CN109970764B - Synthesis method of (S) -1,1,5, 5-tetramethyl dihydro oxazolo [3,4-c ] oxazol-3-one - Google Patents
Synthesis method of (S) -1,1,5, 5-tetramethyl dihydro oxazolo [3,4-c ] oxazol-3-one Download PDFInfo
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Abstract
The invention relates to a synthesis method of (S) -1,1,5, 5-tetramethyl dihydro oxazolo [3,4-c ] oxazol-3-one. Mainly solves the technical problem that the industrial synthesis method is lacked. The synthesis method comprises the following steps: under the protection of ice-water bath and nitrogen, dropwise adding methylsulfonyl chloride into dichloromethane solution of (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyl oxazolidine-3-carboxylic acid tert-butyl ester, 4-dimethylaminopyridine and triethylamine, carrying out ring closure reaction at low temperature, quenching the reaction solution with water, extracting with ethyl acetate, washing, drying, concentrating, and crystallizing a crude product to obtain a target product 1. (S) -1,1,5, 5-tetramethyl dihydro oxazolo [3,4-c ] oxazol-3-one is an important intermediate for the synthesis of phosphatidylinositol-3-kinase (PI 3K) inhibitors.
Description
Technical Field
The invention relates to a synthesis method of (S) -1,1,5, 5-tetramethyl dihydro oxazolo [3,4-c ] oxazol-3-one.
Background
(S) -1,1,5, 5-tetramethyl dihydro oxazolo [3,4-c ] oxazol-3-one is widely used as a medical intermediate, and one application is the synthesis of phosphatidylinositol-3-kinase (PI 3K) inhibitor. Currently, there are few reports on the synthesis of the compound, and the main synthetic routes are as follows:
nowa company (NOVARTIS AG) patent US2013/225574A1 reported that tert-butyl (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylate was reacted under strongly basic conditions (sodium hydrogen/DMF) to give the product, but the yield obtained by this method is not mentioned in the patent. Williams Lorenzo et al reported in Tetrahedron et al that reaction of (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester, starting with 4-fluorobenzonitrile under strongly basic conditions (sodium hydrogen/THF), gave unexpectedly (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one in 71% yield, without obtaining the expected aryl ether product. The above processes all involve the use of hazardous metal reagents and the operating conditions are relatively harsh.
Disclosure of Invention
The invention aims to provide a synthesis method of (S) -1,1,5, 5-tetramethyl dihydro oxazolo [3,4-c ] oxazol-3-one, and mainly solves the technical problem that an industrial synthesis method is lacked.
The technical scheme of the invention is as follows: a synthetic method of (S) -1,1,5, 5-tetramethyl dihydro oxazolo [3,4-c ] oxazol-3-one comprises the following steps: under the protection of ice-water bath and nitrogen, dropwise adding methylsulfonyl chloride into dichloromethane solution of (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyl oxazolidine-3-carboxylic acid tert-butyl ester, 4-dimethylaminopyridine and triethylamine, carrying out ring closure reaction at low temperature, quenching the reaction solution with water, extracting with ethyl acetate, washing, drying, concentrating, and crystallizing a crude product in a mixed solvent to obtain a target product 1.
The synthesis route is as follows:
in the above reaction, the molar ratio of triethylamine to (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester is 3 to 5, preferably 4; the molar ratio of methylsulfonyl chloride to tert-butyl (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylate is 1-3, preferably 2; the molar ratio of the amount of 4-dimethylaminopyridine to tert-butyl (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylate is 1-3, preferably 2; the low temperature means that the reaction temperature is 0-10 ℃, and preferably 5 ℃; the ring closing reaction time is 15-25 hours, preferably 20 hours; the solvent used for crystallizing the crude product is a mixed solvent of ethyl acetate and one of petroleum ether, n-hexane or n-heptane, and preferably a mixed solvent of petroleum ether and ethyl acetate.
The invention has the beneficial effects that: the reaction condition is simple, the operation is convenient, the dangerous reaction and the use of dangerous reagents are not involved, and the target product with high purity and high yield can be obtained through crystallization.
Detailed Description
Example 1:
to a 1000 mL three-necked round-bottomed flask, under nitrogen atmosphere, (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (60.0 g, 0.23 mol), methylene chloride (600 mL), 4-dimethylaminopyridine (56.5 g,0.46 mol), triethylamine (93.0 g, 0.92 mmol) and methanesulfonyl chloride (52.6 g,0.46 mmol) were added dropwise at 5 ℃ and the reaction was allowed to proceed for 20 hours. Water (300 mL) was added to quench the reactionThe layers were separated, the aqueous phase was extracted with dichloromethane (150 mL. times.2), the combined organic phases were washed successively with 10% by mass citric acid (100 mL), saturated brine (100 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give a crude product, which was recrystallized from a mixed solvent of petroleum ether and ethyl acetate (volume ratio: 4: 1) to give the target compound 1 (39.0 g, 0.21mmol, 91%) in high purity.1H NMR (400 MHz, CDCl3) 3.96 (dd, J= 8.6, 6.5 Hz, 1H), 3.88 (dd, J= 8.6, 6.5 Hz, 1H), 3.67 (t, J = 8.6 Hz, 1H), 1.65 (s, 3H), 1.46 (s, 3H), 1.37 (s, 3H), 1.30 (s, 3H) ppm；LC-MS (ESI): m/z 186.1 [M+H]+；[a]D 25=+43.63（c=1.0,CHCl3）。
Example 2:
to a 1000 mL three-necked round-bottomed flask, under nitrogen atmosphere, (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (60.0 g, 0.23 mol), methylene chloride (600 mL), 4-dimethylaminopyridine (56.5 g,0.46 mol), triethylamine (46.5 g,0.46 mmol) and methanesulfonyl chloride (52.6 g,0.46 mmol) were added dropwise at 5 ℃ and the reaction was allowed to proceed for 20 hours. The reaction was quenched with water (300 mL), the layers were separated, the aqueous phase was extracted with dichloromethane (150 mL. times.2), the combined organic phases were washed successively with 10% by mass citric acid (100 mL), saturated brine (100 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give a crude product, which was recrystallized from a mixed solvent of petroleum ether and ethyl acetate (volume ratio: 4: 1) to give the target compound 1 (33.4 g, 0.18 mmol, 78%) in high purity.
Example 3:
to a 1000 mL three-necked round-bottomed flask, under nitrogen atmosphere, (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (60.0 g, 0.23 mol), methylene chloride (600 mL), 4-dimethylaminopyridine (56.5 g,0.46 mol), triethylamine (116.3 g, 1.15 mmol) and methanesulfonyl chloride (52.6 g,0.46 mmol) were added dropwise at 5 ℃ and the reaction was allowed to proceed for 20 hours. The reaction was quenched with water (300 mL), the layers were separated, the aqueous phase was extracted with dichloromethane (150 mL. times.2), the combined organic phases were washed successively with 10% by mass citric acid (100 mL), saturated brine (100 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give a crude product, which was recrystallized from a mixed solvent of petroleum ether and ethyl acetate (volume ratio: 4: 1) to give the target compound 1 (36.4 g, 0.20 mmol, 85%) in high purity.
Example 4:
to a 1000 mL three-necked round-bottomed flask, under nitrogen atmosphere, (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (60.0 g, 0.23 mol), methylene chloride (600 mL), 4-dimethylaminopyridine (56.5 g,0.46 mol), triethylamine (93.0 g, 0.92 mmol) and methanesulfonyl chloride (26.3 g, 0.23 mmol) were added dropwise at 5 ℃ and the reaction was allowed to proceed for 20 hours. The reaction was quenched with water (300 mL), the layers were separated, the aqueous phase was extracted with dichloromethane (150 mL. times.2), the combined organic phases were washed successively with 10% by mass citric acid (100 mL), saturated brine (100 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give a crude product, which was recrystallized from a mixed solvent of petroleum ether and ethyl acetate (volume ratio: 4: 1) to give the target compound 1 (22.3 g, 0.12 mmol, 52%) in high purity.
Example 5:
to a 1000 mL three-necked round-bottomed flask, under nitrogen atmosphere, (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (60.0 g, 0.23 mol), methylene chloride (600 mL), 4-dimethylaminopyridine (56.5 g,0.46 mol), triethylamine (93.0 g, 0.92 mmol) and methanesulfonyl chloride (78.9 g, 0.69 mmol) were added dropwise at 5 ℃ and the reaction was allowed to proceed for 20 hours. The reaction was quenched with water (300 mL), the layers were separated, the aqueous phase was extracted with dichloromethane (150 mL. times.2), the combined organic phases were washed successively with 10% by mass citric acid (100 mL), saturated brine (100 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give a crude product, which was recrystallized from a mixed solvent of petroleum ether and ethyl acetate (volume ratio: 4: 1) to give the target compound 1 (37.3 g, 0.20 mmol, 87%) in high purity.
Example 6:
to a 1000 mL three-necked round-bottomed flask, tert-butyl (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylate (60.0 g, 0.23 mol), methylene chloride (600 mL), 4-dimethylaminopyridine (56.5 g,0.46 mol), triethylamine (93.0 g, 0.92 mmol) and methanesulfonyl chloride (52.6 g,0.46 mmol) were added dropwise at 0 ℃ under nitrogen, and the reaction was incubated for 30 hours. The reaction was quenched with water (300 mL), the layers were separated, the aqueous phase was extracted with dichloromethane (150 mL. times.2), the combined organic phases were washed successively with 10% by mass citric acid (100 mL), saturated brine (100 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give a crude product, which was recrystallized from a mixed solvent of petroleum ether and ethyl acetate (volume ratio: 4: 1) to give the target compound 1 (38.6 g, 0.21mmol, 90%) in high purity.
Example 7:
to a 1000 mL three-necked round-bottomed flask, under nitrogen atmosphere, (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (60.0 g, 0.23 mol), methylene chloride (600 mL), 4-dimethylaminopyridine (56.5 g,0.46 mol), triethylamine (93.0 g, 0.92 mmol) and methanesulfonyl chloride (52.6 g,0.46 mmol) were added dropwise at 10 ℃ and the reaction was allowed to proceed for 20 hours. The reaction was quenched with water (300 mL), the layers were separated, the aqueous phase was extracted with dichloromethane (150 mL. times.2), the combined organic phases were washed successively with 10% by mass citric acid (100 mL), saturated brine (100 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give a crude product, which was recrystallized from a mixed solvent of petroleum ether and ethyl acetate (volume ratio: 4: 1) to give the target compound 1 (30.0 g, 0.16 mmol, 70%) in high purity.
Example 8:
to a 1000 mL three-necked round-bottomed flask, under nitrogen atmosphere, (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (60.0 g, 0.23 mol), methylene chloride (600 mL), 4-dimethylaminopyridine (56.5 g,0.46 mol), triethylamine (93.0 g, 0.92 mmol) and methanesulfonyl chloride (52.6 g,0.46 mmol) were added dropwise at 5 ℃ and the reaction was allowed to proceed for 15 hours. The reaction was quenched with water (300 mL), the layers were separated, the aqueous phase was extracted with dichloromethane (150 mL. times.2), the combined organic phases were washed successively with 10% by mass citric acid (100 mL), saturated brine (100 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give a crude product, which was recrystallized from a mixed solvent of petroleum ether and ethyl acetate (volume ratio: 4: 1) to give the target compound 1 (34.3 g, 0.19 mmol, 80%) in high purity.
Example 9:
to a 1000 mL three-necked round-bottomed flask, under nitrogen atmosphere, (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (60.0 g, 0.23 mol), methylene chloride (600 mL), 4-dimethylaminopyridine (56.5 g,0.46 mol), triethylamine (93.0 g, 0.92 mmol) and methanesulfonyl chloride (52.6 g,0.46 mmol) were added dropwise at 5 ℃ and the reaction was allowed to proceed for 25 hours. The reaction was quenched with water (300 mL), the layers were separated, the aqueous phase was extracted with dichloromethane (150 mL. times.2), the combined organic phases were washed successively with 10% by mass citric acid (100 mL), saturated brine (100 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give a crude product, which was recrystallized from a mixed solvent of petroleum ether and ethyl acetate (volume ratio: 4: 1) to give the target compound 1 (38.1 g, 0.21mmol, 89%) in high purity.
Example 10:
to a 1000 mL three-necked round-bottomed flask, under nitrogen atmosphere, (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (60.0 g, 0.23 mol), methylene chloride (600 mL), 4-dimethylaminopyridine (56.5 g,0.46 mol), triethylamine (93.0 g, 0.92 mmol) and methanesulfonyl chloride (52.6 g,0.46 mmol) were added dropwise at 5 ℃ and the reaction was allowed to proceed for 20 hours. The reaction was quenched with water (300 mL), the layers were separated, the aqueous phase was extracted with dichloromethane (150 mL. times.2), the combined organic phases were washed successively with 10% by mass citric acid (100 mL), saturated brine (100 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give a crude product, which was recrystallized from a mixed solvent of n-hexane and ethyl acetate (volume ratio: 4: 1) to give the target compound 1 (36.9 g, 0.20 mmol, 86%) in high purity.
Example 11:
to a 1000 mL three-necked round-bottomed flask, under nitrogen atmosphere, (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (60.0 g, 0.23 mol), methylene chloride (600 mL), 4-dimethylaminopyridine (56.5 g,0.46 mol), triethylamine (93.0 g, 0.92 mmol) and methanesulfonyl chloride (52.6 g,0.46 mmol) were added dropwise at 5 ℃ and the reaction was allowed to proceed for 20 hours. The reaction was quenched with water (300 mL), the layers were separated, the aqueous phase was extracted with dichloromethane (150 mL. times.2), the combined organic phases were washed successively with 10% by mass citric acid (100 mL), saturated brine (100 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give a crude product, which was recrystallized from a mixed solvent of n-heptane and ethyl acetate (volume ratio: 4: 1) to give the target compound 1 (35.1 g, 0.19 mmol, 82%) with high purity.
Claims (13)
1. A synthetic method of (S) -1,1,5, 5-tetramethyl dihydro oxazolo [3,4-c ] oxazol-3-one is characterized by comprising the following steps: the method comprises the following steps: under the conditions of ice-water bath and nitrogen protection, dropwise adding methylsulfonyl chloride into dichloromethane solution of (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyl oxazolidine-3-carboxylic acid tert-butyl ester, 4-dimethylaminopyridine and triethylamine, performing ring closure reaction at low temperature, quenching the reaction solution with water, extracting with ethyl acetate, washing, drying, concentrating, and crystallizing a crude product in a mixed solvent to obtain a target product 1; the synthesis route is as follows:
2. the method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one as claimed in claim 1, wherein: the molar ratio of triethylamine to (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester was 3-5.
3. The method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one as claimed in claim 2, wherein: the molar ratio of triethylamine to (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester was 4.
4. The method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one as claimed in claim 1, wherein: the molar ratio of methylsulfonyl chloride to tert-butyl (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylate was 1-3.
5. The method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one as claimed in claim 4, wherein: the molar ratio of methylsulfonyl chloride to tert-butyl (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylate was 2.
6. The method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one as claimed in claim 1, wherein: the molar ratio of 4-dimethylaminopyridine to (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester is 1-3.
7. The method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one as claimed in claim 6, wherein: the molar ratio of 4-dimethylaminopyridine to (S) -4- (1-hydroxy-1-methylethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester was 2.
8. The method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one as claimed in claim 1, wherein: the low temperature means that the reaction temperature is 0-10 ℃.
9. The method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one according to claim 8, wherein: the reaction temperature was 5 ℃.
10. The method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one as claimed in claim 1, wherein: the ring closing reaction time is 15-25 hours.
11. The method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one according to claim 10, wherein: the ring-closing reaction time was 20 hours.
12. The method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one as claimed in claim 1, wherein: the mixed solvent is a mixed solvent of ethyl acetate and one of petroleum ether, n-hexane or n-heptane.
13. The method for synthesizing (S) -1,1,5, 5-tetramethyldihydrooxazolo [3,4-c ] oxazol-3-one according to claim 12, wherein: the mixed solvent is a mixed solvent of petroleum ether and ethyl acetate.
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| CN104144926A (en) * | 2012-02-24 | 2014-11-12 | 诺华股份有限公司 | Oxazolidin- 2 -one compounds and uses thereof as pi3ks inhibitors |
| WO2018086531A1 (en) * | 2016-11-08 | 2018-05-17 | 正大天晴药业集团股份有限公司 | Sulfonamides compound serving as cccdna inhibitor |
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| CN104144926A (en) * | 2012-02-24 | 2014-11-12 | 诺华股份有限公司 | Oxazolidin- 2 -one compounds and uses thereof as pi3ks inhibitors |
| WO2018086531A1 (en) * | 2016-11-08 | 2018-05-17 | 正大天晴药业集团股份有限公司 | Sulfonamides compound serving as cccdna inhibitor |
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| Grignard Reactions to Chiral Oxazolidine Aldehydes;Lorenzo Williams，等;《Tetrahedron》;19961231;第52卷(第36期);第11673-11694页，尤其参见第11683,11692页 * |
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