CN103992212B - Synthesis method for cis-benvitimod, and applications of cis-benvitimod - Google Patents

Abstract

The invention discloses a synthesis method for cis-benvitimod, and applications of cis-benvitimod. The synthesis method comprises the following steps: by taking 3,5-dihydroxy-4-isopropylbenzoic acid as a raw material, sequentially performing methylation, reduction, oxidization, condensation, decarboxylation and demethylation to finally synthesize cis-benvitimod, the purity of the prepared high-purity product cis-benvitimod achieves 95-99%, and the cis-benvitimod can be used for detecting the content of cis-benvitimod as a standard substance in the synthesis of trans-benvitimod; according to the synthesis method, the defects that the cis-benvitimod is low in content, instable in properties and difficult to separate in the prior art can be overcome, a method for analyzing and detecting important impurities in the preparation process of the trans-benvitimod preparation process can be established. The synthesis method is applicable to synthesis of cis-benvitimod, the prepared product is used for detecting the content of cis-benvitimod as a standard substance in the synthesis process of trans-benvitimod.

Description

The synthetic method of cis-phenylene modder and the application of cis-phenylene moder

technical field

The invention belongs to the field of pharmacy, and relates to the synthesis and application of a stilbene compound, in particular to a synthesis method of cis-styrene moder and an application of cis-styrene moder.

Background technique

The toxicity of impurities in the original drug and preparation of chemically synthesized drugs, especially genotoxicity, is an important factor affecting drug safety. Most impurities in drugs have potential biological activity. The adverse reactions of drugs in clinical use are not only related to the pharmacological activity of the drug itself, but also have a lot to do with the impurities in the drug. Some impurities can interact with medicines, directly affect the safety and effectiveness of medicines, and even produce toxic effects. The control of drug impurities plays a key role in ensuring the efficacy of drugs and reducing the adverse reactions of drugs. The study of impurities is an important aspect of pharmaceutical research, which runs through the entire pharmaceutical research. Whether the impurities in the drug can be reasonably and effectively controlled is directly related to the quality controllability and safety of the drug.

Benvitimod is a new generation of anti-inflammatory drugs that can be used to treat a variety of major autoimmune diseases, such as psoriasis, eczema, pyogenic colitis and various allergic diseases. Benzene Moder is a stilbene compound, including cis-trans isomers. Trans-Benzene Moder has strong physiological activity and stable physical and chemical properties, while cis-Benzene Moder is mainly trans-Benzene By-products during the synthesis of moder, cis-isomer impurities are unavoidable in traditional methods for synthesizing moder of benzene, such as the Wittig reaction.

As the main impurity in the synthesis of trans-phenylene moder, whether it is for drug detection or monitoring during the reaction, the establishment of the synthesis and analysis method of cis-benzyl moder is of great significance. The content of this impurity is very low in the traditional synthesis method of Benzene Moder, and the cis compound is extremely unstable and easily converted into a trans structure, so it is difficult to separate the cis compound according to the previous synthesis method. Its synthetic method has not been reported in the previous literature. Therefore, it is very important to find a synthetic route of cis-benzene moder.

The synthetic method of cis-stilbene compounds, in the prior art, has had a lot of reports, but, the method reaction raw material of synthesizing cis-product in the prior art and source of reagent are difficult, and used catalyst is more expensive, and cost is relatively high. High, difficult to operate, not conducive to mass production, such as:

①Gaukroger K, John A. Hadfield. Novel syntheses of cis and transisomers of combretastatin A-4[J].J. Org. Chem, 2001, (66): 8135-8138, substituted styryl bromide and substituted Phenylboronic acid is used as a raw material, and the Suzuki coupling reaction under the catalysis of palladium is used to obtain the cis compound, and the reaction process is as follows:

This method has high yield and good structural selectivity, but the source of reaction raw materials is difficult and the catalyst is relatively expensive, which limits the use of this method.

②Felix N, Ngassa, Erick A, Lindsey, Brandon E, Haines. The first Cu- and amine-free Sonogashira-type cross-coupling in the C-6 -alkynylation of protected 2'-deoxyadenosine [J]. Tetrahedron Letters, 2009 ,(65): 4085-4091, using substituted phenylacetylenes to be easily catalyzed by Pd/CaCO ₃ , Fe ₂ (CO) ₉ , Pd(OAc) _{2 ,} etc. to produce cis compounds. The reaction process is as follows:

The advantage of this method is that alkynes are stereospecifically reduced under the action of a catalyst, which overcomes the cis-trans isomerism phenomenon in the Wittig reaction, but because the reaction needs to be performed at -78°C, it is not conducive to operation, and the source of reagents is difficult and the price is high , increase cost, is not conducive to mass production.

③Belluci G, Chiappe C, Moro G Lo. Crown ether catalyzed stereospecific synthesis of Z-and E-stilbenes by Wittig reaction in a solid-liquid two-phases system[J].Tetrahedron Letters, 1996, (37): 4225-4228 , using Pd(PPh ₃ ) ₄ as a catalyst, the organozinc reagent is coupled with a halide to generate a cis compound, and the reaction process is as follows:

The method has the advantages of good selectivity and high cis yield; the disadvantage is that the operation is difficult and the catalyst is expensive.

④Wang Zhixin, Zhang Xuejing, Zhou Yue, Zou Yongshun, Synthesis of trans-3,4',5 trihydroxystilbene. Chinese Pharmaceutical Sciences, 2005,14(4); 204-208, reported that the trans compound was dissolved in DMSO In it, make a solution with a certain concentration, react under 365nm ultraviolet irradiation, and convert it into a cis compound. The reaction process is shown in the following formula:

However, this method has strict requirements on solution concentration preparation and reaction time.

Contents of the invention

The technical problem to be solved in the present invention is to provide a kind of synthetic method of cis-phenylene moder, take 3,5-dihydroxyl-4-isopropyl benzoic acid as raw material, successively undergo methylation, reduction, oxidation, Condensation, decarboxylation and demethylation reactions finally synthesize cis-benzene olefin modder, and the prepared cis-benzene olefin moder has a purity of 95-99%;

Another object of the present invention is to provide an application of the cis-phenylene moder prepared by the above method, which can be used as a standard in the synthesis of trans-styrene moder for detecting the cis-styrene moder. Content; Overcame the shortcomings in the prior art that it was difficult to separate due to the low content and unstable properties of cis-Benzene Moder, and established an analysis and detection method for an important impurity in the preparation process of trans-Benzene Moder.

In order to solve the problems of the technologies described above, the technical solution adopted in the present invention is:

A kind of synthetic method of cis-phenylene modad, it uses 3,5-dihydroxyl-4-isopropyl benzoic acid as raw material, synthesizes 3,5-dimethoxy-4-isopropylate through methylation reaction successively Propyl benzoate, reduction reaction to synthesize 3,5-dimethoxy-4-isopropylbenzyl alcohol, oxidation reaction to synthesize 3,5-dimethoxy-4-isopropylbenzaldehyde, condensation reaction to synthesize 3, 5-dimethoxy-4-isopropyl stilbene acid, decarboxylation reaction to synthesize 3, 5-dimethoxy-4-isopropyl stilbene, and finally demethylation reaction to synthesize cis-benzene en mod.

As a limitation of the present invention, the reaction scheme of the above-mentioned synthetic method is as follows:

.

As a further limitation of the above limitations, the synthetic method is carried out in the following steps:

(1) Methylation reaction

Mix 3,5-dihydroxy-4-isopropylbenzoic acid and anhydrous potassium carbonate at a molar ratio of 1:3~5, add it to DMF, and stir at room temperature; then, under the cooling of an ice-salt bath, Slowly add methyl iodide dropwise; rise to room temperature after the dropwise addition, and react for 2-3 hours; add water and stir after the reaction, extract with ethyl acetate, concentrate to obtain 3,5-dimethoxy-4-isopropylbenzoic acid Esters, the yield is 90-95%, and the purity is 95-99%; wherein:

The molar ratio of 3,5-dihydroxy-4-isopropylbenzoic acid to methyl iodide is 1:3~5;

The weight volume ratio of 3,5-dihydroxy-4-isopropylbenzoic acid to DMF is 1:20~30g/mL;

(2) Reduction reaction

Mix and stir tetrahydrofuran, 3,5-dimethoxy-4-isopropyl benzoate and sodium borohydride at room temperature with a molar ratio of 1:4~6, heat to reflux, slowly add methanol dropwise, and react 4~ After 6 hours, add 3-5L of water and stir, extract with ethyl acetate, wash with water, and remove the solvent by rotary evaporation to obtain a white solid, namely 3,5-dimethoxy-4-isopropylbenzyl alcohol, with a yield of 94-98%. The purity is 95-99%; where:

The dosage ratio of 3,5-dimethoxy-4-isopropyl benzoate, methanol and tetrahydrofuran is 1:1～3:10～20g/mL/mL;

(3) Oxidation reaction

Mix and stir 3,5-dimethoxy-4-isopropylbenzyl alcohol, DMSO and acetic anhydride, react at room temperature for 2-3 hours, add water and stir, extract with ethyl acetate, wash with water, dry, and concentrate to obtain 3,5- Dimethoxy-4-isopropylbenzaldehyde, the yield is 90-95%, and the purity is 95-99%; wherein:

The dosage ratio of 3,5-dimethoxy-4-isopropylbenzyl alcohol, DMSO and acetic anhydride is 1:10~15:2~3g/mL/mL;

The invention adopts DMSO as an oxidizing agent, has mild reaction conditions, safe and simple operation and high yield.

The present invention has adopted multiple oxidizing agent to test, but, adopt PCC, CrO3/concentrated sulfuric acid and Collins reagent, because toxicity is bigger, endanger environment and experimenter, and in the reaction process, wall sticking is serious, and reaction is incomplete, and aftertreatment is very difficult When adopting potassium dichromate as oxygenant, because oxidizing property is stronger, the corresponding aldehyde product that forms is less, directly oxidized into acid; When adopting active manganese dioxide, aluminum isopropoxide as oxygenant, yield is lower, Aftertreatment is more difficult; This shows that not all oxidizing agents that can oxidize alcohols into aldehydes in the prior art can be used in the present invention, and its consumption also has a great influence on the reaction result. Using 3,5-di The weight-to-volume ratio of methoxy-4-isopropylbenzyl alcohol, DMSO and acetic anhydride is 1:10-15:2-3g/mL/mL, which exceeds the upper limit of the ratio, and the excess of DMSO and acetic anhydride is difficult in the post-treatment process. In addition to cleaning, it will increase the difficulty of post-processing, waste reagents, and the phenomenon of incomplete reaction will occur if the lower limit of the ratio is exceeded, and the yield will be low.

(4) Condensation reaction

Mix 3,5-dimethoxy-4-isopropylbenzaldehyde and phenylacetic acid with a molar ratio of 1:1, add to acetic anhydride, stir to dissolve, add sodium acetate, heat up to 135°C, and react 6- After 8 hours, after cooling down to room temperature, add dilute acid to adjust the pH to 2-3, extract with ethyl acetate, concentrate, add saturated sodium bicarbonate solution to adjust the pH to 7-8, stir for 2-3 hours, extract with dichloromethane, and the aqueous phase Add dilute hydrochloric acid to adjust the pH to 2-3, filter the yellow solid, namely 3, 5-dimethoxy-4-isopropyl stilbene acid, the yield is 94-98%, and the purity is 80-85%; :

The molar ratio of 3,5-dimethoxy-4-isopropylbenzaldehyde to sodium acetate is 1:2~4;

The weight/volume ratio of 3,5-dimethoxy-4-isopropylbenzaldehyde to acetic anhydride is 1:20~30g/mL;

This step is a key step of the present invention, and it is particularly critical to control the ratio of the cis-product. The reaction conditions provided by the present invention maximize the content of the cis-product and ensure a higher yield.

Mostly adopt toluene as solvent in the prior art, add a small amount of acetic anhydride, reflux reaction at 110 ℃, but adopt toluene as solvent, the yield is lower 60-90%, adopt acetic anhydride as solvent in the present invention, yield It can reach more than 94%.

The present invention adopts anhydrous sodium acetate as the basic catalyst, the post-treatment is simple and easy, and the yield is high.

The present invention has adopted multiple basic catalysts to test, but, when adopting triethylamine as the basic catalyst, the yield is low; Adopt anhydrous potassium carbonate and anhydrous potassium fluoride, stick to the wall in the reaction process serious, reaction solution It is a black viscous liquid, and the aftertreatment is very difficult; when adopting anhydrous potassium acetate as the basic catalyst, although the aftertreatment is relatively simple, the yield is low; thus it can be seen that not all basic catalysts in the prior art All can be used in the present invention, and its consumption is also very big to reaction result influence, adopts 3, the mol ratio of 5-dimethoxy-4-isopropyl benzaldehyde and sodium acetate is 1:2-4, When the weight-to-volume ratio of 3,5-dimethoxy-4-isopropylbenzaldehyde to acetic anhydride is 1g:20-30mL, the reaction is complete and the yield is high. Acetic anhydride exceeding the upper limit of the ratio is excessive, which is difficult to remove in the post-treatment process, increases the difficulty of post-treatment, and wastes reagents; the lower limit of the ratio is incomplete and the yield is low.

(5) Decarboxylation reaction

Add 3,5-dimethoxy-4-isopropyl stilbenic acid and copper powder with a molar ratio of 1:6~8 to quinoline, react at 180°C for 3-5h, cool down to room temperature, add Ethyl acetate was stirred, filtered, the filtrate was washed with dilute hydrochloric acid until the water layer was colorless, the water phase was reverse-phase extracted with ethyl acetate, the organic layers were combined, washed with saturated brine until neutral, and spin-dried to obtain 3,5- Dimethoxy-4-isopropyl stilbene, the yield is 90-95%, and the purity is 75-80%; wherein:

The weight/volume ratio of 3,5-dimethoxy-4-isopropyl stilbenic acid to quinoline is 1:15~20g/mL;

It is the key to this step to control the cis product from being converted into a stable trans product, so the control of reaction molar ratio, temperature, reaction time and post-treatment is very important.

The traditional decarboxylation method is to react at 210-230°C, but the high temperature is easy to aggravate the inversion of cis-benzene alkene modd, and finally the trans-benzylene modd is the main one. Therefore, the present invention uses better decarboxylation reagent copper powder and On the basis of quinoline, the reaction temperature is strictly controlled, and finally the content of cis-phenylene moder is 75-80%.

The invention adopts copper powder and quinoline as the decarboxylation reagent, and the aftertreatment is simple and easy, and the yield is high.

The present invention has adopted multiple decarboxylation reagents to test, but, adopt acetic acid and sulfuric acid to reflux reaction at 110 ℃, yield is relatively low; Adopt sodium chloride and DMSO to decarboxylate at 180 ℃, or DMSO and water decarboxylate under reflux conditions DMSO is difficult to evaporate during post-treatment, and the yield is not high; decarboxylation under 60% sulfuric acid reflux condition is used, and the yield is low; decarboxylation is carried out under room temperature using concentrated hydrochloric acid, and it is difficult to decarboxylate under mild conditions, and the yield is low. Low; use p-toluenesulfonic acid and water to react at 100 °C, the toxicity is relatively high, and the yield is not high; use lithium chloride, DMSO and water to react at 130 °C, lithium chloride is expensive and the cost is high, And DMSO is difficult to remove during aftertreatment; It can be seen that not all decarboxylation reagents in the prior art can be used in the present invention, and its consumption also has a great influence on the reaction result. - The molar ratio of 4-isopropyl stilbenic acid to copper powder is 1:6-8, and the weight/volume ratio of 3,5-dimethoxy-4-isopropyl stilbenic acid to quinoline is 1g: 15-20mL, if the upper limit of the ratio is exceeded, copper powder and quinoline are excessive, and it is difficult to remove them in post-treatment, which increases the difficulty of post-processing and wastes reagents. If the lower limit of the ratio is exceeded, the reaction will be incomplete and the yield will be low.

(6) Demethylation reaction

Put 3,5-dimethoxy-4-isopropyl stilbene in toluene, stir in an ice bath, cool down to 0°C, slowly add N,N-dimethylaniline after dissolving, add in batches without Aluminum trichloride in water, after stirring for 0.5h, rise to room temperature, heat to 100°C and react for 2-3h, then cool down to 60°C, separate the toluene layer while hot, add dilute hydrochloric acid to the water phase and stir to adjust the pH value to 2 -3, extraction with ethyl acetate, washing with water, and concentration to obtain the target product, cis-benzenemod, with a yield of 92-98% and a purity of 70-80%. After separation, the yield is 65-75% and the purity is 95-99%; of which:

The weight/volume ratio of 3,5-dimethoxy-4-isopropylstilbene to toluene is 1:15~20g/mL;

The molar ratio of 3,5-dimethoxy-4-isopropylstilbene to N,N-dimethylaniline and anhydrous aluminum trichloride is 1:5～7:5～7.

The usual demethylation method is a reflux reaction at 110°C. If the temperature is too high, it is easy to aggravate the inversion of the cis-benzene alkene mode, and finally the trans-benzene alkene mode is the main one. Therefore, the present invention selects a better demethylation method. On the basis of the methyl reagent N,N-dimethylaniline and anhydrous aluminum trichloride, the ratio of reactants and the reaction temperature are strictly controlled, and finally the content of cis-phenylene modd is 70-80% , the purity after separation is as high as 95-99%.

The invention adopts N,N-dimethylaniline and anhydrous aluminum trichloride as demethylation reagents, and has simple operation and high yield.

The present invention has adopted multiple demethylation reagents to test, but, adopt must hydrochloride and pyridine hydrobromide as demethylation reagent, toxicity is bigger, endanger environment and experimenter, and reaction temperature is higher, product structure The type is basically the trans configuration; when BBr ₃ /dichloromethane is used as the demethylation reagent, because BBr ₃ is extremely volatile, it must be added dropwise at a low temperature of -70 to 80°C, the reaction conditions are harsh, and the operation is difficult; When trimethylsilane is used as demethylation reagent, because trimethylsilane is easy to volatilize, it is not easy to store, it is difficult to operate, and the yield is low; when using concentrated HI solution as demethylation reagent, the cost is increased, and the yield is not high ; When using 40% HBr/acetic acid as the demethylation reagent, the yield is low; when using sodium dodecyl mercaptide/DMF as the demethylation reagent, it needs to be reacted at 190 ° C, the reaction temperature is higher, and the product is basically trans configuration; thus it can be seen that not all demethylation reagents in the prior art can be used in the present invention, and its consumption also has a great influence on the reaction result, adopting 3,5-dimethoxy- The weight/volume ratio of 4-isopropyl stilbene and toluene is 1g:15-20mL; 3,5-dimethoxy-4-isopropyl stilbene and N,N-dimethylaniline, The reaction molar ratio of anhydrous aluminum trichloride is 1:5～7:5～7. Exceeding the upper limit of the ratio will increase the difficulty of post-processing and waste reagents, and exceeding the lower limit of the ratio will result in incomplete reaction and low yield.

The present invention also provides an application of the cis-phenylene moder prepared by the above synthesis method, which can be used as a standard in the synthesis of the trans-styrene moder to detect the content of the cis-styrene moder.

As a limitation of the present invention, the method for detecting the content of cis-phenylene modad is to adopt HPLC: the chromatographic column is Nucleosil 5 C18; the column temperature is 20°C; the detection wavelength is 318nm; the mobile phase is 50:50 by volume Acetonitrile and water; the flow rate is 0.6mL/min, and the injection volume is 5μL.

Owing to having adopted above-mentioned technical scheme, the technical progress that the present invention obtains compared with prior art is:

The present invention uses 3,5-dihydroxy-4-isopropylbenzoic acid as raw material, and finally synthesizes cis-benzene modad through methylation, reduction, oxidation, condensation, decarboxylation and demethylation reactions in sequence, and the prepared The purity of cis-Benzene Moder is 95-99%; the prepared high-purity product can be used as a standard in the synthesis of trans-Benzene Moder to detect the content of cis-Benzene Moder. The synthetic method of the present invention overcomes the shortcoming that is difficult to separate due to the low content and unstable properties of cis-phenylene modad in the prior art, and establishes the analysis and analysis of an important impurity in the preparation process of trans-phenylene moder Detection method.

The invention is suitable for synthesizing cis-phenylene moder, and the prepared product is used as a standard product in the synthesis process of trans-benzyl moder, and is used for content detection of cis-benzyl moder.

The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments.

Description of drawings

Fig. 1 is the ¹ HNMR figure of cis-phenylene modder in Example 1 of the present invention;

Fig. 2 is the ¹ HNMR figure of trans-phenylene Moder in Example 1 of the present invention;

Fig. 3 is the HPLC figure of cis-phenylene modder in the embodiment of the present invention 1;

Fig. 4 is the HPLC figure of trans-benzene alkene modder in the embodiment of the present invention 1;

Fig. 5 is an HPLC chart of the cis-trans phenylene modder mixture in Example 1 of the present invention.

Detailed ways

Embodiment 1 A kind of synthetic method of cis-benzene alkene modder and the application of the prepared cis-benzyl alkene moder

The synthetic method of this cis-benzene alkene mode reacts according to the following route:

The specific preparation process is carried out according to the following steps:

(1) Methylation reaction

Mix 195.12g (1mol) of 3,5-dihydroxy-4-isopropylbenzoic acid and 414.57g (3mol) of anhydrous potassium carbonate, add 5000ml of DMF, stir at room temperature, and then cool in an ice-salt bath 425.85g (3mol) of methyl iodide was slowly added dropwise, and after the dropwise addition was completed, it was raised to room temperature and reacted for 2h. After the reaction was completed, it was stirred with water, extracted with ethyl acetate, and concentrated to obtain 3,5-dimethoxy-4- Isopropyl benzoate; 93% yield, 99% purity.

(2) Reduction reaction

Mix and stir 3000ml of tetrahydrofuran, 240g (1mol) of 3,5-dimethoxy-4-isopropylbenzoate and 151.40g (4mol) of sodium borohydride at room temperature, heat to reflux, and slowly add 400ml of After reacting for 4 hours, add 3L of water and stir, extract with ethyl acetate, wash with water, and remove the solvent by rotary evaporation to obtain a white solid, and obtain 3,5-dimethoxy-4-isopropylbenzyl alcohol; the yield is 96% , with a purity of 99%.

(3) Oxidation reaction

Mix and stir 212g (1mol) of 3,5-dimethoxy-4-isopropylbenzyl alcohol, 800ml of DMSO and 500ml of acetic anhydride, react at room temperature for 2 hours, add water and stir, extract with ethyl acetate, wash with water, and dry , concentrated to 3,5-dimethoxy-4-isopropylbenzaldehyde; the yield was 94%, and the purity was 99%.

(4) Condensation reaction

Add 209.18g (1mol) of 3,5-dimethoxy-4-isopropylbenzaldehyde and 136.15g (1mol) of phenylacetic acid into 5000ml of acetic anhydride, stir to dissolve, add 246.09g of sodium acetate, Heat up to 135°C, react for 6 hours, then cool down to room temperature, add dilute acid to adjust the pH to 2, extract with ethyl acetate, concentrate, add saturated sodium bicarbonate solution to adjust the pH to 7, stir for 2 hours, extract with dichloromethane, water Add dilute hydrochloric acid to adjust the pH to 2, and filter the yellow solid to obtain 3, 5-dimethoxy-4-isopropyl stilbene acid; the yield is 96%, and the purity is 80%.

(5) Decarboxylation reaction

Add 327g (1mol) of 3,5-dimethoxy-4-isopropyl stilbenic acid and 384g (6mol) of copper powder into 5000ml of quinoline, react at 180°C for 3h, then cool down to room temperature, Add ethyl acetate to stir, filter, and wash the filtrate with dilute hydrochloric acid until the water layer is colorless, then reverse-phase extract the water phase with ethyl acetate, combine the organic layers, wash with saturated brine until neutral, and spin dry to obtain 3,5- Dimethoxy-4-isopropylstilbene; 92% yield, 77% purity.

(6) Demethylation reaction

Put 282.32g (1mol) of 3,5-dimethoxy-4-isopropyl stilbene in 4000ml of toluene, stir in an ice bath, cool down to 0°C, dissolve and slowly add 605.9g (5mol) Add 666.7g (5mol) of anhydrous aluminum trichloride in batches to N,N-dimethylaniline, stir for 0.5h, rise to room temperature, heat to 100°C for 2h, cool down to 60°C, and Separate the toluene layer, add dilute hydrochloric acid to the water phase and stir to adjust the pH value to 2, extract with ethyl acetate, wash with water, and concentrate to obtain cis-benzene moder; the yield of the crude product is 95%, and the purity is 74%. After separation by column chromatography, using 300-400 mesh silica gel, the pure product of cis-phenylene moder was isolated with a yield of 68% and a purity of 98.5%. The NMR diagram of the obtained cis-phenylene modd is shown in Figure 1, and the NMR data are as follows:

¹ H NMR (CDCl ₃ , 500 Hz, δ: ppm), 7.255 (m, 5H), 6.558 (d, 1H), 6.402 (d, 1H), 6.218 (s, 2H), 4.872 (s, 2H), 3.423 (m, 1H), 1.359 (q, 6H). Coupling constant J =12.

The NMR diagram of trans-benzenemoder is shown in Figure 2, and the NMR data are as follows:

¹ H NMR (CDCl ₃ , 500 Hz, δ: ppm), 7.477 (d, 2H), 7.360 (t, 2H), 6.969 (q, 2H), 6.501 (s, 1H), 4.722 (s, 2H), 3.486 (m, 1H), 1.380 (t, 6H). Coupling constant J =16.

HPLC conditions for pure cis-phenylene moder: the chromatographic column is Nucleosil 5 C18; the column temperature is 20°C; the detection wavelength is 318nm; the mobile phase is composed of acetonitrile and water with a volume ratio of 50:50; the flow rate is 0.6mL/ min, the injection volume was 5 μL; the cis-phenylene modad peaked at a retention time of 18.423 min, with a content of 96.39%, see Figure 3. Trans-Benzene Moder peaked at 17.630min at the retention time, and the content was 99.8%, see accompanying drawing 4. After the two are mixed, the peak of trans-benzene alkene mode is 17.664min at the retention time, and the peak of cis-benzene alkene mode is 18.458 min at the retention time, see accompanying drawing 5.

To detect the stability of the prepared cis-phenylene modder and explore its storage conditions, the following stability investigation experiments were carried out:

1. Stability experiments conducted in accordance with the Pharmacopoeia (Chinese Pharmacopoeia 2010 Edition)

Note: The values in the above table are the content (%) of cis-benzene modad.

2. Lighting condition experiment

Note: The values in the above table are the content (%) of cis-benzene modad.

3. Temperature condition experiment

Note: The values in the above table are the content (%) of cis-phenylene moder, and they should be stored under dark conditions.

4. Long-term stability experiment

Note: The values in the above table are the content (%) of cis-phenylene moder, and they should be stored under dark conditions.

According to the above test, it can be seen that the cis-styrene moder prepared in this example is stable, and the storage conditions of the prepared cis-styrene moder should be below 0° C. and kept away from light.

Embodiment 2-6 The synthetic method of cis-phenylene moder

Embodiments 2-6 are respectively a synthetic method of cis-phenylene modder, and its synthetic process is similar to that of Example 1, the only difference being the technical parameters involved therein, specifically as shown in the following table:

Embodiment 7 condition test

In this example, the technical parameters in Examples 1-6 were selectively screened, and it was found that the type and amount of reagents used had a great influence on the reaction.

1. The oxidizing agent and its dosage in the reaction step (3) have been selected. Not all oxidizing agents in the prior art can react under mild conditions and have a high yield. See the following table for details:

Finally determine that DMSO/acetic anhydride is the oxidizing agent, and then its dosage is tested, and it is found that the proportioning relationship and dosage of the two have a greater influence on the reaction, as shown in the following table:

It can be seen from the above table that the weight volume ratio of 3,5-dimethoxy-4-isopropylbenzyl alcohol, DMSO and acetic anhydride is 1:10～15:2～3g/mL/mL, exceeding The upper limit of the proportion of DMSO and acetic anhydride is excessive, which is difficult to remove in the post-treatment process, increases the difficulty of post-treatment, and wastes reagents. If the lower limit of the proportion is exceeded, the phenomenon of incomplete reaction will occur, and the yield will be low.

2. Select the basic catalyst used in the condensation reaction. Not all basic catalysts in the prior art can react with mild conditions and have a high yield. See the following table for details:

As can be seen from the above table, choosing anhydrous sodium acetate as the basic catalyst in the condensation reaction, the post-treatment is relatively simple, and the reaction yield is high.

Finally determine that anhydrous sodium acetate is an alkaline catalyst, and its consumption is tested afterward, and it is found that the proportioning relation of the two and the influencing factors of the consumption are relatively large to the reaction, specifically as shown in the following table:

As can be seen from the above table, it can be seen from the above table that the molar ratio of 3,5-dimethoxy-4-isopropylbenzaldehyde to sodium acetate is 1:2-4,3,5 - When the weight-to-volume ratio of dimethoxy-4-isopropylbenzaldehyde to acetic anhydride is 1g:20-30mL, the reaction is complete and the yield is high. Acetic anhydride exceeding the upper limit of the ratio is excessive, which is difficult to remove in the post-treatment process, increases the difficulty of post-treatment, and wastes reagents; the lower limit of the ratio is incomplete and the yield is low.

Reaction temperature and reaction time have also been selected simultaneously, specifically as shown in the following table:

It can be seen from the above table that the reaction temperature of the condensation reaction is selected to be 135°C to achieve a higher reaction yield, and the content of the cis product is also higher.

It can be seen from the above table that the reaction time of the condensation reaction is selected to be 6-8h to achieve a higher reaction yield, and the content of the cis product is also higher.

3. Select the decarboxylation reagent used in the decarboxylation reaction. Not all decarboxylation reagents in the prior art can make the reaction with mild conditions, and the yield is high. The specific content is shown in the following table:

It can be seen from the above table that copper powder/quinoline can be selected as the reagent for the decarboxylation reaction to achieve a higher reaction yield and the post-treatment is simple.

It is finally determined that copper powder/quinoline is the decarboxylation reagent, and then its dosage is tested, and it is found that the proportioning relationship and dosage of the two have a greater impact on the reaction, as shown in the following table:

As can be seen from the above table, it can be seen from the above table that the molar ratio of 3,5-dimethoxy-4-isopropyl stilbenic acid and copper powder is 1:6-8,3, The weight/volume ratio of 5-dimethoxy-4-isopropyl stilbenic acid to quinoline is 1g: 15-20mL, which exceeds the upper limit of the ratio, and copper powder and quinoline are excessive, and it is difficult to remove them after post-treatment, increasing Difficulties in post-processing, waste of reagents, incomplete reaction if the ratio exceeds the lower limit, and low yield.

Reaction temperature and reaction time have also been selected simultaneously, specifically as shown in the following table:

 

It can be seen from the above table that the reaction temperature of the decarboxylation reaction is selected to be 180°C to achieve a higher reaction yield, and the content of the cis product is also higher.

It can be seen from the above table that the reaction time of the decarboxylation reaction is selected to be 3-5h to achieve a higher reaction yield, and the content of the cis product is also higher.

4. The demethylation reagent used in the demethylation reaction is selected. Not all demethylation reagents in the prior art can react with mild conditions, and the yield is high. See the following table for details:

It can be seen from the above table that the choice of N,N-dimethylaniline/anhydrous AlCl ₃ as the demethylation reagent can achieve a higher reaction yield, the operation is simple, and the content of the cis product is also higher.

Finally, N,N-dimethylaniline/anhydrous AlCl ₃ was determined as the demethylation reagent, and then its dosage was tested, and it was found that the proportion relationship and dosage of the two had a great influence on the reaction, as shown in the table below :

As can be seen from the above table, it can be seen from the above table that the weight/volume ratio of 3,5-dimethoxy-4-isopropyl stilbene to toluene is 1g:15-20mL; , The molar ratio of 5-dimethoxy-4-isopropyl stilbene to N,N-dimethylaniline and anhydrous aluminum trichloride is 1:5～7:5～7. Exceeding the upper limit of the ratio will increase the difficulty of post-processing and waste reagents, and exceeding the lower limit of the ratio will result in incomplete reaction and low yield.

Reaction temperature and reaction time have also been selected simultaneously, specifically as shown in the following table:

It can be seen from the above table that if the reaction temperature of the demethylation reaction is 100°C, a higher reaction yield can be achieved, and the content of the cis product is also higher.

It can be seen from the above table that the reaction time of the demethylation reaction is selected to be 6-8h to achieve a higher reaction yield, and the content of the cis product is also higher.

5. The condition test was carried out on the HPLC method of cis-phenylene modder, and finally determined: the chromatographic column is Nucleosil 5 C18; the column temperature is 20°C; the detection wavelength is 318nm; the mobile phase is composed of acetonitrile and acetonitrile with a volume ratio of 50:50 Water composition; the flow rate is 0.6mL/min, and the injection volume is 5μL.

When preparing the detection solution, if methanol is used for sample preparation, since the cis product is very unstable in methanol, it can be converted into a trans product in a short time, and if acetonitrile/water is used for sample preparation, the cis product Relatively stable, so acetonitrile/water is selected as the mobile phase to ensure better and more accurate detection results.

The specific screening process is as follows:

It can be seen from the above table that the HPLC separation conditions of cis-trans benzene alkene modder are selected as acetonitrile/water=50:50, and the flow rate is 0.6mL/min, which can achieve better separation of cis-trans benzene alkene moder.

Claims (3)

1. a synthetic method for cis benzene alkene not moral, it is characterized in that:it is with 3,5-dihydroxyl-4-isopropyl acid is raw material, successively through methylation reaction synthesis 3,5-dimethoxy-4 '-isopropyl acid ester, reduction reaction synthesis 3,5-dimethoxy-4 '-isopropylbenzyl alcohol, oxidizing reaction synthesis 3,5-dimethoxy-4 '-propylbenzyl aldehyde, condensation reaction synthesis 3,5-dimethoxy-4 '-isopropyl toluylene acid, decarboxylic reaction synthesis 3,5-dimethoxy-4 '-isopropyl toluylene, eventually passes demethylating reaction synthesizing cis benzene alkene not moral;

Its synthetic method is reacted according to following route:

；

It carries out according to following steps order:

(1) methylation reaction

3,5-dihydroxyl-4-isopropyl acid, Anhydrous potassium carbonate are mixed with mol ratio 1:3 ~ 5, joins in DMF, at room temperature stir; Then, under the cooling of cryosel bath, slowly drip methyl iodide; Room temperature is risen to, reaction 2-3h after dropwising; Add water stirring after completion of the reaction, extraction into ethyl acetate, concentrated, obtains 3,5-dimethoxy-4 '-isopropyl acid ester; Wherein:

The mol ratio of 3,5-dihydroxyl-4-isopropyl acid and methyl iodide is 1:3 ~ 5;

The weightmeasurement ratio of 3,5-dihydroxyl-4-isopropyl acid and DMF is 1:20 ~ 30g/mL;

(2) reduction reaction

Be 3 of 1:4 ~ 6 by tetrahydrofuran (THF), mol ratio, 5-dimethoxy-4 '-isopropyl acid ester and sodium borohydride mixed at room temperature stir, be heated to backflow, slowly drip methyl alcohol, after reaction 4 ~ 6h, 3 ~ the 5L that adds water stirs, extraction into ethyl acetate, washing, revolves and steams except desolventizing obtains white solid, i.e. 3,5-dimethoxy-4 's-isopropylbenzyl alcohol; Wherein:

The amount ratio of 3,5-dimethoxy-4 '-isopropyl acid ester, methyl alcohol and tetrahydrofuran (THF) is 1:1 ~ 3:10 ~ 20g/mL/mL;

(3) oxidizing reaction

By 3,5-dimethoxy-4 '-isopropylbenzyl alcohol, DMSO and acetic anhydride mix and blend, after room temperature reaction 2-3h, add water stirring, extraction into ethyl acetate, washing, dry, concentrates to obtain 3,5-dimethoxy-4 's-propylbenzyl aldehyde; Wherein:

The amount ratio of 3,5-dimethoxy-4 '-isopropylbenzyl alcohol, DMSO and acetic anhydride is 1:10 ~ 15:2 ~ 3g/mL/mL;

(4) condensation reaction

Be 3,5-dimethoxy-4 's-propylbenzyl aldehyde and the toluylic acid mixing of 1:1 by mol ratio, add in acetic anhydride, stirring and dissolving, adds sodium-acetate, is heated to 135 DEG C, after reaction 6-8h, adding rare acid for adjusting pH after being down to room temperature is 2-3, extraction into ethyl acetate, concentrated, add saturated sodium bicarbonate solution and regulate pH to be 7 ~ 8, after stirring 2-3h, dichloromethane extraction, aqueous phase adds dilute hydrochloric acid and adjusts pH to be 2 ~ 3, filters yellow solid, i.e. 3,5-dimethoxy-4 's-isopropyl toluylene acid; Wherein:

The mol ratio of 3,5-dimethoxy-4 '-propylbenzyl aldehyde and sodium-acetate is 1:2 ~ 4;

The weight/volume of 3,5-dimethoxy-4 '-propylbenzyl aldehyde and acetic anhydride is 1:20 ~ 30g/mL;

(5) decarboxylic reaction

Be that the acid of 3,5-dimethoxy-4 's-isopropyl toluylene and the copper powder of 1:6 ~ 8 joins in quinoline by mol ratio, 180 DEG C react 3-5h after, be down to room temperature, add ethyl acetate to stir, filter, filtrate is colourless to water layer with dilute hydrochloric acid washing, aqueous phase uses ethyl acetate reversed phase extraction again, merge organic layer, saturated common salt water washing, to neutral, is spin-dried for, obtain 3,5-dimethoxy-4 '-isopropyl toluylene; Wherein:

3,5-dimethoxy-4 '-isopropyl toluylene acid is 1:15 ~ 20g/mL with the weight/volume of quinoline;

(6) demethylating reaction

3,5-dimethoxy-4 '-isopropyl toluylene is placed in toluene, stirs in ice bath, be cooled to 0 DEG C, after dissolving, slowly add DMA, add aluminum trichloride (anhydrous) in batches, after stirring 0.5h, rise to room temperature, after being heated to 100 DEG C of reaction 2-3h, being cooled to 60 DEG C, separating toluene layer while hot, in aqueous phase, add dilute hydrochloric acid stirring and adjusting pH value is 2-3, extraction into ethyl acetate, washing, concentrated, obtain target product cis benzene alkene not moral; Wherein:

The weight/volume of 3,5-dimethoxy-4 '-isopropyl toluylene and toluene is for being 1:15 ~ 20g/mL;

The mol ratio of 3,5-dimethoxy-4 '-isopropyl toluylene and DMA, aluminum trichloride (anhydrous) is 1:5 ~ 7:5 ~ 7.

2. an application for cis benzene alkene not moral, it is characterized in that:use synthetic method described in claim 1 to prepare cis benzene alkene not moral, using described cis benzene alkene not moral in the synthesis of trans benzene alkene not moral as standard substance, for detecting the content of cis benzene alkene not moral.

3. the application of cis benzene alkene according to claim 2 not moral, it is characterized in that:the content detecting cis benzene alkene not moral adopts the method for HPLC, and chromatographic column is Nucleosil 5 C18; Column temperature is 20 DEG C; Determined wavelength is 318nm; Moving phase by volume ratio be 50: 50 acetonitrile and water form; Flow velocity is 0.6mL/min, and sample size is 5 μ L.