CN102850331A - 4, 6-dichloro-2-methyl-5-(1-acetyl-2-imidazoline-2-yl)-aminopyrimidine preparation method - Google Patents
4, 6-dichloro-2-methyl-5-(1-acetyl-2-imidazoline-2-yl)-aminopyrimidine preparation method Download PDFInfo
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Abstract
The invention discloses a 4, 6-dichloro-2-methyl-5-(1-acetyl-2-imidazoline-2-yl)-aminopyrimidine preparation method. The preparation method includes: firstly, feeding concentrated nitric acid and concentrated sulfuric acid into diethyl malonate for nitrifying diethyl malonate to obtain diethyl 2-nitromalonate; secondly, enabling the diethyl 2-nitromalonate and acetamidine hydrochloride to cyclize to obtain 2-methyl-5-nitro-4, 6-dihydroxypyrimidine under the action of 12N hydrochloric acid; thirdly, chloridizing the 2-methyl-5-nitro-4, 6-dihydroxypyrimidine with sulfoxide chloride serving as a chlorinating agent and hydrogenating and reducing the chloridized 2-methyl-5-nitro-4, 6-dihydroxypyrimidine with Raney nickel; and finally, condensing a product obtained in the third step and acetyl imidazo-2-one, so that 4, 6-dichloro-2-methyl-5-(1-acetyl-2-imidazoline-2-yl)-aminopyrimidine is obtained. The preparation method is short in reaction time, higher than 80% in yield and simple and convenient to operate as reaction processes are carried out under the normal pressure, the 4, 6-dichloro-2-methyl-5-(1-acetyl-2-imidazoline-2-yl)-aminopyrimidine is low in production cost, phosphorus wastewater is avoided, and emission of waste gases, wastewater and industrial residues is low.
Description
Technical field
The present invention relates to a kind of compound field with pyrimidine structure and glyoxaline structure, particularly relate to 4,6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) preparation method of aminopyrimidine compounds.
Background technology
Moxonidine is widely used antihypertensive drug.In recent years, the world market was increasing to the demand of moxonidine intermediate, just with annual 20% speed increase.
Traditional method is take B amidine hydrochloric acid salt as raw material, through cyclization, nitrated, chlorination, reduction, addition dehydration, alcoholysis salify, and synthetic product, overall yield is 24.8%.In chlorination reaction, take phosphorus oxychloride as chlorizating agent, productive rate is 92.8%.In reduction reaction, take iron powder as reductive agent, carry out wet distillation after finishing reaction.There is inherent defect in the method: nitrated after (1) first cyclization, and cause yield to reduce; (2) chloridization process is take phosphorus oxychloride as chlorizating agent, and charging capacity is excessive, and Distillation recovery phosphorus oxychloride energy consumption is large, and workshop hygiene requires high; (3) reducing process employing " iron powder " is reductive agent, is the technique that has been eliminated, and the wastewater flow rate of iron mud is large, and is seriously polluted,
Environmental protection pressure is large.
Summary of the invention
The object of the present invention is to provide a kind of cost low, environmental friendliness, three-waste pollution thing discharging few 4,6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) preparation method of aminopyrimidine.
Technical solution of the present invention is:
A kind of 4,6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) preparation method of aminopyrimidine, it is characterized in that: in turn include the following steps:
(1) in diethyl malonate, drops into concentrated nitric acid and the vitriol oil, carry out nitratedly in 20～60 ℃, obtain 2-nitro-diethyl malonate;
(2) with 2-nitro-diethyl malonate, under the hydrochloric acid effect of 12N, become 2-methyl-5-nitro-4 with the B amidine hydrochloric acid salt cyclization, the 6-dihydroxy-pyrimidine;
(3) the 2-methyl-5-nitro-4 that step (2) is obtained, the 6-dihydroxy-pyrimidine carries out chlorination with sulfur oxychloride as chlorizating agent, and chlorination temperature is controlled at 30～80 ℃;
(4) adopt the Raney's nickel hydro-reduction;
(5) product that step (4) is obtained and the condensation of acetyl imidazole ketone obtain product 4,6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) aminopyrimidine compounds.
When step (1) was nitrated to diethyl malonate, diethyl malonate, concentrated nitric acid, vitriol oil three's mol ratio was 1:1 ~ 50:1 ~ 50.
2-nitro-diethyl malonate, B amidine hydrochloric acid salt, hydrochloric acid three's mol ratio is 1:1 ~ 10:1 ~ 30 in the step (2).
Step (3) when making chlorizating agent with sulfur oxychloride, 2-methyl-4, the mol ratio of 6-dihydroxyl-5-nitro-pyrimidine and sulfur oxychloride is 1:1 ~ 10.
Catalyzer and 2-methyl-4 in the step (4), the mol ratio of 6-two chloro-5-nitro-pyrimidines is 0.01～10:1.
Step (5) is to carry out in the presence of thionyl chloride, and the product that obtains of step (4) and acetyl imidazole ketone, thionyl chloride three's mol ratio is 1:1-3:1-5.
Chemosynthesis reaction equation of the present invention is as follows:
Production line of the present invention is 5 steps such as nitrated, cyclization, chlorination, reduction, docking, and self-produced acylate.Reaction times is short, and yield is high, and yield is more than 80%; Reaction process is carried out under normal pressure, and is easy and simple to handle; The low production cost of product, and without the phosphorus-containing wastewater generation, the three wastes are less.
The invention will be further described below in conjunction with embodiment.
Embodiment
A kind of 4,6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) preparation method of aminopyrimidine, in turn include the following steps:
(1) in diethyl malonate, drops into concentrated nitric acid and the vitriol oil, carry out nitratedly in 20～60 ℃ (20 ℃, 40 ℃, 60 ℃ of examples), obtain 2-nitro-diethyl malonate;
(2) with 2-nitro-diethyl malonate, under the hydrochloric acid effect of 12N, become 2-methyl-5-nitro-4 with the B amidine hydrochloric acid salt cyclization, the 6-dihydroxy-pyrimidine;
(3) the 2-methyl-5-nitro-4 that step (2) is obtained, the 6-dihydroxy-pyrimidine carries out chlorination with sulfur oxychloride as chlorizating agent, and chlorination temperature is controlled at 30～80 ℃ (30 ℃, 55 ℃, 80 ℃ of examples);
(4) adopt the Raney's nickel hydro-reduction;
(5) product that step (4) is obtained and the condensation of acetyl imidazole ketone obtain product 4,6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) aminopyrimidine compounds.
When step (1) was nitrated to diethyl malonate, diethyl malonate, concentrated nitric acid, vitriol oil three's mol ratio was 1:1 ~ 50:1 ~ 50(example 1:1:1,1:25:25,1:50:50).
2-nitro-diethyl malonate, B amidine hydrochloric acid salt, hydrochloric acid three's mol ratio is 1:1 ~ 10:1 ~ 30(example 1:1:1,1:5:15,1:10:30 in the step (2)).
Step (3) is when making chlorizating agent with sulfur oxychloride, and 2-methyl-4, the mol ratio of 6-dihydroxyl-5-nitro-pyrimidine and sulfur oxychloride is 1:1 ~ 10(example 1:1,1:5,1:10).
Catalyzer and 2-methyl-4 in the step (4), the mol ratio of 6-two chloro-5-nitro-pyrimidines are 0.01～10:1(example 0.01:1,5:1,10:1).
Step (5) is to carry out in the presence of thionyl chloride, and the product that obtains of step (4) and acetyl imidazole ketone, thionyl chloride three's mol ratio is 1:1-3:1-5(example 1:1:1,1:3:5,1:2:3).
Claims (6)
1. one kind 4,6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) preparation method of aminopyrimidine, it is characterized in that: in turn include the following steps:
(1) in diethyl malonate, drops into concentrated nitric acid and the vitriol oil, carry out nitratedly in 20～60 ℃, obtain 2-nitro-diethyl malonate;
(2) with 2-nitro-diethyl malonate, under the hydrochloric acid effect of 12N, become 2-methyl-5-nitro-4 with the B amidine hydrochloric acid salt cyclization, the 6-dihydroxy-pyrimidine;
(3) the 2-methyl-5-nitro-4 that step (2) is obtained, the 6-dihydroxy-pyrimidine carries out chlorination with sulfur oxychloride as chlorizating agent, and chlorination temperature is controlled at 30～80 ℃;
(4) adopt the Raney's nickel hydro-reduction;
(5) product that step (4) is obtained and the condensation of acetyl imidazole ketone obtain product 4,6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) aminopyrimidine compounds.
2. according to claim 14, the 6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) preparation method of aminopyrimidine, it is characterized in that: when step (1) was nitrated to diethyl malonate, diethyl malonate, concentrated nitric acid, vitriol oil three's mol ratio was 1:1 ~ 50:1 ~ 50.
3. according to claim 1 and 24, the 6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) preparation method of aminopyrimidine, it is characterized in that: 2-nitro-diethyl malonate, B amidine hydrochloric acid salt, hydrochloric acid three's mol ratio is 1:1 ~ 10:1 ~ 30 in the step (2).
4. according to claim 1 and 24, the 6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) preparation method of aminopyrimidine, it is characterized in that: step (3) is when making chlorizating agent with sulfur oxychloride, 2-methyl-4, the mol ratio of 6-dihydroxyl-5-nitro-pyrimidine and sulfur oxychloride is 1:1 ~ 10.
5. according to claim 1 and 24, the 6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) preparation method of aminopyrimidine, it is characterized in that: catalyzer and 2-methyl-4 in the step (4), the mol ratio of 6-two chloro-5-nitro-pyrimidines is 0.01～10:1.
6. according to claim 1 and 24, the 6-two chloro-2-methyls-5-(1-acetyl-2-tetrahydroglyoxaline-2-yl) preparation method of aminopyrimidine, it is characterized in that: step (5) is to carry out in the presence of thionyl chloride, and the product that obtains of step (4) and acetyl imidazole ketone, thionyl chloride three's mol ratio is 1:1-3:1-5.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483268A (en) * | 2013-09-17 | 2014-01-01 | 常州大学 | Method for preparing 4, 6-dichloro-2-methyl-5-nitro pyrimidine |
| CN115057847A (en) * | 2022-07-26 | 2022-09-16 | 山东百启生物医药有限公司 | Preparation method of 4, 6-dichloro-5- (1, 3-dioxolane-2-yl) -2-methylpyrimidine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020045633A1 (en) * | 1999-02-01 | 2002-04-18 | Schoemaker Regina Geertruida | Use of moxonidine for postmyocardial infarction treatment |
| WO2005039639A2 (en) * | 2003-10-10 | 2005-05-06 | Solvay Pharmaceuticals Gmbh | Pharmaceutical composition comprising a selective i1 imidazoline receptor agonist and an angiotensin ii receptor blocker |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020045633A1 (en) * | 1999-02-01 | 2002-04-18 | Schoemaker Regina Geertruida | Use of moxonidine for postmyocardial infarction treatment |
| WO2005039639A2 (en) * | 2003-10-10 | 2005-05-06 | Solvay Pharmaceuticals Gmbh | Pharmaceutical composition comprising a selective i1 imidazoline receptor agonist and an angiotensin ii receptor blocker |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483268A (en) * | 2013-09-17 | 2014-01-01 | 常州大学 | Method for preparing 4, 6-dichloro-2-methyl-5-nitro pyrimidine |
| CN103483268B (en) * | 2013-09-17 | 2015-10-14 | 常州大学 | The preparation method of a kind of 4,6-bis-chloro-2-methyl-5-nitro pyrimidine |
| CN115057847A (en) * | 2022-07-26 | 2022-09-16 | 山东百启生物医药有限公司 | Preparation method of 4, 6-dichloro-5- (1, 3-dioxolane-2-yl) -2-methylpyrimidine |
| CN115057847B (en) * | 2022-07-26 | 2024-01-26 | 山东百启生物医药有限公司 | Preparation method of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine |
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Effective date of registration: 20180808 Address after: 226400 No. 9, Chen Gao Industrial Park, dugong Town, Rudong County, Nantong, Jiangsu. Patentee after: Shanghai Xudong Hepu Nantong Pharmaceutical Co., Ltd. Address before: 226400 No. 9, Chen Gao Industrial Park, dugong Town, Rudong County, Nantong, Jiangsu. Patentee before: Fu Aiqing |