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One-pot preparation method of pitavastatin calcium intermediate
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A technology of pitavastatin calcium and intermediates, which is applied in the field of pharmaceutical synthesis, can solve the problems of heavy metals or low yield, difficult processing and the like, and achieves the effects of low cost, simple post-processing, and suitability for industrialized large-scale production.
Active Publication Date: 2021-11-16
HINYE PHARM CO LTD
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[0005] The existing literature reports the synthesis of pitavastatin calcium intermediate Ⅱ (4R, 6S)-6-[[(1E)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]vinyl In the preparation method of ]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate, either dangerous materials are used, or there are heavy metals or the yield is low, or the post-processing is difficult, etc.
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Embodiment 1
[0046]In a 3L reaction flask, add 100.00g (280.71mmol) of the parent nucleusbromide and 700ml (7v) of dimethyl sulfoxide, stir and heat to 50°C, add 87.40g (1.18eq, 333.21mmol) of triphenylphosphorus, and keep the reaction for 3h After cooling to about 25°C, add 100.00g (1.35eq, 378.95mmol) side chainaldehyde and 128.25g (3.00eq, 842.13mmol) DBU, stir at 30°C for 5h, add water after the reaction to quench the reaction, add toluene for extraction, organic The phase was concentrated and crystallized with isopropanol to obtain 118.4 g of pitavastatin calcium intermediate with a yield of 81%.
[0049] In a 1L reaction flask, add 30.00g (84.21mmol) of the parent nucleusbromide and 210ml (7v) of dimethyl sulfoxide, stir and heat to 55°C, add 27.61g (1.25eq, 105.26mmol) of triphenylphosphorus, and keep the reaction for 3h After cooling to about 30°C, add 30.00g (1.3eq, 109.47mmol) side chainaldehyde and 250ml (3eq, 252.63mmol) bis(trimethylsilyl) lithiumamide (LiHMDS), stir at 30°C for 5h, and add after the reaction is complete The reaction was quenched with water, extracted with ethyl acetate, the organic phase was concentrated and crystallized with isopropanol to obtain 32.70 g of pitavastatin calcium intermediate with a yield of 75%.
Embodiment 3
[0051] In a 500ml reaction flask, add 10.00g (28.08mmol) of the parent nucleusbromide and 70ml (7v) of dimethyl sulfoxide, stir and heat to 50°C, add 10.30g (1.4eq, 39.30mmol) of triphenylphosphorus, keep the reaction for 3h , add 12.33g (1.7eq, 47.73mmol) side chainaldehyde and 2.85g (2.5eq, 70.20mmol) triethylamine, stir at 50 ° C for 5h, after the reaction is completed, add water to quench the reaction, add toluene for extraction, the organic phase is concentrated and used Isopropanol was crystallized to obtain 10.8 g of pitavastatin calcium intermediate with a yield of 74%.
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Abstract
The invention provides a one-pot preparation method of a pitavastatincalcium intermediate. The one-pot preparation method comprises the following steps: S1) subjecting3-bromomethyl-2-cyclopropyl-4-(4'-fluorophenyl)quinoline to reacting with triphenylphosphine in an organic solvent to obtain a phosphonium salt; and S2) adding an alkaline compound and (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate into a system, and carrying out a reaction so as to obtain the pitavastatincalcium intermediate as shown in a formula II. The pitavastatincalcium intermediate as shown in the formula II is prepared through the one-pot method, production time and cleaning time are shortened, raw materials are easy to obtain and low in cost, reaction conditions are mild, aftertreatment is simple, product loss caused by centrifugation can be reduced, yield is increased, total yield reaches 70%-80%, purity reaches 99% or above, and the method is more suitable for industrial large-scale production.
Description
technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a one-pot preparation method of a pitavastatin calcium intermediate. Background technique [0002] PitavastatinCalcium (Pitavastati Calcium, compound of formula I) is the first fully synthetic HMG-CoA reductase inhibitor developed by Nissan Chemical Co. Known as the "super statin", according to the reported data, pitavastatin calcium has a very good lipid-lowering effect and is the strongest lipid-lowering drug so far. The mechanism of action of statins is 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reduction inhibitors, which can competitively inhibit the activity of HMG-CoA reductase. Recent studies have also found that statins can not only significantly reduce blood lipids, but also protect cardiovascular function. [0003] [0004] (4R, 6S)-6-[[(1E)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]vinyl]-2,2-dimethyl-1, 3-Dioxane-4-acetic acid tert-butyl est...
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