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Preparation method of chiral bisoprolol fumarate

A bisoprolol fumarate and chirality technology is applied in the field of preparation of chiral bisoprolol fumarate intermediates and chiral bisoprolol fumarate, which can solve the problems of low purity of a single configuration and achieve the Conducive to industrialized production, simple process and easy-to-obtain raw materials

Pending Publication Date: 2021-01-08
江苏悦兴医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The synthesis of chiral bisoprolol fumarate reported in the literature has a single configuration with low purity

Method used

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  • Preparation method of chiral bisoprolol fumarate
  • Preparation method of chiral bisoprolol fumarate
  • Preparation method of chiral bisoprolol fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of 4-((2-isopropoxyethoxy)methyl)phenyl mesylate

[0036]

[0037] Add 21.1g (100mmol) of p-isopropoxyethoxymethylphenol I and 250ml of acetonitrile into a 500ml three-necked flask, stir until the system is completely dissolved and drop below 10°C, add 11.5g (100mmol) of methylsulfonyl chloride in batches ), the temperature was raised to 60° C., and the reaction was continued for 4 hours, and the reaction was detected by TLC. The reaction solution was washed with 10% sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure to obtain 26.4 g of 4-((2-isopropoxyethoxy)methyl)phenyl methanesulfonate III as a white solid, with a yield of 91.6%.

[0038] ESI-MS (m / z): [M+H] 290.1.

[0039] 1 HNMR (500MHz, DMSO-d6, δppm): 1.13-1.14 (d, 6H), 3.52-3.56 (m, 4H), 3.58 (s, 3H), 3.67 (m, 1H), 4.82 (s, 2H), 7.06 (d, 2H), 7.32 (d, 2H).

Embodiment 2

[0041] Preparation of (S)-2-((4-((2-isopropoxyethoxy)methyl)phenoxy)methyl)oxirane

[0042]

[0043] Add 14.4g (50mmol) of 4-((2-isopropoxyethoxy)methyl)phenyl mesylate, 5g (50mmol) of triethylamine and 200mL of toluene into a 500ml reaction flask, and stir until the system is completely dissolve. 3.7 g (50 mmol) of R-glycidyl alcohol was slowly added, and the reaction was continued at 70° C. for 2 hours, and the reaction was detected by TLC. The reaction solution was poured into 50 mL of ice water, extracted with toluene, and the organic phase was dried and distilled. The residue was 12.8 g of oil, yield 96.2%.

[0044] ESI-MS (m / z): [M+H] 267.2

[0045] 1 H-NMR (CDCl3, δppm), δ: 1.17-1.78 (d, 6H, 2CH3), 2.74-2.75 (dd, 1H), 2.90-2.91 (dd, 1H), 3.35-3.36 (m, 1H), 3.60 (s, 4H), 3.70 (s, 1H), 3.97-3.98 (dd, 1H), 4.20-4.21 (dd, 1H), 4.51 (s, 2H), 6.88 and 7.28 (dd, 4H).

Embodiment 3

[0047] Preparation of (S)-bisoprolol:

[0048]

[0049] In a 100mL three-necked flask, 5.30g (0.02mol) of compound (S)-2-((4-((2-isopropoxyethoxy)methyl)phenoxy)methyl)oxirane Dissolve in 20mL of methanol, add 20mL of isopropylamine, stir and react at 40-45°C for 3 hours, distill to dryness under reduced pressure, wash with water, extract with toluene, dry the organic phase, and distill to obtain 6.15g of light yellow oil (S)-bisoprol Er, the yield is 97.2%.

[0050] ESI-MS(m / z): [M+H]326.3

[0051] 1 H-NMR (CDCl3, δppm), δ: 1.15-1.16 (d, 6H), 1.17-1.18 (d, 6H), 2.88-2.90 (m, 3H), 3.61-3.62 (m, 4H), 3.95-3.96 (m, 2H), 3.96 (s, 2H), 4.02-4.03 (m, 1H, NH), 6.87-6.88 (d, 2H), 7.26-.27 (d, 2H).

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Abstract

The invention provides a preparation method of chiral bisoprolol fumarate. The preparation method comprises the following steps: preparation of (S)-bisoprolol fumarate and preparation of (R)-bisoprolol fumarate. According to the preparation method of the chiral bisoprolol fumarate, provided by the invention, isopropoxyethoxymethylphenol and sulfonyl chloride are subjected to esterification reaction to generate a sulfonate compound, the compound reacts with chiral epoxypropanol to generate a chiral epoxy compound, the compound is subjected to a ring-opening reaction to obtain chiral bisoprolol,and the chiral bisoprolol is subjected to a salt forming reaction to obtain chiral bisoprolol fumarate, wherein the obtained product is high in single configuration purity, so that the method has themain advantages that the raw materials are easy to obtain, the process is simple, economical and environment-friendly, and industrial production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and specifically relates to a chiral bisoprolol fumarate intermediate and a preparation method of the chiral bisoprolol fumarate. Background technique [0002] Bisoprolol fumarate is a new generation of selective β1-adrenergic receptor blockers with high selectivity, and has become one of the first-choice drugs for the treatment of essential hypertension and angina pectoris. Bisoprolol fumarate has one chiral center and two enantiomers in R / S configuration. At present, the drug is supplied in the form of racemate in the reports of clinical medication, pharmacology and toxicology research. According to literature reports, the β-receptor blocking effect of bisoprolol fumarate (S)-enantiomer is 80 times that of (R)-enantiomer, and the bioavailability of (S)-enantiomer is (R ) - 1.5 times the enantiomer. The synthesis of chi...

Claims

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Application Information

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IPC IPC(8): C07C213/04C07C217/34C07C57/15C07C51/41C07D303/23C07C303/28C07C309/66
CPCC07C213/04C07C51/412C07D303/23C07C303/28C07B2200/07C07C309/66C07C217/34C07C57/15
Inventor 翟富民
Owner 江苏悦兴医药技术有限公司
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