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Synthesis method of 3-n-butyl-1-(3H)-isobenzofuranone

A technology of furanone and isobenzene, applied in the field of medicine, can solve problems such as tedious, unsuitable for industrial production, and complicated

Pending Publication Date: 2020-07-07
JIANGSU SIMCERE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Yet, in the technical field, this route all lacks the method for controlling Grignard reaction by-product phthalide (also known as isobenzofuranone), to obtain high-purity 3-n-butyl-1 (3H)-isobenzene Furanone requires a lot of complex and cumbersome operations, and the yield is low (usually <50%). For example, some use multiple column chromatography operations for purification, and some use tedious repeated operations of adjusting base and acid for purification. , not suitable for industrial production

Method used

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  • Synthesis method of 3-n-butyl-1-(3H)-isobenzofuranone
  • Synthesis method of 3-n-butyl-1-(3H)-isobenzofuranone
  • Synthesis method of 3-n-butyl-1-(3H)-isobenzofuranone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Synthesis of 3-n-butyl-1 (3H)-isobenzofuranone (without additive)

[0045] O-formylbenzoic acid (5.00 g, 33.3 mmol) was dissolved in tetrahydrofuran (20.0 mL) to obtain a tetrahydrofuran solution of o-formylbenzoic acid. Add 2mol / L tetrahydrofuran solution of n-butylmagnesium chloride (36.6ml, 73.3mmol) into a 250mL three-necked flask. After cooling down to -10°C, add the tetrahydrofuran solution of o-formylbenzoic acid dropwise into the tetrahydrofuran solution of n-butylmagnesium chloride, and control the internal temperature at -10-10°C. After dropping, the reaction was continued at 25° C. until the end of the reaction monitored by HPLC. Adjust the pH to 2-3 with 4 mol / L hydrochloric acid, separate the layers, extract the aqueous layer with ethyl acetate (50 mL×2), combine the organic phases, and wash with saturated brine (100 mL). After the organic phase was concentrated, 6.23 g of 3-n-butyl-l(3H)-isobenzofuranone was obtained. The HPLC purity is 87.2%...

Embodiment 2

[0046] Example 2: Synthesis of 3-n-butyl-1(3H)-isobenzofuranone (addition of Lewis acid)

[0047] O-formylbenzoic acid (5.00 g, 33.3 mmol) was dissolved in tetrahydrofuran (20.0 mL) to obtain a tetrahydrofuran solution of o-formylbenzoic acid. Add 2mol / L tetrahydrofuran solution of n-butylmagnesium chloride (36.6ml, 73.3mmol) and 0.65g Lewis acid into a 250mL three-necked flask. After cooling down to -10°C, add the tetrahydrofuran solution of o-formylbenzoic acid dropwise into the tetrahydrofuran solution of n-butylmagnesium chloride, and control the internal temperature at -10 to 10°C. After dropping, the reaction was continued at 25° C. until the end of the reaction monitored by HPLC. Adjust the pH to 2-3 with 4 mol / L hydrochloric acid, separate the layers, extract the aqueous layer with ethyl acetate (50 mL×2), combine the organic phases, and wash with saturated brine (100 mL). After concentration of the organic phase, 3-n-butyl-l(3H)-isobenzofuranone was obtained.

[00...

Embodiment 3

[0051] Example 3: Synthesis of 3-n-butyl-1 (3H)-isobenzofuranone (addition of CuI)

[0052] O-formylbenzoic acid (5.00 g, 33.3 mmol) was dissolved in tetrahydrofuran (25.0 mL) to obtain a tetrahydrofuran solution of o-formylbenzoic acid. Add 2mol / L tetrahydrofuran solution of n-butylmagnesium bromide (36.6ml, 73.3mmol) and 0.65g CuI into a 250mL three-necked flask. After cooling down to 0°C, add the tetrahydrofuran solution of o-formylbenzoic acid dropwise into the tetrahydrofuran solution of n-butylmagnesium bromide, and control the internal temperature at 0-25°C. After dropping, the reaction was continued at 25° C. until the end of the reaction monitored by HPLC. Adjust the pH to 1-2 with 3 mol / L hydrochloric acid, separate the layers, extract the aqueous layer with isopropyl acetate (50 mL×2), combine the organic phases, and wash with saturated brine (100 mL). After the organic phase was concentrated, 6.25 g of 3-n-butyl-l(3H)-isobenzofuranone was obtained. The HPLC puri...

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Abstract

The invention discloses a method for synthesizing 3-n-butyl-1-(3H)-isobenzofuranone. The method comprises the following steps: synthesizing 3-n-butyl-1-(3H)-isobenzofuranone; mixing a Grignard reagentwith Lewis acid; adding o-formylbenzoic acid into the reaction system, adjusting the pH value to be acidic by an acidic reagent, extracting the reaction product by using an organic solvent, and concentrating the reaction product to remove the organic solvent to obtain 3-n-butyl-1-(3H)-isobenzofuranone. The method is simple to operate, does not need a complicated post-treatment process, and has the advantages of high product purity, low cost and certain industrial prospects.

Description

technical field [0001] The invention relates to a synthesis process for preparing anti-ischemic drug 3-n-butyl-l(3H)-isobenzofuranone, which belongs to the field of medicine. Background technique [0002] 3-n-butyl-l(3H)-isobenzofuranone, also known as apigenin A, is the main component of a volatile oil extracted from celery seed, and can also be synthesized artificially; clinical research results show that 3 -n-butyl-l(3H)-isobenzofuranone can improve the damage of central nervous system function in patients with acute ischemic stroke, and can promote the improvement of neurological deficit. Clinically, it is mainly used for the improvement of neurological deficit in patients with acute ischemic stroke. [0003] Since 3-n-butyl-l(3H)-isobenzofuranone is a liquid volatile oil, it cannot be purified by conventional recrystallization methods. Existing 3-n-butyl-l (3H)-isobenzofuranone preparation method mainly is first to prepare 3-n-butyl-l (3H)-isobenzofuranone, and then t...

Claims

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Application Information

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IPC IPC(8): C07D307/88
CPCC07D307/88
Inventor 王元强廖明毅肖承涛陈宝龙任晋生
Owner JIANGSU SIMCERE PHARMA
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