CN110143941B - Synthesis method of intermediate of balusavir mefene - Google Patents
Synthesis method of intermediate of balusavir mefene Download PDFInfo
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
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Abstract
The invention provides a synthesis method of a intermediate of Barosavirenz. The invention provides a synthesis method of a compound III, which is prepared by 3 steps of reaction, so that the yield is improved, and the production is easy to control; simultaneously, providing a synthesis method of a compound IV, namely, reacting the compound III and diphenyl disulfide through one-pot autocatalytic cycle to generate the compound IV; and a method for preparing intermediate VIII of the Barosavirenz intermediate by the reaction. The preparation method discovers 'one-pot autocatalytic cycle' reaction, solves the problems of severe toxicity and control of thiophenol, and provides a safe and industrialized synthesis method suitable for the Barosavirenz.
Description
Technical Field
The invention relates to a synthesis method of a medical intermediate, in particular to a newly discovered method for 'one-pot autocatalytic cycle' reaction and preparation of a balosulfamate intermediate.
Background
Influenza is an acute respiratory infectious disease caused by influenza virus, and the world health organization predicts about 300 to 500 ten thousand influenza cases per year, causing about 25 to 50 ten thousand deaths. Barrosavirtup ester is a novel anti-influenza drug developed by salt Yeyi company, is approved to be marketed in Japan in 2018, 2 and 23 months, and is used for treating influenza A and B of adults and children. Barrosavirtup is the first anti-influenza drug with a novel action mechanism in recent 20 years, and transcription and replication of the influenza virus are inhibited by inhibiting cap-dependent endonuclease of the influenza virus. The action mechanism of the existing anti-influenza drugs is to prevent the virus from spreading in vivo by targeting Neuraminidase (Neuraminidase). Compared with the medicines, the Barrosavirtude targeting acts on the earlier stage of the virus replication cycle, and the effect is quicker. The balusavir acetate is used as a new generation anti-influenza drug and has great research and development significance and market prospect.
At present, the synthesis method of the balosulfamate is mainly formed by connecting an upper fragment and a lower fragment of a compound parent nucleus structure.
Patent CN109311911A discloses a method for preparing the lower fragment intermediate 8-difluorodibenzo [ b, e ] thiaheptacyclo-11 (6H) -ol (i.e. compound 19 in the following scheme).
In the operation process of step 1 in CN109311911A, the diisopropylamine steam has large irritation to respiratory tract, eyes and skin; in addition, diisopropylamine is flammable and its vapors mixed with air can form explosive mixtures. In the step, 2 times of low-temperature sensitive reactions are involved, and reagents, solvents and the like are strictly removed of water, so that diisopropylamine needs to be re-steamed, a large amount of steam is exposed, and potential hazards exist. In addition, the method also relates to the timing problem of adding the methanol, otherwise, byproducts and the like are generated, and the control in the production is not easy. This step is not suitable for industrial production. Step 2, using a reagent thiophenol which is malodorous and has extremely high toxicity when inhaled, and is listed in a list of controlled chemicals, namely highly toxic chemicals, the purchase and the use of which are limited, thereby putting higher requirements on the construction of production plants and being not suitable for commercial production.
CN109134428A discloses a method for synthesizing a lower fragment intermediate 8-difluorodibenzo [ b, e ] thiaheptacyclo-11 (6H) -alcohol.
In the route, 2-bromomethyl-3, 4-difluorophenylacetonitrile is used as a raw material, on one hand, cyano preparation relates to virulent tube products such as potassium cyanide and sodium cyanide, and on the other hand, the cyano preparation route by using amide is longer, and the raw material price is very high. In industrial production, the raw materials are difficult to obtain due to control and the cost is high.
CN109504721A discloses a method for preparing Barosavirenz ester, which comprises the following steps
In the method, the carboxyl is on a thiophenol ring, and Friedel-crafts reaction is difficult to perform with difluorobenzene, and the yield is difficult to control.
CN109721585A discloses 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e]A method for preparing thiazepin-11-one, which comprises 4 steps of reaction. Firstly, 2, 3-difluoro-6-halogenated benzyl alcohol as an initial material undergoes nucleophilic substitution reaction to generate 2, 3-difluoro-6-halogenated benzyl halide, then undergoes nucleophilic substitution reaction with diphenyl disulfide in the presence of sodium borohydride and sodium hydroxide to generate 2, 3-difluoro-6-halogenated benzyl sulfide, and finally undergoes Grignard reaction to synthesize 3, 4-difluoro-2- ((phenylsulfanyl) methylBasic) benzoic acid, finally performing Friedel-crafts acylation reaction to obtain 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ]]Thiazepin-11-one. In the step 1, 40% hydrobromic acid is adopted for bromination reaction in the reaction, and the hydrobromic acid is strong in acid and strong in corrosivity, so that equipment is easily damaged, and the environmental protection problem needs to be paid attention to; phosphorus tribromide is adopted for bromination reaction in the step 3, so that the yield is low, and the Grignard reagent has high requirements on anhydrous and oxygen-free reaction and is not suitable for industrial production; in addition, a large amount of CO is used in the production2Special equipment is required. In addition, the total yield calculated according to the highest yield of the reaction in each step of the example is only 35.7%, the production cost is greatly increased, and the method is not suitable for industrial mass production.
In conclusion, the existing synthetic routes of fragment intermediates under the balosulfate are few, and the problems exist, so that a new synthetic method needs to be developed.
Disclosure of Invention
The invention provides a synthetic method of a Barrosavirtuer intermediate, which has low cost and simple and controllable production conditions and is suitable for a synthetic route of industrial mass production.
The specific technical scheme of the invention is as follows:
firstly, the invention provides a synthesis method of an intermediate with a structure shown as a compound III, wherein the method is carried out by adopting 3 steps of reaction, and the reaction yield is high, simple and controllable.
The synthesis of the compound III comprises the following reaction steps:
wherein R is1，R2Is independently selected from C1～C6Alkyl, or may be linked through C-C, O, N to form a 3-to 6-membered heterocyclic ring.
Further, R1-N-R2Is selected from
In particular, the above route is carried out in 3 steps, in which,
(1) synthesis of Compound I, comprising steps 1a) and 1b)
Step 1a)3, 4-difluorobenzoic acid reacts with acyl chloride to generate 3, 4-difluorobenzoyl chloride,
step 1b) reacting 3, 4-difluorobenzoyl chloride with R in a mixed solvent of an organic solvent and water1、R2Reacting disubstituted amino with the action of an inorganic base to form a compound I, wherein R1，R2Defined as described in (1).
Further, the air conditioner is provided with a fan,
the acyl chloride in step 1a) is selected from phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride or phosphorus oxychloride, preferably oxalyl chloride; the solvent is one or more selected from N 'N-dimethylformamide, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, dioxane, toluene and pyridine, preferably N' N-dimethylformamide and dichloromethane; the reaction temperature is 0-40 ℃, and room temperature is preferred;
the inorganic base in the step 1b) is one or more selected from potassium carbonate, sodium hydroxide and potassium hydroxide, and is preferably potassium carbonate; the organic solvent is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, dioxane, N' N-dimethylformamide and acetonitrile, and is preferably dichloromethane; the reaction temperature is 0-40 ℃, and room temperature is preferred.
(2) Synthesis of Compound II
In step 2, the Li reagent is selected from n-butyl lithium, tert-butyl lithium and lithium diisopropylamide, and n-butyl lithium is preferred; the ligand is optional tetramethylethylenediamine or tetramethylpiperidine, preferably tetramethylethylenediamine; the solvent is selected from one or more of tetrahydrofuran, n-hexane and cyclohexane, and is preferably tetrahydrofuran; the temperature is-80 ℃ to room temperature. Preferably, the temperature is naturally raised after the dropwise addition at the temperature of between 80 ℃ below zero and 75 ℃ below zero.
(3) Synthesis of Compound III
In the step 3, the acid is selected from any one of hydrochloric acid and dilute sulfuric acid, preferably hydrochloric acid; the solvent is one or more of optional water, dioxane, acetic acid and formic acid, and is preferably water; the temperature is from room temperature to reflux, preferably reflux.
The invention adopts 3 steps of reaction, and the yield of each step is respectively as follows: more than 90 percent, more than 100 percent and more than 90 percent, the comprehensive yield is more than 85 percent, the yield is greatly improved, the production cost is greatly reduced, the problem that the industrial production of preparing the 4, 5-difluoro-3-hydroxy isobenzofuran-1 (3H) -ketone (compound III) by 3, 4-difluorobenzoic acid in one step is difficult to realize is well solved, the potential danger caused by the generation of a large amount of diisopropylamine steam is avoided, and the method is very suitable for industrial mass production.
Further, the invention provides a method for synthesizing an intermediate shown as a compound IV with the following structure.
The synthesis of the compound IV comprises the following synthetic routes:
further, water may be optionally added to the reaction, and preferably, the water may be a catalyst amount.
Further, the phosphine reagent is selected from triphenylphosphine, tri-n-butylphosphine, preferably triphenylphosphine.
Further, the catalyst is selected from D-camphorsulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid and ethanesulfonic acid, and is preferably p-toluenesulfonic acid.
Further, the solvent used is an aprotic solvent, preferably an aromatic hydrocarbon solvent.
Further, the solvent used is selected from one or more of toluene, benzene and xylene, and toluene is preferred.
Further, the reaction temperature is 40-80 ℃, and preferably 60 ℃.
CN109311911A adopts thiophenol highly toxic pipe products, the diphenyl disulfide used in the invention has no odor, high safety, no national control, convenient transportation and use, and is very suitable for industrial mass production; compared with CN109721585A, 2, 3-difluoro-6-halogenated benzyl halide and diphenyl disulfide react in the presence of sodium borohydride and sodium hydroxide, the intermediate 4, 5-difluoro-3-hydroxyisobenzofuran-1 (3H) -ketone is easy to hydrolyze in the presence of sodium borohydride and sodium hydroxide, the ketone in the intermediate is reduced to alcohol to generate a byproduct, the reaction with diphenyl disulfide is difficult to realize, and the design concept is different. Furthermore, in order to avoid the problems of large exposure of thiophenol and post-treatment of thiophenol in the reaction of generating thiophenol by diphenyl disulfide, the invention adopts a one-pot reaction without special treatment, and is very suitable for industrial continuous operation.
Furthermore, the above-mentioned route is actually a "one-pot autocatalytic cycle" reaction, i.e. thiophenol produced by first step diphenyl disulfide in the presence of triphenylphosphine and water reacts with compound iii in second step to produce compound iv and water; the water generated in the second step further catalyzes the first step reaction to generate thiophenol which is then used for the second step reaction, and meanwhile, the water generated in the second step is continuously consumed to promote the forward reaction; and the steps are circulated in turn. Water is optionally added to the reaction, and the amount of water used may be that of the catalyst.
Further, the present invention provides a method for synthesizing an intermediate represented by the following compound VII.
Synthesis of (III) Compound VII
The compound III is synthesized by adopting the prior art or the route (I), then reacts with a thiophenic reagent or the route (II) to generate a compound IV, then the ring opening is carried out to obtain 3, 4-difluoro-2-thiophenylmethylbenzoic acid, then the compound IV is heated and cyclized in the presence of polyphosphoric acid to generate a compound 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ketone, and finally the target 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol is obtained by reduction.
Further, the specific experimental conditions are as follows:
in the step 1a), the acyl chloride is oxalyl chloride, the solvent is dichloromethane and N' N-dimethylformamide, and the reaction temperature is room temperature;
in the step 1b), the inorganic base is potassium carbonate, the organic solvent is dichloromethane, and the reaction temperature is room temperature;
in the step 2, the Li reagent is n-butyllithium, the ligand is tetramethylethylenediamine, the solvent is tetrahydrofuran, and the temperature is-80-room temperature;
in the step 3, the acid is hydrochloric acid, and the temperature is between room temperature and reflux;
in the step 4, the phosphine reagent is triphenylphosphine, the catalyst is p-toluenesulfonic acid, the used solvent is toluene, and the reaction temperature is 60 ℃.
The invention has the following beneficial effects:
firstly, a preparation method of a compound III is provided, potential danger caused by generation of a large amount of diisopropylamine steam is avoided, and the problem that a 1-step method in the prior art is difficult to realize industrially is solved.
Secondly, thiophenol has special odor which is difficult to bear, and can affect the normal work of personnel in a large range in the using process; and thiophenol is extremely toxic, has severe irritation, is easy to be absorbed by human body and invade human body by percutaneous absorption, and is listed in the control catalog. The invention uses diphenyl disulfide to replace thiophenol, avoids the harm of special smell and toxicity of the thiophenol to workers in use, solves the problem of use control, and is beneficial to industrial production.
Thirdly, the invention provides a one-pot autocatalytic cycle reaction, which avoids the excessive exposure of thiophenol due to the limitation of water quantity in the reaction process, reduces the harm to experimenters and the pollution to the environment in the production process, and solves the toxicity problem; meanwhile, the water generated by the reaction is continuously consumed, so that the reaction can be further promoted to form a circulating reaction, and the method is suitable for industrial production.
Detailed description of the preferred embodiments
The following examples illustrate specific process steps of the present invention, but are not intended to limit the scope of the invention in any way.
Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
Example 1: preparation of compound I N, N-diethyl-3, 4-difluorobenzamide
31.62g of 3, 4-difluoro (difluoro-ethyl) -benzene were put into a reaction flaskBenzoic acid, 500ml dichloromethane and 5ml N' N-dimethylformamide are stirred at room temperature, 48.22g oxalyl chloride is dripped in, the mixture is stirred at room temperature for 1 hour after dripping, the solvent is evaporated to dryness under reduced pressure, 200ml dichloromethane is added to dissolve residual oily matters, diethylamine aqueous solution is directly dripped in (60.81 g potassium carbonate and 26.26g diethylamine hydrochloride are dissolved in 200ml water), the mixture is stirred at room temperature after dripping, an organic layer is separated, an aqueous phase is extracted by dichloromethane, the organic layers are combined, the mixture is washed by saturated common salt solution, anhydrous sodium sulfate is dried, and the oily matters are filtered and evaporated to dryness under reduced pressure to obtain 39.23. The yield is 92.1 percent,1H NMR(400MHz,CDCl3)δ7.13～7.25(m,3H),3.52 (br m,2H),3.27(br m,2H),1.21(br m,3H),1.16(br m,3H)；MS(ESI)m/z(M+H)+: 214.2
example 2: preparation of compound IIN, N-diethyl-2-formyl-3, 4-difluorobenzamide
26.00g N, N-diethyl-3, 4-difluorobenzamide, 250ml tetrahydrofuran and 18.42g tetramethylethylenediamine are put into a reaction bottle, the temperature is reduced to-80 ℃, 84ml 1.6M N-butyllithium is dripped, stirring is carried out for 1h after dripping is finished, 22.30g N' N-dimethylformamide is dripped, refrigerant liquid is removed for reaction after dripping is finished, diluted hydrochloric acid is used for quenching reaction, an organic layer is separated, an aqueous phase is extracted by ethyl acetate, the organic layers are combined, oil-like substances 29.50g are obtained after reduced pressure evaporation, and the yield is 100%.1H NMR(400MHz,CDCl3)δ10.33(s,1H),7.41～7.46(m,1H),7.03～7.07(m,1H), 3.56(q,J＝7.2Hz,2H),3.06(q,J＝7.2Hz,2H),1.30(t,J＝7.2Hz,2H),1.02(t,J ＝7.2Hz,2H)；MS(ESI)m/z(M+H)+:242.1
Example 3: preparation of compound III 4, 5-difluoro-3-hydroxyisobenzofuran-1 (3H) -one
29.50g N, N-diethyl-2-formyl-3, 4-difluorobenzamide and 200ml of 6M hydrochloric acid are put into a reaction bottle, the temperature is raised to 100 ℃, the mixture is stirred for 2.5 hours, 100ml of X4 dichloromethane is used for extraction, an organic layer is separated, purified water and saturated saline solution are used for washing, anhydrous sodium sulfate is used for drying, filtration and reduced pressure evaporation are carried out, and 20.98g of brown solid is obtained, and the yield is 92.4%.1H NMR(400MHz,CDCl3)δ7.66～7.70(m,1H),7.40～7.50(m,1H),6.78(s, 1H),4.54(br s,1H)；(MS-ESI)m/z(M-H)-:185.0
Example 4: preparation of compound IV 4, 5-difluoro-3-thiophenyl isobenzofuran-1 (3H) -ketone
20.00g of 4, 5-difluoro-3-hydroxyisobenzofuran-1 (3H) -ketone, 200ml of toluene, 14.08g of diphenyl disulfide, 16.92g of triphenylphosphine and 2.04g of p-toluenesulfonic acid are put into a reaction bottle, stirred for 24H at 60 ℃, cooled to room temperature, washed by 100ml of X41M sodium hydroxide, washed by purified water and saturated saline, dried by anhydrous sodium sulfate, filtered, decompressed and evaporated to dryness, and the obtained solid is added with n-heptane, pulped at room temperature, filtered, leached by n-heptane, decompressed and evaporated to dryness to obtain 27.1g of white solid, and the yield is 90.1%.1H NMR(400MHz,CDCl3)δ 7.44～7.53(m,4H),7.22～7.36(m,3H),6.76(s,1H)
Example 5: preparation of compound V3, 4-difluoro-2-thiophenylmethylbenzoic acid
Adding 12.46g of aluminum trichloride and 100ml of toluene into a reaction bottle, cooling to 0 ℃, stirring, dripping a toluene solution of 1,1,3, 3-tetramethyldisiloxane (12.55g of toluene is dissolved in 50ml of toluene), heating to room temperature after dripping, stirring for 30min, dissolving 20.00g of 4, 5-difluoro-3-thiophenyl isobenzofuran-1 (3H) -ketone in 50ml of toluene, slowly dripping into the reaction system, stirring for 3 hours at room temperature, dripping a sulfuric acid aqueous solution, separating an organic layer, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, depressurizing, steaming, adding n-heptane into the obtained solid, pulping in an ice water bath, filtering, leaching with n-heptane, drying to obtain 18.21g of a white solid, wherein the yield is 91.7%.1H NMR(400MHz, CDCl3)δ7.84～7.88(m,1H),7.34～7.37(m,2H),7.27(m,1H),7.25(m,2H),7.13(m, 1H),4.60(ds,2H)；MS(ESI)m/z(M-H)-:279.0
Example 6: preparation of compound VI 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ketone
20g of 3, 4-difluoro-2-thiophenylmethylbenzoic acid and 100g of polyphosphoric acid are put into a 100ml reaction bottle and stirred for 4 hours at 120 ℃, ice water is dropped after cooling, extraction is carried out by ethyl acetate, washing is carried out by sodium bicarbonate aqueous solution, washing is carried out by saturated saline solution, drying is carried out by anhydrous sodium sulfate, filtration is carried out, reduced pressure evaporation is carried out, dried by n-heptane, pulping is carried out by n-heptane, cooling is carried out, filtration is carried out, 17.2g of solid is obtained, and the yield is 92.1H NMR(400MHz,CDCl3)δ8.18～8.22(m,1H), 7.35～7.45(m,3H),7.27～7.32(m,1H),7.17～7.12(m,1H),4.14(ds,2H)；MS(ESI) m/z(M+H)+:263.1
Example 7: preparation of compound VII 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol
15g of 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] was put into a reaction flask]Carrying out cooling on thiazepin-11-ketone, 50ml of ethanol and 5ml of water in an ice water bath, adding sodium borohydride for multiple times, slowly dripping acetone after complete reaction, evaporating the solvent to dryness under reduced pressure, adding purified water, pulping, filtering, and drying to obtain a solid 14.8g, wherein the yield is 97%.1H NMR(400 MHz,CDCl3)δ7.44～7.50(m,1H),7.11～7.22(m,4H),6.99～7.06(m,1H),6.10(d,J＝3.2Hz,1H),4.70(dd,J＝14.4；1.2Hz 1H),4.20(dd,J＝14.4；1.2Hz,1H),2.68(d, J＝3.6Hz,1H)；MS(ESI)m/z(M+H-H2O)+:247.1。
Claims (10)
1. The synthesis method of the compound IV is characterized in that the synthesis route is as follows:
wherein the catalyst is selected from the group consisting of D-camphorsulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, optionally with the addition of trace amounts of water.
2. The method of synthesis according to claim 1, wherein the water is water by means of air or water in a solvent.
3. The synthesis method according to claim 1, wherein the phosphine reagent is selected from triphenylphosphine and tri-n-butylphosphine, the solvent is selected from one or more of toluene, benzene and xylene, and the reaction temperature is 40-80 ℃.
4. The synthesis method according to claim 1, wherein the phosphine reagent is triphenylphosphine, the catalyst is p-toluenesulfonic acid, the solvent is toluene, and the reaction temperature is 60 ℃.
5. The method of claim 1, wherein compound iii is prepared by:
wherein R is1，R2Independently selected from C1～C6The alkyl groups may be linked together via C-C, O, N to form a 3-to 6-membered heterocyclic ring.
6. The method of claim 5, wherein 3, 4-difluorobenzoic acid is reacted with an acid chloride to form 3, 4-difluorobenzoyl chloride in step 1, and the 3, 4-difluorobenzoyl chloride is reacted with R in a mixed solvent of an organic solvent and water1、R2The disubstituted amino reacts under the action of inorganic base to generate a compound I,
the acyl chloride is oxalyl chloride, the solvent is dichloromethane and N' N-dimethylformamide, and the reaction temperature is room temperature;
the inorganic base is potassium carbonate, the organic solvent is dichloromethane, and the reaction temperature is room temperature;
in the step 2, the Li reagent is n-butyllithium, the ligand is tetramethylethylenediamine, the solvent is tetrahydrofuran, and the temperature is-80-room temperature;
in step 3, the acid is hydrochloric acid and the temperature is between room temperature and reflux.
7. A method for synthesizing an intermediate VII,
the method is characterized by comprising the following steps: preparing a compound IV by any synthesis method of claims 1-6, then opening the ring to obtain a compound V3, 4-difluoro-2-thiophenylmethylbenzoic acid, then heating the ring to perform cyclization in the presence of polyphosphoric acid to generate a compound VI 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-one, and finally reducing the compound to obtain a target VII 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol.
8. The synthesis method according to claim 7, characterized in that the specific experimental conditions are as follows: in the step of preparing the compound IV, a phosphine reagent is triphenylphosphine, the catalyst is p-toluenesulfonic acid, a used solvent is toluene, and the reaction temperature is 60 ℃.
9. A synthetic method of an intermediate VII comprises the following steps:
wherein R is1，R2Independently selected from C1～C6The alkyl groups may be linked together via C-C, O, N to form a 3-to 6-membered heterocyclic ring,
firstly, preparing a compound III by the method, then preparing a compound IV by any one of the synthesis methods of claims 1 to 4, then opening the ring to obtain a compound V3, 4-difluoro-2-thiophenylmethylbenzoic acid, then heating the ring to perform cyclization in the presence of polyphosphoric acid to generate a compound VI 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-one, and finally reducing the compound to obtain a target VII 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol.
10. The synthesis method according to claim 9, characterized in that the specific experimental conditions are as follows:
in the step 1,3, 4-difluorobenzoic acid reacts with acyl chloride to generate 3, 4-difluorobenzoyl chloride, and the 3, 4-difluorobenzoyl chloride reacts with R in a mixed solvent of an organic solvent and water1、R2The disubstituted amino reacts under the action of inorganic base to generate a compound I,
the acyl chloride is oxalyl chloride, the solvent is dichloromethane and N' N-dimethylformamide, and the reaction temperature is room temperature;
the inorganic base is potassium carbonate, the organic solvent is dichloromethane, and the reaction temperature is room temperature;
in the step 2, the Li reagent is n-butyllithium, the ligand is tetramethylethylenediamine, the solvent is tetrahydrofuran, and the temperature is-80-room temperature;
in the step 3, the acid is hydrochloric acid, and the temperature is between room temperature and reflux;
in the step of preparing the compound IV, a phosphine reagent is triphenylphosphine, the catalyst is p-toluenesulfonic acid, a used solvent is toluene, and the reaction temperature is 60 ℃.
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| CN112812095A (en) * | 2021-01-29 | 2021-05-18 | 成都安满生物医药科技有限公司 | Synthesis method of baroxavir pivoxil intermediate |
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