CN111533752A - Preparation method of tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-formic acid ester - Google Patents
Preparation method of tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-formic acid ester Download PDFInfo
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- CN111533752A CN111533752A CN202010428555.1A CN202010428555A CN111533752A CN 111533752 A CN111533752 A CN 111533752A CN 202010428555 A CN202010428555 A CN 202010428555A CN 111533752 A CN111533752 A CN 111533752A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Abstract
The invention relates to a preparation method of tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-formic acid ester, which mainly solves the technical problem that no proper synthesis method exists in the existing compound. The method adopts a 3-step method for synthesis, and comprises the first step of reacting 1-BOC-3-oxoylidene-azetidine serving as a starting raw material with allyl bromide under the action of zinc powder to generate 3-allyl-3-hydroxy azetidine-1-carboxylic acid tert-butyl ester; secondly, reacting 3-allyl-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester with liquid bromine to generate tert-butyl-3- (2, 3-dibromopropyl) -3-hydroxyazetidine-1-formate; in the third step, tert-butyl-3- (2, 3-dibromopropyl) -3-hydroxyazetidine-1-carboxylate is reacted with potassium carbonate as a base to produce tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-carboxylate. The invention is a useful intermediate or product for the synthesis of many drugs.
Description
Technical Field
The invention relates to a synthetic method of tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-formic acid ester.
Background
Tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-formate and related derivatives have important applications in pharmaceutical chemistry and organic synthesis, and have good prospects. However, no synthetic method of the compound is reported at present. Therefore, the development of a synthesis method which has the advantages of cheap raw materials, easy obtainment of raw materials, convenient operation, easy batch production control and proper overall yield is very significant.
Disclosure of Invention
The invention aims to develop a preparation method of tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-formic acid ester, which has cheap raw materials, convenient operation, amplification and high yield in three steps. Mainly solves the technical problem that the compound has no proper synthesis method at present.
The technical scheme of the invention is as follows: a preparation method of tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-formic acid ester comprises the following steps: synthesizing by a 3-step method, namely, in the first step, taking 1-BOC-3-oxoidene-azetidine as a starting material and reacting with allyl bromide under the action of zinc powder; or directly reacting with an allyl Grignard reagent to produce 3-allyl-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester; secondly, reacting 3-allyl-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester with liquid bromine to generate tert-butyl-3- (2, 3-dibromopropyl) -3-hydroxyazetidine-1-formate; in the third step, tert-butyl-3- (2, 3-dibromopropyl) -3-hydroxyazetidine-1-carboxylate is reacted with potassium carbonate as a base to produce tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-carboxylate. The reaction formula is as follows:
in the process, the first step is as follows: the solvent is tetrahydrofuran and water, and the reaction temperature is 10-20 ℃; secondly, taking dichloromethane as a solvent, and reacting for 2 hours at the temperature of-30 to-10 ℃; in the third step, the solvent is acetonitrile and stirred overnight (12-16 hours) at 82 ℃.
The invention has the beneficial effects that: the reaction process is reasonable in design, 1-BOC-3-subunit-azetidine which is cheap and easy to obtain and can be produced in a large scale is adopted, tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-formic acid ester is synthesized through three steps, the synthesis cost is saved, and the large-scale production can be carried out.
Detailed Description
Example 1
Synthesis of tert-butyl 3-allyl-3-hydroxyazetidine-1-carboxylate
76 g of zinc powder is added into 1L of saturated ammonium chloride solution, 500 mL of tetrahydrofuran solution of 100 g of compound 1 and 300 mL of tetrahydrofuran solution of 142 g of allyl bromide are sequentially added into the reaction solution at 10 ℃, and the reaction solution 20 is obtained after the dropwise additionoC stirred overnight. The reaction was filtered, the filter cake was washed with 500 mL tetrahydrofuran, the aqueous phase was extracted four times with 500 mL ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 119 g of compound 2 as an oil in 95% yield.
Example 2
Synthesis of tert-butyl 3-allyl-3-hydroxyazetidine-1-carboxylate
1 g of compound 1 is dissolved in 10 mL of anhydrous tetrahydrofuran, 8 mL of 1M allyl Grignard reagent is slowly added dropwise at 0 ℃, the reaction solution is slowly heated to 20 ℃, and stirring is continued for 2 hours. After the reaction, the reaction solution was poured into a saturated ammonium chloride solution, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a silica gel column to obtain 1 g of pure product with a yield of 80%.
Synthesis of tert-butyl-3- (2, 3-dibromopropyl) -3-hydroxyazetidine-1-carboxylate
Compound 2 is dissolved in 1.2L of dichloromethane, -30oUnder C, 113 g of liquid bromine is added into the reaction system drop by drop, and after the dropwise addition is finished, the reaction solution is at-10 DEGoC, stirring for 2 hours. The reaction solution was poured into a 10% sodium sulfite solution by mass, the organic phase was separated, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3149 g of a compound, yield: 85 percent.
Synthesis of tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-carboxylic acid ester
100 g of Compound 3 in 1.7L of acetonitrile, 20o74 g of potassium carbonate was added to the reaction solution under the condition of C, and the reaction was heated to 82 ℃ and stirred overnight. The reaction mixture was concentrated to remove the solvent, 500 mL of water was added, and the mixture was extracted 4 times with 500 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 4 as a white solid in 80% yield.
H NMR (400MHz, CHLOROFORM-d) = 4.491-4.485 (m, 1 H), 4.451-4.444(m, 1 H), 4.4235-4.082 (m, 4 H), 3.927-3.903 (d,J= 9.6, 1 H), 2.611-2.578 (2H), 1.423 (s, 9H)。
Claims (4)
1. A preparation method of tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-formic acid ester is characterized by comprising the following steps: the method comprises the following steps: synthesizing by a 3-step method, namely, in the first step, taking 1-BOC-3-oxoidene-azetidine as a starting material and reacting with allyl bromide under the action of zinc powder; or directly reacting with an allyl Grignard reagent to produce 3-allyl-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester; secondly, reacting 3-allyl-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester with liquid bromine to generate tert-butyl-3- (2, 3-dibromopropyl) -3-hydroxyazetidine-1-formate; in the third step, tert-butyl-3- (2, 3-dibromopropyl) -3-hydroxyazetidine-1-carboxylate is reacted with potassium carbonate as a base to produce tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-carboxylate.
2. The process according to claim 1, wherein the tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-carboxylic acid ester is prepared by the following steps: the first step of the method is characterized in that a solvent is tetrahydrofuran and water, and the reaction temperature is 10-20 ℃.
3. The process according to claim 1, wherein the tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-carboxylic acid ester is prepared by the following steps: and step two, the solvent is dichloromethane, the reaction temperature is-30 to-10 ℃, and the reaction time is 2 hours.
4. The process for producing t-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-carboxylic acid ester according to claim 1, wherein: and thirdly, stirring the mixture at 82 ℃ overnight by using acetonitrile as a solvent.
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| CN202010428555.1A CN111533752A (en) | 2020-05-20 | 2020-05-20 | Preparation method of tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-formic acid ester |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113200997A (en) * | 2021-05-07 | 2021-08-03 | 上海合全医药有限公司 | Synthesis method of 2, 5-dioxa-8-azaspiro [3.5] nonane and salt thereof |
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| WO2009108827A1 (en) * | 2008-02-29 | 2009-09-03 | Wyeth | Fused tricyclic pyrazolo[1, 5-a]pyrimidines, methods for preparation and uses thereof |
| CN105732638A (en) * | 2016-01-22 | 2016-07-06 | 成都倍特药业有限公司 | Bruton tyrosine kinase inhibitor with spiro or bridge ring structure and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009108827A1 (en) * | 2008-02-29 | 2009-09-03 | Wyeth | Fused tricyclic pyrazolo[1, 5-a]pyrimidines, methods for preparation and uses thereof |
| CN105732638A (en) * | 2016-01-22 | 2016-07-06 | 成都倍特药业有限公司 | Bruton tyrosine kinase inhibitor with spiro or bridge ring structure and preparation method thereof |
Non-Patent Citations (3)
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| ANIRBAN KAR，等: "A facile access to natural and unnatural dialkylsubstituted maleic anhydrides", 《TETRAHEDRON LETTERS》 * |
| DAVID BONNAFFE，等: "5-Methoxy-pentono-1,4-lactones from (R)-2-Hydroxy-5-methoxy3-pentenoic Acid Obtained by Bioreduction of the 2-Oxo Acid", 《TETRAHEDRON》 * |
| ZHAOBIN WANG，等: "Catalytic Enantioselective Intermolecular Desymmetrization of Azetidines", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113200997A (en) * | 2021-05-07 | 2021-08-03 | 上海合全医药有限公司 | Synthesis method of 2, 5-dioxa-8-azaspiro [3.5] nonane and salt thereof |
| CN113200997B (en) * | 2021-05-07 | 2023-10-03 | 上海合全医药有限公司 | Synthesis method of 2, 5-dioxa-8-azaspiro [3.5] nonane and salt thereof |
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