JP2734646B2 - Novel synthetic method of 2,2-difluorocarboxylic acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing a 2,2-difluorocarboxylic acid derivative.

Research on fluorine modification of physiologically active substances has become increasingly active in recent years, and with this trend, expectations for a new synthesis method capable of synthesizing various fluorine-containing compounds more efficiently have increased. In synthesizing such a fluorine atom-containing physiologically active substance, it is necessary and sometimes useful to use an intermediate containing a fluorine atom. The present inventors have developed an efficient method for synthesizing synthetic intermediates having various difluoromethylene groups (Japanese Patent Application Laid-Open No.
48229, JP-A-63-233937, etc.). The present inventors will continue to study and develop a new method capable of synthesizing various 2,2-difluorocarboxylic acid derivatives by adding a difluoroacetic acid group conjugately to a 3,3-dialkoxypropene derivative. It has been reached.

The present invention relates to a novel method for producing such a 2,2-difluorocarboxylic acid derivative, that is, the following invention.

A 2,3-difluoroketene silyl acetal represented by the following formula [I] is reacted with a 3,3-dialkoxypropene derivative represented by the following formula [II], represented by the following formula [III]: A method for producing a 2,2-difluorocarboxylic acid derivative.

However, R ¹ and R ⁸ represent a residue of a monohydric alcohol, and R ² and R ⁸
R ^3, R ⁴ are identical or different alkyl group, an aryl group, an aralkyl ^{group, R 5, R 6, R} 7 are the same or different hydrogen atom, an alkyl group, an aryl group, an aralkyl group, R ⁹ Represents a hydrogen atom or a monohydric alcohol residue.

In the present invention, 2,2-difluoro represented by the formula [I] In the rockettensilyl acetals, R ¹ represents a monohydric alcohol residue, and usually an alkyl group having 1 to 10 carbon atoms or a benzyl group is employed. The alkyl group may be a straight chain alkyl group or a branched alkyl group, but is preferably a lower alkyl group having 1 to 4 carbon atoms such as a methyl group and an ethyl group. R ² , R ³ and R ⁴ represent the same or different alkyl groups. In particular, a compound in which all of R ² , R ³ and R ⁴ are a methyl group or an ethyl group, or a compound in which ^two of R ² , R ³ and R ⁴ are a methyl group and the remaining one is a t-butyl group is preferable. . The 2,2-difluoroketene silyl acetal can be obtained by a method already reported by the present inventors (“Tetrahedron”).
Lett., Vol. 29, p. 1803 (1988)), the corresponding difluorohaloacetic acid derivative (containing an iodine, bromine or chlorine atom as a halogen atom) and an organic silyl compound are treated with a zero-valent compound such as zinc. It is synthesized by reacting in the presence of a metal reactant. Although it can be subjected to a desired reaction after isolation from the reaction system, it is preferably used as it is in the next reaction without isolation because it is extremely unstable to moisture. Such 2,2-difluoroketene silyl acetal is represented by the formula [II].
Addition to a dialkoxypropene derivative followed by hydrolysis affords 2,2 of the formula [III] -Converted to difluorocarboxylic acid derivatives.

Here, in the formula [II], R ⁵ , R ⁶ , and R ⁷ represent a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and have various characteristic groups that are inert to the reaction in the present invention. May be. A hydroxyl group which may be protected as a characteristic group,
Examples include an ester group, a halogen atom, a sulfide group, a sulfonyl group, a nitro group, a nitrile group, a protected amino group and an imino group. R ⁸ represents a residue of a monohydric alcohol, and usually employs an alkyl group having 1 to 10 carbon atoms, a benzyl group or the like. The alkyl group may be a straight chain alkyl group or a branched alkyl group, but is preferably a lower alkyl group having 1 to 4 carbon atoms such as a methyl group and an ethyl group.

In the formula [III], R ⁹ represents a hydrogen atom or a residue of a monohydric alcohol, and is usually the same group as R ¹ or a hydrogen atom.

The amount of the unsaturated compound used relative to 2,2-difluoroketene silyl acetal produced in the reaction system is not particularly limited, but is preferably about 0.01 to 1 equivalent. Particularly preferably, about 0.1 to 0.5 equivalent is preferable. The reaction can be carried out without solvent, but it is preferable to use a solvent. As the solvent, a solvent which dissolves the raw materials and products and is non-reactive is suitable, and acetonitrile, tetrahydrofuran, diethyl ether, 1,4-dioxane, dimethoxyethane, dimethylformamide, dimethylsulfoxide, benzene and the like are used. However, acetonitrile is particularly preferred. The reaction is carried out at a temperature of about -20 to 80 ° C, preferably 0 ° C to room temperature.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples. As a reference example, a derivative of 5,5-difluorolysine 1 which is expected to be widely used in research on the development of biologically active substances such as inhibition of various enzymes by the synthetic route shown in Scheme 1 starting from 2 which is the target compound of the present invention. The synthesis example of was described.

Example 1.2 2,2-Difluoro-5-ethoxy-3-phenyl-4
-Methyl pentenoate Under an argon atmosphere, zinc dust (220 mg, 3.3 mmol) was suspended in acetonitrile (3 ml), and a solution of methyl difluoroiodoacetate (708 mg, 3 mmol) in acetonitrile (2 ml) was added under ice cooling over 5 minutes. Add. After stirring at the same temperature for 5 minutes, triethylchlorosilane (0.55 ml, 3.3 mmol) is added, and the mixture is stirred for 5 minutes. Under ice-cooling, cinnamaldehyde diethyl acetal (309 mg, 1.5 mmol) is added, and the mixture is stirred for 30 minutes. A 3% aqueous hydrochloric acid solution is added to the reaction solution, and the mixture is stirred at room temperature for 10 minutes, and extracted with ether. The ether layer is washed with a 5% aqueous sodium hydrogen carbonate solution and brine, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 60: 1) to give the title compound (71 mg, yield 17%).

Properties: colorless oil IR cm ^-1 : 1779,1651. ¹ H-NMR (CDCl ₃ ) δ: 7.25-7.38 (5H, m), 6.44 (1H, d, J = 12.6Hz), 5.05 (1H, dd, J = 10.0Hz, 12.6Hz), 3.91 (1H, ddd, J = 10.0, J _HF = 14.4, 17.9 Hz), 3.76 (3H, s), 3.75-3.82 (2H, m), 1.27 (3H, J = 7 Hz). ¹⁹ F-NMR (CDCl ₃ ): 47.2 (d, J = 14 Hz), −47.5 (d, J = 18 Hz).

MS m / z: 270 (M +), 250 (M + -HF), 225 (M + -OEt), 221 (M + -CO 2 Me), 161 (M + -CF 2 CO 2 Me).

2. (E) Methyl 2,2-difluoro-5-ethoxy-4-pentenoate (2) Methyl difluoroiodoacetate (944 mg,
4mmol), zinc powder (290mg, 4.4mmol), trimethylchlorosilane, (0.56ml, 4.4mmol) acetonitrile (6ml), and then acrolein diethyl acetal (260m
g, 2.0 mmol) under ice-cooling and stirring at the same temperature for 30 minutes. After extraction, the residue was purified by silica gel column chromatography (pentane-ether 30: 1) to obtain 90 mg of 2 (23% yield).

Properties: colorless oily substance IR cm ^-1 : 1767,1658. ¹ H-NMR (CDCl ₃ ) δ: 6.35 (1 H, d, J = 12.7 Hz), 4.60 (1 H, dt, J = 12.7, 7.7 Hz), 3.86 (3 H, s), 3.73 (2 H, q, J = 7.0Hz), 2.68 (2H, dt, J = 8.0, J HF = 15.8Hz), 1.26 (3H, t, J = 7.0Hz). ¹⁹ F-NMR (Et ₂ O): −43.0 (t, J = 16 Hz).

MS m / z: 194 (M ⁺ ), 174 (M ⁺ -HF).

High resolution MS: 194.0767 _{(Calculated: C 8 H 12 F 2 O} 3, 194.0754).

Reference Example Synthesis of (±) 5,5-difluorolysine (1) Methanol solution of 2,2-difluoro-5-ethoxy-4-pentenylazide (compound of 3 in Scheme 1) 2 (768 mg, 3.96 mmol) ( Under ice-cooling, sodium borohydride (166 mg, 3.96 mmol) was added to the mixture, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with ether, then 2% hydrochloric acid was added, and the mixture was stirred.
Extract twice. The ether extract was washed with a 5% aqueous sodium hydrogen carbonate solution and brine, dried, concentrated under reduced pressure, and the residue was used for the next reaction.

Diisopropylethylamine (1.52 ml, 8.7 mmol) was added to a methylene chloride (8 ml) solution of this residue, and then trifluoromethanesulfonic anhydride (0.73 ml, 4.36 mmol) was added under cooling with dry ice-acetone. Stir for 30 minutes. A 5% aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted with ether. 2% hydrochloric acid,
The extract was washed with a 5% aqueous sodium hydrogen carbonate solution and brine, dried, concentrated under reduced pressure, and used for the next reaction.

To a solution of the residue in dimethylformamide (10 ml) was added sodium azide (286 mg, 3.96 mmol), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ether. The ether extract is dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (pentane-ether 30: 1) to obtain 3.

Property of 3: colorless oily substance ¹ H-NMR (CDCl ₃ ) δ: 6.29 (1H, d, J = 13 Hz, 5-H), 4.60 (1H, dt, J = 13, 7.5 Hz), 3.69 (2H, q, J = 7 Hz), 3.38 (2H, t, J _HF = 12 Hz), 2.47 (2 H, dt, J = 7.5 Hz, J _HF = 16 Hz), 1.20 (3 H, t, J = 7 Hz).

N-benzoyl-2,2-difluoro-5-ethoxy-4
-Pentenylamide (4) Triphenylphosphine (713m3) in a THF solution (9ml) of 3
g, 2.72 mmol) and stirred at room temperature for 30 minutes, followed by water (0.5m
l) and stir for 10 minutes. Next, triethylamine (0.7 ml, 5 mmol) and benzoyl chloride (573 mg, 4.08 mmol)
Stir at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ether. The ether layer was washed with a 5% aqueous sodium hydrogen carbonate solution and brine, dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate 5: 1). Thus, 582 mg of 4 (55% in total yield from 2) was obtained.

Property of 4: colorless oily substance ¹ H-NMR (CDCl ₃ ) δ: 7.15-7.90 (5H, m), 7.00 (1H, brs, NH), 6.45 (1H, d, J = 13.0 Hz), 4.70 (1H , dt, J = 13.0,7.5Hz), 3.83 (2H, dt, J = 7.0, J _HF = 13.5Hz), 3.70 (2H, q, J = 7.0Hz), 2.48 (2H, dt, J = 7.5, J _HF = 16Hz), 1.20 (3H, t, J = 7Hz). ¹⁹ F-NMR (CDCl ₃ ): -40.3 (m).

(±) 5,5-difluorolysine (1) 4 (250 mg, 0.93 mmol) in THF-water mixed solution (1: 1, 4 m
After adding 0.2 ml of concentrated hydrochloric acid to g) and stirring at room temperature for 1 hour, the reaction solution is extracted with ether. The ether extract is washed with a 5% aqueous sodium hydrogen carbonate solution and brine in that order, and then dried.
After concentration under reduced pressure, the residue was used for the next reaction.

In a dioxane solution (3.2 ml) of this residue, ammonium chloride (100 mg, 1.86 mmol) and potassium cyanide (120 mg, 1.
82 mmol) and concentrated aqueous ammonia (2.3 ml).
Stir for hours. A 5% aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted three times with ether. The ether layer was washed with brine, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate 1: 2.5) to obtain 230 mg of aminonitrile derivative 5 (yield 92%).

5 (115 mg, 0.43 mmol) was added with 6N hydrochloric acid,
Heat for hours. After cooling, ether was added to the reaction solution and extracted with water. The aqueous layer was further washed with ether, concentrated under reduced pressure, and the residue was purified by ion-exchange resin (IR-120B) chromatography (5% aqueous ammonia) to obtain the desired 1
mg (74% yield).

Property of ¹ : white crystal mp: 230 ° C. ¹ H-NMR (D ₂ O) δ: 3.60 (1 H, t, J = 5.5 Hz), 2.90 (2 H, t, J _HF = 15.4 Hz), 1.80-2.00 ( 4H, m).

MS m / z (SIMS): 183 (M + + H).

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 59/58 C07C 59/58 67/00 67/00 69/708 69/708 A 69/734 69/734 Z

Claims (1)

(57) [Claims] 1. A 2,2-difluoroketene silyl acetal represented by the following formula [I] and a compound represented by the following formula [II]:
A method for producing a 2,2-difluorocarboxylic acid derivative represented by the following formula [III], which comprises reacting a 3,3-dialkoxypropene derivative. However, R ¹ and R ⁸ represent a monohydric alcohol residue, and R ² , R ³ and R
⁴ represents the same or different alkyl group, aryl group, aralkyl group, R ⁵ , R ⁶ , R ⁷ are the same or different hydrogen atom,
Alkyl group, an aryl group, an aralkyl group, R ⁹
Represents a hydrogen atom or a monohydric alcohol residue.