* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With benzyltriethylammonium bromide; potassium hydroxide In isopropyl alcohol at 80℃;
Take 400g of intermediate II plus 2L isopropanol in three-necked flask and dissolved, and then followed by adding 30g potassium hydroxide and 10g of triethylbenzylammonium bromide, stirred and heated to reflux for 80°C 5 to 6 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure to dryness. The residue was added 2L of methylene chloride and 2L of water, stirred for 10 minutes, standing layer, the aqueous phase was added dropwise under ice-cooling dilute hydrochloric acid to adjust pH = 4.5, was stirred for one hour ice bath, suction filtered and the filter cake washed with purified water to pH = 7, after the cake was dried to give 260g, tested, HPLC purity of 96.11percent. (See Fig. 3). In reaction flask 130g butyric clevidipine important crude intermediate and 650ml of ethyl acetate wad added, the mixture was stirred and heated to 40°C , maintained for 10 minutes, filtered hot and the filter cake was dried to give a pale yellow solid 122g, that is an important intermediate clevidipine butyrate. By HPLC purity of 99.09percent (see Figure 4), yield 93percent.The total yield of the preparation of the present invention obtained by the acid clevidipine important intermediates 53percent.
1.43 kg
Stage #1: With tetra-(n-butyl)ammonium iodide In isopropyl alcohol at 20℃; for 4 h; Industrial scale Stage #2: With hydrogenchloride In water at 20℃; for 2 h; Industrial scale
A mixture of 2,3-dichlorobenzaldehyde (0.9 kg, 5.14 mol), methyl acetoacetate (0.6 kg, 5.14 mol) and cyanoethyl 3-aminocrotonate (0.88 kg, 5.71 mol) Mol), pyridine (22g, 0.28mol) was added to isopropanol (15 L) and reacted at 80 ° C for 10 h. Cooling the temperature, filtering to obtain solid, the obtained solid by adding isopropyl alcohol (5L) recrystallization, filtration to get compound 3-(2-cyanoethyl) 5-methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.8kg, 4.37mol). Compound III (1.8kg, 4.37mol) Was dissolved in isopropanol (20L) 1M Bu4NI 5.24L (5.2mol) solution was added at room temperature Stir for 4 h, The solvent was evaporated and addedWater (18 L), dilute hydrochloric acid(1M) at 20 ° C adjusted PH5-6, And stirred at this temperature for 2h, a yellow precipitate formation,Filtration was solid 1. 43kg,Yield: 78.0percent (based on 2,3-dichlorobenzaldehyde).
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 8, p. 1579 - 1589
[2] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 1, p. 108 - 116
[3] Patent: CN105367487, 2016, A, . Location in patent: Paragraph 0021
[4] Patent: CN103242220, 2016, B, . Location in patent: Paragraph 0040; 0051-0052
2
[ 74073-22-6 ]
[ 123853-39-4 ]
Yield
Reaction Conditions
Operation in experiment
91.32%
Stage #1: at 35 - 40℃; Reflux; Large scale Stage #2: With sodium hydroxide In isopropyl alcoholLarge scale
The 3-amino-crotonic acid cyanogen ethyl ester 1.0 kg (6.49mol) inputs 5.5L isopropanol, inputs under stirring 2,3- two chlorine Asia phenmethyl acetyl methyl acetate 2.0 kg (7.32mol), heating to reflux reaction 6-8h, after the reaction is ended cooling to 35-45°C, inputs potassium hydroxide 550.0g (9.80mol), preserving heat and stirring 2-4h, subsequently inputs 60.0g activated carbon decolourizations 5-15min, filtering, filtrates in 30-40 °C dropwise 1mol/L hydrochloric acid solution to adjust pH value to 5-6, filtering, 40-50 °C decompression drying to obtain the intermediate-4 - (2,3-dichlorophenyl) - 1,4-dihydro -2,6-dimethyl-5-methoxy carbonyl-3-pyridine carboxylic acid 2.11 kg, yield 91.32percent.
Reference：
[1] Patent: CN105461619, 2016, A, . Location in patent: Paragraph 0065; 0066; 0067
3
[ 91189-59-2 ]
[ 123853-39-4 ]
Yield
Reaction Conditions
Operation in experiment
20%
With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In methanol at 70℃; Reflux
To about 1.03g 2.8mmol S13 compound prepared above was dissolved in 15mL of methanol was added Into approximately 260mg of 1.14mmol TEBAc a concentration of 40percent NaOH 2.5mL, at 70 ° C Under stirring at reflux, the reaction overnight, the methanol was removed by rotary evaporation, diluted with water, 2mol / L hydrochloric PH is 2-3 to the reaction system in the precipitated solid was filtered to give the product S14200mg, yield To 20percent,
With trifluoroacetic acid In dichloromethane at 20℃; for 2.5 h;
4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate-(tert-butyl) methylester(1) (412 mg, 1mmol) dissolved in dichloromethane (10 ml), by adding trifluoroacetic acid (1.5mmol), 20 °C stirring 2.5h, turns on lathe does solvent, cyclohexane and a small amount of ethyl acetate is added, solid precipitation, filtration, a small amount of cold ethyl acetate filter cake washing, drying, the obtained product (IV) 267 mg, yield 75.2percent (to 1 parts).
With benzyltriethylammonium bromide; potassium hydroxide; In isopropyl alcohol; at 80℃;
Take 400g of intermediate II plus 2L isopropanol in three-necked flask and dissolved, and then followed by adding 30g potassium hydroxide and 10g of triethylbenzylammonium bromide, stirred and heated to reflux for 80C 5 to 6 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure to dryness. The residue was added 2L of methylene chloride and 2L of water, stirred for 10 minutes, standing layer, the aqueous phase was added dropwise under ice-cooling dilute hydrochloric acid to adjust pH = 4.5, was stirred for one hour ice bath, suction filtered and the filter cake washed with purified water to pH = 7, after the cake was dried to give 260g, tested, HPLC purity of 96.11%. (See Fig. 3). In reaction flask 130g butyric clevidipine important crude intermediate and 650ml of ethyl acetate wad added, the mixture was stirred and heated to 40C , maintained for 10 minutes, filtered hot and the filter cake was dried to give a pale yellow solid 122g, that is an important intermediate clevidipine butyrate. By HPLC purity of 99.09% (see Figure 4), yield 93%.The total yield of the preparation of the present invention obtained by the acid clevidipine important intermediates 53%.
1.43 kg
A mixture of 2,3-dichlorobenzaldehyde (0.9 kg, 5.14 mol), methyl acetoacetate (0.6 kg, 5.14 mol) and cyanoethyl 3-aminocrotonate (0.88 kg, 5.71 mol) Mol), pyridine (22g, 0.28mol) was added to isopropanol (15 L) and reacted at 80 C for 10 h. Cooling the temperature, filtering to obtain solid, the obtained solid by adding isopropyl alcohol (5L) recrystallization, filtration to get compound 3-(2-cyanoethyl) 5-methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.8kg, 4.37mol). Compound III (1.8kg, 4.37mol) Was dissolved in isopropanol (20L) 1M Bu4NI 5.24L (5.2mol) solution was added at room temperature Stir for 4 h, The solvent was evaporated and addedWater (18 L), dilute hydrochloric acid(1M) at 20 C adjusted PH5-6, And stirred at this temperature for 2h, a yellow precipitate formation,Filtration was solid 1. 43kg,Yield: 78.0% (based on 2,3-dichlorobenzaldehyde).
4-(2,3-Dichloro-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-(2-{4-[(2,6-dimethyl-phenylcarbamoyl)-methyl]-piperazin-1-yl}-ethyl) ester 5-methyl ester[ No CAS ]
4-(2,3-Dichloro-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-{3-[(3,3-diphenyl-propyl)-methyl-amino]-2,2-dimethyl-propyl} ester 5-methyl ester[ No CAS ]
(B) Similarly, proceeding as in part (A) above but substituting the appropriate starting materials for 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine, the following optically resolved compounds are prepared: 2,6-dimethyl-3-carbomethoxy-4-(2-nitrophenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carbomethoxy-4-(3-chlorophenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carbomethoxy-4-(2-chlorophenyl)-5-carboxy- 1,4-dihydropyridine; (--2,6-dimethyl-3-carbomethoxy-4-(2,3-dichlorophenyl)-5-carboxy-1,4-dihydropyridine, mp=225 C., [alpha]D20 =-28.5, c=5, DMF; 2,6-dimethyl-3-carbomethoxy-4-(4-methylphenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carbomethoxy-4-(3-cyanophenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carbomethoxy-4-(3-trifluoromethylphenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carbomethoxy-4-(3-trifluoromethoxyphenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carboethoxy-4-(2-nitrophenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carboethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carboethoxy-4-(3-chlorophenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carboethoxy-4-(2-chlorophenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carboethoxy-4-(2,3-dichlorophenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carboethoxy-4-(4-methylphenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carboethoxy-4-(3-cyanophenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carboethoxy-4-(3-trifluoromethylphenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carboethoxy-4-(3-trifluoromethoxyphenyl)-5-carboxy-1,4-dihydropyridine; 2,6-dimethyl-3-carboisopropoxy-4-(2-nitrophenyl)-5-carboxy-1,4-dihydropyridine;
13
[ 33657-49-7 ]
[ 123853-39-4 ]
clevidipine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.2%
With potassium carbonate; lithium iodide; In N,N-dimethyl-formamide; at 70℃; for 4h;
<strong>[123853-39-4]4-(2',3'-dichlorophenyl)-2,6-dimethyl-5-(methoxycarbonyl)-1,4-dihydropyridin-3-carboxylic acid</strong> (20.0g, 56.2mmol), Potassium carbonate (32.lg, 232.5 mmol), lithium iodide (3.86 g, 23.2 mmol) was addedDMF (300 ml), and chloromethyl n-butyrate was added(31.6 g, 232.5 mmol) at 70 C for 4 h. The reaction solution was cooled to roomThe organic layer was separated, dried and the solvent was removed. A solid precipitated and a pale yellow solid was obtained by filtration. The filter cake was washed with 250 ml of methanol / water (100 ml)(1/1, volume ratio) to obtain 61.6 g of a solid, 87.2% yield.
66%
With potassium carbonate; In 1,4-dioxane; water; for 4h;Reflux;
Example 3 - Synthesis of 3-butanoyloxymethoxycarbonyl-5-methoxycarbonyl-4- (2,3-dichlorophenyl)-2,6-dimethyl-1 ,4-dihydropyridine [0022] Purified carboxylic acid 2 (5.00g, 14 mmol) and potassium carbonate (1 .94g, 14 mmol) were suspended in a mixture of 1 ,4-dioxane (25ml_) and water (1 .25ml_). Chloromethyl butyrate (3.26g, 24 mmol) was added and the reaction mixture was refluxed for 4h. The reaction mixture was cooled to room temperature, and heptane (17ml_) and silica gel were added. The solids were filtered off and washed with a mixture of 1 ,4-dioxane and heptane. Isopropanol (20ml_) and water (75ml_) were added to the combined filtrates. The resulting solution was stirred at room temperature and the formed solids were collected by filtration and washed with a mixture of water and isopropanol followed by heptane. Drying for 48h under high vacuum at 40C gave the title compound as an off-white powder (4.20g, 66% yield). Analysis by HPLC indicates a purity of 99.03%, with no impurity 6 being detected.
65%
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;
Compound 7 (300 mg, 0.83 mmol), NaHC03 (150 mg, 1.66 mmol) was dissolved in DMF (8 ml), compound 8 (170 mg, 1.24 mmol) was added under N2 and heated to 80 C reflux, 4 hours The organic layer was washed with saturated brine, dried over anhydrous NaS04 and separated by column chromatography to obtain clovipid butyrate (250 mg,65% yield)
The free acid form of compound 1 is suitably prepared by basic hydrolysis of cyanoethyl ester 2, described above. Then the free acid can be reacted with solid TMAH, optionally in the form of a hydrate, in dioxane solvent. It is also preferred to add a small amount of water, e.g. 2-10% v/v, to the reaction, so as to obtain crude material of suitable quality.[0009] This reaction to produce the tetramethylammonium salt of compound 1 can be conducted at room temperature, with stirring. After substantial completion of the reaction, the chloromethyl butyrate is preferably added to the same reaction vessel, without recovering the carboxylate. The alkylation process proceeds under reflux conditions. When the reaction is complete, the reaction mixture is allowed to cool to some degree, and the organic phase containing the desired solid product is subjected to filtration to recover the solids. After suitable washing and drying, crude clevidipine butyrate is obtained.[0010] It is preferred according to the invention to subject the crude product to crystallization from a solution in mixed dichloromethane/heptane solvent. This step not only eliminates most of the impurities, but also significantly improves the colour of the final product, so as to yield an off-white solid. Repeating this crystallization step will produce a white solid. A final crystallization from isopropanol/water is also preferably conducted, for further removal of impurities.[0011] The invention is further described, for illustrative purposes, in the following specific experimental example. Specific Description of the Most Preferred Embodiment[0012] To free acid compound 1 , 4-(2,3-dichlorophenyl)-1 ,4-dihydro-2,6- dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid (50. Og, 140 mmol) and solid Me4NOH»5H2O (30.5g, 168 mmol) were added dioxane (250ml_) and water (12.5ml_), and the resulting suspension was stirred at room temperature for 45 min. Chloromethyl butyrate (33. Og, 242 mmol) was added and the reaction mixture was refluxed for 5h. Once the reaction was complete, heptane (250ml_) was added.[0013] The aqueous layer was removed, and silica gel was added to the organic phase. The suspension was stirred for 30 min., after which the solids were removed by filtration and washed with a 1 : 1 mixture of heptane and dioxane. The filtrate and wash were combined, and isopropanol (250m L) and deionized water (750ml_) were added. After agitating for 18h, the solids were collected by filtration, washed with a mixture of isopropanol and deionized water, then with heptane. The crude clevidipine butyrate was dried under high vacuum at 40C until constant weight (54.0g, 1 18 mmol, 84% yield) was achieved.[0014] Crude clevidipine butyrate (50. Og, 1 10 mmol) was dissolved in dichloromethane (200ml_) and heptane (800ml_) was added to the solution. After stirring for 2h, the solids were collected by filtration and washed with a mixture of dichloromethane and heptane, followed by heptane. The clevidipine butyrate was then dried under high vacuum at 40C for 16h to give an off-white solid (40.5g, 89 mmol, 81 % yield).[0015] For the final crystallization, clevidipine butyrate (40. Og, 88 mmol) was dissolved in hot isopropanol (400ml_). With the solution still hot, deionized water (400ml_) was added and the mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with a mixture of deionized water and isopropanol, followed by heptane. Drying under high vacuum at 40C gave clevidipine butyrate as an off white solid (36.6g, 80 mmol, 91 % yield).
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;Inert atmosphere;Product distribution / selectivity;
Example-5: Preparation of Clevidipine:100 gm of 1 ,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl-3- pyridinecarboxylic acid and 35.4 gm of Sodium bicarbonate is stirred in DMF under nitrogen atmosphere. 49.9 gm of Chloromethyl butyrate was added and reaction mixture was heated at about 80C for 4 hrs. The solvent was distilled out and residue was treated with methylene chloride. The obtained reaction mass was washed with water and the methylene chloride layer was dried over sodium sulphate. Methylene chloride was distilled out under vacuum. Diisopropyl ether (800 ml) was added to the residual mass and stirred at 25-30C for one hour. The reaction mass was filtered, the wet cake was washed with diisopropyl ether to give crude clevidipine (Wt. = 97.5 gms HPLC Purity > 99%).
Example 1 - Synthesis of crude 5-methoxycarbonyl-4-(2,3-dichlorophenyl)-2,6- dimethyl-1 ,4-dihydropyridine-3-carboxylic acid[0020] The starting materials 2,2,6-trimethyl-4/-/-1 ,3-dioxin-4-one (89.2g, 0.63 mol) and 3-hydroxypropionitrile (44.6g, 0.63 mol) were heated in an oil bath at 120C for 3h, during which acetone (the reaction byproduct) was distilled off. The reaction mixture was cooled to room temperature, and isopropanol (570ml_), methyl 3-aminocrotonate (65.7g, 0.57 mol) and 2,3-dichlorobenzaldehyde (100.0g, 0.57 mol) were added. The reaction mixture was heated to reflux, and some of the isopropanol (340m L) was distilled off. The reaction mixture was then cooled in an ice-water bath and dichloromethane (230m L) and a solution of NaOH (28.7g, 0.72 mol) in water (290ml_) were added. After stirring at room temperature for several hours, the reaction mixture was diluted with water and the layers were separated. The aqueous phase was extracted once more with dichloromethane, after which it was cooled in an ice-water bath and phosphoric acid (85%, 25ml_) was added. After precipitation and stirring, the solids were collected by filtration and washed with water. Drying under high vacuum at 40C gave carboxylic acid 2 as a yellow powder (126 g, 62% yield). Analysis by HPLC indicates a purity of 89.23%, with 3.17% of diacid 5 present.
With sodium hydroxide; In methanol; water;Purification / work up;
Example 2 - Purification of 5-methoxycarbonyl-4-(2,3-dichlorophenyl)-2,6- dimethyl-1 ,4-dihydropyridine-3-carboxylic acid[0021] The crude carboxylic acid 2 from Example 1 (126g, 0.35 mol) was dissolved in a mixture of methanol (230ml_) and a solution of NaOH (34. Og, 0.85 mol) in water (230ml_). The solution was extracted with dichloromethane, and brine was added to the aqueous layer. The solids were collected by filtration and then re-suspended in water and stirred vigorously for 2h, after which the reaction mixture was cooled in an ice-water bath and phosphoric acid (85%, 21 ml_) was added. The solids were collected by filtration and washed with water. After drying under vacuum at 40C, compound 2 was suspended in a 1 : 1 mixture of acetone and heptane and vigorously stirred for 2h. The solids were collected by filtration and washed with heptane. Drying under high vacuum at 40C gave carboxylic acid 2 as a beige powder (95 g, 75% yield, 46%overall yield). Analysis by HPLC indicates a purity of 97.28%, with 0.13% of diacid 5 present.
16
[ 74073-26-0 ]
[ 123853-39-4 ]
Yield
Reaction Conditions
Operation in experiment
75.2%
With trifluoroacetic acid; In dichloromethane; at 20℃; for 2.5h;
4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate-(tert-butyl) methylester(1) (412 mg, 1mmol) dissolved in dichloromethane (10 ml), by adding trifluoroacetic acid (1.5mmol), 20 C stirring 2.5h, turns on lathe does solvent, cyclohexane and a small amount of ethyl acetate is added, solid precipitation, filtration, a small amount of cold ethyl acetate filter cake washing, drying, the obtained product (IV) 267 mg, yield 75.2% (to 1 parts).
With sulfuric acid; In ethyl acetate; at 10 - 15℃;Product distribution / selectivity;
Example-2: Preparation of 1 ,4-dihydro-2,6-dimethyl-4-(2',3'-dichlorophenyl)-5- methoxycarbonyl3-pyridine carboxylic acid.100 gm of tert-butyl-4-(2',3'-dichlorophenyl)-2,6-dimethyl-1 ,4-dihydropyridine-3,5- dicarboxylate was added to a cooled mixture of 400 ml con. Sulfuric acid in 300 ml ethyl acetate and reaction mass stirred at 10-15C and quenched in crushed ice and water. The reaction mass was filtered and washed with water. The wet cake was stirred with 300 ml acetone at 45-50C. The reaction mass was cooled, filtered and washed with acetone (50 ml), wet cake was dried under vacuum to provide title compound. (Wt=35 gm Purity > 99 %)
3-(5-((6-chloro-1,2,3,4-tetrahydroacridine-9-yl)amino)pentyl) 5-methyl 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With potassium carbonate; In N,N-dimethyl-formamide; at 30 - 50℃;Inert atmosphere;
The 75mg about 0.21mmol prepared above S14,80mg, about 0.21mmol compound S12,55mg about 0.4mmol K2CO3 in single-neck flask, 5mL DMF, in a nitrogen atmosphere Heated to 50 C, the reaction 2h, cooled to 30 C overnight reaction, until the reaction is complete, add 20mL Water was added and extracted with chloroform, the organic phases were pooled washed with water and saturated brine, dried over anhydrous sodium sulfate Dry, filtered, and solvent was removed by rotary evaporation, the residue was purified by column chromatography to give the present invention provides Compound 9,46mg, a yield of 35%.
4-(-2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl ester (II)(500g, 1.35mol) was added to methanesulfonic acid (1000g),Heat to the reaction temperature of 80 C with stirring,And stirred at this temperature for 3h,The reaction temperature is reduced to 5-10 C, filtered, and the filter cake is washed with a small amount of cold methanesulfonic acid.Drying to obtain 476.2g of product (I),Yield: 99%.
20%
With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide; In methanol; at 70℃;Reflux;
To about 1.03g 2.8mmol S13 compound prepared above was dissolved in 15mL of methanol was added Into approximately 260mg of 1.14mmol TEBAc a concentration of 40% NaOH 2.5mL, at 70 C Under stirring at reflux, the reaction overnight, the methanol was removed by rotary evaporation, diluted with water, 2mol / L hydrochloric PH is 2-3 to the reaction system in the precipitated solid was filtered to give the product S14200mg, yield To 20%,
3-methyl 5-(2,2,2-trichloroethyl) 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate[ No CAS ]
[ 123853-39-4 ]
Yield
Reaction Conditions
Operation in experiment
73%
With acetic acid; zinc; In tetrahydrofuran; at 20℃;
Compound 6 (1g, 2.05mmol) was dissolved intetrahydrofuran / acetic acid (10/1) mixed solvent was added Zn dust (1.3g, 20.5mmol),stirred at room temperature overnight. The resulting solution was concentrated solvent was distilled off, add DMF After removal of the dissolved residual Zndust was filtered, the majority of DMF was distilled off under reducedpressure, water was added to precipitate large amount of solid, Filtration cakewas washed with PE: EA = 20: 1 eluent leaching, after oven-dried to givecompound 7 (0.54 g, 73% yield).
4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid (p-methoxybenzyl) methyl ester[ No CAS ]
[ 123853-39-4 ]
Yield
Reaction Conditions
Operation in experiment
89.1%
With hydrogenchloride; In ethanol; ethyl acetate; at 0℃; for 1.5h;
4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid (p-methoxybenzyl) methyl ester (8) (714 g, 1.5 mol)Add ethanol (5 L), cool to 0 C,Dropwise with stirring1N Hydrochloric acid-Ethyl acetate solution (1.8 mol),After stirring for 1.5 h, the filter cake was washed with an appropriate amount of cold ethanol and dried to give 475.8 g of product (IV) in 89.1% yield (8 parts).
With formic acid; In acetonitrile; at 30℃; for 0.5h;
Compound 10 (4.9 g, 10 mmol)Acetonitrile (50 ml), At 30 C Dropwise Formic acid (13 mmol),Stirring 0.5h,Precipitation of solid,filter,The filter cake was washed with a small amount of cold acetonitrile and dried, yielding 2.72 g of product (IV) in 76.5% (in 10 parts).
With hydrogen bromide; In ethyl acetate; at 10℃; for 3h;
Compound 12 (12 g, 24 mmol) Was added to ethyl acetate (100 ml)Cooling in an ice-water bath Dropping 1N hydrobromic acid-Ethyl acetate solution (24 mmol),10 C stirring 3h,The filter cake was washed with a small amount of ethyl acetate,drying,To obtain 6.4 g of a product (IV) in 75% yield (12 parts).
Compound 14 (5 0g, 9 mmol)) Was dissolved in ethanol (50 ml) Raney-Ni (0.25 g) was added,10 C hydrogen gas mixing 4h, filter,Concentrated, added with ethanol (10 ml)filter,Filter cake drying,To give the product IV (2.4 g, yield: 73% (12 parts).
With hydrogen iodide; In ethanol; dichloromethane; at 30℃; for 5h;
Compound 16 (0.1 g, 0.17 mmol) Dichloromethane was added(10 ml),30 C A solution of IN hydroiodic acid-Ethanol solution (0.25 mmol),30 C stirring 5h, filter cake with a small amount of dichloromethane washing, drying, the product IV 0.05g, yield:83% (in 16).
4-(2,3-dichlorophenyl),1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid-((1,1-dimethyl)benzoic)methyl ester[ No CAS ]
[ 123853-39-4 ]
Yield
Reaction Conditions
Operation in experiment
80.1%
With hydrogenchloride; In ethyl acetate; at -10℃; for 1h;
4-(2,3-dichlorophenyl),1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid-((1,1-dimethyl)benzoic)methyl ester(4.74 g, 0.01 mol)Ethyl acetate was added(50 ml), Cooled to -10 C,Dropwise with stirring1N Hydrochloric acid-Ethyl acetate solution(0.01 mol 1). The mixture was stirred for 1 h and filtered. The filter cake was washed with cold ethyl acetate and dried to give 2.85 g of the product (IV) in 80.1% yield (4 parts).
4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid-(phenylmethyl) methyl ester[ No CAS ]
[ 123853-39-4 ]
Yield
Reaction Conditions
Operation in experiment
96.7%
With palladium 10% on activated carbon; hydrogen; In methanol; at 30℃; for 8h;
4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid-(phenylmethyl) methyl ester(6) (446 g, 1 mol)Was added to methanol (3 L)The weight percentage is added 10% Pd / C (4.46 g),Hydrogen gas at 30 C for 8h,Pd / C was filtered off, concentrated, and a solid precipitated. The cake was washed with a suitable amount of cold methanol to give 344.2 g of product (IV). Yield: 96.7% (6 parts).
3-amino-2-butenoic acid 2-cyanoethyl ester[ No CAS ]
[ 123853-39-4 ]
Yield
Reaction Conditions
Operation in experiment
91.32%
The 3-amino-crotonic acid cyanogen ethyl ester 1.0 kg (6.49mol) inputs 5.5L isopropanol, inputs under stirring 2,3- two chlorine Asia phenmethyl acetyl methyl acetate 2.0 kg (7.32mol), heating to reflux reaction 6-8h, after the reaction is ended cooling to 35-45C, inputs potassium hydroxide 550.0g (9.80mol), preserving heat and stirring 2-4h, subsequently inputs 60.0g activated carbon decolourizations 5-15min, filtering, filtrates in 30-40 C dropwise 1mol/L hydrochloric acid solution to adjust pH value to 5-6, filtering, 40-50 C decompression drying to obtain the intermediate-4 - (2,3-dichlorophenyl) - 1,4-dihydro -2,6-dimethyl-5-methoxy carbonyl-3-pyridine carboxylic acid 2.11 kg, yield 91.32%.
4-(2,3-dichlorophenyl)-2,6-dimethyl dihydropyridine-3,5-dicarboxylic acid methyl(butyryloxymethyl) ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92.89%
With potassium carbonate; In acetonitrile; for 4 - 6h;Reflux; Large scale;
Step 1 preparation of intermediate 2.0 kg (5.61mol) inputs 10L in acetonitrile, inputs under stirring chloro-butyrate 850g (6.22mol) and potassium carbonate 860g (6.22mol), heating to reflux reaction 4-6h, cooling to room temperature, filter, filtrates in 40-50 C concentrated under reduced pressure to dry, subsequently joined 4L ethyl acetate, reflux is dissolved, and 45g activated carbon decolourizations 5-15min, hot filtering, filtrates in 30-40 C dropwise 7L-hexane crystallization, filtration, 40-50 C decompression drying to obtain the butyric acid clevidipine 2.38 kg, yield 92.89%.
Chemistry
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