CN106928244B - A kind of preparation method of 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane - Google Patents
A kind of preparation method of 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane Download PDFInfo
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- CN106928244B CN106928244B CN201710066759.3A CN201710066759A CN106928244B CN 106928244 B CN106928244 B CN 106928244B CN 201710066759 A CN201710066759 A CN 201710066759A CN 106928244 B CN106928244 B CN 106928244B
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- 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 present invention relates to 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane preparation methods, it is low mainly to solve the production not perfect rate of route in existing synthesis technology, reaction is not easy to control, the technical problems such as experimental implementation inconvenience, the present invention prepares 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane using 2- nitrogen-tertbutyloxycarbonyl -7- carbonyl -5- oxygen-spiral shell [3.4] octane -8- Ethyl formate as starting material, by three-step reaction.Reaction equation is as follows:
Description
Technical field
The present invention relates to 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane synthetic methods.
Background technique
2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane and relevant derivative in pharmaceutical chemistry and
There is important application in organic synthesis, there is fabulous prospect.But at present there is no complete synthetic route reports.Therefore, one is developed
Cheap raw material is easy to get, easy to operate, and reaction is easy to produce in batches control, the suitable great meaning of synthetic method of overall yield.
Summary of the invention
It is a kind of cheap with raw material the purpose of the present invention is developing, it is easy to operate, it can amplify, three step higher yields 2-
Nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane preparation method.Mainly solving the compound at present does not have
The technical issues of suitable for industrialized process for preparing.
A kind of technical solution of the present invention: system of 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane
Preparation Method, comprising the following steps: synthesized using 3 footworks, the first step, with 2- nitrogen-tertbutyloxycarbonyl -7- carbonyl -5- oxygen-spiral shell
[3.4] octane -8- Ethyl formate obtains 2- nitrogen-tertiary butyloxycarbonyl by trifyl on trifluoromethanesulfanhydride anhydride for starting material
Base -7- trifluoro methylsulfonyl oxygen -5- oxygen-spiral shell [3.4] octane -8- Ethyl formate；Second step, 2- nitrogen-tertbutyloxycarbonyl -7- fluoroform
Sulphonyl oxygen -5- oxygen-spiral shell [3.4] octane -8- Ethyl formate restores under 10% palladium carbon and hydrogen atmosphere and obtains 2- nitrogen-tertiary butyloxycarbonyl
Base -5- oxygen-spiral shell [3.4] octane -8- Ethyl formate；Third step, 2- nitrogen-tertbutyloxycarbonyl -5- oxygen-spiral shell [3.4] octane -8- formic acid
2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell can be obtained by adding lithium borohydride or Lithium Aluminium Hydride to be stirred to react in ethyl ester
[3.4] octane；Reaction equation is as follows:
In above-mentioned technique, step 1: solvent is anhydrous methylene chloride, reaction temperature is 0-20 DEG C；Second step, solvent are second
Alcohol, reaction temperature are 30 DEG C, and the reaction time is 6 hours；Third step, solvent are anhydrous tetrahydro furan, and reaction temperature is 0-80 DEG C,
Reaction time 1 hour.
Beneficial effects of the present invention: rationally, which employs cheap and easy to get, energy large-scale productions for reaction process design of the present invention
Raw material -2- nitrogen-tertbutyloxycarbonyl -7- carbonyl -5- oxygen-spiral shell [3.4] octane -8- Ethyl formate, synthesized 2- by three steps
Nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane, has saved synthesis cost, and can be produced on a large scale.
Specific embodiment
Nitrogen-tertbutyloxycarbonyl -7- trifluoro methylsulfonyl oxygen -5- oxygen-spiral shell [3.4] octane -8- Ethyl formate synthesis
100 gram 1 is added in 500 milliliters of dichloromethane solutions, room temperature adds 50 grams of triethylamines, and fluoroform is added dropwise at 0 DEG C
Yellow acid acid anhydride simultaneously stirs 1 hour at 20 DEG C, after reaction, adds water (1.0 L) at 0 DEG C of reaction system, methylene chloride (500
ML*2), organic phase anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give 2 yellow oil of compound, yield: 98%.
The synthesis of nitrogen-tertbutyloxycarbonyl -5- oxygen-spiral shell [3.4] octane -8- Ethyl formate
100 g of compound 2 are dissolved in 1.5 liters of ethanol solutions, at 30 DEG C plus 20 gram of 10% palladium carbon, 30 DEG C of stirrings 6 are small
When.Reaction solution is filtered with diatomite after reaction, filtrate decompression is concentrated to get yellow oil, crude product is obtained, yield:
98%.
Embodiment 1
The synthesis of 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane
5 g of compound 3 are dissolved in 50 milliliters of anhydrous tetrahydrofuran solutions, add 0.67 gram of Lithium Aluminium Hydride at 0 DEG C in batches,
0.67 milliliter of water of dropwise addition after being stirred 1 hour at 20 DEG C, mass percentage concentration 10% sodium hydroxide, 0.67 milliliter of solution quenching reaction,
Add sodium sulphate dry, organic phase is concentrated under reduced pressure to give crude product, and silica gel column purification obtains product, yield: 40%.
Embodiment 2
The synthesis of 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane
5 g of compound 3 are dissolved in 50 milliliters of anhydrous tetrahydrofuran solutions, at 0 DEG C in batches plus 0.6 gram of lithium borohydride, 0
Ammonium chloride saturated solution (100 mL) quenching reaction is added dropwise after stirring 1 hour at DEG C, methylene chloride extracts (50 mL*3), organic
Phase anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product, and silica gel column purification obtains product, yield: 90%.
Embodiment 3
The synthesis of 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane
5 g of compound 3 are dissolved in 50 milliliters of anhydrous tetrahydrofuran solutions, add 0.6 gram of lithium borohydride at 0 DEG C in batches,
Ammonium chloride saturated solution (100 mL) quenching reaction is added dropwise after stirring 1 hour at 20 DEG C, methylene chloride extracts (50 mL*3), has
Machine phase anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product, and silica gel column purification obtains product, yield: 70%.
Embodiment 4
The synthesis of 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane
5 g of compound 3 are dissolved in 50 milliliters of anhydrous tetrahydrofuran solutions, add 0.6 gram of lithium borohydride at 20 DEG C in batches,
Ammonium chloride saturated solution (100 mL) quenching reaction is added dropwise after stirring 1 hour at 80 DEG C, methylene chloride extracts (50 mL*3), has
Machine phase anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product, and silica gel column purification obtains product, yield: 25%.
1H-NMR (MeOD): 4.05 (m, 1H), 3.81 (m, 1H), 3.81-3.87 (m, 4H), 1.94-
1.69 (m, 3H), 1.38 (s, 9H)。
Claims (4)
1. a kind of 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane preparation method, characterized in that including
Following steps: it is synthesized using 3 footworks, the first step, with 2- nitrogen-tertbutyloxycarbonyl -7- carbonyl -5- oxygen-spiral shell [3.4] octane -8- first
Acetoacetic ester obtains 2- nitrogen-tertbutyloxycarbonyl -7- trifluoro methylsulphur by trifyl on trifluoromethanesulfanhydride anhydride for starting material
Acyl-oxygen -5- oxygen-spiral shell [3.4] octane -8- Ethyl formate；Second step, 2- nitrogen-tertbutyloxycarbonyl -7- trifluoro methylsulfonyl oxygen -5- oxygen -
Spiral shell [3.4] octane -8- Ethyl formate restores under 10% palladium carbon and hydrogen atmosphere obtains 2- nitrogen-tertbutyloxycarbonyl -5- oxygen-spiral shell
[3.4] octane -8- Ethyl formate；Third step, 2- nitrogen-tertbutyloxycarbonyl -5- oxygen-spiral shell [3.4] octane -8- Ethyl formate is by adding
Lithium borohydride or Lithium Aluminium Hydride, which are stirred to react, can be obtained 2- nitrogen-tertbutyloxycarbonyl -8- (methylol) -5- oxygen-spiral shell [3.4] octane.
2. a kind of 2- nitrogen according to claim 1-tertbutyloxycarbonyl-8- (methylol)-5- oxygen-spiral shell [3.4] octane system
Preparation Method, it is characterized in that: first step solvent be anhydrous methylene chloride, 0-20 DEG C of reaction temperature.
3. a kind of 2- nitrogen according to claim 1-tertbutyloxycarbonyl-8- (methylol)-5- oxygen-spiral shell [3.4] octane system
Preparation Method, it is characterized in that: second step solvent is ethyl alcohol, reaction temperature is 30 DEG C, and the reaction time is 6 hours.
4. a kind of 2- nitrogen according to claim 1-tertbutyloxycarbonyl-8- (methylol)-5- oxygen-spiral shell [3.4] octane system
Preparation Method, it is characterized in that: third step solvent is anhydrous tetrahydro furan, reaction temperature is 0-80 DEG C, the reaction time 1 hour.
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