CN106674047A - Method for preparing 3-cyano-4-isopropoxybenzoic acid - Google Patents
Method for preparing 3-cyano-4-isopropoxybenzoic acid Download PDFInfo
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- CN106674047A CN106674047A CN201611223256.4A CN201611223256A CN106674047A CN 106674047 A CN106674047 A CN 106674047A CN 201611223256 A CN201611223256 A CN 201611223256A CN 106674047 A CN106674047 A CN 106674047A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing 3-cyano-4-isopropoxybenzoic acid, comprising the following steps: step 1, preparing 3-aldehyde-4-ethyl hydroxybenzoate from ethyl p-hydroxybenzoate; step 2, preparing 3-cyano-4-ethyl hydroxybenzoate from the 3-aldehyde-4-ethyl hydroxybenzoate; step 3, preparing 3-cyano-4-ethyl isopropoxybenzoate from the 3-cyano-4-ethyl hydroxybenzoate; and step 4, preparing 3-cyano-4-isopropoxybenzoic acid from the 3-cyano-4-ethyl isopropoxybenzoate. The method for preparing the 3-cyano-4-isopropoxybenzoic acid has the following advantages: (1) use of virulent cyanide, namely cuprous cyanide in the prior art is avoided, so the method is more suitable to be industrialized; (2) cyano groups are prepared from aldehyde groups, which is efficient, direct and suitable for mass production; and (3) all the raw materials are cheap and easily available and have obvious advantages in cost.
Description
Technical field
The invention belongs to technical field of organic synthesis, more particularly, to one kind 3- cyano group -4- isopropoxy benzoic acid is prepared
Method.
Background technology
The traditional handicraft for preparing 3- cyano group -4- isopropoxy benzoic acid is as follows：
The defect that the ratio of technique presence is larger is the Cupricin. that hypertoxic cyanide is employed in technical process, in reality
Have in the market of border than larger hazardness.
The content of the invention
It is an object of the invention to provide a kind of method for preparing 3- cyano group -4- isopropoxy benzoic acid, it is intended in solution
State problem.
To achieve these goals, the technical scheme is that design one kind prepares 3- cyano group -4- isopropoxy benzene first
The method of acid, comprises the steps：
1) magnesium chloride, triethylamine, paraformaldehyde, dichloromethane, 60 DEG C of oil bath heating are added in ethylparaben
Overnight.After being cooled to room temperature, the aqueous solution of concentrated hydrochloric acid dilution is slowly added into, filters insoluble matter, DCM is extracted several times, sodium sulfate
It is dried, filtration is spin-dried for, obtains 3- aldehyde radicals -4-HBA ethyl ester；
2) by the 3- obtained in previous step aldehyde radicals -4-HBA ethyl ester and oxammonium hydrochloride., acetonitrile/N, N- diformazans
Base Methanamide adds chloroacetic chloride, 80 DEG C of heated and stirred 2 hours.After being cooled to room temperature, EA is added, washed several times, water phase back extraction
Take several times, be associated with organic layer, sodium sulfate is dried, filter, be threaded to half-dried, separate out solid, sucking filtration, EA is washed several times, obtained
Pink crude product, sucking filtration, dichloromethane is washed several times, obtains pink solid, as 3- cyano group -4-HBA ethyl ester；
3) by the 3- obtained in previous step cyano group -4-HBA ethyl ester and isopropyl bromide, potassium carbonate, acetonitrile/
DMF, 80 DEG C are stirred overnight.After being cooled to room temperature, add water some, be completely dissolved to potassium carbonate, add second
Acetoacetic ester, separates water phase, and organic faciess are washed several times, merges water phase, and ethyl acetate is extracted several times, merges organic faciess, is spin-dried for
Obtain yellow oil, i.e. 3- cyano group -4- isopropoxy ethyl benzoate；
4) by the 3- cyano group -4- isopropoxies ethyl benzoate obtained in previous step and sodium hydroxide, tetrahydrofuran,
60 DEG C are stirred 0.5 hour.Room temperature is cooled to, adds ethyl acetate to extract several times, separate water phase, be neutralized with hydrochloric acid to acidity,
A large amount of white solids, sucking filtration are separated out, vacuum drying waits until white solid, i.e. 3- cyano group -4- isopropoxy benzoic acid.
The advantages of the present invention are：A kind of side for preparing 3- cyano group -4- isopropoxy benzoic acid of the present invention
The advantage of method has：1) Cupricin. using hypertoxic cyanide in former technique is avoided, industrialization is more suitable for；2) by aldehyde radical
Cyano group is prepared, efficiently directly, is adapted to a large amount of productions；3) all raw materials are cheap and easily-available, and cost advantage is obvious.
Description of the drawings
Fig. 1 is the flow chart of the present invention.
Specific embodiment
With reference to the accompanying drawings and examples, the specific embodiment of the present invention is further described.Following examples are only
For clearly illustrating technical scheme, and can not be limited the scope of the invention with this.
Embodiment：
1) add in 50L reactions kettle, ethylparaben (2.75kg, 16.4mol), magnesium chloride (3.2kg,
32.8mol), triethylamine (9.3L, 82mol), paraformaldehyde (3.9kg, 131.2mol), dichloromethane (18L), 60 DEG C of oil bath adds
Heat (44 DEG C of interior temperature) is overnight.After being cooled to room temperature, the aqueous solution of 5L concentrated hydrochloric acid dilution is slowly added into, filters insoluble matter, DCM extractions
4 times, sodium sulfate is dried, and filtration is spin-dried for.Directly next step reaction.
2) previous step raw material, oxammonium hydrochloride. (1.14kg) and acetonitrile/DMF are added in 50L reactions kettle
(10L/2.5L) chloroacetic chloride (1.17L), 80 DEG C of heated and stirred 2 hours, are added.After being cooled to room temperature, EA10L, 5L washings are added
Twice, water phase back extraction once, merges organic layer, and sodium sulfate is dried, and filters, and is threaded to big half-dried, a large amount of solids of precipitation, directly takes out
Filter, EA is washed twice, obtains pink crude product, and sucking filtration, dichloromethane (a small amount of ethyl acetate of mixing) is washed 2 times, obtains pink solid
Body 1336.5g sterlings, two step yields 42%.
3) in 50L reactions kettle, previous step sterling (1.12kg, 6.15mol), isopropyl bromide (1L, 10.65mol), carbon are added
Sour potassium (2.1kg, 15.19mol), acetonitrile/DMF (5L/1L), 80 DEG C are stirred overnight.After being cooled to room temperature,
Water 8L is added, is completely dissolved to potassium carbonate, add ethyl acetate 5L, separate water phase, organic phases washed with water 2 times.Merge water phase, second
Acetoacetic ester is extracted 3 times, merges organic faciess, moist, is spin-dried for obtaining yellow oil (about 2.75kg), direct next step reaction.
4) previous step crude product is added in 50L reactions kettle, 2N sodium hydroxide (5L), tetrahydrofuran (2L), 60 DEG C of stirrings 0.5 are little
When.After being cooled to room temperature, add ethyl acetate to extract 2 times, separate water phase, with 12N hydrochloric acid acidity is neutralized to, separate out a large amount of whites
Solid, sucking filtration, vacuum drying obtains 1.21kg white solids, two step yields 83%, HPLC detection purity 98.3%.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, on the premise of without departing from the technology of the present invention principle, some improvements and modifications can also be made, these improvements and modifications
Also should be regarded as protection scope of the present invention.
Claims (1)
1. a kind of method for preparing 3- cyano group -4- isopropoxy benzoic acid, it is characterised in that comprise the steps：
1) magnesium chloride, triethylamine, paraformaldehyde, dichloromethane are added in ethyl p-hydroxybenzoate, 60 DEG C of oil bath heating is overnight.
After being cooled to room temperature, the aqueous solution of concentrated hydrochloric acid dilution is slowly added into, filters insoluble matter, DCM is extracted several times, and sodium sulfate is dried,
Filtration is spin-dried for, and obtains 3- aldehyde radicals -4-HBA ethyl ester；
2) by the 3- obtained in previous step aldehyde radicals -4-HBA ethyl ester and oxammonium hydrochloride., acetonitrile/N, N- dimethyl methyls
Amide adds chloroacetic chloride, 80 DEG C of heated and stirred 2 hours.After being cooled to room temperature, EA is added, washed several times, if water phase back extraction
Dry time, organic layer is associated with, sodium sulfate is dried, and filters, is threaded to half-dried, separate out solid, sucking filtration, EA is washed several times, obtains pink
Color crude product, sucking filtration, dichloromethane is washed several times, obtains pink solid, as 3- cyano group -4-HBA ethyl ester；
3) by the 3- obtained in previous step cyano group -4-HBA ethyl ester and isopropyl bromide, potassium carbonate, acetonitrile/N, N-
Dimethylformamide, 80 DEG C are stirred overnight.After being cooled to room temperature, add water some, be completely dissolved to potassium carbonate, add acetic acid second
Ester, separates water phase, and organic faciess are washed several times, merges water phase, and ethyl acetate is extracted several times, merges organic faciess, is spin-dried for yellow
Color grease, i.e. 3- cyano group -4- isopropoxy ethyl benzoate；
4) by the 3- cyano group -4- isopropoxies ethyl benzoate obtained in previous step and sodium hydroxide, tetrahydrofuran, 60 DEG C
Stirring 0.5 hour.Room temperature is cooled to, adds ethyl acetate to extract several times, separate water phase, be neutralized with hydrochloric acid to acidity, separated out
A large amount of white solids, sucking filtration, vacuum drying waits until white solid, i.e. 3- cyano group -4- isopropoxy benzoic acid.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611223256.4A CN106674047A (en) | 2016-12-27 | 2016-12-27 | Method for preparing 3-cyano-4-isopropoxybenzoic acid |
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| CN201611223256.4A CN106674047A (en) | 2016-12-27 | 2016-12-27 | Method for preparing 3-cyano-4-isopropoxybenzoic acid |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111559967A (en) * | 2020-06-04 | 2020-08-21 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-amino-2-hydroxy-3-isopropoxybenzoic acid |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891649A (en) * | 2010-07-06 | 2010-11-24 | 荆州市腾飞化工有限公司 | Novel 3-cyano methyl benzoate preparing method |
| WO2011072488A1 (en) * | 2009-12-18 | 2011-06-23 | Glaxo Group Limited | Oxadiazole substituted indazole derivatives for use as sphingosine 1-phosphate 1 (s1p1) receptor agonists |
| CN102911254A (en) * | 2011-08-02 | 2013-02-06 | 上海唐润医药科技有限公司 | HCV (hepatitis C virus) protease inhibitor |
| CN102964313A (en) * | 2012-11-27 | 2013-03-13 | 周广连 | Synthetic method of febuxostat |
-
2016
- 2016-12-27 CN CN201611223256.4A patent/CN106674047A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011072488A1 (en) * | 2009-12-18 | 2011-06-23 | Glaxo Group Limited | Oxadiazole substituted indazole derivatives for use as sphingosine 1-phosphate 1 (s1p1) receptor agonists |
| CN101891649A (en) * | 2010-07-06 | 2010-11-24 | 荆州市腾飞化工有限公司 | Novel 3-cyano methyl benzoate preparing method |
| CN102911254A (en) * | 2011-08-02 | 2013-02-06 | 上海唐润医药科技有限公司 | HCV (hepatitis C virus) protease inhibitor |
| CN102964313A (en) * | 2012-11-27 | 2013-03-13 | 周广连 | Synthetic method of febuxostat |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111559967A (en) * | 2020-06-04 | 2020-08-21 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-amino-2-hydroxy-3-isopropoxybenzoic acid |
| CN111559967B (en) * | 2020-06-04 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-amino-2-hydroxy-3-isopropoxybenzoic acid |
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