JPH0940601A - Method for producing optically active ketone derivative and optically active ketone derivative - Google Patents

Abstract

(57) Abstract: An object of the present invention is to provide an optically active ketone derivative useful as an agricultural and pharmaceutical intermediate, and a stereoselectively high yield thereof, and an industrially advantageous production method. It is a thing. SOLUTION: Formula [1] (Wherein R ¹ represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group, etc., and R ² represents a lower alkyl group or a halogen atom) and a compound represented by the formula [2]: (Wherein the R ³ is a lower alkyl group or a halogen atom, R ⁴
Represents a lower alkyl group or a lower alkoxycarbonylmethyl group, and the carbon atom marked with * has the [R] -configuration or the [S] -configuration. ), A compound represented by the formula [3]: And a method of producing a compound represented by the formula [4] (In the formula, R ⁵ represents a nitro group, an alkyl group or a phenyl group, R ⁶ represents a lower alkyl group, and R ⁷ represents a lower alkoxycarbonylmethyl group.).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention is disclosed in JP-A-2-56468 and JP-A-6-192098, which are useful as optically active pharmaceutical agents, agricultural chemicals and the like, for example, pharmaceutical agents having an excellent cardiotonic action or platelet aggregation inhibitory action. Formula [5] described

Embedded image The present invention relates to a method for producing an optically active ketone derivative useful as a synthetic intermediate of an optically active compound represented by and an optically active ketone derivative.

[0002]

2. Description of the Related Art Org. Chem. 56 , 1963
-6 (1991) describes a method of synthesizing an optically active ketone derivative using acetanilide and an optically active acid chloride.

[0003]

[Chemical 6] (In the formula, X represents Br or Cl, r ¹ represents hydrogen or an acetyl group, and r ² and r ³ represent hydrogen, a methyl group, a butyl group or a benzyl group.) However, this method is represented by the above formula [5]. [6] which is an important intermediate of the compound represented by

[0004]

[Chemical 7] When it is applied to the optically active acid chloride of, isomerization occurs, and the target compound of formula [7]

[0005]

Embedded image Is obtained only as a by-product, and the main product is isomerized formula [8]

[0006]

Embedded image Met. Moreover, it was very difficult to separate the two.

The coupling reaction between an optically inactive acid chloride and an organotin compound is described in, for example, J. Am. Chem. S
oc. , 113 , 2319-21 (1991), the following reaction is described, but there is no description that it is applicable to an optically active ketone derivative.

[0008]

Embedded image As a general rule, the development of pharmaceuticals having an asymmetric carbon is carried out using optically active compounds, and research on methods for producing optically active compounds has become an important issue.

[Problems to be Solved by the Invention]

It is an object of the present invention to provide an optically active ketone derivative useful as an intermediate for agricultural and pharmaceutical products and a stereoselectively high yield thereof and an industrially advantageous production method.

[Means for Solving the Problems]

The present invention includes: Formula [1]

Embedded image (Wherein R ¹ represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group, a phenyl group, an alkoxy group or an alkylthio group, and R ² represents a lower alkyl group or a halogen atom), and a compound represented by the formula: [2]

[0011]

[Chemical 12] (In the formula, R ³ is a lower alkyl group or a halogen atom,
⁴ represents a lower alkyl group or a lower alkoxycarbonylmethyl group, and the carbon atom marked with * has [R] -configuration or [S] -configuration. However, R ³ and R ⁴ are not the same alkyl group at the same time. ), A compound represented by the formula [3]

[0012]

Embedded image (Wherein R ¹ , R ³ , R ⁴ and * have the same meanings as described above), and 1. Formula [4]

[0013]

Embedded image (In the formula, R ⁵ is a nitro group, an alkyl group or a phenyl group, R ⁶ is a lower alkyl group, R ⁷ is a lower alkoxycarbonylmethyl group, and * has the same meaning as described above.). Is a compound.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the production method of the present invention, the compound represented by the formula [1] and the compound represented by the formula [2] are usually subjected to a coupling reaction in the presence of a palladium catalyst in an inert solvent. It is done by

[0015]

Embedded image (In the formula, R ¹ , R ² , R ³ , R ⁴ and * have the same meanings as described above.)

The palladium catalyst used in the present invention includes PdCl ₂ , PdCl ₂ (PPh ₃ ) ₂ and PdCl.
₂ (CH ₃ CN) ₂ , PdCl ₂ (PhCN) ₂ , Pd (OAc)
₂ , Pd (PPh ₃ ) _{4 and the} like. The coupling reaction is carried out in a solvent inert to the reaction, such as ethers such as THF and dioxane, toluene, DMF, HMPA, and N-methylpyrrolidone, preferably 0 ° C to 150 ° C, preferably 2 ° C.
It is carried out at a temperature of 0 ° C to 70 ° C. The amount of the catalyst used is not particularly limited, but is usually 1 to 1 / 10,000 mol, preferably 0.1 to 0.10 mol per mol of the tin compound of the formula [1].
It can be used in an amount within the range of 001 mol. After completion of the reaction, the desired product can be obtained by performing usual post-treatment. By the above reaction, the desired optically active ketone derivative of the formula [3] can be usually obtained with an optical purity of 50 to 95%. The structures of the compounds of the present invention are IR, NM
It was determined from R, Mass, etc.

【Example】

Example 1 Production of (3R) -3- (4-nitrobenzoyl) butyric acid methyl ester

[0018]

Embedded image

Bis (triphenylphosphine) palladium dichloride (0.07 g) and (4-nitrophenyl) tributyltin (2.06 g) were suspended in THF (10 ml) to prepare (2
R) -3-Methoxycarbonyl-2-methylpropionic acid (optical purity 95%) of acid chloride derived from 0.9
9 g was added and refluxed for 8 hours. After cooling, THF was distilled off under reduced pressure, an aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 30 minutes. After adding chloroform and stirring, the mixture was filtered through Celite, and the filtrate was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give 0.88 g of the oily desired product.
Obtained. NMR δ1.25 ppm (d, 3H), 2.5 (d
d, 1H), 3.0 (dd, 1H), 3.65 (s, 3
H), 3.9 (m, 1H), 8.15 (d, 2H),
8.35 (d, 3H) HPLC 90% ee Column: CHIRALPAK
AS (Daicel chemistry) UV: 254 nm Moving layer: Ethanol: Hexane = 1: 9 Flow rate: 1 ml / min

[Reference Example] Production of (2R) -3-methoxycarbonyl-2-methylpropionic acid chloride

[0021]

Embedded image

100 g of (2R) -3-methoxycarbonyl-2-methylpropionic acid was added to 70 ml of dichloromethane.
And was added to 200 g of thionyl chloride. 1 DMF
0 drop was added and the mixture was refluxed for 1 hour. After distilling off excess thionyl chloride and the solvent under reduced pressure, the residue was distilled under reduced pressure to obtain 105.4 g of the desired product.
(Bp 50-60 ° C./0.5-5 mmHg) was obtained.

[0023]

According to the production method of the present invention, an optically active ketone derivative can be produced industrially advantageously. The optically active derivative of the present invention is useful as an intermediate for the synthesis of agricultural drugs. For example, JP-A-2-56468 and JP-A-6-192098.
It is useful as a synthetic intermediate for producing an optically active compound of the compound having a cardiotonic action or a platelet aggregation inhibitory action described in 1.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 49/84 9049-4H C07C 49/84 C 67/343 67/343 69/738 9546-4H 69 / 738 Z 201/12 201/12 205/56 205/56 319/20 319/20 323/62 323/62 // C07B 61/00 300 C07B 61/00 300 C07M 7:00

Claims (2)

[Claims] 1. A formula [1]: (Wherein R ¹ represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group, a phenyl group, an alkoxy group or an alkylthio group, and R ² represents a lower alkyl group or a halogen atom); [2] [Chemical Formula 2] (In the formula, R ³ is a lower alkyl group or a halogen atom,
⁴ represents a lower alkyl group or a lower alkoxycarbonylmethyl group, and the carbon atom marked with * has [R] -configuration or [S] -configuration. However, R ³ and R ⁴ are not the same alkyl group at the same time. ), A compound represented by the formula [3]: (Wherein R ¹ , R ³ , R ⁴ and * have the same meanings as described above). 2. A formula [4]: (In the formula, R ⁵ is a nitro group, an alkyl group or a phenyl group, R ⁶ is a lower alkyl group, R ⁷ is a lower alkoxycarbonylmethyl group, and the carbon atom with * is [R].
-Configuration or [S] -configuration)