Synthetic method for bisoprolol fumarate process impurities

A technology for bisoprolol fumarate and process impurities, which is applied in the field of chemical pharmacy to achieve the effects of cheap raw materials, improved accurate positioning and qualitative, and simple operation

Inactive Publication Date: 2018-05-01
江苏悦兴医药技术有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

After retrieval, there is no bibliographical report about the synthesis of this impurity yet, therefore, the synthetic method that provides two kinds of bisoprolol fumarate is used for the preparation of impurity standard substance has important practical significance

Method used

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  • Synthetic method for bisoprolol fumarate process impurities
  • Synthetic method for bisoprolol fumarate process impurities
  • Synthetic method for bisoprolol fumarate process impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Example 1: Preparation of (4-(2-isopropoxyethoxy)phenyl)methanol (5)

[0015]

[0016] Add 4-hydroxybenzyl alcohol (100.0g, 0.805mol), 2-(2-chloroethoxy)propane (118.42g, 0.966mol), triethylamine (122.19, 1.21mol) into a 1000ml three-necked flask, and start stirring , the temperature was raised to 40° C., and detected by TLC, it was found that the raw material 4-hydroxybenzyl alcohol disappeared after 2 hours of reaction, and the reaction ended. Add 200ml of water, 400ml of dichloromethane, separate the aqueous phase and wash with 100ml of dichloromethane for 3 times, combine the organic phase, wash the organic phase with 100ml of saturated saline for 3 times, reduce the organic phase to 150ml, add silica gel and continue vacuum distillation to dryness , the residue was subjected to silica gel column chromatography and eluted with dichloromethane-methanol (80:1) to obtain 48.25 g of an oily substance, 28.51%. 1 HNMR (600MHz, DMSO-d6, δppm): 1.25(t, 6H), 3.21(m, 2H),...

Embodiment 2

[0017] Example 2: Preparation of 2-((((4-(2-isopropoxyethoxy)benzyl)oxy)methyl)oxirane (2)

[0018]

[0019] Add (4-(2-isopropoxyethoxy)phenyl)methanol (46g, 0.219mol) and 130ml methanol to a 500ml three-necked flask and stir, add p-toluenesulfonic acid (2.5g, 0.015mol), The temperature of oxirane-2-ylmethanol (201.48 g, 2.19 mol) was raised to 40° C., and the reaction was carried out for 4 h, and the reaction was detected by TLC. Add 25% NaOH solution, 200ml of water, and 600ml of dichloromethane, wash the aqueous phase with 100ml of dichloromethane for 3 times, combine the organic phases, and wash the organic phase with 100ml of saturated brine for 3 times. The organic phase was rotary evaporated to obtain 49.23 g of oil, with a yield of 84.47%. HPLC detection 98.49%.

[0020] 1 HNMR (600MHz, DMSO-d6, δppm): 1.25(t, 6H), 2.34(m, 1H), 2.61(m, 1H), 2.85(m, 1H), 3.21(m, 2H), 3.36(m, 1H), 3.60(s, 1H), 3.62(m, 1H), 3.71(t, 2H), 4.42(t, 2H), 4.72(s, 2H), 6.28(d, 2H), 6.86(d...

Embodiment 3

[0021] Example 3: Preparation of 1-((4-(2-isopropoxyethoxy)benzyl)oxy)-3-(isopropylamino)propan-2-ol (1)

[0022]

[0023] Add 2-((((4-(2-isopropoxyethoxy)benzyl)oxy)methyl)oxirane (45g, 0.169mol), isopropylamine (29.95g , 0.507mol), ethanol 50ml stirring, 60 ℃ of stirring 2 hours, TLC detection reaction finishes.Add 200ml water, 400ml dichloromethane, separate liquid and discard the water phase, rotary steam the organic phase to obtain oily matter 30.35g yield 76.36%, HPLC 98.66% detected.

[0024] 1 HNMR (600MHz, DMSO-d6, δppm): 1.10(t, 6H), 1.25(t, 6H), 2.04(t, 1H), 2.58(m, 1H), 2.83(m, 1H), 2.97(m, 1H), 3.21(m, 2H), 3.46(t, 2H), 3.54(s, 1H), 3.60(s, 1H), 3.71(t, 2H), 3.76(m, 1H), 4.42(t, 2H ), 4.72 (s, 2H), 6.28 (d, 2H), 6.86 (d, 2H).

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Abstract

The invention discloses a synthetic method for two bisoprolol fumarate process impurities, and belongs to the technical field of chemical medicines. The method provided by the invention takes p-hydroxybenzyl alcohol as a starting material, and the p-hydroxybenzyl alcohol reacts with 2-(2-chloroethoxy)propane to form (4-(2-isopropoxyethoxy)phenyl)methanol; the compound (4-(2-isopropoxyethoxy)phenyl)methanol reacts with oxirane-2-ylmethanol to form 2-((((4-(2-isopropoxyethoxy)benzyl)oxy)methyl)oxirane; and the compound 2-((((4-(2-isopropoxyethoxy)benzyl)oxy)methyl)oxirane reacts with isopropylamine (7) to form 1-((4-(2-isopropoxyethoxy)benzyl)oxy)-3-(isopropylamino) propan-2-ol, the synthesized high-purity bisoprolol fumarate impurities can be used as impurity standard products in the detection analysis of a finished product of bisoprolol fumarate, thereby improving the accuracy positioning and qualitatively of impurities in bisoprolol fumarate finished-product detection analysis, facilitating reinforcement of the control of the impurities, and improving the quality of the finished product of the bisoprolol fumarate.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, in particular to two kinds of bisoprolol fumarate process impurity 2-((((4-(2-isopropoxyethoxy)benzyl)oxy)methyl)epoxy Synthetic method of ethane, 1-((4-(2-isopropoxyethoxy)benzyl)oxy)-3-(isopropylamino)propan-2-ol. Background technique [0002] Bisoprolol fumarate is a long-acting β1-receptor blocker with high cardioselectivity. It is clinically used for the treatment of angina pectoris, arrhythmia and hypertension. It has a high affinity for the β1-receptors of bronchial and vascular smooth muscle, thereby dilating blood vessels and lowering blood pressure. It blocks the neuroendocrine system, and more importantly, targets the mechanism of myocardial remodeling, prevents and delays the development of myocardial remodeling, improves myocardial compliance, and significantly improves left ventricular diastolic function, so that the enlarged left ventricular cavity gradually returns to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D303/24C07D301/00C07C213/02C07C213/04C07C217/28
CPCC07D303/24C07C41/16C07C213/02C07C213/04C07D301/00C07C43/23C07C217/28
Inventor 赵旺明花海堂李惠武张静石文革
Owner 江苏悦兴医药技术有限公司
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