CN103319493B - A kind of method of synthesizing 1-methylol-3-hydrogen-2-oxa-diamantane and derivative thereof - Google Patents
A kind of method of synthesizing 1-methylol-3-hydrogen-2-oxa-diamantane and derivative thereof Download PDFInfo
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- CN103319493B CN103319493B CN201210072719.7A CN201210072719A CN103319493B CN 103319493 B CN103319493 B CN 103319493B CN 201210072719 A CN201210072719 A CN 201210072719A CN 103319493 B CN103319493 B CN 103319493B
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Abstract
The present invention relates to a kind of method of synthesizing 1-methylol-3-hydrogen-2-oxa-diamantane and derivative thereof, the method with 7-methylene radical two ring-[3.3.1]-nonane-3-ketone (I) for raw material is through sodium borohydride reduction, the intermediate (II) obtained is without the need to purifying, namely direct and metachloroperbenzoic acid reaction obtains 1-methylol-3-hydrogen-2-oxa-diamantane and derivative (III) thereof, and its reaction formula is as follows:
Description
Technical field
The present invention relates to a kind of method of synthesizing 1-methylol-3-hydrogen-2-oxa-diamantane and derivative thereof.
Background technology
Diamantane is a kind of cage mounted stable hydrocarbon.The rigidity system had due to it and high symmetrical structure determine the physicochemical property of its uniqueness.Diamantane and derivative thereof are all widely used in various fields such as medicine, agricultural chemicals, functional polymer, tensio-active agent, sensitive materialss.This compounds is mainly used in anti-influenza type A virus in medical, along with going deep into of research, finds that adamantane derivative has multiple biological activity.Alcohols in diamantane is a member important in adamantane compound, and it is the precursor of the multiple high-activity drug synthesis such as adapalene and Rimantadine, for the prevention and therapy of A type influenza.
1-methylol-3-hydrogen-2-oxa-the diamantane that the present invention relates to, it contain active function groups methylol, can as the Module-embedding of new drug development in potential drug compound, for transforming existing medicines structure, or for exploring the structure activity relationship of drug candidate body in new drug development.Because of but a kind of important new drug development template or intermediate.
At present, the method of bibliographical information synthesis oxa-adamantane compound mainly contains following several method, under the acidic conditions of epoxy ketone, cyclisation (such as: Tetrahedron, 1997,3467), the nucleophilic reagent cyclisation of diketone (such as: Tetrahedron66 (2010) 7399-7404; Tetrahedron, Vol.52, No.16, pp.5867-5880,1996etc), the metal catalytic cyclisation of enol is (such as: J.Org.Chern., Vol.38, No.20,19733462-3466; JournalofOrganometallicChemistry, 292 (1985) 93-104) and the nucleophilic reagent cyclisation (such as: Synlett2008,405 – 409) of epoxy ketone.
The synthetic method of current bibliographical information synthesis 1-methylol-2-oxa-adamantane compound is also very limited, and 3-position does not have the synthesis of substituent 1-methylol-2-oxa-adamantane compound to yet there are no report.Last example above-mentioned is a kind of wherein method (Synlett2008,405 – 409) of 1-methylol-2-oxa-adamantane compound of synthesizing 3-and replacing, and its reaction formula is as follows:
This route is from ketenes, and metachloroperbenzoic acid epoxidation, closes ring and obtain 3-position methyl substituted 1-methylol-2-oxa-adamantane compound while the carbonyl of grignard reagent attack subsequently.The method is that the negative oxygen ion serialization attack epoxy construction produced after grignard reaction obtains product, and the shortcoming of the method 3-position to have substituting group (as methyl, vinyl etc.).3-position cannot be synthesized without the 1-methylol-3-hydrogen-2-oxa-adamantane compound replaced by method above.
Summary of the invention
The object of this invention is to provide a kind of method of synthesizing 1-methylol-3-hydrogen-2-oxa-diamantane.
For realizing object of the present invention, technical scheme of the present invention is:
Synthesize a method for 1-methylol-3-hydrogen-2-oxa-diamantane and derivative thereof, it is characterized in that, comprise the following steps:
(1) 7-methylene radical two ring-[3.3.1]-nonane-3-ketone (I) and sodium borohydride, in acid solvent, generate 7-methylene radical two ring-[3.3.1]-nonane-3-alcohol (II)-15 DEG C to 50 DEG C reactions; Wherein, R is selected from: hydrogen, C
1-C
6alkyl, aromatic base, benzyl, alkoxyl group;
(2) 7-methylene radical two ring-[3.3.1]-nonane-3-alcohol (II) and metachloroperbenzoic acid, in acid solvent, at-15 DEG C at 50 DEG C, reaction generates epoxide, then, under acidic conditions effect, epoxide open loop also cyclisation simultaneously obtains 1-methylol-3-hydrogen-2-oxa-diamantane (III);
Its reaction formula is as follows:
The different positions of substituent R on diamantane ring outside 1-, 2-or 3-position.
In the preferred embodiment of the present invention, the acid solvent in step (1) and step (2) is selected from alcohols, ethers, ester class or halogenated hydrocarbon solvent.
In the preferred embodiment of the present invention, the temperature of reaction in described step (2) is 0 DEG C ~ 50 DEG C.
The method of this synthesis 1-methylol-3-hydrogen-2-oxa-diamantane (III) is easy and simple to handle, and productive rate is high.
Embodiment
Below in conjunction with specific embodiment, illustrate the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition." room temperature " represents the temperature between 16 DEG C to 25 DEG C, unless stated otherwise.
Embodiment 1:
1.1 synthesis 7-methylene radical two ring-[3.3.1]-nonane-3-alcohol
By compound 7-methylene radical two ring-[3.3.1]-nonane-3-ketone (14g, 93mmol) be dissolved in THF/MeOH (100mL/20mL), ice-water bath is cooled to less than 10 DEG C, slowly divide 5 batches and add sodium borohydride (6g, 158mmol), add rear reaction and be warming up to stirring at room temperature 5 hours.Be spin-dried for, with ethyl acetate/water (200mL/100mL) dilution, organic phase separates rear anhydrous sodium sulfate drying, is spin-dried for obtain crude product 14g, and this thick product is directly used in the next step.
1.2 synthesis 1-methylol-2-oxa-diamantane
Compound 7-methylene radical two ring-[3.3.1]-nonane-3-alcohol is dissolved in methylene dichloride (250mL), cool to 0 DEG C, divide 5 batches and add metachloroperbenzoic acid (37.3g, 184mmol), allow after adding to be warmed up to room temperature, stirring is spent the night.TLC detection reaction terminates, and is cooled to 0 DEG C, and filter, the cold methylene dichloride (100mL) of filter cake washs.The organic phase merged uses saturated sodium thiosulfate solution washing successively, saturated sodium carbonate washs, saturated common salt water washing, anhydrous sodium sulfate drying, filtering and concentrating is to dry, faint yellow oily compound 1-methylol-2-oxa-diamantane (6.3g, the total recovery of (1) and (2) step is 40%) is obtained with silica gel column chromatography.
1HNMR(400Hz，CDCl
3)δppm:4.05～4.10(m，1H)，3.29～3.31(d，2H)，2.09～2.15(m，3H)，1.72～1.92(m，6H)，1.47(d，2H)，1.57(d，2H)。
MS-ESI: theoretical value .168; Actual value: 169.1 (M+H); 191.1 (M+Na).
Claims (1)
1. synthesize a method for 1-methylol-3-hydrogen-2-oxa-diamantane, it is characterized in that, comprise the following steps:
(1) 7-methylene radical two ring-[3.3.1]-nonane-3-ketone (I) and sodium borohydride, in acid solvent, generate 7-methylene radical two ring-[3.3.1]-nonane-3-alcohol (II)-15 DEG C to 50 DEG C reactions;
(2) 7-methylene radical two ring-[3.3.1]-nonane-3-alcohol (II) and metachloroperbenzoic acid, in acid solvent, epoxy compounds is generated-15 DEG C to 50 DEG C reactions, then, under acidic conditions effect, epoxide open loop also cyclisation simultaneously obtains 1-methylol-3-hydrogen-2-oxa-diamantane (III); Wherein, R is selected from: H;
Its reaction formula is as follows:
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1280560A (en) * | 1997-12-05 | 2001-01-17 | 阿斯特拉曾尼卡英国有限公司 | Adamantane derivatives |
| US20070232838A1 (en) * | 2004-06-24 | 2007-10-04 | Yoshiharu Iwabuchi | Alcohol Oxidation Catalyst and Method of Synthesizing the Same |
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2012
- 2012-03-19 CN CN201210072719.7A patent/CN103319493B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1280560A (en) * | 1997-12-05 | 2001-01-17 | 阿斯特拉曾尼卡英国有限公司 | Adamantane derivatives |
| US20070232838A1 (en) * | 2004-06-24 | 2007-10-04 | Yoshiharu Iwabuchi | Alcohol Oxidation Catalyst and Method of Synthesizing the Same |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis of 7-Hydroxymethyl-7-hydroxybicyclo[3,3,1]nonan-3-one and Its Ttransformation Leading to 1-Hydroxy-4-protoadamantanone;Wang Ya lou，等;《HECHENG HUAXUE》;19990331;第7卷(第1期);第86-89页 * |
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