CN111943921A - Preparation method of butylphthalide - Google Patents
Preparation method of butylphthalide Download PDFInfo
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- CN111943921A CN111943921A CN201910413544.3A CN201910413544A CN111943921A CN 111943921 A CN111943921 A CN 111943921A CN 201910413544 A CN201910413544 A CN 201910413544A CN 111943921 A CN111943921 A CN 111943921A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Abstract
The invention discloses a preparation method of butylphthalide, which takes phthalic anhydride as a starting material to prepare the butylphthalide through condensation, hydrolysis, reduction and esterification. The preparation method has the advantages of easily obtained reaction raw materials, simple operation, relatively mild reaction conditions and low equipment requirement, can obtain the raw material medicine with the purity of more than 99.80 percent and meeting the medicinal requirement without rectification, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of preparation of medical compounds, and particularly relates to a preparation method of butylphthalide.
Background
Butylphthalide, apigenin, english name: dl-3-n-butylphthalamide, chemical name: racemic-3-n-butylphthalide with a chemical structural formula:
the medicine is a chemical new medicine developed in China, blocks multiple pathological links of ischemic brain injury, improves acute ischemic stroke nerve function impairment, and improves the living ability and the living quality of patients through the effects of reconstructing microcirculation in cerebral ischemic areas, inhibiting nerve cell apoptosis, protecting mitochondria, eliminating free radicals, resisting platelet aggregation, inhibiting thrombosis, reducing inflammatory reaction, protecting vascular endothelial cells and the like.
Regarding the preparation method of butylphthalide, the literature reports methods mainly include:
chinese patent CN101962374 discloses a preparation method of butylphthalide, which uses phthalic anhydride as raw material, and obtains an intermediate o-valeryl benzoic acid through addition reaction with a Grignard reagent of halogenated butane, and then butyl phthalide is obtained through reduction by sodium borohydride and acidic cyclization. The Grignard reagent used in the method is a solid-liquid mixture and is quite active, the Grignard reagent needs to be dripped into a low-temperature (-below 10 ℃) system containing phthalic anhydride, the Grignard reagent is difficult to transfer, great potential safety hazards exist in the preparation and use of the Grignard reagent, a large number of byproducts are generated, low-temperature reaction is involved, the requirement on reaction equipment is high, the obtained intermediate is liquid, the purification is difficult, and the method is not suitable for industrial production.
Chinese patent CN107216298A discloses a method for preparing butylphthalide, which comprises the steps of using phthalic anhydride as a raw material, obtaining butylphthalide through condensation with valeric anhydride, using Raney nickel as a catalyst, carrying out hydrogenation reaction on the butenyl phthalide in an alcohol solvent, reducing pressure to obtain a first intermediate (crude butylphthalide), mixing the crude butylphthalide, sodium hydroxide and water for reaction, washing the reaction system with dichloromethane, adding the alcohol solvent, adjusting acid for reaction to obtain hydroxypentylbenzoic acid, and carrying out cyclization reaction on the hydroxypentylbenzoic acid in an acidic organic solvent to obtain the butylphthalide. According to the method, raney nickel is used for hydrogenation reduction of butenyl phthalide, flammable reagents of raney nickel and hydrogen are used, potential safety hazards exist, the purity of the prepared crude product of the butenyl phthalide is low and is about 97%, the purification of a finished product is difficult, in addition, heavy metal nickel is easy to exceed the standard, and the method is not suitable for industrial production.
Chinese patent CN105859670B discloses a preparation method of high-purity butylphthalide, which comprises the steps of reacting o-carboxybenzaldehyde with a Grignard reagent to prepare a crude butylphthalide product, rectifying the crude butylphthalide product at 1-2 mbar, collecting fractions at 130-140 ℃, dividing the obtained fractions into hydroxypentyl benzoic acid alkali metal salts, and cyclizing with hydrochloric acid to obtain butylphthalide with the HPLC purity of more than 99.90%. The method for preparing the crude butylphthalide uses a high-risk Grignard reagent, is not beneficial to safe production, and the crude butylphthalide needs to be purified by one-time high-temperature high-vacuum rectification, has high requirements on rectification equipment, is easy to generate degradation products in the high-temperature rectification process, and is not easy to remove in the post-treatment process.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.
Aiming at the defects of the prior art, the invention provides the preparation method of butylphthalide, which has the advantages of easily obtained reaction raw materials, simple operation, relatively mild reaction conditions, low requirement on equipment, small environmental pollution and suitability for industrial production. Aiming at the characteristic that the finished butylphthalide product liquid is difficult to purify (most of intermediates obtained by synthesizing butylphthalide in literature reports are liquid and difficult to purify), the invention creatively uses two carboxylate solids (compound III and compound IV) as intermediates of a synthetic route, and the quality of the intermediates and the finished butylphthalide product is greatly improved by recrystallizing and purifying the two solid intermediates; in addition, when the compound II (butylene phthalide) is prepared, the butylene phthalide with the purity of more than 80 percent is collected to be used for preparing the compound III by simple distillation, and the compound III with the purity of more than 99 percent can be prepared, and the single impurity of the compound III is not more than 0.2 percent.
In an embodiment of the present invention, the present invention provides a method for preparing butylphthalide, comprising the steps of:
(1) carrying out condensation reaction on the compound I and valeric anhydride to obtain a compound II;
(2) carrying out hydrolysis reaction on the compound II obtained in the step (1) to obtain a compound III;
(3) sequentially carrying out reduction reaction, cyclization reaction 1 and ring opening reaction on the compound III obtained in the step (2) to obtain a compound IV;
(4) performing cyclization reaction 2 on the compound IV obtained in the step (3) to obtain a compound V, namely butylphthalide;
wherein, M in the compound III1And M in Compound IV2Each independently an alkali metal ion, preferably sodium, potassium or lithium.
In some embodiments of the invention, in step (1), compound I is reacted with pentanoic anhydride over a catalyst to provide compound II; here, the catalyst is selected from any one of sodium acetate, sodium propionate, sodium butyrate and sodium valerate, and preferably the catalyst is sodium valerate.
In a preferred embodiment, in the step (1), the compound I, the valeric anhydride and part of sodium valerate are mixed and reacted, and the reaction temperature is 130-160 ℃, preferably 135-145 ℃; and then adding the rest sodium valerate to continue the reaction, wherein the temperature for continuing the reaction is 160-190 ℃, and preferably 175-185 ℃.
In a preferred embodiment, in the step (1), the compound I, the valeric anhydride and part of sodium valerate are mixed and reacted at a temperature of 135-145 ℃ until no gas is generated, and then the rest sodium valerate is added into the reaction system, and the mixture is kept at a temperature of 175-185 ℃ and the reaction is continued for 1 hour to obtain the compound II.
In a preferred embodiment, in the step (1), the molar ratio of the compound I to the valeric anhydride to the catalyst (preferably sodium valerate) is 1: 1-3: 0.2-2, and the molar ratio of the compound I to the valeric anhydride to the catalyst (preferably sodium valerate) is 1: 1-2: 0.2-1.
In some embodiments of the invention, in step (2), compound II is subjected to a hydrolysis reaction with a basic substance to give compound III. Preferably, the compound II is hydrolyzed by alkaline substances in a reaction solvent to obtain a compound III; here, the reaction solvent is selected from at least one of water, methanol and ethanol, and preferably the reaction solvent is methanol; the alkaline substance is one or two selected from potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium carbonate, lithium carbonate and sodium carbonate, and preferably, the alkaline substance is sodium hydroxide.
In some embodiments of the present invention, in the step (2), the reaction temperature of the hydrolysis reaction is 0 ℃ to 100 ℃, preferably, the reaction temperature is 50 ℃ to 70 ℃.
In some embodiments of the present invention, in the step (2), after the hydrolysis reaction is completed, the compound III is obtained through a crystallization step, wherein a crystallization solvent used in the crystallization step is one of ethyl acetate, tetrahydrofuran and methyl tert-butyl ether, and preferably the crystallization solvent is methyl tert-butyl ether.
In a preferred embodiment, in the step (2), the compound II is added into a methanol solution of sodium hydroxide, and hydrolysis reaction is carried out at 25-35 ℃ to obtain the compound III.
In a more preferred embodiment, in the step (2), the molar ratio of the compound II to sodium hydroxide is 1: 1-2, and preferably, the molar ratio of the compound II to sodium hydroxide is 1: 1.0-1.5.
In some embodiments of the present invention, in step (3), compound III is subjected to a reduction reaction, a cyclization reaction 1 and a ring-opening reaction in sequence to obtain compound IV, wherein the reduction reaction is reduced by sodium borohydride, the cyclization reaction 1 is performed by hydrochloric acid, and the ring-opening reaction is performed by potassium hydroxide, sodium hydroxide or lithium hydroxide. Preferably, the reduction reaction, the cyclization reaction 1 or the ring-opening reaction are each independently carried out in at least one solvent selected from the group consisting of water, methanol, ethanol and tetrahydrofuran.
In some embodiments of the present invention, in the step (3), the reaction temperature of the reduction reaction is 60 to 100 ℃, preferably 90 to 100 ℃; the reaction temperature of the cyclization reaction 1 is 30-50 ℃, and preferably 40-50 ℃; the reaction temperature of the ring-opening reaction is 50-70 ℃, and preferably 60-70 ℃.
In some embodiments of the present invention, in the step (3), after the ring-opening reaction is completed, compound IV is obtained through a crystallization step, wherein the crystallization solvent used in the crystallization step is at least one crystallization solvent selected from the group consisting of ethyl acetate, isopropyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran, and preferably the crystallization solvent is ethyl acetate.
In a preferred embodiment, in the step (3), the compound III is reacted with sodium borohydride under the catalysis of sodium hydroxide, and then the compound IV is obtained by hydrochloric acid cyclization and potassium hydroxide ring opening.
In a more preferred embodiment, in the step (3), the compound III is dissolved in water, sodium borohydride aqueous solution containing sodium hydroxide is slowly dripped into the water, and after the dripping is finished, the temperature is raised to 90-100 ℃ for reduction reaction; after the reduction reaction is finished, adding hydrochloric acid into the reaction system to adjust the pH value of the system to be 1-4, and carrying out cyclization reaction 1; after the cyclization reaction 1 is finished, adding a methanol aqueous solution of potassium hydroxide into the cyclization concentrate, and heating for reflux reaction to obtain a compound IV.
In a more preferred embodiment, in the step (3), the molar ratio of the compound III to the sodium borohydride to the sodium hydroxide is 1:0.3 to 1:0.1 to 0.5, and preferably the molar ratio of the compound III to the sodium borohydride to the sodium hydroxide is 1:0.6 to 1:0.1 to 0.2.
In some embodiments of the invention, in step (4), compound IV is subjected to cyclization reaction 2 under acidic conditions to give compound V.
In some embodiments, in the step (4), the reaction temperature of the cyclization reaction 2 is 30 to 50 ℃, preferably 40 to 50 ℃.
In some embodiments of the present invention, in the step (4), the cyclization reaction 2 is performed in at least one solvent selected from the group consisting of water, methanol, ethanol, isopropanol, and tetrahydrofuran.
In some embodiments of the present invention, in the step (4), after the cyclization reaction 2 is completed, a crystallization step is performed to obtain the compound V, wherein a crystallization solvent used in the crystallization step is one of ethyl acetate and isopropyl acetate, preferably ethyl acetate.
In a preferred embodiment, in the step (4), the acidic condition is under the action of hydrochloric acid, and preferably, the pH value of the system when the cyclization reaction 2 is carried out is 1-4, preferably 1-3, and more preferably 1-2.
In a more preferable embodiment, in the step (4), the compound IV is dissolved in water, hydrochloric acid is added dropwise to control the pH of the system to be 1-2, and the reaction is carried out at 40-50 ℃ to obtain the compound V.
Compared with the prior art, the invention provides the preparation method of butylphthalide, which is suitable for industrial production and is prepared by using phthalic anhydride and valeric anhydride as starting materials.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims hereof.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
In the embodiment of the invention, the detection method of related substances of each intermediate of butylphthalide comprises the following steps: HPLC method
A chromatographic column: using phenyl silane bonded silica gel as filler (SUPELCOSIL LC-DP column 250mm × 4.6mm, phi 5 μm or equivalent chromatography column)
Detection wavelength: 227nm
Column temperature: 40 deg.C
Flow rate: 1.5ml/min
Mobile phase A: with 0.01mol/L potassium dihydrogen phosphate solution (pH adjusted to 3.0 with dilute phosphoric acid) -acetonitrile (70:30)
Mobile phase B: with 0.01mmol/L potassium dihydrogen phosphate solution (pH adjusted to 3.0 with dilute phosphoric acid) -methanol-acetonitrile (20:40:40)
Gradient elution was performed as follows:
| time of day | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 5 | 100 | 0 |
| 35 | 70 | 30 |
| 50 | 40 | 60 |
| 55 | 40 | 60 |
| 55.01 | 100 | 0 |
| 65 | 100 | 0 |
Test solution: taking a proper amount of the product, precisely weighing, dissolving with diluent (methanol), diluting to obtain a solution containing about 1mg per 1ml, and shaking to obtain a test solution.
The detection method of the butyl phthalide finished product ethyl acetate residue comprises the following steps: GC method
A chromatographic column: a capillary column taking 6 percent of cyanopropylphenyl-94 percent of dimethyl polysiloxane as stationary liquid (or with similar polarity) as a chromatographic column
And (3) sample introduction mode: a headspace sampling method;
chromatographic parameters: carrier gas: nitrogen gas; flow rate of carrier gas: 2.0 ml/min; the split ratio is as follows: 10: 1;
a detector: a hydrogen flame ionization detector FID; detector temperature: 300 ℃; sample inlet temperature: 220 ℃;
column temperature: the initial temperature is 40 ℃, the temperature is increased to 140 ℃ at the speed of 10 ℃/min after the initial temperature is maintained for 6min, the temperature is increased to 240 ℃ at the speed of 30 ℃/min, and the initial temperature is maintained for 5 min;
headspace equilibrium temperature: 100 ℃; headspace equilibrium time: and (3) 30 min.
Test solution: taking about 0.1g of the product, precisely weighing, placing in a 10ml headspace bottle, precisely adding 1ml of N, N-dimethylformamide to dissolve, and sealing to obtain a test solution; an appropriate amount of ethyl acetate was precisely weighed, dissolved in N, N-dimethylformamide and quantitatively diluted to give a solution containing about 0.5mg per 1ml, precisely weighed 1ml, placed in a 10ml headspace bottle, and sealed to give a control solution.
EXAMPLE 1 preparation of Compound II
Adding the compound I (148g, 1mol), valeric anhydride (279g, 1.5mol) and sodium valerate (62g, 0.5mol) into a 1L three-necked bottle, and heating to 135-145 ℃ to react under mechanical stirring until no gas is generated, wherein the reaction lasts for about 3 hours; then, sodium valerate (62g, 0.5mol) is added into the system, the temperature is raised to 175-185 ℃, the reaction is kept for 1 hour, and HPLC (high performance liquid chromatography) detection shows that the raw materials are completely reacted (1.5% of the compound 1 is remained). After the reaction is completed, reducing the temperature of the system to 90-100 ℃, distilling under reduced pressure to remove low-boiling point reagents to obtain a reddish brown concentrate, then reducing the temperature of the system to room temperature, adding 450g of purified water into the concentrate, adjusting the pH of the system to 8-9 by using ammonia water, extracting twice by using 450ml of dichloromethane, washing twice by using 450g of saturated saline solution, removing a solvent under reduced pressure to obtain a reddish brown oily liquid, distilling under reduced pressure to collect distillate at 140-180 ℃/5-10 mmHg to obtain 150g of light yellow oily liquid, namely a compound II, wherein the purity of (Z/E) is 86.79%, and the yield is 79%.
EXAMPLE 2 Compound III (M)1As sodium ion) preparation
600g of methanol and 33.2g of sodium hydroxide were added to a 2L three-necked flask, and dissolved with stirring, 120g of the compound II prepared in example 1 was added dropwise thereto, and the mixture was reacted at 25 ℃ to 35 ℃ for 1 hour after completion of the addition, followed by detection by HPLC and completion of the reaction of the starting material (compound II was not detected). Reducing the temperature of the system to 0-10 ℃, dropwise adding 720g of methyl tert-butyl ether into the system, after the dropwise adding, keeping the temperature and crystallizing for 2 hours, carrying out suction filtration, and carrying out vacuum drying on a filter cake at 40 ℃ to obtain 131g of light orange solid, namely a compound III (M1 is sodium ions), wherein the purity is 99.36%, the maximum single impurity content is 0.19%, and the yield is 90%.
EXAMPLE 3 Compound IV (M)2As potassium ion) preparation
In a 2L three-necked flask, 488g of purified water, Compound III (M) prepared in example 2 was added1Sodium ions) (107g, 0.47mol), stirring and dissolving, controlling the temperature to be 0-10 ℃, dropwise adding a mixed solution of sodium borohydride (21.55g, 0.38mol), sodium hydroxide (4.0g, 0.1mol) and 122g of water, raising the temperature to 90-100 ℃ after dropwise adding, reacting for 2 hours, and detecting by HPLC (high performance liquid chromatography) until the raw materials are completely reacted (0.05 percent of compound III remains). Cooling to 40-50 ℃, dropwise adding concentrated hydrochloric acid into the concentrated solution, adjusting the pH value to 1-2, carrying out heat preservation reaction for 2 hours, extracting with 480g of ethyl acetate, washing the obtained organic phase twice with 480g of purified water, washing twice with 480g of saturated saline solution, carrying out vacuum concentration, adding 480g of methanol, 120g of water and 32g of potassium hydroxide into the concentrated solution, heating to 60-70 ℃, carrying out heat preservation reaction for 2 hours, cooling to 40-50 ℃, carrying out vacuum concentration to separate out a large amount of solids, adding 244g of ethyl acetate into the concentrate, continuously cooling to 0-10 ℃, crystallizing for 5 hours, carrying out suction filtration, and carrying out vacuum drying on the filter cake at 50 ℃ to obtain 105g of white powder solid, namely a compound IV (M2 is potassium ion), wherein the purity is 99.91%, the maximum single impurity is 0.03%, and the yield is 85%.
EXAMPLE 4 preparation of Compound V
Into a 1L three-necked flask was charged 300g of purified water, Compound IV (M) prepared in example 32Potassium ion) 100g, stirring and dissolving, heating to 40-50 ℃, dropwise adding concentrated hydrochloric acid about 50g into the system, adjusting the pH of the system to 1-2, carrying out heat preservation reaction for 2 hours, and carrying out HPLC (high performance liquid chromatography) detection to ensure that the raw material completely reacts (0.02% of compound IV remains). Adding 300g of ethyl acetate into the system for extraction, washing an organic layer twice with 300g of purified water, washing an organic layer twice with 300g of saturated sodium bicarbonate, washing a saturated saline solution twice with 480g of saturated saline solution, drying 25g of anhydrous sodium sulfate for 1 hour, performing suction filtration, adding 2g of activated carbon into a filtrate for decoloring for 1 hour, performing suction filtration, filtering the filtrate through a 0.45-micron microporous filter membrane, and filtering the obtained filtrate through a membrane filtration deviceAnd (3) removing the solvent ethyl acetate by pressure concentration until the residual solvent ethyl acetate is less than 0.5 percent by GC detection, stopping concentration to obtain 70g of colorless transparent liquid, namely the compound V, namely the butyl phthalide finished product, wherein the yield is 90 percent, the purity of the finished product is 99.89 percent (by HPLC detection), the maximum single impurity is 0.02 percent, and the residual of the finished product ethyl acetate is 0.05 percent (by GC detection).
EXAMPLE 5 preparation of Compound II
In a 1L three-necked flask, heating compound I (148g, 1mol), valeric anhydride (279g, 1.5mol) and sodium acetate (40.5g, 0.5mol) to 135-145 ℃ for reaction under mechanical stirring until no gas is generated, and reacting for about 3 hours; then, sodium acetate (40.5g, 0.5mol) is added into the system, the temperature is raised to 175-185 ℃, the reaction is kept for 1 hour, and HPLC detection shows that the raw material is completely reacted (1.3 percent of compound I remains). After the reaction is completed, reducing the temperature of the system to 90-100 ℃, distilling under reduced pressure to remove a low-boiling point reagent to obtain a reddish brown concentrate, then reducing the temperature of the system to room temperature, adding 450g of water into the residue, adjusting the pH of the system to 8-9 by using ammonia water, extracting twice by using 450ml of chloroform, washing twice by using 450g of saturated saline solution, removing a solvent under reduced pressure to obtain a reddish brown oily liquid, distilling under reduced pressure to collect a fraction of 140-180 ℃/5-10 mmHg to obtain 145g of a light yellow oily liquid, namely a compound II, wherein the purity of (Z/E) is 87.02%, and the yield is 77%.
EXAMPLE 6 Compound III (M)1As sodium ion) preparation
Adding 300g of ethanol and 33.2g of sodium hydroxide into a 2L three-necked bottle, reducing the temperature of the system to 20-25 ℃, slowly dropwise adding 120g of the compound II prepared in example 5, after dropwise adding, heating to 55-65 ℃ for reaction for 1 hour, and detecting by HPLC (high performance liquid chromatography), wherein the raw material is completely reacted (the compound II is not detected). Reducing the temperature of the system to 0-10 ℃, dropwise adding 720g of ethyl acetate into the system, keeping the temperature for crystallization for 2 hours after the dropwise adding is finished, carrying out suction filtration, and carrying out vacuum drying on a filter cake at 40 ℃ to obtain 102g of light orange solid, namely the compound III (M)1Sodium ion) with a purity of 99.10%, maximum single impurity of 0.20%, yield of 70%.
EXAMPLE 7 preparation of Compound IV (M2 is Potassium ion)
400g of water were added to a 2L three-necked flask and prepared in example 6Compound III (M) of (2)1Sodium ions) (89g, 0.39mol), stirring and dissolving, controlling the temperature to be 0-10 ℃, dropwise adding a mixed solution of sodium borohydride (16.70g, 0.31mol), sodium hydroxide (2.80g, 0.07mol) and 122g of water, raising the temperature to 70-80 ℃ after dropwise adding, reacting for 2 hours, and detecting by HPLC (high performance liquid chromatography) until the raw materials are completely reacted (0.05 percent of compound III is remained). And cooling to 40-50 ℃, dropwise adding concentrated hydrochloric acid into the mixture, adjusting the pH to 2-3, and reacting for 2 hours in a heat preservation manner. Adding 400g of ethyl acetate into a system for extraction, sequentially washing an organic layer twice with 400g of purified water, washing an saturated salt solution twice with 400g of saturated salt solution, carrying out desolventizing under reduced pressure, adding 400g of methanol, 100g of water and 26g of potassium hydroxide into a residual solution, heating to 60-70 ℃, reacting for 2 hours, cooling to 40-50 ℃, carrying out desolventizing under reduced pressure until a large amount of solids are separated out, adding 200g of tetrahydrofuran into the residual solution, continuously cooling to 0-10 ℃, crystallizing for 5 hours, carrying out suction filtration, and carrying out vacuum drying on a filter cake at 50 ℃ to obtain 80.7g of white solids, namely a compound IV (M2 is potassium ions), wherein the purity is 99.90%, the maximum single impurity is 0.03%, and the yield is 84%.
EXAMPLE 8 preparation of Compound V
240g of purified water, Compound IV (M) prepared in example 7, was charged in a 1L three-necked flask2Potassium ion) 80g, stirring and dissolving, heating to 40-50 ℃, dropwise adding about 40g of concentrated hydrochloric acid into the system, adjusting the pH of the system to 2-3, carrying out heat preservation reaction for 2 hours, and carrying out HPLC (high performance liquid chromatography) detection to ensure that the raw material completely reacts (0.02% of compound IV remains). Adding 240g of ethyl acetate into the system for extraction, washing an organic layer twice with 240g of purified water, washing a saturated sodium bicarbonate twice with 240g of saturated sodium bicarbonate, washing a saturated saline solution twice with 480g of saturated saline solution, drying 20g of anhydrous sodium sulfate for 1 hour, performing suction filtration, adding 2g of activated carbon into a filtrate for decoloring for 1 hour, performing suction filtration, filtering the filtrate through a 0.45-micron microporous filter membrane, performing reduced pressure concentration on the obtained filtrate to remove a solvent ethyl acetate, stopping concentration until the residual solvent ethyl acetate is less than 0.5% by GC (gas chromatography), obtaining 54g of colorless transparent liquid, namely a compound V, namely a finished product of butylphthalide, wherein the purity of the finished product is 99.79% (HPLC detection), the maximum single impurity is 0.06%, the residual content of the finished product ethyl acetate is 0.03% (GC.
Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.
Claims (10)
1. The preparation method of butylphthalide comprises the following steps:
(1) carrying out condensation reaction on the compound I and valeric anhydride to obtain a compound II;
(2) carrying out hydrolysis reaction on the compound II obtained in the step (1) to obtain a compound III;
(3) sequentially carrying out reduction reaction, cyclization reaction 1 and ring opening reaction on the compound III obtained in the step (2) to obtain a compound IV;
(4) performing cyclization reaction 2 on the compound IV obtained in the step (3) to obtain a compound V, namely butylphthalide;
wherein, M in the compound III1And M in Compound IV2Each independently an alkali metal ion, preferably sodium, potassium or lithium.
2. The preparation method according to claim 1, wherein in the step (1), the compound I is reacted with valeric anhydride under the action of a catalyst to obtain a compound II; here, the catalyst is selected from any one of sodium acetate, sodium propionate, sodium butyrate and sodium valerate, and preferably, the catalyst is sodium valerate;
the molar ratio of the compound I to the valeric anhydride to the catalyst is 1: 1-3: 0.2-2, and preferably the molar ratio of the compound I to the valeric anhydride to the catalyst is 1: 1-2: 0.2-1.
3. The preparation method according to claim 2, wherein in the step (1), the compound I, the valeric anhydride and part of sodium valerate are mixed and reacted, and the reaction temperature is 130-160 ℃, preferably 135-145 ℃; and then adding the rest sodium valerate to continue the reaction, wherein the temperature for continuing the reaction is 160-190 ℃, and preferably 175-185 ℃.
4. The preparation method according to claim 3, wherein in the step (1), the compound I, the valeric anhydride and part of sodium valerate are mixed and reacted at the temperature of 135-145 ℃ until no gas is generated, and then the rest sodium valerate is added into the reaction system, and the mixture is subjected to heat preservation at the temperature of 175-185 ℃ and the reaction is continued for 1 hour to obtain the compound II.
5. The preparation process according to claim 1, wherein in the step (2), the compound II is subjected to hydrolysis reaction with an alkaline substance to obtain a compound III; preferably, the compound II is hydrolyzed by alkaline substances in a reaction solvent to obtain a compound III; here, the reaction solvent is selected from at least one of water, methanol and ethanol, and preferably the reaction solvent is methanol; the alkaline substance is one or two selected from potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium carbonate, lithium carbonate and sodium carbonate, and preferably, the alkaline substance is sodium hydroxide.
6. The preparation method according to claim 1 or 5, wherein in the step (2), the hydrolysis reaction is performed at a reaction temperature of 0 ℃ to 100 ℃, preferably at a reaction temperature of 25 ℃ to 35 ℃; or
After the hydrolysis reaction is finished, a crystallization step is carried out to obtain a compound III, wherein a crystallization solvent used in the crystallization step is one of ethyl acetate, tetrahydrofuran and methyl tert-butyl ether, and preferably the crystallization solvent is methyl tert-butyl ether;
more preferably, in the step (2), the compound II is added into a methanol solution of sodium hydroxide, and hydrolysis reaction is carried out at 25-35 ℃ to obtain a compound III;
the molar ratio of the compound II to sodium hydroxide is 1: 1-2, and preferably, the molar ratio of the compound II to sodium hydroxide is 1: 1.0-1.5.
7. The preparation method according to claim 1, wherein in the step (3), the compound III is subjected to reduction reaction, cyclization reaction 1 and ring-opening reaction in sequence to obtain a compound IV, wherein the reduction reaction is reduced by sodium borohydride, the cyclization reaction 1 is performed by hydrochloric acid, and the ring-opening reaction is performed by potassium hydroxide, sodium hydroxide or lithium hydroxide; preferably, the reduction reaction, the cyclization reaction 1 or the ring-opening reaction are each independently carried out in at least one solvent selected from the group consisting of water, methanol, ethanol and tetrahydrofuran.
8. The production method according to claim 1 or 7, wherein in the step (3), the reaction temperature of the reduction reaction is 60 to 100 ℃, preferably 90 to 100 ℃; the reaction temperature of the cyclization reaction 1 is 30-50 ℃, and preferably 40-50 ℃; the reaction temperature of the ring-opening reaction is 50-70 ℃, and preferably 60-70 ℃;
after the ring-opening reaction is completed, performing a crystallization step to obtain a compound IV, wherein a crystallization solvent used in the crystallization step is at least one selected from the group consisting of ethyl acetate, isopropyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran, and preferably the crystallization solvent is ethyl acetate;
preferably, the compound III reacts with sodium borohydride under the catalysis of sodium hydroxide, and then the compound IV is obtained through hydrochloric acid cyclization and potassium hydroxide ring opening;
more preferably, dissolving the compound III in water, dropwise adding a sodium borohydride aqueous solution containing sodium hydroxide, and raising the temperature to 90-100 ℃ to perform a reduction reaction after dropwise adding; after the reduction reaction is finished, adding hydrochloric acid into the reaction system to adjust the pH value of the system to be 1-4, and carrying out cyclization reaction 1; after the cyclization reaction 1 is finished, adding a methanol aqueous solution of potassium hydroxide into the cyclization concentrate, and heating for reflux reaction to obtain a compound IV;
the molar ratio of the compound III to the sodium borohydride to the sodium hydroxide is 1: 0.3-1: 0.1-0.5, and preferably the molar ratio of the compound III to the sodium borohydride to the sodium hydroxide is 1: 0.6-1: 0.1-0.2.
9. The preparation process according to claim 1, wherein in the step (4), compound IV is subjected to cyclization reaction 2 under acidic conditions to obtain compound V;
preferably, the acidic condition is under the action of hydrochloric acid, and more preferably, the pH value of the system in the cyclization reaction 2 is 1-4, preferably 1-3, and more preferably 1-2.
10. The preparation method according to claim 1 or 9, wherein in the step (4), the reaction temperature of the cyclization reaction 2 is 30-50 ℃, preferably 40-50 ℃;
the cyclization reaction 2 is carried out in at least one solvent selected from the group consisting of water, methanol, ethanol, isopropanol and tetrahydrofuran; or
After the cyclization reaction 2 is finished, obtaining a compound V through a crystallization step, wherein a crystallization solvent used in the crystallization step is one of ethyl acetate and isopropyl acetate, preferably ethyl acetate;
more preferably, the compound IV is dissolved in water, hydrochloric acid is dripped to control the pH of the system to be 1-2, and the reaction is carried out at 40-50 ℃ to obtain a compound V.
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