JP2734647B2 - Method for producing 2,2-difluorocarboxylic acid derivative - Google Patents

Description

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

Compounds in which a fluorine atom has been introduced into a physiologically active substance or a substance similar thereto are expected to have new physiological activity by the fluorine atom, and are therefore subject to various studies in the field of development of a physiologically active substance. 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 efficient synthesis methods of synthetic intermediates having various difluoromethylene groups (JP-A-63-48229, JP-A-63-233937, etc.). The present inventors have continued to study and have pioneered a new method capable of synthesizing various 2,2-difluorocarboxylic acid derivatives by adding a difluoroacetic acid group to an unsaturated compound.

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

Reacting 2,2-difluoroketene silyl acetal represented by the following formula [I] with an unsaturated compound represented by the following formula [II], and subjecting the resulting adduct to further hydrolysis or electrophilic addition. A method for producing a 2,2-difluorocarboxylic acid derivative represented by the following formula [III]:

However, R ¹ represents a monohydric alcohol residue, and R ² , R ³ , R ⁴
Are the same or different and represent an alkyl group, an aryl group or an aralkyl group; R ⁵ , R ⁶ and R ⁷ are the same or different and represent a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, and R ⁸ is a hydrogen atom or 1 Represents the residue of a hydric alcohol. A represents an electron-withdrawing group such as a formyl group, an acyl group, an ester group, an amide group, and a nitro group. Alternatively, R ⁷ and A together represent a keto group-containing alkylene group. X represents a hydrogen atom or a halogen atom.

In the present invention, 2,2-difluoro represented by the formula [I] In the oketene cereal acetal, R ¹ represents a residue of a monohydric alcohol, and usually an alkyl group having 1 to 10 carbon atoms, a benzyl group or the like 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, R ² , R ³ , R ⁴ are all methyl groups,
Alternatively, a compound that is 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 converted to 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 used for the unsaturated compound represented by the formula [II]. By addition, followed by hydrolysis or, if desired, an electrophilic addition reaction to give 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.

A is a formyl group, an acyl group, an ester group, an amide group,
Represents an electron-withdrawing group such as a nitro group. X represents a hydrogen atom or a halogen atom.

In the formula [III], R ⁸ represents a hydrogen atom or a monohydric alcohol residue, and is usually the same group as R ¹ or a hydrogen atom.

As an intermediate of this reaction, when A is a derivative of a carbonyl group such as a formyl group, an acyl group, an ester group, an amide group in the unsaturated compound represented by the formula [II], it is represented by the following formula [IV] Enol silyl ether is formed.

Here, R ⁹ represents one substituent of the carbonyl group of A. That is, when A is a formyl group, an acyl group, an ester group, or an amide group, R ⁹ is a hydrogen atom, an alkyl group, an alkoxy group, or an amino group, respectively.

Such a synthetic intermediate can be isolated as it is, if desired. However, by subjecting it to a known hydrolysis reaction, 2,2-difluorocarboxylic acid wherein X is a hydrogen atom in the above formula [III] is obtained. By converting into a derivative or treating with an electrophilic halogenating agent such as bromine, iodine or N-halosuccinimide, 2,2-difluorocarboxylic acid wherein X is a halogen atom in the above formula [III] Can be converted to derivatives.

When an unsaturated compound in which A is a nitro group in the formula [II] is used for the reaction, it is not easy to isolate an intermediate corresponding to the formula [IV]. It is preferable to convert the compound into a 2,2-difluorocarboxylic acid derivative represented by the formula [III] by subjecting it to an electrophilic halogenation reaction.

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.

According to the present invention, (1) an easy reaction and a high yield, and (2) an easily available unsaturated compound is used as a substrate, so that it is possible to produce an extremely large variety of 2,2-difluorocarboxylic acid derivatives. It is possible. Furthermore,
As shown in the reference example of Scheme 1, 4,4-difluoroglutamic acid 1 is an important new substance that is expected to be widely applied in the development research of physiologically active substances such as various oxygen inhibitors.
And derivatives thereof can be obtained efficiently using the target compound 2 of the present invention as a starting material.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

Example 1 (reference example). (E) Methyl 2,2-difluoro-3-phenyl-5-triethylsiloxy-4-pentenoate Under an argon atmosphere, zinc dust (287 mg, 4.4 mmol) was suspended in acetonitrile (3 ml), and difluorofluorocarbon was added under ice cooling. A solution of methyl iodoacetate (944 mg, 4 mmol) in acetonitrile (3 ml) is added over 5 minutes. After further stirring at the same temperature for 5 minutes, triethylchlorosilane (0.73 ml, 4.4 mmol)
Is added and stirred for 5 minutes. Then, a solution of cinnamaldehyde (264 mg, 2 mmol) in acetonitrile (2 ml) is added at −15 ° C., and the mixture is stirred for 30 minutes. The reaction solution is diluted with ether (15 ml), and after adding a 2.5% aqueous solution of sodium bicarbonate, insolubles are filtered using celite. The filtrate was extracted with ether, and the ether layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 200: 1) to give 181 mg (yield) of the title compound.
25%).

Properties: colorless oil IR cm ^-1 : 1780,1760,1660. ¹ H-NMR (CDCl ₃ ) δ: 7.25-7.40 (5H, m), 6.45 (1H, d, J = 11.9Hz), 5.30 (1H, dd, J = 11.9Hz, 10.1Hz), 3.90 (1H, _{ddd, J = 10.1, J HF} = 13.7,18.1Hz), 3.75 (3H, s), 0.98 (9H, t), 0.65 (6H, q). ¹⁹ F-NMR (CDCl ₃ ): -47.0 (d, J = 14 Hz), -47.7 (d, J = 18 Hz).

MS m / z: 356 (M +), 327 (M + -Et), 247 (M + -CF 2 CO 2 Me).

High resolution MS: 356.1608 (calculated value: C ₁₈ H ₂₁ −F ₂ O ₃ Si, 356.161
7) Methyl 2.2,2-difluoro-2- (3-oxocyclohexyl) acetate Zinc dust (287 mg, 4.4 mmol) was suspended in acetonitrile (3 ml) under an argon atmosphere, and methyl difluoroiodoacetate (944 mg, 4 mmol) in acetonitrile (3 ml) is added over 5 minutes. The mixture was further stirred at the same temperature for 5 minutes, and then trimethylchlorosilane (0.55 ml, 4.4 mmo) was added.
After l) was added and the mixture was stirred for 5 minutes, 2-cyclohexenone (192 mg, 2 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes. 3% Hydrochloric acid is added to the reaction solution, stirred at room temperature for 10 minutes, and extracted with ether. The ether layer is washed with a 5% aqueous solution of sodium bicarbonate and brine in that order, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to give the title compound (390 mg, yield 95).
%)Obtained.

Properties: colorless oily substance IR cm ^-1 : 1773,1718. ¹ H-NMR (CDCl ₃ ) δ: 3.90 (3H, s), 1.30-2.90 (9H, m). ¹⁹ F-NMR (CDCl ₃ ): −50.8 (d, J = 2.0 Hz), −51.0 (d, J = 2.0 Hz).

MS m / z: 206 (M +), 186 (M + -HF), 97 High Resolution MS:. 206.0776 _{(Calculated: C 9 H 12 F 2 O} 3, 206.0753).

3.2,2-Difluoro-5-oxo-3-phenylhexanoic acid methyl difluoroiodoacetate (708 mg, 3 mmol) zinc dust (220 mg, 3.3 mmol), trimethylchlorosilane (0.42 ml,
After reacting 3.3 mmol) and acetonitrile (6 ml) in the same manner as above, benzalacetone (220 mg, 1.5 mmol) is added under ice cooling, and the mixture is stirred for 30 minutes. 3% hydrochloric acid was added to the reaction mixture,
Extract with ether. The ether layer is washed with a 5% aqueous solution of sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate 8: 1) to give 245 mg (64% yield) of the title compound.

Properties: colorless crystal mp: 79 ° C IR cm ^-1 : 1775,1723. ¹ H-NMR (CDCl ₃ ) δ: 7.30 (5H, m), 4.05 (1H, m), 3.63 (3H, s), 3.0-3.1 (2H, m), 2.05 (3H, s). ¹⁹ F-NMR (CDCl ₃ ): −43.2 (dd, J _FF = 256, J _HF = 15 Hz), −51.5 (dd, J _FF = 256, J _HF = 19 Hz), MS m / z: 256 (M ⁺ ), 236,216.

High resolution MS: 256.0909 _{(Calculated: C 13 H 14 F 2 O} 3, 256.090
9).

4.2 Methyl 2,2-difluoro-3-phenyl-4-nitrobutanoate The same treatment as in the above example was carried out except that β-nitrostyrene (224 mg, 1.5 mmol) was used in place of the benzalacetone in the above example. After purification (hexane-ethyl acetate 8: 1), 260 mg (yield 67%) of the title compound was obtained.

Properties: colorless crystals mp: 40.5 ° C IR cm ^-1 : 1779,1562. ¹ H-NMR (CDCl ₃ ) δ: 7.25-7.40 (5H, m), 5.06 (1H, dd, J = 5.1,13.8 Hz), 4.88 (1H, dd, J = 9.5,13.8 Hz), 4.39 (1H , ddt, J = 5.1,9.6, J _HF = 9.6,20.6Hz) 3.70
(3H, s). ¹⁹ F-NMR (CDCl ₃ ): −40.8 (dd, J _FF = 259, J _HF = 10 Hz), −51.2 (dd, J _FF = 259, J _HF = 20.6 Hz), MS m / z: 259 (M ⁺ ), 221.

Methyl 5.4-bromo-2,2-difluoro-3-phenyl-5-oxohexanoate In the same manner as above, methyl difluoroiodoacetate (708 mg, 3 m
mol), zinc dust (220 mg, 3.3 mmol), triethylchlorosilane (0.55 ml, 3.3 mmol), and acetonitrile (6 ml), and benzalacetone (220 mg, 1.5 mmol) was added under ice-cooling. Stir for minutes. Water (10m
l) and extract with ether. The ether layer is washed with a 5% aqueous solution of sodium bicarbonate and brine in that order, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was treated with acetonitrile (5m
l) and dissolved in N-bromosuccinimide (267 mg, 1.5 mm
ol) and stir at room temperature for 30 minutes. Purification by silica gel column chromatography (hexane-ethyl acetate 9: 1)
180 mg of the less polar diastereomer (36% yield) and 93 mg of the more polar isomer were obtained (19% yield).

Low polar isomer: colorless crystal mp: 43 ° C. IR cm ⁻¹ : 1779,1725. _{^{1 H-NMR (CDCl 3)}} δ: 7.20-7.45 (5H, m), 4.87 (1H, d, J = 11Hz), 4.25 (1H, td, J = 10.7, J HF = 10.7,18.2Hz), 3.68 (3H, s), 2.47 (3H, s). ¹⁹ F-NMR (CDCl ₃ ): −39.0 (dd, J _FF = 256, J _HF 11 Hz), −48.8 (dd, J _FF = 256, J _HF 18 Hz), MS m / z: 336 (M ⁺ , ⁸¹ [Br]), 334 (M ⁺ , ⁷⁹ [Br]), 225 (M ⁺ , -Br).

High resolution MS: 333.9968 _{(Calculated: C 13 H 13 F 2 -BrO} 3, 334.001
Five).

Highly polar isomer: colorless crystal mp: 62 ° C. IR cm ⁻¹ : 1778,1729. _{^{1 H-NMR (CDCl 3)}} δ: 7.22-7.35 (5H, m), 4.85 (1H, d, J = 11.3Hz), 4.26 (1H, td, J = 11.3, J HF = 11.3,17.9Hz), 3.76 (3H, s), 2.07 (3H, s). ¹⁹ F-NMR (CDCl ₃ ): -44.0 (d, J _HF = 11.5 Hz), -44.7 (d, J _HF 17 Hz), MS m / z: 225 (M ⁺ , -Br) High resolution MS: 255.0817 ( _{calculated: C 13 H 13 F 2 O} 2 (M + Br), 25
5.0831).

Reference Example 4,4-difluoroglutamic acid (Scheme 1
In the same manner as above, methyl difluoroiodoacetate (3.
3 g, 14 mmol), zinc dust (1 g, 15.4 mmol), triethylchlorosilane (2.6 ml, 15.4 mmol), acetonitrile (25 ml)
After the reaction, 3-acryloyl (4R) -benzyl-2-oxazolidinone (1.3 g, 5.6 mmol) is added, and the mixture is stirred at room temperature for 15 hours. Water is added to the reaction mixture and the mixture is extracted with ether. The ether layer is washed with a 5% aqueous solution of sodium bicarbonate and brine in that order, and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure,
The residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 755 mg of 2 (40% yield).

Property of 2: colorless oily substance IR cm ^-1 : 1780-1800, 1700-1720. _{^{1 H-NMR (CDCl 3)}} δ: 7.18-7.40 (5H, m), 4.67 (1H, tdd, J = 3.3,7.5,9.5Hz), 4.22 (1H, dd, J = 7.6,9.1Hz), 4.18 (1H, dd, J = 3.3,9.1Hz), 3.90 (3H, s), 3.29 (1H, dd, J = 3.3,13.4Hz), 3.12-3.25 (2H, m), 2.78 (1H, dd, J = 9.6,13.4Hz), 2.47−2.60 (2H, m). ¹⁹ F-NMR (CDCl ₃ ): -43.7 (t, J = 17 Hz), MS m / z: 341 (M ⁺ ), 282,250.

High resolution MS: 341.1074 (calculated: C ₁₆ H ₁₇ F ₂ O ₅ −N, 341.107
4) Under an argon atmosphere, diisopropylethylamine (0.46) was added to a solution of 2 (750 mg, 2.2 mmol) in methylene chloride (10 ml).
Then, a solution of dibutyl boron triflate in methylene chloride (2.4 mmol) is added dropwise at -78 ° C. The resulting solution is transferred to a solution of N-bromosuccinimide (430 mg, 2.4 mmol) in methylene chloride (5 ml) cooled to -78 ° C using a stainless steel tube. After stirring at the same temperature for 30 minutes, a 2N hydrochloric acid solution is added to the reaction solution, and the mixture is extracted with ether (3 times). The ether layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to medium pressure liquid chromatography (hexane: ethyl acetate 4.5: 1) to recover 170 mg (23%) of 2 and 170 mg (yield 40%) of 3.

Property of 3: Oily substance IR cm ^-1 : 1780,1700. ¹ H-NMR (CDCl ₃ ) δ: 7.22-7.40 (5H, m), 5.92 (1H, dd, J = 4.2,9.6 Hz), 4.71 (1H, dddd, J = 3.4,3.4,7.8,9.4 Hz) , 4.28 (1H, dd, J = 7.9,9.1Hz), 4.22 (1H, dd, J = 3.2,9.2Hz), 3.89 (3H, s), 3.35 (1H, ddt, J = 9.7,15.2, J _HF) = 15.2Hz), 3.28 (1H, dd, J = 3.4,13.5Hz), 2.81 (1H, dd, J = 10.0,13.5Hz). ¹⁹ F-NMR (CDCl ₃ ): -42.0 (t, J = 15.5 Hz), MS m / z: 419 (M ⁺ ), 340 (M ⁺ -Br), 243,217.

To a solution of 3 (538 mg, 1.28 mmol) in dimethylformamide (12 ml) was added sodium azide (124 mg, 1.92 mmol), and the mixture was stirred at room temperature for 2 hours. Water is added to the reaction solution, and the mixture is extracted with ether (three times). The ether layer is dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane: ethyl acetate 4: 1) to give 229 mg of 4 (47% yield).

Property of 4: Oily substance [α] _D : −33.54 (c = 4.54, CHCl ₃ ).

IR cm ^-1 : 2120,1785,1708. ¹ H-NMR (CDCl ₃ ) δ: 7.18-7.40 (5H, m), 5.35 (1H, dd, J = 5.4,8.0Hz), 4.71 (1H, dddd, J = 3.3,3.3,7.7,9.2Hz) , 4.30 (1H, dd, J = 7.7,9.9Hz), 4.25 (1H, dd, J = 3.7,9.2Hz), 3.93 (3H, s), 3.32 (1H, dd, J = 3.4,13.4Hz), 2.78 (1H, dd, J = 9.7,13.5Hz), 2.78 (1H, ddt, J = 5.3,13.5, J HF = 15.0Hz), 2.65 (1H, ddt, J = 8.0,15.1, J HF = 15.1Hz ). ¹⁹ F-NMR (CDCl ₃ ): −38.2 (t, J = 15.0 Hz), −38.5 (t, J = 15.0 Hz).

MS m / z: 354 (M + -N 2), 323,204.

4 (350 mg, 0.92 mmol) in a tetrahydrofuran-water mixed solution (3 ml / 1 ml) was added to lithium hydroxide (115 mg, 2.7
6 mmol) and stirred at the same temperature for 30 minutes. After washing the reaction solution with ether (three times), a 2% aqueous hydrochloric acid solution is added until it becomes acidic. Extract with ether (4 times), dry and concentrate under reduced pressure. 10% palladium-carbon (50 mg) is added to a methanol solution (3 ml) of the residue, and the mixture is stirred overnight under a hydrogen atmosphere. After filtration and concentration under reduced pressure, the obtained crude crystals were washed with ether to obtain 110 mg (yield: 65%) of the target 4,4-difluoroglutamic acid (1).

Property of 1: white crystal [α] _D : −5.38 (c = 1.04, H ₂ O).

IR cm ^-1 : 2120,1785,1708. ¹ H-NMR (D ₂ O) δ: 4.18 (1 H, dd, J = 3.4,8.4 Hz), 2.70 (1 H, ddt, J = 3.4,14.0, J _HF = 16.0 Hz), 2.53 (1H, ddt, J = 8.4,14.0, J _HF = 16.0Hz). ¹⁹ F-NMR (CDCl ₃ ): −38.9 (t, J = 16.0 Hz), MS m / z: 354 (M ⁺ −N ₂ ), 323,204.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 59/74 C07C 59/74 69/716 69/716 Z 69/738 69/738 Z 205/58 205/58 233/04 233 / 04 233/11 233/11

Claims (1)

(57) [Claims] An adduct formed by reacting a 2,2-difluoroketene silyl acetal represented by the following formula [I] with an unsaturated compound represented by the following formula [II] is further hydrolyzed or electrophilically added. A process for producing a 2,2-difluorocarboxylic acid derivative represented by the following formula [III], which is subjected to a reaction. However, R ¹ represents a residue of a monohydric alcohol, R ² , R ³ , and R ⁴ are the same or different, and represent an alkyl group, an aryl group, and an aralkyl group, and R ⁵ , R ⁶ , and R ⁷ are the same or different. Hydrogen atom,
Alkyl group, an aryl group, an aralkyl group, R ⁸
Represents a hydrogen atom or a monohydric alcohol residue. A represents an electron-withdrawing group such as a formyl group, an acyl group, an ester group, an amide group, and a nitro group. Alternatively, R ⁷ and A together represent a keto group-containing alkylene group. X represents a hydrogen atom or a halogen atom.