CN113024471A - Synthetic method of 4, 6-dichloro-2-propylmercapto-5-amino piperidine - Google Patents
Synthetic method of 4, 6-dichloro-2-propylmercapto-5-amino piperidine Download PDFInfo
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- CN113024471A CN113024471A CN201911354100.3A CN201911354100A CN113024471A CN 113024471 A CN113024471 A CN 113024471A CN 201911354100 A CN201911354100 A CN 201911354100A CN 113024471 A CN113024471 A CN 113024471A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention discloses a synthetic method of 4, 6-dichloro-2-propylmercapto-5-amino piperidine. The synthesis steps comprise: (1) dissolving diethyl aminomalonate with a protecting group and thiourea in an organic solvent, and reacting under the catalysis of alkali to obtain a compound 1; (2) dissolving the compound 1 in a sodium hydroxide or potassium hydroxide solution, adding an organic solvent, and then adding bromopropane into the mixed solvent to perform a propane alkylation reaction to obtain a compound 2; (3) removing amino protecting groups from the compound 2 to obtain a compound 3; (4) adding organic base and a chlorinating agent into the compound 3 for chlorination reaction to obtain a target compound 4. The synthetic method has the advantages of high propane alkylation reaction selectivity, no need of high-risk nitration reaction, no need of high-solid waste metal reduction nitro reaction and high-cost metal catalytic hydrogenation step, and is low in equipment cost, easy to obtain and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of preparation of raw material medicines and intermediates, and particularly relates to a preparation method of a ticagrelor intermediate 4, 6-dichloro-2-propylmercapto-5-aminopyridine.
Background
Ticagrelor is a platelet adenosine diphosphate P2Y12 receptor antagonist developed by Aslicon, which has reversible binding, direct action and oral administration, and is mainly used for treating patients with acute coronary syndrome and reducing the incidence rate of thrombotic cardiovascular diseases. The drug was approved by the european union first in 12 months in 2010, 7 months in 2011 and then approved by the FDA, in 2012, ticagrelor was approved to enter china under the trade name of doubly linda. Currently, the two major guidelines of the european cardiology institute have listed the recommended levels of ticagrelor prior to clopidogrel, so that patients who cannot use ticagrelor will use clopidogrel.
The structure of ticagrelor has been disclosed by the company asikang in WO9905143 and has the following structural formula:
in the synthetic route of ticagrelor, 4, 6-dichloro-2-propylmercapto-5-amino pyridine is a key intermediate, and the structure of the intermediate is as follows:
the synthesis of 4, 6-dichloro-2-propylmercapto-5-aminopiperidine currently used by most enterprises is as follows, which is disclosed in patent WO 2011036479:
the synthetic method uses nitric acid for nitration, the potential safety hazard of the reaction is large, and the generated waste acid is seriously polluted. In the nitro reduction process, if the catalytic hydrogenation condition is used, the catalyst is easy to be poisoned, and the cost is higher; if metal reduction is used, a large amount of waste slag (iron sludge) is generated and it is difficult to filter in the post-treatment process.
In patent CN105884694 it is also reported that 4, 6-dichloro-2-propanemercapto-5-amino piperidine is prepared after the introduction of a nitro group at position 2 of malonic acid diester to give 2-nitromalonic acid diester.
The advance of the nitration of the hazardous reaction to the first step in this route does not substantially solve the problem of this route.
The preparation of the intermediate 4, 6-dichloro-2-propylmercapto-5-aminopiperidine starting from 2-aminomalonic acid diester is also reported in patent CN 107089984.
Although this route can avoid nitration and nitro reduction, we have found that repeating this route results in poor yields of the reaction due to poor reaction of the starting materials and high levels of impurities in the propane alkylation step.
Disclosure of Invention
The invention aims to provide a preparation method of a ticagrelor intermediate 4, 6-dichloro-2-propylmercapto-5-aminopyridine, and aims to solve the technical problems of more impurities and low reaction yield of propane alkylation reaction in the existing synthetic route.
The inventors, while repeating the synthetic route of patent CN107089984, for the propane alkylation step:
in this step, the adjustment of the amounts of bromopropane and sodium hydroxide, the reaction temperature, and the reaction time does not allow the raw materials to be completely reacted or the impurity ratio to be reduced. The raw materials are difficult to react, a large amount of impurities are generated at low temperature, and the impurities are analyzed to be a disubstituted impurity product. In order to solve the problem, firstly, the propyl group on the sulfur of thiourea is considered to be protected, and the reaction steps are as follows:
the obtained propylthiourea reacts with 2-diethyl aminomalonate to construct a heterocycle, and the reaction steps are as follows:
experiments prove that the reaction cannot be realized.
The inventors then considered the protection of the amino group to avoid propane alkylation of the amino group, leading to the synthesis scheme of the present invention.
The technical scheme adopted by the invention for solving the problems is as follows:
the synthetic route is as follows:
the synthesis steps comprise:
(1) dissolving a raw material compound 1 and thiourea in an organic solvent, and reacting under the catalysis of alkali to obtain a compound 2;
(2) dissolving the compound 2 in an alkali solution, adding an organic solvent, and then adding halopropane into the mixed solvent to perform propane alkylation reaction to obtain a compound 3;
(3) compound 3 deprotection group R3To obtain a compound 4;
(4) adding organic base and a chlorinating agent into the compound 4 for chlorination reaction to obtain a target compound 5;
the R is1，R2Is C1-C4Alkyl groups of (a); r3Is acyl or amino protecting group. Preferably, said R is1，R2Is ethyl, R3Is acetyl. Preferably, the organic solvent in step (1) is selected from one or more of methanol, ethanol, isopropanol, acetonitrile, DMF, NMP, 1, 2-dichloroethane; the alkali is selected from one of sodium methoxide, sodium ethoxide, sodium hydride and sodium amide.
Preferably, the molar ratio of compound 1, thiourea and base in step (1) is 1: 1.0-2.0: 1.2 to 2.5, the reaction temperature is controlled to be 20 to 100 ℃, and the reaction is carried out for 2 to 10 hours under the protection of nitrogen.
Preferably, the organic solvent added in step (2) is selected from methanol, ethanol, isopropanol, acetonitrile, toluene, hexane, cyclohexane, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, DMF, DMSO, NMP.
Preferably, when the halopropane is added in the step (2), the halopropane is slowly dripped into the mixed solvent at the temperature of-5 ℃; the halopropane is preferably bromopropane or iodopropane, and is more preferably bromopropane.
Preferably, the alkali solution in the step (2) is preferably sodium hydroxide or potassium hydroxide solution, the mass percentage concentration of the sodium hydroxide or potassium hydroxide in the solution is 8-12%, and the reaction temperature is 20-30 ℃.
Preferably, said R is3Acetyl, propionyl, butyryl or amino protecting groups Cbz and Boc.
Preferably, said R is3When the compound is acetyl, the compound 2 is dissolved in a mixed solvent of methanol and hydrochloric acid solution in the step (3), wherein the volume ratio of the methanol to the hydrochloric acid solution is 3-5:1, and the molar concentration of hydrochloric acid in the solution is 4-8 mol/L; the reaction temperature is 40-60 ℃.
Preferably, the organic base in step (4) is one of diisopropylethylamine, triethylamine, trimethylamine, N-dimethylaniline and N, N-diethylaniline; the chlorinating agent is one of phosphorus oxychloride, phosphorus pentachloride and thionyl chloride.
Preferably, in the step (4), the organic base is N, N-diethylaniline, and the chlorinating agent is phosphorus oxychloride; the dosage ratio of the compound 3, the organic base and the chlorinating agent is 10 mmol: 20-30 mmol: 10-20 mL.
Compared with the prior art, the invention has the following beneficial effects:
the invention protects the amino in the raw material diethyl aminomalonate, thereby avoiding the propane alkylation of the amino, and the invention has high selectivity of the propane alkylation of the sulfenyl in the synthesis step and improves the reaction yield.
2, the method does not need high-risk nitration reaction, high-solid waste metal reduction nitro reaction and high-cost metal catalytic hydrogenation step, has cheap and easily-obtained equipment, and is suitable for industrial production.
Detailed Description
The technical solution of the present invention will be described below with reference to specific examples. The starting materials and reagents used in the present invention are commercially available.
Example 1
20 g of diethyl 2-acetamidomalonate and 9.8 g of thiourea are dissolved in 260mL of ethanol, nitrogen is replaced, 14.4 g of sodium ethoxide is added in portions under the protection of nitrogen, and the mixture is heated to reflux for reaction for 4-5 h. After the reaction is finished, cooling the reaction system to 0 ℃, filtering, leaching filter cakes by 26ml of ethanol, and drying to obtain 16.4 g of light yellow solid with yield of 80 percent1H-NMR(400MHz,DMSO)δ12.33(s,2H),9.04(s,1H),1.87(s,3H)。
Example 2
Dissolving 10 g of raw material in 20mL of 10% sodium hydroxide solution, adding 7mL of methanol, cooling to 0 ℃, slowly adding 6.72 g of bromopropane dropwise, heating to room temperature (20-30 ℃) after the dropwise addition is finished, reacting, detecting by HPLC (high performance liquid chromatography), adjusting the pH value to 1 by using hydrochloric acid after the reaction is completed, filtering, washing, and drying to obtain 9.6 g of solid with the yield of 88%. Product of1H-NMR(400MHz,DMSO)δ8.89(s,1H),3.08(t,J＝7.1Hz,2H),1.96(s,3H),1.71–1.57(m,2H),0.96(t,J＝7.3Hz,3H)。
In the propane alkylation reaction, the following results are found in experiments: the acetyl groups can fall off due to the overhigh concentration or temperature of sodium hydroxide in the system, so that impurities are increased, and the yield is reduced. The reaction progress is retarded by reducing the sodium hydroxide alkali concentration or by too low a temperature. If sodium carbonate, sodium bicarbonate and no alkali are used, the reaction is not carried out, and the concentration of the alkali sodium hydroxide is controlled to be about 10 percent, preferably between 8 and 12 percent.
Comparative example 2
3.62 g of raw material is added into 25mL of methanol at 0 ℃, then 5mL of water is added, 9.84 g of bromopropane is added dropwise, the temperature is raised to 50 ℃, the mixture is stirred for 2h, TLC detection is carried out, more raw material is remained, meanwhile, more impurities are generated, the PH is adjusted to 3 by hydrochloric acid, filtration, washing and drying are carried out, 1.52 g of solid is obtained, and the yield is 38%.
Example 3
10 g of raw material is placed in a flask, 40mL of methanol and 10mL of HCl solution (6M) are added, the temperature is raised to 50 ℃ for reaction, and after the conversion of the raw material is finished, 10.5 g of white solid with the content of 92 percent and the yield of 98.9 percent is obtained by decompression and concentration. Product of1H-NMR(400MHz,DMSO)δ3.11(t,J＝7.2Hz,2H),1.72–1.60(m,2H),1.01–0.91(m,3H)。
Example 4
20 g of raw materials are placed in a flask, 42.6 g of N, N-diethylaniline is added, 100mL of phosphorus oxychloride is dropwise added under the protection of nitrogen, and the temperature is raised to reflux after the dropwise addition is finished. After the reaction is finished, cooling to room temperature, slowly pouring the reaction liquid into stirred ice water, controlling the temperature to be below 10 ℃, adjusting the pH to 7 by using ammonia water, extracting by using ethyl acetate (100mL x 2), combining organic phases, washing by using 10mL of water and washing by using 50mL of saturated salt solution, concentrating to obtain a crude product, adding 100mL of n-heptane, heating to 40-45 ℃, stirring for 1 hour, cooling to 0-5 ℃, preserving heat for 1 hour, filtering, leaching the solid by using 10mL of heptane, drying the solid to obtain 17.4 g, wherein the yield is 87%. Of the product1H-NMR(400MHz,DMSO)δ5.872(s,2H),3.017(t,J＝7.2Hz,2H),1.689-1.635(m，2H),0.994-0.933(m,3H)。
The above description is only a part of the preferred embodiments of the present invention, and the present invention is not limited to the contents of the embodiments. It will be apparent to those skilled in the art that various changes and modifications can be made within the spirit of the invention, and any changes and modifications made are within the scope of the invention.
Claims (10)
1. A method for synthesizing 4, 6-dichloro-2-propanemercapto-5-amino piperidine comprises the following steps:
the synthesis steps comprise:
(1) dissolving a raw material compound 1 and thiourea in an organic solvent, and reacting under the catalysis of alkali to obtain a compound 2;
(2) dissolving the compound 2 in an alkali solution, adding an organic solvent, and then adding halopropane into the mixed solvent to perform propane alkylation reaction to obtain a compound 3;
(3) compound 3 deprotection group R3To obtain a compound 4;
(4) adding organic base and a chlorinating agent into the compound 4 for chlorination reaction to obtain a target compound 5;
the R is1，R2Is C1-C4Alkyl groups of (a); r3Is acyl or amino protecting group.
2. The method of synthesizing 4, 6-dichloro-2-propanemercapto-5-aminopiperidine according to claim 1, wherein: the organic solvent in the step (1) is selected from one or more of methanol, ethanol, isopropanol, acetonitrile, DMF, NMP and 1, 2-dichloroethane; the alkali is selected from one of sodium methoxide, sodium ethoxide, sodium hydride and sodium amide.
3. The method of synthesizing 4, 6-dichloro-2-propanemercapto-5-aminopiperidine according to claim 1, wherein: the molar ratio of the compound 1, the thiourea and the alkali in the step (1) is 1: 1.0-2.0: 1.2 to 2.5, the reaction temperature is controlled to be 20 to 100 ℃, and the reaction is carried out for 2 to 10 hours under the protection of nitrogen.
4. The method of synthesizing 4, 6-dichloro-2-propanemercapto-5-aminopiperidine according to claim 1, wherein: the organic solvent added in the step (2) is selected from methanol, ethanol, isopropanol, acetonitrile, toluene, hexane, cyclohexane, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, DMF, DMSO and NMP.
5. The method of synthesizing 4, 6-dichloro-2-propanemercapto-5-aminopiperidine according to claim 1, wherein: slowly dripping the halogenated propane into the mixed solvent at the temperature of minus 5-5 ℃ when the halogenated propane is added in the step (2); the halopropane is preferably bromopropane or iodopropane, and more preferably bromopropane.
6. The method of synthesizing 4, 6-dichloro-2-propanemercapto-5-aminopiperidine according to claim 1, wherein: in the step (2), the alkali solution is preferably sodium hydroxide or potassium hydroxide solution, the mass percentage concentration of the sodium hydroxide or potassium hydroxide in the solution is 8-12%, and the reaction temperature is 20-30 ℃.
7. The method of synthesizing 4, 6-dichloro-2-propanemercapto-5-aminopiperidine according to claim 1, wherein: the R is3Acetyl, propionyl, butyryl or amino protecting groups Cbz and Boc.
8. The method of synthesizing 4, 6-dichloro-2-propanemercapto-5-aminopiperidine according to claim 1, wherein: the R is3When the compound is acetyl, the compound 2 is dissolved in a mixed solvent of methanol and hydrochloric acid solution, the volume ratio of the methanol to the hydrochloric acid solution is 3-5:1, and the molar concentration of hydrochloric acid in the solution is 4-8 mol/L; the reaction temperature is 40-60 ℃.
9. The method of synthesizing 4, 6-dichloro-2-propanemercapto-5-aminopiperidine according to claim 1, wherein: the organic base in the step (4) is one of diisopropylethylamine, triethylamine, trimethylamine, N-dimethylaniline and N, N-diethylaniline; the chlorinating agent is one of phosphorus oxychloride, phosphorus pentachloride and thionyl chloride.
10. The method of synthesizing 4, 6-dichloro-2-propanemercapto-5-aminopiperidine according to claim 1, wherein: in the step (4), the organic base is N, N-diethylaniline, and the chlorinating agent is phosphorus oxychloride; the dosage ratio of the compound 3, the organic base and the chlorinating agent is 10 mmol: 20-30 mmol: 10-20 mL.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103772295A (en) * | 2014-01-26 | 2014-05-07 | 苏州立新制药有限公司 | Preparation method of Ticagrelor intermediate 4,6-dichloro-2-(mercaptopropionic)-5-aminopyrimidine |
| CN103923020A (en) * | 2014-04-02 | 2014-07-16 | 黄河三角洲京博化工研究院有限公司 | Preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine |
| CN104520278A (en) * | 2012-08-06 | 2015-04-15 | 埃南蒂亚有限公司 | A process for the preparation of an intermediate for a triazolopyrimidine carbonucleoside |
| CN105884694A (en) * | 2014-12-30 | 2016-08-24 | 上海复星医药产业发展有限公司 | Preparing method for ticagrelor intermediate 4,6-dichloro-2-tri-sulfydryl-5-aminopyrimidine |
| CN107089984A (en) * | 2017-04-11 | 2017-08-25 | 荆楚理工学院 | A kind of synthetic method of Ticagrelor |
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- 2019-12-25 CN CN201911354100.3A patent/CN113024471A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104520278A (en) * | 2012-08-06 | 2015-04-15 | 埃南蒂亚有限公司 | A process for the preparation of an intermediate for a triazolopyrimidine carbonucleoside |
| CN103772295A (en) * | 2014-01-26 | 2014-05-07 | 苏州立新制药有限公司 | Preparation method of Ticagrelor intermediate 4,6-dichloro-2-(mercaptopropionic)-5-aminopyrimidine |
| CN103923020A (en) * | 2014-04-02 | 2014-07-16 | 黄河三角洲京博化工研究院有限公司 | Preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine |
| CN105884694A (en) * | 2014-12-30 | 2016-08-24 | 上海复星医药产业发展有限公司 | Preparing method for ticagrelor intermediate 4,6-dichloro-2-tri-sulfydryl-5-aminopyrimidine |
| CN107089984A (en) * | 2017-04-11 | 2017-08-25 | 荆楚理工学院 | A kind of synthetic method of Ticagrelor |
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