CN101279948B - Synthetic method of 4,6- dichloro-5-(2-methoxyphenoxy)-2,2'-dipyridine - Google Patents
Synthetic method of 4,6- dichloro-5-(2-methoxyphenoxy)-2,2'-dipyridine Download PDFInfo
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Abstract
The invention discloses a method to prepare 4,6-dichloro-5-(2- anisyl-phenoxyl)2-2`-bipyrimidine, a key intermediate compound for Bosentan which is a first-line drug for curing pulmonary hypertension. So 4,6-dichloro-5-(2- anisyl-phenoxyl)2-2`-bipyrimidine is of great market value. The method adopts reasonable processing route and takes ethyl malonate as material to produce 4,6-dichloro-5-(2- anisyl-phenoxyl)2-2`-bipyrimidine through halogenation, etherification, cyclization and chloro-substitution. The method is reduced in procedures, simple in process, high in yield and low in cost, with little pollution to the environment; therefore the method is applicable in industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of pharmaceutical intermediate, be specifically related to a kind of intermediate 4 of medicine bosentan, 6-two chloro-5-(2-methoxyl group phenoxy group)-2, the synthetic method of 2 '-two pyrimidines.
Background technology
One line medicine bosentan of treatment pulmonary hypertension, its synthetic route is as follows:
As the intermediate of synthetic this medicine, 4,6-two chloro-5-(2-methoxyl group phenoxy group)-2,2 '-two pyrimidines have huge marketable value.
4,6-two chloro-5-(2-methoxyl group phenoxy group)-2,2 '-two pyrimidines, outward appearance is the light brown solid, English name 4,6-dichloro-5-(2-methoxy-phenoxy)-2-2 '-bipyrimidine, CAS 150728-13-5.The synthetic method of this compound mainly comprises following 5 steps at present:
1) diethyl malonate makes the 2-chloro diethyl malonate through chlorination, and yield 64%, this reaction method are open in U.S. Pat 5292740;
2) reaction of 2-chloro diethyl malonate and hydroxyanisole makes 2-(2-methoxyl group phenoxy group) diethyl malonate, yield 70%, and referring to Caton, Michael P.L.; Hurst, Derek T.; McOmie, John F.W.; Hunt, Roy R., Journal of the Chemical Society[Section] C:Organic (1967), (13), 1204-9;
3) 2-cyanopyrimidine and ammonium benzene sulfonate react under 230-250 ℃ high temperature and obtain 2-pyrimidine carbonamidine benzene sulfonate, yield 42%, referring to Jong Chan Lee, Yong Hun Bae, and Suk-Kyu Chang, Bulletin of the Korean chemical society, (1967), 24 (4), 407-408;
4) 2-pyrimidine carbonamidine benzene sulfonate and 2-(2-methoxyl group phenoxy group) diethyl malonate reaction obtain 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6 (1H, 5H)-diketone, yield 57%, referring to Hironori Harada, a,
*Jun-ichi Kazami, a Susumu Watanuki, Bioorganic﹠amp; Medicinal Chemistry, 9 (11), 2955-2968; 2001;
5) product that step 4 is obtained obtains 4 through chloro, 6-two chloro-5-(2-methoxyl group phenoxy group)-2, and 2 '-two pyrimidines, yield 75%, referring to Hironori Harada, a,
*Jun-ichi Kazami, a SusumuWatanuki, Bioorganic﹠amp; Medicinal Chemistry, 9 (11), 2955-2968; 2001.
In the such scheme, when preparation 2-pyrimidine carbonamidine benzene sulfonate, need under 230-250 ℃ condition, react, and be reflected under the condition of no solvent and carry out, just form a monoblock solid after the reaction cooling, be difficult to operation, be difficult to amplify and produce, so be not suitable for suitability for industrialized production; In addition, the total recovery of this route five steps reaction is low, only has 8%.
Therefore be necessary to seek a kind of suitable suitability for industrialized production and the high preparation technology of yield.
Summary of the invention
The object of the invention provides a kind of synthetic 4,6-two chloro-5-(2-methoxyl group phenoxy group)-2, the method for 2 '-two pyrimidines, this method has been simplified intermediate steps, has reduced running cost, reduces production cycle and cost, improve production efficiency, be fit to be applied to large-scale industrialization production.
For achieving the above object, the technical solution used in the present invention is: a kind of synthetic 4, and 6-two chloro-5-(2-methoxyl group phenoxy group)-2, the method of 2 '-two pyrimidines, with the diethyl malonate is raw material, makes through halo, etherificate, cyclization and chloro four-step reaction, specifically may further comprise the steps:
(1) halo: diethyl malonate obtains compound a through behind the halogenating reaction---2-halo diethyl malonate;
(2) etherificate: with step (1) gained halo diethyl malonate and hydroxyanisole reacting generating compound b---2-(2-methoxyl group phenoxy group) diethyl malonate;
(3) cyclization: prepare compound c---5-(2-methoxyl group phenoxy group) [2 with step (2) gained etherificate product 2-(2-methoxyl group phenoxy group) diethyl malonate, 2 '-Sulfadiazine Compound]-4,6 (1H, 5H)-diketone, its method is, according to the 2-cyanopyrimidine, the sodium alkoxide alcoholic solution, ammonium salt, 2-(2-methoxyl group phenoxy group) diethyl malonate, basic catalyst, the mass ratio of alcohol is 1: 0～20: 0.4～2: 0.5～2: 0.2～1.2: 5～20, under 25～110 ℃, obtain 5-(2-methoxyl group phenoxy group) [2 through ring-closure reaction, 2 '-Sulfadiazine Compound]-4,6 (1H, 5H)-diketone;
(4) with step (3) gained compound process chlorination synthetic compound d--4,6-two chloro-5-(2-methoxyl group phenoxy group)-2,2 '-two pyrimidines.
In the technique scheme, described sodium alkoxide alcoholic solution is a kind of in methanol solution of sodium methylate, sodium methylate ethanolic soln, sodium ethylate methanol solution or the alcohol sodium alcohol solution, and the concentration (quality percentage composition) of sodium alkoxide in alcohol is 0.2～2.0%; Described ammonium salt is a kind of in ammonium chloride, ammonium sulfate, ammonium acetate, paratoluenesulfonic acid ammonium salt or the ammonium benzene sulfonate; Described basic catalyst is a kind of in sodium hydroxide, potassium hydroxide, sodium hydrogen, sodium methylate, sodium ethylate, triethylamine, diisopropyl ethyl amine, pyridine, piperidines or the 4-Dimethylamino pyridine; Described alcohol is a kind of in methyl alcohol, ethanol, the Virahol.
Optimized technical scheme, the temperature of reaction of described step (3) is 60～90 ℃.
In the technique scheme, preferred (the quality percentage composition) 1% of the concentration of sodium alkoxide in alcohol; The preferred ammonium benzene sulfonate of described ammonium salt; The preferred sodium hydroxide of described basic catalyst; Described pure preferred alcohol.The yield of step (3) can reach 85%.
Above, described step (1) detailed process is: the mass ratio according to diethyl malonate, solvent, catalyzer, halogenating agent is 1: 0～25: 0～4: 0.5～1.5, under 25～100 ℃ temperature, make 2-halo diethyl malonate through halogenating reaction, preferable reaction temperature is 70～80 ℃, described solvent is selected from trichloromethane, 1, a kind of in 2-ethylene dichloride, tetracol phenixin, acetonitrile or the propionitrile, preferred 1, the 2-ethylene dichloride; Described catalyzer is selected from a kind of in methylsulphonic acid, Phenylsulfonic acid, Sulphanilic Acid, p-methyl benzenesulfonic acid or the trifluoromethane sulfonic acid, preferred Sulphanilic Acid or Phenylsulfonic acid.The yield of step (1) can reach 93%.
Described step (2) detailed process is: the mass ratio according to 2-halo diethyl malonate, solvent, basic catalyst, hydroxyanisole is 1: 5～15: 0.2～0.8: 0.5～1, under 30～120 ℃ temperature, make 2-(2-methoxyl group phenoxy group) diethyl malonate, preferred 50～70 ℃ of temperature of reaction through etherificate; Described solvent is selected from 1, a kind of in 2-ethylene dichloride, tetracol phenixin, toluene, acetonitrile, propionitrile, acetone, 2-butanone, methyl alcohol or the ethanol, preferred acetonitrile; Described basic catalyst refers to a kind of in yellow soda ash, salt of wormwood, sodium hydrogen, sodium methylate, sodium ethylate, sodium hydroxide or the potassium hydroxide, preferred carbonic acid.The yield of step (2) can reach 90%.
Described step (4) detailed process is: according to 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6 (1H, 5H)-mass ratio of diketone, phosphorus oxychloride, organic bases is 1: 1.5～10: 0～1.2, descend reaction and make 4 at 0～120 ℃, 6-two chloro-5-(2-methoxyl group phenoxy group)-2,2 '-two pyrimidines, preferable reaction temperature is 80～90 ℃, described organic bases is triethylamine, diisopropyl ethyl amine, N, a kind of in accelerine or the 4-Dimethylamino pyridine, preferred N, accelerine.The yield of step 4 can reach 92%.
Technique scheme can be represented with following formula:
Because the technique scheme utilization, the present invention compared with prior art has following advantage:
1. the present invention utilizes ring-closure reaction directly to prepare 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6 (1H, 5H)-diketone, be not only two steps are combined into a step, and be reflected under the solvent and carry out, reactant can be not fixed, handled easily, intermediate operation step and running cost have been reduced, shortened the production cycle, improved yield when having reduced cost, total recovery of the present invention can reach 63.6%;
2. became for four steps owing to simplified reaction process, and do not relate to high-temperature high-voltage reaction, be more suitable for industrialization.
Embodiment
Below in conjunction with embodiment the present invention is further described:
Embodiment one:
(1) preparation of 2-halo diethyl malonate (a):
In the 100L reactor, add 1,2-ethylene dichloride 64L, diethyl malonate 6.4KG, Phenylsulfonic acid 11KG adds NCS 5.4KG at last.Be warming up to 60-80 ℃ of reaction 5-8 hour.Decompression steams 1, and the 2-ethylene dichloride then adds in the 30L water, stirs separatory, water layer is with 1, and the 2-ethylene dichloride extracts 20L * 3, and organic layer merges, and washes with 10L, organic layer adds the 6KG anhydrous sodium sulfate drying, 3 hours after-filtration, evaporated under reduced pressure, product 7.24KG weak yellow liquid, yield 93%.
(2) preparation of 2-(2-methoxyl group phenoxy group) diethyl malonate (b):
In the 50L reactor, add 25L acetonitrile, 3.5KG yellow soda ash, drip methyl catechol 2.73KG, drip the 5L acetonitrile solution of 4.27KG 2-halo diethyl malonate after adding again, to drip and finish, a temperature control 60-80 ℃ reaction is spent the night.Reaction solution cooling, centrifugal, be concentrated into driedly, pour in the 10L water, stir, leave standstill, layering, water layer uses 1 again, and 2-ethylene dichloride 10L extracts 1 time, merges organic layer, wash 1 time with 5 premium on currency, merge the organic layer drying, be evaporated to driedly, the residuum underpressure distillation gets product 5.59KG, yield 90%.
(3) 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6 (1H, 5H)-preparation of diketone (c):
In the 50L reactor, add 35 liters of ethanol, 400G sodium ethylate, 1.5KG 2-cyanopyrimidine, be warming up to 50-60 ℃ of reaction and spend the night.Add ammonium benzene sulfonate 2.55KG, heating reflux reaction 5-8 hour.Add sodium hydroxide 1.73KG in batches, stirred 30-50 minute, drip the 5L ethanolic soln of 3.41KG 2-(2-methoxyl group phenoxy group) diethyl malonate (b), drip and finish back flow reaction 5-7 hour.Add in the entry, dissolved solids, dripping hydrochloric acid is regulated PH to 3-4, separates out solid, and centrifugal, the gained solid washes with water 3 times, and the filter cake oven dry gets product 3.83KG, yield 85% (in the 2-cyanopyrimidine).
(4) 4,6-two chloro-5-(2-methoxyl group phenoxy group)-2, the preparation of 2 '-two pyrimidines (d):
In the 20L reactor, (1H, 5H)-diketone (c), 2KG N, accelerine is warming up to 80-100 ℃ of reaction 6-8 hour to add 15L phosphorus oxychloride, 3KG 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6.Decompression steams remaining phosphorus oxychloride, and residuum is added in a large amount of trash ices, add methylbenzene extraction, washing, concentrate do crude product, recrystallizing methanol gets light brown solid phase prod 3KG, purity 99%Min (HPLC), yield 89.4%.
(5) products obtained therefrom is carried out instrumental analysis:
1HNMR (CDCl
3) δ 8.95 (d, 2H, 4 ' H, 6 ' H), 7.49 (t, 1H, 5 ' H), 6.94-7.10,7.58-7.60 (m, 4H, benzene ring hydrogen), 3.99 (s, 3H ,-OCH
3) ppm
MS(ESI)m/e：349(M+H)
+
Embodiment two:
(1) preparation of 2-halo diethyl malonate (a):
In the 100L reactor, add acetonitrile 64L, diethyl malonate 6.4KG, tosic acid 13KG adds NBS 7.2KG at last.Be warming up to 50-70 ℃ of reaction 4-6 hour.Decompression steams acetonitrile, then adds in the 30L water, stirs separatory, and water layer is with 1, the 2-ethylene dichloride extracts 20L * 3, and organic layer merges, and with the 10L washing, organic layer adds the 6KG anhydrous sodium sulfate drying, 3 hours after-filtration, evaporated under reduced pressure, product 7.75KG weak yellow liquid, yield 81%.
(2) preparation of 2-(2-methoxyl group phenoxy group) diethyl malonate (b):
In the 50L reactor, add 25L acetone, 3.5KG sodium methylate, drip methyl catechol 2.73KG, drip the 5L acetone soln of 4.27KG 2-halo diethyl malonate after adding again, to drip and finish, a temperature control 40-60 ℃ reaction is spent the night.Reaction solution cools off slightly, and is centrifugal, and centrifugate is concentrated into dried, pour in the 10L water, stir, leave standstill, layering, water layer use 1 again, and 2-ethylene dichloride 10L extracts 1 time, merge organic layer, wash 1 time with 5 premium on currency, merge the organic layer drying, be evaporated to dried, the residuum underpressure distillation gets product 5.16KG, yield 83%.
(3) 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6 (1H, 5H)-preparation of diketone (c):
In the 50L reactor, add 30 liters of Virahols, 500G sodium methylate, 1.5KG 2-cyanopyrimidine, be warming up to 50-60 ℃ of reaction and spend the night.Add ammonium chloride 1KG, heat 70-90 ℃ of reaction 5-8 hour.Add sodium methylate 2KG in batches, stirred 30 minutes, drip the 5L aqueous isopropanol of 3.41KG 2-(2-methoxyl group phenoxy group) diethyl malonate (b), drip and finish, heat 70-90 ℃ of reaction 5-7 hour.Add in the entry, dissolved solids, dripping hydrochloric acid is regulated PH to 4-5, separates out solid, and centrifugal, the gained solid washes with water 3 times, and the filter cake oven dry gets product 3.78KG, yield 75% (in the 2-cyanopyrimidine).
(4) 4,6-two chloro-5-(2-methoxyl group phenoxy group)-2, the preparation of 2 '-two pyrimidines (d):
In the 20L reactor, (1H 5H)-diketone (c), 1.8KG triethylamine, is warming up to 80-100 ℃ of reaction 6-8 hour to add 15L phosphorus oxychloride, 3KG 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6.Decompression steams remaining phosphorus oxychloride, and decompression steams remaining phosphorus oxychloride, and residuum is added in a large amount of trash ices, add methylbenzene extraction, washing, concentrate do crude product, recrystallizing methanol gets light brown solid phase prod 2.38KG, purity 98.5%Min (HPLC), yield 71%.
(5) products obtained therefrom is carried out instrumental analysis:
1HNMR (CDCl
3) δ 8.95 (d, 2H, 4 ' H, 6 ' H), 7.49 (t, 1H, 5 ' H), 6.94-7.10,7.58-7.60 (m, 4H, benzene ring hydrogen), 3.99 (s, 3H ,-OCH
3) ppm
MS(ESI) m/e：349(M+H)
+
Embodiment three:
(1) preparation of 2-halo diethyl malonate (a):
In the 100L reactor, add tetracol phenixin 50L, diethyl malonate 6.4KG, methylsulphonic acid 8KG adds NCS 4.8KG at last.Be warming up to 70-80 ℃ of reaction 5-7 hour.Decompression steams tetracol phenixin, then adds in the 30L water, stirs separatory, water layer dichloromethane extraction 20L * 3, organic layer merges, and with the 10L washing, organic layer adds the 6KG anhydrous sodium sulfate drying, 3 hours after-filtration, evaporated under reduced pressure, product 5.06KG weak yellow liquid, yield 65%.
(2) preparation of 2-(2-methoxyl group phenoxy group) diethyl malonate (b):
In the 50L reactor, add 40L ethanol, 2KG sodium methylate, drip methyl catechol 2.7KG, drip the 5L ethanolic soln of 4.27KG 2-halo diethyl malonate after adding again, to drip and finish, back flow reaction is spent the night.Reaction solution cooling, centrifugal, be concentrated into driedly, pour in the 10L water, stir, leave standstill, layering, water layer uses 1 again, and 2-ethylene dichloride 10L extracts 1 time, merges organic layer, wash 1 time with 5 premium on currency, merge the organic layer drying, be evaporated to driedly, the residuum underpressure distillation gets product 4.84KG, yield 78%.
(3) 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6 (1H, 5H)-preparation of diketone (c):
In the 50L reactor, add 38 liters of methyl alcohol, 450G sodium methylate, 1.5KG 2-cyanopyrimidine, be warming up to 50-60 ℃ of reaction and spend the night.Add the 2.3KG ammonium acetate, heating reflux reaction 5-8 hour.Add potassium tert.-butoxide 4.5KG in batches, stirred 30-50 minute, drip the 5L methanol solution of 3.41KG 2-(2-methoxyl group phenoxy group) diethyl malonate (b), drip and finish back flow reaction 5-7 hour.Add in the entry, dissolved solids, dripping hydrochloric acid is regulated PH to 3-4, separates out solid, and centrifugal, the gained solid washes with water 3 times, and the filter cake oven dry gets product 3.31KG, yield 73.5% (in the 2-cyanopyrimidine).
(4) 4,6-two chloro-5-(2-methoxyl group phenoxy group)-2, the preparation of 2 '-two pyrimidines (d):
In the 20L reactor, (1H 5H)-diketone (c), 2KG 4-dimethylamino pyridine, is warming up to 80-100 ℃ of reaction 6-8 hour to add 10L phosphorus oxychloride, 3KG 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6.Decompression steams remaining phosphorus oxychloride, and decompression steams remaining phosphorus oxychloride, and residuum is added in a large amount of trash ices, add methylbenzene extraction, washing, concentrate do crude product, recrystallizing methanol gets light brown solid phase prod 2.62KG, purity 98.7%Min (HPLC), yield 78%.
(5) products obtained therefrom is carried out instrumental analysis:
1HNMR (CDCl
3) δ 8.95 (d, 2H, 4 ' H, 6 ' H), 7.49 (t, 1H, 5 ' H), 6.94-7.10,7.58-7.60 (m, 4H, benzene ring hydrogen), 3.99 (s, 3H ,-OCH
3) ppm
MS(ESI) m/e：349(M+H)
+
Embodiment four:
(1) preparation of 2-halo diethyl malonate (a):
In the 100L reactor, add acetonitrile 50L, diethyl malonate 6.4KG, Phenylsulfonic acid 8KG adds NCS 5.5KG at last.Be warming up to 50-70 ℃ of reaction 5-7 hour.Decompression steams acetonitrile, then adds in the 30L water, stirs separatory, water layer dichloromethane extraction 20L * 3, organic layer merges, and with the 10L washing, organic layer adds the 6KG anhydrous sodium sulfate drying, 3 hours after-filtration, evaporated under reduced pressure, product 5.22KG weak yellow liquid, yield 67%.
(2) preparation of 2-(2-methoxyl group phenoxy group) diethyl malonate (b):
In the 50L reactor, add 35L 2-butanone, 2KG sodium ethylate, drip methyl catechol 2.7KG, drip the 5L 2-butanone solution of 4.27KG 2-halo diethyl malonate after adding again, drip and finish, be warming up to 70-80 ℃ of reaction and spend the night.Reaction solution cooling, centrifugal, be concentrated into driedly, pour in the 10L water, stir, leave standstill, layering, water layer uses 1 again, and 2-ethylene dichloride 10L extracts 1 time, merges organic layer, wash 1 time with 5 premium on currency, merge the organic layer drying, be evaporated to driedly, the residuum underpressure distillation gets product 4.72KG, yield 76%.
(3) 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6 (1H, 5H)-preparation of diketone (c):
In the 50L reactor, add 35 liters of Virahols, 500G sodium ethylate, 1.5KG 2-cyanopyrimidine, be warming up to 60-70 ℃ of reaction and spend the night.Add 253KG ammonium sulfate, be warming up to 70-80 ℃ of reaction 5-6 hour.Add potassium hydroxide 3.2KG in batches, stirred 30-50 minute, drip the 5L methanol solution of 3.41KG 2-(2-methoxyl group phenoxy group) diethyl malonate (b), drip and finish back flow reaction 5-7 hour.Add in the entry, dissolved solids, dripping hydrochloric acid is regulated PH to 3-4, separates out solid, and centrifugal, the gained solid washes with water 3 times, and the filter cake oven dry gets product 2.84KG, yield 63% (in the 2-cyanopyrimidine).
(4) 4,6-two chloro-5-(2-methoxyl group phenoxy group)-2, the preparation of 2 '-two pyrimidines (d):
In the 20L reactor, (1H 5H)-diketone (c), 1.9KG diisopropyl ethyl amine, is warming up to 100-120 ℃ of reaction 6-8 hour to add 13L phosphorus oxychloride, 3KG 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6.Decompression steams remaining phosphorus oxychloride, and decompression steams remaining phosphorus oxychloride, and residuum is added in a large amount of trash ices, add methylbenzene extraction, washing, concentrate do crude product, recrystallizing methanol gets light brown solid phase prod 2.4KG, purity 99.3%Min (HPLC), yield 71.5%.
(5) products obtained therefrom is carried out instrumental analysis:
1HNMR (CDCl
3) δ 8.95 (d, 2H, 4 ' H, 6 ' H), 7.49 (t, 1H, 5 ' H), 6.94-7.10,7.58-7.60 (m, 4H, benzene ring hydrogen), 3.99 (s, 3H ,-OCH
3) ppm
MS(ESI) m/e：349(M+H)
+。
Claims (6)
1. one kind is synthesized 4,6-two chloro-5-(2-methoxyl group phenoxy group)-2, and the method for 2 '-two pyrimidines is a raw material with the diethyl malonate, may further comprise the steps:
(1) halo: diethyl malonate obtains 2-halo diethyl malonate through behind the halogenating reaction;
(2) etherificate: step (1) gained 2-halo diethyl malonate and hydroxyanisole reaction are generated 2-(2-methoxyl group phenoxy group) diethyl malonate;
(3) with step (2) gained etherificate product 2-(2-methoxyl group phenoxy group) diethyl malonate reaction obtain 5-(2-methoxyl group phenoxy group) [2,2 '-Sulfadiazine Compound]-4,6 (1H, 5H)-diketone;
(4) step (3) gained compound is synthesized 4 through chlorination, 6-two chloro-5-(2-methoxyl group phenoxy group)-2,2 '-two pyrimidines;
It is characterized in that: described step (3) is ring-closure reaction, its method is, mass ratio according to 2-cyanopyrimidine, sodium alkoxide alcoholic solution, ammonium salt, 2-(2-methoxyl group phenoxy group) diethyl malonate, basic catalyst, alcohol is 1: 0～20: 0.4～2: 0.5～2: 0.2～1.2: 5～20, under 25～110 ℃, obtain 5-(2-methoxyl group phenoxy group) [2 through ring-closure reaction, 2 '-Sulfadiazine Compound]-4,6 (1H, 5H)-diketone.
2. according to claim 1 synthetic 4,6-two chloro-5-(2-methoxyl group phenoxy group)-2, the method of 2 '-two pyrimidines, it is characterized in that: described sodium alkoxide alcoholic solution is selected from a kind of in methanol solution of sodium methylate, sodium methylate ethanolic soln, sodium ethylate methanol solution or the alcohol sodium alcohol solution, and the concentration (quality percentage composition) of sodium alkoxide in alcohol is 0.2～2.0%.
3. according to claim 1 synthetic 4,6-two chloro-5-(2-methoxyl group phenoxy group)-2, the method for 2 '-two pyrimidines is characterized in that: described ammonium salt is selected from a kind of in ammonium chloride, ammonium sulfate, ammonium acetate, paratoluenesulfonic acid ammonium salt or the ammonium benzene sulfonate.
4. according to claim 1 synthetic 4,6-two chloro-5-(2-methoxyl group phenoxy group)-2, the method of 2 '-two pyrimidines is characterized in that: described basic catalyst is selected from a kind of in sodium hydroxide, potassium hydroxide, sodium hydrogen, sodium methylate, sodium ethylate, triethylamine, diisopropyl ethyl amine, pyridine, piperidines or the 4-Dimethylamino pyridine.
5. according to claim 1 synthetic 4,6-two chloro-5-(2-methoxyl group phenoxy group)-2, the method for 2 '-two pyrimidines is characterized in that: described alcohol is selected from a kind of in methyl alcohol, ethanol or the Virahol.
6. synthesize 4 according to claim 1 is described, 6-two chloro-5-(2-methoxyl group phenoxy group)-2, the method for 2 '-two pyrimidines is characterized in that: the temperature of reaction of described step (3) is 60～90 ℃; The concentration (quality percentage composition) of sodium alkoxide in alcohol is 1%; Described ammonium salt is an ammonium benzene sulfonate; Described basic catalyst is a sodium hydroxide; Described alcohol is ethanol.
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| US6136971A (en) * | 1998-07-17 | 2000-10-24 | Roche Colorado Corporation | Preparation of sulfonamides |
| CN1335839A (en) * | 1999-09-03 | 2002-02-13 | 埃科特莱茵药品有限公司 | Bis-sulfonamides |
| CN1425007A (en) * | 2000-01-25 | 2003-06-18 | 弗·哈夫曼-拉罗切有限公司 | Preparation of sulfonamides |
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2008
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US5292740A (en) * | 1991-06-13 | 1994-03-08 | Hoffmann-La Roche Inc. | Sulfonamides |
| US6136971A (en) * | 1998-07-17 | 2000-10-24 | Roche Colorado Corporation | Preparation of sulfonamides |
| CN1335839A (en) * | 1999-09-03 | 2002-02-13 | 埃科特莱茵药品有限公司 | Bis-sulfonamides |
| CN1425007A (en) * | 2000-01-25 | 2003-06-18 | 弗·哈夫曼-拉罗切有限公司 | Preparation of sulfonamides |
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| HarringtonP.J.etal.ResearchandDevelopmentofaSecond-GenerationProcessforBosentan an Endothelin Receptor Antagonist.Organic Process Research & Development6.2002 |
| 杨宁等.内皮素受体阻断剂波生坦的合成.中国药物化学杂志15 4.2005,15(4),230-234. |
| 杨宁等.内皮素受体阻断剂波生坦的合成.中国药物化学杂志15 4.2005,15(4),230-234. * |
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| CN101279948A (en) | 2008-10-08 |
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