* 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 hydrogenchloride In methanol; dichloromethane at 0 - 10℃; for 1 h; Large scale
The manidipine alkali 2.25 kg added to the dichloromethane 6.75 L, methanol 4.5 L after dissolving cooling to 0 - 10 °C, drops of concentrated hydrochloric acid 1.07 L, after adding, thermal insulation stirring reaction 1 h, then adding methyl tert-butyl ether 13.5 L, then stirring 1 h, a large number of solid precipitation, filtering, washing the cake with a small amount of methyl tert-butyl ether, dichloromethane is used for the filter cake 22 L reflux beating 1 h, cooling to room temperature, filtering. A small amount of methyl tert-butyl ether cake washing, 40 - 50 °C blast drying, to obtain 2.05 kg yellow solid. The yield is 81.8percent, purity 99.8869percent, HPLC Atlas see Figure 2.
Reference:
[1] Patent: CN108218765, 2018, A, . Location in patent: Paragraph 0046; 0047
[2] Patent: WO2011/23954, 2011, A2, . Location in patent: Page/Page column 18
[3] Patent: US2012/232091, 2012, A1, . Location in patent: Page/Page column 6
2
[ 89226-75-5 ]
[ 89226-50-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
With sodium hydroxide In waterCooling with ice
Weigh 12g of sodium hydroxide, was added 18mL of water, to prepare a 40percent aqueous sodium hydroxide solution, while cooling on ice.Weigh manidipine hydrochloride (20.5 g of) was added and stirred mechanically assembled of three ice-bath cooled flask (a 500 mL), and then water (100mL).Open stirred, ice-cold 40percent sodium hydroxide solution is added dropwise to the previously prepared ice bath cooled three-necked flask.Ethyl acetate was added during the addition (90mL).After all the lye was added, stirring was stopped and rested stratification.Aqueous phase measured pH to 11 to 12, and liquid separation.The aqueous phase was extracted twice with ethyl acetate (30mL × 2), and the combined organic phase was washed with water (50 mL), saturated sodium chloride solution (50 mL) and washed once each.Then, the organic phase was dried over anhydrous sodium sulfate (15g) for 2 hours.Filter, 35 solvent was removed by evaporation under reduced pressure.As a yellow solid manidipine free base, yield 98percent
Reference:
[1] Patent: CN105439942, 2016, A, . Location in patent: Paragraph 0040; 0041; 0042
3
[ 39562-17-9 ]
[ 89226-50-6 ]
Yield
Reaction Conditions
Operation in experiment
91.43%
at 40 - 75℃; for 6.5 h;
(50 g, 0.132 mol) of β-aminocrotonic acid diphenylmethylpiperazine ethyl ester2- (3-nitrobenzylidene) acetoacetate (49.30 g, 0.198 mol)Was added to a reaction flask equipped with absolute ethanol (180 ml)The temperature in the reactor was raised to 40 ° C over 1 h,And insulation 1h;The temperature in the reactor was then raised to 75 ° C in 1 h,And insulation 0.5h,Continue to heat to reflux,Reflux 3h,After the reaction was complete, the crude of manilide was obtained,And then cooled to 0 ° C overnight,The resulting filter cake was recrystallized from 90 mL of methanol to give 73.62 g of a white solid,The yield was 91.43percent.
Reference:
[1] Patent: CN106380442, 2017, A, . Location in patent: Paragraph 0018; 0020; 0022
Reference:
[1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 9, p. 3787 - 3797
6
[ 10527-64-7 ]
[ 89226-50-6 ]
Reference:
[1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 9, p. 3787 - 3797
[2] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 9, p. 3787 - 3797
With hydrogenchloride; In methanol; dichloromethane; at 0 - 10℃; for 1.0h;Large scale;
The manidipine alkali 2.25 kg added to the dichloromethane 6.75 L, methanol 4.5 L after dissolving cooling to 0 - 10 C, drops of concentrated hydrochloric acid 1.07 L, after adding, thermal insulation stirring reaction 1 h, then adding methyl tert-butyl ether 13.5 L, then stirring 1 h, a large number of solid precipitation, filtering, washing the cake with a small amount of methyl tert-butyl ether, dichloromethane is used for the filter cake 22 L reflux beating 1 h, cooling to room temperature, filtering. A small amount of methyl tert-butyl ether cake washing, 40 - 50 C blast drying, to obtain 2.05 kg yellow solid. The yield is 81.8%, purity 99.8869%, HPLC Atlas see Figure 2.
With hydrogenchloride; In isopropyl alcohol; acetone;pH 1 - 1.5;
Example 2Preparation of Manidipine DihydrochlorideManidipine base was dissolved in acetone (15 ml). The pH of the solution was adjusted to 1-1.5 with IPA-HCI solution with constant stirring to get manidipine Dihydrochloride. The reaction mass was filtered and dried for 2 hours (yield: 3 gm).
With hydrogenchloride; In ipa; acetone;pH 1 - 1.5;
Example 2 Preparation of Manidipine Dihydrochloride Manidipine base was dissolved in acetone (15 ml). The pH of the solution was adjusted to 1-1.5 with IPA-HCl solution with constant stifling to get manidipine Dihydrochloride. The reaction mass was filtered and dried for 2 hours (yield: 3 gm).
Weigh 12g of sodium hydroxide, was added 18mL of water, to prepare a 40% aqueous sodium hydroxide solution, while cooling on ice.Weigh manidipine hydrochloride (20.5 g of) was added and stirred mechanically assembled of three ice-bath cooled flask (a 500 mL), and then water (100mL).Open stirred, ice-cold 40% sodium hydroxide solution is added dropwise to the previously prepared ice bath cooled three-necked flask.Ethyl acetate was added during the addition (90mL).After all the lye was added, stirring was stopped and rested stratification.Aqueous phase measured pH to 11 to 12, and liquid separation.The aqueous phase was extracted twice with ethyl acetate (30mL × 2), and the combined organic phase was washed with water (50 mL), saturated sodium chloride solution (50 mL) and washed once each.Then, the organic phase was dried over anhydrous sodium sulfate (15g) for 2 hours.Filter, 35 solvent was removed by evaporation under reduced pressure.As a yellow solid manidipine free base, yield 98%
With O,O′-di-p-anisoyl-D-tartaric acid In hexane; ethyl acetate for 2h;
5 Preparation of (S) -mandidipine by resolution of D - (+) - di-p-methoxybenzoyltartaric acid
The mannitine free base (610 mg) obtained in Example 1 was added, and ethyl acetate and n-hexane were addedHeptane (10.0 mL, ethyl acetate: n-heptane = 1: 1) was dissolved. Then, stirD - (+) - di-p-anisoyltartaric acid (418 mg) was added to the reaction flask with stirring, and the solutionAfter clarification, a white solid precipitated. Stirring was continued for 2 hours, filtered and the cake was used in small amountsSolvent (ethyl acetate: n-heptane = 1: 1). The resulting filter cake was then dried in a vacuum ovenAnd dried at 45 ° C for 2 hours to give a white solid.The resulting white solid was added to 15 mL of ice water, 15 mL of ethyl acetate was added,And then dropping 40% sodium hydroxide solution, adjust the water phase pH to 11 ~ 12, liquid separation. Water phase with BEthyl acetate (3 x 10 mL). The organic phases were combined, washed with water (15 mL) and saturated sodium chloride solutionWashed with water, dried over anhydrous sodium sulfate (2 g) for 2 hours, and filtered. The filtrate was evaporated under reduced pressureTo (S) -magnidipine as a white solid, 81% yield, ee: 98.3%.