CN104151252B - One prepares the method for [6-isopropyl-4-(4-fluorophenyl)-2-sulfenyl-5-base] formic acid esters - Google Patents
One prepares the method for [6-isopropyl-4-(4-fluorophenyl)-2-sulfenyl-5-base] formic acid esters Download PDFInfo
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
The present invention relates to the preparation method of a kind of chemical intermediate, be specifically related to the preparation method of [6 isopropyl 4 (4 fluorophenyl) 2 sulfenyl 5 base] formic acid esters.The present invention is mainly that raw material reacts with 4-Fluorobenzaldehyde, isobutyryl acetas and sulfenyl substituted isourea sulfate, then prepares target product through photosensitized oxidation reaction.The preparation method of the present invention can be greatly improved the quality of production, reduces production cost, alleviates patient burden, have broad prospects in commercial Application.
Description
Technical field
The present invention relates to the preparation method of a kind of chemical intermediate, be specifically related to [6-isopropyl-4-(4-
Fluorophenyl)-2-sulfenyl-5-base] preparation method of formic acid esters.
Background technology
[6-isopropyl-4-(4-fluorophenyl)-2-sulfenyl-5-base] formic acid esters is synthesis fat-reducing medicament Rosuvastain
Important intermediate during the calcium of spit of fland.Rosuvastain calcium is a kind of selectivity Hydroxymethylglutaryl list acyl coenzyme A
(HMG-CoA) reductase inhibitor, is also inhibitor or the derivant of cytochrome P 450 enzymes.Rui Shu cuts down
Statin calcium is as a kind of potent fat-reducing medicament, it is possible to decrease the T-CHOL of rising, LDL-cholesterol, glycerol
Three acid esters and ApoB, increase HDL-cholesterol level, be used for treating hyperlipemia, it is adaptable to constitutional height gallbladder
The treatment of sterin mass formed by blood stasis.Rosuvastain calcium first by Japan Shionogi Seiyaku Kabushiki Kaisha research, after by
AstraZeneca (AstraZeneca) company develops production the earliest, in the U.S., Japan, Europe, China
Etc. multiple countries and regions list, Chinese trade name determining, trade name " CRESTOR ".Country's food at present
There is a Nanjing first sign in the domestic drugmaker that the approval of product Drug Administration produces, composite tablet, honest becomes a fine day
Etc. multiple companies.
Key intermediate [6-isopropyl-4-(4-the fluorophenyl)-2-of synthesizing rosuvastatin spit of fland calcium in prior art
Sulfenyl-5-base] formic acid esters (hereinafter referred to as compound III) conventional method is: by 4-Fluorobenzaldehyde,
Isobutyryl acetas and sulfenyl isourea hydrochlorate by condensation and first generate 6-isopropyl-4-with being cyclized two steps
(4-fluorophenyl)-2-sulfenyl-3,6-dihydro-pyrimidin-5-formic acid, further aromatization turns to compound III.
Aromatization generally uses tetrachloroquinone or the 2,3-dichloro having high toxicity and burning to produce dusty gas
-5,6-dicyano-1,4-benzoquinone (DDQ), potassium permanganate or manganese oxide MnO2, copper compound and peroxide uncle
The oxidation systems such as butanol combination are (such as WO03097614；WO2007074391；WO2008059519；WO
2005030758；US5260440).
But, above-mentioned reaction is required to heating, is unfavorable for operation, and atom utilization is the highest, reaction
Yield is relatively low, is substantially reduced the yield of product, increases production cost.Secondly, reaction uses the oxygen of equivalent
Agent is poisonous, relatively big to harm, brings difficulty the most also to target product post processing, and separation process is numerous
Trivial, the existence of residue will be substantially reduced the quality of product, and environment also causes load and harm.Therefore,
In the urgent need to the low energy consumption of a kind of energy, atom utilization height, product yield height, good product quality and production cost
The reaction path of low environmental protection, solves the problem that above-mentioned prior art exists.
Summary of the invention
Present invention aim at providing a kind of new [6-isopropyl-4-(4-fluorophenyl)-2-sulfenyl-5-base] first
The preparation method of acid esters, to overcome shortcoming present in prior art.The preparation method of the present invention can carry significantly
The high quality of production, reduces production cost, alleviates patient burden, have broad prospects in commercial Application.
The method reactions steps of described synthesis [6-isopropyl-4-(4-fluorophenyl)-2-sulfenyl-5-base] formic acid esters
As follows:
Wherein R1 is selected from alkyl or the aryl of C6-C12 of C1-C6；R2 selected from C1-C6 alkyl or
The aryl of C6-C12.
Condensation reaction described in step 1, with 4-Fluorobenzaldehyde and isobutyryl acetas as raw material, reacts usage amount
Mol ratio be 1:0.8-1.3, the response time is 20-26 hour, and reaction temperature is room temperature, in reaction add
The piperidines of catalytic amount and acetic acid.
Cyclization described in step 2 is by the product Compound I of step 1 and sulfenyl substituted isourea sulfate
Carrying out reacting generating compound II, reaction dissolvent is HMPA or its similar phosphoric triamide class is spread out
Biology, the response time of reaction is 19-24 hour, and the reaction temperature of reaction is 70-140 DEG C.
The product Compound II of step 2 is carried out aromatization and prepares by the photosensitized oxidation reaction described in step 3
Obtaining compound III, oxidant used is the oxygen in air.
The described light source employed in 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；Further preferably normal domestic use is incandescent
Lamp, electricity-saving lamp, white LED lamp, the various monochromatic LED lamps of 400nm-550nm or more than 400nm filter
The high voltage mercury lamp of electro-optical device, xenon lamp.
Adding appropriate alkali in described photosensitivity reaction, described alkali is organic base or inorganic base.
Preferably alkali is potassium carbonate, sodium carbonate, potassium acetate, disodium hydrogen phosphate, potassium hydroxide or sodium hydroxide.
The tetra-n-butyl ammonium salt that catalyst is eosin used in described photosensitized oxidation reaction, unvarnished
Eosin sodium salt or oxa anthracenes dyestuff.
In described photosensitized oxidation reaction, the usage amount mol ratio of compound ii, catalyst and alkali is
1:0.01-0.03:0-4。
In described photosensitized oxidation reaction, solvent used is organic solvent or organic solvent and the mixed solvent of water.
Described organic solvent methanol, dichloromethane, ethyl acetate, ether, acetone, toluene, normal hexane,
Petroleum ether or HMPA, preferably methanol or dichloromethane.
Described organic solvent and water volume ratio are the mixed solvent of 5-10:0-1.
It is preferably methanol-water or dichloromethane-water volume ratio is the mixed solvent of 9:1.
Reactant is reacted under the conditions of the radiation of visible light of uncovered blowing air 2～7 hours, preferably 2-3 hour,
Room temperature reaction.After reaction terminates, add appropriate ethyl acetate, respectively with water, saturated ammonium chloride washing, remove
Go inorganic base regulation system to subacidity.Organic facies adds a small amount of activated carbon and removes pigment, then through anhydrous sulfur
Acid sodium is dried, and is spin-dried for.Petroleum ether is used to obtain target product [6-isopropyl with dichloromethane mixed solvent recrystallization
Base-4-(4-fluorophenyl)-2-sulfenyl-5-base] formic acid esters.
Laboratory micro prepares post-processing approach: reaction after terminating liquid in reaction bottle poured into one dry
In conical flask, after addition anhydrous sodium sulfate is dried 20 minutes, it is spin-dried for organic solvent and obtains crude product, then carry out
Column chromatography purification, the use petroleum ether to the petroleum ether mixed solvent gradient elution than ethyl acetate 100:1, it is thus achieved that
Colourless oily target product.
Prepare post-processing approach in a large number: add appropriate ethyl acetate, respectively with water, saturated ammonium chloride washing,
Remove inorganic base regulation system to subacidity.Organic facies adds a small amount of activated carbon and removes pigment, then through nothing
Aqueous sodium persulfate is dried, and is spin-dried for.Petroleum ether is used to obtain colorless solid with dichloromethane mixed solvent recrystallization
Target product.
Solvent in described column chromatography procedure is selected from the alkane of C1-C12, the halogenated hydrocarbons of C1-C2, the ester of C2-C4
Or the ether of C2-C6 or cyclo other compounds, the mixed solvent of its any two or more solvent is as pouring
Lotion.
The technology design of the present invention is the acidity of the active hydrogen utilizing the atom N on dihydropyrimidine compound II,
React with the additive basic potassium carbonate in system and generate exposed N anion, reduce dihydropyrimidine compound
Oxidizing potential so that more efficiently carry out photosensitized oxidation aromatisation, it is thus achieved that target product compound III.
The present invention program compared to the prior art advantage is:
1, using the oxygen in air as oxidant in photosensitized oxidation reaction, aboundresources, cheap and convenient easily
, it is to avoid the use of harmful oxidant, more safely and effectively.
2, in photosensitized oxidation reaction, light source is the visible ray that wavelength is more than or equal to 400nm, light source abundance,
The sunlight that even can directly utilize nature replaces light source, beneficially commercial production, reduces cost.
3, the use of non-metal optical catalyst the most a small amount of in photosensitized oxidation reaction, reduces synthesis cost,
Avoid the use of the noble metal photocatalysts such as common Ru and Ir, solve catalyst in prior art and become
Point residual or the loaded down with trivial details problem of last handling process, be greatly improved the quality of product, also reduce medicine cost.
4, photosensitized oxidation reaction adds appropriate alkali, the atom N on recycling dihydropyrimidine compound II
The acidity of active hydrogen reacts, and generates exposed N anion, reduces the oxygen of dihydropyrimidine compound II
Change current potential so that more efficiently carry out photosensitized oxidation aromatisation and obtain target product, improve in reactant
Atom utilization, reduces side reaction so that reaction yield is high, beneficially industrialized production.
5, photosensitized oxidation operation is simple, and reaction condition is gentle, meets the requirement of environmental protection, reacts institute
Taking time short, reaction can be obtained by, through simple post processing, the product that purity is higher, the most instead after terminating
After should terminating, solvent can also recycling further.
Compared to the prior art, production cost is low, react safe efficient and environmental protection for technical solution of the present invention,
Fully demonstrate actual production meaning and the industrial application value of the invention, be particularly suitable for industrialized production
Demand.
Detailed description of the invention
Further describing the present invention below by specific embodiment, the feature of the present invention will be along with describing display
Ground is clearer, but protection scope of the present invention is not limited to this.It should be appreciated by those skilled in the art
It is that, as long as without departing under the spirit of the present invention and example ranges, carry out the ins and outs of the present invention repaiies
Within changing and replacing the technical scope each falling within the present invention.
Unless otherwise defined, skill belonging to the present invention uses all technology and implication and the present invention of scientific terminology
The implication that art field those of ordinary skill is generally understood that is identical.Generally, the present invention use name and following reality
Proved recipe method is all well known in the art or conventional.
The synthesis of embodiment 1:4-methyl-2-(4-fluorobenzylidene)-3-oxopentanoic
In the round-bottomed flask of a 250mL, add suitable agitation magneton, add methyl isobutyrylacetate
(19.23g, 133.4mmol), 4-Fluorobenzaldehyde (12.9g, 106.4mmol), isopropanol 76.0mL, piperidines
720 μ L, acetic acid 420 μ L, reactant mixture is room temperature reaction 22h under condition of nitrogen gas, and reaction is molten after terminating
Being spin-dried under agent decompression, the dichloromethane of residue crude product 50mL dissolves, and uses saturated sodium bicarbonate 100mL
Washing 3 times, anhydrous magnesium sulfate is dried, and removes anhydrous magnesium sulfate and solvent after being dried, it is thus achieved that brownish red oil
Shape thing 4-methyl-2-(4-fluorobenzylidene)-3-oxopentanoic I, yield is 95.4%, direct plunges into
Next step, TLC Rf0.39 (PE/EA=5:1), product is characterized by nuclear-magnetism further1H NMR(400MHz,
CDCl3): 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).
The synthesis of embodiment 2:4-methyl-2-(4-fluorobenzylidene)-3-oxopentanoic acid methyl ester
In the round-bottomed flask of a 250mL, add suitable agitation magneton, add ethyl isobutyryl
(21.10g, 133.4mmol), 4-Fluorobenzaldehyde (20.97g, 172.9mmol), isopropanol 76.0mL, piperazine
Pyridine 720 μ L, acetic acid 420 μ L, reactant mixture then room temperature reaction 22h under condition of nitrogen gas, reaction knot
After bundle, solvent is spin-dried under decompression, and the dichloromethane of remaining crude product 50mL dissolves, and uses unsaturated carbonate hydrogen
Sodium 100mL washes 3 times, and anhydrous magnesium sulfate is dried, and removes anhydrous magnesium sulfate and solvent after being dried, it is thus achieved that
Compound 2-(4-fluorobenzylidene)-3-oxo-4-methylpentanoic acid ethyl ester I as 1:1Z and E mixture,
For light yellow liquid, yield is 83.9%, direct plunges into next step, TLC Rf0.36 (PE/EA=5:1), produces
Thing is characterized by nuclear-magnetism further1H NMR(400MHz,CDCl3):δ7.73(s,1Ha),7.51(s,1
Hb),7.34-7.47(m,4Ha&b),7.02-7.09(m,4Ha&b),4.25-4.35(m,4Ha&b),3.14(m,1
Hb),2.71(m,1Ha),1.25-1.36(m,6Ha&b), 1.17 (d, J=7.2Hz, 6Hb), 1.08 (d, J=7.2
Hz,6Ha)。
The synthesis of embodiment 3:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester
In the round-bottomed flask of a 150mL, add suitable agitation magneton, add compound 4-methyl-2-(4-
Fluorobenzylidene)-3-oxopentanoic 44.68g, sulfidomethyl isourea sulfate 28.24g, the six of 65mL
Methyl phosphoric triamide HMPA, reacts on N2100 DEG C of reaction 22h under the conditions of gas, reaction is down to room after terminating
Temperature, reactant mixture ether extracts three times, and saturated sodium bicarbonate solution is washed and washed, and organic facies is with anhydrous
Sodium sulfate is dried, and solvent low pressure is spin-dried for, it is thus achieved that crude product column chromatography purification (PE → PE/EtOAc=100:1),
Product is lurid semisolid, and yield is 61.4%.
1H NMR(400MHz,CDCl3):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,
CDCl3):δ167.1,161.2,159.9,138.9,128.9,100.1,59.1,52.4,24.4,14.9,13.4
ppm.MS(ESI):calcd for[C16H20FN2O2S]+:323.12,found323.29。
The synthesis of embodiment 4:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylic acid, ethyl ester
In the round-bottomed flask of a 150mL, add suitable agitation magneton, add compound 4-methyl-2-(4-
Fluorobenzylidene) the sulfidomethyl isourea sulfate of-3-oxopentanoic acid methyl ester 44.68g, 28.24g, 65mL's
HMPA HMPA, reacts on N2100 DEG C of reaction 22h under the conditions of gas, reaction is down to after terminating
Room temperature, reactant mixture ether extracts three times, and saturated sodium bicarbonate solution is washed and washed, organic facies nothing
Aqueous sodium persulfate is dried, and solvent low pressure is spin-dried for, it is thus achieved that crude product column chromatography purification (PE → PE/EtOAc=100:1),
Product is lurid grease, and yield is 66.2%.
1H NMR(400MHz,CDCl3): δ 7.26 (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,CDCl3):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[C17H22FN2O2S]+:
337.14,found337.39。
The synthesis of embodiment 5:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-pyrimidine-5-carboxylic acid's methyl ester
Under air conditions, add in the reaction tube of 15mL and suitably stir magneton, 32.3mg (0.10
Mmol) 6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, the four of eosin
N-butyl TBA-eosinY1.2mg (0.1mmol%) and potassium carbonate K2CO327.64mg(0.40
Mmol), being sequentially added into 5.0ml methanol and 0.5ml water, reaction tube is open in air at 3W450nm
Blue led light irradiation under, react 2.5h, after having reacted, reactant mixture is concentrated in vacuo, remaining
Crude product dissolves with a small amount of dichloromethane, and crude product is obtained by column chromatography for separation (PE → PE/EtOAc=30:1)
Obtain aromatization products, the solid 30.4mg of yellow, productivity 95%.
1H NMR(400MHz,CDCl3): δ 7.65 (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.13C
NMR(100MHz,CDCl3): δ 173.2,172.8,168.8,164.0 (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[C16H18FN2O2S]+:321.1073,found321.1066。
The synthesis of embodiment 6:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-pyrimidine-5-carboxylic acid's methyl ester
Under air conditions, add in the reaction tube of 15mL and suitably stir magneton, 32.3mg (0.10mmol)
6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, the tetra-n-butyl ammonium of eosin
Salt TBA-eosinY1.2mg (0.3mmol%) and potassium carbonate K2CO327.64mg (0.20mmol), adds
5.0ml methanol, reaction tube is open in air under the blue led light irradiation of 3W450nm, reacts 2.5h,
After having reacted, reactant mixture is concentrated in vacuo, and remaining crude product dissolves with a small amount of dichloromethane, slightly
Product obtains aromatization products, the solid of yellow by column chromatography for separation (PE → PE/EtOAc=30:1)
28.2mg, productivity 93.8%.
The synthesis of embodiment 7:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-pyrimidine-5-carboxylic acid's methyl ester
Under air conditions, add in the reaction tube of 15mL and suitably stir magneton, 32.3mg (0.10mmol)
6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, the tetra-n-butyl ammonium of eosin
Salt TBA-eosinY1.2mg (0.1mmol%) and sodium carbonate Na2CO310.6mg (0.10mmol), then
Adding 5.0mL methanol, reaction tube is open in air under the blue led light irradiation of 3W450nm,
Reaction 2.5h, after having reacted, reactant mixture is concentrated in vacuo, and remaining crude product is with a small amount of dichloromethane
Dissolving, crude product obtains aromatization products by column chromatography for separation (PE → PE/EtOAc=30:1), yellow
Solid 22.70mg, productivity 92%.
The synthesis of embodiment 8:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-pyrimidine-5-carboxylic acid's methyl ester
Under air conditions, add in the reaction tube of 15mL and suitably stir magneton, 32.3mg (0.10mmol)
6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, the tetra-n-butyl ammonium of eosin
Salt TBA-eosinY1.2mg (0.1mmol%), is subsequently adding 5.0mL benzotrifluoride, and reaction tube is open to
In air under the blue led light irradiation of 3W450nm, react 2.5h, after having reacted, reaction mixing
Thing is concentrated in vacuo, and remaining crude product dissolves with a small amount of dichloromethane, and crude product passes through column chromatography for separation
(PE → PE/EtOAc=30:1) obtains aromatization products, the solid 26.50mg of yellow, productivity 85.7%.
The synthesis of embodiment 9:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-pyrimidine-5-carboxylic acid's methyl ester
Under air conditions, add in the reaction tube of 15mL and suitably stir magneton, 32.3mg (0.10mmol)
6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, the tetra-n-butyl ammonium of eosin
Salt TBA-eosinY1.2mg (0.1mmol%) and potassium acetate 19.6mg (0.20mmol), is subsequently adding 5.0
ML dichloromethane, reaction tube is open in air under the blue led light irradiation of 3W450nm, reaction
2.5h, after having reacted, reactant mixture is concentrated in vacuo, and remaining crude product is molten with a small amount of dichloromethane
Solving, crude product obtains aromatization products, consolidating of yellow by column chromatography for separation (PE → PE/EtOAc=30:1)
Body 29.50mg, productivity 94.1%.
The synthesis of embodiment 10:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-pyrimidine-5-carboxylic acid's methyl ester
Under air conditions, add in the reaction tube of 15mL and suitably stir magneton, 32.3mg (0.10mmol)
6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, the tetra-n-butyl ammonium of eosin
Salt TBA-eosinY1.2mg (0.1mmol%) and disodium hydrogen phosphate 17.9mg (0.05mmol), then adds
Entering 5.0mL acetonitrile, reaction tube is open in air under the blue led light irradiation of 3W450nm, instead
Answering 2.5h, after having reacted, reactant mixture is concentrated in vacuo, and remaining crude product is with a small amount of dichloromethane
Dissolving, crude product obtains aromatization products by column chromatography for separation (PE → PE/EtOAc=30:1), yellow
Solid 16.70mg, productivity 94.6%.
The synthesis of embodiment 11:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-pyrimidine-5-carboxylic acid's methyl ester
Under air conditions, add in the reaction tube of 15mL and suitably stir magneton, 32.3mg (0.10
Mmol) 6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, the four of eosin
N-butyl TBA-eosinY1.2mg (0.1mmol%) and carbon tetrabromide 19.4 μ L (0.20mmol),
It is subsequently adding 5.0mL methanol, clogs with turned welt plug, with needle tubing by Bubbling method deoxygenation 30min.Then wax
Envelope reaction tube, is placed under the blue led light photograph of 3W450nm, reacts 2.5h.After having reacted,
Reactant mixture is concentrated in vacuo, and remaining crude product dissolves with a small amount of dichloromethane, and crude product passes through post layer
Analysis separates (PE → PE/EtOAc=30:1) and obtains aromatization products, the solid 22.72mg of yellow, productivity
81%.
The synthesis of embodiment 12:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-pyrimidine-5-carboxylic acid's methyl ester
Under air conditions, add in the reaction tube of 15mL and suitably stir magneton, 32.3mg (0.10
Mmol) 6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylate methyl ester, the four of eosin
N-butyl TBA-eosinY1.2mg (0.1mmol%) and bromo chloroform 19.7 μ L (0.20mmol),
It is subsequently adding 5.0mL methanol, clogs with turned welt plug, with needle tubing by Bubbling method deoxygenation 30min.Then wax
Envelope reaction tube, is placed under the blue led light photograph of 3W450nm, reacts 2.5h.After having reacted,
Reactant mixture is concentrated in vacuo, and remaining crude product dissolves with a small amount of dichloromethane, and crude product passes through post layer
Analysis separates (PE → PE/EtOAc=30:1) and obtains aromatization products, the solid 22.68mg of yellow, productivity
84.2%.
The synthesis of embodiment 13:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-pyrimidine-5-carboxylic acid's methyl ester
Gram pilot test: under air conditions, add suitable magnetic stirring bar in the round-bottomed flask of 500mL,
1.932g (6.0mmol) 6-isopropyl-2-sulfidomethyl-4-(4-fluorophenyl)-1,4-dihydro-pyrimidin-5-carboxylate methyl ester,
Tetra-n-butyl ammonium salt TBA-eosinY67.8mg (0.1mmol%) of eosin and potassium hydroxide 0.672g (12
Mmol), being then sequentially added into 300mL methanol and 30mL water, round-bottomed flask is open in air be exposed to
Under extraneous sunlight, reacting 7h, after having reacted, reactant mixture is dried by anhydrous sodium sulfate,
Decompression distillation for removing methanol, adds appropriate ethyl acetate, respectively with water, saturated ammonium chloride washing, removes
Inorganic base regulation system are to subacidity.Organic facies adds a small amount of activated carbon and removes pigment, then through anhydrous sulfur
Acid sodium is dried, and is spin-dried for.Remaining crude product petroleum ether/dichloromethane (50:1) recrystallization obtains the crystalline substance of yellow
Shape solid 1.632g, productivity 95%.
The synthesis of embodiment 14:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-pyrimidine-5-carboxylic acid's ethyl ester
Under air conditions, add in the reaction tube of 15mL and suitably stir magneton, 33.6mg (0.10mmol)
6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylic acid, ethyl ester, the tetra-n-butyl ammonium of eosin
Salt TBA-eosinY1.2mg (0.1mmol%) and sodium hydroxide 0.26mg (0.40mmol), the most successively
Adding 5.0ml methanol and 0.5ml water, reaction tube is open in air the blue led lamp at 3W450nm
Under irradiation, reacting 2h, after having reacted, reactant mixture is concentrated in vacuo, and remaining crude product is with a small amount of
Dichloromethane dissolves, and crude product obtains aromatization products by column chromatography for separation (PE → PE/EtOAc=30:1),
The solid 32.4mg of white, productivity 97%.
1H NMR(400MHz,CDCl3):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,CDCl3):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 C17H20FN2O2S
[M+H]+m/z335.1230,found335.1224。
The synthesis of embodiment 15:6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-pyrimidine-5-carboxylic acid's ethyl ester
Gram pilot test: under air conditions, add suitable magnetic stirring bar in the round-bottomed flask of 500mL,
2.016g (6.0mmol) 6-isopropyl-4-(4-fluorophenyl)-2-sulfidomethyl-1,4-dihydro-pyrimidin-5-carboxylic acid, ethyl ester,
Tetra-n-butyl ammonium salt TBA-eosinY67.8mg (0.1mmol%) of eosin and potassium carbonate K2CO31.658g
(12mmol) adding in reaction tube, then 300mL methanol and 30mL water are sequentially added into, round-bottomed flask
It is open in air be exposed under extraneous sunlight, reacts 6h.After having reacted, reactant mixture leads to
Crossing anhydrous sodium sulfate dried, reduce pressure distillation for removing methanol, adds appropriate ethyl acetate, respectively with water,
Saturated ammonium chloride washs, and removes inorganic base regulation system to subacidity.Organic facies adds a small amount of activated carbon and removes
Remove pigment, then be dried through anhydrous sodium sulfate, be spin-dried for.Remaining crude product petroleum ether/dichloromethane (50:1)
Recrystallization obtains crystalline solid 1.7g of white, productivity 96.2%.
Claims (11)
1. the method preparing [6-isopropyl-4-(4-fluorophenyl)-2-sulfenyl-5-base] formic acid esters, its feature exists
In being that raw material reacts with 4-Fluorobenzaldehyde, isobutyryl acetas and sulfenyl substituted isourea sulfate,
Preparing through photosensitized oxidation reaction, reactions steps is as follows again:
Wherein R1 is selected from alkyl or the aryl of C6-C12 of C1-C6；R2 selected from C1-C6 alkyl or
The aryl of C6-C12；
In described photosensitized oxidation reaction, oxidant used is the oxygen in air；
The described light source employed in photosensitized oxidation reaction is that wavelength is more than or equal to the visible of 400nm
Light；
The described tetra-n-butyl ammonium salt that catalyst is eosin used in photosensitized oxidation reaction.
2. the method for claim 1, it is characterised in that employed in described photosensitized oxidation reaction
Light source is the visible ray of wavelength 400nm-550nm.
3. the method for claim 1, it is characterised in that employed in described photosensitized oxidation reaction
Light source is the various monochromes of normal domestic use electric filament lamp, electricity-saving lamp, white LED lamp, 400nm-550nm
LED or more than the high voltage mercury lamp of 400nm filtering apparatus, xenon lamp.
4. the method for claim 1, it is characterised in that add alkali in described photosensitivity reaction, described
Alkali be organic base or inorganic base.
5. method as claimed in claim 4, it is characterised in that the alkali added in described photosensitivity reaction is carbon
Acid potassium, sodium carbonate, potassium acetate, disodium hydrogen phosphate, potassium hydroxide or sodium hydroxide.
6. the method as described in claim 4 or 5, it is characterised in that chemical combination in described photosensitized oxidation reaction
The usage amount mol ratio of thing II, catalyst and alkali is 1:0.01-0.03:0-4.
7. the method for claim 1, it is characterised in that used molten in described photosensitized oxidation reaction
Agent is organic solvent or organic solvent and the mixed solvent of water.
8. method as claimed in claim 7, it is characterised in that used molten in described photosensitized oxidation reaction
Agent is Methanol+Water.
Method the most according to claim 1, it is characterised in that 4-Fluorobenzaldehyde in described condensation reaction
It is 1:0.8-1.3 with the mol ratio of isobutyryl acetas usage amount.
Method the most according to claim 9, it is characterised in that the reaction temperature of described condensation reaction
For room temperature, the response time is 20-26 hour.
11. methods according to claim 1, it is characterised in that the reaction dissolvent of described cyclization
For HMPA, the response time of reaction is 19-24 hour, and the reaction temperature of reaction is
70-140℃。
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