CN102304094B - Preparation method of sulfadoxine and intermediate thereof - Google Patents
Preparation method of sulfadoxine and intermediate thereof Download PDFInfo
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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
The invention belongs to sulfa drugs preparing technical field, particularly the preparation method of a kind of sulphormethoxine and intermediate thereof.
Background technology
Sulphormethoxine, chemistry 4-(p-amino benzene sulfonyl)-5 by name, 6-dimethoxypyridin, structural formula is as follows:
Sulphormethoxine can be used for treating general inflammation clinically, as upper respiratory tract infection tonsillitis, bacillary dysentery enteritis, skin infections etc., also can with other medicine compatibilities, treatment pulmonary tuberculosis, lymphoid tuberculosis; It also has certain curative effect to leprosy (crazy) disease, also can treat malaria, and in addition, sulphormethoxine also can be made the prophylactic of rheumatic disease.During for such use, it is long that sulphormethoxine has curative effect, the feature that toxicity is low.
Sulphormethoxine has experienced several generations' research and development, domesticly in the eighties, starts development, and its production technique experience situ production of three to five years is progressively stable.Domestic sulphormethoxine traditional technology has been implemented nearly 30 years, goes through several generations' improvement, is limited to the condition restriction of scientific effort, comprises the restriction of novel material, new technology etc., does not have more suitably technique to substitute traditional technology always.Traditional sulphormethoxine makes as follows:
Step (1):
Step (2):
Step (3):
Step (4):
Step (5):
There is following problem in above-mentioned technique:
1, step (1) Ke Shi reaction is carried out raw material in sodium ethylate/ethanolic soln, and after decarbonylation, by first fractionation, remove low-boiling-point substance and (comprise unreacted raw material, intermediate A 3 etc.), then fractionation obtains intermediate 2-methoxyl group-propanedioic acid methyl ethyl ester, and the purity lower (generally lower than 92%) of the method gained 2-methoxyl group-propanedioic acid methyl ethyl ester is unfavorable for follow-up reaction, particularly, in large trial production, affected quality and the yield of sulphormethoxine product.
2, step (2) ring-closure reaction gained cyclocomplex is of poor quality: traditional method separates out cyclocomplex under acidic conditions, gained cyclocomplex (A5) can exist with hydroxylic species and two kinds of forms of hydroxyl sodium salt, because hydroxylic species has certain solubleness in water, make must repeatedly apply mechanically the mother liquor of ring-closure reaction in traditional technology, and make the salt concentration in mother liquor quite large because applying mechanically mother liquor, cause cyclocomplex (wherein having nearly 40% salt) of poor quality, the shortcomings such as material is clamminess, difficult oven dry; And the environment of slant acidity is to equipment pipe, whizzer, drying room all produces corrosive nature, and production site is not easy to clean.
3, the preparation of step (3) muriate (A6) must adopt N, accelerine is as catalyzer, make the recovery of catalyzer and apply mechanically the expense that generation is larger, and, muriate quality is garnet, to next step condensation reaction, be obviously disadvantageous, the color and luster of condensation reaction is partially red, directly can have influence on finished product (quality) color and luster partially yellow.
4, step (5) first oxidizing reaction adopts sodium methylate/methanol solution, in post-processing stages, reclaiming methyl alcohol is difficult for to the greatest extent, and recovery stage may cause bottoms material in (product) reactor to be heated inhomogeneous longer heat-up time, cause local superheating, produce decomposing phenomenon, and the color and luster of crude product is not ideal enough.
To sum up, the highest 65% left and right that only reaches of the total recovery of traditional method, production cost is higher, and the quality of product is to be further improved in addition.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, and a kind of preparation method of improved sulphormethoxine is provided.
The present invention also will provide a kind of preparation method of improved sulphormethoxine intermediate simultaneously.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
A preparation method for sulphormethoxine, it comprises the following step of carrying out successively:
(1), methoxy menthyl acetate and excessive oxalic acid diethyl ester are reacted under the existence of sodium ethylate generate 3-methoxyl group-oxosuccinic acid methyl ethyl ester, and make the further decarbonylation of 3-methoxyl group-oxosuccinic acid methyl ethyl ester obtain 2-methoxyl group-propanedioic acid methyl ethyl ester;
(2), step (1) gained 2-methoxyl group-propanedioic acid methyl ethyl ester is reacted under the existence of sodium methylate with methane amide and generate cyclocomplex;
(3), make step (2) gained cyclocomplex and phosphorus oxychloride reaction generate 4,6-dichloro-5-methoxy pyrimidine;
(4), make step (3) gained 4,6-dichloro-5-methoxy pyrimidine with SULFAMIDE sodium generation condensation reaction is generated to 4-(p-amino benzene sulfonyl)-5-methoxyl group-6-chloropyrimide;
(5), make step (4) gained 4-(p-amino benzene sulfonyl) 5-methoxyl group-6-chloropyrimide generation first oxidizing reaction generate 4-(p-amino benzene sulfonyl)-5,6-dimethoxypyridin,
In step (2), controlling gained cyclocomplex exists with anhydrous hydroxyl sodium-salt form;
In step (3), step (2) gained cyclocomplex and phosphorus oxychloride are refluxed at temperature 70 C～120 ℃, insulation reaction is more than 30 minutes, generate described 4,6-dichloro-5-methoxy pyrimidine.
According to further embodiment of the present invention: in step (3), after reaction finishes, reclaim under reduced pressure phosphorus oxychloride is dry to material, add trieline to dilute, then diluent is joined in 75 ℃ of following water, stir, stratification, repeatedly, the extracting solution that merges trieline, regulate pH to 6～7, standing branch vibration layer, puts into still pot Distillation recovery trieline by feed liquid, reclaim under reduced pressure is to flowing out without trieline again, blowing, is dried and obtains content at more than 98.5% muriate, and wherein dissolvent residual is less than 1%.Wherein, can adopt sodium bicarbonate aqueous solution or water to regulate pH to 6～7 of described extracting solution.
For reaching control step (2) cyclocomplex, with anhydrous hydroxyl sodium-salt form, exist, can take following method to realize: after the end of step (2) reaction, first normal temperature reclaims methyl alcohol, reclaim under reduced pressure, to not going out methyl alcohol, then adds water again, and normal pressure reclaims water methanol, centrifugation, after drying discharging, be dried, obtain moisture content at the cyclocomplex below 0.5%, wherein the cyclocomplex content of hydroxyl sodium-salt form is more than 92%.
According to the present invention, the reaction of step (2) is preferably carried out at 65 ℃～72 ℃ of temperature.The preferred implementation process of step (2) is as follows: in dry reactor, drop into liquid methanol sodium, stir, be heated to 60 ℃～68 ℃, add methane amide, then add step (1) gained 2-methoxyl group-propanedioic acid methyl ethyl ester, between 65 ℃～72 ℃ of control temperature, insulation refluxes more than 0.5 hour, finishes reaction.
Preferably, in step (1), described sodium ethylate is solid form, and the reaction that generates 3-methoxyl group-oxosuccinic acid methyl ethyl ester is carried out at temperature 45 C～65 ℃; After decarbonylation finishes, through separation column vacuum fractionation, reclaim low-boiling-point substance, described low-boiling-point substance is to be present in system all boiling points lower than the material of 2-methoxyl group-propanedioic acid methyl ethyl ester, divide and go after low-boiling-point substance, without separation column, direct cooling residual reaction liquid obtains purity and is more than or equal to 2-methoxyl group-propanedioic acid methyl ethyl ester of 95%.
According to further embodiment of the present invention: in step (1), the implementation process that generates the reaction of 3-methoxyl group-oxosuccinic acid methyl ethyl ester is: in dry reactor, add methoxy menthyl acetate and excessive oxalic acid diethyl ester, under agitation condition, solid sodium ethanol is dropped in reactor, and control reacting liquid temperature and be no more than 65 ℃, react after 3～5 hours, then at 45～65 ℃ of temperature insulation reaction more than 0.5 hour.Wherein: the preferred molar ratio of methoxy menthyl acetate and oxalic acid diethyl ester is 1: 1.02～1.18.
According to a preferred aspect of the present invention, after the reaction that generates 3-methoxyl group-oxosuccinic acid methyl ethyl ester finishes, reaction solution is first used to anhydrous organic solvent diluting, with inorganic aqueous acid, regulating pH is afterwards 1～2, standing, layering, wherein organic solvent layer reclaims after organic solvent, at 175～200 ℃ of temperature, normal pressure heat-insulating carries out decarbonylation for 2～5 hours.More specifically, by the reaction solution of dilution is cooled to below 15 ℃, joins and be cooled to the adjusting of carrying out described pH in 10 ℃ of following mixed solutions that formed by water, mineral acid and trieline.The organic solvent of dilution use is preferably trieline, and reclaims trieline by air distillation.Described mineral acid is preferably hydrochloric acid.The present invention also preferably adds trichloroethylene solvent in the low-boiling-point substance obtaining through fractionation, and vacuum fractionation is collected the part of just boiling, and obtains content at more than 90% oxalic acid diethyl ester.This oxalic acid diethyl ester can be applied mechanically.
The another technical scheme that the present invention takes is: a kind of preparation method of sulphormethoxine intermediate, and described sulphormethoxine intermediate is 4,6-dichloro-5-methoxy pyrimidine, described preparation method comprises the steps:
The first step: react under the existence of sodium methylate with methane amide and generate cyclocomplex by 2-methoxyl group-propanedioic acid methyl ethyl ester;
Second step: by the first step gained cyclocomplex and phosphorus oxychloride reaction, generated the step of 4,6-dichloro-5-methoxy pyrimidine,
Wherein, controlling the first step reaction gained cyclocomplex exists with anhydrous hydroxyl sodium-salt form;
In second step reaction, the first step gained cyclocomplex and phosphorus oxychloride are refluxed at temperature 70 C～120 ℃, insulation reaction is more than 30 minutes, 4 described in generating, 6-dichloro-5-methoxy pyrimidine.
More specifically, in the first step, after reaction finishes, first normal temperature reclaims methyl alcohol, then reclaim under reduced pressure is to not going out methyl alcohol, then add water, normal pressure reclaims water methanol, and centrifugation is dry after drying discharging, obtain moisture content at the cyclocomplex below 0.5%, wherein the cyclocomplex content of hydroxyl sodium-salt form is more than 92%.
In second step, after reaction finishes, reclaim under reduced pressure phosphorus oxychloride is dry to material, add trieline to dilute, then diluent is joined in 75 ℃ of following water, stir, stratification, repeatedly, merges the extracting solution of trieline, regulate pH to 6～7, standing branch vibration layer, puts into still pot Distillation recovery trieline by feed liquid, reclaim under reduced pressure is to flowing out without trieline again, blowing, is dried and obtains content at more than 98.5% muriate, and wherein dissolvent residual is less than 1%.
Synthetic route of the present invention is expressed as follows by chemical equation:
Owing to taking above technical scheme, the present invention compared with prior art tool has the following advantages:
By control step (2) gained cyclocomplex, the form with anhydrous hydroxyl sodium salt exists in the present invention, make when carrying out next step chlorination reaction, can not adopt N, N-xylidene(s) is made catalyzer, thereby can reduce costs and improve muriatic quality, finally improve the quality of sulphormethoxine.
The production cost of sulphormethoxine intermediate of the present invention is low, and purity is high, is conducive to reduce the production cost of sulphormethoxine and improves sulphormethoxine quality of finished.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the invention is not restricted to following examples.
Embodiment 1 preparation 2-methoxyl group-propanedioic acid methyl ethyl ester (A4)
(1) reaction equation is as follows:
(2) charge ratio is in Table 1.
Table 1
| Material name | Charging capacity (kg) | Molecular weight | Mol ratio |
| A1 (methoxy menthyl acetate) | 175 | 104 | 1 |
| A2 (oxalic acid diethyl ester) | 280 | 146 | 1.14 |
| Solid sodium ethanol | 130 | 68 | 1.12 |
(3) specific operation process is as follows:
By reactor dry (normal batch reaction reactor does not need washing), methoxy menthyl acetate is mixed in mixed ester pot with oxalic acid diethyl ester, and be cooled to below 10 ℃, add reactor, under agitation condition, solid sodium ethanol is poured in reactor into (sodium ethylate packing should not tear zero open, while feeding intake, should take sodium ethylate minimum package as unit, gradation is poured into), exothermic heat of reaction, control temperature of reaction and surpass 65 ℃, then be incubated more than 0.5 hour between 45～65 ℃ of temperature, make to react completely.
In dilution pot, add 280 liters of trielines (note: the trieline of dilution use should be anhydrous), dilution pot is first chilled to below 30 ℃ in advance, and reaction feed liquid is put into dilution pot, stirs cooling.Then feed liquid is pressed into acidifying storage tank.
In acidifying pot, put into 500 liters, water, 30% 200 liters of hydrochloric acid, 350 liters of trielines, are cooled to, below 10 ℃, add reaction solution, control temperature below 15 ℃, and (acidity must reach in pH=1～2! Peaceful acid is alkali not), static after acidifying, separate trieline layer and enter transfer pot, and be pressed in layering pot.Water layer is used trieline layer 200,200,200,150 repeatedly, 150,150,350 liters of extractions, and 350 liters of last extracting solution covers are used in down to be criticized.Trieline layer is treated stratification, and trieline layer below enters reinforced high-order.Normal pressure reclaims trichloroethylene solvent, and in final control, temperature is to 105～110 ℃, then reclaim under reduced pressure, does not finally go out to trieline, the trieline of recovery through water washing to recyclable applying mechanically after pH value 6～7.180 ± 2 ℃ of interior temperature, vacuum tightness-0.04～-0.053MPa, decarbonylation 4 hours, then underpressure distillation, collect vacuum tightness >=-0.095MPa, and temperature is Ke Shi thing A4 at 170 ± 10 ℃, finally steams to 180～190 ℃.Finally obtain, Ke Shi thing A4 content >=95% (GC), obtains weight range: 220～240kg
Embodiment 2 prepares cyclocomplex-hydroxyl sodium salt (A5)
(1) reaction equation is as follows:
(2) charge ratio is in Table 2.
Table 2
| Material name | Charging capacity (kg) | Molecular weight | Mol ratio |
| A4 (Ke Shi thing) | 240 | 176 | 1 |
| Methane amide | 186 | 45 | 3.37 |
| Liquid methanol sodium | 830 | 54 | 3.46 |
(3) specific operation process is as follows:
First that reactor is dry, drop into liquid methanol sodium, stir, be heated to 60～68 ℃, add methane amide, then add equably step (1) gained A4, it is 65～70 ℃ that control adds fashionable temperature, joining day is 1～1.5 hour, adds completely, and insulation reaction is more than 0.5 hour.Normal temperature reclaims methyl alcohol, then reclaim under reduced pressure methyl alcohol is to not going out, and then add water 1000L, normal pressure reclaims has water methanol to clarification, outlet temperature is cooled to below 40 ℃, starts discharging, centrifuge dehydration, dry discharging, enter recirculating air oven drying finally obtain moisture content below 0.5% and cyclocomplex-hydroxyl sodium salt HPLC content be more than or equal to cyclocomplex-hydroxyl sodium salt A5 of 92%.Every batch of positive lot number can obtain 200～212kg cyclocomplex-hydroxyl sodium salt.
Embodiment 3 prepares muriate (A6)
(1) reaction equation is as follows:
(2) charge ratio is in Table 3.
Table 3
| Material name | Charging capacity (kg) | Molecular weight | Mol ratio |
| A5 (cyclocomplex of embodiment 2 preparations) | 240 | 186 | 1 |
| Phosphorus Oxychloride | 825 | 153 | 4.17 |
| Trieline | 900 | 131 | / |
(3) specific operation process is as follows:
In reactor, (cover tightly pot cover), be pressed into the Phosphorus Oxychloride of getting ready in advance.Open and reflux and hydrogen chloride gas absorption unit, lead to and be steam heated to 40 ℃, steam off heats up naturally, start slowly to add cyclocomplex-hydroxyl sodium salt (A5), control adds speed, (adding the string temperature phenomenon that fashionable attention has burst, approximately ten to 20 minutes), add remaining cyclocomplex-hydroxyl sodium salt, within approximately 0.5～1.5 hour, add.Suitably need to be cooling, can open water quench to control interior temperature, open hydrogen chloride absorption device.Add after hydroxyl sodium salt, stablize after ten minutes, open heating (steam), to interior temperature, rise to 110～120 ℃ (117 ℃) and reflux and be incubated.Insulation is more than 0.5 hour, and reaction finishes (hydrogen chloride tail gas seldom).
In reclaiming Phosphorus Oxychloride pot (drying), reclaim under reduced pressure Phosphorus Oxychloride is dry to material, and steam off valve is cooled to 90～100 ℃, and the trieline 900L in a high position is put into and reclaims pot, stirs.In hydrolyzer, add water 1500kg, start and stir and open cooling, make hydrolysis temperature be no more than 75 ℃, the chlorated liquid of the trieline dilution in concentrating pan is added in hydrolyzer.After hydrolyzed solution stirs, layering in static 10 minutes, separates trieline layer position and extracts for the first time.While extracting for the second time, add 300 liters of trielines, while extracting for the third time, be pressed into 200 liters of trielines.(note: whether need to extract for the 4th time, see chloride in extracting solution for the third time number determine).United extraction liquid, in washing pot, neutralizes pH6.5～7 with soda ash, and closes pot cover and stop stirring, and washes 30 minutes with water and surveys pH6.5～7 with test paper, and washing is finished, and closes water, and standing 10 minutes, branch vibration layer, feed liquid is pressed into high-order storage tank; Put into still pot and reclaim trieline, steam off, then reclaim under reduced pressure is to flowing out without trieline, blowing, natural air drying obtains content at more than 98.5% muriate to dry, and wherein dissolvent residual is less than 1%, muriate A6 fusing point >=52 ℃, obtain weight range: 190～210kg.
Embodiment 4 preparation 4-(p-amino benzene sulfonyl)-5-methoxyl group-6-chloropyrimide (A7) (1) reaction equations:
(2) charge ratio is in Table 4.
Table 4
| Material name | Charging capacity (kg) | Molecular weight | Mol ratio |
| A6 (muriates of embodiment 3 preparations) | 88 | 179 | 1 |
| Sulfanilamide (SN) sodium | 200～210 | 194 | 1.93 |
| Dimethyl formamide (DMF) | 270 | 73 | / |
| Hydrochloric acid | 60 | 38 | / |
(3) specific operation process is as follows:
Under room temperature, 270kg dimethyl formamide is dropped in dry condensation reaction pot, start stirring, drop into half sulfanilamide (SN) sodium, then drop into 72kg 5-methoxyl group-4,6-dichloro pyrimidine (A 6), finally drops into half sulfanilamide (SN) sodium of remainder in the lump.Naturally be warming up to 60 ℃, survey pH value 8～9, when (available chilled water modulation) controls temperature to 90 ± 2 ℃, survey pH value 8～9 and be incubated 1.5 hours; Insulation finishes, and drives vacuum pump, reclaims D.M.F, controls vacuum tightness >=-0.098MPa, and outlet temperature is 120～130 ℃ (interior temperature). and yield is in 250Kg left and right (recyclable the applying mechanically of DMF moisture≤3.0% of recovery); Then the hot water that adds 500Kg90～100 ℃, after all dissolving, is pressed into cooling pan, prepares in advance cooling pan and adds water at 300～400L; Then, then 6 add 10～15% hydrochloric acid, and regulating pH is 7.0～7.2, is cooled to 15～20 ℃, centrifugation sulfanilamide (SN), be washed with water to mother liquid coming clear till, dry; Temperature, at 70 ± 2 ℃, drips 10～15% hydrochloric acid acid out, acid out endpoint pH 3.8～4.1, and it is slow that sedimentation speed is wanted, and is controlled at 20～40 minutes, and then centrifuge dehydration is clarified with 90 ℃ of above hot wash to liquid outlets, dries discharging; In 110 ± 5 ℃ dry 1.5～3 hours, cooling discharging, please test analysis, content >=90%, fusing point >=193 ℃, moisture≤0.5%, condenses A7 obtains weight range: 120～130kg.
Embodiment 5 prepares sulphormethoxine (A8)
(1) reaction equation:
(2) charge ratio is referring to table 5.
Table 5
| Material name | Charging capacity (kg) | Molecular weight | Mol ratio |
| A7 (condensess of embodiment 4 preparations) | 240 | 324.5 | 1 |
| Methyl alcohol | 960 | 32 | / |
| Solid sodium hydroxide | 103 | 40 | 3.66 |
| Gac | 20 | 12 | / |
| Glacial acetic acid | 100 | 60 | / |
(3) concrete operations are as follows:
A methyl alcohol suction high position is put into reactor, and opening clamp packs into water coolant, opens reverse flow valve, drops into solid sodium hydroxide, opens stirring, controls temperature and does not surpass 60 ℃; Stablize after 10 minutes, drop into condenses, be slowly warming up to 69～72 ℃, reflux insulation more than 0.5 hour, reaction finishes; Closing volume valve, normal pressure reclaims anhydrous methanol, then reclaim under reduced pressure is not to going out methyl alcohol depending on cup, closes without water valve and opens and have water valve, more than adding the about 100Kg of water, more than continuing to reclaim and having water methanol to 80 ℃, feed liquid is pressed into dissolving pan; With 25～30% hydrochloric acid, reacting liquid pH value is transferred to 9.5～10.5, adds water and make the about 2000L of total amount, pour gac 20Kg into, 60 ℃ of insulation decolourings 1 hour; Decolouring is finished, feed liquid is back to clearly through pressure filter, is delivered to crude product clarifying kettle, at 60 ℃ of above glacial acetic acid solutions that slowly drip, to pH value 4.5～6 be terminal, after stirring repetition measurement pH value is errorless, centrifuge dehydration, washes with water, dry discharging and obtain Sulphadoxine crude product (damp product) A8, weight loss on drying≤20%, content >=98%, obtains weight range: 250～280kg.
The refining sulphormethoxine finished product that obtains of embodiment 6
Table 6
| Material name | Charging capacity (kg) | Molecular weight | Mol ratio |
| A8 (embodiment 5 obtain | Complete batch | 310.33 | 1 |
| Sulphadoxine crude product) | |||
| Purified water | 2000 | 18 | / |
| Calcium hydroxide | 20 | 74.08 | / |
| Gac | 12.5 | 12 | / |
| Glacial acetic acid | 35 | 60 | / |
In Decolouring pot, add purified water, calcium hydroxide, heating; Under stirring, add crude product, more than adjusting pH value to 9 it is entirely molten, adds gac, and temperature is more than 60 ℃, and insulation is more than 0.5 hour; Through pressure filter, be back to clearly, by being covered with the monolithic pressure filter of two metafiltration cloth one deck filter paper, be delivered in clean fine work crystallizing pan, more than 60 ℃, drip glacial acetic acid solution, to pH value 4.5～6, repetition measurement pH value is constant, purified water wash crystallization pot for centrifuge dehydration, and filter cake washs to liquid outlet and clarifies by purified water, centrifuge dripping 30 minutes, discharging; Damp product uniform spreading, in drip pan, is put into heat-circulation oven dry, be cooled to 45 ℃ with bottom discharge.Pulverize and sieve after (determining smashing fineness according to customer requirement), pack finished product turnover barrel into, weigh, please test analysis, analyze qualified after, send into and mix post and mix, produce to obtain weight range: 200～210kg for every batch; Mixing, wrapping process: after production batch analysis is qualified, several batches of finished products need mix through V-type rotary blender, mix 10 minutes at every turn, static, put into one by one finished barrel, weigh, after QC sampling inspection is qualified, packing (25kg/ bucket forms 500kg/ business and criticizes) warehouse-in.
The above embodiments 1 to 6 have formed the integral production technique of sulphormethoxine, and on the whole, it has following features:
1, technique is succinct, easy to operate, and the quality of product is improved.
2, starting material unit consumption has larger decline, and this is because the technique after improving is very easy to operate, produces highly stable; Raw materials cost drops to 110,000 left and right from 150,000 left and right, and by producing 400 tons of left and right per year, this technique is brought considerable economic benefit.
3, the maintenance of equipment and maintenance are improved greatly, fully demonstrate in cyclization, on the post of chlorination reaction.
4, production environment is improved greatly, owing to stopping using N, and N-xylidene(s), production plant does not have N completely, the taste of N-xylidene(s).
5, the application of this technique, has greatly improved the discharge of the three wastes, has alleviated the pressure of environmental protection treatment.The aftertreatment wastewater flow rate in chlorination post reduces, and through simple process after the phosphoric acid solution of high density, by phosphate fertilizer plant, be converted into phosphate fertilizer and be generalized to agriculture production later, the phosphorus that reduces every year up to a hundred tons discharges.
Above the present invention is described in detail; its object is to allow the personage who is familiar with this art can understand content of the present invention and be implemented; can not limit the scope of the invention with this; the equivalence that all spirit according to the present invention are done changes or modifies, and all should be encompassed in protection scope of the present invention.
Claims (10)
1. a preparation method for sulphormethoxine, it comprises the following step of carrying out successively:
(1), methoxy menthyl acetate and excessive oxalic acid diethyl ester are reacted under the existence of sodium ethylate generate 3-methoxyl group-oxosuccinic acid methyl ethyl ester, and make the further decarbonylation of 3-methoxyl group-oxosuccinic acid methyl ethyl ester obtain 2-methoxyl group-propanedioic acid methyl ethyl ester;
(2), step (1) gained 2-methoxyl group-propanedioic acid methyl ethyl ester is reacted under the existence of sodium methylate with methane amide and generate cyclocomplex;
(3), make step (2) gained cyclocomplex and phosphorus oxychloride reaction generate 4,6-dichloro-5-methoxy pyrimidine;
(4), make step (3) gained 4,6-dichloro-5-methoxy pyrimidine with SULFAMIDE sodium generation condensation reaction is generated to 4-(p-amino benzene sulfonyl)-5-methoxyl group-6-chloropyrimide;
(5), make step (4) gained 4-(p-amino benzene sulfonyl) 5-methoxyl group-6-chloropyrimide generation first oxidizing reaction generate 4-(p-amino benzene sulfonyl)-5,6-dimethoxypyridin,
It is characterized in that:
In step (2), controlling gained cyclocomplex exists with anhydrous hydroxyl sodium-salt form;
In step (3), step (2) gained cyclocomplex and phosphorus oxychloride are refluxed at temperature 70 C～120 ℃, insulation reaction is more than 30 minutes, generate described 4,6-dichloro-5-methoxy pyrimidine.
2. the preparation method of a kind of sulphormethoxine according to claim 1, it is characterized in that: in step (3), after reaction finishes, reclaim under reduced pressure phosphorus oxychloride is dry to material, add trieline to dilute, then diluent is joined in 75 ℃ of following water, stir, stratification, repeatedly, the extracting solution that merges trieline, regulate pH to 6～7, standing branch vibration layer, feed liquid is put into still pot Distillation recovery trieline, reclaim under reduced pressure is to flowing out without trieline again, blowing, be dried and obtain content at more than 98.5% muriate, wherein dissolvent residual is less than 1%.
3. the preparation method of a kind of sulphormethoxine according to claim 2, is characterized in that: in step (3), adopt sodium bicarbonate aqueous solution or water to regulate pH to 6～7 of described extracting solution.
4. the preparation method of a kind of sulphormethoxine according to claim 1, it is characterized in that: after the end of step (2) reaction, first normal temperature reclaims methyl alcohol, reclaim under reduced pressure, to not going out methyl alcohol, then adds water again, and normal pressure reclaims water methanol, centrifugation, after drying discharging, be dried, obtain moisture content at the cyclocomplex below 0.5%, wherein the cyclocomplex content of hydroxyl sodium-salt form is more than 92%.
5. the preparation method of a kind of sulphormethoxine according to claim 4, is characterized in that: the reaction of step (2) is carried out at 65 ℃～72 ℃ of temperature.
6. the preparation method of a kind of sulphormethoxine according to claim 5, it is characterized in that: described in step (2), the implementation process of reaction is as follows: in dry reactor, drop into liquid methanol sodium, stir, be heated to 60 ℃～68 ℃, add methane amide, then add step (1) gained 2-methoxyl group-propanedioic acid methyl ethyl ester, control between 65 ℃～72 ℃ of temperature, insulation refluxes more than 0.5 hour, finishes reaction.
7. the preparation method of sulphormethoxine according to claim 1, is characterized in that: control the purity of step (1) gained 2-methoxyl group-propanedioic acid methyl ethyl ester more than 95wt%.
8. a preparation method for sulphormethoxine intermediate, described sulphormethoxine intermediate is 4,6-dichloro-5-methoxy pyrimidine, described preparation method comprises the steps:
The first step: react under the existence of sodium methylate with methane amide and generate cyclocomplex by 2-methoxyl group-propanedioic acid methyl ethyl ester;
Second step: by the first step gained cyclocomplex and phosphorus oxychloride reaction, generated the step of 4,6-dichloro-5-methoxy pyrimidine,
It is characterized in that: control the first step reaction gained cyclocomplex and exist with anhydrous hydroxyl sodium-salt form;
In second step reaction, the first step gained cyclocomplex and phosphorus oxychloride are refluxed at temperature 70 C～120 ℃, insulation reaction is more than 30 minutes, 4 described in generating, 6-dichloro-5-methoxy pyrimidine.
9. the preparation method of a kind of sulphormethoxine intermediate according to claim 8, it is characterized in that: in the first step, after reaction finishes, first normal temperature reclaims methyl alcohol, then reclaim under reduced pressure is to not going out methyl alcohol, then add water, normal pressure reclaims water methanol, and centrifugation is dry after drying discharging, obtain moisture content at the cyclocomplex below 0.5%, wherein the cyclocomplex content of hydroxyl sodium-salt form is more than 92%.
10. the preparation method of a kind of sulphormethoxine intermediate according to claim 8, it is characterized in that: in second step, after reaction finishes, reclaim under reduced pressure phosphorus oxychloride is dry to material, add trieline to dilute, then diluent is joined in 75 ℃ of following water, stir, stratification, repeatedly, the extracting solution that merges trieline, regulate pH to 6～7, standing branch vibration layer, feed liquid is put into still pot Distillation recovery trieline, reclaim under reduced pressure is to flowing out without trieline again, blowing, be dried and obtain content at more than 98.5% muriate, wherein dissolvent residual is less than 1%.
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| CN103910687B (en) * | 2014-03-10 | 2016-05-11 | 常熟市南湖实业化工有限公司 | The preparation method of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine |
| CN104003942A (en) * | 2014-03-10 | 2014-08-27 | 常熟市南湖实业化工有限公司 | 5-methoxyl-4,6-dichloropyrimidine preparing method capable of preventing temperature fluctuation phenomenon from occurring |
| CN103864700B (en) * | 2014-03-10 | 2016-08-24 | 常熟市金申医化制品有限责任公司 | The preparation method of 5-methoxyl group-4,6-dihydroxy pyrimidine disodium |
| CN103864701B (en) * | 2014-03-10 | 2016-08-24 | 常熟市金申医化制品有限责任公司 | The preparation method of 4-sulfanilamide-5-methoxyl group-6-chloropyrimide |
| CN104910081A (en) * | 2014-03-15 | 2015-09-16 | 菏泽市方明制药有限公司 | Preparation method of sulfachloropyrazine sodium |
| CN104326988B (en) * | 2014-09-30 | 2016-06-08 | 大连九信生物化工科技有限公司 | A kind of synthetic method of 2,4-dichloro-5-methoxy pyrimidines |
| CN104557735B (en) * | 2014-12-04 | 2017-03-22 | 重庆康乐制药有限公司 | Preparation method of sulfadoxine |
| 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 |
| CN105085255B (en) * | 2015-08-12 | 2018-03-09 | 内蒙古佳瑞米精细化工有限公司 | A kind of synthesis technique of the oxo succinate of 2 alkoxy of imidazolinone herbicide intermediate 3 |
| CN105153044A (en) * | 2015-09-15 | 2015-12-16 | 桂林南药股份有限公司 | Method for one-pot synthesis of sulfadoxine by monitoring reaction progress through HPLC |
| CN109557200A (en) * | 2018-11-23 | 2019-04-02 | 重庆康乐制药有限公司 | A method of use gas chromatography monitoring methoxyl group oxalacetic acid methyl ethyl ester decarbonylation for methoxy propyl diacid methyl ethyl ester reaction end |
| CN111484456A (en) * | 2020-05-11 | 2020-08-04 | 常熟市金申医化制品有限责任公司 | Refining process of 5-methoxy-4, 6-dichloropyrimidine |
| CN114874148A (en) * | 2022-03-09 | 2022-08-09 | 江苏金申医药科技有限公司 | Sulfadoxine fine processing technology |
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