CN113402425A - Preparation method of high-purity tert-butyl carbazole - Google Patents
Preparation method of high-purity tert-butyl carbazole Download PDFInfo
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- CN113402425A CN113402425A CN202110670667.2A CN202110670667A CN113402425A CN 113402425 A CN113402425 A CN 113402425A CN 202110670667 A CN202110670667 A CN 202110670667A CN 113402425 A CN113402425 A CN 113402425A
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Abstract
The invention relates to the technical field of drug synthesis, in particular to a preparation method of high-purity tert-butyl carbazole, which comprises the following steps: dissolving hydrazine hydrate in alcohol or ether solvent, and adding inorganic acid or organic acid to generate hydrazine hydrate mono-acid salt; condensing hydrazine hydrate mono-acid salt and di-tert-butyl dicarbonate, neutralizing with alkali after the reaction is finished, extracting with a solvent, concentrating, and crystallizing with a weak-polarity solvent to obtain a tert-butyl carbazole product. The preparation method of tert-butyl carbazole provided by the invention can obtain a high-purity product (not less than 99.5%), has high yield (not less than 90%), is simple to operate, and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of high-purity tert-butyl carbazole.
Background
tert-Butyl carbazole (tert-Butyl carbazole), also known as tert-Butyl carbazate, tert-Butyl carbalate, and the like. It can be used as a starting material for the preparation of tert-butoxycarbonyl-azide, a reagent that introduces a tert-butoxycarbonylamino group protection; can also be used as a reagent for synthesizing sulfonyl hydrazide and carboxyl hydrazide; the compound is used for carrying out palladium-catalyzed cross-coupling reaction with vinyl halide to generate N-tert-butyloxycarbonyl-N-alkenyl hydrazine; reagents for solid phase polypeptide synthesis and optical purity determination of alpha-aminoaldehydes; can be condensed with aldehyde to form hydrazone which can be used as an intermediate for synthesizing the HIV-1 protease inhibitor. Can be widely applied to the industries of medicines, high molecular compounds and dyes.
The preparation methods of tert-butyl carbazole reported in the literature at present mainly include the following methods:
the method comprises the following steps: louis A.Carpino uses sodium tert-butoxide to react with carbonyl sulfide to obtain (O) -tert-butoxy sodium thiosulfate, then reacts with methyl iodide to generate methylthio formic acid tert-butyl ester, and then reacts with hydrazine hydrate to obtain tert-butyl carbazole. (Carpino, Louis A. New amino-protecting groups in organic synthesis [ J ]. Accounts of Chemical Research,1973,6(6):191-198.) the synthetic route is used for the first time to prepare the tertiary butyl carbazole and is applied to the protection process of amino groups, but the synthetic process has the requirements of high price of medicines, overlong reaction time and other conditions, only can prepare small-batch products, and is difficult to realize industrialization.
The method 2 comprises the following steps: PCT International publication No. WO2001040163A1 reports that tert-butyl chloride is obtained by reacting sodium tert-butoxide with triphosgene, and hydrazine hydrate is reacted to obtain tert-butylcarbazole. The reaction process of the synthetic route can generate highly toxic phosgene, phosgene leakage is easy to generate, the process safety risk is higher, and the requirement on the tightness of process equipment is higher.
The method 3 comprises the following steps: tert-butyl phenoxyformate is obtained by condensation of phenyl chloroformate with tert-butanol and then with hydrazine hydrate to obtain tert-butyl carbazole, (Organic Synthesis, col. Vol.5, p.166(1973) Vol.44, p.20 (1964)). This route uses phenyl chloroformate, which is relatively expensive, and produces phenol as a by-product that is difficult to remove.
The method 4 comprises the following steps: reacting ethyl chloroformate with tert-butyl alcohol to generate tert-butyl ethoxyformate, and reacting with hydrazine hydrate to obtain tert-butyl carbazole. The ethyl chloroformate used in this route is a highly toxic article regulated by the police department.
The method 5 comprises the following steps: the chinese patent publication No. CN101823986A discloses a method for obtaining tert-butyl carbazole by directly reacting di-tert-butyl dicarbonate with hydrazine hydrate, the route is simple, and the used raw material di-tert-butyl dicarbonate has better safety. However, the process of the patent has the disadvantages that the purity of the obtained product is not high, and the product has a byproduct of di-tert-butyl azidodicarboxylate impurity which is difficult to remove.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a preparation method of tertiary butyl carbazole, which has higher product purity and simple and easily obtained raw materials.
The technical scheme for solving the technical problems is as follows:
a preparation method of high-purity tert-butyl carbazole comprises the following steps:
(1) dissolving hydrazine hydrate in alcohol or ether solvent, and adding inorganic acid or organic acid to generate hydrazine hydrate mono-acid salt;
(2) condensing hydrazine hydrate mono-acid salt and di-tert-butyl dicarbonate, neutralizing with alkali after the reaction is finished, extracting with a solvent, concentrating, and crystallizing with a weak-polarity solvent to obtain a tert-butyl carbazole product.
Preferably, the alcohol or ether solvent in step (1) is selected from methanol, ethanol, tert-butanol or ethylene glycol dimethyl ether.
Preferably, the mass ratio of hydrazine hydrate to solvent in the step (1) is 1: 1-5; further, preferably, the mass ratio of hydrazine hydrate to solvent in the step (1) is 1: 1 to 2.
Preferably, the inorganic acid in the step (1) is selected from one or more of hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid is selected from one or more of formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, citric acid and the like.
Preferably, the molar ratio of hydrazine hydrate to inorganic acid or organic acid in the step (1) is 1:0.5 to 1.5; further, the molar ratio of hydrazine hydrate to inorganic acid or organic acid in the step (1) is 1: 1.0 to 1.2; further, the molar ratio of hydrazine hydrate to inorganic acid or organic acid in the step (1) is 1: 1.0 to 1.05.
Preferably, the molar ratio of the hydrazine hydrate mono-acid salt to the di-tert-butyl dicarbonate in the step (2) is 1: 0.4-0.8; further, the molar ratio of the hydrazine hydrate mono-acid salt to the di-tert-butyl dicarbonate is 1: 0.5-0.6. The molar amount of the hydrazine hydrate mono-acid salt is calculated according to the feeding amount of the hydrazine hydrate in the step (1).
The temperature of the dropwise adding of the di-tert-butyl dicarbonate is controlled to be 0-20 ℃, and the dropwise adding time is 0.5-4 hours; further, the temperature of the dropwise adding of the di-tert-butyl dicarbonate is controlled to be 5-10 ℃, and the dropwise adding time is 1-2 hours.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.
The preparation method of tert-butyl carbazole provided by the invention can obtain a high-purity product (not less than 99.5%), has high yield (not less than 90%), is simple to operate, and is suitable for industrial large-scale production.
Drawings
FIG. 1 is a hydrogen spectrum of t-butylcarbazole obtained according to the embodiment of the present invention.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
adding 350g (molecular weight is 50.1, 5.6mol) of 80% hydrazine hydrate and 444g of methanol into a 5L four-neck flask, dropwise adding 724g (molecular weight is 36.5, 6.2mol) of 31% hydrochloric acid while stirring, and cooling to 0-10 ℃; 610g of di-tert-butyl dicarbonate (molecular weight 218.2, 2.8mol) is added dropwise, and the dropwise addition is completed within about 4 to 6 hours. After the dropwise addition is finished, preserving the heat for 2 hours at the temperature of 0-10 ℃, sampling, controlling the gas chromatography until the di-tert-butyl dicarbonate disappears, and finishing the reaction; transferring the reaction solution to a separating funnel, standing, layering, removing a water phase (lower layer), and concentrating an organic phase (upper layer) to recover a solvent; the concentrated solution was extracted with ethyl acetate, concentrated to dryness under reduced pressure, and recrystallized from petroleum ether to give 339.8g of a white solid with a purity of 99.9% (molecular weight 132.2, 2.57mol) and a yield of 91.8% (based on di-tert-butyl dicarbonate).
Example 2:
adding 350g (molecular weight is 50.1, 5.6mol) of 80% hydrazine hydrate and 700g of methanol into a 5L four-neck flask, dropwise adding 658g (molecular weight is 36.5, 5.6mol) of 31% hydrochloric acid while stirring, and cooling to 0-10 ℃; 733g (molecular weight: 218.2, 3.4mol) of di-tert-butyl dicarbonate was added dropwise over about 4 to 6 hours. After the dropwise addition is finished, preserving the heat for 2 hours at the temperature of 0-10 ℃, sampling, controlling the gas chromatography until the di-tert-butyl dicarbonate disappears, and finishing the reaction; transferring the reaction solution to a separating funnel, standing, layering, removing a water phase (lower layer), and concentrating an organic phase (upper layer) to recover a solvent; the concentrated solution was extracted with ethyl acetate, concentrated to dryness under reduced pressure, and recrystallized from petroleum ether to give 312.4g of a white solid with a purity of 99.9% (molecular weight 132.2, 2.36mol) and a yield of 94.4% (based on di-tert-butyl dicarbonate).
Example 3:
adding 350g (molecular weight is 50.1, 5.6mol) of 80% hydrazine hydrate and 500g of ethanol into a 5L four-neck flask, dropwise adding 790g (molecular weight is 36.5, 6.7mol) of 31% hydrochloric acid while stirring, and cooling to 0-10 ℃; 610g of di-tert-butyl dicarbonate (molecular weight 218.2, 2.8mol) is added dropwise, and the dropwise addition is completed within about 4 to 6 hours. After the dropwise addition is finished, preserving the heat for 2 hours at the temperature of 0-10 ℃, sampling, controlling the gas chromatography until the di-tert-butyl dicarbonate disappears, and finishing the reaction; transferring the reaction solution to a separating funnel, standing, layering, removing a water phase (lower layer), and concentrating an organic phase (upper layer) to recover a solvent; the concentrated solution was extracted with ethyl acetate, concentrated to dryness under reduced pressure, and recrystallized from petroleum ether to give 336.8g of a white solid with a purity of 99.8% (molecular weight 132.2, 2.54mol) and a yield of 90.8% (based on di-tert-butyl dicarbonate).
Example 4:
adding 350g (molecular weight is 50.1, 5.6mol) of 80% hydrazine hydrate and 460g of methanol into a 5L four-neck flask, dropwise adding 691g (molecular weight is 36.5, 5.9mol) of 31% hydrochloric acid while stirring, and cooling to 0-10 ℃; 672g of di-tert-butyl dicarbonate (with the molecular weight of 218.2 and 3.1mol) is dropwise added for about 4 to 6 hours. After the dropwise addition is finished, preserving the heat for 2 hours at the temperature of 0-10 ℃, sampling, controlling the gas chromatography until the di-tert-butyl dicarbonate disappears, and finishing the reaction; transferring the reaction solution to a separating funnel, standing, layering, removing a water phase (lower layer), and concentrating an organic phase (upper layer) to recover a solvent; extracting the concentrated solution with ethyl acetate, concentrating under reduced pressure to dryness, recrystallizing with petroleum ether to obtain white solid 309.8g, purity 99.9% (molecular weight 132.2, 2.34mol), yield 93.7% (calculated by di-tert-butyl dicarbonate)
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (10)
1. A preparation method of high-purity tert-butyl carbazole is characterized by comprising the following steps:
(1) dissolving hydrazine hydrate in alcohol or ether solvent, and adding inorganic acid or organic acid to generate hydrazine hydrate mono-acid salt;
(2) condensing hydrazine hydrate mono-acid salt and di-tert-butyl dicarbonate, neutralizing with alkali after the reaction is finished, extracting with a solvent, concentrating, and crystallizing with a weak-polarity solvent to obtain a tert-butyl carbazole product.
2. The method for preparing high-purity tert-butyl carbazole according to claim 1, wherein the alcohol or ether solvent in step (1) is selected from methanol, ethanol, tert-butanol or ethylene glycol dimethyl ether.
3. The method for preparing high-purity tert-butylcarbazole according to claim 1, wherein the mass ratio of hydrazine hydrate to solvent in step (1) is 1: 1 to 5.
4. The method for producing high-purity t-butylcarbazole according to claim 3, wherein the mass ratio of hydrazine hydrate to the solvent in the step (1) is 1: 1 to 2.
5. The process for preparing high purity t-butylcarbazole according to claim 1, wherein the inorganic acid in the step (1) is selected from one or more of hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid is selected from one or more of formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, citric acid and the like.
6. The method for preparing high purity t-butylcarbazole according to claim 1, wherein the molar ratio of hydrazine hydrate to inorganic or organic acid in step (1) is 1:0.5 to 1.5.
7. The method for preparing high-purity t-butylcarbazole according to claim 6, wherein the molar ratio of hydrazine hydrate to inorganic or organic acid in step (1) is 1: 1.0 to 1.2.
8. The method for preparing high purity t-butylcarbazole according to claim 7, wherein the molar ratio of hydrazine hydrate to inorganic or organic acid in step (1) is 1: 1.0 to 1.05.
9. The method for preparing high-purity tert-butyl carbazole according to claim 1, wherein the molar ratio of hydrazine hydrate mono-acid salt to di-tert-butyl dicarbonate in step (2) is 1: 0.4-0.8.
10. The method for preparing high-purity tert-butyl carbazole according to claim 1, wherein the temperature of dropwise adding di-tert-butyl dicarbonate is controlled to be 0-20 ℃ and the dropwise adding time is 0.5-4 hours.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101823986A (en) * | 2009-12-02 | 2010-09-08 | 江苏大康实业有限公司 | Preparation method for tert-butyl carbazate |
| CN105121446A (en) * | 2014-03-20 | 2015-12-02 | 宝洁公司 | Stannous fluorescent probe |
| CN106565531A (en) * | 2016-10-31 | 2017-04-19 | 苏州汉德创宏生化科技有限公司 | Synthesis method for pharmaceutically acceptable salt of alkylhydrazine |
| CN108003062A (en) * | 2017-12-25 | 2018-05-08 | 常州吉恩药业有限公司 | A kind of synthetic method of list BOC protections bisamination compound |
| CN108602762A (en) * | 2016-01-29 | 2018-09-28 | 贝兰迪克有限责任公司 | Linkers and its purposes in the method for purified peptide |
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- 2021-06-17 CN CN202110670667.2A patent/CN113402425A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101823986A (en) * | 2009-12-02 | 2010-09-08 | 江苏大康实业有限公司 | Preparation method for tert-butyl carbazate |
| CN105121446A (en) * | 2014-03-20 | 2015-12-02 | 宝洁公司 | Stannous fluorescent probe |
| CN108602762A (en) * | 2016-01-29 | 2018-09-28 | 贝兰迪克有限责任公司 | Linkers and its purposes in the method for purified peptide |
| CN106565531A (en) * | 2016-10-31 | 2017-04-19 | 苏州汉德创宏生化科技有限公司 | Synthesis method for pharmaceutically acceptable salt of alkylhydrazine |
| CN108003062A (en) * | 2017-12-25 | 2018-05-08 | 常州吉恩药业有限公司 | A kind of synthetic method of list BOC protections bisamination compound |
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