CN102241612B - Synthetic method of compound 2-cyclopropyl-1-(2-fluorophenyl)-2-carbonyl ethyl p-methylbenzensulfonate - Google Patents
Synthetic method of compound 2-cyclopropyl-1-(2-fluorophenyl)-2-carbonyl ethyl p-methylbenzensulfonate Download PDFInfo
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Abstract
The invention discloses a synthetic method of a medicinal prasugrel intermediate, i.e., compound 2-cyclopropyl-1-(2-fluorophenyl)-2-carbonyl ethyl p-methylbenzensulfonate, belonging to the technical field of chemical synthesis. The method comprises the following steps of: making o-fluorobenzaldehyde serving as an initial raw material with chloroform and sodium hydroxide to obtain o-fluoromandelic acid; esterifying, protecting with methoxyl chloromethane and hydrolyzing to obtain 2-(2-fluorophenyl)-2-( methoxyl) acetic acid; performing amidation, Grignard reaction and deprotection to obtain 1-cyclopropyl-1-(2-fluorophenyl)-2-hydroxyacetophenone serving as a key intermediate; and making the 1-cyclopropyl-1-(2-fluorophenyl)-2-hydroxyacetophenone react with paratoluensulfonyl chloride to obtain a target product. The method has the advantages of readily-available raw materials, low cost, high yield, short reaction period, high efficiency, low pollutant emission and environmental friendliness.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate to a kind of intermediate preparation method of synthetic drugs prasugrel, relate in particular to a kind of compound 2-cyclopropyl-1-(2-fluorophenyl)-synthetic method of 2-carbonyl ethyl p-toluenesulfonic esters.
Background technology
Prasugrel chemistry 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4 by name, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine, be the oral antiplatelet drug by the common exploitation of Japanese Sankyo company and U.S. Eli Lilly company, and gone on the market by FDA (Food and Drug Adminstration) (FDA) approval on July 10th, 2009.This medicine is mainly used in accepting the patient of angioplasty treatment, causes the risk of having a heart attack with reduction postoperative thrombosis; Also be used for antiplatelet treatment, can reduce the incidence of acute coronary syndrome patient myocardial infarction greatly.
The chemical structural formula of prasugrel:
At present, the intermediate of synthetic prasugrel mainly contains five kinds, and its structural formula is as follows:
Its synthetic method has following six kinds of methods at present:
Method one: Japanese Patent WO2008108291A1 and European patent EP 0542411A2 disclose a kind of synthetic method of prasugrel intermediate, and its synthetic line is as follows:
This method is to be starting raw material with adjacent fluorobenzyl bromide, and itself and cyclopropylniitrile generation grignard reaction are obtained the cyclopropanone compound, and a halogen atom is introduced at the ortho position on carbonyl again.
Method two: patent WO2011042918A2 discloses a kind of synthetic method of prasugrel intermediate, and its synthetic line is as follows:
This method is that to adopt 2-(2-fluorophenyl) acetic acid be raw material, through amidation, obtains cyclopropyl-2-luorobenzyl ketone behind the grignard reaction, in that reaction is converted into 1-cyclopropyl carbonyl-2-benzyl-fluorobenzyl halogen with bromide reagent.
The defective of above-mentioned two kinds of methods is that the selectivity of the halogenating reaction on the carbonyl ortho position is relatively poor, and productive rate is lower.
Method three: Czechoslovakia Zentiva drugmaker (publication number: WO2009006859A2) and US Patent No. 20100228033A1 a kind of synthetic method of prasugrel intermediate is disclosed, its synthetic line is as follows:
This method is to be initial feed with adjacent fluorobenzaldehyde, with trimethylammonium itrile group silicon it is carried out addition, and the grignard reagent with cyclopropyl reacts then, then converts it into methanesulfonates with methylsulfonyl chloride.
Method four:
Chinese patent CN101402593A, CN101402642A, CN101402643A disclose a kind of synthetic method of prasugrel intermediate, and its synthetic line is as follows:
This method is to be initial feed and isopropenyl acetate reaction rear oxidation with cyclopropyl-2-luorobenzyl ketone, then converts it into methanesulfonates with methylsulfonyl.The cost of material of this method is somewhat expensive, and environmental pollution is bigger, and labor protection is bigger, and productive rate is not high, so this method is not suitable for suitability for industrialized production.
Method five: patent WO2011023027A1 discloses a kind of synthetic method of prasugrel intermediate, and its synthetic line is as follows
This method is that employing two chlordantoins are halide reagent, and acetic acid flavor lyase is converted into 1-cyclopropyl carbonyl-2-benzyl-fluorobenzyl halogen with adjacent luorobenzyl cyclopropyl ketone.
Method six: CN101735241A discloses a kind of synthetic method of prasugrel intermediate:
The cost of material of this method is somewhat expensive and toxicity is bigger, and environmental pollution is bigger, and labor protection is bigger, and productive rate is not high, so this method is not suitable for suitability for industrialized production.
Summary of the invention
The objective of the invention is to the problem that exists at prior art, a kind of synthetic compound 2-cyclopropyl-1-(2-fluorophenyl be provided)-novel method of 2-carbonyl ethyl p-toluenesulfonic esters.
Synthetic compound 2-cyclopropyl of the present invention-1-(2-fluorophenyl)-method of 2-carbonyl ethyl p-toluenesulfonic esters; be initial feed with adjacent fluorobenzaldehyde; obtain adjacent fluorine amygdalic acid with chloroform, sodium hydroxide reaction earlier; hydrolysis obtains the 2-(2-fluorophenyl after esterification, the protection of methoxymethyl chlorine again)-2-(methoxy methoxy base) acetic acid; behind amidation, grignard reaction, deprotection, obtain key intermediate 1-cyclopropyl-2-(2-fluorophenyl then)-2-hydroxyl ethyl ketone; last and Tosyl chloride reacts, and obtains target product.Its concrete processing step is as follows:
(1) adjacent fluorine amygdalic acid is synthetic
Under the effect of phase-transfer catalyst, adjacent fluorobenzaldehyde, chloroform, alkali be with the mol ratio of 1:2:6 ~ 1:4:14, in 40 ~ 80 ℃ of reaction 48 ~ 60h down, is cooled to room temperature, tells lower floor's chloroform; Water is regulated pH=1 ~ 2 with 1 ~ 3mol/L hydrochloric acid soln, uses ethyl acetate extraction, and column chromatography for separation obtains adjacent fluorine amygdalic acid.
Described phase-transfer catalyst is trimethyl benzyl ammonia chloride, triethyl benzyl ammonia chloride, etamon chloride, tetraethylammonium bromide or Tetrabutyl amonium bromide.Wherein preferentially select Tetrabutyl amonium bromide.The consumption of phase-transfer catalyst is 0.06 ~ 0.1 times of adjacent fluorobenzaldehyde molar weight.
Described alkali is the sodium hydroxide of mass concentration 40 ~ 50% or the aqueous solution of potassium hydroxide.
Reaction formula is as follows:
(2) adjacent fluorine methyl mandelate is synthetic
Be solvent with methyl alcohol, under the effect of the vitriol oil, in 70 ~ 80 ℃ of 3 ~ 5h that reflux down, after reacting completely, be cooled to room temperature, under agitation add saturated aqueous sodium carbonate and produce to there being gas; Solvent evaporated, ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates, and obtains adjacent fluorine methyl mandelate.
The consumption of the vitriol oil is 0.05 ~ 0.1 times of adjacent fluorine amygdalic acid molar weight.
Reaction formula is as follows:
(3) 2-(2-fluorophenyl)-and 2-(methoxy methoxy base) methyl acetate synthetic
Under nitrogen protection, be solvent with the methylene dichloride, under the effect of sodium hydride, adjacent fluorine methyl mandelate and methoxymethyl chlorine are with the mol ratio of 1:3 ~ 1:5, in 70 ~ 80 ℃ of 18 ~ 20h that reflux down; Reaction is used the saturated ammonium chloride cancellation after finishing, and uses saturated sodium bicarbonate, water, saturated common salt water washing more successively, and anhydrous magnesium sulfate drying concentrates, and column chromatography for separation gets the 2-(2-fluorophenyl)-2-(methoxy methoxy base) methyl acetate.
The consumption of sodium hydride is 1 ~ 1.2 times of adjacent fluorine methyl mandelate molar weight.
Reaction formula is as follows:
(4) 2-(2-fluorophenyl)-and 2-(methoxy methoxy base) acetic acid synthetic
Being solvent (volume ratio of methyl alcohol and water is 1:0.8 ~ 1:1.0), the 2-(2-fluorophenyl)-2-(methoxy methoxy base with the mixing solutions of methyl alcohol and water) methyl acetate and alkali is with the mol ratio of 1:2 ~ 1:2.5, room temperature reaction 3-5h, reaction finishes the back solvent evaporated; Hydrochloric acid with 1 ~ 3mol/L is adjusted to pH=1 ~ 2 with water; Ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates, and obtains the 2-(2-fluorophenyl)-2-(methoxy methoxy base) acetic acid.
Reaction formula is as follows:
(5) 2-(2-fluorophenyl)-N-methoxyl group-2-(methoxy methoxy base)-N-methylacetamide synthetic:
Be solvent with toluene, under nitrogen protection, 2-(2-fluorophenyl)-and 2-(methoxy methoxy base) acetic acid and acylating reagent be with the mol ratio of 1:0.5 ~ 1:1, in 60 ~ 80 ℃ of reaction 1 ~ 2h down; Be cooled to room temperature after having reacted, add saturated NaHCO
3Aqueous solution cancellation, ethyl acetate extraction, anhydrous magnesium sulfate drying, column chromatography for separation gets the 2-(2-fluorophenyl)-N-methoxyl group-2-(methoxy methoxy base)-the N-methylacetamide.
Used amidation reagent is P (NMeOMe)
3
Reaction formula is as follows:
(6) 1-cyclopropyl-2-(2-fluorophenyl)-and 2-(methoxy methoxy base) ethyl ketone synthetic
Being solvent with the tetrahydrofuran (THF), under the nitrogen protection, is initiator with the glycol dibromide, the 2-(2-fluorophenyl)-N-methoxyl group-2-(methoxy methoxy base)-N-methylacetamide and Grignard reagent be with the mol ratio of 1:1 ~ 1:3, at room temperature reacts 3 ~ 5h; After having reacted, add the saturated aqueous ammonium chloride cancellation, ethyl acetate extraction, anhydrous magnesium sulfate drying, column chromatography for separation gets 1-cyclopropyl-2-(2-fluorophenyl)-2-(methoxy methoxy base) ethyl ketone.
The consumption of initiator glycol dibromide is the 2-(2-fluorophenyl)-N-methoxyl group-2-(methoxy methoxy base)-0.01 ~ 0.03 times of N-methylacetamide.
Reaction formula is as follows:
(7) 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyl ethyl ketone synthetic
Be solvent with methyl alcohol, 1-cyclopropyl-2-(2-fluorophenyl)-and 2-(methoxy methoxy base) ethyl ketone and concentrated hydrochloric acid be with the mol ratio of 1:0.03 ~ 1:0.05, in 50 ~ 60 ℃ of reaction 3 ~ 5h; After reaction finishes, regulate the pH value to neutral, ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates, column chromatography for separation obtains 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyl ethyl ketone.
Reaction formula is as follows:
(8) 2-cyclopropyl-1-(2-fluorophenyl)-2-carbonyl ethyl p-toluenesulfonic esters
Be solvent with the methylene dichloride, under the nitrogen protection, 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyl ethyl ketone, triethylamine, Tosyl chloride be with the mol ratio of 1:1:1 ~ 1:1.2:1.2, in 0 ~ 5 ℃ of reaction 5 ~ 6h; To neutral, isolated organic phase, water, saturated NaCl solution washing successively, anhydrous magnesium sulfate drying concentrates, column chromatography for separation obtains target product 2-cyclopropyl-1-(2-fluorophenyl with the salt acid for adjusting pH value)-2-carbonyl ethyl p-toluenesulfonic esters.
The consumption of triethylamine is-cyclopropyl-2-(2-fluorophenyl)-1.0 ~ 1.2 times of 2-hydroxyl ethyl ketone molar weight.
Reaction formula is as follows:
The product acid esters that the present invention synthesizes detects through nuclear magnetic spectrogram, hydrogen spectrum and to show, successfully synthesizes compound 2-cyclopropyl-1-(2-fluorophenyl)-the 2-carbonyl ethyl is to the pure product of toluene sulphur.
The present invention is relative, and prior art has the following advantages:
1, the present invention adopts raw material cheap and easy to get, and low-cost, high yield has synthesized 2-cyclopropyl-1-(2-fluorophenyl)-2-carbonyl ethyl p-toluenesulfonic esters.
2, lack reaction time, efficient is higher.
3, the material toxicity of Cai Yonging is less, and is environmentally friendly.
Embodiment
Below by concrete experimental example to the synthetic 2-cyclopropyl of the present invention-1-(2-fluorophenyl)-method of 2-carbonyl ethyl p-toluenesulfonic esters does detailed explanation.
(1) adjacent fluorine amygdalic acid is synthetic
Accurately (0.01mol, 1.24g), (0.0006mol 0.19g) puts in the three-necked flask that 20mL chloroform (being solvent, also is reactant) and thermometer are housed Tetrabutyl amonium bromide the adjacent fluorobenzaldehyde of weighing, and mixing stirs 15min down at 60 ℃.Dropwise adding 5.6g(mass concentration 40% by dropping funnel then) aqueous solution of sodium hydroxide reacts, and constantly stirs.Finish, holding temperature is 60 ℃ and continues reaction 60 hours.After the reaction end, add the dilution of 100mL water and reaction solution is cooled to room temperature, tell lower floor's chloroform.Water is regulated pH to 1 with the 3mol/L hydrochloric acid soln, with ethyl acetate extraction (3 * 20 mL), merges organic phase and concentrating under reduced pressure.Obtain the adjacent fluorine amygdalic acid of yellow oily crude product.Column chromatography (silica gel, 200-300; Sherwood oil: ethyl acetate=1:1) separation obtains 115-117 ℃ of pure product 1.2g. fusing point, productive rate: 70%.
1HNMR (CD
3OD, 400 MHz)，δ (ppm): 7.48-7.44 (m, 1H), 7.36-7.31 (m, 1H), 7.19-7.15 (m, 1H), 7.11-7.07 (m, 1H), 5.39 (s, 1H)。
13CNMR (CD
3OD, 100 MHz), δ (ppm): 175.51, 161.77 (d, J
CF = 246.7 Hz), 131.21 (d, J
CF = 8.4 Hz), 129.93 (d, J
CF = 3.5 Hz), 128.34 (d, J
CF = 14.4Hz), 125.44 (d, J
CF = 3.5 Hz), 116.41 (d, J
CF =22.0 Hz), 67.89。
(2) preparation of adjacent fluorine methyl mandelate
In the 100mL round-bottomed flask, add adjacent fluorine amygdalic acid (1.7g, 0.1mol), 20mL methyl alcohol, the 1mL vitriol oil, then to 70 ℃, backflow 3h.After the reaction end, be cooled to room temperature, under agitation add saturated sodium carbonate solution and produce to there being gas.Solvent evaporated, water layer merges organic phase and uses anhydrous magnesium sulfate drying with ethyl acetate extraction (3 * 20 mL), concentrates and obtains product 1.82 g, 46 ~ 47 ℃ of fusing points, productive rate: 98%.
1HNMR (CDCl
3, 400 MHz)，δ (ppm): 7.40-7.36 (m, 1H), 7.33-7.26 (m, 1H), 7.15-7.11 (m, 1H), 7.08-7.03 (m, 1H), 5.41 (d, J=5.4 Hz), 3.76 (s, 1H), 3.74 (s, 3H)。
13CNMR (CDCl
3, 100 MHz), δ (ppm): 173.42, 160.15 (d, J
CF = 248.3 Hz), 130.07 (d, J
CF = 8.2 Hz), 128.50 (d, J
CF = 3.5 Hz), 125.58 (d, J
CF = 13.7 Hz), 124.17 (d, J
CF = 3.5 Hz), 115.45 (d, J
CF =21.4 Hz), 67.17 (d, J
CF = 3.5 Hz), 52.84。
(3) 2-(2-fluorophenyl)-and 2-(methoxy methoxy base) methyl acetate synthetic
In the 100mL round-bottomed flask, (0.85g, 0.005mol), (0.006mol, 0.15g) (0.006mol 0.39g), under nitrogen protection, is heated to 70 ℃ of backflow 18h to NaH with methoxymethyl chlorine to add adjacent fluorine methyl mandelate.TLC detects question response finish after, use the saturated ammonium chloride cancellation, use saturated sodium bicarbonate, water, anhydrous magnesium sulfate drying is used in the saturated common salt water washing, concentrated crude product.Column chromatography (silica gel, 200-300; Sherwood oil: ethyl acetate=5:1) separation obtains pure product 0.95g.Productive rate: 83%.
1HNMR (CDCl
3, 400 MHz)，δ (ppm): 7.49-7.46 (m, 1H), 7.36-7.30 (m, 1H), 7.18-7.14 (m, 1H), 7.10-7.06 (m, 1H), 5.51 (s, 1H), 4.74 (d, J=47.2 Hz, 2H), 3.74-3.73 (m, 3H), 3.39-3.37 (m, 3H)。
13CNMR (CDCl
3, 100 MHz), δ (ppm): 170.63, 160.35 (d, J
CF = 248.6 Hz), 130.42 (d, J
CF = 8.2 Hz), 128.96 (d, J
CF = 3.2 Hz), 124.36 (d, J
CF = 3.5 Hz), 123.68 (d, J
CF = 14.3 Hz), 115.56 (d, J
CF =21.6 Hz), 95.18, 69.90 (d, J
CF = 3.0Hz), 55.90, 52.39。
(4) 2-(2-fluorophenyl)-and 2-(methoxy methoxy base) acetic acid synthetic
In the 100mL round-bottomed flask, with the 2-(2-fluorophenyl)-2-(methoxy methoxy base) (1.2g 0.005mol) is dissolved in the 40mL methyl alcohol methyl acetate, adds KOH (0.73g, 0.013mol) water (40mL) solution under cryosel is bathed.Naturally rose to stirring at room 3 hours, reaction finishes the back solvent evaporated, with the aqueous hydrochloric acid of 1mol/L water is adjusted to pH=2, with ethyl acetate extraction (3 * 20 mL), merges the organic phase anhydrous magnesium sulfate drying, the concentrated crude product 1g that obtains.Productive rate: 93%.
1HNMR (CDCl
3, 400 MHz)，δ (ppm): 7.48-7.44 (m, 1H), 7.38-7.33 (m, 1H), 7.19-7.15 (m, 1H), 7.12-7.07 (m, 1H), 5.51 (s, 1H), 4.73 (d, J=40.6 Hz, 2H), 3.39-3.38 (m, 3H)。
13CNMR (CDCl
3, 100 MHz), δ (ppm): 174.91, 160.51 (d, J
CF = 249.1 Hz), 130.82 (d, J
CF = 8.2 Hz), 129.22 (d, J
CF = 3.1 Hz), 124.46 (d, J
CF = 3.6 Hz), 123.10 (d, J
CF = 14.3 Hz), 115.76 (d, J
CF =21.4 Hz), 95.19, 70.13 (d, J
CF = 2.7 Hz), 56.08。
(5) 2-(2-fluorophenyl)-N-methoxyl group-2-(methoxy methoxy base)-N-methylacetamide synthetic:
In the 50mL three-necked bottle, P (NMeOMe)
3(3mmol 0.64g) is dissolved in the 10ml toluene, adds the 2-(2-fluorophenyl)-2-(methoxy methoxy base) acetic acid (3mmol, 0.65g); under nitrogen protection, mixture is heating 1h under 80 ℃, detects through TLC; after raw material reaction is intact, be cooled to room temperature, add saturated NaHCO
3Aqueous solution cancellation reaction.Use extracted with diethyl ether, anhydrous magnesium sulfate drying.Column chromatography (silica gel, 200-300; Sherwood oil: ethyl acetate=2:1) compound 0.75g, productive rate: 92%.
1HNMR (CDCl
3, 400 MHz)，δ (ppm): 7.55-7.51 (m, 1H), 7.35-7.29 (m, 1H), 7.18-7.14 (m, 1H), 7.10-7.06 (m, 1H), 5.92 (s, 1H), 4.74 (d, J=36.1 Hz, 2H), 3.74 (s, 3H), 3.38 (s, 3H), 3.17 (s, 3H)。
13CNMR (CDCl
3, 100 MHz), δ (ppm): 173.63, 160.30 (d, J
CF = 246.9 Hz), 130.28 (d, J
CF = 8.4 Hz), 129.49 (d, J
CF = 3.0 Hz), 124.53 (d, J
CF = 3.1 Hz), 124.09 (d, J
CF = 14.5 Hz), 115.32 (d, J
CF =21.1 Hz), 95.18, 67.26 (d, J
CF = 2.3 Hz), 60.97 (d, J
CF = 3.8 Hz), 55.85 (d, J
CF = 3.1 Hz), 32.43。
(6) 1-cyclopropyl-2-(2-fluorophenyl)-and 2-(methoxy methoxy base) ethyl ketone synthetic
(0.0066mol 0.16g), adds 10mL THF solution again under the nitrogen protection, drip 0.1mL BrCH to add magnesium chips in the 100mL three-necked bottle of reflux condensing tube, dropping funnel is housed
2CH
2The Br initiation reaction, slow dropping cyclopropane bromide (0.0022mol, THF solution (10mL) 0.8g) is treated the magnesium chips completely dissolve, solution is canescence, slowly drip the 2-(2-fluorophenyl again)-N-methoxyl group-2-(methoxy methoxy base)-the N-methylacetamide (0.0022mol, THF solution (20mL) 0.6g). detect through TLC, after raw material reaction is intact, use the saturated ammonium chloride cancellation, isolate organic layer, anhydrous magnesium sulfate drying, concentrate crude product.Column chromatography (silica gel, 200-300; Sherwood oil: ethyl acetate=6:1) separation obtains pure product 0.5g, productive rate: 91%.
1HNMR (CDCl
3, 400 MHz)，δ (ppm): 7.42-7.32 (m, 2H), 7.19-7.08 (m, 2H), 5.63 (s, 1H), 4.72 (d, J=28.6 Hz, 2H), 3.38 (s, 3H), 2.21-2.07 (m, 1H), 1.13-1.00 (m, 2H), 0.96-0.79 (m, 2H)。
13CNMR (CDCl
3, 100 MHz), δ (ppm): 206.47, 160.74 (d, J
CF = 246.2 Hz), 130.40 (d, J
CF = 7.6 Hz), 129.58 (d, J
CF = 3.8 Hz), 124.09 (d, J
CF = 14.5 Hz), 123.73 (d, J
CF = 3.1 Hz), 115.70 (d, J
CF =21.3 Hz), 95.14, 55.94, 17.63, 11.74 (d, J
CF = 6.1 Hz)。
(7) 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyl ethyl ketone synthetic
In the 100mL round-bottomed flask, with 1-cyclopropyl-2-(2-fluorophenyl)-2-(methoxy methoxy base) (0.48g 0.002mol) is dissolved in the 20mL methyl alcohol ethyl ketone, at room temperature adds concentrated hydrochloric acid 0.1mL.50 ℃ were stirred 5 hours down.Detect through TLC, reaction adds saturated NaHCO after finishing
3The aqueous solution is regulated pH value to neutral, uses ethyl acetate extraction (3 * 20 ml) again, merges the organic phase anhydrous magnesium sulfate drying, concentrates and obtains crude product.Column chromatography (silica gel, 200-300; Sherwood oil: ethyl acetate=10:1) separation obtains pure product 0.35g, productive rate: 90%.
1HNMR (CDCl
3, 400 MHz)，δ (ppm): 7.37-7.26 (m, 2H), 7.19-7.09 (m, 2H), 5.59 (d, J=4.0 Hz, 1H), 4.36 (d, J=4.3 Hz, 1H), 1.90-1.88 (m, 1H), 1.19-1.16 (m, 1H), 1.09-0.97 (m, 2H), 0.88-0.82 (m, 1H)。
13CNMR (CDCl
3, 100 MHz), δ (ppm): 208.84, 160.63 (d, J
CF = 246.8 Hz), 130.27 (d, J
CF = 7.4 Hz), 129.13 (d, J
CF = 3.8 Hz), 125.51 (d, J
CF = 3.1 Hz), 124.72 (d, J
CF = 14.2 Hz), 115.79 (d, J
CF =10.6 Hz), 73.59, (d, J
CF = 3.8 Hz), 17.19 (d, J
CF = 2.2 Hz), 12.42 (d, J
CF = 12.9 Hz)。
(8) 2-cyclopropyl-1-(2-fluorophenyl)-2-carbonyl ethyl p-toluenesulfonic esters
Under the nitrogen protection, with 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyl ethyl ketone (0.001mol 0.19g) under agitation is dissolved in the methylene dichloride of 50mL, and the adding triethylamine (0.0012mol, 0.12g).After above-mentioned solution is cooled to 0 ℃, slowly drip and contain Tosyl chloride (0.0012mol, 0.23g) dichloromethane solution (10mL), stir after 5 hours, extremely neutral with 1mol/L salt acid for adjusting pH value, isolated organic phase, after water, the saturated sodium-chloride washing, anhydrous magnesium sulfate drying.Concentrate at last crude product.Column chromatography (silica gel, 200-300; Sherwood oil: ethyl acetate=6:1) separation obtains pure product 0.32g.Fusing point: 82 ~ 84 ℃, productive rate 92%.
1HNMR (CDCl
3, 400 MHz)，δ (ppm): 7.72 (d, J=7.9 Hz, 2H), 7.33-7.28 (m, 1H), 7.26-7.22 (m, 3H), 7.09-7.05 (m, 1H), 7.01-6.97 (m, 1H), 6.18 (s, 1H), 2.40 (s, 3H), 2.20-2.14 (m, 1H), 1.12-1.07 (m, 1H), 1.04-0.97 (m, 2H), 0.92-0.87 (m, 1H)。
13CNMR (CDCl
3, 100 MHz), δ (ppm): 202.34, 160.14 (d, J
CF = 248.4 Hz), 144.94, 133.41, 131.42 (d, J
CF = 8.4 Hz), 129.72 (d, J
CF = 3.1 Hz), 127.87 (d, J
CF = 15.2 Hz), 124.56 (d, J
CF = 3.1 Hz), 120.95 (d, J
CF =3.7 Hz),115.76 (d, J
CF =21.3 Hz), 79.15, 21.60, 17.58, 12.55 (d, J
CF = 15.2 Hz)。
Claims (1)
1. compound 2-cyclopropyl-1-(2-fluorophenyl)-and the synthetic method of 2-carbonyl ethyl p-toluenesulfonic esters, comprise following processing step:
(1) adjacent fluorine amygdalic acid is synthetic
Under the effect of phase-transfer catalyst, adjacent fluorobenzaldehyde, chloroform, alkali be with the mol ratio of 1:2:6 ~ 1:4:14, in 40 ~ 80 ℃ of reaction 48 ~ 60h down, is cooled to room temperature, tells lower floor's chloroform; Water is regulated pH=1 ~ 2 with 1 ~ 3mol/L hydrochloric acid soln, uses ethyl acetate extraction, and column chromatography for separation obtains adjacent fluorine amygdalic acid;
Described phase-transfer catalyst is trimethyl benzyl ammonia chloride, triethyl benzyl ammonia chloride, etamon chloride, tetraethylammonium bromide or Tetrabutyl amonium bromide;
Described alkali is the sodium hydroxide of mass concentration 40-50% or the aqueous solution of potassium hydroxide;
(2) adjacent fluorine methyl mandelate is synthetic
Be solvent with methyl alcohol, under the effect of the vitriol oil, in 70 ~ 80 ℃ of 3 ~ 5h that reflux down, after reacting completely, be cooled to room temperature, under agitation add saturated aqueous sodium carbonate and produce to there being gas; Solvent evaporated, ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates, and obtains adjacent fluorine methyl mandelate;
(3) 2-(2-fluorophenyl)-and 2-(methoxy methoxy base) methyl acetate synthetic
Under nitrogen protection, be solvent with the methylene dichloride, under the effect of sodium hydride, adjacent fluorine methyl mandelate and methoxymethyl chlorine are with the mol ratio of 1:3 ~ 1:5, in 70 ~ 80 ℃ of 18 ~ 20h that reflux down; Reaction is used the saturated ammonium chloride cancellation after finishing, and uses saturated sodium bicarbonate, water, saturated common salt water washing more successively, and anhydrous magnesium sulfate drying concentrates, and column chromatography for separation gets the 2-(2-fluorophenyl)-2-(methoxy methoxy base) methyl acetate;
(4) 2-(2-fluorophenyl)-and 2-(methoxy methoxy base) acetic acid synthetic
Mixing solutions with methyl alcohol and water is solvent, the 2-(2-fluorophenyl)-2-(methoxy methoxy base) methyl acetate and alkali is with the mol ratio of 1:2 ~ 1:2.5, room temperature reaction 3 ~ 5h; Reaction finishes the back solvent evaporated, with the hydrochloric acid of 1 ~ 3mol/L water is adjusted to pH=1 ~ 2; Ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates, and obtains the 2-(2-fluorophenyl)-2-(methoxy methoxy base) acetic acid; Described alkali is the sodium hydroxide of mass concentration 40-50% or the aqueous solution of potassium hydroxide.
(5) 2-(2-fluorophenyl)-N-methoxyl group-2-(methoxy methoxy base)-N-methylacetamide synthetic:
Be solvent with toluene, under nitrogen protection, 2-(2-fluorophenyl)-and 2-(methoxy methoxy base) acetic acid and acylating reagent be with the mol ratio of 1:0.5 ~ 1:1, in 60 ~ 80 ℃ of reaction 1 ~ 2h down; Be cooled to room temperature after having reacted, add saturated NaHCO
3Aqueous solution cancellation, ethyl acetate extraction, anhydrous magnesium sulfate drying, column chromatography for separation gets the 2-(2-fluorophenyl)-N-methoxyl group-2-(methoxy methoxy base)-the N-methylacetamide;
Described acylating reagent is P (NMeOMe)
3
(6) 1-cyclopropyl-2-(2-fluorophenyl)-and 2-(methoxy methoxy base) ethyl ketone synthetic
Being solvent with the tetrahydrofuran (THF), under the nitrogen protection, is initiator with the glycol dibromide, the 2-(2-fluorophenyl)-N-methoxyl group-2-(methoxy methoxy base)-N-methylacetamide and Grignard reagent be with the mol ratio of 1:1 ~ 1:3, at room temperature reacts 3 ~ 5h; After having reacted, add the saturated aqueous ammonium chloride cancellation, ethyl acetate extraction, anhydrous magnesium sulfate drying, column chromatography for separation gets 1-cyclopropyl-2-(2-fluorophenyl)-2-(methoxy methoxy base) ethyl ketone; Described Grignard reagent is cyclopropyl bromination magnesium;
(7) 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyl ethyl ketone synthetic
Be solvent with methyl alcohol, 1-cyclopropyl-2-(2-fluorophenyl)-and 2-(methoxy methoxy base) ethyl ketone and concentrated hydrochloric acid be with the mol ratio of 1:0.03 ~ 1:0.05, in 50 ~ 60 ℃ of reaction 3 ~ 5h; After reaction finishes, regulate the pH value to neutral, ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates, column chromatography for separation obtains 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyl ethyl ketone;
(8) 2-cyclopropyl-1-(2-fluorophenyl)-2-carbonyl ethyl p-toluenesulfonic esters
Be solvent with the methylene dichloride, under the nitrogen protection, 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyl ethyl ketone, triethylamine, Tosyl chloride be with the mol ratio of 1:1:1 ~ 1:1.2:1.2, in 0 ~ 5 ℃ of reaction 5 ~ 6h; To neutral, isolated organic phase, water, saturated NaCl solution washing successively, anhydrous magnesium sulfate drying concentrates, column chromatography for separation obtains target product 2-cyclopropyl-1-(2-fluorophenyl with the salt acid for adjusting pH value)-2-carbonyl ethyl p-toluenesulfonic esters.
2. compound 2-cyclopropyl-1-(2-fluorophenyl according to claim 1)-and the synthetic method of 2-carbonyl ethyl p-toluenesulfonic esters, it is characterized in that: the consumption of the described phase-transfer catalyst of step (1) is 0.06 ~ 0.1 times of adjacent fluorobenzaldehyde molar weight.
3. compound 2-cyclopropyl-1-(2-fluorophenyl according to claim 1)-and the synthetic method of 2-carbonyl ethyl p-toluenesulfonic esters, it is characterized in that: in the step (2), the consumption of the vitriol oil is 0.05 ~ 0.1 times of adjacent fluorine amygdalic acid molar weight.
4. compound 2-cyclopropyl-1-(2-fluorophenyl according to claim 1)-and the synthetic method of 2-carbonyl ethyl p-toluenesulfonic esters, it is characterized in that: the consumption of the described sodium hydride of step (3) is 1.0 ~ 1.2 times of adjacent fluorine methyl mandelate molar weight.
5. compound 2-cyclopropyl-1-(2-fluorophenyl according to claim 1)-synthetic method of 2-carbonyl ethyl p-toluenesulfonic esters, it is characterized in that: in the step (6), the consumption of initiator glycol dibromide is the 2-(2-fluorophenyl)-N-methoxyl group-2-(methoxy methoxy base)-0.01 ~ 0.03 times of N-methylacetamide.
6. compound 2-cyclopropyl-1-(2-fluorophenyl according to claim 1)-synthetic method of 2-carbonyl ethyl p-toluenesulfonic esters, it is characterized in that: in the step (8), the consumption of triethylamine is 2-cyclopropyl-2-(2-fluorophenyl)-1 ~ 1.2 times of 2-hydroxyl ethyl ketone molar weight.
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