) of L-isoleucine and 1.14 L of 1N sulfuric acid aqueous solution was cooled and stirred at 0 ° C. or lower while stirring and stirring 150 mL of an aqueous solution of 78.9 g (1.14 mol) of sodium nitrite.
It dripped over minutes. During this time, the internal temperature was maintained at 0-5 ° C. The reaction was then stirred at 0-5 ° C for 1.5 hours and at room temperature overnight.
Extraction was performed 3 times (1.2 L in total) with diethyl ether, the ether layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. By distilling off the solvent, 52.01 g of the crude title compound was obtained as a pale yellow oil (yield 52%).

1H-NMR (400MHz, CDCl ₃ ) δ; 4.19 (1H, d,
J = 4 Hz), 1.95-1.84 (1H, m), 1.50-1.16 (2H, m), 1.0
2 (3H, d, J = 7 Hz), 0.93 (3H, t, J = 7 Hz).

Example 2 Methyl [3R- [3a, 6a (S *), 9ab]]-6-[[(2S, 3S)-
1-oxo-2-hydroxy-3-methylpentyl] amino]
-Octahydro-5-oxothiazolo [3,2-a] azepine
-3-carboxylate

[0053]

[Chemical 49]

(2S, 3S) -2-Hydroxy-3-methylpentanoic acid 0.208 mg (1.57 mmol), methyl [3R- (3a, 6a, 9ab)] -6
-Amino-5-oxo-octahydrothiazolo [3,2-a] azepine-3-carboxylate While stirring a solution of 366 mg (1.50 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere, 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride 316 mg (1.65 mmol), N-methylmorpholine 16
7 mg (1.65 mmol), 1-hydroxybenztriazole 253 m
g (1.65 mmol) was added sequentially and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. 1N hydrochloric acid for the organic layer,
The extract was washed with water, saturated sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 479 mg of the crude title compound as a white solid (yield 89%).

1H-NMR (400MHz, CDCl ₃ ) δ; 7.59 (1H, br
d, J = 6 Hz), 5.26 (1H, dd, J = 7, 3 Hz), 5.05 (1H,
d, J = 9 Hz), 4.60 (1H, ddd, J = 2, 7, 10 Hz), 4.00
(1H, dd, J = 3, 6 Hz), 3.80 (3H, s), 3.28 (1H, dd, J
= 12, 3 Hz), 3.20 (1H, dd, J = 7, 12 Hz), 2.75 (1H, b
rs), 2.08-1.82 (6H, m), 1.75-1.62 (1H, m), 1.46-1.35
(1H, m), 1.28-1.18 (1H, m), 0.99 (3H, d, J = 7 Hz),
0.89 (3H, d, J = 8 Hz).

Example 3 Methyl [3R- [3a, 6a (S *), 9ab]]-6-[[(2R, 3S)-
1-oxo-2-bromo-3-methylpentyl] amino] -o
Kutahydro-5-oxothiazolo [3,2-a] azepine-3-
Carboxylate

[0057]

[Chemical 50]

Methyl [3R- [3a, 6a (S *), 9ab]]-6-
[[(2S, 3S) -1-oxo-2-hydroxy-3-methylpentyl] amino] -octahydro-5-oxothiazolo [3, 2
-a] Azepine-3-carboxylate 475 mg (1.325 mmol),
Triphenylphosphine 521 mg (1.99 mmol), pyridine 0.
While stirring 16 mL (1.98 mmol) of 15 mL of an acetonitrile solution at room temperature under a nitrogen atmosphere, 0.102 mL (1.98 mmol) of bromine was added. The mixture was stirred at room temperature for 20 minutes, and then heated under reflux for 3.5 hours.
The reaction mixture was concentrated, dichloromethane was added to the residue, and the mixture was washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography. Hexane: Ethyl acetate = Elute gradually from 8: 1 to 5: 1 to give the title compound
310 mg was obtained as a colorless amorphous substance (yield 56%).

1H-NMR (400MHz, CDCl ₃ ) δ; 7.84 (1H, br
d, J = 6 Hz), 5.29 (1H, dd, J = 2, 6 Hz), 5.03 (1H,
d, J = 9 Hz), 4.53 (1H, ddd, J = 1, 6, 11 Hz), 4.45
(1H, d, J = 4 Hz), 3.80 (3H, s), 3.29 (1H, dd, J = 2,
12 Hz), 3.21 (1h, dd, J = 7, 12 Hz), 1.90-2.14 (6H,
m), 1.66-1.76 (1H, m), 1.30-1.51 (2H, m), 0.94 (3H, d,
J = 6 Hz), 0.93 (3H, t, J = 7 Hz).

[0060]Example 4 Methyl [3R- [3a, 6a (S *), 9ab]]-6-[[(2S, 3S)-
1-oxo-2-acetylthio-3-methylpentyl] ami
No]-Octahydro-5-oxothiazolo [3,2-a] aze
Pin-3-carboxylate

[0061]

[Chemical 51]

Methyl [3R- [3a, 6a (S *), 9ab]]-6-
[[(2R, 3S) -1-oxo-2-bromo-3-methylpentyl]
Amino] -octahydro-5-oxothiazolo [3,2-a]
10 mL of an azepine-3-carboxylate 285 mg (0.676 mmol) acetonitrile solution was added with stirring under cooling at 0 ° C. in a nitrogen atmosphere while adding 100 mg (0.876 mmol) of potassium thioacetate, followed by stirring at room temperature overnight. Ethyl acetate was added to the reaction solution, which was acidified with 1N hydrochloric acid and the organic layer was separated. The organic layer was further washed with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (256 mg) as a pale brown oil (yield 91
%).

1H-NMR (400MHz, CDCl ₃ ) δ; 7.41 (1H,
d, J = 6 Hz), 5.28 (1H, dd, J = 2, 6Hz), 5.02 (1H,
d, J = 9 Hz), 4.54 (1H, dd, J = 6, 10 Hz), 4.54 (1H,
dd, J = 6, 10 Hz), 3.79 (3H, s), 3.28 (1H, dd, J = 2,
12 Hz), 3.20 (1H, dd, J = 6 Hz, 12 Hz), 2.38 (3H,
s), 1.82-2.14 (6H, m), 1.51-1.70 (2H, m), 1.10-1.22
(1H, m), 0.99 (3H, d, J = 7 Hz), 0.88 (3H, t, J = 8
Hz).

Example 5 [3R- [3a, 6a (S *), 9ab]]-6-[[(2S, 3S) -1-oxo
-2-Thio-3-methylpentyl] amino] -octahydro
-5-oxothiazolo [3,2-a] azepine-3-carboxylic acid

[0065]

[Chemical 52]

Methyl [3R- [3a, 6a (S *), 9ab]]-6-
[[(2S, 3S) -1-oxo-2-acetylthio-3-methylpentyl] amino] -octahydro-5-oxothiazolo [3,
2-a] Azepine-3-carboxylate 200 mg (0.48 mmol)
A mixture of 8 ml of degassed ethanol and 0 ° C under nitrogen atmosphere
1N lithium hydroxide aqueous solution degassed with stirring
3.8 ml was added and the resulting mixture was stirred at room temperature for 50 minutes. To the resulting mixture was added 2N aqueous hydrochloric acid solution (2.9 ml) at 0 ° C. to make the mixture acidic, and the resulting mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The residual solid was recrystallized from hexane-methylene chloride to give the title compound (150 mg) as white crystals (yield 87%).

1H-NMR (400MHz, CDCl ₃ ) δ; 7.69 (1H,
d, J = 6Hz), 5.29 (1H, dd, J = 2, 6Hz), 5.07 (1H, t
like, J = 6 Hz), 4.62 (1H, dd, J = 6, 10Hz), 3.36 (1H,
dd, J = 2, 12Hz), 3.20 (1H, dd, J = 6, 12Hz), 1.90
-2.10 (6H, m), 1.87 (1H, d, J = 8Hz), 1.55-1.74 (2H,
m), 1.24 (1H, m), 1.00 (3H, d, J = 7 Hz), 0.90 (3H,
t, J = 7 Hz).

Example 6 [3R- [3a, 6a (S *), 9ab]]-6-[[(2S, 3S) -1-oxo
-2-Bromo-3-methylpentyl] amino] -octahydr
Ro-5-oxothiazolo [3,2-a] azepine-3-carvone
acid

[0069]

[Chemical 53]

Methyl [3R- [3a, 6a (S *), 9ab]]-6-
[[(2R, 3S) -1-oxo-2-bromo-3-methylpentyl]
Amino] -octahydro-5-oxothiazolo [3,2-a]
While stirring azepine-3-carboxylate (238 mg, 0.565 mmol) in ethanol (3 ml) at 0 ° C., 1N aqueous lithium hydroxide solution (0.68 ml) was added, and the mixture was returned to room temperature for 1 hour and 30 minutes.
Stir for minutes. The reaction solution is cooled, acidified with 1N hydrochloric acid,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 230 mg of the title compound as a colorless amorphous substance (quantitative yield).

1H-NMR (400MHz, CDCl ₃ ) δ; 7.96 (1H, br
d, J = 6 Hz), 5.31 (1H, dd, J = 2, 6 Hz), 5.08 (1H,
d, J = 9 Hz), 4.58-4.68 (1H, m), 4.47 (1H, d, J = 4 H
z), 3.18-3.40 (2H, m), 1.90-2.16 (6H, m), 1.66-1.80 (1
H, m), 1.33-1.51 (2H, m), 0.94 (3H, d, J = 6 Hz), 0.9
3 (3H, t, J = 7 Hz).

Example 7 3R- [3a, 6a (S *), 9ab]]-6-[[(2S, 3S) -1-oxo
-2-Acetylthio-3-methylpentyl] amino] -oct
Tahydro-5-oxothiazolo [3,2-a] azepine-3-ca
Rubonic acid

[0073]

[Chemical 54]

[3R- [3a, 6a (S *), 9ab]]-6-[[(2S,
3S) -1-Oxo-2-thio-3-methylpentyl] amino]-
Octahydro-5-oxothiazolo [3,2-a] azepine-3
-200 mg (0.55 mmol) of carboxylic acid and 0.058 ml (0.61
mmol) acetonitrile-tetrahydrofuran (1: 1) 6 ml
The solution was added dropwise to a solution of 22 mg (0.17 mmol) of cobalt (II) chloride in acetonitrile (5 ml). The resulting mixture was stirred for 7 hours, concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residual solid was recrystallized from ethyl acetate-diethyl ether-hexane to give the title compound (180 mg) as white crystals (yield 85%).

1H-NMR (400MHz, CDCl ₃ ) δ; 7.44 (1H,
d, J = 6Hz), 5.30 (1H, dd, J = 2, 7Hz), 5.05 (1H, t
like, J = 5 Hz), 4.60 (1H, dd, J = 6, 11Hz), 3.97 (1
H, d, J = 7Hz), 3.35 (1H, dd, J = 2, 12Hz), 3.21 (1H, dd,
J = 6, 12 Hz), 2.38 (3H, s), 1.86-2.14 (6H, m), 1.
52-1.72 (2H, m), 1.10-1.24 (1H, m), 1.00 (3H, d, J = 7H
z), 0.88 (3H, t, J = 7 Hz).

Example 8 3R- [3a, 6a (S *), 9ab]]-6-[[(2S, 3S) -1-oxo
-2-Acetylthio-3-methylpentyl] amino] -oct
Tahydro-5-oxothiazolo [3,2-a] azepine-3-ca
Rubonic acid

[0077]

[Chemical 55]

[3R- [3a, 6a (S *), 9ab]]-6-[[(2R,
3S) -1-Oxo-2-bromo-3-methylpentyl] amino]
-Octahydro-5-oxothiazolo [3,2-a] azepine
To 8 ml of a solution of 172 mg (0.422 mmol) of -3-carboxylic acid in dimethylsulfoxide was added 58 mg (0.508 mmol) of potassium thioacetate, and the resulting mixture was stirred at about 80 ° C. for 6 hours. The reaction mixture was cooled, acidified with 1N hydrochloric acid, water was further added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (119 mg) as white crystals (yield
70%).

[0079]

INDUSTRIAL APPLICABILITY The present invention uses, as a starting material, natural L-isoleucine, which is very inexpensive and can be supplied in large quantities, and efficiently
A hydroxycarboxylic acid amide derivative (IV) was synthesized, and (2S, 3S) -3-methyl-2 represented by the general formula (V) was produced in a shorter step.
-It is a feature that the production method can lead to an opentanoic acid derivative. That is, it is a method for producing a (2S, 3S) -3-methyl-2-opentanoic acid derivative with low cost, high yield, and good operability, which is a very industrially advantageous method.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Masanori Mizuno 1-1-17 Doikita, Hasaki-machi Kashima-gun, Ibaraki Prefecture (72) Inventor Kazutoshi Miyake 1-56-51 Sakae-cho, Ushiku-shi, Ibaraki (56) References International Publication 94/10193 (WO, A1) (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 513/04 361 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. The general formula (V) [Wherein R ^2a means a protecting group for carboxylic acid,
R ³ , R ⁴ , and R ⁵ each independently represent a hydrogen atom, a lower alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group,
R ⁶ and R ⁷ each independently represent a hydrogen atom, a lower alkyl group, an optionally substituted aryl group, or an optionally substituted arylalkyl group. ] The α-hydroxycarboxylic acid amide derivative represented by the formula (I) [Wherein R ¹ represents a hydrogen atom or an acyl group, and R ^1
3 , R ⁴ , R ⁵ , R ⁶ , and R ⁷ have the same meanings as the group in the formula (V) . ] (2S, 3S) -3-Methyl-2
-A method for producing a (2S, 3S) -3-methyl-2-thiopentanoic acid derivative represented by the above general formula (I), characterized by comprising a step of obtaining a thiopentanoic acid derivative. 2. α-Hydroxycarboxylic acid (III) And the general formula (IV) [Wherein R ^2a , R ³ , R ⁴ , R ⁵ , R ⁶ and R are
⁷ has the same meaning as the group in the general formula (V) described in claim 1 . ] By coupling an amine derivative represented by the general formula (V) [Wherein R ^2a , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are contracted
It has the same meaning as the group in the general formula (V) described in claim 1 . ] To obtain an α-hydroxycarboxylic acid amide derivative,
This is acylthiolated and optionally hydrolyzed to give a compound of the general formula (I) [In the formula, R ¹ has the same meaning as the group in the general formula of claim 1 wherein ^{(I), R 3, R} 4, R 5, R 6, R 7 , a request
It has the same meaning as the group in the general formula (V) described in item 1 . Represented by] (2S, 3S) -3- that have a step of obtaining methyl 2- Chiopentan acid derivative, represented by the general formula (I) (2
Process for producing S, 3S) -3-methyl-2-thiopentanoic acid derivative. 3. L-isoleucine (II) Hydroxylation of α-hydroxycarboxylic acid (III) And this and the general formula (IV) [Wherein R ^2a , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are contracted
It has the same meaning as the group in the general formula (V) described in claim 1 . ] By coupling an amine derivative represented by the general formula (V) [Wherein R ^2a , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are contracted
It has the same meaning as the group in the general formula (V) described in claim 1 . ] To obtain an α-hydroxycarboxylic acid amide derivative,
This is acylthiolated and optionally hydrolyzed to give a compound of the general formula (I) [In the formula, R ¹ has the same meaning as the group in the general formula of claim 1 wherein ^{(I), R 3, R} 4, R 5, R 6, R 7 is 請
It is synonymous with the said group in General formula (V) of the claim 1 . ]
Having the step of obtaining a (2S, 3S) -3-methyl-2-thiopentanoic acid derivative represented by
A method for producing a (2S, 3S) -3-methyl-2-thiopentanoic acid derivative . 4. The general formula (V) [Wherein R ^2a , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are contracted
It has the same meaning as the group in the general formula (V) described in claim 1 . Represented by α- hydroxycarboxylic acid amide derived body] and halo <br/> Gen of the general formula (VI) [In the formula, X means a halogen atom. R ^2a ,
R < ³ >, R < ⁴ >, R < ⁵ >, R < ⁶ >, R < ⁷ > has the same meaning as the group in the general formula (V) of claim 1 . ] The α-halogencarboxylic acid amide derivative represented by the following formula is obtained, and this is acylthiolated, and hydrolyzed if necessary to give a compound of the general formula
(I) [In the formula, R ¹ has the same meaning as the group in the general formula of claim 1 wherein ^{(I), R 3, R} 4, R 5, R 6, R 7 , a request
It has the same meaning as the group in the general formula (V) described in item 1 . ] (2S, 3S) -3-Methyl-2-thiopentanoic acid derivative
Represented by the above general formula (I) (2S,
3S) -3-Methyl-2-thiopentanoic acid derivative production method. 5. The general formula (V) [Wherein R ^2a , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are contracted
It has the same meaning as the group in the general formula (V) described in claim 1 . Represented by α- hydroxycarboxylic acid amide derived body] and halo <br/> Gen of the general formula (VI) [Wherein R ^2a , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are contracted
X has the same meaning as the group in formula (V) described in claim 1.
Is the same as the group in the general formula (VI) described in claim 4 . ] The α-halogencarboxylic acid amide derivative represented by [ Wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each defined in claim 1.
Has the same meaning as the group in the general formula (V), X is a request
It has the same meaning as the group in the general formula (VI) described in item 4 . ] The α-halocarboxylic acid derivative represented by the formula (I) is obtained by further acylthiolating it. [In the formula, R ¹ has the same meaning as the group in the general formula of claim 1 wherein ^{(I), R 3, R} 4, R 5, R 6, R 7 , a request
It has the same meaning as the group in the general formula (V) described in item 1 . ] (2S, 3S) -3-Methyl-2-thiopentanoic acid derivative
(2S, represented by the general formula (I) above.
Process for producing 3S) -3-methyl-2-thiopentanoic acid derivative . 6. The general formula (VIII) [Wherein R ¹ represents a hydrogen atom or an acyl group,
R ³ , R ⁴ and R ⁵ each independently represent a hydrogen atom, a lower alkyl group, an aryl group which may be substituted, or a heteroaryl group which may be substituted, and R ⁶
And R ⁷ each independently represent a hydrogen atom, a lower alkyl group, an optionally substituted aryl group, or an optionally substituted arylalkyl group, and R ⁸ is a hydrogen atom or a carboxyl group-protecting group. Means However, R
^{The case where 3} , R ⁴ and R ⁵ are simultaneously hydrogen atoms is excluded. ] The (2S, 3S) -3-methyl-2- thiopentanoic acid derivative shown by these.