CN103910684A - Preparation method of 4,6-dihydroxy-5-methoxypyrimidine sodium - Google Patents
Preparation method of 4,6-dihydroxy-5-methoxypyrimidine sodium Download PDFInfo
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- CN103910684A CN103910684A CN201410083346.2A CN201410083346A CN103910684A CN 103910684 A CN103910684 A CN 103910684A CN 201410083346 A CN201410083346 A CN 201410083346A CN 103910684 A CN103910684 A CN 103910684A
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- dihydroxyl
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- ethyl ester
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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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of 4,6-dihydroxy-5-methoxypyrimidine sodium. The preparation method comprises following steps: (a) sodium methylate is delivered into a dried container, is stirred and heated to 65 to 68 DEG C, methanamide is added, 2-methoxypropandioic acid ethyl methyl ester is added dropwise, and reaction is carried out at a temperature of 65 to 70 DEG C for 2 to 6h so as to obtain a mixture; and (b) the mixture is subjected to distillation at 25 to 80 DEG C so as to remove methanol, is cooled to 10 to 15 DEG C, and is centrifuged so as to collect a solid material. According to the preparation method of 4,6-dihydroxy-5-methoxypyrimidine sodium, sodium methylate and methanamide are delivered into the dried container, and 2-methoxypropandioic acid ethyl methyl ester is added dropwise, so that on the one hand, damage on reaction caused by residual water in the container is prevented, and on the other hand, the drop-by-drop adding manner is beneficial for controlling of adding speed of 2-methoxypropandioic acid ethyl methyl ester, the reaction temperature can be controlled more accurately, side reaction is inhibited, and yield of needed products is increased.
Description
Technical field
The present invention relates to a kind of preparation method of sulphormethoxine intermediate, be specifically related to a kind of preparation method of 4,6-dihydroxyl-5-methoxy pyrimidine sodium.
Background technology
Sulphormethoxine, chemistry 4-(p-amino benzene sulfonyl)-5 by name, 6-dimethoxypyridin, be generally used for the treatment of inflammation, as upper respiratory tract infection tonsillitis, bacillary dysentery enteritis, skin infections etc., also can coordinate with other drug, be used for the treatment of pulmonary tuberculosis, lymphoid tuberculosis.Sulphormethoxine has experienced several generations' research and development, and its production technique is progressively stable, is specially following preparation process:
Step (1):
Step (2):
Step (3):
Step (4):
Step (5):
Wherein, 4,6-dihydroxyl-5-methoxy pyrimidine sodium is the intermediate of preparation in step (2), and its productive rate directly affects productive rate and the cost of sulphormethoxine.Granted publication number is that the Chinese invention patent of CN102304095B discloses a kind of 4, the preparation method of 6-dihydroxyl-5-methoxy pyrimidine sodium, by successively add sodium methylate, methane amide, methoxy propyl diacid methyl ethyl ester in container, at 60～70 ℃, react and make for 1～1.5 hour.But reaction between sodium methylate, methane amide and methoxy propyl diacid methyl ethyl ester is violent, and discharge amount of heat, easily cause reactor temperature sharply to raise, cause dangerous generation, be unfavorable for the security control of production plant.
Summary of the invention
The present invention seeks to provide in order to overcome the deficiencies in the prior art a kind of and can reduce 4 of reaction severity, the preparation method of 6-dihydroxyl-5-methoxy pyrimidine sodium.
For achieving the above object, the technical solution used in the present invention is: a kind of preparation method of 4,6-dihydroxyl-5-methoxy pyrimidine sodium, comprises the following steps:
(a) sodium methylate is dropped in dry container, stir and be heated to 65～68 ℃, add wherein methane amide, drip subsequently methoxy propyl diacid methyl ethyl ester, within 2～6 hours, obtain mixture 65～70 ℃ of reactions;
(b) described mixture is placed in to distillation for removing methanol under 25～80 ℃ of conditions, is cooled to subsequently 10～15 ℃, centrifugal collection solid.
Optimally, the mol ratio of described methoxy propyl diacid methyl ethyl ester and methane amide is 1: 3～4.
Optimally, in step (a), the time for adding of described methoxy propyl diacid methyl ethyl ester 1～1.5 hour.
Optimally, in step (b), described mixture distillation adds water after removing methyl alcohol wherein again, and at 80～85 ℃, residual first alcohol and water is removed in distillation.
Optimally, in step (b), described solid collection is placed in circulation baking oven and is dried 10～30 hours.
Further, in step (b), described solid is placed in that circulation baking oven is dry is placed on 135～145 ℃, vacuum tightness higher than under the condition of-0.08Mpa dry 4～5 hours.
Because technique scheme is used, the present invention compared with prior art has following advantages: the present invention 4, the preparation method of 6-dihydroxyl-5-methoxy pyrimidine sodium, by add sodium methylate and methane amide in dry container, drip subsequently methoxy propyl diacid methyl ethyl ester, can prevent on the one hand the carrying out of moisture damage reaction residual in container, adopt on the other hand the mode dripping to be conducive to control the speed that adds of methoxy propyl diacid methyl ethyl ester, thereby control more accurately the temperature of reaction, suppress side reaction, improve the yield of required product.
Embodiment
The present invention 4, the preparation method of 6-dihydroxyl-5-methoxy pyrimidine sodium, comprise the following steps: (a) sodium methylate is dropped in dry container, stir and be heated to 65～68 ℃, add wherein methane amide, drip subsequently methoxy propyl diacid methyl ethyl ester, within 2～6 hours, obtain mixture 65～70 ℃ of reactions; (b) described mixture is placed in to distillation for removing methanol under 25～80 ℃ of conditions, is cooled to subsequently 10～15 ℃, centrifugal collection solid.By add sodium methylate and methane amide in dry container, drip subsequently methoxy propyl diacid methyl ethyl ester, can prevent on the one hand the carrying out of moisture damage reaction residual in container, adopt on the other hand the mode dripping to be conducive to control the speed that adds of methoxy propyl diacid methyl ethyl ester, thereby control more accurately the temperature of reaction, suppress side reaction, improve the yield of required product.
Can participate in reaction completely in order to ensure more expensive methoxy propyl diacid methyl ethyl ester, methane amide should be excessive, and the mol ratio of itself and methoxy propyl diacid methyl ethyl ester is preferably 1: 3～and 4.And the rate of addition of methoxy propyl diacid methyl ethyl ester can not be too fast, can not be too slow, time for adding is preferably 1～1.5 hour.Because methyl alcohol residual in mixture is difficult to remove totally, in step (b), after distillation for removing methanol, add water again wherein, at 80～85 ℃, residual first alcohol and water is removed in distillation.After 4,6-dihydroxyl-5-methoxy pyrimidine sodium prepares, to be used for the carrying out of next step reaction, must guarantee that it is in drying regime, therefore preferably be placed in circulation baking oven and be dried 10～30 hours; Then be placed in 135～145 ℃, vacuum tightness higher than under the condition of-0.08Mpa further dry 4～5 hours.
Below in conjunction with specific embodiment, the present invention is described in more detail:
Embodiment 1
This example provides a kind of preparation method of 4,6-dihydroxyl-5-methoxy pyrimidine sodium, and concrete charge ratio is as shown in table 1:
Table 1 reaction raw materials and charge ratio thereof
Specific operation process is as follows:
(a) first 830kg sodium methylate is dropped in dry ring-closure reaction pot, be heated with stirring to 65～68 ℃, add 186kg methane amide, then evenly drip methoxy propyl diacid methyl ethyl ester, controlling dropping temperature is 65～70 ℃, time for adding 1～1.5 hour.Dropwise, in 65～70 ℃ of insulation reaction 4 hours;
(b) normal temperature (25～30 ℃) Distillation recovery methyl alcohol is after 1～1.5 hour, till 80 ℃ of underpressure distillation did not extremely go out methyl alcohol about 2～3 hours, and then the 500L that adds water, normal pressure reclaims had water methanol about approximately 0.5～1 hour, in the time that temperature reaches 80～85 ℃, stop distillation; Be cooled to subsequently 10～15 ℃, discharging, centrifuge dehydration, rejection filter flows out to absence of liquid, taking-up was put into circulation oven drying about 20 hours, controlled vapor pressure 3～5kg, then turned round drying under reduced pressure again, controlling drying temperature is 140 ± 5 ℃, and vacuum tightness is higher than-0.08Mpa, dry 4～5 hours.
Above-described embodiment is only explanation technical conceive of the present invention and feature; its object is to allow person skilled in the art can understand content of the present invention and implement according to this; can not limit the scope of the invention with this; all equivalences that spirit is done according to the present invention change or modify, within all should being encompassed in protection scope of the present invention.
Claims (6)
1. one kind 4, the preparation method of 6-dihydroxyl-5-methoxy pyrimidine sodium, is characterized in that, comprises the following steps:
(a) sodium methylate is dropped in dry container, stir and be heated to 65～68 ℃, add wherein methane amide, drip subsequently methoxy propyl diacid methyl ethyl ester, within 2～6 hours, obtain mixture 65～70 ℃ of reactions;
(b) described mixture is placed in to distillation for removing methanol under 25～80 ℃ of conditions, is cooled to subsequently 10～15 ℃, centrifugal collection solid.
2. according to claim 14, the preparation method of 6-dihydroxyl-5-methoxy pyrimidine sodium, is characterized in that: described methoxy propyl diacid methyl ethyl ester and the mol ratio of methane amide are 1: 3～4.
3. according to claim 14, the preparation method of 6-dihydroxyl-5-methoxy pyrimidine sodium, is characterized in that: in step (a), and the time for adding of described methoxy propyl diacid methyl ethyl ester 1～1.5 hour.
4. according to claim 14, the preparation method of 6-dihydroxyl-5-methoxy pyrimidine sodium, it is characterized in that: in step (b), described mixture distillation adds water after removing methyl alcohol wherein again, at 80～85 ℃, residual first alcohol and water is removed in distillation.
5. according to claim 14, the preparation method of 6-dihydroxyl-5-methoxy pyrimidine sodium, is characterized in that: in step (b), described solid collection is placed in circulation baking oven dry 10～30 hours.
6. according to claim 54, the preparation method of 6-dihydroxyl-5-methoxy pyrimidine sodium, it is characterized in that: in step (b), described solid is placed in that circulation baking oven is dry is placed on 135～145 ℃, vacuum tightness higher than under the condition of-0.08Mpa dry 4～5 hours.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410083346.2A CN103910684A (en) | 2014-03-10 | 2014-03-10 | Preparation method of 4,6-dihydroxy-5-methoxypyrimidine sodium |
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| CN201410083346.2A CN103910684A (en) | 2014-03-10 | 2014-03-10 | Preparation method of 4,6-dihydroxy-5-methoxypyrimidine sodium |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447327A (en) * | 2014-12-13 | 2015-03-25 | 常熟市金申医化制品有限责任公司 | Preparation method of methyl ethyl methoxymalonate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RO63267A2 (en) * | 1974-01-09 | 1978-02-20 | Medicamente Intreprinderea De | PROCESS FOR OBTAINING 4,6-DIHYDROXY-5-METHOXYPYRIMIDINE |
| CN102304095A (en) * | 2011-09-23 | 2012-01-04 | 常熟市南湖实业化工有限公司 | Preparation method of sulfadoxine |
| CN102311393A (en) * | 2011-09-23 | 2012-01-11 | 常熟市金申医化制品有限责任公司 | Preparation method of sulfadoxine |
| CN102617488A (en) * | 2012-03-06 | 2012-08-01 | 常熟市金申医化制品有限责任公司 | Process for preparing sulfadoxine |
-
2014
- 2014-03-10 CN CN201410083346.2A patent/CN103910684A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RO63267A2 (en) * | 1974-01-09 | 1978-02-20 | Medicamente Intreprinderea De | PROCESS FOR OBTAINING 4,6-DIHYDROXY-5-METHOXYPYRIMIDINE |
| CN102304095A (en) * | 2011-09-23 | 2012-01-04 | 常熟市南湖实业化工有限公司 | Preparation method of sulfadoxine |
| CN102311393A (en) * | 2011-09-23 | 2012-01-11 | 常熟市金申医化制品有限责任公司 | Preparation method of sulfadoxine |
| CN102617488A (en) * | 2012-03-06 | 2012-08-01 | 常熟市金申医化制品有限责任公司 | Process for preparing sulfadoxine |
Non-Patent Citations (1)
| Title |
|---|
| 上海第二制药厂: "周效磺胺中间体4，6-双羟基-5-甲氧基嘧啶合成工艺的改进", 《医药工业》, no. 1, 31 December 1973 (1973-12-31), pages 42 - 43 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447327A (en) * | 2014-12-13 | 2015-03-25 | 常熟市金申医化制品有限责任公司 | Preparation method of methyl ethyl methoxymalonate |
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