CN104151252A - Preparation method of [6-isopropyl-4- (4-fluorophenyl)-2-thio-5-yl]formate - Google Patents
Preparation method of [6-isopropyl-4- (4-fluorophenyl)-2-thio-5-yl]formate Download PDFInfo
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Abstract
The invention relates to a preparation method of a pharmaceutical chemical intermediate and particularly relates to a preparation method of [6-isopropyl-4- (4-fluorophenyl)-2-thio-5-yl]formate. According to the method, p-fluorobenzaldehyde, isobutyryl acetate and thio-substituted isourea sulfate are mainly adopted as raw materials and reacted and then subjected to photosensitized oxidation reaction to obtain the target product. By virtue of the preparation method disclosed by the invention, the production quality can be greatly improved, the production cost is reduced, the burden on patients is alleviated and the method has broad prospects in industrial applications.
Description
Technical field
The present invention relates to a kind of preparation method of chemical intermediate, be specifically related to the preparation method of [6-sec.-propyl-4-(4-fluorophenyl)-2-sulfenyl-5-yl] manthanoate.
Background technology
[6-sec.-propyl-4-(4-fluorophenyl)-2-sulfenyl-5-yl] manthanoate is the important intermediate in synthetic fat-reducing medicament rosuvastain calcium process.Rosuvastain calcium is a kind of selectivity Hydroxymethylglutaryl list acyl coenzyme A (HMG-CoA) reductase inhibitor, is also inhibitor or the inductor of cytochrome P 450 enzymes.Rosuvastain calcium, as a kind of potent fat-reducing medicament, can reduce total cholesterol, LDL-cholesterol, tri-glyceride and the ApoB of rising, increases HDL-cholesterol level, is used for the treatment of hyperlipidaemia, is applicable to the treatment of primary hypercholesterolemia.First rosuvastain calcium is studied by Japanese Shionogi Seiyaku Kabushiki Kaisha, after develop the earliest production by AstraZeneca (AstraZeneca) company, in multiple countries and regions listing such as the U.S., Japan, Europe, China, Chinese trade(brand)name determining, trade(brand)name " CRESTOR ".There is Nanjing first sign in the domestic drugmaker that at present State Food and Drug Administration's approval is produced, and composite tablet honestly multiple companies such as becomes a fine day.
The key intermediate of synthesizing rosuvastatin spit of fland calcium in prior art [6-sec.-propyl-4-(4-fluorophenyl)-2-sulfenyl-5-yl] the conventional method of manthanoate (hereinafter to be referred as compound III) is: first generate 6-sec.-propyl-4-(4-fluorophenyl)-2-sulfenyl-3 by p-Fluorobenzenecarboxaldehyde, isobutyryl acetic ester and sulfenyl isourea hydrochloride by condensation and with cyclisation two steps, 6-dihydro-pyrimidin-5-formic acid, more further aromatization turns to compound III.In aromatization, conventionally use the tetrachlorobenzoquinone or 2 that has high toxicity and burning to produce dusty gas, 3-bis-chloro-5, the oxidation systems such as 6-dicyano-Isosorbide-5-Nitrae-benzoquinones (DDQ), potassium permanganate or manganese oxide MnO2, copper compound and peroxy tert-butyl alcohol coupling are (as WO03097614; WO2007074391; WO2008059519; WO2005030758; US5260440).
But, in above-mentioned reaction, all need heating, be unfavorable for operation, and atom utilization is not high, reaction yield is lower, greatly reduces the output of product, increases production cost.Secondly, in reaction, use the oxygenant of equivalent poisonous, larger to harm, bring difficulty also to target product aftertreatment simultaneously, sepn process is loaded down with trivial details, and the existence of residue will reduce the quality of product greatly, also environment is caused to load and harm.Therefore, in the urgent need to a kind of can less energy-consumption, atom utilization is high, product yield is high, the reaction path of good product quality and the low environmental protection of production cost, solves the problem that above-mentioned prior art exists.
Summary of the invention
The object of the invention is to provide a kind of preparation method of new [6-sec.-propyl-4-(4-fluorophenyl)-2-sulfenyl-5-yl] manthanoate, to overcome the shortcoming existing in prior art.Preparation method of the present invention can improve the quality of production greatly, reduces production costs, and relieve patient ' s burden has broad prospects in industrial application.
The method reactions steps of described synthetic [6-sec.-propyl-4-(4-fluorophenyl)-2-sulfenyl-5-yl] manthanoate is as follows:
Wherein R1 is selected from the alkyl of C1-C6 or the aryl of C6-C12; R2 is selected from the alkyl of C1-C6 or the aryl of C6-C12.
Condensation reaction described in step 1 is taking p-Fluorobenzenecarboxaldehyde and isobutyryl acetic ester as raw material, and the mol ratio of reaction usage quantity is 1:0.8-1.3, and the reaction times is 20-26 hour, and temperature of reaction is room temperature, adds piperidines and the acetic acid of catalytic amount in reaction.
The isourea vitriol of the product chemical compounds I of step 1 and sulfenyl replacement is carried out reacting generating compound II by cyclization described in step 2, reaction solvent is HMPA or its similar phosphoryl triamide analog derivative, the reaction times of reaction is 19-24 hour, and the temperature of reaction of reaction is 70-140 DEG C.
Photosensitized oxidation reaction described in step 3 is carried out aromatization by the product compound ii of step 2 and is prepared compound III, and oxygenant used is the oxygen in atmosphere.
The light source adopting in described photosensitized oxidation reaction is the visible ray that wavelength is more than or equal to 400nm.
Preferred light source is the visible ray of wavelength 400nm-550nm; The further preferred various monochromatic LED lamps of normal domestic use incandescent light, electricity-saving lamp, white LED lamp, 400nm-550nm or be greater than high voltage mercury lamp, the xenon lamp of 400nm filtering apparatus.
In described photosensitized reaction, add appropriate alkali, described alkali is organic bases or mineral alkali.
Preferred alkali is salt of wormwood, sodium carbonate, Potassium ethanoate, Sodium phosphate dibasic, potassium hydroxide or sodium hydroxide.
Tetra-n-butyl ammonium salt, ungroomed eosin sodium salt or oxa anthracenes dyestuff that the catalyzer using in described photosensitized oxidation reaction is eosin.
In described photosensitized oxidation reaction, the usage quantity mol ratio of compound ii, catalyzer and alkali is 1:0.01-0.03:0-4.
In described photosensitized oxidation reaction, solvent used is the mixed solvent of organic solvent or organic solvent and water.
Described organic solvent methyl alcohol, methylene dichloride, ethyl acetate, ether, acetone, toluene, normal hexane, sherwood oil or HMPA, be preferably methyl alcohol or methylene dichloride.
Described organic solvent and water volume ratio are the mixed solvent of 5-10:0-1.
Be preferably the mixed solvent that methanol-water or methylene dichloride-water volume ratio are 9:1.
Reactant is reacted 2～7 hours under the radiation of visible light condition of uncovered blowing air to preferably 2-3 hour, room temperature reaction.After reaction finishes, add appropriate ethyl acetate, water, saturated ammonium chloride washing, remove mineral alkali regulation system to subacidity respectively.Organic phase adds a small amount of activated carbon to remove pigment, then passes through anhydrous sodium sulfate drying, is spin-dried for.Use sherwood oil and methylene dichloride mixed solvent recrystallization to obtain target product [6-sec.-propyl-4-(4-fluorophenyl)-2-sulfenyl-5-yl] manthanoate.
Laboratory micropreparation post-treating method: after reaction finishes, liquid in reaction bottle is poured in a dry Erlenmeyer flask, add anhydrous sodium sulfate drying after 20 minutes, be spin-dried for organic solvent and obtain crude product, then carry out column chromatography purification, use sherwood oil than the mixed solvent gradient elution of ethyl acetate 100:1, obtains colourless oily target product to sherwood oil.
Prepare in a large number post-treating method: add appropriate ethyl acetate, water, saturated ammonium chloride washing, remove mineral alkali regulation system to subacidity respectively.Organic phase adds a small amount of activated carbon to remove pigment, then passes through anhydrous sodium sulfate drying, is spin-dried for.Use sherwood oil and methylene dichloride mixed solvent recrystallization to obtain the target product of colorless solid.
Solvent in described column chromatography process is selected from the alkane of C1-C12, halohydrocarbon, the ester of C2-C4 or the ether of C2-C6 or the cyclo other compounds of C1-C2, and the mixed solvent of its any two or more solvent is as eluent.
Technical conceive of the present invention is the acidity of utilizing the reactive hydrogen of the N atom in dihydropyrimidine compound II, react with the additive basic salt of wormwood in system and generate exposed N negatively charged ion, reduce the oxidizing potential of dihydropyrimidine compound, make to carry out more efficiently photosensitized oxidation aromizing, obtain target product compound III.
The present invention program compared to the prior art advantage is:
1, in photosensitized oxidation reaction using the oxygen in atmosphere as oxygenant, aboundresources, cheaply and be conveniently easy to get, avoided the use of harmful oxygenant, more safe and effective.
2, in photosensitized oxidation reaction, light source is the visible ray that wavelength is more than or equal to 400nm, and light source source is abundant, even can directly utilize natural sunlight to replace light source, is conducive to industrial production, reduces costs.
3, the use of extremely a small amount of non-metal optical catalyzer in photosensitized oxidation reaction, reduce synthetic cost, avoid the use of the common precious metal such as Ru and Ir photocatalyst, the residual of catalyst component in prior art or problem that last handling process is loaded down with trivial details are solved, greatly improve the quality of product, also reduced medicine cost.
4, in photosensitized oxidation reaction, add appropriate alkali, the acidity of the reactive hydrogen of the N atom in recycling dihydropyrimidine compound II is reacted with it, generate exposed N negatively charged ion, reduce the oxidizing potential of dihydropyrimidine compound II, make to carry out more efficiently photosensitized oxidation aromizing and obtain target product, improved the atom utilization in reactant, reduce side reaction, make reaction yield high, be conducive to suitability for industrialized production.
5, photosensitized oxidation operation is simple, reaction conditions gentleness, meets the requirement of environmental protection, and reaction required time is short, after reaction finishes, just can obtain through simple aftertreatment the product that purity is higher, reaction finishes the further recycling of rear solvent in addition.
Compared to the prior art, production cost is low, reaction is safe, efficient and environmental protection for technical solution of the present invention, has fully demonstrated actual production meaning and the industrial application value of the invention, is particularly suitable for the demand of suitability for industrialized production.
Embodiment
Further describe the present invention below by specific embodiment, feature of the present invention will be explicitly clearer along with describing, but protection scope of the present invention is not limited to this.It should be appreciated by those skilled in the art, as long as do not departing under spirit of the present invention and example ranges, within the amendment that ins and outs of the present invention are carried out and replacement all fall into technical scope of the present invention.
Unless otherwise defined, the implication that all technology that the present invention uses and the implication of scientific terminology are understood conventionally with the technical field of the invention those of ordinary skill is identical.Conventionally name and following experimental technique that, the present invention uses are all well known in the art or conventional.
Synthesizing of embodiment 1:4-methyl-2-(4-fluorobenzene methylene radical)-3-oxopentanoic acid methyl esters
In the round-bottomed flask of a 250mL, add suitable stirring magneton, add isobutyryl methyl acetate (19.23g, 133.4mmol), p-Fluorobenzenecarboxaldehyde (12.9g, 106.4mmol), Virahol 76.0mL, piperidines 720 μ L, acetic acid 420 μ L, reaction mixture is room temperature reaction 22h under condition of nitrogen gas, reaction finishes to be spin-dried under rear solvent decompression, residue crude product dissolves with the methylene dichloride of 50mL, wash 3 times with saturated sodium bicarbonate 100mL, anhydrous magnesium sulfate drying, after being dried, remove anhydrous magnesium sulfate and solvent, obtain red-brown oily matter 4-methyl-2-(4-fluorobenzene methylene radical)-3-oxopentanoic acid methyl esters I, yield is 95.4%, directly drop into next step, TLC R
f0.39 (PE/EA=5:1), product further characterizes by nuclear-magnetism
1h NMR (400MHz, CDCl
3): δ 7.74 (s, 1H), 7.40 (q, J=3.4Hz, 2H), 7.06 (q, J=8.5Hz, 2H), 3.77 (d, J=5.7Hz, 3H), 2.75 (m, 1H), 1.08 (d, J=6.9Hz, 6H).
Synthesizing of embodiment 2:4-methyl-2-(4-fluorobenzene methylene radical)-3-oxopentanoic acid ethyl ester
In the round-bottomed flask of a 250mL, add suitable stirring magneton, add ethyl isobutyryl (21.10g, 133.4mmol), p-Fluorobenzenecarboxaldehyde (20.97g, 172.9mmol), Virahol 76.0mL, piperidines 720 μ L, acetic acid 420 μ L, reaction mixture is room temperature reaction 22h under condition of nitrogen gas then, reaction finishes rear solvent and is spin-dried under decompression, remaining crude product dissolves with the methylene dichloride of 50mL, wash 3 times with saturated sodium bicarbonate 100mL, anhydrous magnesium sulfate drying, after being dried, remove anhydrous magnesium sulfate and solvent, obtain compound 2-(4-fluorobenzene methylene radical)-3-oxo-4-methylvaleric acid ethyl ester I as 1:1Z and E mixture, for light yellow liquid, yield is 83.9%, directly drop into next step, TLC R
f0.36 (PE/EA=5:1), product further characterizes by nuclear-magnetism
1h NMR (400MHz, CDCl
3): δ 7.73 (s, 1H
a), 7.51 (s, 1H
b), 7.34-7.47 (m, 4H
a & b), 7.02-7.09 (m, 4H
a & b), 4.25-4.35 (m, 4H
a & b), 3.14 (m, 1H
b), 2.71 (m, 1H
a), 1.25-1.36 (m, 6H
a & b), 1.17 (d, J=7.2Hz, 6H
b), 1.08 (d, J=7.2Hz, 6H
a).
Synthesizing of embodiment 3:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-carboxylate methyl ester
In the round-bottomed flask of a 150mL, add suitable stirring magneton, add compound 4-methyl-2-(4-fluorobenzene methylene radical)-3-oxopentanoic acid methyl esters 44.68g, thiomethyl isourea vitriol 28.24g, the HMPA HMPA of 65mL, reacts on N
2the lower 100 DEG C of reaction 22h of gas condition, after finishing, reaction is down to room temperature, reaction mixture extracted with diethyl ether three times, saturated sodium bicarbonate solution is washed and is washed, organic phase anhydrous sodium sulfate drying, solvent low pressure is spin-dried for, the crude product column chromatography purification (PE → PE/EtOAc=100:1) of acquisition, product is lurid semisolid, and yield is 61.4%.
1H?NMR(400MHz,CDCl
3):δ7.22(m,2H),6.97(m,2H),5.57(brs,1H),4.15(s,1H),3.62(s,3H),2.43(s,3H),1.16(d,J＝6.8Hz,6H)ppm.
13C?NMR(100MHz,CDCl
3):δ167.1,161.2,159.9,138.9,128.9,100.1,59.1,52.4,24.4,14.9,13.4ppm.MS(ESI):calcd?for[C
16H
20FN
2O
2S]
+:323.12,found323.29。
Synthesizing of embodiment 4:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-carboxylic acid, ethyl ester
In the round-bottomed flask of a 150mL, add suitable stirring magneton, add compound 4-methyl-2-(4-fluorobenzene methylene radical)-3-oxopentanoic acid ethyl ester 44.68g, the thiomethyl isourea vitriol of 28.24g, the HMPA HMPA of 65mL, reacts on N
2the lower 100 DEG C of reaction 22h of gas condition, after finishing, reaction is down to room temperature, reaction mixture extracted with diethyl ether three times, saturated sodium bicarbonate solution is washed and is washed, organic phase anhydrous sodium sulfate drying, solvent low pressure is spin-dried for, the crude product column chromatography purification (PE → PE/EtOAc=100:1) of acquisition, product is lurid oily matter, and yield is 66.2%.
1H?NMR(400MHz,CDCl
3):δ7.26(t,J＝6.0Hz,2H),6.96(t,J＝8.8Hz,2H),6.43(brs,1H),5.58(brs,1H),4.08(q,J＝7.2Hz,3H),2.44(s,3H),1.20-1.12(m,9H)ppm.
13C?NMR(100MHz,CDCl
3):δ166.4,163.2,160.8,140.6,128.4,128.3,115.2,115.0,59.8,53.4,19.9,14.1,13.5ppm.MS(ESI):calcd?for[C
17H
22FN
2O
2S]
+:337.14,found337.39。
Synthesizing of embodiment 5:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-pyrimidine-5-carboxylic acid methyl esters
Under air conditions, in the reaction tubes of 15mL, add suitable stirring magneton, 32.3mg (0.10mmol) 6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, tetra-n-butyl ammonium salt TBA-eosinY1.2mg (0.1mmol%) and the salt of wormwood K of eosin
2cO
327.64mg (0.40mmol), add successively 5.0ml methyl alcohol and 0.5ml water, reaction tubes is open in air under the blue led light irradiation of 3W450nm, reaction 2.5h, after having reacted, reaction mixture vacuum concentration, remaining crude product dissolves with a small amount of methylene dichloride, crude product obtains aromizing product by column chromatography for separation (PE → PE/EtOAc=30:1), yellow solid 30.4mg, productive rate 95%.
1H?NMR(400MHz,CDCl
3):δ7.65(q,J＝5.4Hz,2H),7.13(q,J＝8.6Hz,2H),3.70(s,3H),3.11-3.16(m,1H),2.62(s,3H),1.31(d,J＝6.8Hz,6H)ppm.
13CNMR(100MHz,CDCl
3):δ173.2,172.8,168.8,164.0(d,J＝253.6Hz),133.8(d,J＝3.2Hz),130.3(d,J＝9.0Hz),119.9,115.7(d,J＝21.4Hz),52.6,33.4,21.7,14.2.HRMS(ESI):calcd?for[C
16H
18FN
2O
2S]
+:321.1073,found321.1066。
Synthesizing of embodiment 6:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-pyrimidine-5-carboxylic acid methyl esters
Under air conditions, in the reaction tubes of 15mL, add suitable stirring magneton, 32.3mg (0.10mmol) 6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, tetra-n-butyl ammonium salt TBA-eosinY1.2mg (0.3mmol%) and the salt of wormwood K of eosin
2cO
327.64mg (0.20mmol), add 5.0ml methyl alcohol, reaction tubes is open in air under the blue led light irradiation of 3W450nm, reaction 2.5h, after having reacted, reaction mixture is by vacuum concentration, remaining crude product dissolves with a small amount of methylene dichloride, crude product obtains aromizing product by column chromatography for separation (PE → PE/EtOAc=30:1), yellow solid 28.2mg, productive rate 93.8%.
Synthesizing of embodiment 7:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-pyrimidine-5-carboxylic acid methyl esters
Under air conditions, in the reaction tubes of 15mL, add suitable stirring magneton, 32.3mg (0.10mmol) 6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, tetra-n-butyl ammonium salt TBA-eosinY1.2mg (0.1mmol%) and the sodium carbonate Na of eosin
2cO
310.6mg (0.10mmol), then add 5.0mL methyl alcohol, reaction tubes is open in air under the blue led light irradiation of 3W450nm, reaction 2.5h, after having reacted, reaction mixture vacuum concentration, remaining crude product dissolves with a small amount of methylene dichloride, crude product obtains aromizing product by column chromatography for separation (PE → PE/EtOAc=30:1), yellow solid 22.70mg, productive rate 92%.
Synthesizing of embodiment 8:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-pyrimidine-5-carboxylic acid methyl esters
Under air conditions, in the reaction tubes of 15mL, add suitable stirring magneton, 32.3mg (0.10mmol) 6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-1, 4-dihydro-pyrimidin-5-carboxylate methyl ester, the tetra-n-butyl ammonium salt TBA-eosinY1.2mg (0.1mmol%) of eosin, then add 5.0mL phenylfluoroform, reaction tubes is open in air under the blue led light irradiation of 3W450nm, reaction 2.5h, after having reacted, reaction mixture vacuum concentration, remaining crude product dissolves with a small amount of methylene dichloride, crude product obtains aromizing product by column chromatography for separation (PE → PE/EtOAc=30:1), yellow solid 26.50mg, productive rate 85.7%.
Synthesizing of embodiment 9:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-pyrimidine-5-carboxylic acid methyl esters
Under air conditions, in the reaction tubes of 15mL, add suitable stirring magneton, 32.3mg (0.10mmol) 6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-1, 4-dihydro-pyrimidin-5-carboxylate methyl ester, the tetra-n-butyl ammonium salt TBA-eosinY1.2mg (0.1mmol%) of eosin and Potassium ethanoate 19.6mg (0.20mmol), then add 5.0mL methylene dichloride, reaction tubes is open in air under the blue led light irradiation of 3W450nm, reaction 2.5h, after having reacted, reaction mixture is by vacuum concentration, remaining crude product dissolves with a small amount of methylene dichloride, crude product obtains aromizing product by column chromatography for separation (PE → PE/EtOAc=30:1), yellow solid 29.50mg, productive rate 94.1%.
Synthesizing of embodiment 10:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-pyrimidine-5-carboxylic acid methyl esters
Under air conditions, in the reaction tubes of 15mL, add suitable stirring magneton, 32.3mg (0.10mmol) 6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-1, 4-dihydro-pyrimidin-5-carboxylate methyl ester, the tetra-n-butyl ammonium salt TBA-eosinY1.2mg (0.1mmol%) of eosin and Sodium phosphate dibasic 17.9mg (0.05mmol), then add 5.0mL acetonitrile, reaction tubes is open in air under the blue led light irradiation of 3W450nm, reaction 2.5h, after having reacted, reaction mixture is by vacuum concentration, remaining crude product dissolves with a small amount of methylene dichloride, crude product obtains aromizing product by column chromatography for separation (PE → PE/EtOAc=30:1), yellow solid 16.70mg, productive rate 94.6%.
Synthesizing of embodiment 11:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-pyrimidine-5-carboxylic acid methyl esters
Under air conditions, in the reaction tubes of 15mL, add suitable stirring magneton, 32.3mg (0.10mmol) 6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, the tetra-n-butyl ammonium salt TBA-eosinY1.2mg (0.1mmol%) of eosin and carbon tetrabromide 19.4 μ L (0.20mmol), then add 5.0mL methyl alcohol, clog with turned welt plug, with needle tubing by Bubbling method deoxygenation 30min.Then the reaction tubes of sealing with wax, and the blue led light that is placed in 3W450nm according under, reaction 2.5h.After having reacted, reaction mixture is by vacuum concentration, and remaining crude product dissolves with a small amount of methylene dichloride, and crude product obtains aromizing product by column chromatography for separation (PE → PE/EtOAc=30:1), yellow solid 22.72mg, productive rate 81%.
Synthesizing of embodiment 12:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-pyrimidine-5-carboxylic acid methyl esters
Under air conditions, in the reaction tubes of 15mL, add suitable stirring magneton, 32.3mg (0.10mmol) 6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, the tetra-n-butyl ammonium salt TBA-eosinY1.2mg (0.1mmol%) of eosin and bromo chloroform 19.7 μ L (0.20mmol), then add 5.0mL methyl alcohol, clog with turned welt plug, with needle tubing by Bubbling method deoxygenation 30min.Then the reaction tubes of sealing with wax, and the blue led light that is placed in 3W450nm according under, reaction 2.5h.After having reacted, reaction mixture is by vacuum concentration, and remaining crude product dissolves with a small amount of methylene dichloride, and crude product obtains aromizing product by column chromatography for separation (PE → PE/EtOAc=30:1), yellow solid 22.68mg, productive rate 84.2%.
Synthesizing of embodiment 13:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-pyrimidine-5-carboxylic acid methyl esters
Gram scale test: under air conditions, in the round-bottomed flask of 500mL, add suitable magnetic stirring bar, 1.932g (6.0mmol) 6-sec.-propyl-2-thiomethyl-4-(4-fluorophenyl)-1, 4-dihydro-pyrimidin-5-carboxylate methyl ester, the tetra-n-butyl ammonium salt TBA-eosinY67.8mg (0.1mmol%) of eosin and potassium hydroxide 0.672g (12mmol), then add successively 300mL methyl alcohol and 30mL water, round-bottomed flask is open in air and is exposed under extraneous solar light irradiation, reaction 7h, after having reacted, reaction mixture is by after anhydrous sodium sulfate drying, methyl alcohol is removed in underpressure distillation, add appropriate ethyl acetate, water respectively, saturated ammonium chloride washing, remove mineral alkali regulation system to subacidity.Organic phase adds a small amount of activated carbon to remove pigment, then passes through anhydrous sodium sulfate drying, is spin-dried for.Remaining sherwood oil/methylene dichloride for crude product (50:1) recrystallization obtains yellow crystalline solid 1.632g, productive rate 95%.
Synthesizing of embodiment 14:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-pyrimidine-5-carboxylic acid ethyl ester
Under air conditions, in the reaction tubes of 15mL, add suitable stirring magneton, 33.6mg (0.10mmol) 6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-1, 4-dihydro-pyrimidin-5-carboxylic acid, ethyl ester, the tetra-n-butyl ammonium salt TBA-eosinY1.2mg (0.1mmol%) of eosin and sodium hydroxide 0.26mg (0.40mmol), then add successively 5.0ml methyl alcohol and 0.5ml water, reaction tubes is open in air under the blue led light irradiation of 3W450nm, reaction 2h, after having reacted, reaction mixture is by vacuum concentration, remaining crude product dissolves with a small amount of methylene dichloride, crude product obtains aromizing product by column chromatography for separation (PE → PE/EtOAc=30:1), the solid 32.4mg of white, productive rate 97%.
1H?NMR(400MHz,CDCl
3):δ7.67-7.64(m,2H),7.15-7.11(m,2H),4.18(q,J＝7.2Hz,2H),3.21-3.15(m,1H),2.62(s,3H),1.32(d,J＝6.4Hz,6H),1.10(t,J＝7.2Hz,3H)ppm.
13C?NMR(100MHz,CDCl
3):δ173.1,172.6,168.2,165.1,162.5(d,J＝300.0Hz),133.9(d,J＝3.0Hz),130.4(d,J＝8.0Hz),120.2,115.5(d,J＝21.0Hz),61.8,33.2,21.6,14.2,13.7ppm.HRMS(ESI):calcd?for?C
17H
20FN
2O
2S[M+H]
+m/z335.1230,found335.1224。
Synthesizing of embodiment 15:6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-pyrimidine-5-carboxylic acid ethyl ester
Gram scale test: under air conditions, in the round-bottomed flask of 500mL, add suitable magnetic stirring bar, 2.016g (6.0mmol) 6-sec.-propyl-4-(4-fluorophenyl)-2-thiomethyl-1,4-dihydro-pyrimidin-5-carboxylic acid, ethyl ester, tetra-n-butyl ammonium salt TBA-eosinY67.8mg (0.1mmol%) and the salt of wormwood K of eosin
2cO
31.658g (12mmol) adds in reaction tubes, and then 300mL methyl alcohol and 30mL water add successively, and round-bottomed flask is open in air and is exposed under extraneous solar light irradiation, reaction 6h.After having reacted, reaction mixture is by after anhydrous sodium sulfate drying, and methyl alcohol is removed in underpressure distillation, adds appropriate ethyl acetate, and water, saturated ammonium chloride washing, remove mineral alkali regulation system to subacidity respectively.Organic phase adds a small amount of activated carbon to remove pigment, then passes through anhydrous sodium sulfate drying, is spin-dried for.Remaining sherwood oil/methylene dichloride for crude product (50:1) recrystallization obtains white crystalline solid 1.7g, productive rate 96.2%.
Claims (14)
1. prepare the method for [6-sec.-propyl-4-(4-fluorophenyl)-2-sulfenyl-5-yl] manthanoate for one kind, it is characterized in that with p-Fluorobenzenecarboxaldehyde, the isourea vitriol that isobutyryl acetic ester and sulfenyl replace is that raw material reacts, through photosensitized oxidation, reaction prepares again, and reactions steps is as follows:
Wherein R1 is selected from the alkyl of C1-C6 or the aryl of C6-C12; R2 is selected from the alkyl of C1-C6 or the aryl of C6-C12.
2. the method for claim 1, is characterized in that in described photosensitized oxidation reaction, oxygenant used is the oxygen in atmosphere.
3. the method for claim 1, is characterized in that the light source adopting in described photosensitized oxidation reaction is the visible ray that wavelength is more than or equal to 400nm.
4. the method for claim 1, is characterized in that the light source adopting in described photosensitized oxidation reaction is the visible ray of wavelength 400nm-550nm.
5. the method for claim 1, is characterized in that the light source adopting in described photosensitized oxidation reaction is the various monochromatic LED lamps of normal domestic use incandescent light, electricity-saving lamp, white LED lamp, 400nm-550nm or high voltage mercury lamp, the xenon lamp that is greater than 400nm filtering apparatus.
6. the method for claim 1, is characterized in that adding alkali in described photosensitized reaction, and described alkali is organic bases or mineral alkali.
7. method as claimed in claim 6, is characterized in that the alkali adding in described photosensitized reaction is salt of wormwood, sodium carbonate, Potassium ethanoate, Sodium phosphate dibasic, potassium hydroxide or sodium hydroxide.
8. the method for claim 1, tetra-n-butyl ammonium salt, ungroomed eosin sodium salt or oxa anthracenes dyestuff that the catalyzer using in the photosensitized oxidation reaction described in it is characterized in that is eosin.
9. the method for claim 1, is characterized in that the usage quantity mol ratio of compound ii, catalyzer and alkali in described photosensitized oxidation reaction is 1:0.01-0.03:0-4.
10. the method for claim 1, is characterized in that in described photosensitized oxidation reaction, solvent used is the mixed solvent of organic solvent or organic solvent and water.
11. methods as claimed in claim 10, is characterized in that in described photosensitized oxidation reaction, solvent used is Methanol+Water.
12. according to the method described in claim 1-10, and in the condensation reaction described in it is characterized in that, the mol ratio of p-Fluorobenzenecarboxaldehyde and isobutyryl acetic ester usage quantity is 1:0.8-1.3.
13. methods according to claim 12, is characterized in that the temperature of reaction of described condensation reaction is room temperature, and the reaction times is 20-26 hour.
14. according to the method described in claim 1-10, it is characterized in that the reaction solvent of described cyclization is HMPA or its similar phosphoryl triamide analog derivative, and the reaction times of reaction is 19-24 hour, and the temperature of reaction of reaction is 70-140 DEG C.
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| US5260440A (en) * | 1991-07-01 | 1993-11-09 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives |
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| US5260440A (en) * | 1991-07-01 | 1993-11-09 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives |
Non-Patent Citations (2)
| Title |
|---|
| CHRISTOPHER K. PRIER ET.AL.: "Visible Light Photoredox Catalysis with Transition Metal Complexes:Applications in Organic Synthesis", 《CHEM. REV.》 * |
| JAGAN M. R. NARAYANAM ET.AL.: "Visible light photoredox catalysis: applications in organic synthesis", 《CHEM. SOC. REV.》 * |
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