CN113402469A - Preparation method of 6- (3-chloropropyl) amino-1, 3-dimethyluracil - Google Patents
Preparation method of 6- (3-chloropropyl) amino-1, 3-dimethyluracil Download PDFInfo
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- CN113402469A CN113402469A CN202110764724.3A CN202110764724A CN113402469A CN 113402469 A CN113402469 A CN 113402469A CN 202110764724 A CN202110764724 A CN 202110764724A CN 113402469 A CN113402469 A CN 113402469A
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- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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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Abstract
The invention belongs to the technical field of drug synthesis processes, and provides a preparation method of 6- (3-chloropropyl) amino-1, 3-dimethyluracil, which takes 6- (3-hydroxypropyl) amino-1, 3-dimethyluracil as a raw material and uses thionyl chloride for chlorination to obtain 6- (3-chloropropyl) amino-1, 3-dimethyluracil. The reaction directly uses thionyl chloride as a reaction reagent and a solvent, the yield can reach more than 85 percent, the highest yield can reach more than 90 percent, and the highest purity can reach more than 98 percent. Compared with the prior art, the method has the advantages that the yield and the purity are obviously improved, the post-treatment is convenient, the post-treatment solvent can be recycled, and more importantly, 1, 2-dichloroethane which can cause cancers and is harmful to human and environment is avoided. When the method is used for synthesizing the antihypertensive drug urapidil, the solvent types are reduced, the analysis of 1, 2-dichloroethane residual solvent in the drug quality analysis is avoided, and the method is a green and safe preparation method which is very suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis processes, and particularly relates to a preparation method of 6- (3-chloropropyl) amino-1, 3-dimethyluracil.
Background
The 6- (3-chloropropyl) amino-1, 3-dimethyluracil is an important intermediate for synthesizing the antihypertensive drug urapidil.
The chemical structure of urapidil is not similar to that of prazosin, and it has the functions of blocking postsynaptic receptors and peripheral alpha 2 receptors, but the former is the main one. In addition, the compound also has the function of activating central 5 hydroxytryptamine 1A receptors, and can reduce sympathetic feedback of brain-extending cardiovascular regulation center to play a role in reducing blood pressure. The product has larger vasodilatation effect on vein than artery, and does not affect intracranial blood pressure when lowering blood pressure. The product can reduce the load before and after the heart and the mean pulmonary artery pressure, improve the output of the heart beat and the cardiac output, reduce the resistance of the renal blood vessels, and has no obvious influence on the heart rate. It can be used for treating hypertension (oral administration) with diuretic antihypertension agent and beta-blocker; also used for hypertension crisis and hypertension elevation controlled lowering (intravenous injection) before, during and after operation.
The synthetic route reported by Zuojun et al (J.J.China pharmaceutical industry 2000, 31 (7): 294-. The yield of chlorinated product obtained, operating under literature conditions, is only 80% with a purity of 95%.
No report about no solvent exists in the chlorination step in the prior art, the solvent is involved in the reaction, the used solvent is 1, 2-dichloroethane, and chloroform (Zhou army red Urapidil synthesis and polymorphism analysis [ D ]. Tianjin: Tianjin university, 2007), wherein 1, 2-dichloroethane and chloroform are used as the solvent for the chlorination reaction, because of high boiling point, the removal is difficult, more important it is a solvent which is known to be carcinogenic and harmful to human and environment, and the residual solvent of 1, 2-dichloroethane is required to be analyzed in the quality standard of the Urapidil bulk drug at the later stage, so that the cost of drug synthesis and drug quality analysis is increased, and the cost of labor protection and the pressure on environmental protection are increased.
Disclosure of Invention
The invention aims to provide a preparation method for synthesizing 6- (3-chloropropyl) amino-1, 3-dimethyluracil, which is convenient to operate, high in yield, green and safe.
The invention is realized by the following technical scheme:
the invention provides a preparation method of 6- (3-chloropropyl) amino-1, 3-dimethyl uracil, which comprises the steps of using 6- (3-hydroxypropyl) amino-1, 3-dimethyl uracil as a raw material, using thionyl chloride to chlorinate to obtain 6- (3-chloropropyl) amino-1, 3-dimethyl uracil, and then carrying out aftertreatment by using an organic solvent, wherein the organic solvent is acetone, 95% acetone, 75% acetone, ethanol and ethyl acetate, and preferably 95% acetone.
The post-processing method comprises the following steps: after the reaction is finished, directly distilling at 45-50 ℃ under reduced pressure to remove excessive thionyl chloride, then adding an organic solvent precooled to 5-15 ℃, cooling to below 0 ℃, preserving heat, stirring for 2-3h, and carrying out suction filtration. And (4) leaching with an organic solvent, and drying by blowing at 70-80 ℃ for 10-12 h.
The synthetic route of the invention is as follows:
the mol ratio of the 6- (3-hydroxypropyl) amino-1, 3-dimethyl uracil II to the thionyl chloride is 1.0: 0.5 to 30.0, preferably 1.0: 2.5 to 3.0, the reaction temperature is 35 to 80 ℃, preferably 50 to 55 ℃, and the reaction time is 0.5 to 10 hours, preferably 0.5 to 1.0 hour.
And carrying out post-treatment by adopting a solvent, wherein the organic solvent is acetone, 95% acetone, 75% acetone, ethanol and ethyl acetate, and the preferred solvent is 95% acetone.
In the reaction, when the mol ratio of the 6- (3-hydroxypropyl) amino-1, 3-dimethyl uracil II to the thionyl chloride is 1.0: 2.5-3.0, the reaction temperature is 50-55 ℃, the reaction time is 0.5-1.0 hour, and when the post-treatment is carried out by adopting 95% acetone, the yield of the obtained 6- (3-chloropropyl) amino-1, 3-dimethyluracil reaches over 90%, and the purity reaches over 98%.
In the synthesis method of the invention, thionyl chloride is directly used as a reaction reagent and a solvent, 1, 2-dichloroethane which is a solvent with high toxicity is removed, and acetone, 95% acetone, 75% acetone, ethanol or ethyl acetate is treated after the reaction, so that the synthesis process is more green and safe when the synthetic method is used for synthesizing the antihypertensive drug urapidil, the operation is more convenient, the industrial amplification is very facilitated, the synthesis cost is reduced, the variety of the solvent is reduced, the cost of residual solvent analysis in the drug quality analysis is reduced, the damage to the environment is reduced, the requirement of labor protection is reduced, the 6- (3-hydroxypropyl) amino-1, 3-dimethyluracil II which is used as a raw material can be conveniently prepared by condensing 6-amino-1, 3-dimethyluracil and 3-aminopropanol, the raw materials are cheap and easy to obtain, and the thionyl chloride can be recycled and reused. The invention has mild condition, high yield up to more than 85 percent, maximum up to more than 90 percent and maximum purity up to more than 98 percent.
Drawings
FIG. 1 is an ESI-MS diagram of 6- (3-chloropropyl) amino-1, 3-dimethyluracil.
FIG. 2 is a schematic representation of 6- (3-chloropropyl) amino-1, 3-dimethyluracil1H-NMR chart.
FIG. 3 is a liquid phase diagram of 6- (3-chloropropyl) amino-1, 3-dimethyluracil.
Detailed Description
Example 1
Effect of different molar ratios of 6- (3-hydroxypropyl) amino-1, 3-dimethyluracil ii to thionyl chloride on product yield and purity:
the reaction is carried out according to the reaction equation, the molar ratio of the 6- (3-hydroxypropyl) amino-1, 3-dimethyl uracil II to the thionyl chloride is changed, the reaction temperature is fixed at 50 ℃, the reaction time is 2 hours, and after the reaction is finished, the excessive thionyl chloride is directly distilled and removed under reduced pressure at 45 ℃ (the thionyl chloride can be recovered and reused). Then adding 95% acetone pre-cooled to 5-15 deg.C, cooling to below 0 deg.C, stirring for 2 hr, and vacuum filtering. Rinsing with 95% acetone, and air drying at 70 deg.C for 10-12 hr.
The results are shown in table 1:
TABLE 1
Example 2
The procedure is as in example 1, fixing the molar ratio of 6- (3-hydroxypropyl) amino-1, 3-dimethyluracil II to thionyl chloride: 1: reaction time 0.5 h, work-up procedure as in example 1, effect of different reaction temperatures on product yield and purity.
The results are shown in table 2:
TABLE 2
Example 3
The procedure is as in example 1, fixing the molar ratio of 6- (3-hydroxypropyl) amino-1, 3-dimethyluracil II to thionyl chloride: 1: temperature 50 ℃ and workup procedure as in example 1, effect of different reaction times on product yield and purity.
The results are shown in Table 3:
TABLE 3
Example 4
The procedure is as in example 1, fixing the molar ratio of 6- (3-hydroxypropyl) amino-1, 3-dimethyluracil II to thionyl chloride: 1: 3, temperature 50 ℃, reaction time 30 minutes, effect of different post-treatment organic solvents on product yield and purity.
The results are shown in Table 4:
TABLE 4
| Organic solvent | Acetone (II) | 95% acetone | 75% acetone | Ethanol | Ethyl acetate |
| Yield (%) | 93.8％ | 92.1％ | 74.2％ | 57.3％ | 88.7％ |
| Purity (%) | 83.3％ | 98.5％ | 98.9％ | 99.0％ | 80.6％ |
Example 5
Adding 25.5L (41.8kg,351.8mol) of thionyl chloride into a 300L reaction tank, cooling to below 5 ℃, adding 30.0kg of 6- (3-hydroxypropyl) amino-1, 3-dimethyluracil (140.7mol) into the reaction tank in batches, controlling the temperature below 5 ℃ during the addition, keeping the temperature at 50-55 ℃ for reaction for 0.5 hour after the addition is finished, and detecting by TLC (DCM: MeOH is 10: 1) to react completely. Evaporating the solvent to dryness under reduced pressure at 45 ℃, adding 95% acetone prepared from 5kg of drinking water 95kg of acetone, and then cooling to 0-5 ℃ for 2 hours. Centrifuging, leaching with 20L of 95% acetone, and discharging. Drying with air blast at 65-75 deg.C for 10-12 hr until the water content is less than or equal to 1%, to obtain white or light yellow powder about 30.0Kg, with yield of 92.1%, melting point of 152-.
(column: Agilent ZORBAX Eclipse Plus C184.6X 250mm, 5 μm detection wavelength 268nm column temperature: flow rate at 35 ℃: sample introduction volume of 1mL/min is 10 muL of test solution: taking a proper amount of the product, precisely weighing, adding a methanol-water (10:90) solution for dissolving, and quantitatively diluting to prepare a solution containing about 0.5mg per 1 ml. Mobile phase: octadecylsilane chemically bonded silica is used as a filling agent; acetonitrile was used as mobile phase a and water as mobile phase B, and gradient elution was performed according to the following table.
TABLE 5
The measurement method comprises precisely measuring the sample solution, injecting into liquid chromatograph, and recording chromatogram.
And (3) confirming the structure of the product:
m.p.：152-156℃
ESI-MS：232.09[M+H]+；254.08[M+Na]+
1H NMR(400MHz,Chloroform-d)δ6.22(brs,1H),5.31(brs,1H),3.66(dd,J＝6.4,5.5Hz,2H),3.52(s,3H),3.44(t,J＝6.7Hz,2H),3.37(s,3H),2.19(p,J＝6.5Hz,2H).
example 6
Preparation of 6- (3-chloropropyl) amino-1, 3-dimethyluracil
TABLE 6
The results show that: the mol ratio of the 6- (3-hydroxypropyl) amino-1, 3-dimethyl uracil II to the thionyl chloride is 1: 0.5-20 ℃, the reaction temperature is 35-60 ℃, and the reaction time is 0.5-2, the yield of the prepared 6- (3-chloropropyl) amino-1, 3-dimethyl uracil reaches more than 85%, but the purity is different. And when the mol ratio of the 6- (3-hydroxypropyl) amino-1, 3-dimethyl uracil II to the thionyl chloride is 1.0: 2.5-3.0, the reaction temperature is 50-55 ℃, the reaction time is 0.5-1.0 hour, 95% acetone is selected as the post-treatment organic solvent, the yield of the 6- (3-chloropropyl) amino-1, 3-dimethyluracil prepared under the reaction conditions is up to more than 90%, and the purity is more than 98%.
Claims (10)
1. A preparation method of 6- (3-chloropropyl) amino-1, 3-dimethyluracil (I) is characterized in that: taking 6- (3-hydroxypropyl) amino-1, 3-dimethyl uracil as a raw material, and chlorinating with thionyl chloride to obtain 6- (3-chloropropyl) amino-1, 3-dimethyl uracil;
2. the process for producing 6- (3-chloropropyl) amino-1, 3-dimethyluracil (I) as claimed in claim 1, wherein: the mol ratio of the 6- (3-hydroxypropyl) amino-1, 3-dimethyl uracil (II) to the thionyl chloride is 1.0: 1.0 to 30.0.
3. The process for producing 6- (3-chloropropyl) amino-1, 3-dimethyluracil (I) as claimed in claim 1, wherein: the mol ratio of the 6- (3-hydroxypropyl) amino-1, 3-dimethyl uracil (II) to the thionyl chloride is 1.0: 2.5 to 3.0.
4. A process for the preparation of 6- (3-chloropropyl) amino-1, 3-dimethyluracil (i) as claimed in any of claims 1 to 3, which comprises: the reaction temperature is 35-80 ℃.
5. A process for the preparation of 6- (3-chloropropyl) amino-1, 3-dimethyluracil (i) as claimed in any of claims 1 to 3, which comprises: the reaction temperature is 50-55 ℃.
6. A process for the preparation of 6- (3-chloropropyl) amino-1, 3-dimethyluracil (i) as claimed in any of claims 1 to 3, which comprises: the reaction time is 0.5 to 10 hours.
7. A process for the preparation of 6- (3-chloropropyl) amino-1, 3-dimethyluracil (i) as claimed in any of claims 1 to 3, which comprises: the reaction time is 0.5 to 1.0 hour.
8. A process for the preparation of 6- (3-chloropropyl) amino-1, 3-dimethyluracil (i) as claimed in any of claims 1 to 7, which comprises: the mol ratio of the 6- (3-hydroxypropyl) amino-1, 3-dimethyl uracil (II) to the thionyl chloride is 1.0: 2.5 to 3.0 ℃, the reaction temperature is 50 to 55 ℃, and the reaction time is 0.5 to 1.0 hour.
9. A process for the preparation of 6- (3-chloropropyl) amino-1, 3-dimethyluracil (i) as claimed in any of claims 1 to 8, which comprises: and carrying out post-treatment by adopting an organic solvent.
10. A process for the preparation of 6- (3-chloropropyl) amino-1, 3-dimethyluracil according to claim 9, which comprises: the organic solvent is acetone, 95% acetone, 75% acetone, ethanol, and ethyl acetate.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20230099857A (en) * | 2021-12-28 | 2023-07-05 | 주식회사 한서켐 | New process for preparing intermediate of urapidil |
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| WO2015127873A1 (en) * | 2014-02-25 | 2015-09-03 | 上海海雁医药科技有限公司 | Arylamino pyramidine compound and application thereof, and pharmaceutical compositions and pharmaceutically acceptable compositions prepared therefrom |
| CN110655446A (en) * | 2019-10-22 | 2020-01-07 | 邹平铭兴化工有限公司 | Chemical synthesis method of chloroisobutane |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015127873A1 (en) * | 2014-02-25 | 2015-09-03 | 上海海雁医药科技有限公司 | Arylamino pyramidine compound and application thereof, and pharmaceutical compositions and pharmaceutically acceptable compositions prepared therefrom |
| CN110655446A (en) * | 2019-10-22 | 2020-01-07 | 邹平铭兴化工有限公司 | Chemical synthesis method of chloroisobutane |
Non-Patent Citations (5)
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| WEN LI等: "New and efficient technique for the synthesis of Urapidil using -cyclodextrin as an inverse phase-transfer catalyst", 《APPLIED CATALYSIS A: GENERAL》 * |
| 刘鹰翔主编: "《药物合成反应》", 31 August 2017 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20230099857A (en) * | 2021-12-28 | 2023-07-05 | 주식회사 한서켐 | New process for preparing intermediate of urapidil |
| KR102638538B1 (en) | 2021-12-28 | 2024-02-20 | 주식회사 한서켐 | New process for preparing intermediate of urapidil |
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