CN114874061B - Preparation method of prasugrel intermediate and analogues thereof - Google Patents

Preparation method of prasugrel intermediate and analogues thereof Download PDF

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CN114874061B
CN114874061B CN202210494537.2A CN202210494537A CN114874061B CN 114874061 B CN114874061 B CN 114874061B CN 202210494537 A CN202210494537 A CN 202210494537A CN 114874061 B CN114874061 B CN 114874061B
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prasugrel
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CN114874061A (en
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张卫东
王金鑫
张宇
田赛赛
柳润辉
李秋豪
解世泽
吕帅澎
桑冀威
夏丁丁
李艳川
韩心雨
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Second Military Medical University SMMU
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Abstract

The invention discloses a preparation method of prasugrel intermediate and analogues thereof, which comprises the following steps:

Description

Preparation method of prasugrel intermediate and analogues thereof
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a prasugrel intermediate and an analogue thereof.
Background
Prasugrel is a platelet adenosine diphosphate receptor inhibitor, a novel drug which is jointly developed by Sankyo corporation and Gift corporation in Japan, is a prodrug which is not active per se, and is effectively converted into an active metabolite thereof in vivo for treating thrombus, thereby having good anticoagulation effect and good bioavailability. The specific structure is as follows:
a compound shown in the formula I, prasugrel, has the chemical name of 2-acetoxyl-5- (alpha-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine.
The currently disclosed prasugrel synthesis method mainly comprises the following steps:
in the patent application publication No. CN981092209, a synthetic process is disclosed, starting from a compound of formula (II), which is brominated and then reacted with 4,5,6,7 a-tetrahydrothieno [3,2-c ] pyridin-2-one hydrochloride to give 5- (. Alpha. -cyclopropylcarbonyl-2-fluorobenzyl) -2-carbonyl-4, 5,6,7 a-tetrahydrothieno [3,2-c ] pyridine, followed by acetic anhydride in the presence of sodium hydrogen and DMF to give prasugrel (I). The method is characterized in that thiophene ketone is directly condensed with halohydrocarbon during butt joint, and has the defects that ketone carbonyl on the thiophene ketone has hydroxyketone interconversion, ether compounds can be formed during condensation, the selectivity is poor, column chromatography purification is required for post-treatment, and more dangerous sodium hydrogen is required to be used during acetylation. The method has the disadvantages of high cost, complex operation and inapplicability to industrial production.
Also disclosed in the patent application publication No. US5874581 is a synthetic process starting from a compound of formula (II), which is chlorinated and then reacted with 2-tert-butyldimethylsilyloxy-4, 5,6,7 a-tetrahydrothieno [3,2-c ] pyridine to give 2-tert-butyldimethylsilyloxy-5- (. Alpha. -cyclopropylcarbonyl-2-fluorobenzyl) -2-carbonyl-4, 5,6,7 a-tetrahydrothieno [3,2-c ] pyridine, followed by acetic anhydride in the presence of 4-dimethylaminopyridine and triethylamine to give prasugrel (I). The method can protect the ketocarbonyl of the thiophene ketone, improve the selectivity of the condensation reaction, prolong the reaction step, increase the equipment cost and reduce the yield.
As can be seen from these processes, the compound of formula (II) is a key intermediate for the synthesis of prasugrel, and the current methods for synthesizing the compound of formula (II) mainly include:
patent application publication No. US5288726 discloses the Grignard reaction of o-fluorobenzyl bromide as a starting material with cyclopropanecarbonitrile to give a compound of formula (II). The process requires strict anhydrous conditions, and simultaneously uses anhydrous diethyl ether as a solvent, so that the diethyl ether has low boiling point, is easy to volatilize, has increased risk, has more strict reaction conditions, has low yield, and is not beneficial to industrial production.
Patent application publication number WO2011042918A2 discloses that 2- (2-fluorophenyl) acetic acid is used as a raw material, DCC is used as an activator, weinreb amide is obtained through amidation, and the Weinreb amide is reacted with cyclohexane grignard reagent to obtain a compound shown in formula (II). The method requires strict anhydrous conditions, the obtained product is complex, the post-treatment is difficult, the reaction conditions are more severe, the yield is low, and the method is not beneficial to industrial production.
In the patent application with publication No. CN104418718A, 2-fluorophenylacetate is used as a starting material, and is subjected to acylation reaction with cyclopropanecarbonyl chloride to prepare the compound shown in the formula (II) through hydrolysis. The method needs a large amount of carbon disulfide, has strong malodor smell, and is not beneficial to industrial production; the acyl chloride needs to be prepared in advance, and the operation procedure is increased.
Patent application publication No. CN104418718A discloses that fluorobenzene is used as a starting material, stannic chloride is used as a Lewis acid catalyst, and the fluorobenzene is reacted with 1-bromo-3-alkene-butan-2-one to obtain 1- (2-fluorophenyl) -3-alkene-butan-2-one, and then reacted with thioylide reagent dimethyl methylene sulfide or dimethyl methylene oxysulfide to prepare cyclopropane, so that a compound shown in a formula (II) is obtained. The method needs to prepare the reagent, increases operation steps, and reduces production efficiency; the Lewis acid stannic chloride which is easy to absorb water is needed to be used, so that the tin tetrachloride has strong corrosiveness and increases the danger of industrial production.
In view of the good market value of prasugrel, there is still a need for a method for preparing prasugrel intermediates with simple process, mild conditions and high yield.
Disclosure of Invention
The invention aims to provide a safe, green and efficient preparation method of prasugrel intermediate and analogues thereof.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the first aspect of the invention provides a preparation method of prasugrel intermediate and analogues thereof, which comprises the following steps:
dissolving a ligand and a transition metal catalyst in a solvent, uniformly mixing by ultrasonic, adding a compound II, a compound III, alkali and a photocatalyst, filling argon for protection at room temperature, and carrying out illumination reaction to obtain a prasugrel intermediate shown in a formula I and an analogue thereof;
the molar ratio of the ligand, the transition metal catalyst, the compound II, the alkali, the photocatalyst and the compound III is (0.05-0.2): (0.2-5.0): (1.0-5.0): (0.01-0.1): 1; preferably 0.067:0.067:0.67:2:0.013:1.
In the compound III, R 1 Selected from C1-C20 straight chain alkyl, C1-C20 branched alkyl, phenyl and C3-C6 cycloalkyl;
in the compound II, X is selected from chlorine and bromine;
R 2 selected from fluorine, hydrogen, C1-C20 linear alkyl, C1-C20 branched alkyl, C1-C20 linear alkoxy, C1-C20 branched alkoxy;
R 3 selected from fluorine, hydrogen, C1-C20 linear alkyl, C1-C20 branched alkyl, C1-C20 linear alkoxy, C1-C20 branched alkoxy and nitro;
R 4 selected from fluorine, hydrogen, C1-C20 linear alkyl, C1-C20 branched alkyl, C1-C20 linear alkoxy, C1-C20 branched alkoxy and nitro;
R 5 selected from fluorine, hydrogen, C1-C20 linear alkyl, C1-C20 branched alkyl, C1-C20 linear alkoxy, C1-C20 branched alkoxy and nitro;
R 6 selected from fluorine, hydrogen, C1-C20 straight chain alkyl, C1-C20 branched chain alkyl, C1-C20 straight chain alkoxy, C1-C20 branched chain alkoxy and nitro.
More preferably, in said compound III, R 1 Selected from-CH (CH) 3 ) 2 Phenyl, cyclopropane, CH 3 CH 2 -, a part of a cyclopentylalkyl group.
More preferably, in said compound II, X is selected from bromine;
R 2 selected from fluorine, hydrogen, methyl, methoxy, ethyl, ethoxy;
R 3 selected from fluorine, hydrogen, methyl, methoxy, ethyl, ethoxy, nitro;
R 4 selected from fluorine, hydrogen, methyl, methoxy, ethyl, ethoxy, nitro;
R 5 selected from fluorine, hydrogen, methyl, methoxy, ethyl, ethoxy, nitro;
R 6 selected from fluorine, hydrogen, methyl, methoxy, ethyl, ethoxy, and nitro.
Most preferably, the compound III is selected from one of the following compounds:
most preferably, the compound II is selected from one of the following compounds:
the ligand is selected from (1R, 2R) -N, N '-dimethyl-1, 2-diphenyl-1, 2-diethylamine, 2' -biquinoline, bis ((3 aS,8 aR) -8,8 a-dihydro-3 aH-indeno [1,2-d ] oxazol-2-yl) methane, (S) -4- (tert-butyl) -2- (isoquinolin-1-yl) -4, 5-dihydro-oxazol,
R 11 、R 12 、R 13 、R 14 、R 15 And R is 16 Each independently selected from t-butyl, trifluoromethyl, methoxy, methyl, carboxyl (COOH), ester (COOCH) 3 ) Cyano, benzyl, phenyl, isopropyl, cl, H; 4,4 '-di-tert-butyl-2, 2' -bipyridine is preferred.
The transition metal catalyst is selected from nickel bromide, nickel bromide hexahydrate, nickel bromide ethylene glycol dimethyl ether complex, nickel bromide diethylene glycol dimethyl ether complex, nickel chloride ethylene glycol dimethyl ether complex, nickel diacetone, nickel iodide; nickel bromide ethylene glycol dimethyl ether complex is preferred.
The solvent is selected from acetone, acetonitrile, dichloromethane, water, dichloroethane, nitromethane, dimethyl sulfoxide, preferably acetone.
The base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; sodium carbonate is preferred.
The photocatalyst is selected from tetrabutylammonium decatungstate and sodium decatungstate; tetrabutylammonium decatungstate is preferred.
The wavelength range of the photoreaction is 365 to 415 nm, preferably 390 nm.
The time of the light reaction is 1 to 24 hours, preferably 3 hours; the temperature is less than 40 ℃, preferably 35 ℃.
By adopting the technical scheme, the invention has the following advantages and beneficial effects:
compared with comparative example 1, the preparation method of prasugrel intermediate and analogues thereof greatly improves the yield from 51% to 96%; the method is characterized in that the method comprises the steps of preparing weinreb amide, neopentyl borate substrate and Grignard reagent from 2 steps, and shortening the reaction to 1 step by using ready-made aldehyde and halide to directly obtain the product; the reaction time is reduced from tens of hours to 3 hours, and the production efficiency is greatly improved; the used substrate is cheap and easy to obtain (cyclopropylaldehyde is 5.60/g; 1-bromomethyl-2-fluorobenzene is 1.20/g;3- (methoxy (methyl) amino) -3-oxo propionic acid is 3635/g), so that the production cost is reduced; the synthesis raw materials mainly comprise benzyl halide and aldehyde, and the irritation is small. The invention synthesizes the prasugrel intermediate and the analogues thereof by utilizing the photocatalytic coupling reaction at normal temperature and normal pressure, does not need to heat and use a Grignard reagent, has simple synthesis process, is easy to operate, obviously improves the synthesis yield, generates inorganic salt except the product after the reaction, has little environmental pollution and is environment-friendly. The invention can ensure that the quality of the whole product is further improved, ensure that the life of people is further improved, and has wide application prospect and market demand.
Detailed Description
In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and that this invention is not limited to the details given herein.
Example 1
A magnetic stirrer was placed in a dry reaction flask, and argon was used to protect the flask, 4 '-di-tert-butyl-2, 2' -bipyridine (0.002 mol,0.54 g), nickel bromide ethylene glycol dimethyl ether complex (0.002 mol,0.62 g) and 100mL of acetone were added to dissolve the complex, and after stirring until the solution became homogeneous, sodium carbonate (0.06 mol,6.36 g), tetrabutylammonium decatungstate (0.0004 mol,1.328 g), 1-bromomethyl-2-fluorobenzene (0.02 mol,3.76 g) and cyclopropylaldehyde (0.03 mol,2.10 g) were added to the flask in this order, followed by argon. After sealing, the reaction flask is irradiated under 390 nm light source, the light source is separated from the reaction flask by about 6 cm, the temperature is reduced by a fan, the temperature is controlled to be 35 ℃, 100mL of acetone is added for dilution after 3 hours, the concentration is reduced, and the prasugrel intermediate in the formula I is obtained by directly separating and purifying through column chromatography (n-hexane: ethyl acetate=19:1).
The nuclear magnetic pattern data are: 1 H NMR(500MHz,CDCl 3 ):δ7.11-7.32(m,4H),3.87(s,2H),1.92-2.06(m,1H),1.03-1.17(m,2H),0.82-0.98(m,2H)； 13 C NMR(126MHz,CDCl 3 ):δ206.9,161.0,131.6,128.8,124.1,121.8,115.3,43.5,20.0,11.2.HRMS(m/z):[M+H] + calcd for C 11 H 12 FO + 179.0794,found 179.0796.
example 2
A magnetic stirrer was placed in a dry reaction flask, and argon was used to protect the flask, 4 '-di-tert-butyl-2, 2' -bipyridine (0.01 mmol,2.7 mg), nickel bromide ethylene glycol dimethyl ether complex (0.01 mmol,3.1 mg) and 2.0mL of acetone were added to dissolve the complex, and after stirring the solution until it became homogeneous, sodium carbonate (0.30 mmol,31.8 mg), tetrabutylammonium decatungstate (0.002 mmol,6.6 mg), 1-bromomethyl-2-fluorobenzene (0.10 mmol,18.8 mg) and benzaldehyde (0.15 mmol,15.9 mg) were added to the flask in this order, and argon was used to protect the flask. After sealing, the mixture was irradiated with light under 390 nm light source, the distance between the light source and the reaction flask was about 6 cm, the temperature was lowered by a fan, the temperature was controlled at 35 ℃, 2.0mL of acetone was added after 3 hours for dilution, and the mixture was concentrated under reduced pressure, and the mixture was directly separated and purified by column chromatography (n-hexane: ethyl acetate=19:1), to obtain 19.9 mg of the product.
The nuclear magnetic pattern data are: 1 H NMR(500MHz,CDCl 3 ):δ8.06–8.03(m,2H),7.61–7.56(m,1H),7.50–7.45(m,2H),7.31–7.22(m,2H),7.13–7.07(m,2H),4.32(s,2H)； 13 C NMR(126MHz,CDCl 3 ):δ196.4,161.0,136.6,133.5,131.9,129.0,128.7,124.2,122.2,121.8,115.6,38.9.HRMS(m/z):[M+Na] + calcd for C 14 H 11 FONa + 237.0686,found 237.0682.
example 3
A magnetic stirrer was placed in a dry reaction flask, and argon was used to protect the flask, 4 '-di-tert-butyl-2, 2' -bipyridine (0.01 mmol,2.7 mg), nickel bromide ethylene glycol dimethyl ether complex (0.01 mmol,3.1 mg) and 2.0mL of acetone were added to dissolve the complex, and after stirring the solution until it became homogeneous, sodium carbonate (0.30 mmol,31.8 mg), tetrabutylammonium decatungstate (0.002 mmol,6.6 mg), 1-bromomethyl-2-methylbenzene (0.10 mmol,18.4 mg) and benzaldehyde (0.15 mmol,15.9 mg) were added to the flask in this order, and argon was used to protect the flask. After sealing, the mixture was irradiated with light under 390 nm light source, the light source was separated from the reaction flask by about 6 cm, the temperature was lowered by a fan, the temperature was controlled at 35 ℃, 2.0mL of acetone was added after 3 hours for dilution, and the mixture was concentrated under reduced pressure, and the mixture was directly separated and purified by column chromatography (n-hexane: ethyl acetate=19:1), to obtain 20.0 mg of the product.
The nuclear magnetic pattern data are: 1 H NMR(500MHz,CDCl 3 ):δ8.01(d,J＝8.0Hz,2H),7.54(t,J＝8.0Hz,1H),7.45((t,J＝8.0Hz,2H),7.18–7.09(m,4H),4.26(s,2H),2.23(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ197.4,136.8,133.5,133.2,130.3,130.4,128.6,128.4,127.3,126.2,77.6,77.2,76.8,43.5,19.9.HRMS(m/z):[M+Na] + calcd for C 15 H 14 ONa + 233.0937,found 233.0935.
example 4
A magnetic stirrer was placed in a dry reaction flask, and argon was used to protect the flask, 4 '-di-tert-butyl-2, 2' -bipyridine (0.01 mmol,2.7 mg), nickel bromide ethylene glycol dimethyl ether complex (0.01 mmol,3.1 mg) and 2.0mL of acetone were added to dissolve the complex, and after stirring the solution until it became homogeneous, sodium carbonate (0.30 mmol,31.8 mg), tetrabutylammonium decatungstate (0.002 mmol,6.6 mg), 2-bromomethyl-1-fluoro-4-nitrobenzene (0.10 mmol,23.3 mg) and isobutyraldehyde (0.15 mmol,10.8 mg) were added to the flask in this order, followed by argon. After sealing, the mixture was irradiated with light under 390 nm light source, the distance between the light source and the reaction flask was about 6 cm, the temperature was lowered by a fan, the temperature was controlled at 35 ℃, 2.0mL of acetone was added after 3 hours for dilution, and the mixture was concentrated under reduced pressure, and the mixture was directly separated and purified by column chromatography (n-hexane: ethyl acetate=19:1), to obtain 19.4 mg of the product.
Nuclear magnetic pattern dataThe method comprises the following steps: 1 H NMR(500MHz,CDCl 3 ):δ8.18(ddd,J＝8.8,4.5,2.9,1H),8.12(dd,J＝6.2,2.9,1H),7.20(t,J＝8.8,1H),3.90(s,2H),2.79(m,1H),1.20(d,J＝6.8,6H)； 13 C NMR(126MHz,CDCl 3 ):δ208.8,164.5,144.3,127.8,124.8,123.8,116.1,41.0,40.1,18.2.HRMS(m/z):[M+H] + calcd for C 11 H 13 FNO 3 + 226.0801,found 226.0804.
example 5
A magnetic stirrer was placed in a dry reaction flask, and argon was used to protect the flask, 4 '-di-tert-butyl-2, 2' -bipyridine (0.01 mmol,2.7 mg), nickel bromide ethylene glycol dimethyl ether complex (0.01 mmol,3.1 mg) and 2.0mL of acetone were added to dissolve the complex, and after stirring the solution until it became homogeneous, sodium carbonate (0.30 mmol,31.8 mg), tetrabutylammonium decatungstate (0.002 mmol,6.6 mg), 1-bromomethyl-2-methoxybenzene (0.10 mmol,20.0 mg) and cyclopropylaldehyde (0.15 mmol,10.5 mg) were added to the flask in this order, followed by argon. After sealing, the mixture was irradiated with light under 390 nm light source, the distance between the light source and the reaction flask was about 6 cm, the temperature was lowered by a fan, the temperature was controlled at 35 ℃, 2.0mL of acetone was added after 3 hours for dilution, and the mixture was concentrated under reduced pressure, and the mixture was directly separated and purified by column chromatography (n-hexane: ethyl acetate=9:1), to obtain 15.6 mg of the product.
The nuclear magnetic pattern data are: 1 H NMR(500MHz,CDCl 3 ):δ7.29-7.21(m,1H),7.18-7.13(m,1H),6.96-6.85(m,2H),3.80(s,3H),3.79(s,2H),2.00-1.90(m,1H),1.06-0.99(m,2H),0.84-0.76(m,2H)； 13 C NMR(126MHz,CDCl 3 ):δ208.7,157.5,131.1,128.3,123.7,120.6,110.5,55.3,45.0,19.6,10.8.HRMS(m/z):[M+Na] + calcd for C 12 H 15 O 2 + 191.0994,found 191.0991.
comparative example 1
Copper trifluoromethane sulfonate (54.3 mg, 0.150mmol,0.300 eq.) 2-fluorophenyl neopentyl borate (312 mg, 1.50mmol,3.00 eq.) 1.25mL N, N-dimethylaniline, 3- (methoxy (methyl) amino) -3-oxopropionic acid (73.6 mg, 0.500mmol,1.00 eq.) was added to the reaction flask, after mixing and stirring for 10 minutes, 0.42mL triethylamine was added, after 80 hours, aqueous ammonium chloride and ethyl acetate were added to dilute, the organic phases were combined, washed with aqueous potassium hydroxide and saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography (n-hexane/ethyl acetate=3:2) to give weinreb amide (64.1 mg, 65%).
A tetrahydrofuran solution of cyclopropylmagnesium bromide (1.37 mL,0.365M,2.2 eq.) was added to the sealed flask under nitrogen, weinreb amide (46.0 mg, 0.23mmol,1.0 eq.) was dissolved in tetrahydrofuran (0.17 mL), and the flask was heated at 45℃for 1 hour. After cooling to 0deg.C, it was quenched with 1M HCl solution (1.0 mL), added water (5 mL), and extracted with ethyl acetate (3X 10 mL). The organic layer was washed with brine (5 mL) and water (5 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo. The mixture was purified by column chromatography (hexane/ethyl acetate=10:1) to give the compound of formula II (31.9 mg, 78%) as a pale yellow oil.
TABLE 1
Step (a) Yield%
Example 1 1 96
Example 2 1 93
Example 3 1 95
Example 4 1 86
Example 5 1 82
Comparative example 1 2 51
Compared with comparative example 1, the yield is greatly improved from 51% to 96%; the method is characterized in that the method comprises the steps of preparing weinreb amide, neopentyl borate substrate and Grignard reagent from 2 steps, and shortening the reaction to 1 step by using ready-made aldehyde and halide to directly obtain the product; the reaction time is reduced from tens of hours to 3 hours, and the production efficiency is greatly improved; the used substrate is cheap and easy to obtain (cyclopropylaldehyde: 5.60/g; 1-bromomethyl-2-fluorobenzene: 1.20/g;3- (methoxy (methyl) amino) -3-oxopropionic acid: 3635/g), so that the production cost is reduced.
Example 6
Screening of the photocatalyst:
in a 4 ml dry reaction flask, 4 '-di-tert-butyl-2, 2' -bipyridine (10. Mu. Mol,2.7 mg, 0.1 eq), nickel bromide ethylene glycol dimethyl ether complex (10. Mu. Mol,3.1 mg, 0.1 eq), 2.0ml acetone (0.05M) were added, and the solution was dissolved by sonication until it became homogeneous, followed by sodium carbonate (0.30 mmol,31.8 mg, 3.0 eq), photocatalyst (1.0 to 5.0. Mu. Mol,0.01 to 0.05 eq), 1-bromomethyl-2-fluorobenzene (0.10 mmol,18.8 mg, 1.0 eq), and cyclopropylaldehyde (0.15 mmol,10.5 mg, 1.5 eq) in that order. Under the protection of argon at room temperature, 390 nm light source is illuminated, the temperature is reduced by a fan (the control temperature is lower than 40 ℃ and is about 35 ℃), and the reaction is carried out for 3 hours.
The photocatalyst screening is shown in table 2:
TABLE 2
Tetrabutylammonium decatungstate and sodium decatungstate were used as photocatalysts, respectively, and the same reaction was catalyzed at the same amount (2.0. Mu. Mol,0.02 eq.) with the best yield (96%) of tetrabutylammonium decatungstate. Both decreasing and increasing the amount of tetrabutylammonium decatungstate resulted in a decrease in yield (1.0. Mu. Mol,0.01 eq., 73%; 5.0. Mu. Mol,0.05 eq., 83%). The most preferred conditions are tetrabutylammonium decatungstate (2.0. Mu. Mol,0.02 eq.).
Example 7
Screening of transition metal nickel catalyst:
in a 4 ml dry reaction flask, 4 '-di-tert-butyl-2, 2' -bipyridine (10. Mu. Mol,2.7 mg), transition metal nickel catalyst (10. Mu. Mol), 2.0ml acetone (0.05M) were added and sonicated until the solution was homogeneous, followed by sodium carbonate (0.30 mmol,31.8 mg), tetrabutylammonium decatungstate (2.0. Mu. Mol,6.6 mg), 1-bromomethyl-2-fluorobenzene (0.10 mmol,18.8 mg, 1.0 eq), cyclopropylaldehyde (0.15 mmol,10.5 mg, 1.5 eq) were added in this order. Under the protection of argon at room temperature, 390 nm light source is illuminated, the temperature is reduced by a fan (the control temperature is lower than 40 ℃ and is about 35 ℃), and the reaction is carried out for 3 hours.
The screening of the transition metal nickel catalyst is shown in table 3:
TABLE 3 Table 3
Transition metal nickel catalysts Dosage of Yield%
Nickel bromide 10μmol 84
Nickel bromide hexahydrate 10μmol 91
Nickel bromide ethylene glycol dimethyl ether complex 10μmol 96
Nickel bromide diethylene glycol dimethyl ether compound 10μmol 92
Nickel chloride 10μmol 84
Nickel chloride glycol dimethyl ether complex 10μmol 91
Nickel diacetylacetonate 10μmol 32
Nickel iodide 10μmol 27
The same reaction was catalyzed with the same amount (10. Mu. Mol) using each of the various transition metal nickel catalysts, with the best yield (96%) of nickel bromide ethylene glycol dimethyl ether complex, other nickel bromide, nickel chloride catalysts could be used, and the yield of nickel iodide was poor. The most preferred is nickel bromide ethylene glycol dimethyl ether complex (10. Mu. Mol).
Example 8
Screening of ligands:
in a 4 ml dry reaction flask, ligand (10. Mu. Mol), nickel bromide ethylene glycol dimethyl ether complex (10. Mu. Mol,3.1 mg) and 2.0ml acetone (0.05M) were added, sonicated until the solution was homogeneous, followed by sodium carbonate (0.30 mmol,31.8 mg), tetrabutylammonium decatungstate (2.0. Mu. Mol,6.6 mg), 1-bromomethyl-2-fluorobenzene (0.10 mmol,18.8 mg, 1.0 eq), cyclopropylaldehyde (0.15 mmol,10.5 mg, 1.5 eq) were added in this order. Under the protection of argon at room temperature, 390 nm light source is illuminated, the temperature is reduced by a fan (the control temperature is lower than 40 ℃ and is about 35 ℃), and the reaction is carried out for 3 hours.
Ligand screening is shown in table 4:
TABLE 4 Table 4
Ligand Dosage of Yield%
2,2' -biquinoline 10μmol 71
4,4 '-Di-tert-butyl-2, 2' -bipyridine 10μmol 96
4,4 '-bis (trifluoromethyl) -2,2' -bipyridine 10μmol 72
4,4 '-dimethoxy-2, 2' -bipyridine 10μmol 53
2,2' -bipyridines 10μmol 73
5,5 '-dimethyl-2, 2' -bipyridine 10μmol 69
6,6 '-dicyano-2, 2' -bipyridine 10μmol 58
2, 2-bis (2-oxazoline) 10μmol 62
The same reaction was catalyzed with the same amount (10. Mu. Mol) using each ligand, and the best yield (96%) of 4,4 '-di-tert-butyl-2, 2' -bipyridine was obtained, and other catalysts such as biquinoline, bipyridine, bisoxazole were used in relatively low yields. The most preferred conditions are 4,4 '-di-tert-butyl-2, 2' -bipyridine (10. Mu. Mol).
Example 9
Screening of alkali:
in a 4 ml dry reaction flask, 4 '-di-tert-butyl-2, 2' -bipyridine (10. Mu. Mol,2.7 mg), nickel bromide ethylene glycol dimethyl ether complex (10. Mu. Mol,3.1 mg) and 2.0ml acetone (0.05M) were sequentially added and sonicated until the solution was homogeneous, followed by base (0.30 mmol), tetrabutylammonium decatungstate (2.0. Mu. Mol,6.6 mg), 1-bromomethyl-2-fluorobenzene (0.10 mmol,18.8 mg, 1.0 eq), cyclopropylaldehyde (0.15 mmol,10.5 mg, 1.5 eq) were sequentially added. Under the protection of argon at room temperature, 390 nm light source is illuminated, the temperature is reduced by a fan (the control temperature is lower than 40 ℃ and is about 35 ℃), and the reaction is carried out for 3 hours.
The alkali screening is shown in table 5:
TABLE 5
Alkali Dosage of Yield%
Sodium carbonate 0.30mmol 96
Sodium bicarbonate 0.30mmol 91
Potassium carbonate 0.30mmol 88
Potassium bicarbonate 0.30mmol 78
Sodium carbonate 0.11mmol 41
Sodium carbonate 0.20mmol 82
The same reaction was catalyzed with the same amount (0.30 mmol) of each base, and sodium carbonate was used in the best yield (96%), sodium bicarbonate, potassium carbonate, potassium bicarbonate were also used. Reducing the amount of sodium carbonate resulted in a reduced yield (0.11 mmol,41%;0.20mmol, 82%). Sodium carbonate (0.30 mmol) is the most preferred condition.
Example 10
Screening a solvent:
in a 4 ml dry reaction flask, 4 '-di-tert-butyl-2, 2' -bipyridine (10. Mu. Mol,2.7 mg), nickel bromide ethylene glycol dimethyl ether complex (10. Mu. Mol,3.1 mg) and solvent were sequentially added, and the solution was sonicated until it became homogeneous, followed by sodium carbonate (0.30 mmol,31.8 mg), tetrabutylammonium decatungstate (2.0. Mu. Mol,6.6 mg), 1-bromomethyl-2-fluorobenzene (0.10 mmol,18.8 mg, 1.0 eq), and cyclopropylaldehyde (0.15 mmol,10.5 mg, 1.5 eq) were sequentially added. Under the protection of argon at room temperature, 390 nm light source is illuminated, the temperature is reduced by a fan (the control temperature is lower than 40 ℃ and is about 35 ℃), and the reaction is carried out for 3 hours.
The solvent screening is shown in table 6:
TABLE 6
The same reaction was catalyzed with the same concentration (0.05M) using each solvent, and the best yields (96%) of acetone, methylene chloride, acetonitrile, water, dichloroethane, nitromethane, and dimethyl sulfoxide were not suitable. Increasing the concentration of the reaction system resulted in a decrease in yield (0.09 m, 86%). The most preferred condition is acetone (0.05M).
The foregoing description is only illustrative of the preferred embodiment of the present invention, and is not to be construed as limiting the invention, but is to be construed as limiting the invention to any and all simple modifications, equivalent variations and adaptations of the embodiments described above, which are within the scope of the invention, may be made by those skilled in the art without departing from the scope of the invention.

Claims (1)

1. A process for the preparation of prasugrel intermediates and analogues thereof comprising the steps of:
dissolving a ligand and a transition metal catalyst in a solvent, uniformly mixing by ultrasonic, adding a compound II, a compound III, alkali and a photocatalyst, filling argon for protection at room temperature, and carrying out illumination reaction to obtain a prasugrel intermediate shown in a formula I and an analogue thereof;
the molar ratio of the ligand, the transition metal catalyst, the compound II, the base, the photocatalyst and the compound III is 0.067:0.067:0.67:2:0.013:1;
the compound III is selected from one of the following compounds:
the compound II is selected from one of the following compounds:
the ligand is 4,4 '-di-tert-butyl-2, 2' -bipyridine;
the transition metal catalyst is selected from nickel bromide ethylene glycol dimethyl ether complex;
the solvent is selected from acetone;
the base is selected from sodium carbonate;
the photocatalyst is selected from tetrabutylammonium decatungstate and sodium decatungstate;
the wavelength of the illumination reaction is 390 nanometers;
the time of the illumination reaction is 3 hours; the temperature was 35 ℃.
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
N-heterocyclic carbene-palladium-imine complex catalyzed a-arylation of ketones with aryl and heteroaryl chlorides under air atmosphere;H.-Y. Lu et al.;《Tetrahedron Letters》;第61卷;第152124(1-6)页 *
Nickel/Photo-Cocatalyzed Acyl C-H Benzylation of Aldehydes with Benzyl Chlorides;Xian tang Li, et al;《Eur. J. Org. Chem》;第17卷;第e202200214 (1 of 4)页 *

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