CN113636983A - Preparation method of (-) -Cytoxane and (+) -4-epi-Cytoxane - Google Patents

Preparation method of (-) -Cytoxane and (+) -4-epi-Cytoxane Download PDF

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CN113636983A
CN113636983A CN202110843241.2A CN202110843241A CN113636983A CN 113636983 A CN113636983 A CN 113636983A CN 202110843241 A CN202110843241 A CN 202110843241A CN 113636983 A CN113636983 A CN 113636983A
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吴正治
龙伯华
胡胜全
汪梦霞
李利民
李子雯
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Shenzhen Institute of Gerontology
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
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Abstract

The invention discloses a preparation method of (-) -Cytoxane and (+) -4-epi-Cytoxane, which takes D-p-hydroxyphenylglycine as a raw material, obtains an intermediate 2 through methyl esterification reaction under the catalysis of thionyl chloride, and then obtains an intermediate 3 through protecting amino with Boc anhydride; reacting potassium carbonate serving as alkali with methyl iodide under the condition of acetonitrile reflux to obtain a compound 4; reducing methyl ester by using a sodium borohydride/lithium chloride system to obtain a primary alcohol compound 5; then IBX is used for oxidizing primary alcohol to obtain an intermediate 6, then the intermediate 6 and acetone cyanohydrin react to obtain an intermediate 7 through SN2 reaction, then a methanol solution of hydrogen chloride is used for refluxing to obtain an intermediate 8, the intermediate 8 reacts with triphosgene to obtain two five-membered ring compound compounds 9 and 10, and finally sodium borohydride is used for reducing respectively to obtain (-) -Cytoxane and an isomer (+) -4-epi-Cytoxane thereof. The synthetic route of the invention is convenient to operate.

Description

Preparation method of (-) -Cytoxane and (+) -4-epi-Cytoxane
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of a Th2 cell type II cytokine cell specificity inhibitor (-) -Cytoxazone and an isomer (+) -4-epi-Cytoxazone thereof.
Background
The Cytoxazone compound has four isomers, wherein (-) -Cytoxazone is a natural product.
(-) -Cytoxane is a microbial metabolite isolated from Streptomyces (Streptomyces sp.) in Hiroshima. It and diastereoisomer (+) -4-epi-Cytoxazone can selectively inhibit Th2 cell (ineffective to Th1 cell) to produce II type cell factor, so that it has excellent application foreground and may be used in treating various kinds of cell factor disorder diseases, such as malignant lymphoma, rheumatism, etc.
(+) -4-epi-Cytoxazone also has stronger antibacterial activity against gram-positive bacteria (Bacillus subtilis) and gram-negative bacteria (Escherichia coli) than (-) -Cytoxazone.
Cytoxazone has completed its full chemical synthesis since its discovery by many research groups. However, the synthetic route of the Cytoxazone reported in the literature at present has the problems of high reagent price, poor stereoselectivity, inconvenient experimental operation, harsh reaction conditions, long route, low total yield and the like, and is difficult to meet various research requirements.
Disclosure of Invention
In order to solve the problems in the prior art, the embodiment of the invention provides a preparation method of a Th2 cell type II cytokine cell specific inhibitor (-) -Cytoxazone and an isomer (+) -4-epi-Cytoxazone thereof. The technical scheme is as follows:
in a first aspect, the preparation method of the cell specificity inhibitor (-) -Cytoxazone of Th2 cell type II cell cytokine comprises the following steps:
(1) dissolving D-p-hydroxyphenylglycine in methanol, cooling to 0 ℃ in an ice water bath, slowly dropwise adding thionyl chloride, and heating for reflux reaction after 30 minutes of dropwise adding to obtain an intermediate 2;
(2) dissolving the intermediate 2 in a tetrahydrofuran/water mixed solvent, adding sodium bicarbonate and Boc anhydride, and reacting at room temperature to obtain an intermediate 3;
(3) dissolving the intermediate 3 in acetonitrile, adding potassium carbonate and methyl iodide, and heating and refluxing to react to obtain a compound 4;
(4) dissolving the compound 4 in a tetrahydrofuran/ethanol mixed solvent, adding sodium borohydride and lithium chloride under the ice-water bath condition, and reacting at room temperature after 30 minutes to obtain a compound 5;
(5) dissolving the compound 5 in DMSO, adding IBX, and reacting at room temperature to obtain an intermediate 6;
(6) dissolving the intermediate 6 in dichloromethane, adding triethylamine and acetone cyanohydrin, and reacting at room temperature to obtain an intermediate 7;
(7) dissolving the intermediate 7 in methanol, cooling to 0 ℃ in an ice water bath, slowly dropwise adding acetyl chloride, heating for reflux reaction after 30 minutes of dropwise adding, and concentrating under reduced pressure to obtain an intermediate 8;
(8) dissolving the intermediate 8 in tetrahydrofuran, cooling to 0 ℃ in an ice-water bath, adding N, N-diisopropylethylamine and triphosgene, heating to room temperature after 30 minutes, and reacting to obtain compounds 9 and 10;
(9) dissolving the compound 9 in a tetrahydrofuran/water mixed solvent, adding sodium borohydride under the ice-water bath condition, and reacting at room temperature after 30 minutes to obtain (-) -Cytoxone;
the structural formula of the intermediate 2 is
Figure BDA0003179825440000021
The structural formula of the intermediate 3 is
Figure BDA0003179825440000022
The structural formula of the compound 4 is
Figure BDA0003179825440000023
The structural formula of the compound 5 is
Figure BDA0003179825440000031
The structural formula of the intermediate 6 is
Figure BDA0003179825440000032
The intermediate 7 has a structural formula
Figure BDA0003179825440000033
The structural formula of the intermediate 8 is
Figure BDA0003179825440000034
The structural formula of the compound 9 is
Figure BDA0003179825440000035
The structural formula of the compound 10 is
Figure BDA0003179825440000041
Further, the molar ratio of D-p-hydroxyphenylglycine thionyl chloride to sodium bicarbonate solid to Boc anhydride to potassium carbonate solid to methyl iodide in the steps (1) to (4) is 1:3-5:3-5:1-1.02:3-5: 1.2-2.
Preferably, the molar ratio of D-p-hydroxyphenylglycine to thionyl chloride to sodium bicarbonate solid to Boc anhydride to potassium carbonate solid to methyl iodide in the steps (1) to (4) is 1:3:3:1:3: 1.5.
Further, the reflux reaction in the step (1) is carried out for 3h-5h, and after the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain a compound 2.
Further, in the step (2), the reaction is carried out for 10h to 15h at room temperature, the reaction solution is concentrated under reduced pressure after the reaction is completed, the concentrated reaction solution is extracted by ethyl acetate, organic phases are combined, the organic phases are washed by saturated saline solution and then separated, anhydrous sodium sulfate is added into the organic phases for drying, and the filtrate is concentrated and drained after filtration to obtain the compound 3.
Further, in the step (3), heating and refluxing for 5-10 h, cooling to room temperature after complete reaction, filtering the reaction solution, washing filter residues with ethyl acetate, and concentrating the filtrate under reduced pressure to obtain the compound 4.
Further, the molar ratio of the compound 4 to the sodium borohydride to the lithium chloride in the step (4) is 1:2-4: 2-4; reacting for 3-6 h at room temperature, concentrating the reaction solution under reduced pressure after the reaction is completed, adding water and ethyl acetate to dissolve a concentrated product, then slowly dropwise adding concentrated hydrochloric acid to quench the residual lithium borohydride, extracting the aqueous phase by using ethyl acetate, combining organic phases, washing the organic phase by using saturated saline solution, separating the liquid, adding anhydrous sodium sulfate into the organic phase for drying, filtering, concentrating the filtrate, and draining to obtain a compound 5.
Preferably, the molar ratio of the compound 4 to the sodium borohydride to the lithium chloride in the step (4) is 1:3: 3.
Further, the molar ratio of the compound 5 in the steps (5) to (8) to IBX to triethylamine to acetone cyanohydrin to acetyl chloride to N, N-diisopropylethylamine to triphosgene is 1:1.2-2:1.2-2:1.2-2:20-40:3-5: 1.0-1.2.
Preferably, the molar ratio of the compound 5 to IBX to triethylamine to acetone cyanohydrin to acetyl chloride to N, N-diisopropylethylamine to triphosgene in the steps (5) to (8) is 1:1.5:1.2:1.2:30:4: 1.0.
Further, in the step (5), the reaction is carried out for 2h-3h at room temperature, water is added to dilute the reaction solution after the reaction is completed, then ethyl acetate is used for extraction, insoluble substances are removed by filtration, the aqueous phase is continuously extracted by ethyl acetate, organic phases are combined, the organic phase is washed by saturated saline solution and then separated, anhydrous sodium sulfate is added into the organic phase for drying, and the intermediate 6 is obtained by filtration and concentration.
Further, the reaction is carried out for 2h to 3h at room temperature in the step (8), water is added to dilute the reaction solution after the reaction is completed, dichloromethane is used for extraction, the combined organic phase is washed by 1M diluted hydrochloric acid and saturated saline solution in sequence, anhydrous sodium sulfate is used for drying and then filtration, the filtrate is concentrated, and the white solid compounds 9 and 10 are obtained by flash column chromatography by taking petroleum ether and ethyl acetate as eluent and taking the ratio of 3:2 as eluent.
Further, in the step (9), the molar ratio of the compound 9 to the sodium borohydride is 1:2-4, the reaction is carried out for 4h-6h at room temperature, reduced pressure concentration is carried out after the reaction is completed, the concentrated product is dissolved by adding water and ethyl acetate, then concentrated hydrochloric acid is slowly dripped to quench the residual sodium borohydride, the water phase is extracted by ethyl acetate, the organic phase is combined, the organic phase is washed by saturated saline solution and then is separated, anhydrous sodium sulfate is added into the organic phase for drying, and the (-) -Cytoxazone is obtained after the concentration and the draining after the filtration.
Preferably, the molar ratio of the compound 9 to the sodium borohydride in the step (9) is 1: 3.
In a second aspect, the preparation method of the Th2 cell type II cytokine cell specific inhibitor (+) -4-epi-Cytoxazone comprises the following steps:
(1) dissolving D-p-hydroxyphenylglycine in methanol, cooling to 0 ℃ in an ice water bath, slowly dropwise adding thionyl chloride, and heating for reflux reaction after 30 minutes of dropwise adding to obtain an intermediate 2;
(2) dissolving the intermediate 2 in a tetrahydrofuran/water mixed solvent, adding sodium bicarbonate and Boc anhydride, and reacting at room temperature to obtain an intermediate 3;
(3) dissolving the intermediate 3 in acetonitrile, adding potassium carbonate and methyl iodide, and heating and refluxing to react to obtain a compound 4;
(4) dissolving the compound 4 in a tetrahydrofuran/ethanol mixed solvent, adding sodium borohydride and lithium chloride under the ice-water bath condition, and reacting at room temperature after 30 minutes to obtain a compound 5;
(5) dissolving the compound 5 in DMSO, adding IBX, and reacting at room temperature to obtain an intermediate 6;
(6) dissolving the intermediate 6 in dichloromethane, adding triethylamine and acetone cyanohydrin, and reacting at room temperature to obtain an intermediate 7;
(7) dissolving the intermediate 7 in methanol, cooling to 0 ℃ in an ice water bath, slowly dropwise adding acetyl chloride, heating for reflux reaction after 30 minutes of dropwise adding, and concentrating under reduced pressure to obtain an intermediate 8;
(8) dissolving the intermediate 8 in tetrahydrofuran, cooling to 0 ℃ in an ice-water bath, adding N, N-diisopropylethylamine and triphosgene, heating to room temperature after 30 minutes, and reacting to obtain compounds 9 and 10;
(9) dissolving the compound 10 in a tetrahydrofuran/water mixed solvent, adding sodium borohydride under the ice-water bath condition, and reacting at room temperature after 30 minutes to obtain (+) -4-epi-Cytoxane;
the structural formula of the intermediate 2 is
Figure BDA0003179825440000061
The structural formula of the intermediate 3 is
Figure BDA0003179825440000062
The structural formula of the compound 4 is
Figure BDA0003179825440000063
The structural formula of the compound 5 is
Figure BDA0003179825440000064
The structural formula of the intermediate 6 is
Figure BDA0003179825440000065
The intermediate 7 has a structural formula
Figure BDA0003179825440000066
The structural formula of the intermediate 8 is
Figure BDA0003179825440000071
The structural formula of the compound 9 is
Figure BDA0003179825440000072
The structural formula of the compound 10 is
Figure BDA0003179825440000073
Further, the molar ratio of D-p-hydroxyphenylglycine thionyl chloride to sodium bicarbonate solid to Boc anhydride to potassium carbonate solid to methyl iodide in the steps (1) to (4) is 1:3-5:3-5:1-1.02:3-5: 1.2-2.
Preferably, the molar ratio of D-p-hydroxyphenylglycine to thionyl chloride to sodium bicarbonate solid to Boc anhydride to potassium carbonate solid to methyl iodide in the steps (1) to (4) is 1:3:3:1:3: 1.5.
Further, the reflux reaction in the step (1) is carried out for 3h-5h, and after the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain a compound 2.
Further, in the step (2), the reaction is carried out for 10h to 15h at room temperature, the reaction solution is concentrated under reduced pressure after the reaction is completed, the concentrated reaction solution is extracted by ethyl acetate, organic phases are combined, the organic phases are washed by saturated saline solution and then separated, anhydrous sodium sulfate is added into the organic phases for drying, and the filtrate is concentrated and drained after filtration to obtain the compound 3.
Further, in the step (3), heating and refluxing for 5-10 h, cooling to room temperature after complete reaction, filtering the reaction solution, washing filter residues with ethyl acetate, and concentrating the filtrate under reduced pressure to obtain the compound 4.
Further, the molar ratio of the compound 4 to the sodium borohydride to the lithium chloride in the step (4) is 1:2-4: 2-4; reacting for 3-6 h at room temperature, concentrating the reaction solution under reduced pressure after the reaction is completed, adding water and ethyl acetate to dissolve a concentrated product, then slowly dropwise adding concentrated hydrochloric acid to quench the residual lithium borohydride, extracting the aqueous phase by using ethyl acetate, combining organic phases, washing the organic phase by using saturated saline solution, separating the liquid, adding anhydrous sodium sulfate into the organic phase for drying, filtering, concentrating the filtrate, and draining to obtain a compound 5.
Preferably, the molar ratio of the compound 4 to the sodium borohydride to the lithium chloride in the step (4) is 1:3: 3.
Further, the molar ratio of the compound 5 in the steps (5) to (8) to IBX to triethylamine to acetone cyanohydrin to acetyl chloride to N, N-diisopropylethylamine to triphosgene is 1:1.2-2:1.2-2:1.2-2:20-40:3-5: 1.0-1.2.
Preferably, the molar ratio of the compound 5 to IBX to triethylamine to acetone cyanohydrin to acetyl chloride to N, N-diisopropylethylamine to triphosgene in the steps (5) to (8) is 1:1.5:1.2:1.2:30:4: 1.0.
Further, in the step (5), the reaction is carried out for 2h-3h at room temperature, water is added to dilute the reaction solution after the reaction is completed, then ethyl acetate is used for extraction, insoluble substances are removed by filtration, the aqueous phase is continuously extracted by ethyl acetate, organic phases are combined, the organic phase is washed by saturated saline solution and then separated, anhydrous sodium sulfate is added into the organic phase for drying, and the intermediate 6 is obtained by filtration and concentration.
Further, the reaction is carried out for 2h to 3h at room temperature in the step (8), water is added to dilute the reaction solution after the reaction is completed, dichloromethane is used for extraction, the combined organic phase is washed by 1M diluted hydrochloric acid and saturated saline solution in sequence, anhydrous sodium sulfate is used for drying and then filtration, the filtrate is concentrated, and the white solid compounds 9 and 10 are obtained by flash column chromatography by taking petroleum ether and ethyl acetate as eluent and taking the ratio of 3:2 as eluent.
Further, in the step (9), the molar ratio of the compound 10 to the sodium borohydride is 1:2-4, the reaction is carried out for 4h-6h at room temperature, reduced pressure concentration is carried out after the reaction is completed, water and ethyl acetate are added to the concentrated product for dissolution, then concentrated hydrochloric acid is slowly dripped to quench the residual sodium borohydride, the ethyl acetate is used for extracting the water phase, the organic phase is combined, the organic phase is washed by saturated saline solution and then is subjected to liquid separation, anhydrous sodium sulfate is added into the organic phase for drying, and the (+) -4-epi-Cytoxane is obtained after the concentration and the draining after the filtration.
Preferably, the molar ratio of the compound 10 to the sodium borohydride in the step (9) is 1: 3.
The technical scheme provided by the embodiment of the invention has the following beneficial effects: the method takes cheap and easily-obtained D-p-hydroxyphenylglycine as a raw material, firstly obtains an intermediate 2 through methyl esterification reaction under the catalysis of thionyl chloride, and then obtains an intermediate 3 through protecting amino with Boc anhydride; then potassium carbonate is used as alkali to react with methyl iodide under the condition of acetonitrile reflux to obtain a compound 4; reducing the methyl ester of the compound 4 by using a sodium borohydride/lithium chloride system to obtain a primary alcohol compound 5; then IBX is used for oxidizing primary alcohol to obtain an intermediate 6, then the intermediate 6 and acetone cyanohydrin are subjected to SN2 reaction to obtain an intermediate 7, then a methanol solution of hydrogen chloride is used for refluxing to obtain an intermediate 8, and finally the intermediate 8 and triphosgene are reacted to obtain two five-membered ring compound compounds 9 and 10. The compounds 9 and 10 are diastereoisomers, have large difference in polarity, can be quickly separated by silica gel column chromatography, and finally are respectively reduced by sodium borohydride to obtain (-) -Cytoxane and an isomer (+) -4-epi-Cytoxane thereof. The synthetic route of the invention has convenient operation, good stereoselectivity, mild reaction conditions, simple separation and purification, higher total yield and can be used for amplified preparation. The adopted raw materials are nontoxic, the production process is pollution-free, the environment is friendly, and good conditions are created for industrial mass production and commercialization of products.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in further detail below.
Examples
The preparation method of (-) -Cytoxane and (+) -4-epi-Cytoxane adopts D-p-hydroxyphenylglycine as a starting raw material and finally prepares a target product through four steps. The reaction scheme is as follows:
Figure BDA0003179825440000091
(1) synthesis of Compound 4
Dissolving the compound 1 (D-p-hydroxyphenylglycine, 10g and 60mmol) in methanol (150mL), cooling to 0 ℃ in an ice water bath, slowly dropwise adding thionyl chloride (13mL and 180mmol), heating for reflux reaction for 3 hours after 30 minutes of complete dropwise addition, and concentrating under reduced pressure to obtain an intermediate 2.
Figure BDA0003179825440000101
Dissolving the intermediate 2 in a tetrahydrofuran/water mixed solvent (1:1, 200mL), adding sodium bicarbonate solid (15.1g, 180mmol) and an equivalent of Boc anhydride (13.8mL, 60mmol), reacting at room temperature for 10h, concentrating under reduced pressure, extracting with ethyl acetate (200mL) for three times, combining organic phases, washing with saturated saline (200mL), separating, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain an intermediate 3.
Figure BDA0003179825440000102
Intermediate 3 was dissolved in acetonitrile (150mL), potassium carbonate solid (24.9g, 180mmol) and methyl iodide (5.6mL, 90mmol) were added and the reaction was heated under reflux for 6 h. After the reaction is completed, the reaction product is cooled to room temperature, the reaction product is filtered, filter residues are washed twice by ethyl acetate, and the filtrate is decompressed and concentrated to obtain a compound 4, a white solid 16.8g, and the total yield of the three steps is 95%.
Figure BDA0003179825440000103
(R) -2- (tert-Butoxycarbonyl) -2- (4-methoxyphenyl) acetic acid methyl ester
(R)-methyl 2-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)acetate
Compound 4 synthesized by1HNMR,13The product is a pure compound detected by CNMR and HRMS, and the characterization data is as follows: [ alpha ] to]D 25-97.0(c 1.2,CHCl3)；m.p.80-81℃；1H NMR(400MHz, CDCl3)δ7.29(d,J＝7.8Hz,2H),6.89(d,J＝8.8Hz,2H),5.52(d,J＝6.3Hz,1H), 5.27(d,J＝7.2Hz,1H),3.81(s,3H),3.73(s,3H),1.45(s,9H)；13C NMR(100MHz, CDCl3)δ171.88,159.62,154.80,128.91,128.35,114.25,80.08,56.97,55.25,52.60, 28.27；HR-ESIMS m/z:calculated for C15H21NO5Na+[M+Na]+:318.1420,found 318.1422.
(2) Synthesis of Compound 5
Dissolving a compound 4(16.8g, 57mmol) in a tetrahydrofuran/ethanol mixed solvent (1:1, 300mL), cooling to 0 ℃ in an ice-water bath, adding solid sodium borohydride (6.5g, 171mmol) and lithium chloride (7.2g, 171mmol), stirring for 30 minutes after the addition, removing the ice-water bath, heating to room temperature for reaction for 4 hours, concentrating under reduced pressure, adding a large amount of water (300mL) and ethyl acetate (300mL) for dissolution, slowly dropwise adding concentrated hydrochloric acid to quench the residual lithium borohydride, extracting an aqueous phase twice with ethyl acetate (200mL), combining organic phases, washing with saturated saline (200mL), separating liquid, drying with anhydrous sodium sulfate of the organic phase, filtering and concentrating to obtain a compound 5, wherein the white solid is 15.2g, and the yield is 100%.
Figure BDA0003179825440000111
(R) -tert-butyl 2-hydroxy-1- (4-methoxyphenyl) ethylcarbamate
(R)-tert-butyl 2-hydroxy-1-(4-methoxyphenyl)ethylcarbamate
Compound 5, via1HNMR,13The product is a pure compound detected by CNMR and HRMS, and the characterization data is as follows: [ alpha ] to]D 25-39.0(c 0.6,CHCl3)；m.p.141-142℃；1H NMR(400MHz, CDCl3)δ7.21(d,J＝8.6Hz,2H),6.93–6.83(m,2H),5.27(s,1H),4.71(s,1H), 3.79(s,5H),1.43(s,9H)；13C NMR(100MHz,CDCl3)δ158.98,156.16,131.55, 127.66,114.06,79.87,66.69,56.24,55.22,28.28；HR-ESIMS m/z:calculated for C14H21NO4Na+[M+Na]+:290.1471,found 290.1474.
(3) Synthesis of Compounds 9 and 10
Compound 5(10g, 37.4mmol) was dissolved in DMSO (120mL), IBX (15.7 g, 56.1mmol) was added and the reaction stirred at room temperature for 2h, after completion of the reaction a large amount of water (800mL) was added to dilute the solution, which was then extracted with ethyl acetate (300mL), the insoluble material was removed by filtration, the aqueous phase was extracted twice with ethyl acetate (200mL), the organic phases were combined and washed with saturated brine (300mL), separated, dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 6.
Figure BDA0003179825440000112
Intermediate 6 was dissolved in dichloromethane (200mL), triethylamine (6.3mL, 45mmol) and acetone cyanohydrin (4.1mL, 45mmol) were added, the reaction was stirred at room temperature for 2h, and concentrated under reduced pressure to give intermediate 7.
Figure BDA0003179825440000121
Dissolving the intermediate 7 in methanol (320mL), cooling to 0 ℃ in an ice-water bath, slowly dropwise adding acetyl chloride (80mL, 1.12mol), heating to reflux for 18h after 30 min, and concentrating under reduced pressure to obtain an intermediate 8.
Figure BDA0003179825440000122
Dissolving the intermediate 8 in tetrahydrofuran (300mL), cooling to 0 ℃ in an ice-water bath, adding N, N-diisopropylethylamine (24.8mL, 150mmol) and triphosgene (11.1g, 37.4mmol), heating to room temperature after 30 minutes, reacting for 2 hours, after the reaction is completed, adding a large amount of water (200mL), then extracting with dichloromethane (250mL) for three times, washing the combined organic phases with 1M diluted hydrochloric acid (200mL), saturated saline (200mL), drying with anhydrous sodium sulfate, filtering, concentrating, and performing flash column chromatography with petroleum ether and ethyl acetate (3: 2) as eluent to obtain the compound 10, 3.76g of white solid and 40% of total yield in four steps. The isolation was continued to give compound 9 as a white solid 3.70g, with an overall yield of approximately 40% over the four steps.
Figure BDA0003179825440000123
Compound 9(4R,5R) -4- (4-methoxyphenyl) -2-oxooxazolidine-5-carboxylic acid methyl ester
(4R,5R)-methyl 4-(4-methoxyphenyl)-2-oxooxazolidine-5-carboxylate
Compound 10(4R,5S) -4- (4-methoxyphenyl) -2-oxooxazolidine-5-carboxylic acid methyl ester
(4R,5S)-methyl 4-(4-methoxyphenyl)-2-oxooxazolidine-5-carboxylate
The polarity of the compound 9 and the diastereoisomer 10 is different, the Rf value is different by 0.15, and the compound can be quickly separated and purified by silica gel column chromatography. Although the stereoselectivity of the route is not very good (d.r.1:1), the synthesis steps are shorter, the separation and purification are simpler, the total yield is higher, and the preparation can be amplified.
Synthesized Compound 9, via1HNMR,13The product is a pure compound detected by CNMR and HRMS, and the characterization data is as follows: [ alpha ] to]D 25-94.5(c 1.0,MeOH)；1H NMR(400MHz,CDCl3)δ7.19(d, J＝8.7Hz,2H),6.87(d,J＝8.8Hz,2H),6.31(s,1H),5.25(d,J＝9.3Hz,1H),5.19 (d,J＝9.3Hz,1H),3.79(s,3H),3.31(s,3H)；13C NMR(101MHz,CDCl3)δ166.81, 160.18,158.40,128.78,128.11,113.98,78.10,57.91,55.25,52.00；HR-ESIMS m/z: calculated for C12H13NO5Na+[M+Na]+:274.0794,found 274.0798.
Compound 10, synthesized by1HNMR,13The product is a pure compound detected by CNMR and HRMS, and the characterization data is as follows: [ alpha ] to]D 25+89.0(c 1.0,MeOH)；m.p.90-91℃；1H NMR(400MHz, CDCl3)δ7.29(d,J＝8.2Hz,2H),6.93(d,J＝7.8Hz,2H),6.43(s,1H),4.94(d,J＝ 4.3Hz,1H),4.74(d,J＝4.3Hz,1H),3.87(s,3H),3.82(s,3H)；13C NMR(100MHz, CDCl3)δ168.77,160.13,158.00,130.68,127.24,114.61,80.49,58.79,55.36,53.11； HR-ESIMS m/z:calculated forC12H13NO5Na+[M+Na]+:274.0794,found 274.0798.
(4) Synthesis of (-) -Cytoxazone
Dissolving compound 9(3.70g, 14.7mmol) in tetrahydrofuran/water mixed solvent (10:1, 110mL), cooling to 0 ℃ in ice-water bath, adding sodium borohydride (1.68g, 44.1mmol), raising the temperature to room temperature after 30 minutes, reacting for 5h, concentrating under reduced pressure after the reaction is completed, adding a large amount of water (200mL) and ethyl acetate (300mL) to dissolve, then slowly dropwise adding concentrated hydrochloric acid to quench the residual sodium borohydride, extracting the aqueous phase twice with ethyl acetate (200mL), combining the organic phases, washing with saturated saline (200mL), separating, drying with anhydrous sodium sulfate, filtering and concentrating to obtain (-) -Cytoxane (compound 11) with 2.8g of white solid and 85% yield.
Synthetic (-) -Cytoxane, process for its preparation1HNMR,13The product is a pure compound detected by CNMR and HRMS, and the characterization data is as follows: [ alpha ] to]D 25-73.0(c 1.0,MeOH)；m.p.120-121℃；1H NMR(400 MHz,MeOD)δ7.20(d,J＝8.7Hz,2H),6.94(d,J＝8.7Hz,2H),5.01(d,J＝8.4Hz, 1H),4.84(d,J＝8.4Hz,1H),3.80(s,3H),3.17(dt,J＝12.3,6.1Hz,2H)；13C NMR (100MHz,MeOD)δ162.04,161.37,129.77,129.19,115.01,82.64,62.81,58.56(s), 55.75；HR-ESIMS m/z:calculated for C11H13NO4Na+[M+Na]+:246.0845,found 246.0848.
(5) Synthesis of (+) -4-epi-Cytoxazone
Dissolving compound 10(3.76g, 15.0mmol) in tetrahydrofuran/water mixed solvent (10:1, 110mL), cooling to 0 ℃ in ice-water bath, adding sodium borohydride (1.72g, 45.0mmol), heating to room temperature after 30 minutes of addition, reacting for 5 hours, concentrating under reduced pressure after reaction is completed, adding a large amount of water (200mL) and ethyl acetate (300mL) for dissolution, then slowly dropwise adding concentrated hydrochloric acid to quench the residual sodium borohydride, extracting the water phase with ethyl acetate (200mL) twice, combining organic phases, washing with saturated saline (200mL), separating, drying with anhydrous sodium sulfate, filtering and concentrating to obtain (+) -4-epi-Cytoxane (compound 12), 3.08 g of white solid, and the yield of 92%.
Synthetic (+) -4-epi-Cytoxazone1HNMR,13The product is a pure compound detected by CNMR and HRMS, and the characterization data is as follows:[α]D 25+28.5(c 1.0,MeOH)；m.p.159-160℃；1H NMR(400MHz,MeOD)δ7.30(d,J＝8.6Hz,2H),6.96(d,J＝8.7Hz,2H),4.75(d, J＝6.5Hz,1H),4.37–4.26(m,1H),3.86–3.80(m,1H),3.80(s,3H),3.69(dd,J＝ 12.6,4.3Hz,1H)；13C NMR(100MHz,MeOD)δ161.53,161.31,133.54,128.59, 115.41,86.83,62.46,58.51,55.76；HR-ESIMS m/z:calculated for C11H13NO4Na+ [M+Na]+:246.0845,found 246.0848.
the ee values of the products (-) -Cytoxane and (+) -4-epi-Cytoxane were determined by HPLC and are shown in Table 1.
Total yield of route ee value
(-)-Cytoxazone 32.3％ ＞98％
(+)-4-epi-Cytoxazone 35.0％ ＞98％
The method takes cheap and easily-obtained D-p-hydroxyphenylglycine as a raw material, firstly obtains an intermediate 2 through methyl esterification reaction under the catalysis of thionyl chloride, and then obtains an intermediate 3 through protecting amino with Boc anhydride; then potassium carbonate is used as alkali to react with methyl iodide under the condition of acetonitrile reflux to obtain a compound 4; reducing the methyl ester of the compound 4 by using a sodium borohydride/lithium chloride system to obtain a primary alcohol compound 5; then IBX is used for oxidizing primary alcohol to obtain an intermediate 6, then the intermediate 6 and acetone cyanohydrin are subjected to SN2 reaction to obtain an intermediate 7, then a methanol solution of hydrogen chloride is used for refluxing to obtain an intermediate 8, and finally the intermediate 8 and triphosgene are reacted to obtain two five-membered ring compound compounds 9 and 10. The compounds 9 and 10 are diastereoisomers, have large difference in polarity, can be quickly separated by silica gel column chromatography, and finally are respectively reduced by sodium borohydride to obtain (-) -Cytoxane and an isomer (+) -4-epi-Cytoxane thereof. The synthetic route of the invention has convenient operation, good stereoselectivity, mild reaction conditions, simple separation and purification, higher total yield and can be used for amplified preparation. The adopted raw materials are nontoxic, the production process is pollution-free, the environment is friendly, and good conditions are created for industrial mass production and commercialization of products.
The above-mentioned serial numbers of the embodiments of the present invention are merely for description and do not represent the merits of the embodiments.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (20)

1. A preparation method of a Th2 cell type II cytokine cell specificity inhibitor (-) -Cytoxazone is characterized by comprising the following steps:
(1) dissolving D-p-hydroxyphenylglycine in methanol, cooling to 0 ℃ in an ice water bath, slowly dropwise adding thionyl chloride, and heating for reflux reaction after 30 minutes of dropwise adding to obtain an intermediate 2;
(2) dissolving the intermediate 2 in a tetrahydrofuran/water mixed solvent, adding sodium bicarbonate and Boc anhydride, and reacting at room temperature to obtain an intermediate 3;
(3) dissolving the intermediate 3 in acetonitrile, adding potassium carbonate and methyl iodide, and heating and refluxing to react to obtain a compound 4;
(4) dissolving the compound 4 in a tetrahydrofuran/ethanol mixed solvent, adding sodium borohydride and lithium chloride under the ice-water bath condition, and reacting at room temperature after 30 minutes to obtain a compound 5;
(5) dissolving the compound 5 in DMSO, adding IBX, and reacting at room temperature to obtain an intermediate 6;
(6) dissolving the intermediate 6 in dichloromethane, adding triethylamine and acetone cyanohydrin, and reacting at room temperature to obtain an intermediate 7;
(7) dissolving the intermediate 7 in methanol, cooling to 0 ℃ in an ice water bath, slowly dropwise adding acetyl chloride, heating for reflux reaction after 30 minutes of dropwise adding, and concentrating under reduced pressure to obtain an intermediate 8;
(8) dissolving the intermediate 8 in tetrahydrofuran, cooling to 0 ℃ in an ice-water bath, adding N, N-diisopropylethylamine and triphosgene, heating to room temperature after 30 minutes, and reacting to obtain compounds 9 and 10;
(9) dissolving the compound 9 in a tetrahydrofuran/water mixed solvent, adding sodium borohydride under the ice-water bath condition, and reacting at room temperature after 30 minutes to obtain (-) -Cytoxone;
the structural formula of the intermediate 2 is
Figure FDA0003179825430000011
The structural formula of the intermediate 3 is
Figure FDA0003179825430000012
The structural formula of the compound 4 is
Figure FDA0003179825430000021
The structural formula of the compound 5 is
Figure FDA0003179825430000022
The structural formula of the intermediate 6 is
Figure FDA0003179825430000023
The intermediate 7 has a structural formula
Figure FDA0003179825430000024
The structural formula of the intermediate 8 is
Figure FDA0003179825430000025
The structural formula of the compound 9 is
Figure FDA0003179825430000026
The structural formula of the compound 10 is
Figure FDA0003179825430000031
2. The method of claim 1, wherein the molar ratio of D-p-hydroxyphenylglycine thionyl chloride to sodium bicarbonate solid to Boc anhydride to potassium carbonate solid to methyl iodide in the steps (1) to (4) is 1:3-5:3-5:1-1.02:3-5: 1.2-2.
3. The method according to claim 1, wherein the reflux reaction in step (1) is carried out for 3 to 5 hours, and after the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain the compound 2.
4. The method according to claim 1, wherein in the step (2), the reaction is carried out for 10 to 15 hours at room temperature, the reaction solution is concentrated under reduced pressure after the reaction is completed, the concentrated reaction solution is extracted by ethyl acetate, organic phases are combined, the organic phases are washed by saturated saline solution and then separated, anhydrous sodium sulfate is added into the organic phases for drying, and after filtration, the filtrate is concentrated and drained to obtain the compound 3.
5. The method as claimed in claim 1, wherein in the step (3), the reaction is performed under heating and refluxing for 5h to 10h, the reaction solution is cooled to room temperature after the reaction is completed, the reaction solution is filtered, the filter residue is washed with ethyl acetate, and the filtrate is concentrated under reduced pressure to obtain the compound 4.
6. The method according to claim 1, wherein the molar ratio of the compound 4: sodium borohydride: lithium chloride in the step (4) is 1:2-4: 2-4; reacting for 3-6 h at room temperature, concentrating the reaction solution under reduced pressure after the reaction is completed, adding water and ethyl acetate to dissolve a concentrated product, then slowly dropwise adding concentrated hydrochloric acid to quench the residual lithium borohydride, extracting the aqueous phase by using ethyl acetate, combining organic phases, washing the organic phase by using saturated saline solution, separating the liquid, adding anhydrous sodium sulfate into the organic phase for drying, filtering, concentrating the filtrate, and draining to obtain a compound 5.
7. The method according to claim 1, wherein the molar ratio of the compound 5: IBX: triethylamine: acetone cyanohydrin: acetyl chloride: N, N-diisopropylethylamine: triphosgene in the steps (5) to (8) is 1:1.2-2:1.2-2:1.2-2:20-40:3-5: 1.0-1.2.
8. The method according to claim 1, wherein in the step (5), the reaction is carried out for 2 to 3 hours at room temperature, water is added to dilute the reaction solution after the reaction is completed, then ethyl acetate is used for extraction, insoluble substances are removed by filtration, the ethyl acetate is used for extracting the water phase, the organic phase is combined, the organic phase is washed by saturated saline solution and then separated, anhydrous sodium sulfate is added into the organic phase for drying, and filtration and concentration are carried out to obtain the intermediate 6.
9. The method according to claim 1, wherein in the step (8), the reaction is carried out for 2h to 3h at room temperature, water is added to dilute the reaction solution after the reaction is completed, dichloromethane is used for extraction, the combined organic phase is washed by 1M diluted hydrochloric acid and saturated saline solution in sequence, anhydrous sodium sulfate is used for drying and filtering, the filtrate is concentrated, and the white solid compounds 9 and 10 are obtained by flash column chromatography by using petroleum ether and ethyl acetate 3:2 as eluent.
10. The method as claimed in claim 1, wherein in the step (9), the molar ratio of the compound 9 to the sodium borohydride is 1:2-4, the reaction is carried out at room temperature for 4h-6h, the reaction is carried out after completion, the concentration is carried out under reduced pressure, the concentrated product is dissolved by adding water and ethyl acetate, then concentrated hydrochloric acid is slowly added to quench the residual sodium borohydride, ethyl acetate is used for extracting the aqueous phase, the organic phases are combined, the organic phase is washed by saturated saline solution and then separated, anhydrous sodium sulfate is added to the organic phase for drying, and the mixture is concentrated and drained after filtration, so that (-) -Cytoxazone is obtained.
11. A preparation method of a Th2 cell type II cytokine cell specific inhibitor (+) -4-epi-Cytoxazone is characterized by comprising the following steps:
(1) dissolving D-p-hydroxyphenylglycine in methanol, cooling to 0 ℃ in an ice water bath, slowly dropwise adding thionyl chloride, and heating for reflux reaction after 30 minutes of dropwise adding to obtain an intermediate 2;
(2) dissolving the intermediate 2 in a tetrahydrofuran/water mixed solvent, adding sodium bicarbonate and Boc anhydride, and reacting at room temperature to obtain an intermediate 3;
(3) dissolving the intermediate 3 in acetonitrile, adding potassium carbonate and methyl iodide, and heating and refluxing to react to obtain a compound 4;
(4) dissolving the compound 4 in a tetrahydrofuran/ethanol mixed solvent, adding sodium borohydride and lithium chloride under the ice-water bath condition, and reacting at room temperature after 30 minutes to obtain a compound 5;
(5) dissolving the compound 5 in DMSO, adding IBX, and reacting at room temperature to obtain an intermediate 6;
(6) dissolving the intermediate 6 in dichloromethane, adding triethylamine and acetone cyanohydrin, and reacting at room temperature to obtain an intermediate 7;
(7) dissolving the intermediate 7 in methanol, cooling to 0 ℃ in an ice water bath, slowly dropwise adding acetyl chloride, heating for reflux reaction after 30 minutes of dropwise adding, and concentrating under reduced pressure to obtain an intermediate 8;
(8) dissolving the intermediate 8 in tetrahydrofuran, cooling to 0 ℃ in an ice-water bath, adding N, N-diisopropylethylamine and triphosgene, heating to room temperature after 30 minutes, and reacting to obtain compounds 9 and 10;
(9) dissolving the compound 10 in a tetrahydrofuran/water mixed solvent, adding sodium borohydride under the ice-water bath condition, and reacting at room temperature after 30 minutes to obtain (+) -4-epi-Cytoxane;
the structural formula of the intermediate 2 is
Figure FDA0003179825430000051
The structural formula of the intermediate 3 is
Figure FDA0003179825430000052
The structural formula of the compound 4 is
Figure FDA0003179825430000053
The structural formula of the compound 5 is
Figure FDA0003179825430000054
The structural formula of the intermediate 6 is
Figure FDA0003179825430000061
The intermediate 7 has a structural formula
Figure FDA0003179825430000062
The structural formula of the intermediate 8 is
Figure FDA0003179825430000063
The structural formula of the compound 9 is
Figure FDA0003179825430000064
The structural formula of the compound 10 is
Figure FDA0003179825430000065
12. The method of claim 11, wherein the molar ratio of D-p-hydroxyphenylglycine thionyl chloride to sodium bicarbonate solid to Boc anhydride to potassium carbonate solid to methyl iodide in steps (1) to (4) is 1:3-5:3-5:1-1.02:3-5: 1.2-2.
13. The method according to claim 11, wherein the reflux reaction in step (1) is carried out for 3 to 5 hours, and after the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain compound 2.
14. The method according to claim 11, wherein in the step (2), the reaction is carried out for 10 to 15 hours at room temperature, the reaction solution is concentrated under reduced pressure after the reaction is completed, the concentrated reaction solution is extracted by ethyl acetate, organic phases are combined, the organic phases are washed by saturated saline solution and then separated, anhydrous sodium sulfate is added into the organic phases for drying, and after filtration, the filtrate is concentrated and drained to obtain the compound 3.
15. The method as claimed in claim 11, wherein in the step (3), the reaction is performed under heating and refluxing for 5h to 10h, the reaction solution is cooled to room temperature after the reaction is completed, the reaction solution is filtered, the filter residue is washed with ethyl acetate, and the filtrate is concentrated under reduced pressure to obtain the compound 4.
16. The method according to claim 11, wherein the molar ratio of the compound 4: sodium borohydride: lithium chloride in the step (4) is 1:2-4: 2-4; reacting for 3-6 h at room temperature, concentrating the reaction solution under reduced pressure after the reaction is completed, adding water and ethyl acetate to dissolve a concentrated product, then slowly dropwise adding concentrated hydrochloric acid to quench the residual lithium borohydride, extracting the aqueous phase by using ethyl acetate, combining organic phases, washing the organic phase by using saturated saline solution, separating the liquid, adding anhydrous sodium sulfate into the organic phase for drying, filtering, concentrating the filtrate, and draining to obtain a compound 5.
17. The method according to claim 11, wherein the molar ratio of the compound 5: IBX: triethylamine: acetone cyanohydrin: acetyl chloride: N, N-diisopropylethylamine: triphosgene in the steps (5) to (8) is 1:1.2-2:1.2-2:1.2-2:20-40:3-5: 1.0-1.2.
18. The process according to claim 11, wherein in the step (5), the reaction is carried out at room temperature for 2 to 3 hours, water is added to dilute the reaction solution after the reaction is completed, then ethyl acetate is used for extraction, insoluble substances are removed by filtration, the ethyl acetate is used for extracting the water phase, the organic phase is combined, the organic phase is washed by saturated saline solution and then separated, anhydrous sodium sulfate is added into the organic phase for drying, and filtration and concentration are carried out to obtain the intermediate 6.
19. The method as claimed in claim 11, wherein the reaction is carried out for 2h to 3h at room temperature in the step (8), water is added to dilute the reaction solution after the reaction is completed, dichloromethane is used for extraction, the combined organic phase is washed by 1M diluted hydrochloric acid and saturated saline solution in sequence, anhydrous sodium sulfate is used for drying and filtering, the filtrate is concentrated, and the white solid compounds 9 and 10 are obtained by flash column chromatography by using petroleum ether and ethyl acetate 3:2 as eluent.
20. The method as claimed in claim 11, wherein in the step (9), the molar ratio of the compound 10 to the sodium borohydride is 1:2-4, the reaction is carried out at room temperature for 4h-6h, the reaction is carried out under reduced pressure and concentrated, the concentrated product is dissolved by adding water and ethyl acetate, then concentrated hydrochloric acid is slowly added to quench the residual sodium borohydride, ethyl acetate is used for extracting the aqueous phase, the organic phases are combined, the organic phase is washed by saturated saline solution and then separated, anhydrous sodium sulfate is added to the organic phase for drying, and the organic phase is filtered, concentrated and drained to obtain (+) -4-epi-Cytoxane.
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