CN106674046A - Preparation method of 3-cyano-4-isopropyloxybenzoic acid - Google Patents

Preparation method of 3-cyano-4-isopropyloxybenzoic acid Download PDF

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Publication number
CN106674046A
CN106674046A CN201611223241.8A CN201611223241A CN106674046A CN 106674046 A CN106674046 A CN 106674046A CN 201611223241 A CN201611223241 A CN 201611223241A CN 106674046 A CN106674046 A CN 106674046A
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several times
cyano group
dried
cyano
cooled
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CN201611223241.8A
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Inventor
池永贵
黄轩
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Suzhou Mountain Bamboo Biotechnology Co Ltd
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Suzhou Mountain Bamboo Biotechnology Co Ltd
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Priority to CN201611223241.8A priority Critical patent/CN106674046A/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00Preparation of carboxylic acid nitriles
    • C07C253/30Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00Preparation of carboxylic acid nitriles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00Preparation of carboxylic acid nitriles
    • C07C253/32Separation; Purification; Stabilisation; Use of additives
    • C07C253/34Separation; Purification
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00Preparation of carboxylic acid esters
    • C07C67/30Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/313Preparation 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

Abstract

The invention discloses a preparation method of 3-cyano-4-isopropyloxybenzoic acid. The preparation method comprises steps as follows: step one, methyl 3-formyl-4-hydroxybenzoate is prepared from methyl 4-hydroxybenzoate; step two, methyl 3-cyano-4-hydroxybenzoate is prepared from methyl 3-formyl-4-hydroxybenzoate; step three, methyl 3-cyano-4-isopropoxybenzoate is prepared from the methyl 3-cyano-4-hydroxybenzoate; step four, 3-cyano-4-isopropyloxybenzoic acid is prepared from methyl 3-cyano-4-isopropoxybenzoate. The preparation method of 3-cyano-4-isopropyloxybenzoic acid has the advantages as follows: 1), cuprous cyanide as highly toxic cyanide applied to a conventional technology is not used, and the method is more suitable for industrialization; 2), a cyano group is prepared from a formyl group, and the preparation is efficient, direct and suitable for mass production; 3), all raw materials are inexpensive and easily available, and the cost advantage is remarkable.

Description

A kind of preparation method of 3- cyano group -4- isopropoxy benzoic acid
Technical field
The invention belongs to technical field of organic synthesis, more particularly, to a kind of system of 3- cyano group -4- isopropoxy benzoic acid Preparation 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 preparation method of 3- cyano group -4- isopropoxy benzoic acid, it is intended in solution State problem.
To achieve these goals, the technical scheme is that a kind of 3- cyano group -4- isopropoxy benzoic acid of design Preparation method, comprises the steps:
1) magnesium chloride, triethylamine, paraformaldehyde, dichloromethane, 60 DEG C of oil bath heating are added in methyl parahydroxybenzoate 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 methyl ester;
2) by the 3- obtained in previous step aldehyde radicals -4-HBA methyl 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 methyl ester;
3) by the 3- obtained in previous step cyano group -4-HBA methyl 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 essence of Niobe;
4) by the 3- cyano group -4- isopropoxies essence of Niobe 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 preparation side of 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, 4-HBA methyl ester (2.5kg, 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 1215g sterlings, two step yields 42%.
3) in 50L reactions kettle, previous step sterling (1.09kg, 6.15mol), isopropyl bromide (1L, 10.65mol), carbon are added Sour potassium (2.1kg, 15.19mol), acetonitrile/N,N-dimethylformamide (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 2.5kg), 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 1.1kg 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 preparation method of 3- cyano group -4- isopropoxy benzoic acid, it is characterised in that comprise the steps:
1) magnesium chloride, triethylamine, paraformaldehyde, dichloromethane are added in methyl parahydroxybenzoate, 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 methyl ester;
2) by the 3- obtained in previous step aldehyde radicals -4-HBA methyl 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 methyl ester;
3) by the 3- obtained in previous step cyano group -4-HBA methyl 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 essence of Niobe;
4) by the 3- cyano group -4- isopropoxies essence of Niobe 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.
CN201611223241.8A 2016-12-27 2016-12-27 Preparation method of 3-cyano-4-isopropyloxybenzoic acid Pending CN106674046A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018121051A1 (en) * 2016-12-27 2018-07-05 苏州山青竹生物医药有限公司 Preparation method for methyl 3-cyano-4-isopropoxybenzoate
CN113979871A (en) * 2021-11-30 2022-01-28 江苏同禾药业有限公司 Preparation method of N-methyl-1-naphthylmethylamine and intermediate N-methyl-1-naphthylmethylamine

Citations (3)

* Cited by examiner, † Cited by third party
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
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

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018121051A1 (en) * 2016-12-27 2018-07-05 苏州山青竹生物医药有限公司 Preparation method for methyl 3-cyano-4-isopropoxybenzoate
CN113979871A (en) * 2021-11-30 2022-01-28 江苏同禾药业有限公司 Preparation method of N-methyl-1-naphthylmethylamine and intermediate N-methyl-1-naphthylmethylamine
CN113979871B (en) * 2021-11-30 2023-11-10 江苏同禾药业有限公司 Preparation method of N-methyl-1-naphthylmethylamine and intermediate N-methyl-1-naphthylmethylamine

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Application publication date: 20170517