CN115536624A - Preparation method of 3-n-butenyl phthalide - Google Patents
Preparation method of 3-n-butenyl phthalide Download PDFInfo
- Publication number
- CN115536624A CN115536624A CN202110724277.9A CN202110724277A CN115536624A CN 115536624 A CN115536624 A CN 115536624A CN 202110724277 A CN202110724277 A CN 202110724277A CN 115536624 A CN115536624 A CN 115536624A
- Authority
- CN
- China
- Prior art keywords
- sodium
- phthalic anhydride
- valeryl chloride
- preparation
- valerate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Furan Compounds (AREA)
Abstract
The invention belongs to the technical field of chemical pharmacy, and relates to a preparation method of improved 3-n-butenyl phthalide. The preparation method comprises the following steps: (1) Performing cyclization reaction by using phthalic anhydride, sodium valerate and valeryl chloride; (2) The material ratio is phthalic anhydride, sodium valerate and valeryl chloride = 1: 1-1.5; (3) the cyclization temperature is 190-240 ℃, preferably 200-210 ℃. Compared with the prior art, the invention reports that the butenylphthalide is synthesized by adopting valeryl chloride for the first time, and has the advantages of lower reaction temperature, lower material consumption and less generation of reaction waste so as to meet increasingly strict environmental protection requirements.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and relates to a preparation method of improved 3-n-butenyl phthalide.
Background
Acute cerebral arterial thrombosis and coronary heart disease and myocardial infarction are diseases of ischemic injury caused by thrombosis induced by various factors, and the diseases bring great pain and even life risk to patients. The research of the medicines is always a hot spot and a leading edge of the research and development of the medicines.
The 3-n-butyl phenyl phthalide is widely present in various medicinal plants, not only has the function of resisting platelet aggregation (Biochimica et, biophysica Acta,924 (1987), 375-382), but also has the activity of resisting cerebral ischemia and thrombosis, and simultaneously has obvious relaxation function on animal tracheal smooth muscle. Chinese patent CN200410007520 firstly discloses 2- (alpha-n-pentanoyl) benzoic acid prepared by taking 3-n-butenylphthalide as a precursor and a plurality of 2- (alpha-n-pentanoyl) benzoates thereof, and compared with the 2- (alpha-hydroxypentyl) benzoate and the precursor compound 3-n-butylphthalide in the prior art, the compound has more excellent cardiovascular and cerebrovascular activities and better physical and chemical properties.
The existing preparation process of 3-n-butenyl phthalide comprises the following steps:
lishaosbai, zhang Shaming, etc. (Nature science edition, university of Lanzhou, 1990, 26 (1), 118-119) reported that phthalic anhydride, anhydrous sodium acetate and n-valeric anhydride were used as raw materials, and subjected to cyclization reaction at 300 ℃, after neutralization, column chromatography purification was performed to obtain 3-n-butenylphthalide with a yield of 25%. The route is as follows:
as the process adopts the n-valeric anhydride and the anhydrous sodium acetate to introduce the 3-n-butenyl, the cyclization reaction needs to be carried out at the high temperature of 300 ℃, the requirements on equipment are high in industrial implementation, the energy consumption is high, and the yield can be ensured only by needing a large excess proportion of the n-valeric anhydride and the anhydrous sodium acetate, so that the waste is large.
Jade lotus et al (doctor paper of university of medical science, china, 2006) introduced a cyclization reaction using phthalic anhydride, sodium n-valerate and n-valerate as raw materials, the reaction temperature can be reduced to 200 ℃ for reaction, and 3-n-butyl phthalide is prepared by subsequent neutralization, extraction, drying and distillation. The sodium n-valerate is used, so that the reaction temperature is greatly reduced to 200 ℃ compared with the process adopting sodium acetate. The yield is improved considerably due to the greatly reduced reaction temperature, and the yield is 59%. The route is as follows:
in the process, 3-n-butenyl is still introduced by using n-valeric anhydride, inorganic base is still required to be consumed for neutralization in the subsequent alkalization process, and meanwhile, one molecule of n-valeric acid is inevitably generated, so that the waste of the n-valeric anhydride serving as a reaction material is large, and on the other hand, waste water containing a large amount of sodium valerate is generated, so that the amount of reaction waste is increased, and the environmental protection pressure of subsequent treatment is increased. Material waste and environmental pressure limit the economics and feasibility of this process on an industrial scale.
Hades, li Shao white, etc. (proceedings of the New countryside medical college, 1994 volume 11, periods 3-289) describe the preparation of 3-hydroxy-3-butylphthalide from phthalic anhydride and butyl lithium, followed by dehydration to obtain 3-n-butylphthalide. The feasibility of industrial scale-up is greatly limited by the use of butyl lithium, a dangerous strong base, and the use of benzene as a solvent in the dehydration step. The route is as follows:
li Shao Bai, li Ying, etc. (Nature science edition of Lanzhou university, 1993, 29 (3), 256-258) describe the preparation of o-pentenoic acid by using o-carboxybenzaldehyde as raw material and n-butyltriphenylphosphine bromide and butyl lithium as reactants; then under the action of iodine/potassium iodide, 3-n-butyl-8-iodophthalide is prepared, and then 3-n-butenyl phthalide is prepared by hydrolysis and dehydration. The route is more complicated and has no industrialization potential. The route is as follows:
in view of the above, there is still a need for an improved process for synthesizing 3-n-butenylphthalide, which meets the economic and feasible implementation on an industrial scale, and particularly, needs to have a lower reaction temperature, lower material consumption, higher yield, and less generation of reaction waste so as to meet the increasingly strict environmental requirements.
Disclosure of Invention
The invention aims to provide a novel preparation method of 3-n-butenyl phthalide, which has the advantages of lower reaction temperature, lower material consumption, higher yield and less generation of reaction waste so as to meet increasingly strict environmental requirements.
The inventor of the application, when researching how to improve the preparation method of 3-n-butenyl phthalide in the prior art, unexpectedly finds that the valeryl chloride is adopted to replace valeric anhydride in the prior art, so that the cyclization reaction can be realized at a lower temperature, the consumption of materials can be reduced, a higher yield is obtained, less waste is generated, and the method has great industrial value. The novel preparation method of the 3-n-butyl alkenyl phthalide of the invention is as follows:
phthalic anhydride and sodium valerate are taken as raw materials, valeryl chloride is adopted to replace valeric anhydride, cyclization is carried out at 190-240 ℃, then inorganic base is used for adjusting pH to be neutral or alkalescent, extraction, drying, concentration and reduced pressure distillation are carried out, thus obtaining the 3-n-butyl alkenyl phthalide.
In a preferred embodiment, the present invention provides a novel process for the preparation of 3-n-butenylphthalide, wherein the ratio of the materials (molar ratio) is phthalic anhydride, sodium valerate, valeryl chloride = 1: 1-1.5, preferably 1: 1.25-1.5: 1.25, more preferably 1: 1.25;
in a preferred embodiment, the present invention provides a novel process for the preparation of 3-n-butenylphthalide in which the ring closure temperature is in the range from 190 to 240 ℃, preferably from 200 to 210 ℃.
In a preferred embodiment, the invention provides a preparation method of novel 3-n-butyl alkenyl phthalide, wherein the inorganic base is one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, and sodium carbonate is preferred; sodium carbonate is adopted, on one hand, the alkalinity is moderate, the corrosion to equipment is small, on the other hand, the alkali equivalent is large, and the neutralization can be carried out by adopting a small material quantity; in addition, sodium valerate generated after neutralization can be recycled and used as a reaction raw material for the reaction in the step again, so that the raw material is saved, and the waste discharge is reduced.
In a preferred embodiment, the invention provides a novel preparation method of 3-n-butenyl phthalide, wherein the extraction solvent is one or more of diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, benzene and toluene, preferably dichloromethane and toluene, and further preferably toluene, because toluene has a high extraction yield on the one hand and a high boiling point on the other hand, the yield is high when the solvent is recovered, and the amount of organic solvent in the discharged waste gas is small, which is beneficial to reducing the difficulty of waste gas treatment and reducing the pressure of environmental protection.
As a preferred embodiment of the invention, phthalic anhydride, sodium valerate and valeryl chloride are used as raw materials, heating and cyclization are carried out, then inorganic base is used for adjusting pH to be neutral or alkalescent, extraction, drying, concentration and reduced pressure distillation are carried out, and 3-n-butyl phenyl phthalide is obtained, wherein the material ratio (molar ratio) is phthalic anhydride, sodium valerate and valeryl chloride = 1: 1-1.5, preferably 1: 1.25-1.5: 1.25, more preferably 1: 1.25; the cyclization temperature is in the range of 190-240 ℃, preferably 200-210 ℃; the inorganic base is one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, preferably sodium carbonate; the extraction solvent is one or more of diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, benzene and toluene, preferably dichloromethane and toluene, and more preferably toluene.
The inventor finds that compared with the existing method, the preparation method of the invention has the following advantages:
1. compared with valeric anhydride, valeryl chloride has lower material consumption ratio and lower cost;
2. suitable for relatively low ring closure temperatures;
3. the yield is high;
4. avoids the use of butyl lithium, ether and other dangerous materials, and is safer.
Detailed Description
The following examples may assist those skilled in the art in a more complete understanding of the present invention, but are not intended to limit the scope of the invention in any way.
Comparative example 1: preparation of 3-n-butyl phenyl phthalide by valeric anhydride and sodium acetate
Putting 29.7g (0.2 mol) of phthalic anhydride, 16.5g (0.2 mol) of sodium acetate and 55.8g (0.3 mol) of valeric anhydride into a reaction bottle, heating to 300 ℃, carrying out reflux reaction on the system for 5 hours, stopping heating and cooling;
adding 100ml of water under stirring, heating to 50 ℃, stirring for 2 hours, and cooling; adjusting pH to about 9 with sodium carbonate, extracting with diethyl ether for 5 times, and drying the organic layer with anhydrous sodium sulfate;
filtering to remove a drying agent, removing ether under reduced pressure, performing silica gel column chromatography on the residue, heating the eluent by using chloroform and petroleum ether = 1: 1 as an eluent, and removing the solvent in vacuum to obtain 13.7g of 3-n-butyl phthalide with the yield of 36%.
Comparative example 2: preparation of 3-n-butyl phenyl phthalide by using valeric anhydride and sodium valerate
74.1g (0.5 mol) of phthalic anhydride, 62.4g (0.5 mol) of sodium valerate and 95.4g (0.5 mol) of valeric anhydride are put into a reaction bottle, heated to ensure that the temperature in the system reaches 200 ℃, stirred for reaction for 5 hours, stopped heating and cooled;
adding 80ml of water under stirring, heating and refluxing for 1 hour, and cooling; adjusting pH to about 9 with sodium carbonate, extracting with dichloromethane for 5 times, and drying the organic layer with anhydrous sodium sulfate;
filtering to remove the drying agent, removing the dichloromethane under reduced pressure, distilling the residue under reduced pressure, and collecting the fraction of 155-165 ℃/2mmHg to obtain 48.4g of 3-n-butyl phenyl phthalide with the yield of 51 percent.
EXAMPLE 1 preparation of 3-n-Butenylphthalide from phthalic anhydride, sodium valerate, valeryl chloride (1: 1.5: 1.25)
Putting 61.1g (0.4 mol) of phthalic anhydride, 76g (0.6 mol) of sodium valerate and 59.5g (0.5 mol) of valeryl chloride into a reaction bottle, heating to ensure that the temperature in the system reaches 210 ℃, stirring for 5 hours, stopping heating, and cooling;
adding 400ml of water, adjusting the pH value to 7-8 by using sodium carbonate, and fully stirring for 2 hours. By CH 2 Cl 2 Extracting for 3 times, washing with water, drying with anhydrous sodium sulfate, filtering, and desolventizing;
vacuum distillation is carried out, 155-165 ℃/2mmHg is collected, 60.1g is obtained, and the yield is 77 percent.
EXAMPLE 2 preparation of 3-n-Butenylphthalide from phthalic anhydride, sodium valerate, valeryl chloride (1: 1)
60.5g (0.4 mol) of phthalic anhydride, 50.8g (0.4 mol) of sodium valerate and 50.7g (0.4 mol) of valeryl chloride are put into a reaction bottle, heated to ensure that the temperature in the system reaches 240 ℃, stirred for 4 hours, stopped heating and cooled;
water 400ml was added, the pH was adjusted to about 9 with potassium carbonate, and the mixture was stirred well for 2 hours. Extracting with diethyl ether for 5 times, washing with water, drying with anhydrous sodium sulfate, filtering, and desolventizing;
reduced pressure distillation is carried out, and 155-165 ℃/2mmHg is collected, thus obtaining 43.7g with the yield of 57%.
EXAMPLE 3 preparation of 3-n-Butenylphthalide from phthalic anhydride, sodium valerate, valeryl chloride (1: 1.25)
Putting 60g (0.4 mol) of phthalic anhydride, 60.6g (0.5 mol) of sodium valerate and 59.1g (0.5 mol) of valeryl chloride into a reaction bottle, heating to ensure that the temperature in the system reaches 200 ℃, stirring for 5 hours, stopping heating, and cooling;
400ml of water was added, the pH was adjusted to about 9 with sodium hydroxide, and the mixture was stirred well for 2 hours. Extracting with toluene for 3 times, washing with water, drying with anhydrous sodium sulfate, filtering, and desolventizing;
reduced pressure distillation is carried out, and 155-165 ℃/2mmHg is collected, thus obtaining 49.7g with the yield of 65 percent.
EXAMPLE 4 preparation of 3-n-Butenylphthalide (1: 1.25: 1.5) from phthalic anhydride, sodium valerate, valeryl chloride
60.2g (0.4 mol) of phthalic anhydride, 61.3g (0.5 mol) of sodium valerate and 73.9g (0.6 mol) of valeryl chloride are put into a reaction bottle, heated to ensure that the temperature in the system reaches 220 ℃, stirred for 5 hours, stopped heating and cooled;
400ml of water is added, the pH value is adjusted to 7 to 8 by sodium bicarbonate, and the mixture is fully stirred for 2 hours. By CH 2 Cl 2 Extracting for 3 times, washing with water, drying with anhydrous sodium sulfate, filtering, and desolventizing;
vacuum distillation is carried out, 155-165 ℃/2mmHg is collected, 42.2g is obtained, and the yield is 55%.
EXAMPLE 5 preparation of 3-n-Butenylphthalide (1: 1.25) Using phthalic anhydride, sodium valerate, valeryl chloride
60.6g (0.4 mol) of phthalic anhydride, 65.7g (0.5 mol) of sodium valerate and 58.3g (0.5 mol) of valeryl chloride are put into a reaction bottle, heated to ensure that the temperature in the system reaches 210 ℃, stirred for 5 hours, stopped heating and cooled;
adding 400ml of water, adjusting the pH value to 8-9 by using sodium carbonate, and fully stirring for 2 hours. By CH 2 Cl 2 Extracting for 3 times, washing with water, drying with anhydrous sodium sulfate, filtering, and desolventizing;
reduced pressure distillation, collection of 155-165 deg.C/2 mmHg, 60.8g, yield 79%.
EXAMPLE 6 preparation of 3-n-Butenylphthalide (1: 1.5: 1.25) from phthalic anhydride, sodium valerate and valeryl chloride
Putting 59.6g (0.4 mol) of phthalic anhydride, 69.7g (0.6 mol) of sodium valerate and 58.8g (0.5 mol) of valeryl chloride into a reaction bottle, heating to ensure that the temperature in the system reaches 210 ℃, stirring for 5 hours, stopping heating, and cooling;
400ml of water is added, the pH is adjusted to about 7 to 8 by sodium carbonate, and the mixture is fully stirred for 2 hours. Extracting with toluene for 3 times, washing with water, drying with anhydrous sodium sulfate, filtering, and desolventizing;
vacuum distillation is carried out, and 155-165 ℃/2mmHg is collected, so that 61.3g is obtained, and the yield is 81%.
Claims (10)
1. The preparation method of the 3-n-butyl alkenyl phthalide is characterized by comprising the following steps:
phthalic anhydride, sodium valerate and valeryl chloride are used as raw materials to carry out cyclization reaction shown in the following formula, inorganic base is used for adjusting the pH value to be neutral or alkalescent after the reaction is finished, organic solvent is added for extraction, and the obtained organic solvent is extracted for desolventizing and reduced pressure distillation to obtain butylphthalide;
2. the production method according to claim 1, characterized in that: the material ratio of the phthalic anhydride to the sodium valerate to the valeryl chloride is 1: 1-1.5 according to the mol ratio.
3. The production method according to claim 2, characterized in that: the material ratio of the phthalic anhydride to the sodium valerate to the valeryl chloride is 1: 1.25-1.5: 1.25 by mol ratio.
4. The production method according to claim 3, characterized in that: the material ratio of phthalic anhydride, sodium valerate and valeryl chloride is 1: 1.25 by mol ratio.
5. The process according to claim 1, wherein the ring-closing temperature is in the range of 190 to 240 ℃.
6. The process according to claim 5, wherein the ring-closure temperature is 200 to 210 ℃.
7. The preparation method according to claim 1, wherein the inorganic base is one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.
8. The process according to claim 7, characterized in that the inorganic base is sodium carbonate.
9. The method according to claim 1, wherein the organic solvent used for extraction is one or more selected from the group consisting of diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, benzene, and toluene.
10. The method according to claim 9, wherein the organic solvent used for extraction is preferably dichloromethane, toluene, and more preferably toluene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110724277.9A CN115536624A (en) | 2021-06-29 | 2021-06-29 | Preparation method of 3-n-butenyl phthalide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110724277.9A CN115536624A (en) | 2021-06-29 | 2021-06-29 | Preparation method of 3-n-butenyl phthalide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115536624A true CN115536624A (en) | 2022-12-30 |
Family
ID=84717419
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110724277.9A Pending CN115536624A (en) | 2021-06-29 | 2021-06-29 | Preparation method of 3-n-butenyl phthalide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115536624A (en) |
-
2021
- 2021-06-29 CN CN202110724277.9A patent/CN115536624A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106810426B (en) | Method for synthesizing cannabidiol | |
| CN105348172B (en) | (S) preparation method of the preparation of the mesyl ethamine of 1 (ethyoxyl of 4 methoxyl group 3) phenyl 2 and Apremilast | |
| CN108623456B (en) | Preparation method of butylphthalide and pharmaceutical intermediate thereof | |
| CN109180436A (en) | A kind of synthetic method of phloroglucin | |
| WO2011113228A1 (en) | A process for preparing guaiacol glycidyl | |
| CN105037139A (en) | Preparation method for 2-phenylpropionic acid | |
| CN106748752B (en) | A kind of preparation method of 2,3- naphthalenedicarboxylic acid | |
| CN101747210A (en) | Method for preparing alpha-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and the hydrochloride thereof | |
| CN102317256A (en) | Preparation method for racecadotril | |
| CN100436405C (en) | Prepn of (S)-(+)-2-amino propanol | |
| CN102627626B (en) | Preparation method of 2, 3-thiophenedicarboxaldehyde | |
| CN115536624A (en) | Preparation method of 3-n-butenyl phthalide | |
| CN105503774B (en) | A kind of preparation method of S-1574 intermediate | |
| CN106518944A (en) | Preparation method of methylprednisone | |
| CN103772189B (en) | Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A | |
| CN105330545A (en) | Method for recycling oxalic acid from triazine ring cyclization mother liquor dreg with tin chloride as catalyst | |
| CN105566223A (en) | Crude iminostilbene product recrystallization method | |
| CN112645815A (en) | Preparation method for catalytically synthesizing methyl cinnamate based on eutectic solvent | |
| CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN106966980A (en) | The preparation method of high-purity Eptazocine intermediate | |
| CN107151246A (en) | A kind of preparation method of (R)-praziquantel amine salt and levo-praziquantel | |
| CN103804265B (en) | The synthesis of a kind of Sulpiride or its optical isomer and post-processing approach | |
| CN112341433A (en) | Preparation method of loratadine | |
| CN103772188A (en) | Preparation method of R-(+)-alpha-cyclohexyl mandelic acid | |
| CN101665427B (en) | Process for preparing 5-bromo-n-valeryl bromide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication |