CN115894186B

CN115894186B - Synthesis method of benvimod intermediate

Info

Publication number: CN115894186B
Application number: CN202211494320.8A
Authority: CN
Inventors: 廖焱; 刘凤伟; 杨飞; 赵骞
Original assignee: Jumpcan Pharmaceutical Group Co ltd; Jichuan Shanghai Medical Technology Co ltd
Current assignee: Jumpcan Pharmaceutical Group Co ltd; Jichuan Shanghai Medical Technology Co ltd
Priority date: 2022-11-25
Filing date: 2022-11-25
Publication date: 2024-03-22
Anticipated expiration: 2042-11-25
Also published as: CN115894186A

Abstract

The invention discloses a synthesis method of a present vitamin mod intermediate. Specifically, the invention discloses a synthesis method of 3, 5-dimethoxy-4-isopropylbenzaldehyde, which comprises the following steps: the following oxidation reaction is carried out on 3, 5-dimethoxy-4-isopropylbenzyl alcohol in the presence of an oxidizing agent and a catalyst. The obtained intermediate of the present invention has high purity, high yield, environment friendship, simple post-treatment and suitability for industrial production.

Description

Synthesis method of benvimod intermediate

Technical Field

The invention relates to a synthesis method of a present vitamin mod intermediate.

Background

The vitamin D (Benvitimod) is a new non-hormonal small molecule chemical medicine for treating inflammatory and autoimmune diseases, is separated from a symbiotic bacterial metabolite of soil nematodes, and is the first therapeutic aromatic hydrocarbon receptor modulator (TAMA). Pharmacological studies have shown that the present vmod inhibits lymphocyte protein tyrosine kinase activity; has inhibiting effects on inflammatory cytokine release, inflammatory cell migration and infiltration, abnormal differentiation and proliferation of keratinocytes, neovascularization and vasodilation associated with psoriasis. In 2009, this vitamin mod obtained clinical lot, by 2019, 5, 29, NMPA approved 1 class of innovative drug this vitamin mod cream (euphoric) was marketed for topical treatment of adult light to moderate stability psoriasis vulgaris.

The chemical name of the present vitamin mod is: 5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol having the structural formula:

in the reported synthetic route to valmod, the backbone structure is generally synthesized by a Wittig-Horner condensation reaction, which is carried out between a substituted benzyl diethyl phosphate and a substituted benzaldehyde. The key intermediates involved in this route include 3, 5-dimethoxy-4-isopropylbenzaldehyde, which has the following structural formula:

CN101830764a discloses a method for synthesizing stilbene compounds by Pfitzner-moffatt oxidation, which uses substituted benzyl alcohol as raw material, and uses DMSO, i.e. dimethyl sulfoxide, to prepare corresponding substituted benzaldehyde compounds by Pfitzner-moffatt oxidation. After the reaction, water was added, extraction was performed with ethyl acetate, washing was performed with water, and the solvent was removed by rotary evaporation to obtain 8.72g (41.9 mmol) of the product, yield 88%. Then preparing a target product stilbene compound through Wittig-Horner condensation, wherein the stilbene compound is like bennimod (namely, ben-weimod), and the specific reaction conditions are as follows:

pfitzner-moffatt oxidation uses a mixture of dimethyl sulfoxide (DMSO) and acetic anhydride (activating reagent) as an oxidizing agent to oxidize alcohol compounds to aldehyde compounds via alkoxysulfonium ylide intermediates. One of the byproducts generated during the oxidation reaction is dimethyl sulfide, which is toxic and has malodorous smell, and the excessive discharge will have adverse effect on the ecological environment, so the method is not suitable for large-scale industrial production.

CN1407978A discloses a method for synthesizing 3, 5-dimethoxy-4-isopropylbenzaldehyde by using pyridinium chlorochromate as an oxidant. After the reaction, diethyl ether was added, the layers were separated, the black viscous slurry was rinsed with dry diethyl ether to turn it into a black solid, the combined organic solution was passed through a Floriaol short pad and the solvent was removed by rotary evaporation to give a slurry, which was then crystallized from ethanol/hexane in 75% -80% yield. The reaction yield is not high, and the oxidant pyridine chlorochromate has high toxicity and carcinogenicity, and a large amount of chromium-containing waste liquid generated after the reaction also causes environmental pollution, so that the industrial production is difficult to realize.

CN101838173a discloses a method for synthesizing 3, 5-dimethoxy-4-isopropylbenzaldehyde by using DMSO-sodium bicarbonate as an oxidant. After the reaction is finished, water is added, ethyl acetate is used for extraction, water is used for washing, the solvent is removed by rotary evaporation, and the oxidation product is obtained, and the yield is 86%. This reaction is relatively similar to that of CN101830764a, using DMSO as the oxidant, again producing dimethyl sulfide as a byproduct.

CN104003848A discloses a method for synthesizing 3, 5-dimethoxy-4-isopropylbenzaldehyde by using chromium trioxide pyridinium salt or manganese dioxide as an oxidizing agent. After the reaction, water was added, extraction was performed 5 times with ethyl acetate, ethyl acetate was concentrated, solids were precipitated, and the mixture was filtered and dried to obtain an oxidized product. The reaction adopts chromium trioxide pyridinium salt or manganese dioxide as an oxidant, and the pyridinium chlorochromate has high toxicity and carcinogenicity, and the manganese dioxide has severe reaction and can generate harmful wastes, so that the industrial production is difficult to realize.

The prior art does not adopt an environment-friendly and efficient synthesis method, has the defects of low reaction yield, high reagent toxicity and the like, and can pollute the environment due to byproducts generated by the reaction. When synthesizing 3, 5-dimethoxy-4-isopropylbenzaldehyde, toxic byproducts are more difficult to remove, and the 3, 5-dimethoxy-4-isopropylbenzaldehyde is purified by adopting a recrystallization, extraction or column chromatography separation purification method, so that the process has the defects of complex separation process, long time consumption and large required solvent amount, and is not suitable for industrial mass production in actual production. In order to better popularize the application of the present valmod, a process route applicable to mass production needs to be continuously explored.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects of high production cost, environmental hazard and inapplicability to industrial production in the synthesis method of the key intermediate of the present vitamin mod in the prior art, and to provide the synthesis method of the key intermediate of the present vitamin mod. The obtained intermediate of the present invention has high purity, high yield, environment friendship, simple post-treatment and suitability for industrial production. The invention also provides a new crystal form of the intermediate of the present vitamin mod, which has high purity, is convenient for separation, storage and transportation, and provides great convenience for preparing high-quality end products (namely the present vitamin mod) and simplifying procedures.

The invention solves the technical problems by the following technical proposal:

the invention provides a method for synthesizing 3, 5-dimethoxy-4-isopropylbenzaldehyde, which comprises the following steps: 3, 5-dimethoxy-4-isopropylbenzyl alcohol is subjected to the following oxidation reaction in the presence of an oxidant and a catalyst;

the oxidant is oxygen or air;

the catalyst is selected from one or more of nitrogen-oxygen free radical catalyst, copper catalyst and accelerator.

In the oxidation reaction, the oxidizing agent is preferably air.

In the oxidation reaction, the catalyst is preferably a mixture of a nitroxide catalyst, a copper catalyst and a promoter.

In the course of the oxidation reaction, the reaction mixture, the nitroxide free radical catalyst is selected from 2, 6-tetramethylpiperidine oxide (TEMPO), 4-hydroxy-2, 6-tetramethylpiperidine oxide (4-OH-TEMPO), 4-methoxy-2, 6-tetramethylpiperidine oxide one or more of 4-acetamido-2, 6-tetramethylpiperidine oxide, 4-oxo-2, 6-tetramethylpiperidine oxide and 4-amino-2, 6-tetramethylpiperidine oxide, preferably TEMPO and/or 4-OH-TEMPO, more preferably 4-OH-TEMPO.

In the oxidation reaction, the molar amount of the nitroxide free radical catalyst is 0.5 to 10%, preferably 1 to 5%, more preferably 1 to 4%, even more preferably 1 to 3%, and most preferably 3% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

In the oxidation reaction, the copper catalyst is selected from one or more of cuprous halide, cupric acetate and cupric nitrate trihydrate, preferably from one or more of cuprous chloride (CuCl), cuprous bromide (CuBr), cuprous iodide (CuI), cupric acetate and cupric nitrate trihydrate, further preferably from one or more of CuCl, cuBr and CuI, and more preferably CuCl.

In the oxidation reaction, the molar amount of the copper catalyst is 0.5 to 10%, preferably 1 to 5%, more preferably 1 to 4%, even more preferably 1 to 3%, and most preferably 3% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

In the oxidation reaction, the accelerator is selected from one or more of pyridine, 4-Dimethylaminopyridine (DMAP), N, N, N ', N' -tetramethyl ethylenediamine (TMEDA), N-methylimidazole, triethylamine (TEA) and hexamethylenetetramine, preferably DMAP and/or TMEDA, more preferably TMEDA.

In the oxidation reaction, the molar amount of the promoter is 1 to 20%, preferably 2 to 10%, more preferably 2 to 8%, even more preferably 2 to 6%, and most preferably 6% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

In the oxidation reaction, the molar ratio of the nitroxide free radical catalyst, the copper catalyst and the accelerator is a conventional molar ratio, and may be 1:0.5 to 2:1 to 5, preferably 1:1 to 1.5:1.5 to 3, more preferably 1:1:2.

in the oxidation reaction, the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are respectively 0.5 to 10%, 0.5 to 10% and 1 to 20%, preferably 1 to 5%, 1 to 5% and 2 to 10%, more preferably 1 to 4%, 1 to 4% and 2 to 8%, more preferably 1 to 3%, 1 to 3% and 2 to 6%, most preferably 3%, 3% and 6%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

In the oxidation reaction, the molar ratio of the nitroxide free radical catalyst, the copper catalyst and the accelerator is 1:1:2; the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 0.5 to 10%, 0.5 to 10% and 1 to 20%, preferably 1 to 5%, 1 to 5% and 2 to 10%, more preferably 1 to 4%, 1 to 4% and 2 to 8%, more preferably 1 to 3%, 1 to 3% and 2 to 6%, most preferably 3%, 3% and 6%, respectively, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

In the oxidation reaction, the nitroxide free radical catalyst is TEMPO and/or 4-OH-TEMPO, the copper catalyst is one or more of CuCl, cuBr and CuI, and the accelerator is DMAP and/or TMEDA; the molar ratio of the nitrogen-oxygen free radical catalyst to the copper catalyst to the accelerator is 1:1:2; the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 0.5 to 10%, 0.5 to 10% and 1 to 20%, preferably 1 to 5%, 1 to 5% and 2 to 10%, more preferably 1 to 4%, 1 to 4% and 2 to 8%, more preferably 1 to 3%, 1 to 3% and 2 to 6%, most preferably 3%, 3% and 6%, respectively, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

In the oxidation reaction, the nitroxide free radical catalyst is 4-OH-TEMPO, the copper catalyst is CuCl, and the accelerator is TMEDA; the molar ratio of the nitrogen-oxygen free radical catalyst to the copper catalyst to the accelerator is 1:1:2; the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 0.5 to 10%, 0.5 to 10% and 1 to 20%, preferably 1 to 5%, 1 to 5% and 2 to 10%, more preferably 1 to 4%, 1 to 4% and 2 to 8%, more preferably 1 to 3%, 1 to 3% and 2 to 6%, most preferably 3%, 3% and 6%, respectively, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

The oxidation reaction further comprises a solvent.

The solvent is a solvent conventional in the art, so long as it is capable of dissolving the reactant and does not react therewith; may be selected from one or more of an aromatic solvent (e.g. benzene, toluene or xylene), a halogenated hydrocarbon solvent (e.g. dichloromethane, dichloroethane, dichloropropane or chloroform), a polar aprotic solvent (e.g. acetonitrile, DMF or DMSO), an ether solvent (e.g. tetrahydrofuran, dioxane or ethylene glycol dimethyl ether) and a ketone solvent (e.g. acetone or cyclohexanone), preferably from one or more of a polar aprotic solvent, an ether solvent and a ketone solvent, further preferably from one or more of dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF) and acetone, more preferably from one or more of acetonitrile, THF and acetone, most preferably acetonitrile or THF.

The progress of the oxidation reaction can be monitored by detection methods conventional in the art (e.g., TLC, MS, HPLC or NMR, preferably TLC or HPLC), typically with the disappearance of the starting 3, 5-dimethoxy-4-isopropylbenzyl alcohol or the absence of further reaction as the endpoint of the reaction.

In the synthesis method, there is no particular requirement on the time of the oxidation reaction, and it is usually referred to as the time required from the start of the reaction to the completion of most of the conversion of the reaction raw materials. The completion of most of the conversion means that the content of the reaction raw material 3, 5-dimethoxy-4-isopropylbenzyl alcohol in the reaction liquid of the oxidation reaction is 15% or less, preferably 10% or less, more preferably 5% or less, still more preferably 1% or less, and most preferably 0.5% or less. The amount may be measured by methods conventional in the art including, but not limited to, HPLC, TLC, and the like.

The temperature of the oxidation reaction is a temperature conventional in the art for such reactions and may be low (e.g., 0 ℃), room temperature or high, preferably 10 to 40 ℃, more preferably 15 to 35 ℃, and even more preferably room temperature.

And after the oxidation reaction is finished, post-treatment operation is also carried out.

The post-treatment comprises the following steps: adding water to quench.

The quenching may be performed by adding the reaction solution to water, or by adding water to the reaction solution. The water can be added dropwise, sequentially in batches or integrally at one time.

The quenching is carried out at a suitable temperature. The quenching temperature is any temperature in the range of 0 ℃ to room temperature, preferably 0 to 25 ℃, further preferably 0 to 20 ℃, more preferably 0 to 15 ℃, most preferably 0 to 10 ℃.

The post-treatment further comprises the following steps: separating out solid and separating.

The separation is a conventional separation operation, such as filtration or suction filtration.

In the present invention, the yield of the oxidation reaction product is 90%, preferably 93%, more preferably 95%, and even more preferably 98%.

In the present invention, the purity of the product of the oxidation reaction is 90%, preferably 95%, more preferably 98%, and still more preferably 99.5%.

In a second aspect, the present invention also provides a crystalline form of 3, 5-dimethoxy-4-isopropylbenzaldehyde as described above, having an X-ray powder diffraction pattern with diffraction peaks at the following positions in 2θ: 9.3.+ -. 0.2, 10.3.+ -. 0.2, 11.3.+ -. 0.2, 13.9.+ -. 0.2, 15.7.+ -. 0.2, 17.4.+ -. 0.2, 18.4.+ -. 0.2, 18.9.+ -. 0.2, 20.2.+ -. 0.2, 20.4.+ -. 0.2, 20.7.+ -. 0.2, 22.7.+ -. 0.2, 25.1.+ -. 0.2, 25.5.+ -. 0.2, 25.7.+ -. 0.2, 27.2.+ -. 0.2, 27.9.+ -. 0.2, 28.4.+ -. 0.2, 29.2.+ -. 0.2, 29.7.+ -. 0.2, 30.0.+ -. 0.2, 32.7.+ -. 0.2, 33.7.+ -. 0.2, 34.9.+ -. 0.2, 36.3.+ -. 0.2, 39.2.+ -. 0.2, 40.4.+ -. 0.2 and 42.5.+ -. 0.2.

In a third aspect, the present invention also provides the use of 3, 5-dimethoxy-4-isopropylbenzaldehyde or a crystal form thereof as described above for the preparation of the present vmod compound.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that: the reaction operation is convenient, the raw materials are common and easy to obtain, the cost is low, the reaction condition is mild, the monitoring is easy, and the yield is high; meanwhile, complicated conventional post-treatment and purification steps are omitted, and the purity of the obtained crystal form product is extremely high (> 99.5%). The technical effects of the technical scheme of the invention are one or more of the following effects:

(1) Mild reaction and easy monitoring: the air oxidation reaction has mild condition and high yield, and the reaction progress can be conveniently and accurately monitored by observing the color change during the reaction, namely the reaction is complete from orange to deep blue;

(2) The cost is reduced: the reaction raw materials, the catalyst and the organic solvent are all common and easy to obtain, the cost is low, only about 15g of copper catalyst is needed for each 1 kg of reaction substrate fed after reaction amplification, the total amount of the reagent is about 70g, and the cost is low;

(3) The reaction method is simple and environment-friendly: the post-treatment operation of the invention does not need complicated operations such as filtration, spin drying, extraction, concentration, recrystallization and the like, the reaction liquid or the reaction mixture can be crystallized by adding water, the whole process does not generate solid waste which increases the environmental protection treatment burden, only conventional liquid waste is generated, copper ions in the waste liquid are easy to be removed by inorganic alkali, and the waste liquid treatment is simple and is suitable for industrial production;

(4) The yield and purity of the reaction product are high: the reaction yield exceeds 90%, and the product can be directly precipitated from the quenched reaction liquid in a crystal form with extremely high purity of more than 99.5% after the reaction is finished, and the very ideal reaction yield and purity can be obtained with high repeatability even under the condition of large-scale feeding.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

The technical scheme of the invention is further described below by combining examples. It should be understood that the following examples are illustrative and not intended to limit the scope of the present invention. The instruments, materials, reagents, etc. used in the following examples are all available by conventional commercial means unless otherwise indicated.

Abbreviations and symbols in the context of the present invention have the following meanings:

HPLC conditions: high performance liquid chromatograph (samer flymulti 3000); chromatographic column: ghost-sniper,4.6 mm. Times.50 mm; mobile phase: taking 0.1mol/L ammonium acetate buffer solution (7.7 g of ammonium acetate, 1000ml of water is added for dissolution, ammonia water is used for adjusting the pH value to 9.0) as buffer salt stock solution, methanol-buffer salt stock solution-water (10:10:80) is taken as mobile phase A, and methanol-buffer salt stock solution-water (80:8:12) is taken as mobile phase B; mobile phase gradient: 70% A/30% B- & gt 10% A/90% B- & gt 70% A/30% B for 45min; wavelength: 205nm.

LC-MS conditions: model: agilent liquid chromatography mass spectrometer 1260/6120; ion source: ESI; sample preparation solvent: acetonitrile.

XRPD conditions: bruker D8 ADVANCE X-ray powder diffractometer; measurement conditions: cuKa40kv 40mA, divergent slit 0.6mm, sorrel slit 4.0 °, continuous scan, lynxEye detector, step size: 0.02 DEG, scanning speed, 4 DEG/min, scanning range: 3-60 deg..

In order to facilitate uniform monitoring of the progress of the reaction, unless otherwise specified, the central sampling time points of the following examples and comparative examples under various reaction conditions were set to 20 hours after the start of the reaction, but the actual time for the completion of most of the conversion of the reaction raw materials was likely to be far lower than 20 hours, and may vary depending on the scale of the reaction.

Term interpretation:

content of the medium control product: refers to the content of 3, 5-dimethoxy-4-isopropylbenzaldehyde in the reaction solution, which is the reaction product detected by HPLC after sampling the reaction solution after the reaction is performed for a certain period of time.

The content of the raw materials is controlled: refers to the content of 3, 5-dimethoxy-4-isopropylbenzyl alcohol in the reaction liquid, which is the reaction raw material (or reaction substrate) detected by HPLC after the reaction is usually sampled after a period of time during the oxidation reaction.

Reaction raw materials and reaction substrates: all refer to 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

Example 1

5.00g of 3, 5-dimethoxy-4-isopropylbenzyl alcohol, 123mg of 4-OH-TEMPO, 71mg of CuCl and 166mg of TMEDA are added into a 100mL reaction bottle, 25mL of acetonitrile is added, the reaction bottle is kept in an air environment, the temperature is maintained between 20 ℃ and 25 ℃, the stirring reaction is carried out for 20 hours, and the sample is monitored by HPLC. After the reaction, 10g of the reaction mixture was filtered through 200-300 mesh silica gel, the cake was washed with 20mL of acetonitrile, and the solvent was distilled off from the obtained filtrate under reduced pressure at 40-50℃to obtain 4.82g of a white solid, the yield was 97.37%, and the HPLC purity was 99.11%.

The results show that: the air oxidation is adopted, the reaction condition is mild, the color change of the reaction liquid can be observed during the reaction, namely the reaction is complete from orange to blue, the reaction process is convenient to monitor, and the reaction yield and the purity are high.

Example 2:

5.00g of 3, 5-dimethoxy-4-isopropylbenzyl alcohol, 123mg of 4-OH-TEMPO, 71mg of CuCl and 166mg of TMEDA are added into a 100mL reaction bottle, 25mL of acetonitrile is added, the reaction bottle is kept in an air environment, the stirring reaction is maintained at 20-25 ℃, and the raw material conversion is confirmed to be complete by sampling and inspection HPLC monitoring. After the reaction is finished, dropwise adding the reaction solution into 100mL of ice water at the temperature of 0-10 ℃ to quench, precipitating white solid, continuously stirring for 2 hours, carrying out suction filtration, leaching a filter cake once by using 50mL of ice water, carrying out suction filtration to obtain 4.97g of wet product, drying to obtain 4.70g of white solid, wherein the yield is 94.9%, and the HPLC purity is 99.89%.

Structural characterization data of the product:

¹ H-NMR(400MHz，CDCl ₃ ):δ9.88(s,1H),7.05(s,1H),3.87(s,6H),3.66(dt,J＝13.94,6.72Hz,1H),1.29(d,J＝6.85Hz,6H).

ESI-MS:m/z 209.1[M+H] ⁺ 。

the results show that: the air oxidation is adopted, the reaction condition is mild, the color change of the reaction liquid can be observed during the reaction, namely the reaction is complete from orange to blue, and the reaction progress can be conveniently monitored. The post-treatment is simple and environment-friendly, and the conventional operations such as filtration, concentration spin drying, extraction and the like are not needed, so that the product can be directly separated out and obtained from the system in extremely high purity by adopting a water quenching mode on the premise of keeping high yield. The small amount of catalyst used in the reaction is dissolved in water and is easy to remove, solid waste is not generated in the whole preparation process, only liquid waste which can be treated in a conventional manner is generated, and the method is very suitable for industrial production.

Example 3:

according to the same preparation method as in example 2, TEMPO was used as the nitroxide catalyst, and the reaction scale, reaction conditions and post-treatment operation were the same as in example 2, and the results are shown in Table 1.

TABLE 1 screening of nitroxide free radical catalysts

[1] Proportion: the molar ratio of the nitroxide catalyst/copper catalyst/promoter relative to the reaction raw material is respectively based on the dosage of the reaction raw material 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

The results show that: when TEMPO is used as the nitroxide free radical catalyst, the reaction yield and the product purity are not affected, and the ideal result consistent with 4-OH-TEMPO can be obtained. 4-OH-TEMPO may be preferred where the reaction yield and product purity are not widely different, simply from a commercial cost standpoint, since 4-OH-TEMPO is less expensive and readily available than TEMPO.

Example 4:

the reaction solvents were screened according to the same preparation method as in example 2, and the reaction scale, reaction conditions and post-treatment operation were the same as in example 2, and the results are shown in Table 2.

TABLE 2 screening organic solvents

The results show that: when acetonitrile and THF are used as organic solvents, the reaction result is good, and the yield and purity of the obtained product are ideal; when DMSO and DMF are used as organic solvents, the detection results of the central control product and the central control raw material show that the reaction process is slower, the raw material is incompletely reacted after 20 hours, and the reaction time is required to be prolonged; when acetone is used as an organic solvent, the reaction yield is ideal, the purity of the product is slightly low, but the purity requirement of the next preparation reaction can be met. Therefore, acetonitrile and THF can be preferably used as the organic solvent.

Example 5:

according to the same manner as that of example 2, the promoters were respectively screened in acetonitrile and THF organic solvents, the reaction scale, the reaction conditions and the post-treatment operation were the same as those of example 2, the acetonitrile group reaction time was 20 hours, the THF group reaction time was 28 hours, and the results are shown in tables 3 and 4.

TABLE 3 screening of promoters acetonitrile group

TABLE 4 screening of promoters THF group

The results show that: in acetonitrile and THF organic solvent, TMEDA and DMAP can be used as accelerator to react completely, the reaction yield and purity of both are higher, but the reaction rate of DMAP is slightly slower than that of TMEDA; when pyridine and TEA are used as accelerators, the central control result shows that the raw materials are incompletely reacted after 20 hours, and the reaction time is required to be prolonged. Therefore, TMEDA and DMAP are preferably used as the accelerator, and TMEDA is more preferable.

Example 6:

the copper catalyst was selected in acetonitrile as an organic solvent according to the same preparation method as in example 2, and the reaction scale, reaction conditions and post-treatment operation were the same as in example 2, and the results are shown in Table 5.

Table 5 screening copper catalysts

The results show that: when CuCl, cuBr and CuI are used as copper catalysts, the reaction yield and the product purity are high.

Example 7:

the catalyst was subjected to screening for the proportions of the components according to the same preparation method as in example 2, and the reaction scale, reaction conditions and post-treatment operation were the same as in example 2, and the results are shown in Table 6.

Table 6 ratio of the screening catalyst systems

The results show that: the method is characterized in that the central control detection is carried out at 20 hours after the reaction under the conditions of 3%/3%/6%, the conversion of the reaction raw materials is complete, and the reaction yield and the product purity are both higher; performing central control detection at the condition of 1%/1%/2% for 20 hours after the reaction, wherein most of conversion of the reaction raw materials is not completed, the reaction time is prolonged to 25 hours, the reaction raw materials disappear, and the reaction yield and the product purity are ideal; the reaction time is prolonged to 40 hours under the condition of 0.5%/0.5%/1%, most of conversion is completed by the reaction raw materials, and the reaction yield and the product purity meet the requirements; the reaction with the catalyst in the ratio 0.1%/0.1%/0.2% was continued until after 40 hours a large amount of starting material was still not converted to completion. Therefore, catalyst system ratios of 3%/3%/6%, 1%/1%/2% and 0.5%/0.5%/1% are preferably used, more preferably 3%/3%/6%.

Example 8:

2000g of 3, 5-dimethoxy-4-isopropylbenzyl alcohol is added into a 20L reaction kettle, 10L of acetonitrile is added for stirring and dispersing, 49.14g of 4-OH-TEMPO, 28.24g of CuCl and 66.32g of TMEDA are sequentially added, a charging opening is washed by 2L of acetonitrile, 4L of acetonitrile is added for promoting dissolution, stirring is carried out at room temperature, the solution is orange-colored, air is introduced into the bottom of the reaction solution by using an air pipe until most of raw materials are dissolved, the air is blown for about 9 hours, the reaction solution is changed from orange-colored to dark-colored green, and then the dark-colored green is completely changed into dark-colored blue. After the TLC monitoring is completed, the reaction solution is concentrated, approximately 5L of volume is reserved, 14L of warm water is added and stirred uniformly,

starting refrigeration, setting 0 ℃ and timing when the internal temperature is lower than 10 ℃, stirring and crystallizing for 2 hours, filtering, washing residual substances in the kettle with 15L ice water, discharging water, soaking and washing filter cakes for 5 times, drying the filter cakes, loading the filter cakes in a tray, and vacuum drying the materials (the temperature of the oven is lower than 50 ℃), thereby obtaining a target product which is white solid, wherein the weight is 1937.23g, the yield is 97.8%, and the HPLC purity is 99.93%.

The obtained target product 3, 5-dimethoxy-4-isopropylbenzaldehyde is in a crystal form, and an X-ray powder diffraction pattern of the target product has diffraction peaks at the following positions of 2 theta: 9.3.+ -. 0.2, 10.3.+ -. 0.2, 11.3.+ -. 0.2, 13.9.+ -. 0.2, 15.7.+ -. 0.2, 17.4.+ -. 0.2, 18.4.+ -. 0.2, 18.9.+ -. 0.2, 20.2.+ -. 0.2, 20.4.+ -. 0.2, 20.7.+ -. 0.2, 22.7.+ -. 0.2, 25.1.+ -. 0.2, 25.5.+ -. 0.2, 25.7.+ -. 0.2, 27.2.+ -. 0.2, 27.9.+ -. 0.2, 28.4.+ -. 0.2, 29.2.+ -. 0.2, 29.7.+ -. 0.2, 30.0.+ -. 0.2, 32.7.+ -. 0.2, 33.7.+ -. 0.2, 34.9.+ -. 0.2, 36.3.+ -. 0.2, 39.2.+ -. 0.2, 40.4.+ -. 0.2 and 42.5.+ -. 0.2.

Comparative example 1:

42.00g of 3, 5-dimethoxy-4-isopropylbenzyl alcohol, 160mL of n-heptane and 25mL of ethyl acetate are added into a 500mL reaction flask, stirred until the solid is completely dissolved, and then MnO is slowly added in batches ₂ 80.00g, and stirred under reflux overnight. After the reaction was completed, the reaction mixture was cooled to about 40 ℃, 200-300 mesh silica gel was used as a filler, filtered, and the silica gel column was washed with n-heptane/ethyl acetate=8/1 until the product was completely eluted, and rotary-distilled under reduced pressure to obtain 40.04g of a white solid product in 96.25% yield.

The results show that: by MnO ₂ Oxidation, although the reaction yield is high, the reaction requires addition of MnO with complete dissolution of the starting materials ₂ The system is always in a state of intense boiling in the reaction process, the risk of burning high-temperature organic gas is caused in the amplification production, and n-heptane gas is extremely flammable, so that the reaction has higher risk in the production process; in addition, the black manganese compound generated in the reaction is easy to generateCaking and adhesion are on the surface of the reactor, besides heating and pickling, the caking and adhesion are difficult to remove by other mild modes, the caking and adhesion are difficult to treat in industrial production, a large amount of harmful wastes can be generated, and the safety and environmental protection risks are high.

Comparative example 2:

2.00g of 3, 5-dimethoxy-4-isopropylbenzyl alcohol and 15mL of acetonitrile are added into a 100mL reaction flask, the mixture is stirred at 45 ℃, and Na is added dropwise into the reaction flask ₂ O ₈ S ₂ 2.50g of aqueous solution (7 mL) was stirred for 30 minutes, and TLC monitoring was performed, showing that the starting material had largely disappeared, a large polar species was produced, and it was confirmed that it was not the target product, in comparison to the standard sample.

The results show that: most of the raw materials for the oxidation reaction react, but the target product is not obtained, and the reason is presumably that the reaction is excessively oxidized to generate carboxylic acid and the carboxylic acid is not converted into the target product.

Comparative example 3:

3.00g of 3, 5-dimethoxy benzyl alcohol is added into a three-mouth bottle, 30mL of acetonitrile is added for stirring and dispersing, 4-OH-TEMPO 92mg, cuCl 52mg and TMEDA 124mg are sequentially added, the reaction liquid is gray black, the reaction is carried out overnight under the air condition, the reaction is complete through TLC detection, the system is dark gray liquid, water is slowly added into the system, when 15mL of water is dropwise added, the system is almost unchanged, the dropwise addition is continued, gray liquid drops slowly appear at the beginning, finally the dropwise addition is carried out to 30mL of water, after stirring is continued for half an hour, a small amount of gray solid is precipitated, the gray solid is obtained through filtration, the wet weight is 570mg, and a large amount of gray liquid drops are present in the filtrate. The solid was air-dried to give 396mg of an off-white solid in about 13% yield and 95.12% purity.

Claims

1. The synthesis method of the 3, 5-dimethoxy-4-isopropylbenzaldehyde is characterized by comprising the following steps of: 3, 5-dimethoxy-4-isopropylbenzyl alcohol is subjected to the following oxidation reaction in the presence of an oxidant and a catalyst;

the oxidant is oxygen or air;

the catalyst is a mixture of a nitrogen-oxygen free radical catalyst, a copper catalyst and a promoter;

the nitroxide free radical catalyst is 4-OH-TEMPO; the copper catalyst is cuprous halide;

the accelerator is DMAP and/or TMEDA;

taking the molar usage amount of 3, 5-dimethoxy-4-isopropyl benzyl alcohol as a reference, the molar usage amount of the nitroxide free radical catalyst is 1% -5%;

the molar usage of the copper catalyst is 1% -5%;

the mol dosage of the accelerator is 2% -10%;

the oxidation reaction further comprises a solvent; the solvent is acetonitrile and/or THF;

the molar ratio of the nitroxide free radical catalyst, the copper catalyst and the accelerator is 1:1:2;

the post-treatment operation is also carried out after the oxidation reaction is finished;

the post-treatment comprises the following steps: adding water to quench; the post-treatment further comprises the following steps: separating out solid and separating.

2. The method of synthesis according to claim 1, wherein the oxidizing agent is air.

3. The method of synthesis according to claim 1, wherein the copper catalyst is selected from one or more of CuCl, cuBr and CuI.

4. A method of synthesis according to claim 3, wherein the copper catalyst is CuCl.

5. The method of synthesis according to claim 1, wherein the promoter is TMEDA.

6. The synthesis method according to claim 1, wherein the molar amount of the nitroxide free radical catalyst is 1-4% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

7. The method of claim 6, wherein the molar amount of the nitroxide free radical catalyst is 1% to 3% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

8. The method of claim 7 wherein the nitroxide free radical catalyst is present in an amount of 3% by mole based on the amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol present.

9. The method of claim 1, wherein the copper catalyst is used in a molar amount of 1% to 4% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

10. The method of synthesis according to claim 9, wherein the molar amount of copper catalyst is 1% to 3% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

11. The process of claim 10 wherein the copper catalyst is present in a molar amount of 3% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

12. The synthesis method according to claim 1, wherein the molar amount of the promoter is 2-8% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

13. The synthesis method according to claim 12, wherein the molar amount of the promoter is 2 to 6% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

14. The process of claim 13 wherein the promoter is present in a molar amount of 6% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

15. The method of claim 1, wherein the temperature of the oxidation reaction is 10 to 40 ℃.

16. The method of claim 15, wherein the temperature of the oxidation reaction is 15 to 35 ℃.

17. The method of claim 1, wherein the temperature of the oxidation reaction is room temperature.

18. The synthesis method according to claim 1, wherein the molar amounts of the nitroxide catalyst, the copper catalyst and the promoter are 1 to 4%, 1 to 4% and 2 to 8%, respectively, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol in the oxidation reaction.

19. The method of synthesis according to claim 18, wherein the molar amounts of the nitroxide catalyst, the copper catalyst and the promoter are 1% to 3%, 1% to 3% and 2% to 6%, respectively, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol used in the oxidation reaction.

20. The synthesis according to claim 19, wherein the molar amounts of the nitroxide catalyst, the copper catalyst and the promoter are 3%, 3% and 6%, respectively, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol used in the oxidation reaction.

21. The synthetic method according to claim 1, wherein in the oxidation reaction, the nitroxide free radical catalyst is 4-OH-TEMPO, the copper catalyst is one or more selected from CuCl, cuBr and CuI, and the accelerator is DMAP and/or TMEDA; the molar ratio of the nitrogen-oxygen free radical catalyst to the copper catalyst to the accelerator is 1:1:2; the molar dosages of the nitroxide free radical catalyst, the copper catalyst and the accelerator are respectively 1% -4%, 1% -4% and 2% -8% based on the molar dosage of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

22. The synthetic method according to claim 21, wherein in the oxidation reaction, the nitroxide free radical catalyst is 4-OH-TEMPO, the copper catalyst is one or more selected from CuCl, cuBr and CuI, and the accelerator is DMAP and/or TMEDA; the molar ratio of the nitrogen-oxygen free radical catalyst to the copper catalyst to the accelerator is 1:1:2; the molar dosages of the nitroxide free radical catalyst, the copper catalyst and the accelerator are respectively 1% -3%, 1% -3% and 2% -6% based on the molar dosage of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

23. The synthetic method according to claim 22, wherein in the oxidation reaction, the nitroxide free radical catalyst is 4-OH-TEMPO, the copper catalyst is one or more selected from CuCl, cuBr and CuI, and the accelerator is DMAP and/or TMEDA; the molar ratio of the nitrogen-oxygen free radical catalyst to the copper catalyst to the accelerator is 1:1:2; the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 3%, 3% and 6%, respectively, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

24. The method of claim 1, wherein in the oxidation reaction, the nitroxide free radical catalyst is 4-OH-TEMPO, the copper catalyst is CuCl, and the promoter is TMEDA; the molar ratio of the nitrogen-oxygen free radical catalyst to the copper catalyst to the accelerator is 1:1:2; the molar dosages of the nitroxide free radical catalyst, the copper catalyst and the accelerator are respectively 1% -5%, 1% -5% and 2% -10% based on the molar dosage of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

25. The method of claim 24, wherein in the oxidation reaction, the nitroxide free radical catalyst is 4-OH-TEMPO, the copper catalyst is CuCl, and the promoter is TMEDA; the molar ratio of the nitrogen-oxygen free radical catalyst to the copper catalyst to the accelerator is 1:1:2; the molar dosages of the nitroxide free radical catalyst, the copper catalyst and the accelerator are respectively 1% -4%, 1% -4% and 2% -8% based on the molar dosage of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

26. The method of claim 25, wherein in the oxidation reaction, the nitroxide free radical catalyst is 4-OH-TEMPO, the copper catalyst is CuCl, and the promoter is TMEDA; the molar ratio of the nitrogen-oxygen free radical catalyst to the copper catalyst to the accelerator is 1:1:2; the molar dosages of the nitroxide free radical catalyst, the copper catalyst and the accelerator are respectively 1% -3%, 1% -3% and 2% -6% based on the molar dosage of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

27. The method of claim 26, wherein in the oxidation reaction, the nitroxide free radical catalyst is 4-OH-TEMPO, the copper catalyst is CuCl, and the promoter is TMEDA; the molar ratio of the nitrogen-oxygen free radical catalyst to the copper catalyst to the accelerator is 1:1:2; the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 3%, 3% and 6%, respectively, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.

28. The synthetic method of claim 1 wherein the separation is filtration or suction filtration.