CN106349051A - Preparation method of methyl 2-(4-chloromethylphenyl)propionate - Google Patents
Preparation method of methyl 2-(4-chloromethylphenyl)propionate Download PDFInfo
- Publication number
- CN106349051A CN106349051A CN201610725994.2A CN201610725994A CN106349051A CN 106349051 A CN106349051 A CN 106349051A CN 201610725994 A CN201610725994 A CN 201610725994A CN 106349051 A CN106349051 A CN 106349051A
- Authority
- CN
- China
- Prior art keywords
- acid
- chloromethyl phenyl
- preparation
- methyl propionate
- phenyl
- 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
- DOZZSWAOPDYVLH-UHFFFAOYSA-N CC(C(O)=N)c1ccccc1 Chemical compound CC(C(O)=N)c1ccccc1 DOZZSWAOPDYVLH-UHFFFAOYSA-N 0.000 description 1
- KIFZXXOBDKAFPG-UHFFFAOYSA-N CC(C(O)=O)c1ccc(CCl)cc1 Chemical compound CC(C(O)=O)c1ccc(CCl)cc1 KIFZXXOBDKAFPG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of methyl 2-(4-chloromethylphenyl)propionate. The method comprises the following steps: (1) by using 2-phenylpropionic acid as an initial raw material, mixing the 2-phenylpropionic acid with formaldehyde, dropwisely adding concentrated sulfuric acid at 20-50 DEG C, starting dropwisely adding hydrogen chloride, and heating to 70-100 DEG C to react for 10-30 hours to obtain 2-(4- chloromethylphenyl)propionic acid; and (2) adding the 2-(4- chloromethylphenyl)propionic acid and methanol into a reaction kettle, adding thionyl chloride, keeping the temperature at 45-65 DEG C to react for 12-24 hours, pouring the reaction solution into a right amount of water, removing the water phase, and carrying out reduced pressure rectification on the organic phase to obtain the 2-(4-chloromethylphenyl)propionate. The 2-phenylpropionic acid used as the main raw material is subjected to chloromethylation reaction and esterification reaction to finally prepare the finished product, and the finished product has high purity.
Description
Technical field
The invention belongs to technical field of organic synthesis is and in particular to a kind of preparation of 2- (4- chloromethyl phenyl) methyl propionate
Method.
Background technology
Loxoprofen Sodium (loxoprofen sodium) is first phenoxy propionic acid precursor type NSAID (non-steroidal anti-inflammatory drug)
(nsaids) it is, to be researched and developed by Japanese Sankyo Co., Ltd, and in July, 1986 in Japan's listing, the entitled happy pine of registration goods.Lip river
Suo Luofen sodium is a kind of new nsaids, and this medicine is a prodrug, and itself does not have activity, needs through liver generation after being administered orally
Thank, convert it into its therapeutical effect of competence exertion after trans-oh body, its applied range, can be used for osteoarthritis,
Rheumatoid arthritiss, scapulohumeral periarthritis, lumbago, neck shoulder wrist syndrome etc., be also commonly used for performing the operation, the pain after exodontia and acute on
The diseases such as respiratory inflammation.At present in the listing of many countries such as Japan, Korea S, America and Europe, and growth is powerful.According to statistics,
The market sales revenue reaches 1.8 hundred million dollars within 1992, reaches 25,000,000,000 yen, before belonging to annual sales amount in Japanese sales volume within 1994
The medicine of 20.China is also in recent years starting to produce and in clinical practice, but the complex manufacturing of prior art, production cost
Greatly, pollute greatly, and its product yield is low.
Content of the invention
It is an object of the invention to overcoming above-mentioned deficiency present in prior art, and provide a kind of simple production process,
Product purity is high, 2- (4- chloromethyl phenyl) the methyl propionate preparation method of high income.
The present invention solves the above problems and be the technical scheme is that
A kind of 2- (4- chloromethyl phenyl) methyl propionate preparation method, specifically includes following steps:
(1) preparation of 2- (4- chloromethyl phenyl) propanoic acid
With 2- phenylpropionic acid as initiation material, after 2- phenylpropionic acid and solid formaldehyde are mixed, Deca at 20～50 DEG C
Concentrated sulphuric acid, then begins to Deca hydrogen chloride and is warming up to 70～100 DEG C and enters reaction 10～30 hours, obtain 2- (4- chloromethylbenzene
Base) propanoic acid；
(2) preparation of 2- (4- chloromethyl phenyl) methyl propionate
2- (4- chloromethyl phenyl) propanoic acid and methanol are put in reactor, adds thionyl chloride, at 45～65 DEG C, insulation
After reaction 12～24h, reactant liquor is poured into water, and removes aqueous phase, and organic faciess are obtained 2- (4- chloromethylbenzene through rectification under vacuum
Base) methyl propionate.
Preferably, the mol ratio of 2- phenylpropionic acid, solid formaldehyde and hydrogen chloride described in step (1) is 1:1.5～4:
2.5～7.5.
Preferably, it is characterized in that, concentrated sulphuric acid described in step (1) is 1:0.167 with the mol ratio of 2- phenylpropionic acid
～0.25.
Preferably, the mol ratio of 2- (4- chloromethyl phenyl) described in step (2) propanoic acid, methanol and thionyl chloride is 1:
10～50:0.1～1.
The synthetic route of present invention preparation is:
(1) preparation of 2- (4- chloromethyl phenyl) propanoic acid
(2) preparation of 2- (4- chloromethyl phenyl) methyl propionate
The present invention compared with prior art, has advantages below and an effect: the present invention with 2- phenylpropionic acid as primary raw material,
It is finally made finished product through chloromethylation and esterification, its finished product purity is high, high income.In addition, production technology of the present invention
Simply, material toxicity is low, and low production cost, pollution are little.
Specific embodiment
In order that the objects, technical solutions and advantages of the present invention become more apparent, with reference to embodiments to the present invention
It is further elaborated.It should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not used to
Limit the present invention.
Embodiment 1
(1) 2- (4- chloromethyl phenyl) propanoic acid
2- phenylpropionic acid (150g, 1mol), solid formaldehyde (60g, 2mol) are put in chloromethylation kettle, unlatching is stirred
Mix, be then slowly added dropwise concentrated sulphuric acid (400g, 4mol, 98% concentration), control temperature below 50 DEG C, treat sulphuric acid completion of dropping
Afterwards, Deca hydrogen chloride (253.5g, 2.5mol, 36% concentration), and start to warm up.Temperature control, at 70 DEG C, is reacted 30 hours, is obtained
To 2- (4- chloromethyl phenyl) propanoic acid crude product, through being refining to obtain 67.5g fine work (content is more than 99%).
(2) 2- (4- chloromethyl phenyl) methyl propionate
2- (4- chloromethyl phenyl) propanoic acid (198.5g, 1mol) is dissolved in methanol (320g, 10mol), puts into protochloride
Sulfone (11.9g, 0.1mol), 45 DEG C are stirred 24 hours, and reactant liquor is poured in 500g water, and organic faciess are put into rectification by branch vibration layer
Rectification under vacuum in kettle, obtains 2- (4- chloromethyl phenyl) methyl propionate 191.3g.After testing, the 2- (4- chloromethyl phenyl) third obtaining
Sour methyl ester high purity 99.2%, molar yield 90%.
Embodiment 2:
(1) 2- (4- chloromethyl phenyl) propanoic acid
2- phenylpropionic acid (150g, 1mol), solid formaldehyde (45g, 1.5mol) are put in chloromethylation kettle, opens
Stirring, is then slowly added dropwise concentrated sulphuric acid (500g, 5mol, 98% concentration), controls temperature below 20 DEG C, treats sulphuric acid completion of dropping
Afterwards, Deca hydrogen chloride (507g, 5mol, 36% concentration), and start to warm up.Temperature control, at 85 DEG C, is reacted 20 hours, is obtained 2-
(4- chloromethyl phenyl) propanoic acid crude product, through being refining to obtain 75g fine work (content is more than 99%).
(2) 2- (4- chloromethyl phenyl) methyl propionate
2- (4- chloromethyl phenyl) propanoic acid (198.5g, 1mol) is dissolved in methanol (960g, 30mol), puts into protochloride
Sulfone (71g, 0.6mol), 55 DEG C are stirred 18 hours, and reactant liquor is poured in 700g water, and organic faciess are put into rectifying still by branch vibration layer
Middle rectification under vacuum, obtains 2- (4- chloromethyl phenyl) methyl propionate 197.6g.After testing, 2- (4- chloromethyl phenyl) propanoic acid obtaining
Methyl ester high purity 99.4%, molar yield 93%.
Embodiment 3:
(1) 2- (4- chloromethyl phenyl) propanoic acid
2- phenylpropionic acid (150g, 1mol), solid formaldehyde (120g, 4mol) are put in chloromethylation kettle, opens
Stirring, the then slow concentrated sulphuric acid (600g, 6mol, 98% concentration) dripping, control temperature below 30 DEG C, treat sulphuric acid completion of dropping
Afterwards, Deca hydrogen chloride (760g, 7.5mol), and start to warm up.Temperature control, at 100 DEG C, is reacted 10 hours, is obtained 2- (4- chlorine
Aminomethyl phenyl) propanoic acid crude product, through being refining to obtain 70g fine work (content is more than 99%).
(2) 2- (4- chloromethyl phenyl) methyl propionate
2- (4- chloromethyl phenyl) propanoic acid (198.5g, 1mol) is dissolved in methanol (1600g, 50mol), puts into protochloride
Sulfone (119g, 1mol), 65 DEG C are stirred 12 hours, and reactant liquor is poured in 900g water, branch vibration layer, and organic faciess are put in rectifying still
Rectification under vacuum, obtains 2- (4- chloromethyl phenyl) methyl propionate 201.8g.After testing, 2- (4- chloromethyl phenyl) the propanoic acid first obtaining
Ester high purity 99.5%, molar yield 95%.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all essences in the present invention
Any modification, equivalent and improvement made within god and principle etc., should be included within the scope of the present invention.
Claims (4)
1. a kind of preparation method of 2- (4- chloromethyl phenyl) methyl propionate is it is characterised in that specifically include following steps:
(1) preparation of 2- (4- chloromethyl phenyl) propanoic acid
With 2- phenylpropionic acid as initiation material, after 2- phenylpropionic acid and solid formaldehyde are mixed, the dense sulfur of Deca at 20～50 DEG C
Acid, then begins to Deca hydrogen chloride and is warming up to 70～100 DEG C and enters reaction 10 ~ 30 hours, obtain 2-(4- chloromethyl phenyl) third
Acid；
(2) 2-(4- chloromethyl phenyl) methyl propionate preparation
By 2-(4- chloromethyl phenyl) propanoic acid and methanol puts in reactor, adds thionyl chloride, at 45～65 DEG C, insulation is anti-
After answering 12～24h, reactant liquor is poured in suitable quantity of water, removes aqueous phase, and organic faciess are obtained 2- (4- chloromethyl through rectification under vacuum
Phenyl) methyl propionate.
2. 2- (4- chloromethyl phenyl) methyl propionate preparation method as claimed in claim 1 is it is characterised in that in step (1)
The mol ratio of described 2- phenylpropionic acid, solid formaldehyde and hydrogen chloride is 1:1.5～4:2.5～7.5.
3. 2- (4- chloromethyl phenyl) methyl propionate preparation method as claimed in claim 1 is it is characterised in that in step (1)
Described concentrated sulphuric acid is 1:0.167～0.25 with the mol ratio of 2- phenylpropionic acid.
4. 2- (4- chloromethyl phenyl) methyl propionate preparation method as claimed in claim 1 is it is characterised in that in step (2)
The mol ratio of described 2- (4- chloromethyl phenyl) propanoic acid, methanol and thionyl chloride is 1:10～50:0.1～1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610725994.2A CN106349051A (en) | 2016-08-25 | 2016-08-25 | Preparation method of methyl 2-(4-chloromethylphenyl)propionate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610725994.2A CN106349051A (en) | 2016-08-25 | 2016-08-25 | Preparation method of methyl 2-(4-chloromethylphenyl)propionate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106349051A true CN106349051A (en) | 2017-01-25 |
Family
ID=57855037
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610725994.2A Pending CN106349051A (en) | 2016-08-25 | 2016-08-25 | Preparation method of methyl 2-(4-chloromethylphenyl)propionate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106349051A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56138140A (en) * | 1980-03-31 | 1981-10-28 | Sankyo Co Ltd | Preparation of 2- p-halomethylphenyl propionic acid or its ester |
| US6013832A (en) * | 1997-07-04 | 2000-01-11 | Kolon Industries, Inc. | Process for the production of benzene derivatives |
| CN104710309A (en) * | 2015-02-05 | 2015-06-17 | 浙江普洛医药科技有限公司 | Synthetic methods of loxoprofen sodium and intermediate thereof |
-
2016
- 2016-08-25 CN CN201610725994.2A patent/CN106349051A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56138140A (en) * | 1980-03-31 | 1981-10-28 | Sankyo Co Ltd | Preparation of 2- p-halomethylphenyl propionic acid or its ester |
| US6013832A (en) * | 1997-07-04 | 2000-01-11 | Kolon Industries, Inc. | Process for the production of benzene derivatives |
| CN104710309A (en) * | 2015-02-05 | 2015-06-17 | 浙江普洛医药科技有限公司 | Synthetic methods of loxoprofen sodium and intermediate thereof |
Non-Patent Citations (1)
| Title |
|---|
| 唐文生 等: "非甾体抗炎药洛索洛芬钠的合成改进", 《中国药物化学杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105330586B (en) | A kind of preparation method of Apremilast | |
| CN104045637A (en) | Apixaban preparation method | |
| CN104447443A (en) | Preparation method for apremilast and intermediate of apremilast | |
| CN102241662A (en) | Synthetic method of thiophene-3-ethanol | |
| CN105037139B (en) | A kind of 2 phenylpropionic acid preparation methods | |
| CN107858700A (en) | The electrochemical method for synthesizing of the benzothiazole of 2 substitutions | |
| CN107915622A (en) | A kind of solvent-free 4 chlorine, 3 oxobutyric continuous stream synthetic method and system | |
| CN106349051A (en) | Preparation method of methyl 2-(4-chloromethylphenyl)propionate | |
| CN104628605B (en) | A kind of naphthalene continuous catalysis method of sulfonating and device thereof | |
| CN101279932B (en) | Preparation of N,N'-dicyclohexylurea | |
| CN108383718A (en) | The preparation method of one kind 2,4,5- trifluoro benzene acetic acids | |
| CN103664833B (en) | A kind of preparation method of trifluoro-epoxy propane | |
| CN105461602A (en) | Preparation method of chiral S/R-3-ethoxy-4-methoxy-alpha[(methylsulfonyl)methyl] benzyl alcohol | |
| CN106831549B (en) | A kind of method of asymmetric synthesis of Claritin carbinoxamine | |
| CN106478422A (en) | A kind of preparation method of paranitrophenylacetic acid | |
| CN103145562B (en) | N-ethyl aniline preparation method | |
| CN101585762B (en) | Method for synthesizing 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanoic acid | |
| CN102976927A (en) | Preparation method of calcium alpha-ketoglutarate | |
| CN109232508B (en) | Preparation method of 1, 1-cyclohexyl diacetic anhydride | |
| CN101921208B (en) | Preparation method of formoterol intermediate | |
| CN102344359B (en) | Method for preparing 3-butenoic acid | |
| CN113979854B (en) | Method for electrochemically preparing 2-phenylpropionic acid | |
| CN109627165A (en) | A kind of method of coproduction 2- fluorine propionic ester and ethyl difluoro | |
| CN102399191A (en) | Method for synthesizing analgin | |
| CN116003216B (en) | Preparation method of ibuprofen |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170125 |