CN112574170A - Dibenzo seven-membered ring derivative and preparation method and application thereof - Google Patents
Dibenzo seven-membered ring derivative and preparation method and application thereof Download PDFInfo
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- C07D337/02—Seven-membered rings
- 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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- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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Abstract
The invention relates to a dibenzo seven-membered ring derivative and a preparation method and application thereof, wherein the chemical structure of the dibenzo seven-membered ring derivative is shown as a formula (I), wherein X is1、X2Each independently selected from H, F, Cl, Br or I. The preparation method has easily obtained raw materials, and can ensure continuous supply and production; the raw materials are cheap, so that the cost advantage is achieved; the method does not use thiophenol or sodium thiophenol, is more environment-friendly and is also beneficial to the health of related personnel. 7, 8-difluoro-dibenzo [ b, e ] as one of the products]The thiazepin-11 (6H) -ketone can be further reacted to obtain 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e]Thiepin-11-ol, an important intermediate for its useThe preparation of the medicine of the balosavir can reduce the preparation cost of the balosavir and can also lead the preparation of the balosavir to be more environment-friendly.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a dibenzo-heptatomic ring derivative, a preparation method and application thereof, in particular to 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone, and a preparation method and application thereof.
Background
Influenza is an acute respiratory infectious disease caused by influenza virus, and is fulminant and epidemic throughout the world. Although influenza is acute, it is self-limiting, but it develops into severe influenza due to some complications such as pneumonia, and in a few severe cases, it progresses rapidly and dies due to Acute Respiratory Distress Syndrome (ARDS) and/or exhaustion of multiple organs. During the typical influenza season, the virus can infect 5% to 10% of the population, creating a heavy social and medical burden.
Oseltamivir (tamiflu), as the only oral neuraminidase inhibitor drug in the world at present, is still the dominant position in the global influenza diagnosis and treatment standard. However, compared with oseltamivir, the baloxavir has obvious advantages in the aspects of administration dosage, drug effect, adverse reaction and the like. Studies have shown that balomavir significantly improves the primary virological endpoint compared to placebo and oseltamivir, with the proportion of patients positive for influenza virus in vivo at days 1, 2 and 4 at the start of treatment being significantly lower than the placebo and oseltamivir groups. The time to fever was significantly reduced compared to placebo, where the median time to fever was 42 hours for placebo and 24.5 hours for baroxavir. The adverse reaction is lower than that of the oseltamivir group and the placebo group, the total adverse reaction of the baloxavir is 20.7 percent, and the adverse reaction of the oseltamivir and the placebo group is 24.6 percent and 24.8 percent respectively. The baloxavir can cure influenza within one day by only taking the dose once, while the tamiflu needs to be taken 2 times a day for 5 days continuously; 1 tablet corresponds to 10 tablets of current standard therapy and can continue to take effect for 10 days, so that the market space for the baroxavir is large.
The synthesis of baroxavir and its intermediates can be shown in the following chemical reaction formula, and for its synthesis, it mainly contains three intermediates, i.e. IM1, IM2, IM 3.
Among them, 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol (IM3) is one of the key intermediates for the synthesis of baroxavir, and the synthesis method reported in the patent of the pharmaceutical company of lamivum is shown in the following chemical reaction formula. The line uses 3, 4-difluorobenzoic acid with high price as a raw material, and the intermediate is obtained by lithiation, hydroformylation, reaction with thiophenol to obtain hemiacetal, reduction with silane with high price, PPA catalytic cyclization and reduction with sodium borohydride. The main disadvantages of this route are the high price of the raw materials, the high toxicity of thiophenols and the strong odor of thiophenols.
The IM3 synthesis line disclosed in CN109134428A uses sodium thiophenol, avoids using thiophenol, and has great improvement over the prior art, but the starting material is not easy to obtain. CN109721585A discloses a synthetic line of IM3, which takes diphenyl disulfide as a raw material to generate thiophenol in situ after reduction by sodium borohydride, avoids the thiophenol with high toxicity and stink, solves the problems in the original process line to a great extent, but has the defect that the initial raw material is not easy to obtain.
In conclusion, the prior synthesis process of the Barosavir intermediate in the prior art or the use of virulent and extremely odorous thiophenols as raw materials has problems in purchase and use; or the raw materials which are expensive and not easy to obtain are used, and the raw materials are inconvenient to obtain. The development of a synthetic process line which has easily obtained raw materials, good economy and more environmental protection is particularly necessary.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a dibenzo seven-membered ring derivative and a preparation method and application thereof, and particularly relates to 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -ketone and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a dibenzo-seven-membered ring derivative, which has a chemical structure represented by formula (i):
wherein, X1、X2Each independently selected from H, F, Cl, Br or I.
Preferably, the chemical structural formula of the dibenzo seven-membered ring derivative can be selected from any one of the following:
in a second aspect, the present invention provides a process for the preparation of a dibenzoseven-membered ring derivative as described above, which comprises: carrying out cyclization reaction on a compound shown as a formula (II);
wherein, X1、X2Each independently selected from H, F, Cl, Br or I.
The invention creatively takes the compound shown in the formula (II) as a preparation raw material, and obtains a target product through cyclization, and the yield is high.
Preferably, the cyclization reaction is catalyzed by using polyphosphoric acid, phosphorus pentoxide or trichloroacetic anhydride.
Preferably, the temperature of the cyclization reaction is controlled at 30-120 deg.C, such as 30 deg.C, 40 deg.C, 50 deg.C, 60 deg.C, 70 deg.C, 80 deg.C, 95 deg.C, 110 deg.C or 120 deg.C.
Preferably, after the cyclization reaction is finished, the reaction solution is cooled, quenched, extracted, concentrated and purified.
The present inventors have creatively discovered the above-mentioned suitable cyclization conditions that result in higher yields of the cyclized product.
Preferably, the reagents used for the extraction include methyl tert-butyl ether, dichloromethane, ethyl acetate or alkanes.
The purification mode can be column chromatography.
In a third aspect, the present invention provides a benzoic acid derivative, wherein the chemical structure of the benzoic acid derivative is represented by formula (ii):
wherein, X1、X2Each independently selected from H, F, Cl, Br or I.
Preferably, the chemical structural formula of the benzoic acid derivative may be selected from any one of the following:
preferably, the preparation method of the compound represented by the formula (II) comprises the following steps: carrying out substitution reaction on a compound shown as a formula (III) and thiosalicylic acid to obtain the compound;
The invention also creatively discovers that the compound shown in the formula (II) can be prepared by adopting the compound shown in the formula (III) and thiosalicylic acid as raw materials, the raw materials are easy to obtain and cheap, and the continuous supply and production can be ensured.
Preferably, the temperature of the substitution reaction is controlled at 20-60 deg.C, such as 20 deg.C, 30 deg.C, 40 deg.C, 45 deg.C, 50 deg.C, 55 deg.C or 60 deg.C.
Preferably, the substitution reaction is performed in a solvent, and the solvent includes any one of water, acetone, acetonitrile, N-dimethylformamide or absolute ethyl alcohol, or a combination of at least two of them, such as a combination of acetone and acetonitrile, a combination of acetonitrile and N, N-dimethylformamide, a combination of N, N-dimethylformamide and absolute ethyl alcohol, and the like, and any other possible combination is not described herein in detail.
Preferably, the substitution reaction is performed in the presence of an alkaline substance, the alkaline substance includes any one or a combination of at least two of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, the combination of at least two of sodium carbonate and potassium carbonate, potassium carbonate and sodium hydroxide, sodium carbonate and sodium hydroxide, and the like, and any other feasible combination modes are not repeated herein.
Preferably, after the reaction is completed, the pH is adjusted to 1 to 5 (e.g., pH 1, pH 2, pH 3, pH 4, or pH 5), filtered, and dried.
Preferably, the preparation method of the compound shown in the formula (III) comprises the following steps:
(a) carrying out lithiation and aldehyde reaction on the compound shown in the formula (VI) to obtain a compound shown in a formula (V);
(b) carrying out reduction reaction on the compound shown in the formula (V) in the step (a) to obtain a compound shown in a formula (IV);
(c) performing halogenation reaction on the compound shown in the formula (IV) in the step (b) to obtain a compound shown in a formula (III);
wherein, X1、X2Each independently selected from H, F, Cl, Br or I.
The compound shown as the formula (III) can be prepared by the method, raw materials are easy to obtain, continuous supply and production can be guaranteed, the price is low, and the cost advantage is achieved.
Preferably, the lithiation and hydroformylation reaction is a reaction of a compound represented by formula (vi) with n-butyllithium.
Preferably, the temperature of the lithiation and the hydroformylation reaction is controlled to be-80 to-70 ℃, for example, -80 ℃, -78 ℃, -77 ℃, -76 ℃, -75 ℃, -74 ℃, -72 ℃, or-70 ℃.
Preferably, the reduction reaction is a reaction of the compound represented by the formula (v) with sodium borohydride. In addition to sodium borohydride, potassium borohydride, lithium borohydride or red aluminum may be used.
Preferably, the temperature of the reduction reaction is controlled at 0-40 deg.C, such as 0 deg.C, 5 deg.C, 10 deg.C, 15 deg.C, 20 deg.C, 23 deg.C, 25 deg.C, 30 deg.C, 32 deg.C, 35 deg.C or 40 deg.C.
Preferably, the halogenation reaction is a reaction of the compound shown in the formula (IV) and thionyl chloride or phosphorus oxychloride.
Preferably, the temperature of the halogenation reaction is controlled at 30-100 ℃, such as 30 ℃,40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃ and the like.
The preparation method of the dibenzo seven-membered ring derivative related to the invention can be represented by the following reaction formula:
in a fourth aspect, the present invention provides a compound prepared from the dibenzo seven-membered ring derivative as described above, wherein the structural formula of the compound is shown as formula (VII):
wherein, X1、X2Each independently selected from H, F, Cl, Br or I.
Preferably, the chemical structural formula of the compound may be selected from any one of the following:
in a fifth aspect, the present invention provides a process for producing a compound represented by the formula (vii): the compound shown in the formula (I) is subjected to reduction reaction to obtain the compound.
Preferably, the reducing agent used in the reduction reaction comprises sodium borohydride, potassium borohydride, lithium borohydride or red aluminum, preferably sodium borohydride.
Preferably, the temperature of the reduction reaction is 0-60 ℃, such as 0 ℃, 25 ℃, 26 ℃, 28 ℃, 30 ℃, 32 ℃, 35 ℃, 36 ℃, 38 ℃,40 ℃ or 60 ℃.
Preferably, after the reduction reaction is finished, the reaction solution is transferred to hydrochloric acid for quenching, and an organic phase is separated, concentrated and crystallized.
As a preferred embodiment of the present invention, X1、X2When both are selected from F, the compound shown in the formula (VII) is specifically 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ]]Thiazepin-11-ol.
The preparation method of the 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-alcohol specifically comprises the following steps:
(1) carrying out lithiation and hydroformylation reaction on o-difluorobenzene and n-butyllithium at a temperature of between 80 ℃ below zero and 70 ℃ below zero, transferring a reaction solution into a hydrochloric acid solution after the reaction is finished, quenching, separating an organic phase, and concentrating to obtain 2, 3-difluorobenzaldehyde;
(2) carrying out reduction reaction on the 2, 3-difluorobenzaldehyde obtained in the step (1) and sodium borohydride at 0-40 ℃, transferring the reaction liquid to a hydrochloric acid solution after the reaction is finished, quenching, separating an organic phase, and concentrating to obtain 2, 3-difluorobenzyl alcohol;
(3) performing a halogenation reaction on the 2, 3-difluorobenzyl alcohol obtained in the step (2) and thionyl chloride or phosphorus oxychloride at the temperature of 30-100 ℃, transferring the reaction liquid to ice water for quenching after the reaction is finished, separating an organic phase, and concentrating to obtain the 2, 3-difluorobenzyl chloride;
(4) carrying out substitution reaction on the 2, 3-difluorobenzyl chloride obtained in the step (3) and thiosalicylic acid at the temperature of 40-70 ℃, adjusting the pH to 1-5 after the reaction is finished, filtering and drying to obtain 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid;
(5) performing cyclization catalytic reaction on 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid at 30-120 ℃ by using polyphosphoric acid, phosphorus pentoxide or trichloroacetic anhydride, and cooling, quenching, extracting, concentrating and purifying reaction liquid after the reaction is finished to obtain 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone;
(6) and (3) carrying out reduction reaction on the 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -ketone obtained in the step (5) at 0-60 ℃, transferring the reaction liquid to hydrochloric acid for quenching after the reaction is finished, separating an organic phase, concentrating and crystallizing to obtain 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol, namely the compound.
As a preferred embodiment of the present invention, the 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol can be prepared by the following formula:
in a sixth aspect, the present invention provides the use of a compound as described above for the preparation of baroxavir.
The 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine-11-alcohol serving as an important intermediate can be used for preparing the medicine baroxavir, and the preparation method provides an effective strategy for reducing the preparation cost of the baroxavir and ensuring that the preparation of the baroxavir is more green and environment-friendly.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method of the dibenzo seven-membered ring derivative has easily obtained raw materials, and can ensure continuous supply and production; the raw materials are cheap, so that the cost advantage is achieved; the method does not use thiophenol or sodium thiophenol, is more environment-friendly and is also beneficial to the health of related personnel. The 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone serving as one of the products can be further reacted to obtain 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine-11-ol, which can be used as an important intermediate for preparing the medicine of the balosuvir, so that the preparation cost of the balosuvir can be reduced, and the preparation of the balosuvir is more environment-friendly.
Drawings
FIG. 1 is a MS characterization of 2, 3-difluorobenzaldehyde prepared in example 1;
FIG. 2 is a photograph of 2, 3-difluorobenzaldehyde obtained in example 11H-NMR characterization chart;
FIG. 3 is a MS characterization of 2, 3-difluorobenzyl alcohol prepared in example 1;
FIG. 4 is a drawing showing the preparation of 2, 3-difluorobenzyl chloride obtained in example 11H-NMR characterization chart;
FIG. 5 is a MS (M-1) characterization of 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid prepared in example 4;
FIG. 6 is a MS (M +1) characterization of 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid prepared in example 4;
FIG. 7 is a photograph of 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid prepared in example 41H-NMR characterization chart;
FIG. 8 is a photograph of 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid prepared in example 413C-NMR profile;
FIG. 9 is a MS characterization of 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one prepared in example 8;
FIG. 10 is 7, 8-difluoro-dibenzo [ b, e ] prepared in example 8]Process for preparing thiazepin-11 (6H) -ones1H-NMR characterization chart;
FIG. 11 is 7, 8-difluoro-dibenzo [ b, e ] prepared in example 8]Process for preparing thiazepin-11 (6H) -ones13C-NMR profile;
FIG. 12 is a MS characterization of 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol of example 16;
FIG. 13 shows 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] in example 16]Process for preparing thiazepin-11-ols1H-NMR characterization chart;
FIG. 14 shows 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] in example 16]Process for preparing thiazepin-11-ols13C-NMR characterization chart.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Synthesis of 2, 3-difluorobenzyl chloride (Compound C):
example 1
This example provides a 2, 3-difluorobenzyl chloride, which is prepared by the following steps:
(1) 45g of o-difluorobenzene and 500mL of tetrahydrofuran were added to a 1L reaction flask, stirred and dissolved, and then cooled to-70 ℃. 180mL of 2.5M n-butyllithium tetrahydrofuran solution was added dropwise, and after the addition was completed, the reaction was carried out at-70 ℃ for 2 hours. 35g of anhydrous N, N-dimethylformamide is dropwise added, and after the dropwise addition is finished, the reaction is continued for 2 hours. The reaction solution was transferred to 500mL of 4M hydrochloric acid solution to quench, and the organic phase was separated by standing, the aqueous phase was extracted with methyl tert-butyl ether, the organic phases were combined and concentrated to give 2, 3-difluorobenzaldehyde (Compound A) in a weight of 50g and a yield of 89.2%.
MS and of the obtained 2, 3-difluorobenzaldehyde1H-NMR characterization, the results are shown in FIGS. 1 and 2: MS (M +1): 143.0292, theoretical value 143.0303.1H-NMR(CDCl 3400 MHz): delta ppm 10.37(s,1H, -CHO),7.64-7.68(m,1H, Ar-H),7.42-7.49(m,1H, Ar-H),7.22-7.28(m,1H, Ar-H). The successful preparation of 2, 3-difluorobenzaldehyde (compound A) was demonstrated.
(2) 56g of 2, 3-difluorobenzaldehyde obtained in the step (1) was put into a 1L reaction flask, and 500mL of anhydrous methanol was added and dissolved with stirring to obtain a transparent solution. Cooling to 5 ℃, adding 25g of sodium borohydride, and keeping the temperature at 30 ℃ for reaction for 4 hours after the addition is finished. And (3) adding hydrochloric acid to quench the reaction, extracting the product by methyl tert-ether, combining the extracting solutions, and concentrating to obtain 55g of the product 2, 3-difluorobenzyl alcohol with the yield of 96.7%.
The obtained 2, 3-difluorobenzyl alcohol was subjected to MS characterization, and the results are shown in FIG. 3: MS (M-OH): 127.0350, theoretical value 127.0354. The successful preparation of 2, 3-difluorobenzyl alcohol (compound B) was demonstrated.
(3) 55.7g of 2, 3-difluorobenzyl alcohol obtained in step (2) was charged into a 500mL reaction flask, and 180g N, N-dimethylformamide and 100mL of thionyl chloride were added thereto. Heating the reaction system to 50 ℃ for reaction, after the reaction is finished, dropwise adding the reaction solution into ice water, fully stirring, extracting with methyl tert-ether, combining organic phases, washing with saturated sodium bicarbonate, and concentrating to obtain 51g of a product with the yield of 81.2%.
The obtained 2, 3-difluorobenzyl chloride is subjected to1H-NMR characterization, the results are shown in FIG. 4: the nuclear magnetic data are:1H-NMR(CDCl3,400MHz):7.05-7.26(m,3H,Ar-H),4.63(d,J＝1.2Hz,1H,CH2cl). The success of the preparation of 2, 3-difluorobenzyl chloride (compound C) was demonstrated.
Example 2
This example provides a 2, 3-difluorobenzyl chloride, which is prepared by the following steps:
step (1) and step (2) were in accordance with example 1.
(3) 48g of 2, 3-difluorobenzyl alcohol obtained in step (2) was charged into a 500mL reaction flask, and 100mL of phosphorus oxychloride was further added. Heating the reaction system to 50 ℃ for reaction, after the reaction is finished, concentrating under reduced pressure, dropwise adding the reaction into ice water, fully stirring, extracting with methyl tert-ether, combining organic phases, washing with saturated sodium bicarbonate, and concentrating to obtain 50g of a product with the yield of 92.6%.
Example 3
This example provides a 2, 3-difluorobenzyl chloride, which is prepared by the following steps:
step (1) and step (2) were in accordance with example 1.
(3) 15g of 2, 3-difluorobenzyl alcohol obtained in step (2) was put into a 250mL reaction flask, 50mL of pyridine was added, and 30g of thionyl chloride was added dropwise. Heating to 40 ℃ for reaction, after the reaction is finished, dropwise adding the reaction liquid into ice water for quenching, extracting a product by using methyl tert-ether, and concentrating to obtain 15.8g of the product with the yield of 93.1%.
Synthesis of 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid (compound D):
example 4
This example provides a 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid, which is prepared by the following steps:
20g of sodium carbonate and 200mL of water were put into a reaction flask, and after stirring and dissolving, 150mL of acetone, 15.5g of thiosalicylic acid and 16.2g of 2, 3-difluorobenzyl chloride (compound C) were added, and the temperature was raised to 40 ℃ to react. After the reaction is finished, the temperature is reduced to 10 ℃, the reaction solution is transferred to 200mL of water, the pH value is adjusted to 3 by hydrochloric acid, and 24.4g of the product 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid is obtained after filtration and drying, wherein the yield is 87.1%.
MS (Mass Spectrometry) is carried out on the prepared 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid,1H-NMR and13C-NMR characterization, the results are shown in FIGS. 5-8:
MS (M-1), found 279.0297, theoretical 279.0297.
MS (M +1) found 281.0445, theoretical 281.0442.
1H-NMR(d6-DMSO,400MHz):δppm:13.13(brs,1H,-COOH),7.90(dd,1H,J＝7.8Hz,1.5Hz,Ar-H),7.49-7.57(m,2H,Ar-H),7.30-7.40(m,2H,Ar-H),7.23-7.27(m,H,Ar-H),7.16-7.20(m,H,Ar-H),3.37(s,2H,-CH2-)。
13C-NMR(d6-DMSO,100MHz):δppm 167.69,150.6(J＝144.2Hz,12.5Hz),148.2(J＝145.2,12.6Hz),140.5,132.9,131.4,127.0(J＝2.9Hz),126.9,126.8,126.5,125.3(J＝5.1,1.8Hz),124.9,117.0(16.8Hz),29.4(J＝2.7Hz)。
The above results demonstrate the successful preparation of 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid (compound D).
Example 5
This example provides a 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid, which is prepared by the following steps:
65g of potassium carbonate, 500mL of water and 300mL of acetonitrile were put into a reaction flask, dissolved by stirring, and 45g of thiosalicylic acid was added. 42g of 2, 3-difluorobenzyl chloride (compound C) was added thereto, and the mixture was heated to 50 ℃ and reacted with heat. After the reaction is finished, the temperature is reduced to 10 ℃, the PH value is adjusted to 2 by hydrochloric acid, 61.2g of the 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid is obtained after filtration and drying, and the yield is 84.5%.
Example 6
This example provides a 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid, which is prepared by the following steps:
20g of potassium carbonate and 150ml of N-dimethylformamide are added into a reaction bottle, 15g of thiosalicylic acid and 15g of 2, 3-difluorobenzyl chloride (compound C) are added, and the temperature is raised to 70 ℃ for reaction. After the reaction is finished, the temperature is reduced to 10 ℃, the reaction solution is transferred to 200mL of water, the pH value is adjusted to 1 by hydrochloric acid, and 24.6g of the product 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid is obtained after filtration and drying, wherein the yield is 95.1%.
Example 7
This example provides a 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid, which is prepared by the following steps:
28g of sodium hydroxide, 400mL of water and 200mL of absolute ethanol are added into a reaction flask, stirred and dissolved, and then 45g of thiosalicylic acid is added. 42g of 2, 3-difluorobenzyl chloride (compound C) was added thereto, and the mixture was heated to 60 ℃ to react. After the reaction is finished, the temperature is reduced to 10 ℃, the pH value is adjusted to 1 by hydrochloric acid, and 68.3g of the product 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid is obtained after filtration and drying, with the yield of 94.3%.
Synthesis of 7, 8-difluoro-dibenzo [ b, E ] thiazepin-11 (6H) -one (compound E):
example 8
This example provides a 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one, which is prepared by the following steps:
50g of polyphosphoric acid and 5.6g of 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid (compound D) prepared in example 4 are added into a reaction bottle, the temperature is raised to 95 ℃ for reaction, after the reaction is finished, the temperature is lowered to 10 ℃, 50mL of water is added for quenching reaction, a product is extracted by methyl tert-butyl ether, and after the concentration, the product is purified and separated by column chromatography to obtain 1.1g of white-like solid 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone, and the yield is 21.1%.
For the 7, 8-difluoro-dibenzo [ b, e ] obtained]MS of thiazepin-11 (6H) -one,1H-NMR and13C-NMR characterization, the results are shown in FIGS. 9-11:
MS (M +1): 263.0336, theoretical value 263.0337.
1H-NMR(CDCl3,400MHz):8.22(dd,1H,J＝8.1Hz,1.5Hz,Ar-H),7.38-7.46(m,3H,Ar-H),7.30-7.34(m,1H,Ar-H),7.13-7.19(m,H,Ar-H),4.16(d,2H,J＝1.1Hz,-CH2-)。
13C-NMR(CDCl3,100MHz):δppm:193.4，152.5(J＝253.3,13.2Hz),145.3(J＝247.2,13.6Hz),140.45,137.49(J＝3.51Hz),135.0,133.0,132.6,127.9(J＝13.3Hz),125.9,125.67(J＝7.6,4.5Hz),116.37,116.19,27.21(J＝4.3,2.1Hz)。
The above results demonstrate the successful preparation of 7, 8-difluoro-dibenzo [ b, E ] thiazepin-11 (6H) -one (compound E).
Example 9
This example provides a 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one, which is prepared by the following steps:
adding 50g of polyphosphoric acid, 5.6g of 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid (compound D) and 60mL of sulfolane into a reaction bottle, heating to 110 ℃ for reaction, cooling to 10 ℃ after the reaction is finished, adding 200mL of water for quenching reaction, extracting a product with methyl tert-butyl ether, concentrating, purifying by using column chromatography, and separating to obtain 2.36g of white-like solid 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone with the yield of 45.5%.
Example 10
This example provides a 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one, which is prepared by the following steps:
adding 12.2g of phosphorus pentoxide, 5.6g of 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid (compound D) and 150mL of sulfolane into a reaction bottle, heating to 50 ℃ for reaction, cooling to 10 ℃ after the reaction is finished, adding 200mL of water for quenching reaction, extracting a product by using methyl tert-butyl ether, purifying by using column chromatography after concentration, and separating to obtain 3.92g of white-like solid 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone with the yield of 75.3%.
Example 11
This example provides a 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one, which is prepared by the following steps:
adding 18.2g of phosphorus pentoxide, 5.6g of 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid (compound D) and 100mL of sulfolane into a reaction bottle, heating to 80 ℃ for reaction, cooling to 10 ℃ after the reaction is finished, adding 200mL of water for quenching reaction, extracting a product by using methyl tert-butyl ether, purifying by using column chromatography after concentration, and separating to obtain 2.62g of white-like solid 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone with the yield of 50.3%.
Example 12
This example provides a 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one, which is prepared by the following steps:
adding 27.3g of phosphorus pentoxide, 5.6g of 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid (compound D) and 200mL of sulfolane into a reaction bottle, controlling the temperature to 30 ℃ for reaction, adding 200mL of water for quenching reaction after the reaction is finished, extracting a product by using methyl tert-butyl ether, concentrating, purifying by using column chromatography, and separating to obtain 3.24g of white-like solid 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone with the yield of 62.3%.
Example 13
This example provides a 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one, which is prepared by the following steps:
adding 27.3g of phosphorus pentoxide, 5.6g of 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid (compound D) and 200mL of sulfolane into a reaction bottle, heating to 120 ℃ for reaction, adding 200mL of water for quenching reaction after the reaction is finished, extracting a product by using methyl tert-butyl ether, concentrating, purifying by using column chromatography, and separating to obtain 2.47g of white-like solid 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone with the yield of 47.5%.
Example 14
This example provides a 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one, which is prepared by the following steps:
27.3g of phosphorus pentoxide, 5.6g of 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid (compound D) and 150mL of methanesulfonic acid are added into a reaction bottle, the temperature is raised to 80 ℃ for reaction, after the reaction is finished, 200mL of water is added for quenching reaction, a product is extracted by methyl tert-butyl ether, and after the reaction is concentrated, the product is purified and separated by column chromatography to obtain 1.2g of white-like solid 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone, and the yield is 23.1%.
Example 15
This example provides a 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one, which is prepared by the following steps:
adding 65mL of trichloroacetic anhydride and 5.6g of 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid (compound D) into a reaction bottle, heating to 120 ℃ for reaction, concentrating under reduced pressure after the reaction is finished, and then purifying and separating by using column chromatography to obtain 2.2g of off-white solid 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone with the yield of 42.3%.
Synthesis of 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol (compound F):
example 16
This example provides a 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol, which is prepared by the following steps:
2.2g of sodium borohydride and 60mL of tetrahydrofuran were added to the reaction flask, and 13.2g of 7, 8-difluoro-dibenzo [ b, E ] thiazepin-11 (6H) -one (compound E) was added dropwise and dissolved in 60mL of tetrahydrofuran solution. After the addition, the temperature is raised to 40 ℃ for reaction until the reaction is complete. Quenching the reaction liquid by hydrochloric acid, separating an organic phase, extracting a water phase by methyl tertiary ether, combining the organic phases, concentrating, recrystallizing a crude product by using ethyl ester-n-hexane to obtain 10.2g of white-like solid 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol, wherein the yield is 77.2%.
To the obtained 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ]]MS of thiazepin-11-ol,1H-NMR and13C-NMR characterization, the results are shown in FIGS. 12-14:
MS (M-OH): 247.0389, theoretical value 247.0389.
1H-NMR(CDCl3,400MHz):δppm 7.48-7.50(m,1H,Ar-H),7.15-7.23(m,4H,Ar-H),7.04(q,J＝8.5Hz，1H,Ar-H),6.11(d,1H,J＝3.4Hz,-CHOH),4.69(dd,1H,J＝1.4,14.5Hz,-SCH2-),4.22(dd,1H,J＝1.4,14.4Hz,-SCH2-),2.74(1H,d＝3.64Hz，-OH)。
13C-NMR(CDCl3,100MHz):δppm 25.1,74.7,115.53,115.70,121.15,123.0,123.17,126.07,127.38,128.47,129.52,133.37,137.70,138.58。
The above results demonstrate the successful preparation of 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol (compound F).
Example 17
This example provides a 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol, which is prepared by the following steps:
160mL of anhydrous methanol, 26.4g of 7, 8-difluoro-dibenzo [ b, E ] thiazepin-11 (6H) -one (Compound E) was added to the reaction flask and the temperature was reduced to 10 ℃. 9.1g of sodium borohydride is added in batches, and after the addition is finished, the temperature is raised to 25 ℃ for reaction until the reaction is complete. Dropwise adding water to quench and react, filtering and drying to obtain 24.8g of white-like solid 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-alcohol with the yield of 93.7 percent.
Example 18
This example provides a 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol, which is prepared by the following steps:
50mL of isopropanol, 13.2g of 7, 8-difluoro-dibenzo [ b, E ] thiazepin-11 (6H) -one (Compound E) was added to the reaction flask and the temperature was reduced to 10 ℃. 4.5g of sodium borohydride is added in batches, and after the addition is finished, the temperature is raised to 55 ℃ for reaction until the reaction is complete. Dropwise adding water to quench and react, filtering and drying to obtain white solid 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol 12.5g with the yield of 94.7 percent.
The applicant states that the present invention is illustrated by the above examples, but the present invention is not limited to the above examples, i.e. it is not meant to be dependent on the above examples to practice the present invention. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
Claims (10)
1. A dibenzo-seven-membered ring derivative, which has a chemical structure represented by formula (I):
wherein, X1、X2Each independently selected from H, F, Cl, Br or I.
2. The process for the preparation of a dibenzo-seven-membered ring derivative according to claim 1, which comprises: carrying out cyclization reaction on a compound shown as a formula (II);
wherein, X1、X2Each independently selected from H, F, Cl, Br or I;
preferably, the cyclization reaction is catalyzed by polyphosphoric acid, phosphorus pentoxide or trichloroacetic anhydride;
preferably, the temperature of the cyclization reaction is controlled at 30-120 ℃;
preferably, after the cyclization reaction is finished, cooling, quenching, extracting, concentrating and purifying a reaction solution;
preferably, the reagents used for the extraction include methyl tert-butyl ether, dichloromethane, ethyl acetate or alkanes.
3. A benzoic acid derivative, wherein the benzoic acid derivative is a compound according to claim 2, and has a chemical structure represented by formula (ii):
wherein, X1、X2Each independently selected from H, F, Cl, Br or I.
4. The process according to claim 2, wherein the compound of formula (ii) is prepared by a process comprising: carrying out substitution reaction on a compound shown as a formula (III) and thiosalicylic acid to obtain the compound;
preferably, the temperature of the substitution reaction is controlled at 20-60 ℃;
preferably, the substitution reaction is carried out in a solvent comprising any one of water, acetone, acetonitrile, N-dimethylformamide or absolute ethanol or a combination of at least two thereof;
preferably, the substitution reaction is carried out in the presence of a basic substance comprising any one or a combination of at least two of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide;
preferably, after the reaction is finished, the pH value is adjusted to 1-5, and the mixture is filtered and dried.
5. The method according to claim 4, wherein the compound of formula (III) is prepared by a method comprising the steps of:
(a) carrying out lithiation and aldehyde reaction on the compound shown in the formula (VI) to obtain a compound shown in a formula (V);
(b) carrying out reduction reaction on the compound shown in the formula (V) in the step (a) to obtain a compound shown in a formula (IV);
(c) performing halogenation reaction on the compound shown in the formula (IV) in the step (b) to obtain a compound shown in a formula (III);
wherein, X1、X2Each independently selected from H, F, Cl, Br or I.
6. The method according to claim 5, wherein the lithiation and hydroformylation reaction is a reaction of a compound represented by formula (VI) with n-butyllithium;
preferably, the temperature of the lithiation and the aldehyde reaction is controlled to be-80 to-70 ℃;
preferably, the reduction reaction is a reaction of a compound shown as a formula (V) and sodium borohydride;
preferably, the temperature of the reduction reaction is controlled between 0 and 40 ℃;
preferably, the halogenation reaction is a reaction of the compound shown in the formula (IV) and thionyl chloride or phosphorus oxychloride;
preferably, the temperature of the halogenation reaction is controlled between 30 ℃ and 100 ℃.
7. A compound prepared from a dibenzo-seven-membered ring derivative according to claim 1, having a formula represented by formula (vii):
wherein, X1、X2Each independently selected from H, F, Cl, Br or I.
8. A process for the preparation of a compound according to claim 7, which comprises: the compound shown in the formula (I) is subjected to reduction reaction to obtain the compound;
preferably, the reducing agent used in the reduction reaction comprises sodium borohydride, potassium borohydride, lithium borohydride or red aluminum;
preferably, the reducing agent used in the reduction reaction is sodium borohydride;
preferably, the temperature of the reduction reaction is 0-60 ℃;
preferably, after the reduction reaction is finished, the reaction solution is transferred to hydrochloric acid for quenching, and an organic phase is separated, concentrated and crystallized.
9. The compound of claim 7, wherein X is1、X2Are all selected from F;
preferably, the preparation method of the compound specifically comprises the following steps:
(1) carrying out lithiation and hydroformylation reaction on o-difluorobenzene and n-butyllithium at a temperature of between 80 ℃ below zero and 70 ℃ below zero, transferring a reaction solution into a hydrochloric acid solution after the reaction is finished, quenching, separating an organic phase, and concentrating to obtain 2, 3-difluorobenzaldehyde;
(2) carrying out reduction reaction on the 2, 3-difluorobenzaldehyde obtained in the step (1) and sodium borohydride at 0-40 ℃, transferring the reaction liquid to a hydrochloric acid solution after the reaction is finished, quenching, separating an organic phase, and concentrating to obtain 2, 3-difluorobenzyl alcohol;
(3) performing a halogenation reaction on the 2, 3-difluorobenzyl alcohol obtained in the step (2) and thionyl chloride or phosphorus oxychloride at the temperature of 30-100 ℃, transferring the reaction liquid to ice water for quenching after the reaction is finished, separating an organic phase, and concentrating to obtain the 2, 3-difluorobenzyl chloride;
(4) carrying out substitution reaction on the 2, 3-difluorobenzyl chloride obtained in the step (3) and thiosalicylic acid at the temperature of 40-70 ℃, adjusting the pH to 1-5 after the reaction is finished, filtering and drying to obtain 2- ((2, 3-difluorobenzyl) mercapto) benzoic acid;
(5) performing cyclization catalytic reaction on 2- ((2, 3-difluorobenzyl) sulfenyl) benzoic acid at 30-120 ℃ by using polyphosphoric acid, phosphorus pentoxide or trichloroacetic anhydride, and cooling, quenching, extracting, concentrating and purifying reaction liquid after the reaction is finished to obtain 7, 8-difluoro-dibenzo [ b, e ] thiazepine-11 (6H) -ketone;
(6) and (3) carrying out reduction reaction on the 7, 8-difluoro-dibenzo [ b, e ] thiazepin-11 (6H) -ketone obtained in the step (5) at 0-60 ℃, transferring the reaction liquid to hydrochloric acid for quenching after the reaction is finished, separating an organic phase, concentrating and crystallizing to obtain 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-ol, namely the compound.
10. Use of a compound according to claim 9 for the preparation of baroxavir.
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