Preparation method of sulfadoxine and intermediate thereof

A technology of cycle-acting sulfonamide and intermediates, which is applied in the field of sulfonamide drug preparation, can solve the problems of high production cost, decomposition phenomenon, poor quality of cyclides, etc., and achieves the effects of low production cost and high purity

Inactive Publication Date: 2012-01-04
CHANGSHU NANHU INDAL CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] 1, step (1) Kjeldahl reaction makes raw material carry out in sodium ethylate/ethanol solution, and after decarbonylation, removes low boiler (comprising unreacted raw material, intermediate A3 etc.) by first fractional distillation, then fractional distillation obtains intermediate 2-methoxy-methyl ethyl malonate, the purity of the method's gained 2-methoxy-methyl ethyl malonate is lower (generally lower than 92%), which is unfavorable for subsequent reactions, especially in large During the trial production, the quality and yield of Zhouxiao Sulfa products were affected
[0018] 2, step (2) ring closure reaction gained ring compound quality is poor: traditional method makes ring compound separate out under acidic condition, gained ring compound (A5 ) can exist in two forms of hydroxy substance and hydroxy sodium salt. Because the hydroxy substance has a certain solubility in water, the mother liquor of the cyclization reaction must be applied mechanically repeatedly in the traditional process, and the salt concentration in the mother liquor is equivalent due to the application of the mother liquor. large, resulting in poor quality of cyclic compounds (nearly 40...

Method used

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  • Preparation method of sulfadoxine and intermediate thereof
  • Preparation method of sulfadoxine and intermediate thereof
  • Preparation method of sulfadoxine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1 prepares 2-methoxy-methyl ethyl malonate (A4)

[0053] (1) The reaction equation is as follows:

[0054]

[0055] (2) See Table 1 for the feeding ratio.

[0056] Table 1

[0057] raw material name

Feeding amount (kg)

molecular weight

The molar ratio of

A1 (methyl methoxyacetate)

175

104

1

A2 (diethyl oxalate)

280

146

1.14

Sodium ethylate solid

130

68

1.12

[0058] (3) The specific operation process is as follows:

[0059] Dry the reaction kettle (normal batch reaction reaction kettle does not need to be washed), mix methyl methoxyacetate and diethyl oxalate in a mixed ester pot, and cool to below 10°C, add to the reaction kettle, under stirring conditions, Pour the solid sodium ethoxide into the reaction kettle (the package of sodium ethoxide should not be disassembled, and the minimum package of sodium ethoxide should be used as the unit when feed...

Embodiment 2

[0062] Embodiment 2 prepares cyclic compound-hydroxyl sodium salt (A5)

[0063] (1) The reaction equation is as follows:

[0064]

[0065] (2) The feeding ratio is shown in Table 2.

[0066] Table 2

[0067] raw material name

Feeding amount (kg)

molecular weight

The molar ratio of

A4 (Gradestone)

240

176

1

Formamide

186

45

3.37

liquid sodium methoxide

830

54

3.46

[0068] (3) The specific operation process is as follows:

[0069] Dry the reactor first, put in liquid sodium methoxide, stir, heat to 60-68°C, add formamide, then add A4 obtained in step (1) evenly, control the temperature when adding to 65-70°C, and add time for 1-68°C After 1.5 hours, the addition is completed, and the heat preservation reaction is more than 0.5 hours. Recover methanol at room temperature, then recover methanol under reduced pressure until it does not come out, then add 1000L of water, ...

Embodiment 3

[0070] Embodiment 3 prepares chloride (A6)

[0071] (1) The reaction equation is as follows:

[0072]

[0073] (2) The feeding ratio is shown in Table 3.

[0074] table 3

[0075] raw material name

Feeding amount (kg)

molecular weight

The molar ratio of

A5 (the ring compound that embodiment 2 prepares)

240

186

1

Phosphorus oxychloride

825

153

4.17

Trichlorethylene

900

131

/

[0076] (3) The specific operation process is as follows:

[0077] In the reaction pot (covered tightly), press the pre-prepared phosphorus oxychloride. Turn on the reflux and hydrogen chloride gas absorption device, heat to 40°C with steam, turn off the steam to raise the temperature naturally, start to slowly add the cyclic compound-hydroxy sodium salt (A5), and control the adding speed, (pay attention to the sudden temperature phenomenon when adding, About ten to twenty minutes), add the rest ...

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Abstract

The invention relates to a preparation method of sulfadoxine and an intermediate thereof. The preparation method of sulfadoxine comprises the following steps: (1) reacting methyl methoxyacetate and excessive diethyl oxalate to generate 3-methoxy-2-oxo-methylethyl succinate, and decarbonylating to obtain 2-methoxy-methylethyl malonate; (2) reacting the 2-methoxy-methylethyl malonate and formamide to generate a cyclocompound; (3) reacting the cyclocompound and phosphorus oxychloride to generate chloride; (4) carrying out condensation reaction; and (5) carrying out methoxylation reaction. The obtained cyclocompound in the step (2) is controlled to exist in the form of anhydrous hydroxy sodium salt, so that N,N-dimethylaniline is not needed as a catalyst in the step (3), thereby lowering the cost, enhancing the quality of chloride and finally enhancing the quality of sulfadoxine.

Description

technical field [0001] The invention belongs to the technical field of preparation of sulfonamide drugs, in particular to a preparation method of sulfonamide and its intermediate. Background technique [0002] Sulfonamide, the chemical name is 4-(p-aminobenzenesulfonyl)-5,6-dimethoxypyrimidine, and its structural formula is as follows: [0003] [0004] Sulfonamide can be used clinically to treat general inflammation, such as upper respiratory tract infection tonsillitis, bacillary dysentery enteritis, skin infection, etc. It can also be used in combination with other medicines to treat pulmonary tuberculosis and lymphatic tuberculosis; it also has a certain effect on leprosy (madness). It can also treat malaria. In addition, sulfonamide can also be used as a preventive drug for rheumatic venereal diseases. When used for the above purposes, sulfonamide has the characteristics of long curative effect and low toxicity. [0005] Sulfonamide has gone through several generat...

Claims

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Application Information

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IPC IPC(8): C07D239/69C07D239/34
Inventor 邵香民
Owner CHANGSHU NANHU INDAL CHEM
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