CN110407697A - A kind of synthetic method of 4- formoxyl -3- methyl hydroxybenzoate - Google Patents
A kind of synthetic method of 4- formoxyl -3- methyl hydroxybenzoate Download PDFInfo
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- CN110407697A CN110407697A CN201910802584.7A CN201910802584A CN110407697A CN 110407697 A CN110407697 A CN 110407697A CN 201910802584 A CN201910802584 A CN 201910802584A CN 110407697 A CN110407697 A CN 110407697A
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- methyl hydroxybenzoate
- formoxyl
- synthetic method
- reaction
- temperature
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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
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/58—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
Abstract
The invention discloses a kind of synthetic methods of 4- formoxyl -3- methyl hydroxybenzoate.This method are as follows: using 3- methyl hydroxybenzoate as raw material, obtain 4- formoxyl -3- methyl hydroxybenzoate with polyformaldehyde reaction under the action of lewis acid and organic base.The present invention solves poor selectivity in the prior art；The problem of raw material is expensive, and step is longer and severe reaction conditions.The route reaction cost of material is low, mild condition, and purifying is simple, and product purity is high, amplifies more suitable for technique and produces.
Description
Technical field
The present invention relates to organic chemical industry's intermediate synthesis technical fields, and in particular to a kind of 4- formoxyl -3- hydroxy benzenes first
The synthetic method of sour methyl esters.
Background technique
4- formoxyl -3- methyl hydroxybenzoate is a kind of extremely important pharmaceutical intermediate, is had a extensive future.In this
Mesosome and its derivative, which have been reported to be used as, constructs numerous pharmaceutical drug substance bioactive molecules.GluN2C- selectivity synergist is such as prepared,
The indoles quinolines of folacin receptor targeting, S1P1Receptor antagonist, phosphodiesterase 4 inhibitors, PI3K inhibitor are fed
Newborn animal histone deacetylase inhibitors, JAD inhibitor, proteinase activated receptors 4 (PAR4) inhibitor, M-ChR
Antagonist, NK2 receptor antagonist, renin inhibitor etc..
Currently, the synthetic route about 4- formoxyl -3- methyl hydroxybenzoate, in the prior art generally using following several
Kind synthetic route:
1)
The generation of by-product 3 is had in the method route, yield is general, and is difficult to separate, and is not suitable for amplification production.
2)
Although the route improves route 1, solve the problems, such as selective, has several disadvantages in that
1) cost of material is high；2) it needs to use expensive palladium catalyst；3) reaction of second step needs to use ozone, needs special set
Standby and instrument.
As it can be seen that the synthetic method about 4- formoxyl -3- methyl hydroxybenzoate in the prior art, due to raw material and catalysis
Agent higher cost, the reasons such as purification process make the compound be difficult to amplify metaplasia production.To solve the above problems, the present invention proposes
4- formoxyl -3- methyl hydroxybenzoate is made with higher yield and high-purity in new synthetic method.
Summary of the invention
The object of the present invention is to provide a kind of synthetic methods of 4- formoxyl -3- methyl hydroxybenzoate, have simultaneously
Higher yield and product purity.
Present invention technical solution used for the above purpose is as follows:
A kind of synthetic method of 4- formoxyl -3- methyl hydroxybenzoate, synthetic route is as follows,
The step of synthetic method includes:
In reaction dissolvent, 3- methyl hydroxybenzoate (1) is under the collective effect of lewis acid and organic base, with poly
Formaldehyde reaction generates 4- formoxyl -3- methyl hydroxybenzoate (2).
Preferably, the detailed process of the step of synthetic method are as follows:
S1, under inert gas protection, 3- methyl hydroxybenzoate is added in reaction dissolvent, is slowly divided at low temperature
It criticizes and lewis acid is added, then organic base is added portionwise, paraformaldehyde is finally added portionwise, carry out back flow reaction, until having reacted
Reaction solution is obtained entirely；
S2, the reaction solution is down to room temperature, pours into aqueous acid and be layered after addition ethyl acetate stirring, by lower water
It after mutually separating, then is extracted twice with EA, the organic phase that three secondary clearings are obtained merges, and washing is spin-dried for, and EA mashing is obtained by filtration
4- formoxyl -3- methyl hydroxybenzoate.
Further, the reaction dissolvent includes: acetonitrile, acetone, preferably acetonitrile.
Further, the lewis acid includes: aluminium chloride, zinc chloride, magnesium chloride, preferably magnesium chloride.
Preferably, the organic base includes:
4- dimethylamino pyridine, n,N-diisopropylethylamine, triethylamine, pyridine, preferably triethylamine.
Preferably, the molar ratio of the lewis acid and 3- methyl hydroxybenzoate is 2~5:1, more preferably magnesium chloride
Molar ratio with 3- methyl hydroxybenzoate is 3:1；
The molar ratio of the organic base and 3- methyl hydroxybenzoate is 3~8:1, preferably 3~6:1, more preferably three
The molar ratio of ethamine and 3- methyl hydroxybenzoate is 5:1.
The molar ratio of the paraformaldehyde and 3- methyl hydroxybenzoate is 6:1
Preferably, in the step S1:
The time of the back flow reaction is 12~36 hours, and the temperature of the back flow reaction is 65~90 DEG C, preferably 80
~85 DEG C；
The temperature that reaction system in lewis acid is slowly added portionwise at low temperature be -10~20 DEG C, preferably 0
~10 DEG C.
Preferably, in the step S2: the concentration of the sour water is 1-5M, and more preferably 3M, the sour water is preferably salt
Acid.
Beneficial effect
Due to the implementation of above technical scheme, the present invention has the advantage that compared with prior art
The present invention is anti-with paraformaldehyde under the action of lewis acid and organic base using 3- methyl hydroxybenzoate as raw material
It should obtain 4- formoxyl -3- methyl hydroxybenzoate.The yield of this method be 70%~80%, purity can achieve 99% with
On.Route of the present invention is simple, at low cost, with good economic efficiency and application prospect.
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
The some embodiments recorded in invention, for those of ordinary skill in the art, without creative efforts,
It is also possible to obtain other drawings based on these drawings.
Detailed description of the invention
Invention is further described in detail with reference to the accompanying drawings and detailed description:
Fig. 1 is obtained the nuclear magnetic spectrogram of product by embodiment 1.
Specific embodiment
Technical solution of the present invention will be clearly and completely described below, it is clear that described embodiment is this hair
Bright a part of the embodiment, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art are not having
Every other embodiment obtained under the premise of creative work is made, shall fall within the protection scope of the present invention.
Illustrate technical solution of the present invention below by way of specific embodiment.The equal city of raw materials and reagents used in the present invention
Selling can obtain.
Embodiment 1
Under inert gas protection, compound 1 (3- methyl hydroxybenzoate) (300g, 1.97mol, 1eq) is added to
In acetonitrile (4.5L), when being cooled to 0 DEG C, be slowly added portionwise at such a temperature 3 equivalents anhydrous magnesium chloride (564g,
5.92mol,3eq)；After, triethylamine (995g, 9.85mol, 5eq) is added portionwise in continuation into reaction solution at such a temperature；
After, then paraformaldehyde (354g, 11.8mol, 6eq) is added portionwise into reaction solution at such a temperature, it is warming up to after adding
80 DEG C, reaction solution is obtained to complete within reaction 12 hours.
Reaction solution is down to room temperature, is added ethyl acetate (3L), is stirred 0.5 hour.Reaction solution is poured into the hydrochloric acid of 3M
In (4L) aqueous solution, layering.It being extracted twice after layering with ethyl acetate (1L*2), merges organic phase, washing is spin-dried for, EA mashing,
Filter product 283g (yield: 80%, purity 97%.Fig. 1 is obtained the nuclear magnetic spectrogram of product by embodiment 1, as shown in Figure 1
,1H NMR (600MHz, DMSO) δ 11.08 (s, 1H), 10.37 (s, 1H), 7.75 (d, J=8.1Hz, 1H), 7.60 (d, J=
1.0Hz, 1H), 7.47 (d, J=8.1Hz, 1H), 3.87 (s, 3H)).
Embodiment 2
Under inert gas protection, compound 1 (3- methyl hydroxybenzoate) (152.0g, 1.0mol, 1eq) is added to
In acetonitrile (2.5L), when being cooled to 0 DEG C, be slowly added portionwise at such a temperature 3 equivalents anhydrous zinc chloride (408.9g,
3.0mol,3eq)；After, triethylamine (506g, 5.0mol, 5eq) is added portionwise in continuation into reaction solution at such a temperature；It is complete
Bi Hou, then paraformaldehyde (180g, 6.0mol, 6eq) is added portionwise into reaction solution at such a temperature, 80 are warming up to after adding
DEG C, reaction solution is obtained to complete within reaction 12 hours.
Reaction solution is down to room temperature, is added ethyl acetate (1.5L), is stirred 0.5 hour.Reaction solution is poured into the hydrochloric acid of 3M
In (2L) aqueous solution, layering.It being extracted twice after layering with ethyl acetate (1L*2), merges organic phase, washing is spin-dried for, EA mashing,
Filter to obtain product 137g (yield: 76%, purity 97%).
Embodiment 3
Under inert gas protection, compound 1 (3- methyl hydroxybenzoate) (152.0g, 1.0mol, 1eq) is added to
In acetonitrile (2.5L), when being cooled to 0 DEG C, be slowly added portionwise at such a temperature 3 equivalents anhydrous magnesium chloride (285.6g,
3.0mol,3eq)；After, continuation be added portionwise at such a temperature into reaction solution n,N-diisopropylethylamine (646g,
5.0mol,5eq)；After, then paraformaldehyde (180g, 6.0mol, 6eq) is added portionwise into reaction solution at such a temperature, add
It is warming up to 80 DEG C after complete, reaction 12 hours obtains reaction solution to complete.
Reaction solution is down to room temperature, is added ethyl acetate (1.5L), is stirred 0.5 hour.Reaction solution is poured into the hydrochloric acid of 3M
In (2L) aqueous solution, layering.It being extracted twice after layering with ethyl acetate (1L*2), merges organic phase, washing is spin-dried for, EA mashing,
Filter to obtain product 135g (yield: 75%, purity 97%).
Embodiment 4
Under inert gas protection, compound 1 (3- methyl hydroxybenzoate) (300g, 1.97mol, 1eq) is added to
In acetonitrile (4.5L), when being cooled to -10 DEG C, be slowly added portionwise at such a temperature 3 equivalents anhydrous magnesium chloride (564g,
5.92mol,3eq)；After, triethylamine (995g, 9.85mol, 5eq) is added portionwise in continuation into reaction solution at such a temperature；
After, then paraformaldehyde (354g, 11.8mol, 6eq) is added portionwise into reaction solution at such a temperature, it is warming up to after adding
65 DEG C, reaction solution is obtained to complete within reaction 36 hours.
Reaction solution is down to room temperature, is added ethyl acetate (3L), is stirred 0.5 hour.Reaction solution is poured into the hydrochloric acid of 1M
In (4L) aqueous solution, layering.It being extracted twice after layering with ethyl acetate (1L*2), merges organic phase, washing is spin-dried for, EA mashing,
Filter product 272g (yield: 77%, purity 97%.)
Embodiment 5
Under inert gas protection, compound 1 (3- methyl hydroxybenzoate) (300g, 1.97mol, 1eq) is added to
In acetonitrile (4.5L), when being cooled to 20 DEG C, be slowly added portionwise at such a temperature 3 equivalents anhydrous magnesium chloride (564g,
5.92mol,3eq)；After, triethylamine (995g, 9.85mol, 5eq) is added portionwise in continuation into reaction solution at such a temperature；
After, then paraformaldehyde (354g, 11.8mol, 6eq) is added portionwise into reaction solution at such a temperature, it is warming up to after adding
90 DEG C, reaction solution is obtained to complete within reaction 24 hours.
Reaction solution is down to room temperature, is added ethyl acetate (3L), is stirred 0.5 hour.Reaction solution is poured into the hydrochloric acid of 5M
In (4L) aqueous solution, layering.It being extracted twice after layering with ethyl acetate (1L*2), merges organic phase, washing is spin-dried for, EA mashing,
Filter to obtain product 266g (yield: 75%, purity 97%).
It should be noted that above-described embodiment can be freely combined as needed.The above is only of the invention preferred
Embodiment, it is noted that for those skilled in the art, in the premise for not departing from the principle of the invention
Under, several improvements and modifications can also be made, these modifications and embellishments should also be considered as the scope of protection of the present invention.
Claims (9)
1. a kind of synthetic method of 4- formoxyl -3- methyl hydroxybenzoate, which is characterized in that synthetic route is as follows,
The step of synthetic method includes:
In reaction dissolvent, 3- methyl hydroxybenzoate (1) is under the collective effect of lewis acid and organic base, with paraformaldehyde
Reaction generates 4- formoxyl -3- methyl hydroxybenzoate (2).
2. a kind of synthetic method of 4- formoxyl -3- methyl hydroxybenzoate as described in claim 1, which is characterized in that institute
The detailed process for the step of stating synthetic method are as follows:
S1, under inert gas protection, 3- methyl hydroxybenzoate is added in reaction dissolvent, at low temperature slowly in batches plus
Enter lewis acid, then organic base is added portionwise, paraformaldehyde is finally added portionwise, carries out back flow reaction, until the reaction is complete
To reaction solution；
S2, the reaction solution is down to room temperature, pours into aqueous acid and be layered after addition ethyl acetate stirring, by lower layer's water phase point
It after out, then is extracted twice with EA, the organic phase that three secondary clearings are obtained merges, and washing is spin-dried for, and 4- first is obtained by filtration in EA mashing
Acyl group -3- methyl hydroxybenzoate.
3. a kind of synthetic method of 4- formoxyl -3- methyl hydroxybenzoate as claimed in claim 1 or 2, which is characterized in that
The reaction dissolvent includes:
Acetonitrile, acetone.
4. a kind of synthetic method of 4- formoxyl -3- methyl hydroxybenzoate as claimed in claim 1 or 2, which is characterized in that
The lewis acid includes:
Aluminium chloride, zinc chloride, magnesium chloride.
5. a kind of synthetic method of 4- formoxyl -3- methyl hydroxybenzoate as claimed in claim 1 or 2, which is characterized in that
The organic base includes:
4- dimethylamino pyridine, N, N- diisopropylethylamine, triethylamine, pyridine.
6. a kind of synthetic method of 4- formoxyl -3- methyl hydroxybenzoate according to claim 1 or 2, feature exist
In:
The molar ratio of the lewis acid and 3- methyl hydroxybenzoate is 2~5:1, the organic base and 3- hydroxybenzoic acid first
The molar ratio of ester is 3~8:1, and the molar ratio of the paraformaldehyde and 3- methyl hydroxybenzoate is 6:1.
7. the synthetic method of 4- formoxyl -3- methyl hydroxybenzoate according to claim 2, which is characterized in that the step
In rapid S1:
The time of the back flow reaction is 12~36 hours, and the temperature of the back flow reaction is 65~90 DEG C；
The temperature that reaction system in lewis acid is slowly added portionwise at low temperature is -10~20 DEG C.
8. the synthetic method of 4- formoxyl -3- methyl hydroxybenzoate according to claim 7, which is characterized in that the step
In rapid S1:
The temperature of the back flow reaction is 80~85 DEG C；
The temperature that reaction system in lewis acid is slowly added portionwise at low temperature is 0~10 DEG C.
9. the synthetic method of 4- formoxyl -3- methyl hydroxybenzoate according to claim 2, which is characterized in that the step
In rapid S2:
The concentration of the sour water is 1-5M, when pouring into the stirring in aqueous acid in layering after the addition ethyl acetate stirring
Between be 0.5h.
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Address after: 200433 Room 101, block a, building 11, 128 Xiangyin Road, Yangpu District, Shanghai Applicant after: Shanghai bide Medical Technology Co.,Ltd. Address before: Room 3501, 5th floor, building 2, 1077 Zuchongzhi Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai, 201203 Applicant before: BIDE PHARMATECH Ltd. |
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