CN111377893B - Synthesis method of 3-n-butyl-l (3H) -isobenzofuranone - Google Patents
Synthesis method of 3-n-butyl-l (3H) -isobenzofuranone Download PDFInfo
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Abstract
The invention discloses a method for synthesizing 3-n-butyl-l (3H) -isobenzofuranone, which comprises the steps of firstly mixing Grignard reagent with Lewis acid, then adding o-formylbenzoic acid into a reaction system, regulating pH to be acidic through an acidic reagent, extracting by using an organic solvent, concentrating and removing the organic solvent to obtain the 3-n-butyl-l (3H) -isobenzofuranone.
Description
Technical Field
The invention relates to a synthesis process for preparing an anti-ischemia medicine 3-n-butyl-l (3H) -isobenzofuranone, belonging to the field of medicines.
Background
3-n-butyl-l (3H) -isobenzofuranone, also known as apigenin A, is a main component of volatile oil extracted from celery seeds, and can also be artificially synthesized; clinical research results show that the 3-n-butyl-l (3H) -isobenzofuranone has an improving effect on the injury of the central nervous function of patients with acute ischemic cerebral apoplexy and can promote the improvement of the neurological deficit. The traditional Chinese medicine composition is mainly used for treating the improvement of neurological deficit of patients suffering from acute ischemic cerebral apoplexy.
Since 3-n-butyl-l (3H) -isobenzofuranone is a liquid volatile oil, it cannot be purified by conventional recrystallization methods. The existing preparation method of 3-n-butyl-l (3H) -isobenzofuranone mainly comprises the steps of firstly preparing 3-n-butyl-l (3H) -isobenzofuranone, and then obtaining a finished product through reduced pressure distillation, wherein the purity can only reach about 98% at most, the number of HPLC detection impurities is more, and the color is poor. Or purifying 3-n-butyl-l (3H) -isobenzofuranone by adopting a column chromatography separation method, wherein the color of the obtained 3-n-butyl-l (3H) -isobenzofuranone product is light yellow, more suspended insoluble substances exist, and HPLC (high performance liquid chromatography) shows a plurality of impurity peaks. Some existing preparation processes are as follows:
wang Zhijian et al (CN 101962374) used phthalic anhydride as the starting material to give an o-pentanoylbenzoic acid intermediate by addition with a halobutane Grignard reagent, which was reduced by sodium borohydride and then cyclized to complete the preparation of 3-n-butyl-l (3H) -isobenzofuranone. Although the raw materials used in the method are easy to obtain, a plurality of impurities are generated in the reaction process, so that the 3-n-butyl-l (3H) -isobenzofuranone as a final product needs to be purified by multiple reduced pressure distillation under high temperature and high vacuum (180-185 ℃/1 mmHg), and the industrial production is difficult. The specific synthetic route of the process is as follows:
li Shaobai reports a synthetic route for the preparation of 3-n-butyl-l (3H) -isobenzofuranone starting from phthalic anhydride and n-valeric anhydride (university of Lanzhou journal of Nature science, 1990,26,118-119). The method comprises the steps of firstly heating phthalic anhydride and n-valeric anhydride to a high temperature of 300 ℃ in the presence of anhydrous sodium sulfate to prepare 3-butylidenephthalide, and then hydrogenating the 3-butylidenephthalide by taking Pd/C as a catalyst. The preparation method involves high temperature of 300 ℃, so that the preparation method is unfavorable for industrial scale-up production. The specific synthetic route of the process is as follows:
nakai Ryozo (patent JP 0469325) and Zhang Yihua (university of Chinese medicine journal, 2008,39,392-397, bioorg. Med. CHem. Lett.,2011,21,4210-4214, org. Biomol. Chem.,2011,9,5670-5681) report the preparation of 3-n-butyl-l (3H) -isobenzofuranone by addition reaction with Grignard reagent n-BuMgBr followed by acidification using o-formylbenzoic acid as starting material. The method is simple to operate, but the reported yield difference is large, and particularly, the reported method takes diethyl ether with low flash point as a solvent, the product is oily substance, the purification cannot be carried out by a recrystallization method, the product needs to be purified by a plurality of column chromatography or high-temperature high-vacuum distillation methods, a large amount of toxic chemical reagents are needed to be used in the industrial scale-up production process, the environmental pollution is easy to cause, the industrialization is difficult to realize, and the method is only suitable for preparing samples for research in a laboratory. The specific synthetic route of the process is as follows:
xiaolong (patent CN 105884726A) also uses o-formylbenzoic acid as a raw material, and after addition reaction with a Grignard reagent n-BuMgCl, the 3-n-butyl-l (3H) -isobenzofuranone product is obtained after acid adjustment, then the product is hydrolyzed by an alkaline substance, a solid is separated out after acid adjustment, and the 3-n-butyl-l (3H) -isobenzofuranone intermediate is obtained after filtration; repeating the acid and alkali regulating process, and finally closing the ring and decompressing to eliminate solvent to obtain 3-n-butyl-l (3H) -isobenzofuranone. The method has complex post-treatment process, repeated acid and alkali adjustment, filtration and other processes, low yield, and time and labor waste. The specific synthetic route of the process is as follows:
although the methods disclosed in the art for preparing 3-n-butyl-l (3H) -isobenzofuranone are successful in synthesizing 3-n-butyl-l (3H) -isobenzofuranone, none of the reported processes are suitable for industrial production. In the methods, the o-formylbenzoic acid is used as a starting material and reacts with the Grignard reagent, so that the reaction is easy to control, the cost is low, and the industrialized production is easy to realize. However, in the art, this route lacks a method for controlling the by-product phthalide (also called isobenzofuranone) of grignard reaction, and a large number of complicated and tedious operations are required to obtain high-purity 3-n-butyl-l (3H) -isobenzofuranone, and the yield is low (usually < 50%), for example, some purification is performed by using multiple column chromatography operations, and some purification is performed by using a complicated operation of repeatedly adjusting alkali and adjusting acid, which is not suitable for industrial production.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a process for synthesizing 3-n-butyl-l (3H) -isobenzofuranone, which is simple to operate, does not need a complicated post-treatment process, has high purity of the obtained product, is low in cost and has a certain industrial prospect.
According to the preparation method, lewis acid and Grignard reagent are mixed firstly, then o-formylbenzoic acid is added into a reaction system, the pH is regulated to be acidic by an acidic reagent, organic solvent is used for extraction, and the organic solvent is removed by concentration, so that 3-n-butyl-l (3H) -isobenzofuranone is obtained.
Specifically, the preparation method of the 3-n-butyl-l (3H) -isobenzofuranone comprises the following three steps:
(1) Mixing Lewis acid and Grignard reagent, and adding o-formylbenzoic acid;
(2) The pH value of the acid reagent is regulated to be acidic;
(3) The organic solvent is removed from the organic phase by extraction with an organic solvent.
The Grignard reagent in the step (1) is selected from one of n-butyl magnesium chloride or n-butyl magnesium bromide, and the concentration of the Grignard reagent is selected from 1-2 mol/L, and more preferably 2mol/L.
The concentration of the Grignard reagent in the step (1) is selected from 1 to 2mol/L, more preferably 2mol/L, wherein the solution of the Grignard reagent is an organic solution of the Grignard reagent, preferably a tetrahydrofuran solution of the Grignard reagent.
The preparation method in the step (1) is characterized in that the molar ratio of the o-formylbenzoic acid to the Grignard reagent in the step (1) is 1:2-6, preferably 1:2-4, and more preferably 1:2-3.
The Lewis acid in step (1) is selected from CuI, cuBr, cuCl, cu (OTf) 2 、ZnBr 2 、ZnCl 2 、Zn(OTf) 2 、MgCl 2 Preferably Zn (OTf) 2 、Cu(OTf) 2 、CuI、ZnBr 2 。
The mass ratio of the Lewis acid to the o-formylbenzoic acid in the step (1) is 1:1-30, preferably 1:1-20, and more preferably 1:7-20.
In the step (1), the o-formylbenzoic acid solution is added into the Grignard reagent, and the reaction temperature is controlled to be between-20 and 35 ℃, preferably between-10 and 25 ℃ and more preferably between 10 and 25 ℃ in the dripping process.
And (3) adding the o-formylbenzoic acid solution into the Grignard reagent in the step (1), and adding an acidic reagent to adjust the pH to be acidic after the reaction is finished.
The acidic reagent in step (2) is selected from aqueous solutions of mineral acids or organic acids, preferably aqueous hydrochloric acid.
The pH of the mixture in the step (2) is adjusted to be acidic, and the pH is adjusted to be 1 to 3, preferably 1 to 2.
The organic solvent in the step (3) is one or more selected from ethyl acetate, isopropyl acetate, n-heptane, methyl tertiary butyl ether, methylene dichloride and petroleum ether.
The preparation method of the step (3) is characterized in that the amount of the o-formylbenzoic acid organic solvent per gram in the step (3) is 1-20 mL, preferably 5-20 mL, and more preferably 5-10 mL.
The invention provides a synthetic method of 3-n-butyl-l (3H) -isobenzofuranone, lewis acid is added into a reaction system to obviously inhibit the generation of phthalide (including phthalide ring-opening products), and the residual amount of o-formylbenzoic acid in the obtained products is generally less than 3% or even less than 1%; the content of impurity phthalide (including ring-opened products of phthalide) is generally <10%, even <5%, and the purity of the product is high, so that the post-treatment purification step is simplified.
The synthesis method provided by the invention has the advantages of simplicity in operation, easiness in obtaining raw materials, high yield and low cost, and the prepared 3-n-butyl-l (3H) -isobenzofuranone has high purity, is simple in post-treatment and purification, and has more industrial prospects.
Drawings
Fig. 1: HPLC profile of 3-n-butyl-l (3H) -isobenzofuranone obtained in example 1;
fig. 2: example 2 addition of Cu (OTf) 2 The 3-n-butyl-l (3H) -isobenzofuranone HP obtainedLC spectrogram;
fig. 3: example 2 addition of MgCl 2 The obtained 3-n-butyl-l (3H) -isobenzofuranone HPLC spectrogram;
fig. 4: example 2 addition of ZnBr 2 The obtained 3-n-butyl-l (3H) -isobenzofuranone HPLC spectrogram;
fig. 5: zn (OTf) was added in example 2 2 HPLC profile of 3-n-butyl-l (3H) -isobenzofuranone obtained.
Fig. 6: HPLC profile of 3-n-butyl-l (3H) -isobenzofuranone obtained in example 3.
Fig. 7: HPLC profile of 3-n-butyl-l (3H) -isobenzofuranone obtained in example 4.
Fig. 8: HPLC profile of 3-n-butyl-l (3H) -isobenzofuranone obtained in example 6.
Fig. 9: HPLC profile of 3-n-butyl-l (3H) -isobenzofuranone obtained in example 7.
Description of peaks in the drawings: a represents 3-n-butyl-l (3H) -isobenzofuranone, B represents phthalide, C represents o-formylbenzoic acid, and D represents a phthalide ring-opening product.
Detailed Description
The invention will be described in more detail hereinafter by way of examples, which are given by way of illustration for further explanation, to which the invention is better understood, but should not be construed to limit the invention.
Example 1: synthesis of 3-n-butyl-l (3H) -isobenzofuranone (without additives)
O-formylbenzoic acid (5.00 g,33.3 mmol) was dissolved in tetrahydrofuran (20.0 mL) to give a tetrahydrofuran solution of O-formylbenzoic acid. A2 mol/L solution of n-butylmagnesium chloride in tetrahydrofuran (36.6 mL,73.3 mmol) was added to a 250mL three-necked flask. After the temperature is reduced to-10 ℃, dropwise adding the tetrahydrofuran solution of the o-formylbenzoic acid into the tetrahydrofuran solution of the n-butyl magnesium chloride, and controlling the internal temperature to be between-10 and 10 ℃. After the completion of the addition, the reaction was continued at 25℃until the completion of the HPLC monitoring reaction. The pH was adjusted to 2-3 with 4mol/L hydrochloric acid, the mixture was separated, the aqueous layer was extracted with ethyl acetate (50 mL. Times.2), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase is concentrated to give 6.23g of 3-n-butyl-l (3H) -isobenzofuranone. The HPLC purity is 87.2%, the phthalide content is 9.2%, the phthalide ring-opening product content is 2.0%, and the residual content of the o-formylbenzoic acid is 0.9%. (HPLC pattern is shown in FIG. 1).
Example 2: synthesis of 3-n-butyl-l (3H) -isobenzofuranone (addition of Lewis acid)
O-formylbenzoic acid (5.00 g,33.3 mmol) was dissolved in tetrahydrofuran (20.0 mL) to give a tetrahydrofuran solution of O-formylbenzoic acid. A solution of 2mol/L of n-butylmagnesium chloride in tetrahydrofuran (36.6 mL,73.3 mmol) and 0.65g of Lewis acid were introduced into a 250mL three-necked flask. And cooling to-10, dropwise adding the tetrahydrofuran solution of the o-formylbenzoic acid into the tetrahydrofuran solution of the n-butyl magnesium chloride, and controlling the internal temperature at-10 ℃. After the completion of the addition, the reaction was continued at 25℃until the completion of the HPLC monitoring reaction. The pH was adjusted to 2-3 with 4mol/L hydrochloric acid, the mixture was separated, the aqueous layer was extracted with ethyl acetate (50 mL. Times.2), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase is concentrated to give 3-n-butyl-l (3H) -isobenzofuranone.
The experimental results are shown in Table 1.HPLC patterns are shown in figures 2-5.
Conclusion: as can be seen from the experimental results in Table 1, under the same conditions, the addition of Lewis acid to the reaction system can obviously inhibit the generation of phthalide (including ring-opened products of phthalide), and the effect is particularly obvious when the added Lewis acid is copper salt or zinc salt. The reduction of the phthalide content in the product greatly reduces the difficulty of post-treatment and purification.
Example 3: synthesis of 3-n-butyl-l (3H) -isobenzofuranone (addition of CuI)
O-formylbenzoic acid (5.00 g,33.3 mmol) was dissolved in tetrahydrofuran (25.0 mL) to give a tetrahydrofuran solution of O-formylbenzoic acid. A solution of 2mol/L of n-butylmagnesium bromide in tetrahydrofuran (36.6 mL,73.3 mmol) and 0.65g of CuI were added to a 250mL three-necked flask. After the temperature is reduced to 0 ℃, dropwise adding the tetrahydrofuran solution of the o-formylbenzoic acid into the tetrahydrofuran solution of the n-butylmagnesium bromide, and controlling the internal temperature at 0-25 ℃. After the completion of the addition, the reaction was continued at 25℃until the completion of the HPLC monitoring reaction. The pH was adjusted to 1-2 with 3mol/L hydrochloric acid, the mixture was separated, the aqueous layer was extracted with isopropyl acetate (50 mL. Times.2), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase is concentrated to give 6.25g of 3-n-butyl-l (3H) -isobenzofuranone. The HPLC purity was 93.9%, the phthalide content was 5.1%, the phthalide ring-opened product was not detected, and the o-formylbenzoic acid content was 0.14%.
(HPLC pattern is shown in FIG. 6).
Example 4: synthesis of 3-n-butyl-l (3H) -isobenzofuranone (ZnBr addition) 2 )
O-formylbenzoic acid (5.00 g,33.3 mmol) was dissolved in tetrahydrofuran (30.0 mL) to give a tetrahydrofuran solution of O-formylbenzoic acid. 2mol/L of n-butylmagnesium chloride in tetrahydrofuran (40.0 ml,80.0 mmol), 0.25g of ZnBr 2 Add to 250mL three-necked flask. After the temperature is reduced to 0 ℃, dropwise adding the tetrahydrofuran solution of the o-formylbenzoic acid into the tetrahydrofuran solution of the n-butylmagnesium bromide, and controlling the internal temperature at 0-25 ℃. After the completion of the addition, the reaction was continued at 25℃until the completion of the HPLC monitoring reaction. The pH was adjusted to 2-3 with 4mol/L hydrochloric acid, the mixture was separated, the aqueous layer was extracted with ethyl acetate (50 mL. Times.2), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase is concentrated to give 6.30g of 3-n-butyl-l (3H) -isobenzofuranone. The HPLC purity was 94.9%, the phthalide content was 3.6%, the phthalide ring-opened product content was 0.6%, and the residual content of the o-formylbenzoic acid was 0.2%. (HPLC pattern is shown in FIG. 7).
Example 5: synthesis of 3-n-butyl-l (3H) -isobenzofuranone (Zn (OTf added) 2 )
O-formylbenzoic acid (5.00 g,33.3 mmol) was dissolved in tetrahydrofuran (20.0 mL) to give a tetrahydrofuran solution of O-formylbenzoic acid. 1mol/L of n-butylmagnesium chloride in tetrahydrofuran (73.3 mL,73.3 mmol), 0.50g of Zn (OTf) 2 Add to 250mL three-necked flask. And (3) cooling to 0 ℃, dropwise adding the tetrahydrofuran solution of the o-formylbenzoic acid into the tetrahydrofuran solution of the n-butyl magnesium chloride, and controlling the internal temperature at 0-25 ℃. After the completion of the dropping, the reaction was continued at 25℃until the completion of the HPLC monitoring reaction. The pH was adjusted to 1-2 with 6mol/L hydrochloric acid, the mixture was separated, the aqueous layer was extracted with n-heptane (50 mL. Times.2), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase is concentrated to give 6.27g of 3-n-butyl-l (3H) -isobenzofuranone. The HPLC purity is 93.2%, the phthalide content is 6.1%, the phthalide ring-opening product content is 0.2%, and the residual content of the o-formylbenzoic acid is 0.2%.
Example 6: synthesis of 3-n-butyl-l (3H) -isobenzofuranone (ZnBr addition) 2 )
O-formylbenzoic acid (200 g) was dissolved in tetrahydrofuran (800 mL) to obtain a tetrahydrofuran solution of O-formylbenzoic acid. Tetrahydrofuran solution (1460 ml) of 2mol/L n-butylmagnesium chloride, 10g ZnBr 2 Into a 5L reaction flask. After the temperature is reduced to 10 ℃, dropwise adding the tetrahydrofuran solution of the o-formylbenzoic acid into the tetrahydrofuran solution of the n-butyl magnesium chloride, and controlling the internal temperature to be 10-25 ℃. After the completion of the addition, the reaction was continued at 25℃until the completion of the HPLC monitoring reaction. The pH was adjusted to 1-2 with 6mol/L hydrochloric acid, the mixture was separated, the aqueous layer was extracted with methyl tert-butyl ether (2L. Times.2), and the organic phases were combined and washed with saturated brine (2L). After concentration of the organic phase 251g of 3-n-butyl-l (3H) -isobenzofuranone are obtained. HPLC purity was 95.3% with a phthalide content of 4.3%, phthalide ring-opened product was undetected, and o-formylbenzoic acid was undetected. (HPLC pattern is shown in FIG. 8).
Example 7: purification of 3-n-butyl-l (3H) -isobenzofuranone
Dissolving the 3-n-butyl-L (3H) -isobenzofuranone prepared in the example 6 in 2L of methanol and 2L of water, adding 112g of lithium hydroxide, heating to reflux, reacting for 2 hours, concentrating to remove the methanol, adjusting the pH of the residual aqueous solution to 4-5 by using 15wt% of citric acid aqueous solution, precipitating a large amount of white solid, filtering, leaching a filter cake by water, and pumping to obtain the 3-n-butyl-L (3H) -isobenzofuranone intermediate.
The 3-n-butyl-L (3H) -isobenzofuranone intermediate is added into 800mL of ethyl acetate and 200mL of 6mol/L hydrochloric acid, the mixture is stirred for 2 hours and then separated, the organic phase is washed by water, dried by anhydrous sodium sulfate, filtered and concentrated to obtain 165g of 3-n-butyl-L (3H) -isobenzofuranone pure product with the yield of 65 percent. HPLC purity was 99.7% with 0.04% phthalide, undetected phthalide ring-opened product, and undetected orthoformylbenzoic acid. (HPLC pattern is shown in FIG. 9).
Claims (22)
1. A process for the preparation of 3-n-butyl-l (3H) -isobenzofuranone, characterized in that it comprises the following steps:
(1) Mixing Lewis acid and Grignard reagent, and adding o-formylbenzoic acid;
(2) The pH value of the acid reagent is regulated to be acidic;
(3) The organic solvent is removed from the organic phase by extraction with an organic solvent.
2. A preparation method according to claim 1, wherein the grignard reagent in step 1 is selected from n-butyl magnesium chloride or n-butyl magnesium bromide, and the concentration of the grignard reagent is 1-2 mol/L.
3. A method according to claim 2, characterized in that the grignard reagent concentration is 2mol/L.
4. The preparation method according to claim 1, wherein the molar ratio of the o-formylbenzoic acid to the grignard reagent in the step 1 is 1:2-6.
5. A process according to claim 4, wherein the molar ratio of o-formylbenzoic acid to Grignard reagent in step 1 is 1:2 to 4.
6. The process of claim 5, wherein the molar ratio of o-formylbenzoic acid to Grignard reagent in step 1 is 1:2-3.
7. A process according to claim 1Characterized in that in step 1 the Lewis acid is selected from CuI, cuBr, cuCl, cu (OTf) 2 、ZnBr 2 、ZnCl 2 、Zn(OTf) 2 、MgCl 2 One of which is a metal alloy.
8. A process according to claim 7, wherein in step 1 the Lewis acid is selected from Zn (OTf) 2 、CuI、Cu(OTf) 2 Or ZnBr 2 。
9. A process according to claim 1, characterized in that the mass ratio of lewis acid to o-formylbenzoic acid is 1:1-30.
10. A process according to claim 9, characterized in that the mass ratio of lewis acid to o-formylbenzoic acid is 1:1-20.
11. A process according to claim 10, characterized in that the mass ratio of lewis acid to o-formylbenzoic acid is 1:7-20.
12. The preparation method according to claim 1, wherein in the step 1, the o-formylbenzoic acid is added to the grignard reagent, and the reaction temperature is controlled to be-20-35 ℃.
13. A method according to claim 12, characterized in that the temperature is-10-25 ℃.
14. A method according to claim 13, characterized in that the temperature is 10-25 ℃.
15. A method according to claim 1, characterized in that the acidic reagent is selected from aqueous solutions of mineral acids or organic acids.
16. A method according to claim 15, wherein the acidic reagent is aqueous hydrochloric acid.
17. A process according to claim 1, characterized in that the pH adjustment in step 2 is to an acidity of from 1 to 3.
18. A process according to claim 17, wherein the pH adjustment in step 2 is carried out to an acidity of from 1 to 2.
19. The preparation method according to claim 1, wherein the organic solvent in the step 3 is one or more selected from ethyl acetate, isopropyl acetate, n-heptane, methyl tert-butyl ether, methylene chloride and petroleum ether.
20. A process according to claim 1 or 19, characterized in that the amount of organic solvent per gram of o-formylbenzoic acid in step 3 is 1-20 mL.
21. A process according to claim 20, characterized in that the amount of organic solvent per gram of o-formylbenzoic acid in step 3 is 5-20 mL.
22. A process according to claim 21, characterized in that the amount of organic solvent per gram of o-formylbenzoic acid in step 3 is 5-10 mL.
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