CN1907948A - Preparation method of 4-chloromethyl benzoic acid t-butyl ester - Google Patents
Preparation method of 4-chloromethyl benzoic acid t-butyl ester Download PDFInfo
- Publication number
- CN1907948A CN1907948A CN 200610030491 CN200610030491A CN1907948A CN 1907948 A CN1907948 A CN 1907948A CN 200610030491 CN200610030491 CN 200610030491 CN 200610030491 A CN200610030491 A CN 200610030491A CN 1907948 A CN1907948 A CN 1907948A
- Authority
- CN
- China
- Prior art keywords
- benzoic acid
- chloromethyl benzoic
- preparation
- butyl ester
- chloromethyl
- 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.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
This invention relates to a preparation method for tert-butyl 4-chloromethyl benzoate, belonging to an anticancer drug intermediates preparation technology field. The method comprises adding 4-methyl benzoic acid and organic solvent at a mass ratio of 1.05-1.20 : 1, cooling to 0-10DEG C and irradiating, carrying out substitution reaction with chlorine to obtain 4-chloromethyl benzoic acid, adding the obtained 4-chloromethyl benzoic acid in organic solvent, cooling to -10~10DEG C and dropping thionyl chloride, stirring and dropping potassium tert-butoxide, natural-heating to room temperature and stirring, and desolventizing to obtain the final product. The invention has the advantages of being moderate and easy to control, simple equipment and sufficient raw materials, low cost, and being suitable for industrial production.
Description
Technical field
A kind of preparation method of the 4-chloromethyl benzoic acid tert-butyl ester belongs to the technical field of the method for preparing a kind of antitumor drug intermediate.
Background technology
Cancer is the disease of the serious harm mankind's life and health.Though years of researches have found some corresponding diagnoses and treatment and medicines,, still do not find the method and the medicine of effective treatment so far.At the difficult problem of this world medical circle and pharmacy circle, scientist has carried out extensive studies.Wherein, the 4-chloromethyl benzoic acid tert-butyl ester has a wide range of applications as a kind of intermediate of anti-cancer agent.The downstream antitumor drug of this compound has been proved for human tumor cells model XF-498 etc. significant cytotoxicity.Therefore, the preparation of this compound 4-chloro tolyl acid tert-butyl ester has great importance for the research and development and the treatment for cancer of antitumor drug.
About the complete synthesis report of the 4-chloromethyl benzoic acid tert-butyl ester, one piece of article (Chemicke Listy pro Vedu a Prumysl (1958) is only arranged, 52,1192-3) mention logical chlorine method and can prepare the 4-chloromethyl benzoic acid, but, because do not have suitable technology and cheap raw material, the yield for preparing the 4-chloromethyl benzoic acid with this method is lower.Other has one piece of document to mention with the raw material of the trimethyl carbinol as the reaction of second step, but yield is very low, has only 33.6%, and impurity is more, and aftertreatment is loaded down with trivial details, and reaction preference is relatively poor, costs an arm and a leg, and does not have the value of practical application.
Summary of the invention
The object of the present invention is to provide a kind of complete synthesis preparation method of the 4-chloromethyl benzoic acid tert-butyl ester.Can make this antitumor drug intermediate with method of the present invention, and the gentle easily control of technology, equipment is simple, raw material is sufficient, low price, be easy to suitability for industrialized production.
For reaching above-mentioned purpose, the present invention adopts, and 4-tolyl acid inexpensive, that be easy to get is a starting raw material, replaces through logical chlorine successively, and chloride and esterification finally make the final product 4-chloromethyl benzoic acid tert-butyl ester of the present invention:
Realize that technical scheme of the present invention in turn includes the following steps:
A.4-the preparation of chloromethyl benzoic acid
Earlier according to the 4-tolyl acid: organic solvent=1.05～1.20: 1 times of mass ratio is measured, then 4-tolyl acid and organic solvent are added in the reactor, be cooled under the irradiation of 0～10 ℃ and magnesium lamp, carry out substitution reaction to wherein feeding chlorine, the quality of the chlorine that substitution reaction feeds is 0.45～1.05 times of 4-tolyl acid, the logical chlorine reaction time is 4～6 hours, and drying, removal of solvent under reduced pressure, washing, the oven dry through routine at last makes the 4-chloromethyl benzoic acid;
B.4-the preparation of the chloromethyl benzoic acid tert-butyl ester
In reactor, add 4-chloromethyl benzoic acid and organic solvent that the A step makes, 4-chloromethyl benzoic acid: organic solvent=1.05～2.9: 1 times of mass ratio; Be cooled to-10～10 ℃ and dripping down thionyl chlorides and carry out acyl chloride reaction, according to thionyl chloride: the minim of 4-chloromethyl benzoic acid=1: 1 times of mass ratio adds; The acyl chloride reaction time is 2～4 hours, dropwised the back restir two hours, then according to potassium tert.-butoxide: the amount of 4-chloromethyl benzoic acid=1: 1 times of mass ratio adds potassium tert.-butoxide and carried out esterification 2～4 hours, naturally rise to room temperature～30 ℃ continuation stirring reaction then, reaction finishes the back precipitation, and the solid of gained is exactly the target compound 4-chloromethyl benzoic acid tert-butyl ester.
Described organic solvent is a methylene dichloride, or tetracol phenixin, or chloroform.
The thionyl chloride that the described B step uses is collected 79～80 ℃ of cuts for what newly steam before reacting when specifically being air distillation, i.e. steaming is promptly used.
Biggest advantage of the present invention is that its raw material source is wide, and is in liberal supply, low price.Another one advantage of the present invention is that the reaction conditions gentleness is easy to control, need not complicated experimental installation, is easy to actual industrial production.The present invention also has an advantage to be the productive rate height, and is with low cost.
Embodiment
Embodiment 1
A.4-the preparation of chloromethyl benzoic acid
In the reactor of 5000ml, add 680g 4-tolyl acid and the stirring of 600ml tetracol phenixin, with the cryosel bath mixture is cooled to 0 ℃, mixture placed 400W magnesium lamp irradiation to feed 385g chlorine down in 5 hours, fed to keep reaction mixture temperature to be no more than 10 ℃ in the chlorine process.Stirring reaction is continued in the logical back of finishing, and after TLC showed that reaction finishes, reaction mixture washed with water once, removal of solvent under reduced pressure behind the anhydrous sodium sulfate drying, the solid that obtains with the normal hexane washing are once dried and are obtained white solid 500g, be the 4-chloromethyl benzoic acid, yield 77.2%.
B.4-the preparation of the chloromethyl benzoic acid tert-butyl ester:
In the reactor of 2000ml, add 207g 4-chloromethyl benzoic acid and the stirring of 600ml methylene dichloride, with the cryosel bath mixture is cooled to 0 ℃, in 3 hours, slowly drip 206g thionyl chloride (distill again before the reaction and collect 79～80 ℃ of cuts), keep reaction mixture temperature to be no more than 10 ℃ in the dropping process.Dropwise the back stirring reaction and add the 200g potassium tert.-butoxide after two hours in batches, keep reaction mixture temperature to be no more than 30 ℃ in the reinforced process, stirring reaction is continued in the reinforced back of finishing, and after TLC showed that reaction finishes, reaction mixture is water successively, the saturated common salt water washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, oven dry obtains white solid 340g, be the 4-chloromethyl benzoic acid tert-butyl ester, yield 93.9%.
Embodiment 2
A.4-the preparation of chloromethyl benzoic acid
In the reactor of 5000ml, add 680g 4-tolyl acid and the stirring of 567ml tetracol phenixin, with the cryosel bath mixture is cooled to 10 ℃, mixture placed magnesium lamp irradiation to feed 340g chlorine down in 4 hours, fed to keep reaction mixture temperature to be no more than 10 ℃ in the chlorine process.Stirring reaction is continued in the logical back of finishing, and after TLC showed that reaction finishes, reaction mixture washed with water once, removal of solvent under reduced pressure behind the anhydrous sodium sulfate drying, the solid that obtains with the normal hexane washing are once dried and are obtained white solid 500g, be the 4-chloromethyl benzoic acid, yield 77.2%.
B.4-the preparation of the chloromethyl benzoic acid tert-butyl ester
In the reactor of 2000ml, add 207g 4-chloromethyl benzoic acid and the stirring of 284ml chloroform, with the cryosel bath mixture is cooled to 10 ℃, in 2 hours, slowly drip 206g thionyl chloride (newly steaming), keep reaction mixture temperature to be no more than 10 degree in the dropping process through embodiment 1 same procedure.Dropwise the back stirring reaction and add the 200g potassium tert.-butoxide after two hours in batches, keep reaction mixture temperature to be no more than 30 ℃ in the reinforced process, stirring reaction is continued in the reinforced back of finishing, and after TLC showed that reaction finishes, reaction mixture is water successively, the saturated common salt water washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, oven dry obtains white solid 340g, be the 4-chloromethyl benzoic acid tert-butyl ester, yield 93.9%.
Embodiment 3
A.4-the preparation of chloromethyl benzoic acid
In the reactor of 5000ml, add 680g 4-tolyl acid and the stirring of 648ml tetracol phenixin, with the cryosel bath mixture is cooled to 5 ℃, mixture placed magnesium lamp irradiation to feed 714g chlorine down in 6 hours, fed to keep reaction mixture temperature to be no more than 10 ℃ in the chlorine process.Stirring reaction is continued in the logical back of finishing, and after TLC showed that reaction finishes, reaction mixture washed with water once, removal of solvent under reduced pressure behind the anhydrous sodium sulfate drying, the solid that obtains with the normal hexane washing are once dried and are obtained white solid 500g, be the 4-chloromethyl benzoic acid, yield 77.2%.
B.4-the preparation of the chloromethyl benzoic acid tert-butyl ester:
In the reactor of 2000ml, add 207g 4-chloromethyl benzoic acid and the stirring of 600ml methylene dichloride, mixture is cooled to-10 ℃ with the cryosel bath, in 3 hours, slowly drip the new thionyl chloride that steams of 206g, keep reaction mixture temperature to be no more than 10 degree in the dropping process.Dropwise the back stirring reaction and add the 200g potassium tert.-butoxide after two hours in batches, keep reaction mixture temperature to be no more than 30 ℃ in the reinforced process, stirring reaction is continued in the reinforced back of finishing, and after TLC showed that reaction finishes, reaction mixture is water successively, the saturated common salt water washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, oven dry obtains white solid 340g, be the 4-chloromethyl benzoic acid tert-butyl ester, yield 93.9%.
Claims (3)
1. the preparation method of a 4-chloromethyl benzoic acid tert-butyl ester is characterized in that:
A.4-the preparation of chloromethyl benzoic acid
Earlier according to the 4-tolyl acid: organic solvent=1.05～1.20: 1 times of mass ratio is measured, then 4-tolyl acid and organic solvent are added in the reactor, be cooled under the irradiation of 0～10 ℃ and magnesium lamp, carry out substitution reaction to wherein feeding chlorine, the chlorine that substitution reaction feeds is 0.45～1.05 times of quality of 4-tolyl acid, the logical chlorine reaction time is 4～6 hours, makes the 4-chloromethyl benzoic acid through drying, removal of solvent under reduced pressure, washing, the oven dry of routine;
B.4-the preparation of the chloromethyl benzoic acid tert-butyl ester
In reactor, add 4-chloromethyl benzoic acid and organic solvent that the A step makes, 4-chloromethyl benzoic acid: organic solvent=1.05～2.9: 1 times of mass ratio; Be cooled to-10～10 ℃ and dripping down thionyl chlorides and carry out acyl chloride reaction, according to thionyl chloride: the minim of 4-chloromethyl benzoic acid=1: 1 times of mass ratio adds; The acyl chloride reaction time is 2～4 hours, dropwised the back restir two hours, then according to potassium tert.-butoxide: the amount of 4-chloromethyl benzoic acid=1: 1 times of mass ratio adds potassium tert.-butoxide and carried out esterification 2～4 hours, naturally rise to room temperature～30 ℃ continuation stirring reaction, reaction finishes the back precipitation, and the solid of gained is exactly the target compound 4-chloromethyl benzoic acid tert-butyl ester.
2, the preparation method of a kind of 4-chloromethyl benzoic acid tert-butyl ester according to claim 1 is characterized in that: described organic solvent is a methylene dichloride, or tetracol phenixin, or chloroform.
3, the preparation method of a kind of 4-chloromethyl benzoic acid tert-butyl ester according to claim 1 is characterized in that: the thionyl chloride that the described B step uses is collected 79～80 ℃ of cuts for what newly steam before reacting when specifically being air distillation, i.e. steaming is promptly used.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610030491A CN100575333C (en) | 2006-08-28 | 2006-08-28 | A kind of preparation method of the 4-chloromethyl benzoic acid tert-butyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610030491A CN100575333C (en) | 2006-08-28 | 2006-08-28 | A kind of preparation method of the 4-chloromethyl benzoic acid tert-butyl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1907948A true CN1907948A (en) | 2007-02-07 |
| CN100575333C CN100575333C (en) | 2009-12-30 |
Family
ID=37699201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200610030491A Expired - Fee Related CN100575333C (en) | 2006-08-28 | 2006-08-28 | A kind of preparation method of the 4-chloromethyl benzoic acid tert-butyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100575333C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646204A (en) * | 2015-12-31 | 2016-06-08 | 杭州福斯特药业有限公司 | Synthesis method of m-chloro methyl benzoic acid tert-butyl ester |
| CN109503355A (en) * | 2019-01-03 | 2019-03-22 | 唐更好 | A kind of preparation method of p-chloromethyl benzoic acid |
| CN110343041A (en) * | 2019-07-25 | 2019-10-18 | 润泰化学（泰兴）有限公司 | A kind of 1,3- diol monoester prepares the synthetic method of 1,3- glycol dibasic acid esters |
| CN110981719A (en) * | 2019-12-20 | 2020-04-10 | 黄石市利福达医药化工有限公司 | Preparation method of 3-carboxyl benzaldehyde |
-
2006
- 2006-08-28 CN CN200610030491A patent/CN100575333C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646204A (en) * | 2015-12-31 | 2016-06-08 | 杭州福斯特药业有限公司 | Synthesis method of m-chloro methyl benzoic acid tert-butyl ester |
| CN109503355A (en) * | 2019-01-03 | 2019-03-22 | 唐更好 | A kind of preparation method of p-chloromethyl benzoic acid |
| CN110343041A (en) * | 2019-07-25 | 2019-10-18 | 润泰化学（泰兴）有限公司 | A kind of 1,3- diol monoester prepares the synthetic method of 1,3- glycol dibasic acid esters |
| CN110981719A (en) * | 2019-12-20 | 2020-04-10 | 黄石市利福达医药化工有限公司 | Preparation method of 3-carboxyl benzaldehyde |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100575333C (en) | 2009-12-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Lalrempuia et al. | Effective fixation of CO2 by iridium-catalyzed hydrosilylation | |
| CN1907948A (en) | Preparation method of 4-chloromethyl benzoic acid t-butyl ester | |
| CN101875616B (en) | Levocarnitine compound and new preparation method thereof | |
| Hu et al. | Visible light induced hydrodifluoromethylation of alkenes derived from oxindoles with (difluoromethyl) triphenylphosphonium bromide | |
| CN101676255A (en) | Synthetic method of iodized vegetable fatty acids and their esters | |
| CN113666824A (en) | Cannabidiol-2-propionate and application thereof | |
| CN113336765B (en) | Curcumenol esterified product, preparation method and application of curcumenol esterified product in medicine for treating colorectal cancer | |
| CN106928068A (en) | A kind of tetracyclic diterpene class iso steviol compound and preparation method and application | |
| CN113061104B (en) | Synthetic method of alkyl thioether compound | |
| CN103396330A (en) | Preparation method of N,N-dimethyl glycine ester based on silica gel sulfonic acid serving as catalyst | |
| Zhang et al. | Base controlled (1, 1)-and (1, 2)-hydrophosphination of functionalized alkynes | |
| CN103145636B (en) | 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof | |
| CN101880271A (en) | Synthesis method of 2-thiophene acetylchloride | |
| KR20170005886A (en) | Method for preparing astaxanthin monoesters | |
| CN104693025A (en) | Feeding manner for preparing L-monomenthyl glutarate | |
| CN114314701A (en) | Preparation method of potassium trichloro-ammino platinate and application of potassium trichloro-ammino platinate in preparation of cis-ammonia-water-platinum complex | |
| CN108164561B (en) | Chiral menthyl phenyl phosphonamide compound and preparation method thereof | |
| CN101914112B (en) | Method for preparing butafosfan | |
| CN105646618A (en) | Method for preparing gamithromycin through reductive amination | |
| CN101891772B (en) | Method for preparing disodium 5'-ribonucleotide | |
| CN104910033A (en) | Method for preparing 5-aminolevulinic acid hydrochloride | |
| CN1869030A (en) | Preparation method of doxytasai | |
| CN108101852A (en) | A kind of preparation method of olaparib | |
| CN1187357C (en) | Calcarisporin B1 and extracting method and use in anti-tumor medicine | |
| CN115385837B (en) | Method for preparing astaxanthin by oxidation of canthaxanthin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20091230 Termination date: 20120828 |