Method for preparing difluoroallylboronate and application thereof

Abstract

The present invention relates to a method for preparing difluoroallylboronate and application thereof, and it belongs to a field of compound preparation. A method for preparing difluoroallyl borate ester is using a compound of the formula II and bis (pinacolato) diboron as raw materials in a solvent and in the presence of an iron catalyst and a base according to the following reaction formula, to obtain a compound of the formula I, ##STR00001##
The method of the present invention directly use an inexpensive, commercially available metal iron salt as a catalyst to provide a convenient, low-cost method for preparing difluoroallyl borate ester, and provide a new and effective approach for the synthesis of -aminobutyric acid receptor agonist (III).

Claims

1. A method for preparing difluoroallylboronate, using a compound of the formula II and bis (pinacolato) diboron as raw materials in a solvent in the presence of an iron catalyst and a base according to the following reaction formula, to obtain a compound of the formula I, ##STR00035## Wherein, R.sup.1 is selected from (C1-C10) alkyl, ##STR00036## wherein, m=0-4, n=1-5; R.sup.2 is selected from H, (C1-C6) alkyl; R.sup.3 is selected from H, (C1-C6) alkyl, phenyl, halogen, trifluoromethyl, trifluoromethoxy, (C1-C4) alkoxyl, (C2-C5) ester group; the iron catalyst is at least one of ferrous chloride, ferric chloride, ferrous bromide, ferric bromide, ferric acetylacetonate, ferrous acetylacetonate, and ferrous acetate; the base is selected from at least one of potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, sodium methoxide, lithium methoxide, potassium methoxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate.

2. The method according to claim 1, wherein the R.sup.2 is H or propyl.

3. The method according to claim 1, wherein the R.sup.3 is H, methyl, methoxyl, halogen, trifluoromethyl, tert-butyl, trifluoromethoxy, phenyl.

4. The method according to claim 1, wherein the amount of substance of the base is 0.5 to 3 times of that of the compound of formula II.

5. The method according to claim 4, wherein the amount of substance of the base is 1 to 2 times of that of the compound of formula II.

6. The method according to claim 1, wherein the amount of substance of the bis (pinacolato) diboron is 1 to 3 times of that of the compound of formula II.

7. The method according to claim 6, wherein the amount of substance of the bis (pinacolato) diboron is 1 to 1.5 times of that of the compound of formula II.

8. The method according to claim 1, wherein the amount of substance of the catalyst is 0.1% to 10% of that of the compound of formula II.

9. The method according to claim 1, wherein the reaction temperature of the reaction is 25 C. to solvent reflux temperature, and the reaction time is 10 min to 48 h.

10. Application of the method for preparing the compound of the formula I claimed in claim 1 in the synthesis of -aminobutyric acid receptor agonist (III), wherein, synthesizing 2-(2-((3r,5r,7r)-adamantan-1-yl)-3,3-difluoroallyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane according to the method in claim 1, and then performing the following route: ##STR00037## including the following two-step reaction: {circle around (1)} in toluene solvent, 2-(2-((3r,5r,7r)-adamantan-1-yl)-3,3-difluoroallyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 4-acetylbenzaldehyde react at 60 C. for 10 h-30 h under the catalysis of diphenyl phosphate and benzoic acid, with a molar ratio of 2-(2-((3r,5r,7r)-adamantan-1-yl)-3,3-difluoroallyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 4-acetylbenzaldehyde, diphenyl phosphate and benzoic acid at 1:(1-1.5):0.1:0.1; {circle around (2)} dissolve 1-(4-(3-((3r,5r,7r)-adamantan-1-yl)-2,2-difluoro-1-hydroxybut-3-en-1-yl)phenyl)ethanone in dichloromethane/methanol mixed solvent, introduce ozone by bubbling at 78 C. and maintain the colour of blue for 10 min, then move them at room temperature and introduce argon by bubbling until the reaction system become a colorless clear solution; then cool them to 78 C. again and add dimethyl sulfide under the argon atmosphere, naturally rise to room temperature and react for 10 h-24 h; the molar ratio of 1-(4-(3-((3r, 5r, 7r)-adamantan-1-yl)-2,2-difluoro-1-hydroxybut-3-en-1-yl)phenyl)ethanone and dimethyl sulfide is 1:2, and the volume ratio of dichloromethane and methanol in the mixed solvent is 1:1-3:1.

Description

DETAILED DESCRIPTIONS OF THE PREFERRED EMBODIMENTS

(1) The following non-limiting embodiments are provided to enable a person of ordinary skill in the art to understand the invention, but not to limit the invention in any way.

(2) The test methods described in the following embodiments are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

Embodiment 1

Preparation of 2-phenyl-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 1)

(3) At room temperature, successively add 6.3 mg of catalyst FeCl.sub.2 (0.05 mmol, 5% of the amount of substance of -trifluoromethylstyrene, record as 5 mol %), 8 mL of anhydrous THF, 172 mg of -trifluoromethylstyrene (1 mmol), 279 mg of bis(pinacolato)diboron (1.1 mmol, 1.1 times of molar amount of -trifluoromethylstyrene,), 88 mg of lithium tert-butoxide (1.1 mmol, 1.1 times of molar amount of -trifluoromethylstyrene) in turn to a 25 mL Schlenk bottle with the protection of argon gas. The reaction system is pale yellow turbid solution. Place the solution at 65 C. to react for 12 hours. After the solvent is removed by a rotary evaporator, add 25 mL of water, and extract it with ethyl acetate (315 mL), combine the organic phases and wash them with NaCl saturated solution (210 mL), then dry it over anhydrous Na.sub.2SO4, and obtain the target compound through column chromatography, the packing material is silica gel, the eluent is petroleum ether:ethyl acetate (50:1), and an isolated yield is 92%.

Embodiment 2

Preparation of 2-(2-methoxyphenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 2)

(4) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 2-methoxyl--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 89%.

Embodiment 3

Preparation of 2-(2-chlorophenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 3)

(5) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 2-chloro--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 72%.

Embodiment 4

Preparation of 2-(3-methoxyphenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 4)

(6) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 3-methoxyl--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 90%.

Embodiment 5

Preparation of 2-(3-chlorophenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 5)

(7) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 3-chloro--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 69%.

Embodiment 6

Preparation of 2-(4-methoxyphenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 6)

(8) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 4-methoxyl--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 80%.

Embodiment 7

Preparation of 2-(4-chlorophenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 7)

(9) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 4-chloro--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 96%.

Embodiment 8

Preparation of 2-(4-fluorophenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 8)

(10) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 4-fluoro--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 84%.

Embodiment 9

Preparation of 2-(4-bromophenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 9)

(11) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 4-bromo--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 84%.

Embodiment 10

Preparation of 2-(4-trifluoromethylphenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 10)

(12) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 4-trifluoromethyl--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 86%.

Embodiment 11

Preparation of 2-(4-trifluoromethoxyphenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 11)

(13) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 4-trifluoromethoxy--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 97%.

Embodiment 12

Preparation of 2-(4-tert-butylphenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 12)

(14) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 4-tert-butyl--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 86%.

Embodiment 13

Preparation of 2-(4-phenylphenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 13)

(15) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 4-phenyl--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 95%.

Embodiment 14

Preparation of 2-(4-methoxycarbonylphenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 14)

(16) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 4-methoxycarbonyl--trifluoromethylstyrene, to obtain the target compound, with an isolated yield of 58%.

Embodiment 15

Preparation of 2-(2,4-dimethylphenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 15)

(17) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 3,4-methylenedioxy--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 99%.

Embodiment 16

Preparation of 2-(3,5-dimethylphenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 16)

(18) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 2,4-dimethyl--trifluoromethylstyrene, to obtain the target compound, with an isolated yield of 73%.

Embodiment 17

Preparation of 2-(3,4-methylenedioxyphenyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 17)

(19) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 3,5-dimethyl--trifluoromethylstyrene, to obtain the target compound with an isolated yield of 80%.

Embodiment 18

Preparation of 2-(benzothiophen-2-yl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 18)

(20) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of -trifluoromethyl-2-benzothiophene ethylene, to obtain the target compound with an isolated yield of 73%.

Embodiment 19

Preparation of 2-(1-naphthyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 19)

(21) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of -trifluoromethyl-1-vinylnaphthalene, to obtain the target compound with an isolated yield of 72%.

Embodiment 20

Preparation of 2-(2-phenylethyl)-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 20)

(22) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 2-trifluoromethyl-4-phenyl-1-butene, to obtain the target compound with an isolated yield of 94%.

Embodiment 21

Preparation of 2-(1,1-difluoro-2-phenylhex-1-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 21)

(23) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 1-trifluoromethyl-1-phenylpentene (the mixture of the cis-trans isomerism, with a ratio of cis isomer to trans isomer at 1:2.16), to obtain the target compound with an isolated yield of 67%.

Embodiment 22

Preparation of 2-(2-(difluoromethylene)undecyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 22)

(24) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 2-trifluoromethyl-1-hendecene, to obtain the target compound with an isolated yield of 91%.

Embodiment 23

Preparation of 2-(2-((3r,5r,7r)-adamantan-1-yl)-3,3-difluoroallyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 23)

(25) The procedures are the same as those in the Embodiment 1 except that the -trifluoromethylstyrene is changed to the same molar amount of 3,3,3-trifluoro-2-(adamantane-1-yl)propene, to obtain the target compound with an isolated yield of 76%.

Embodiment 24

Preparation of 2-phenyl-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 1)

(26) The procedures are the same as those in the Embodiment 1 except that the anhydrous THF is changed to anhydrous acetonitrile, to obtain the target compound with a H-NMR yield of 18% (1,1,2,2-tetrachloroethane is used as an internal standard).

Embodiment 25

Preparation of 2-phenyl-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 1)

(27) The procedures are the same as those in the Embodiment 1 except that the anhydrous THF is changed to anhydrous glycol dimethyl ether, to obtain the target compound with a H-NMR yield of 93% (1,1,2,2-tetrachloroethane is used as an internal standard).

Embodiment 26

Preparation of 2-phenyl-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 1)

(28) The procedures are the same as those in the Embodiment 1 except that lithium tert-butoxide is changed to potassium methoxide, to obtain the target compound with a H-NMR yield of 45% (1,1,2,2-tetrachloroethane is used as an internal standard).

Embodiment 27

Preparation of 2-phenyl-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 1)

(29) The procedures are the same as those in the Embodiment 1 except that the molar amount of the lithium tert-butoxide is reduced to 0.6 time, to obtain the target compound with a H-NMR yield of 60% (1,1,2,2-tetrachloroethane is used as an internal standard).

Embodiment 28

Preparation of 2-phenyl-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 1)

(30) The procedures are the same as those in the Embodiment 1 except that the molar amount of bis(pinacolato)diboron is reduced to 0.6 time, to obtain the target compound with a H-NMR yield of 59% (1,1,2,2-tetrachloroethane is used as an internal standard).

Embodiment 29

Preparation of 2-phenyl-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 1)

(31) The procedures are the same as those in the Embodiment 1 except that the catalyst FeCl.sub.2 is reduced to 1 mol %, to obtain the target compound with a H-NMR yield of 17% (1,1,2,2-tetrachloroethane is used as an internal standard).

Embodiment 30

Preparation of 2-phenyl-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 1)

(32) The procedures are the same as those in the Embodiment 1 except that the catalyst FeCl.sub.2 is changed to 10 mol %, to obtain the target compound with a H-NMR yield of 99% (1,1,2,2-tetrachloroethane is used as an internal standard).

Embodiment 31

Preparation of 2-phenyl-3,3-difluoroallyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 1)

(33) The procedures are the same as those in the Embodiment 1 except that the reaction temperature is reduced to 25 C., to the target compound with a H-NMR yield of 34% (1,1,2,2-tetrachloroethane is used as an internal standard).

Embodiment 32

Synthesis of 3-(4-acetylphenyl)-1-((3r,5r,7r)-adamantan-1-yl)-2,2-difluoro-3-hydroxypropan-1-one (Compound III)

(34) {circle around (1)} Successively add 85 mg of 2-(2-((3r,5r,7r)-adamantan-1-yl)-3,3-difluoroallyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2513 mmol), 3 mL of toluene, 37 mg of 4-acetylbenzaldehyde (0.2513 mmol), 6 mg of 10 mol % diphenyl phosphate (0.02513 mmol), and 3 mg of 10 mol % benzoic acid (0.02513 mmol) to a 25 mL Schlenk bottle in an argon atmosphere, sealing the bottle and transfer it to an oil bath at 60 C. react for 24 h. After cooling, the mixture is directly subjected to silica gel column chromatography, with the eluent of petroleum ether:ethyl acetate (5:1), to obtain 58 mg of 1-(4-(3-((3r,5r,7r)-adamantan-1-yl)-2,2-difluoro-1-hydroxybut-3-en-1-yl)phenyl)ethanone with a yield of 64%.

(35) White solid, m.p. 116-118 C., .sup.1H NMR: 7.94 (d, J=7.9 Hz, 2H, ArH), 7.53 (d, J=7.9 Hz, 2H, ArH), 5.36 (s, 1H, CCH.sub.2), 5.25 (s, 1H, CCH.sub.2), 5.04 (dd, J=10.0 Hz, J=13.6 Hz, 1H, ArCH), 3.61 (br, 4H, OH+CH.sub.3), 2.02 (br, 3H, 3CH), 1.80 (br, 6H, 3CH.sub.2), 1.70 (m, 6H, 3CH.sub.2).

(36) {circle around (2)} Successively add 20 mg of 1-(4-(3-((3r,5r,7r)-adamantan-1-yl)-2,2-difluoro-1-hydroxybut-3-en-1-yl)phenyl)ethanone (0.05553 mmol), 3 mL of dichloromethane, 1.5 mL of methanol to a 25 mL Schlenk bottle, cool to 78 C. and introduce ozone by bubbling, and maintain the colour of blue for 10 min, then transfer the bottle at room temperature and introduce argon gas by bubbling until the reaction system becomes colorless and clear solution. Cool down again to 78 C. and keep argon atmosphere, add 7 mg of dimethyl sulfide (0.1110 mmol), naturally rise to the room temperature to react 18 h. Then the mixture is directly subjected to silica gel column chromatography, with the eluent of petroleum ether:ethyl acetate (5:1), to obtain 19 mg of compound III with a yield of 95%.

(37) White solid, m.p. 97-99 C., .sup.1H NMR: 7.94 (d, J=7.4 Hz, 2H, ArH), 7.52 (d, J=7.9 Hz, 2H, ArH), 5.32 (dd, J=6.1 Hz, J=18.0 Hz, 1H, ArCH), 3.28 (br, 1H, OH), 2.59 (s, 3H, CH.sub.3), 2.02 (br, 3H, 3CH), 1.89 (br, 6H, 3CH.sub.2), 1.70 (m, 6H, 3CH.sub.2).

Embodiment 33

Synthesis of 3-(4-acetylphenyl)-1-((3r,5r,7r)-adamantan-1-yl)-2,2-difluoro-3-hydroxypropan-1-one (Compound III)

(38) {circle around (1)} Successively add 169 mg of 2-(2-((3r,5r,7r)-adamantan-1-yl)-3,3-difluoroallyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.5 mmol), 3 mL of toluene, 111 mg of 4-acetylbenzaldehyde (0.75 mmol), 12 mg of 10 mol % diphenyl phosphate (0.05 mmol), and 6 mg of 10 mol % benzoic acid (0.05 mmol) to a 25 mL Schlenk bottle in an argon atmosphere, sealing the bottle and transfer to an oil bath at 65 C. react for 13 h. After cooling, the mixture is directly subjected to silica gel column chromatography, with the eluent of petroleum ether:ethyl acetate (5:1), to obtain 166 mg of 1-(4-(3-((3r,5r,7r)-adamantan-1-yl)-2,2-difluoro-1-hydroxybut-3-en-1-yl)phenyl)ethanone with a yield of 92%.

(39) {circle around (2)} Successively add 20 mg of 1-(4-(3-((3r,5r,7r)-adamantan-1-yl)-2,2-difluoro-1-hydroxybut-3-en-1-yl)phenyl)ethanone (0.05553 mmol), 3 mL of dichloromethane, 1.5 mL of methanol to a 25 mL Schlenk bottle, cool to 78 C. and introduce ozone by bubbling, and maintain the colour of blue for 10 min, then transfer the bottle at room temperature and introduce argon gas by bubbling until the reaction system becomes colorless and clear solution. Cool down again to 78 C. and keep argon atmosphere, add 7 mg of dimethyl sulfide (0.1110 mmol), naturally rise to the room temperature to react 18 h. Then the mixture is directly subjected to silica gel column chromatography, with the eluent of petroleum ether:ethyl acetate (5:1), to obtain 19 mg of compound III with a yield of 95%.