CN110563664A - Method for preparing racemic (4AS,7S,7AS) -tert-butyl-7-hydroxy hexahydro-cyclopenta [ B ] [1,4] oxazine-4 (4AH) -formic acid ester - Google Patents
Method for preparing racemic (4AS,7S,7AS) -tert-butyl-7-hydroxy hexahydro-cyclopenta [ B ] [1,4] oxazine-4 (4AH) -formic acid ester Download PDFInfo
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- CN110563664A CN110563664A CN201910664471.5A CN201910664471A CN110563664A CN 110563664 A CN110563664 A CN 110563664A CN 201910664471 A CN201910664471 A CN 201910664471A CN 110563664 A CN110563664 A CN 110563664A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention aims to develop raceme (4AS,7S,7AS) -tert-butyl-7-hydroxy hexahydro cyclopentadiene [ B ]][1,4]Preparation of oxazine-4 (4AH) -formic acid ester. Mainly solves the technical problem that no synthesis method exists at present. The invention comprises seven steps, and the reaction formula is as follows:
Description
Technical Field
the invention relates to a method for synthesizing raceme (4AS,7S,7AS) -tert-butyl-7-hydroxyhexahydrocyclopentadiene [ B ] [1,4] oxazine-4 (4AH) -formic acid ester.
Background
The racemate (4AS,7S,7AS) -tert-butyl-7-hydroxyhexahydro-cyclopenta [ B ] [1,4] oxazine-4 (4AH) -formylate (CAS: 1932117-26-4) and related derivatives have wide application in medicinal chemistry and organic synthesis. At present, no industrialized synthesis report exists.
Disclosure of Invention
The invention aims to develop a method for synthesizing raceme (4AS,7S,7AS) -tert-butyl-7-hydroxyhexahydrocyclopenta [ B ] [1,4] oxazine-4 (4AH) -formic acid ester. Mainly solves the technical problem that no industrialized synthesis method exists at present.
The technical scheme of the invention is as follows: a method for preparing raceme (4AS,7S,7AS) -tert-butyl-7-hydroxy hexahydro cyclopentadiene [ B ] [1,4] oxazine-4 (4AH) -formic acid ester comprises the following steps, firstly, dissolving a compound 1 and cerium chloride in tetrahydrofuran aqueous solution, carrying out reduction reaction with sodium borohydride to obtain a compound 2, dissolving the compound 2 in tetrahydrofuran solution and a compound 3 in the presence of triphenylphosphine and diisopropyl azodicarboxylate to generate a compound 4, oxidizing double bonds of the compound 4 in dichloroethane by using m-chloroperoxybenzoic acid to form an epoxy compound 5, dissolving the compound 5 in tetrahydrofuran solution, adding tetrabutylammonium fluoride to remove protective groups on oxygen to obtain a compound 6 and a compound 6A, then adding sodium hydroxide into a mixed solution of tert-butyl alcohol, dichloromethane and water, obtaining a key compound 7, dissolving the compound 7 in N, N-dimethylformamide, adding potassium carbonate and thiophenol to remove p-nitrobenzenesulfonyl to obtain a compound 8, dissolving the compound 8 in methanol, adding potassium carbonate and tert-butyloxycarbonyl on di-tert-butyl dicarbonate to obtain a final product 9, wherein the reaction formula is as follows:
the first step is carried out at the temperature of 0-10 ℃ for 1 hour; secondly, stirring at room temperature overnight; thirdly, reacting for 4 hours at 50-60 ℃; fourth, reacting for 4 hours at room temperature; fifthly, reacting at 60 ℃ overnight; the latter two steps were both carried out overnight at room temperature.
the invention has the beneficial effects that: the invention provides a method for synthesizing raceme (4AS,7S,7AS) -tert-butyl-7-hydroxy hexahydro-cyclopenta [ B ] [1,4] oxazine-4 (4AH) -formic acid ester, which is not reported in documents and has a very high application prospect.
Detailed Description
The reaction formula of the invention is as follows:
Example 1: a. compound 1(100g, 1.22 mol) and cerium chloride (454 g, 1.22 mol) were dissolved in 1000 mL of a tetrahydrofuran solution and 500 mL of water, followed by addition of sodium borohydride (32 g, 0.854 mol) in portions at 0-10 ℃. After the addition was complete, stirring was continued for 1 hour. TLC (dichloromethane/methanol volume ratio = 20:1) showed the reaction was complete. To the reaction was added 100 mL of dilute hydrochloric acid and extracted with methyl tert-butyl ether to give crude compound 2.
b. Crude 2 (100g, 1.19 mol) was dissolved in tetrahydrofuran solution (1200 mL), and compound 3 (152 g, 0.42 mol), triphenylphosphine (467 g, 1.79 mol) and diisopropyl azodicarboxylate (361g, 1.79 mol) were added to the reaction and stirred at room temperature overnight. TLC (petroleum ether/ethyl acetate volume ratio = 5:1) indicated complete consumption of starting material. Concentration then gave crude product, which was isolated on column to give compound 4 (112 g, 22%).
c. Compound 4 (174 g, 0.408 mol) was dissolved in 1, 2-dichloroethane (1500 mL), m-chloroperoxybenzoic acid (177 g, 1.02 mol) was added to the solution, and the reaction was carried out at 50-60 ℃ for 4 hours, and TLC (petroleum ether/ethyl acetate volume ratio =1/1) indicated completion of the reaction. After the reaction (375 g) was quenched with sodium thiosulfate, the pH was adjusted to 7-8 with saturated potassium carbonate solution, extracted with dichloromethane, washed with salt, dried, filtered and concentrated to give crude compound 5.
d. Crude 5 (crede g, 0.816 mol) was dissolved in THF (3500 mL), tetrabutylammonium fluoride TBAF (318 g, 1.224 mol) was added, and the reaction was carried out at room temperature for 4 hours. TLC (petroleum ether/ethyl acetate ratio by volume = 1:1) showed the reaction was complete, concentrated, and column separated to give compounds 6 and 6A (1700 g, 67%).
e. Compound 6 and 6A (200 g, 0.61 mol) was dissolved in t-butanol, methylene chloride and water (1000 mL/1000 mL/500 mL), and then sodium hydroxide (98 g, 2.44 mol) was added to the reaction, followed by reaction at 60 ℃ overnight. TLC (petroleum ether/ethyl acetate ratio = 1:1 by volume) showed the reaction was complete, concentrated to give crude product, which was extracted with water and dichloromethane to give crude product 7.
f. Crude 7 was dissolved in N, N-dimethylformamide (500 mL), potassium carbonate (31 g, 0.23 mol) and thiophenol (25 g, 0.18 mol) were added, and the mixture was stirred at room temperature overnight. TLC (petroleum ether/ethyl acetate ratio = 1:1 by volume) showed the reaction was complete and concentrated to give crude 8.
j. Crude compound 8 (0.15 mol) was dissolved in methanol (500 mL) and potassium carbonate (41 g, 0.3 mol) di-tert-butyl dicarbonate (49 g, 0.23 mol) was added. The reaction was stirred at room temperature overnight. TLC (petroleum ether/ethyl acetate volume ratio = 1:1) showed the reaction was complete. Concentration gave the crude product, which was then extracted with dichloromethane by adding a defined volume of water, the organic phase was dried by spinning and separated on a silica gel column to give the desired product (1.1 g, 12%).
δ(CDCl3)= 4.525-4.105 (m, 4H), 3.725-3.215 (m, 3H), 2.376-2.167 (m, 2H), 1.916-1.711 (m, 2H), 1.463 (s, 9H)。
Claims (7)
1. A method for preparing racemic (4AS,7S,7AS) -tert-butyl-7-hydroxyhexahydrocyclopenta [ B ] [1,4] oxazine-4 (4AH) -formic acid ester is characterized in that: the method comprises the following steps: dissolving a compound 1 and cerium chloride in tetrahydrofuran aqueous solution to perform reduction reaction with sodium borohydride to obtain a compound 2, dissolving the compound 2 in the tetrahydrofuran solution and a compound 3 in the presence of triphenylphosphine and diisopropyl azodicarboxylate to generate a compound 4, oxidizing double bonds of the compound 4 into an epoxy compound 5 in dichloroethane by using m-chloroperoxybenzoic acid, dissolving the compound 5 in the tetrahydrofuran solution to remove protective groups on oxygen by adding tetrabutylammonium fluoride to obtain a compound 6 and a compound 6A, dissolving the compound 6 and the compound 6A in a mixed solution of tert-butyl alcohol, dichloromethane and water by adding sodium hydroxide to obtain a key compound 7, dissolving the compound 7 in N, adding potassium carbonate and thiophenol to obtain a compound 8 by removing p-nitrobenzenesulfonyl, seventhly, dissolving the compound 8 in methanol, adding potassium carbonate and tert-butyloxycarbonyl on di-tert-butyl dicarbonate to obtain a final product 9, wherein the reaction formula is as follows:
。
2. The process for producing a racemate (4AS,7S,7AS) -tert-butyl-7-hydroxyhexahydrocyclopenta [ B ] [1,4] oxazin-4 (4AH) -carboxylic acid ester according to claim 1, wherein: the first step is carried out at 0-10 ℃ for 1 hour.
3. The process for producing a racemate (4AS,7S,7AS) -tert-butyl-7-hydroxyhexahydrocyclopenta [ B ] [1,4] oxazin-4 (4AH) -carboxylic acid ester according to claim 1, wherein: the second step was carried out overnight at room temperature.
4. The process for producing a racemate (4AS,7S,7AS) -tert-butyl-7-hydroxyhexahydrocyclopenta [ B ] [1,4] oxazin-4 (4AH) -carboxylic acid ester according to claim 1, wherein: and the third step is that the reaction is carried out for 4 hours at 50-60 ℃.
5. The process for producing a racemate (4AS,7S,7AS) -tert-butyl-7-hydroxyhexahydrocyclopenta [ B ] [1,4] oxazin-4 (4AH) -carboxylic acid ester according to claim 1, wherein: the fourth step was carried out at room temperature for 4 hours.
6. The process for producing a racemic (4AS,7S,7AS) -tert-butyl-7-hydroxyhexahydrocyclopenta [ B ] [1,4] oxazin-4 (4AH) -carboxylic acid ester according to claim 1, wherein the fifth step comprises reacting at 60 ℃ overnight.
7. the process for producing a racemic (4AS,7S,7AS) -tert-butyl-7-hydroxyhexahydrocyclopenta [ B ] [1,4] oxazin-4 (4AH) -carboxylic acid ester according to claim 1, wherein the sixth and seventh steps are carried out overnight at room temperature.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910664471.5A CN110563664A (en) | 2019-07-23 | 2019-07-23 | Method for preparing racemic (4AS,7S,7AS) -tert-butyl-7-hydroxy hexahydro-cyclopenta [ B ] [1,4] oxazine-4 (4AH) -formic acid ester |
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| CN201910664471.5A CN110563664A (en) | 2019-07-23 | 2019-07-23 | Method for preparing racemic (4AS,7S,7AS) -tert-butyl-7-hydroxy hexahydro-cyclopenta [ B ] [1,4] oxazine-4 (4AH) -formic acid ester |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010057126A1 (en) * | 2008-11-14 | 2010-05-20 | Amgen Inc. | Pyridine and pyrimidine derivatives as phosphodiesterase 10 inhibitors |
| CN109796456A (en) * | 2019-01-24 | 2019-05-24 | 石家庄蒎格医药科技有限公司 | New anticancer compound and application thereof |
-
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- 2019-07-23 CN CN201910664471.5A patent/CN110563664A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010057126A1 (en) * | 2008-11-14 | 2010-05-20 | Amgen Inc. | Pyridine and pyrimidine derivatives as phosphodiesterase 10 inhibitors |
| CN109796456A (en) * | 2019-01-24 | 2019-05-24 | 石家庄蒎格医药科技有限公司 | New anticancer compound and application thereof |
Non-Patent Citations (5)
| Title |
|---|
| CA: "CAS-RN：1932117-26-4", 《REGISTRY》 * |
| HUGH NAKAMURA ET AL.: "Synthesis of CPZEN-45: Construction of the 1,4-Diazepin-2-one Core by the Cu-Catalyzed Intramolecular Amidation of a Vinyl Iodide", 《ORG. LETT.》 * |
| JHUMA BHADRA ET AL.: "Internal Oligoguanidinium-Based Cellular Transporter Enhances Antisense Efficacy of Morpholinos in In Vitro and Zebrafish Model", 《BIOCONJUGATE CHEMISTRY》 * |
| LORAND KISS ET AL.: "Substrate-dependent fluorinations of highly functionalized cycloalkanes", 《TETRAHEDRON》 * |
| QIHAI XU ET AL.: "Catalytic Enantioselective Synthesis of Guvacine Derivatives through [4+2] Annulations of Imines with α‑Methylallenoates", 《ORG. LETT.》 * |
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