CN113501828B - 2,8-dioxaspiro [4.5] decane-1-ketone, and preparation method and application thereof - Google Patents
2,8-dioxaspiro [4.5] decane-1-ketone, and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides 2,8-dioxaspiro [4.5] decan-1-one and a preparation method and application thereof, wherein the preparation method comprises the steps of adding a compound 1 into anhydrous tetrahydrofuran, cooling in an ice salt bath, slowly adding alkali under the protection of argon, dropwise adding a compound 2, and after dropwise adding is finished, heating for reaction; after the reaction is completed, extracting with ethyl acetate, and spin-drying to obtain a compound 3, wherein the alkali is preferably potassium tert-butoxide; adding the compound 3 and an acid catalyst into dichloromethane, stirring at room temperature, performing point-plate reaction completely, backwashing, filtering and spin-drying to obtain a compound 4, wherein the acid catalyst is preferably p-toluenesulfonic acid; the preparation method avoids using hazardous reagents such as bromopropylene, (lithium bis (trimethylsilyl) amide) and ozone, and is safer and more environment-friendly; the preparation method has mild reaction conditions, simple and convenient operation, high yield and stable process, and is more suitable for large-scale production; in addition, the method does not need low-temperature oxygen removal, and the reaction is easier to control.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to 2,8-dioxaspiro [4.5] decane-1-one, and a preparation method and application thereof.
Background
2,8-dioxaspiro [4.5] decan-1-one is an important organic synthetic raw material with bifunctional group, and is widely applied to the synthesis of medical intermediates, liquid crystal materials and pesticide intermediates.
The 2,8-dioxaspiro [4.5] decan-1-one is used as a raw material of a plurality of medical intermediates, and the intermediates can be used for synthesizing a plurality of medicaments, such as natural immunosuppressant FR901483 and antitumor alkaloid Pancratistin, and experiments prove that the intermediates have higher specific cytotoxic effect on 60 human cancer cell lines; ankeping (Vincristine) is named as aldehyde Vinblastine, and Vinblastine (Vinblastatine) is an antitumor botanical drug component; lycoramine (Lycoramine) is a drug acting on the nervous system, and antagonists of synthetic dopamine can treat schizophrenia; she Liqiu alkali has effects of exciting central nerve and increasing blood pressure, and can be used for treating facial paralysis, poliomyelitis sequelae, neurasthenia, vertigo, etc.
The alkyl cyclohexyl benzoate liquid crystal series has various excellent performances, is an important direction for the development of Twisted Nematic (TN) liquid crystal, and is also an important component for a high-grade liquid crystal mixing formula. The bifunctional group of 2,8-dioxaspiro [4.5] decan-1-one enables different groups to be conveniently extended, cyclohexyl is successfully embedded into long-chain liquid crystal molecules, is an important synthetic raw material and is used for synthesizing various high-grade liquid crystal molecules.
2,8-dioxaspiro [4.5] decan-1-one is also useful in the synthesis of synthetic insecticides. Such as total synthesis of Agarofuran sesquiterpene, which is a plant pesticide widely used for a long time and has a wide market prospect.
The patent WO2014159224 discloses a synthesis method of 2,8-dioxaspiro [4.5] decan-1-one, which adopts tetrahydropyran-4-carboxylic acid methyl ester as raw material, adopts easily spontaneous combustion LiHMDS [ (lithium bis (trimethylsilyl) amide) ] as alkali at-78 ℃, and reacts with high-toxicity reagent 3-bromopropylene, and the obtained product is subjected to ring closure at-78 ℃ in the presence of ozone and sodium borohydride to obtain the target compound.
The reaction conditions of the above route are harsh, the reaction is required to be carried out at a low temperature of-78 ℃, the whole process is difficult to control, and the method is not suitable for large-scale production; and various dangerous reagents are used in the reaction process, including high-toxicity bromopropylene, liHMDS needing strict waterproofing and toxic gas ozone.
Disclosure of Invention
Aiming at the defects in the prior art, the invention firstly aims at providing a preparation method of 2,8-dioxaspiro [4.5] decan-1-one, which is simple and convenient to operate and stable in process.
It is a second object of the present invention to provide 2,8-dioxaspiro [4.5] decan-1-one as described above.
The third object of the present invention is to provide the use of 2,8-dioxaspiro [4.5] decan-1-one as described above.
In order to achieve the above primary object, the solution of the present invention is:
in order to avoid the trial of high-toxicity reagents in the prior art, the tetrahydropyran-4-carboxylic acid methyl ester of a compound 1 is adopted as a raw material, and is dissociated in the presence of alkali to generate enol anions, so that the enol anions become nucleophilic reagents to attack 2- (2-bromoethoxy) tetrahydro-2H-pyran of a low-toxicity compound 2 and generate 4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) tetrahydro-2H-pyran-4-carboxylic acid methyl ester of a compound 3; in the reaction process, the compound 2 has an electron-withdrawing group, so that the self-reactivity is improved, the use of dangerous reagents and severe low-temperature conditions in the reaction process are avoided, the reaction operation is simplified, and the reaction safety is improved. Deprotecting the compound 3 in an acid catalyst, wherein a lone pair electron exists on the obtained hydroxyl oxygen, the lone pair electron attacks electron-deficient carbonyl carbon, and nucleophilic substitution reaction is carried out to lose one molecule of methanol, so that intramolecular ester exchange ring closing is realized, and a target compound 4 is obtained; the method has high reaction activity, does not need low temperature condition in the reaction process, does not use toxic gas, can obtain the target compound under the room temperature condition, and is more suitable for expanded production.
The specific synthetic route is shown as follows:
the method comprises the following specific steps:
(1) Adding the tetrahydropyran-4-carboxylic acid methyl ester of the compound 1 into anhydrous tetrahydrofuran, cooling the mixture to below-10 ℃ in an ice salt bath, slowly adding alkali under the protection of argon, and maintaining the temperature of a reaction system to be below-10 ℃ in the adding process. After the addition, stirring for 30min, dropwise adding 2- (2-bromoethoxy) tetrahydro-2H-pyran of the compound 2, and after the dropwise addition is finished, heating to 0 ℃ for reaction. Pouring the mixture into ice water after the reaction is completed, extracting the mixture by ethyl acetate, and performing spin drying to obtain 4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) tetrahydro-2H-pyran-4-carboxylic acid methyl ester of a compound 3;
(2) Adding 4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) tetrahydro-2H-pyran-4-carboxylic acid methyl ester of the compound 3 and an acid catalyst into dichloromethane, stirring at room temperature, completely carrying out a spot plate reaction, backwashing, filtering and spin-drying to obtain 2,8-dioxaspiro [4.5] decan-1-one of the compound 4.
Preferably, in the step (1), the base is one or more selected from potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.
Preferably, in step (1), the molar ratio of the tetrahydropyran-4-carboxylic acid methyl ester of the compound 1 to the base is 1 (1-2).
Preferably, in step (1), the reaction time is 2. + -. 0.1h.
Preferably, in the step (2), the acid catalyst is one or more selected from the group consisting of dilute hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid and p-toluenesulfonic acid.
Preferably, in step (2), the molar ratio of methyl 4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) tetrahydro-2H-pyran-4-carboxylate of compound 3 to acid catalyst is 1: (0.05-0.5).
Preferably, in step (2), the stirring time is 12. + -. 0.1h.
In order to achieve the second objective, the solution of the invention is:
2,8-dioxaspiro [4.5] decan-1-one obtained by the preparation method.
In order to achieve the third object, the solution of the invention is:
an application of 2,8-dioxaspiro [4.5] decane-1-ketone as an intermediate.
Due to the adoption of the scheme, the invention has the beneficial effects that:
firstly, the preparation method avoids using hazardous reagents such as bromopropylene, liHMDS, ozone and the like, and is safer and more environment-friendly.
Secondly, the preparation method is simple to operate, mild in condition, high in yield, stable in process and more suitable for large-scale production; in addition, low-temperature and oxygen-free conditions are not needed, and the reaction is easier to control.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 2,8-dioxaspiro [4.5] decan-1-one in example of the present invention.
Detailed Description
The invention provides 2,8-dioxaspiro [4.5] decane-1-one, a preparation method and application thereof.
The present invention will be further described with reference to the following examples.
Example 1:
the preparation method of 2,8-dioxaspiro [4.5] decan-1-one of this example comprises the following steps:
(1) 1000g of tetrahydropyran-4-carboxylic acid methyl ester of a compound 1 is added into 5L of anhydrous tetrahydrofuran, an ice salt bath is cooled to below-10 ℃, 856g of potassium tert-butoxide (t-BuOK) (1.1 eq) are slowly added under the protection of argon, after stirring for 30min, 1450g of 2- (2-bromoethoxy) tetrahydro-2H-pyran of a compound 2 (1 eq) is added dropwise, after the dropwise addition is finished, the temperature is raised to 0 ℃ for reaction for 2H, the TLC (thin layer chromatography) is completely reacted and poured into ice water, ethyl acetate is extracted (1L) 3, saturated saline is backwashed, anhydrous sodium sulfate is dried, and the mixture is dried in a spinning mode to obtain 1775.5g of 4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) tetrahydro-2H-pyran-4-carboxylic acid methyl ester of a compound 3, wherein the yield is 92% and the purity is 98%.
(2) 1740g of methyl 4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) tetrahydro-2H-pyran-4-carboxylate of Compound 3 and 110g of p-toluenesulfonic acid hydrate (0.1 eq) were added to 5L of methylene chloride, stirred at room temperature for 12H, the reaction was complete, the aqueous potassium carbonate solution was backwashed 3 times until the p-toluenesulfonic acid was removed, the organic phase was dried over anhydrous magnesium sulfate, and filtered and spin-dried to give 838g of 2,8-dioxaspiro [4.5] decan-1-one of the title compound 4 in 84% yield and 98.3% purity.
As shown in FIG. 1, nuclear magnetism of 2,8-dioxaspiro [4.5] decan-1-one of example 1:
1 H NMR(400MHz,CDCl 3 )δ4.37-4.22(m,2H),4.04-3.88(m,2H),3.60-3.46(m,2H),2.23(dd,J＝9.1,5.1Hz,2H),1.98(ddd,J＝13.7,8.6,3.7Hz,2H),1.58-1.43(m,2H)。
in order to obtain favorable conditions for synthesizing 2,8-dioxaspiro [4.5] decan-1-one, the invention further studies the influence of the change of reaction conditions in each reaction step on the yield of the reaction product in the step, and intensively discusses key influencing factors of the compounds 1 to 3 in the reaction step (1) and the compounds 3 to 4 in the reaction step (2).
In the step (1), the yield was different when the base composition and the equivalent were different, as shown in table 1.
TABLE 1
| Serial number | Alkali | Equivalent (eq) | Yield (%) |
| Example 1 | Potassium tert-butoxide | 1.1 | 92 |
| Example 2 | Sodium methoxide | 1.1 | 62 |
| Example 3 | Sodium ethoxide | 1.1 | 65 |
| Example 4 | Potassium carbonate | 1.1 | 51 |
| Example 5 | Sodium tert-butoxide | 1.1 | 75 |
| Example 6 | Potassium tert-butoxide | 1 | 87 |
| Example 7 | Potassium tert-butoxide | 1.5 | 82 |
| Example 8 | Potassium tert-butoxide | 2 | 74 |
Examples 2 to 5, compared with example 1, different alkali components were used for the reaction, and the reaction results show that potassium tert-butoxide has better reactivity than sodium methoxide, sodium ethoxide, potassium carbonate and sodium tert-butoxide, so that compound 1 is easier to form enol anions. Examples 6 to 8, compared with example 1, the amount of potassium tert-butoxide used in step 1 was changed, and the reaction results showed that increasing or decreasing the amount of potassium tert-butoxide used in example 1 resulted in a decrease in the reaction yield.
In step (2), when the components and the equivalent of the acid catalyst were different, the yield was also different as shown in table 2.
TABLE 2
Examples 9 to 11, comparative example 1, reactions with different acid catalysts were carried out; the reaction result shows that the p-toluenesulfonic acid has better catalytic activity than dilute hydrochloric acid, dilute sulfuric acid and dilute phosphoric acid. Further, comparative examples 12 to 14 further discuss the amount of p-toluenesulfonic acid used; the reaction results show that on the basis of the example 1, increasing the dosage promotes the occurrence of side reactions, so that the reaction yield is reduced; reducing the amount of the catalyst reduces the reaction rate, so that the reaction yield is reduced under the same reaction time.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments and the generic principles defined herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments. Those skilled in the art should appreciate that many modifications and variations are possible in light of the above teaching without departing from the scope of the invention.
Claims (3)
1. A preparation method of 2,8-dioxaspiro [4.5] decan-1-one is characterized in that: the synthetic route is as follows:
the method comprises the following specific steps:
(1) Adding tetrahydropyran-4-carboxylic acid methyl ester of a compound 1 into anhydrous tetrahydrofuran, cooling an ice salt bath to below-10 ℃, adding alkali at constant temperature under the protection of argon, stirring for 30min after adding, then dropwise adding 2- (2-bromoethoxy) tetrahydro-2H-pyran of a compound 2, heating to 0 ℃ after completing dropwise adding, reacting completely, pouring into ice water, extracting with ethyl acetate, and spin-drying to obtain 4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) tetrahydro-2H-pyran-4-carboxylic acid methyl ester of a compound 3;
(2) Adding 4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) tetrahydro-2H-pyran-4-carboxylic acid methyl ester of compound 3 and an acid catalyst into dichloromethane, stirring at room temperature, completely carrying out a point plate reaction, carrying out backwashing, filtering and spin-drying to obtain 2,8-dioxaspiro [4.5] decan-1-one of compound 4;
in the step (1), the alkali is selected from more than one of potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide;
in the step (1), the reaction time is 2 +/-0.1 h;
in the step (2), the acid catalyst is selected from more than one of dilute hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid and p-toluenesulfonic acid;
in the step (2), the molar ratio of the methyl 4- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) tetrahydro-2H-pyran-4-carboxylate of the compound 3 to the acid catalyst is 1: (0.05-0.5).
2. The process of claim 1 for the preparation of 2,8-dioxaspiro [4.5] decan-1-one, wherein: in the step (1), the mole ratio of the tetrahydropyran-4-carboxylic acid methyl ester of the compound 1 to the base is 1 (1-2).
3. The process of claim 1 for the preparation of 2,8-dioxaspiro [4.5] decan-1-one, wherein: in the step (2), the stirring time is 12 +/-0.1 h.
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| WO2014139326A1 (en) * | 2013-03-13 | 2014-09-18 | Genentech, Inc. | Pyrazolo compounds and uses thereof |
| WO2014159224A1 (en) * | 2013-03-14 | 2014-10-02 | Chdi Foundation, Inc. | Histone deacetylase inhibitors and compositions and methods of use thereof |
| CN107663185A (en) * | 2017-11-14 | 2018-02-06 | 安徽华胜医药科技有限公司 | A kind of synthetic method of butyrolactone derivative |
| CN107690430A (en) * | 2015-05-29 | 2018-02-13 | 巴斯夫欧洲公司 | The method for manufacturing cyclic ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014139326A1 (en) * | 2013-03-13 | 2014-09-18 | Genentech, Inc. | Pyrazolo compounds and uses thereof |
| WO2014159224A1 (en) * | 2013-03-14 | 2014-10-02 | Chdi Foundation, Inc. | Histone deacetylase inhibitors and compositions and methods of use thereof |
| CN107690430A (en) * | 2015-05-29 | 2018-02-13 | 巴斯夫欧洲公司 | The method for manufacturing cyclic ester |
| CN107663185A (en) * | 2017-11-14 | 2018-02-06 | 安徽华胜医药科技有限公司 | A kind of synthetic method of butyrolactone derivative |
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