CN102311393A - Preparation method of sulfadoxine - Google Patents
Preparation method of sulfadoxine Download PDFInfo
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- CN102311393A CN102311393A CN201110285789A CN201110285789A CN102311393A CN 102311393 A CN102311393 A CN 102311393A CN 201110285789 A CN201110285789 A CN 201110285789A CN 201110285789 A CN201110285789 A CN 201110285789A CN 102311393 A CN102311393 A CN 102311393A
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Abstract
A preparation method of sulfadoxine belongs to the field of sulfanilamide antimicrobial drug preparation. Cyclization reaction comprises the following steps of: firstly pouring a sodium methoxide solution into a reactive pan, then successively adding methanamide and methyl ethyl methoxymalonate, keeping warm, recovering methanol, cooling for crystallization, drying by centrifugation, discharging, and drying to obtain 5-methoxy-4,6-disodium dihydroxypyrimidine; Chlorination reaction comprises the following steps of: firstly putting phosphorus oxychloride into a reaction vessel for heating, adding 5-methoxy-4,6-disodium dihydroxypyrimidine into the reaction vessel to react, decompressing and recovering phosphorus oxychloride until the material is dry, cooling, adding trichloro ethylene with uniformly stirring, putting into a hydrolysis pan for hydrolyzation, collecting a trichloro ethylene layer after standing and delaminating, followed by a neutralization reaction, controlling pH value, washing, removing a water layer, recovering trichloro ethylene, and releasing crystals to obtain 5-methoxy-4,6-dichloropyrimidine. The preparation method provided by the invention can be used to guarantee the product purity, prolong the service life of equipment, avoid the damage to the environment and human body, reduce emission, and save energy, and accords with foreign pharmacopoeia standard requirements.
Description
Technical field
The invention belongs to disulfonamide thing preparing technical field, be specifically related to a kind of preparation method of Sulphadoxine
Background technology
The chemistry of Sulphadoxine (SDM) is by name: 4-(to the aminosulfonyl amido) 5,6-dimethoxypyridin; English name is: Sulfadoxine; Latin is by name: Sulphamethoxinum or Sulfadimoxine; Molecular formula is C
12
H
14
O
4
N
4
S; Molecular weight is 310.33.
Sulphadoxine is also claimed sulphormethoxine, fanasil or 4-sulfanilamide (SN)-5; 6 dimethoxypyridins are white or off-white color crystalline powder, mildly bitter flavor, odorless, chance light gradual change look; Be slightly soluble in water, methyl alcohol and ethanol; Be insoluble to ether, dissolve in sodium hydroxide and the diluted mineral acid, belong to the disulfonamide thing.Sulphadoxine has the long and low characteristics of toxicity of curative effect; Can treat general inflammation;, bacillary dysentery enteritis scorching and skin infections etc. like the upper respiratory tract infection flat conductor, and treatment pulmonary tuberculosis, lymphoid tuberculosis etc. are had certain curative effect with other medicine compatibilities, also can treat malaria.Can be used as the prophylactic of rheumatism venereal disease in addition.China is listed Sulphadoxine in " Chinese new high-tech product export list " (2003).
Sulphadoxine is very few in disclosed Chinese patent document, through retrieval, only searches the preparation method of the sulphormethoxine of ZL200410014838.2 introduction.
are at present known also promptly roughly to be had following four kinds by the preparation method of the Sulphadoxine that industry adopted: first method is that methoxyimino acetic acid methyl esters and oxalic acid diethyl ester are made through Ke Shi, cyclization, chlorination, condensation and methoxy reaction; Second method is that ethyl malonate and methane amide cyclization are made through bromination, chlorination, condensation and methoxy reaction; The third method is that the methoxyimino acetic acid methyl esters is made through bromination, cyaniding, cyclization, desulfurization, chlorination, condensation and hydrolysis acid precipitation reaction; The 4th kind of method is that 4-sulfanilamide (SN)-6 methoxy pyrimidine (being RP-7522) bromination, methoxyization and hydrolysis acid precipitation reaction are made.
Back three kinds of methods of
above-mentioned four kinds of methods have common characteristic; That is, all there are bromination and monohydroxy pyrimidine chlorination reaction step, owing to need to use bromine as raw material; Therefore higher to equipment requirements, and human body had certain toxic.In addition, the yield of monohydroxy pyrimidine chlorination reaction is merely about 40%, is difficult to be fit to the industrial amplification production requirement, more properly says the value that does not have suitability for industrialized production.Therefore, people do not think highly of in back three kinds of methods, and generally use first method, and aforesaid ZL200410014838.2 promptly belongs to first method.Though the first method step is many, raw materials used technology is also comparatively ripe all than being prone to acquisition, and yield is also comparatively stable, and is not high to equipment requirements in addition, is easy to produce.
still; Above-mentioned first method also exists people to expect to solve and unsolved all the time up to now technical problem; Particularly: the related substance in the finished product has a certain distance through detecting between 0.5-1% (" Chinese pharmacopoeia Sulphadoxine related substance≤1.0%) with external standards of pharmacopoeia≤0.5%.
produce one of reason of the problems referred to above (related substance is that impurity is high), owing to the ring-closure reaction mother liquid recycle causes product viscosity big through the applicant's analysis for many years; Cause impurity to be wrapped and be difficult to separating; Be difficult for exsiccation again, difficult dry, be prone to impurity is brought in the finished product; And will under acidic conditions, separate out, and the environment of slant acidity all produces corrosive nature to equipment such as pipeline, whizzer and drying room etc.; Two because chlorination reaction is used catalyzer " N, N-xylidene(s) "; Thus except environment is polluted, and toxicity has injury to human body greatly, and the catalyst n that uses; The N-xylidene(s) also must reclaim and apply mechanically; Cause the product quality outward appearance to be garnet, be unfavorable for next step reaction, badly influence the quality of final finished.
On the mirror, be necessary the preparation method of the Sulphadoxine in the prior art is improved, the technical scheme that will introduce below produces under this background
Summary of the invention
task of the present invention is to provide a kind of product viscosity that in ring-closure reaction, is caused by mother liquid recycle that helps avoid to increase and cause impurity to be wrapped and be difficult to separate, be difficult for crystallization and dry difficulty and use the guarantee product purity; Help preventing under sour environment equipment produced heavy corrosion and use protection equipment and prolong work-ing life of equipment, be of value to elimination and in chlorination reaction, use N-N-xylidene(s) catalyzer and use and avoid undermining operator's health and undermine environment and use the remarkable preparation method who improves the Sulphadoxine of quality product.
Task of the present invention is accomplished like this, and a kind of preparation method of Sulphadoxine comprises ring-closure reaction and chlorination reaction, is characterised in that:
Described ring-closure reaction is: in reactor, drop into sodium methoxide solution earlier, and heating under whipped state, then add methane amide and methoxy propyl diacid methyl ethyl ester successively; Temperature of reaction when control adds methoxy propyl diacid methyl ethyl ester, insulation is reclaimed methyl alcohol then and is reclaimed methyl alcohol to continuing to add water to the greatest extent; Crystallisation by cooling, centrifuge dripping, discharging oven dry; Obtain 5-methoxyl group-4,6-dihydroxy-pyrimidine disodium;
described chlorination reaction is: Phosphorus Oxychloride dropped in the reaction kettle heat earlier, and the control Heating temperature, again with described 5-methoxyl group-4,6-dihydroxy-pyrimidine disodium joins said reaction kettle for reaction; Control adds 5-methoxyl group-4, and the temperature of reaction during 6-dihydroxy-pyrimidine disodium finishes back intensification and insulation, and then reclaim under reduced pressure Phosphorus Oxychloride to material is done; Be cooled to design temperature, add and introduce the hydrolyzer hydrolysis, the control hydrolysis temperature after trieline stirs; Treat to collect the trieline layer behind the standing demix, with the solid sodium bicarbonate neutralization, control pH value; Use water washing, branch vibration layer reclaims the trieline after washing; Emit crystallization, obtain 5-methoxyl group-4, the 6-dichloro pyrimidine.
in a concrete embodiment of the present invention, in described ring-closure reaction, the described whipped state temperature of heating adding methane amide down is 60-70 ℃.
are in another concrete embodiment of the present invention; In described ring-closure reaction; Temperature of reaction when described control adds methoxy propyl diacid methyl ethyl ester is that temperature of reaction is controlled to be 65-75 ℃; And the adding mode of methoxy propyl diacid methyl ethyl ester adds for dripping, and the dropping time of methoxy propyl diacid methyl ethyl ester is 60-120min.
in another concrete embodiment of the present invention, in described ring-closure reaction, the time of described insulation is 4-6h, and the temperature of described crystallisation by cooling is less than 25 ℃.
are in another concrete embodiment of the present invention; In described ring-closure reaction, described sodium methoxide solution, methane amide and methoxy propyl diacid methyl ethyl ester three's weight ratio is 3-4: 0.5-1: the mass percent concentration of the described sodium methoxide solution of 0.9-1 is 27-32%.
also have among the concrete embodiment of the present invention, and in described chlorination reaction, described control Heating temperature is to be 70-90 ℃ with heating and temperature control.
more of the present invention and among concrete embodiment, in described chlorination reaction, described control adds 5-methoxyl group-4, the temperature of reaction during 6-dihydroxy-pyrimidine disodium is that temperature of reaction is controlled to be 60-90 ℃.
in described chlorination reaction, describedly finish to heat up in the back and insulation is meant temperature is risen to 100-130 ℃ in of the present invention and then concrete embodiment, soaking time is controlled to be 4-6h.
of the present invention again more and among concrete embodiment, and in described chlorination reaction, the described design temperature that is cooled to is meant and is cooled to 50-90 ℃; Described control hydrolysis temperature is hydrolysis temperature to be controlled to be no more than 30-70 ℃; Described control pH value is that the pH value is controlled to be 6-8.
in again of the present invention and then concrete embodiment, in described chlorination reaction, described Phosphorus Oxychloride, 5-methoxyl group-4, the weight ratio of 6-dihydroxy-pyrimidine disodium and trieline is 3-3.5: 0.9-1: 3-3.5.
One of advantage of
technical scheme provided by the invention; Ring-closure reaction by in the prior art acid out change alkali into and analyse; Can not cause that because of need not to apply mechanically mother liquor product viscosity increases and then generation is wrapped up impurity; Generation has the two hydroxyl sodium salts of crystallinity particulate and is prone to dehydrate, and reduces the finished product of bringing into of impurity, thereby can ensure product purity; Two owing to adopted alkali to analyse, therefore help avoiding undermining equipment, prolong the work-ing life of equipment; Three because chlorination reaction abandoned use N, N-xylidene(s) catalyzer; Thereby be of value to avoid undermining environment with prevent the human injury, simultaneously, because of having abandoned use N; Therefore the N-xylidene(s) can avoid applying mechanically the influence of the finished product outward appearance that is produced, and it is energy-conservation to embody reduction of discharging; Four, adopt by the resulting 5-methoxyl group-4 of chlorination reaction of the present invention, the prepared final finished Sulphadoxine purity of 6-dichloro pyrimidine is high, related substance≤0.5% can meet external standards of pharmacopoeia requirement.
Embodiment
can be expressly understood technical spirit of the present invention and beneficial effect more for the inspector that the makes Patent Office especially public; The applicant general elaborates with the mode of embodiment below; But the description to embodiment all is not the restriction to the present invention program, any according to the present invention done only for pro forma but not substantial equivalent transformation all should be regarded as technical scheme category of the present invention.
Embodiment 1:
The preparation method of
Sulphadoxine provided by the invention comprises ring-closure reaction and chlorination reaction.
Ring-closure reaction is:
With by weight and mass percent concentration be 32% (sodium methoxide solution 1240kg puts into the reactor that is used for ring-closure reaction, and under whipped state, is heated to 70 ℃, then adds methane amide 310kg by weight; And (splash into methoxy propyl diacid methyl ethyl ester 310kg by weight, the temperature of reaction (also can claim dropping temperature) when dripping methoxy propyl diacid methyl ethyl ester is controlled to be 75 ℃, and insulation is insulation reaction 6h in 120min; Reclaim methyl alcohol then and continue to reclaim methyl alcohol and do not ooze, crystallisation by cooling, crystallisation by cooling temperature＜25 ℃ to there being cut to adding water to the greatest extent; The back centrifuge dripping is separated out in crystallization fully; The discharging oven dry obtains 269kg ring-closure reaction product and promptly obtains 5-methoxyl group-4,6-dihydroxy-pyrimidine disodium; For use, wherein: yield is 82.11%;
Chlorination reaction is:
will be heated to 90 ℃ in the Phosphorus Oxychloride 857.5kg input exsiccant reaction kettle by weight, will be 5-methoxyl group-4 again by the product that ring-closure reaction obtains, and 6-dihydroxy-pyrimidine disodium 245kg slowly joins reaction kettle for reaction; Add 5-methoxyl group-4, the temperature of reaction during 6-dihydroxy-pyrimidine disodium is controlled to be 90 ℃, finishes; That is to say adding 5-methoxyl group-4, be warming up to 130 ℃ behind the 6-dihydroxy-pyrimidine, and keep 6h (being insulation reaction 6h) down at these 130 ℃; Insulation reaction finishes the back and does (range estimation reclaim basic absence of liq oozes in the fluid visor) at vacuum tightness>=0.06MPa reclaim under reduced pressure Phosphorus Oxychloride to material, is cooled to 90 ℃ then, adds trieline 857.5kg by weight and stirs the hydrolysis of back introducing hydrolyzer; Hydrolysis temperature is 70 ℃, stops to stir standing demix, collects the trieline layer; And be neutralized to pH8 with solid sodium hydroxide, use water washing, branch vibration layer; Reclaiming the trieline after the washing, specifically is the trieline after the washing to be put into still pot reclaim, and is recycled to trieline and no longer flows out; Emit crystallization, obtain chlorizate, promptly obtain 5-methoxyl group-4; 6-dichloro pyrimidine 195kg, yield are 82.7%.
Embodiment 2:
The preparation method of
Sulphadoxine provided by the invention comprises ring-closure reaction and chlorination reaction.
Ring-closure reaction is:
With by weight and mass percent concentration be that 29.5% sodium methoxide solution 1085kg puts into the reactor that is used for ring-closure reaction, and under whipped state, be heated to 65 ℃, then add methane amide 232.5kg by weight; And in 90min, splash into methoxy propyl diacid methyl ethyl ester 294.5kg by weight, and the temperature of reaction (also can claim dropping temperature) when dripping methoxy propyl diacid methyl ethyl ester is controlled to be 70 ℃, and insulation is insulation reaction 5h; Reclaim methyl alcohol then and continue to reclaim methyl alcohol and do not ooze, crystallisation by cooling, crystallisation by cooling temperature＜25 ℃ to there being cut to adding water to the greatest extent; The back centrifuge dripping is separated out in crystallization fully; The discharging oven dry obtains 253kg ring-closure reaction product and promptly obtains 5-methoxyl group-4,6-dihydroxy-pyrimidine disodium; For use, wherein: yield is 81.29%;
Chlorination reaction is:
will be heated to 80 ℃ in the Phosphorus Oxychloride 796kg input exsiccant reaction kettle by weight, will be 5-methoxyl group-4 again by the product that ring-closure reaction obtains, and 6-dihydroxy-pyrimidine disodium 232.8kg slowly joins reaction kettle for reaction; Add 5-methoxyl group-4, the temperature of reaction during 6-dihydroxy-pyrimidine disodium is controlled to be 75 ℃, finishes; That is to say adding 5-methoxyl group-4, be warming up to 115 ℃ behind the 6-dihydroxy-pyrimidine, and keep 5h (being insulation reaction 5h) down at these 115 ℃; Insulation reaction finishes the back and does (range estimation reclaim basic absence of liq oozes in the fluid visor) at vacuum tightness>=0.06MPa reclaim under reduced pressure Phosphorus Oxychloride to material, is cooled to 70 ℃ then, adds trieline 796kg by weight and stirs the hydrolysis of back introducing hydrolyzer; Hydrolysis temperature is 50 ℃, stops to stir standing demix, collects the trieline layer; And be neutralized to pH7 with solid sodium hydroxide, use water washing, branch vibration layer; Reclaiming the trieline after the washing, specifically is the trieline after the washing to be put into still pot reclaim, and is recycled to trieline and no longer flows out; Emit crystallization, obtain chlorizate, promptly obtain 5-methoxyl group-4; 6-dichloro pyrimidine 195kg, yield are 87.04%.
Embodiment 3:
The preparation method of
Sulphadoxine provided by the invention comprises ring-closure reaction and chlorination reaction.
Ring-closure reaction is:
With by weight and mass percent concentration be that 27% sodium methoxide solution 930kg puts into the reactor that is used for ring-closure reaction, and under whipped state, be heated to 60 ℃, then add methane amide 155kg by weight; And in 60min, splash into methoxy propyl diacid methyl ethyl ester 279kg by weight, and the temperature of reaction (also can claim dropping temperature) when dripping methoxy propyl diacid methyl ethyl ester is controlled to be 65 ℃, and insulation is insulation reaction 4h; Reclaim methyl alcohol then and continue to reclaim methyl alcohol and do not ooze, crystallisation by cooling, crystallisation by cooling temperature＜25 ℃ to there being cut to adding water to the greatest extent; The back centrifuge dripping is separated out in crystallization fully; The discharging oven dry obtains 258kg ring-closure reaction product and promptly obtains 5-methoxyl group-4,6-dihydroxy-pyrimidine disodium; For use, wherein: yield is 87.49%;
Chlorination reaction is:
will be heated to 70 ℃ in the Phosphorus Oxychloride 735kg input exsiccant reaction kettle by weight, will be 5-methoxyl group-4 again by the product that ring-closure reaction obtains, and 6-dihydroxy-pyrimidine disodium 220.5kg slowly joins reaction kettle for reaction; Add 5-methoxyl group-4, the temperature of reaction during 6-dihydroxy-pyrimidine disodium is controlled to be 60 ℃, finishes; That is to say adding 5-methoxyl group-4, be warming up to 100 ℃ behind the 6-dihydroxy-pyrimidine, and keep 4h (being insulation reaction 4h) down at these 100 ℃; Insulation reaction finishes the back and does (range estimation reclaim basic absence of liq oozes in the fluid visor) at vacuum tightness>=0.06MPa reclaim under reduced pressure Phosphorus Oxychloride to material, is cooled to 50 ℃ then, adds trieline 735kg by weight and stirs the hydrolysis of back introducing hydrolyzer; Hydrolysis temperature is 30 ℃, stops to stir standing demix, collects the trieline layer; And be neutralized to pH6 with solid sodium hydroxide, use water washing, branch vibration layer; Reclaiming the trieline after the washing, specifically is the trieline after the washing to be put into still pot reclaim, and is recycled to trieline and no longer flows out; Emit crystallization, obtain chlorizate, promptly obtain 5-methoxyl group-4; 6-dichloro pyrimidine 190kg, yield are 89.54%.
Embodiment 4:
The preparation method of
Sulphadoxine provided by the invention comprises ring-closure reaction and chlorination reaction.
Ring-closure reaction is:
With by weight and mass percent concentration be that 30% sodium methoxide solution 1162.5kg puts into the reactor that is used for ring-closure reaction, and under whipped state, be heated to 67 ℃, then add methane amide 279kg by weight; And in 100min, splash into methoxy propyl diacid methyl ethyl ester 303.8kg by weight, and the temperature of reaction (also can claim dropping temperature) when dripping methoxy propyl diacid methyl ethyl ester is controlled to be 72 ℃, and insulation is insulation reaction 6h; Reclaim methyl alcohol then and continue to reclaim methyl alcohol and do not ooze, crystallisation by cooling, crystallisation by cooling temperature＜25 ℃ to there being cut to adding water to the greatest extent; The back centrifuge dripping is separated out in crystallization fully; The discharging oven dry obtains 281kg ring-closure reaction product and promptly obtains 5-methoxyl group-4,6-dihydroxy-pyrimidine disodium; For use, wherein: yield is 87.52%;
Chlorination reaction is:
will be heated to 85 ℃ in the Phosphorus Oxychloride 833kg input exsiccant reaction kettle by weight, will be 5-methoxyl group-4 again by the product that ring-closure reaction obtains, and 6-dihydroxy-pyrimidine disodium 240kg slowly joins reaction kettle for reaction; Add 5-methoxyl group-4, the temperature of reaction during 6-dihydroxy-pyrimidine disodium is controlled to be 80 ℃, finishes; That is to say adding 5-methoxyl group-4, be warming up to 120 ℃ behind the 6-dihydroxy-pyrimidine, and keep 6h (being insulation reaction 6h) down at these 120 ℃; Insulation reaction finishes the back and does (range estimation reclaim basic absence of liq oozes in the fluid visor) at vacuum tightness>=0.06MPa reclaim under reduced pressure Phosphorus Oxychloride to material, is cooled to 80 ℃ then, adds trieline 833kg by weight and stirs the hydrolysis of back introducing hydrolyzer; Hydrolysis temperature is 60 ℃, stops to stir standing demix, collects the trieline layer; And be neutralized to pH8 with solid sodium hydroxide, use water washing, branch vibration layer; Reclaiming the trieline after the washing, specifically is the trieline after the washing to be put into still pot reclaim, and is recycled to trieline and no longer flows out; Emit crystallization, obtain chlorizate, promptly obtain 5-methoxyl group-4; 6-dichloro pyrimidine 209kg, yield are 90.49%.
Embodiment 5:
The preparation method of
Sulphadoxine provided by the invention comprises ring-closure reaction and chlorination reaction.
Ring-closure reaction is:
With by weight and mass percent concentration be that 28% sodium methoxide solution 1007.5kg puts into the reactor that is used for ring-closure reaction, and under whipped state, be heated to 63 ℃, then add methane amide 186kg by weight; And in 80min, splash into methoxy propyl diacid methyl ethyl ester 285.2kg by weight, and the temperature of reaction (also can claim dropping temperature) when dripping methoxy propyl diacid methyl ethyl ester is controlled to be 68 ℃, and insulation is insulation reaction 4h; Reclaim methyl alcohol then and continue to reclaim methyl alcohol and do not ooze, crystallisation by cooling, crystallisation by cooling temperature＜25 ℃ to there being cut to adding water to the greatest extent; The back centrifuge dripping is separated out in crystallization fully; The discharging oven dry obtains 276kg ring-closure reaction product and promptly obtains 5-methoxyl group-4,6-dihydroxy-pyrimidine disodium; For use, wherein: yield is 91.57%;
Chlorination reaction is:
will be heated to 75 ℃ in the Phosphorus Oxychloride 759.5kg input exsiccant reaction kettle by weight, will be 5-methoxyl group-4 again by the product that ring-closure reaction obtains, and 6-dihydroxy-pyrimidine disodium 225.4kg slowly joins reaction kettle for reaction; Add 5-methoxyl group-4, the temperature of reaction during 6-dihydroxy-pyrimidine disodium is controlled to be 70 ℃, finishes; That is to say adding 5-methoxyl group-4, be warming up to 110 ℃ behind the 6-dihydroxy-pyrimidine, and keep 4h (being insulation reaction 4h) down at these 110 ℃; Insulation reaction finishes the back and does (range estimation reclaim basic absence of liq oozes in the fluid visor) at vacuum tightness>=0.06MPa reclaim under reduced pressure Phosphorus Oxychloride to material, is cooled to 60 ℃ then, adds trieline 759.5kg by weight and stirs the hydrolysis of back introducing hydrolyzer; Hydrolysis temperature is 40 ℃, stops to stir standing demix, collects the trieline layer; And be neutralized to pH6 with solid sodium hydroxide, use water washing, branch vibration layer; Reclaiming the trieline after the washing, specifically is the trieline after the washing to be put into still pot reclaim, and is recycled to trieline and no longer flows out; Emit crystallization, obtain chlorizate, promptly obtain 5-methoxyl group-4; 6-dichloro pyrimidine 201kg, yield are 92.66%.
are by " Chinese Pharmacopoeia 2010 editions " Sulphadoxine finished product [detection method of related substance: get these article, add ethanol-liquor ammoniae fortis (9:1) and process the solution that contains 2.5mg among every 1ml approximately, make need testing solution; Precision is measured in right amount, quantitatively dilutes with ethanol-liquor ammoniae fortis (9:1) and processes the solution that contains 2.5 μ g among every 1ml approximately, compares article solution.Test according to tlc (SOP-QC-214-01); Draw each 10 μ l of above-mentioned two kinds of solution; Put respectively in same be on the silica gel H thin layer plate of tamanori, to be developping agent with 0.1% CMC 99.5 with trichloromethane-methyl alcohol-N (20: 2: 1), launch; Dry, spray makes colour developing with ethanol system paradimethy laminobenzaldehyde.Need testing solution is as showing the impurity spot, with the principal spot of contrast solution relatively, must not be darker.] to adopting the 5-methoxyl group-4 that obtains by present embodiment, the Sulphadoxine finished product detection that the 6-dichloro pyrimidine is prepared, related substance≤0.5%
Claims (10)
1.
A kind of preparation method of Sulphadoxine comprises ring-closure reaction and chlorination reaction, it is characterized in that:
Described ring-closure reaction is: in reactor, drop into sodium methoxide solution earlier, and heating under whipped state, then add methane amide and methoxy propyl diacid methyl ethyl ester successively; Temperature of reaction when control adds methoxy propyl diacid methyl ethyl ester, insulation is reclaimed methyl alcohol then and is reclaimed methyl alcohol to continuing to add water to the greatest extent; Crystallisation by cooling, centrifuge dripping, discharging oven dry; Obtain 5-methoxyl group-4,6-dihydroxy-pyrimidine disodium;
described chlorination reaction is: Phosphorus Oxychloride dropped in the reaction kettle heat earlier, and the control Heating temperature, again with described 5-methoxyl group-4,6-dihydroxy-pyrimidine disodium joins said reaction kettle for reaction; Control adds 5-methoxyl group-4, and the temperature of reaction during 6-dihydroxy-pyrimidine disodium finishes back intensification and insulation, and then reclaim under reduced pressure Phosphorus Oxychloride to material is done; Be cooled to design temperature, add and introduce the hydrolyzer hydrolysis, the control hydrolysis temperature after trieline stirs; Treat to collect the trieline layer behind the standing demix, with the solid sodium bicarbonate neutralization, control pH value; Use water washing, branch vibration layer reclaims the trieline after washing; Emit crystallization, obtain 5-methoxyl group-4, the 6-dichloro pyrimidine.
2. the preparation method of
Sulphadoxine according to claim 1 is characterized in that in described ring-closure reaction, and the described whipped state temperature of heating adding methane amide down is 60-70 ℃.
3. the preparation method of
Sulphadoxine according to claim 1; It is characterized in that in described ring-closure reaction; Temperature of reaction when described control adds methoxy propyl diacid methyl ethyl ester is that temperature of reaction is controlled to be 65-75 ℃; And the adding mode of methoxy propyl diacid methyl ethyl ester adds for dripping, and the dropping time of methoxy propyl diacid methyl ethyl ester is 60-120min.
4. the preparation method of
Sulphadoxine according to claim 1 is characterized in that in described ring-closure reaction the time of described insulation is 4-6h, and the temperature of described crystallisation by cooling is less than 25 ℃.
5. the preparation method of
Sulphadoxine according to claim 1; It is characterized in that in described ring-closure reaction described sodium methoxide solution, methane amide and methoxy propyl diacid methyl ethyl ester three's weight ratio is 3-4: 0.5-1: the mass percent concentration of the described sodium methoxide solution of 0.9-1 is 27-32%.
6. the preparation method of
Sulphadoxine according to claim 1 is characterized in that in described chlorination reaction, and described control Heating temperature is to be 70-90 ℃ with heating and temperature control.
7. the preparation method of
Sulphadoxine according to claim 1; It is characterized in that in described chlorination reaction; Described control adds 5-methoxyl group-4, and the temperature of reaction during 6-dihydroxy-pyrimidine disodium is that temperature of reaction is controlled to be 60-90 ℃.
8. the preparation method of
Sulphadoxine according to claim 1 is characterized in that in described chlorination reaction, and intensification and insulation are meant temperature is risen to 100-130 ℃ after described the finishing, and soaking time is controlled to be 4-6h.
9. the preparation method of
Sulphadoxine according to claim 1 is characterized in that in described chlorination reaction, and the described design temperature that is cooled to is meant and is cooled to 50-90 ℃; Described control hydrolysis temperature is hydrolysis temperature to be controlled to be no more than 30-70 ℃; Described control pH value is that the pH value is controlled to be 6-8.
10.
The preparation method of Sulphadoxine according to claim 1 is characterized in that in described chlorination reaction, described Phosphorus Oxychloride, 5-methoxyl group-4, and the weight ratio of 6-dihydroxy-pyrimidine disodium and trieline is 3-3.5: 0.9-1: 3-3.5
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103864701A (en) * | 2014-03-10 | 2014-06-18 | 常熟市金申医化制品有限责任公司 | Preparation method of 4-sulfanilamide-5-methoxyl-6-chloropyrimidine |
| CN103864700A (en) * | 2014-03-10 | 2014-06-18 | 常熟市金申医化制品有限责任公司 | Method for preparing 5-methoxy-4,6-dihydroxy pyrimidine disodium |
| CN103910684A (en) * | 2014-03-10 | 2014-07-09 | 常熟市南湖实业化工有限公司 | Preparation method of 4,6-dihydroxy-5-methoxypyrimidine sodium |
| 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 |
| CN104557735A (en) * | 2014-12-04 | 2015-04-29 | 重庆康乐制药有限公司 | Preparation method of high-purity sulfadoxine |
| CN110642794A (en) * | 2019-10-30 | 2020-01-03 | 常熟市金申医化制品有限责任公司 | Efficient preparation method of sulfadoxine cyclic compound intermediate |
| CN110694319A (en) * | 2019-10-30 | 2020-01-17 | 常熟市金申医化制品有限责任公司 | High-purity decolorizing and filter pressing process of sulfadoxine |
| CN110762162A (en) * | 2019-10-30 | 2020-02-07 | 常熟市金申医化制品有限责任公司 | High-efficiency safe centrifugation process of sulfadoxine |
| CN112457259A (en) * | 2020-12-08 | 2021-03-09 | 重庆康乐制药有限公司 | Preparation method of sulfadoxine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
| CN103910684A (en) * | 2014-03-10 | 2014-07-09 | 常熟市南湖实业化工有限公司 | Preparation method of 4,6-dihydroxy-5-methoxypyrimidine sodium |
| 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 |
| CN103864700A (en) * | 2014-03-10 | 2014-06-18 | 常熟市金申医化制品有限责任公司 | Method for preparing 5-methoxy-4,6-dihydroxy pyrimidine disodium |
| CN103864701A (en) * | 2014-03-10 | 2014-06-18 | 常熟市金申医化制品有限责任公司 | Preparation method of 4-sulfanilamide-5-methoxyl-6-chloropyrimidine |
| CN104557735B (en) * | 2014-12-04 | 2017-03-22 | 重庆康乐制药有限公司 | Preparation method of sulfadoxine |
| CN104557735A (en) * | 2014-12-04 | 2015-04-29 | 重庆康乐制药有限公司 | Preparation method of high-purity sulfadoxine |
| CN110642794A (en) * | 2019-10-30 | 2020-01-03 | 常熟市金申医化制品有限责任公司 | Efficient preparation method of sulfadoxine cyclic compound intermediate |
| CN110694319A (en) * | 2019-10-30 | 2020-01-17 | 常熟市金申医化制品有限责任公司 | High-purity decolorizing and filter pressing process of sulfadoxine |
| CN110762162A (en) * | 2019-10-30 | 2020-02-07 | 常熟市金申医化制品有限责任公司 | High-efficiency safe centrifugation process of sulfadoxine |
| CN110694319B (en) * | 2019-10-30 | 2022-04-01 | 江苏金申医药科技有限公司 | High-purity decolorizing and filter pressing process of sulfadoxine |
| CN112457259A (en) * | 2020-12-08 | 2021-03-09 | 重庆康乐制药有限公司 | Preparation method of sulfadoxine |
| CN112457259B (en) * | 2020-12-08 | 2024-02-20 | 重庆康乐制药有限公司 | Preparation method of sulfadoxine |
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