CN103923020A - Preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine - Google Patents
Preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine Download PDFInfo
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Abstract
The invention provides a preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine, which comprises the following steps: reacting diethyl malonate and fuming nitric acid at 0-15 DEG C, carrying out acid washing and alkali washing to obtain a compound V, dissolving the compound V in ethanol, adding sodium ethylate and thiocarbamide, and reacting to obtain a compound IV; reacting the compound IV with halogenated n-butane in an alkaline solution to obtain a compound III; chlorinating hydroxy group of the compound III in phosphorus oxychloride containing N,N- dimethylaniline to produce a compound II; and finally, reducing the compound II by using hydrogen in alcohol under the catalytic action of palladium on carbon to obtain the 2-propylthio-4,6-dichloro-5-aminopyrimidine. The method optimizes the technique, lowers the production cost, and enhances the reaction yield.
Description
Technical field
The invention belongs to chemical technology field, particularly a kind of 2-rosickyite base-4, the preparation method of 6-bis-chlorine-5-amido pyrimidines.
Background technology
A kind of novel, the small molecules anticoagulant medicine of the research and development of ADZ6140 (ticagrelor/Brilinta) Shi You Astrazeneca AB, obtain European Union's approval in December, 2010, obtains again U.S. FDA approval in July, 2011.Clinical trial confirms, this medicine is different with prasugrel from thiophene pyridines anticoagulant medicine clopidogrel, can reversibly act on adenosine diphosphate (ADP) (ADP) receptor subtype P2Y12, the platelet aggregation that ADP is caused has obvious restraining effect, and oral rapid-action, can effectively improve acute coronary syndrome (ACS) patient's symptom, be particularly useful for carrying out the patient of coronary artery bypass graft surgery (CABG).
2-rosickyite base-4,6-bis-chlorine-5-amido pyrimidines are important intermediate of ADZ6140.2-rosickyite base-4 of reporting at present, the synthetic route of 6-bis-chlorine-5-amido pyrimidines mainly contains two kinds, and a route is:
This kind of method starting raw material is expensive, nitrated with nitrosonitric acid, may destroy 2-rosickyite base-4, and 6-dihydroxy-pyrimidine, increases by product, thereby causes productive rate to reduce; The second route is:
The shortcoming of this route is that starting raw material is expensive, and cost is higher, and the hydro-reduction of azo-compound needs elevated pressures, severe reaction conditions, and product postprocessing is complicated, is unfavorable for industry amplification, thereby has increased the industrial production cost of ADZ6140.
Summary of the invention
The present invention is from diethyl malonate, through nitrated, close ring, replace, reduction obtains product, nitrated yield is high, and byproduct of reaction is few, convenient post-treatment, thereby 2-rosickyite base-4 have greatly been improved, the synthetic effect of 6-bis-chlorine-5-amido pyrimidines, has solved the deficiencies in the prior art, and then greatly reduces production cost.
In order to realize object of the present invention, the technical scheme adopting is a kind of 2-rosickyite base-4, the preparation method of 6-bis-chlorine-5-amido pyrimidines, and its synthetic route is as follows:
degree, at 0-15 ℃, dropwises, and stirs 2 hours under room temperature, and mixture is poured in frozen water, then uses dichloromethane extraction twice, merges organic layer; The aqueous solution of urea washing of organic layer difference water and concentration 5%; until test friend machine layer starch potassium iodide paper do not develop the color; the sodium carbonate solution extraction that organic layer is 10% by concentration, collects water layer, with concentrated hydrochloric acid, is acidified to pH2～5; then use dichloromethane extraction; collected organic layer, anhydrous sodium sulfate drying, filters; revolve and steam except desolventizing, obtain compound V;
Described, the mass volume ratio of diethyl malonate and nitrosonitric acid is 4:1～1:4g/ml;
2) take rapidly sodium Metal 99.5 and be dissolved in dehydrated alcohol, add step 1) compound V and the thiocarbamide prepared, stir under reflux conditions 2 hours, be cooled to room temperature, with concentrated hydrochloric acid, be acidified to pH2～5, filter, filter cake water and washing with alcohol, dry, obtain compounds Ⅳ;
Described, the mass volume ratio of sodium Metal 99.5 and dehydrated alcohol is 1:10～1:40g/ml;
Described, the mass ratio of compound V and thiocarbamide is 2.5:1～1:1;
3) take compounds Ⅳ and water and put into 250ml round-bottomed flask, then adding concentration is 10%～30% alkaline solution, under room temperature condition, stirs half an hour, solid dissolves completely, adds NMP (N-Methyl pyrrolidone), then adds halo n-propane, under room temperature, react 18 hours, with acid, adjust pH to 2, have a large amount of solids to generate, filter, water, washing with alcohol filter cake, solid drying, weigh, obtain compound III;
Described, the mass volume ratio of compound IV and water is 1:1～1:20g/ml;
Described, the mass ratio of compound IV and alkali is 4:1～1:1;
Described, the mass volume ratio of compound IV and NMP is 5:1～1:2g/ml;
Described, the mass ratio of compound IV and halo n-propane is 3:1～0.5:1;
Described, acid is selected from hydrochloric acid or formic acid or acetic acid or phosphoric acid or sulfuric acid;
Described halo n-propane is selected from n-propyl bromide or propyl iodide;
Described, alkali is selected from lithium hydroxide or sodium hydroxide or potassium hydroxide or salt of wormwood or cesium carbonate;
4) take compound III and put into 100ml round-bottomed flask, add phosphorus oxychloride and DMA, 110 ℃ are reacted 3 hours, are cooled to room temperature, revolve and steam the phosphorus oxychloride of removing, in resistates, slowly add water, ethyl acetate extraction, collects ethyl acetate layer, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain crude product, crude product obtains compound ii with silica gel column chromatography separation;
During by column chromatography separating-purifying compound III, developping agent used is the mixed solvent of ethyl acetate and sherwood oil, and its volume ratio is 0:1～1:100;
Described, the mass volume ratio of compound III and phosphorus oxychloride is 0.7:1～1:10g/ml;
Described, the volume ratio of phosphorus oxychloride and DMA is 20:1～1:1;
5) take compound ii, be dissolved in dehydrated alcohol, add 5% wet palladium carbon, under room temperature, pass into hydrogen, stir 3 hours, put board monitoring until without compound ii, filter, obtain palladium carbon and filtrate, palladium carbon washing with alcohol, and collect; Filtrate is spin-dried for, obtains chemical compounds I;
Described, the mass volume ratio of Compound I I and dehydrated alcohol is 1:100～1:1g/ml;
Described, the mass ratio of Compound I I and palladium carbon is 100:1～1:1;
Described, the flow velocity of hydrogen is 0.1ml～10ml/min;
Preferably, step 3) in, described aqueous sodium hydroxide solution concentration 20%.
Preferably, step 3) in, described alkali is sodium hydroxide.
Concentration described in the present invention is massfraction.
Beneficial effect of the present invention: the route of prior art is all to take pyrimidine ring as starting raw material, then nitrated or make azo-compound, then hydrogenation obtains product, nitrated with nitrosonitric acid, may destroy 2-rosickyite base-4,6-dihydroxy-pyrimidine, by product is increased, thereby cause productive rate to reduce; The hydro-reduction of azo-compound needs elevated pressures, severe reaction conditions, and product postprocessing is complicated, be unfavorable for industry amplification, and the present invention just introduces nitro before building pyrimidine ring, had avoided the drawback of above-mentioned two kinds of methods.Optimize technique, improved reaction yield, reduced production cost.
In sum, the invention provides a kind of 2-of preparation rosickyite base-4, the novel method of 6-bis-chlorine-5-amido pyrimidines.Utilize this method can improve productive rate, reduce production costs, there is the larger prospect of marketing.
Specific embodiment
Below in conjunction with specific embodiment, patent is described further, but not as the restriction to patent content.
Embodiment 1
(1) compound V's is synthetic
Take 20g diethyl malonate and put into 250ml round-bottomed flask, under ice bath, slowly drip 20ml nitrosonitric acid, control temperature below 15 degree.Stirring at room 2 hours, pours mixture in frozen water into, then uses dichloromethane extraction twice, merges organic layer; Organic layer is distinguished the aqueous solution of urea washing of water and 5%, until starch potassium iodide paper does not develop the color.Dichloromethane solution extracts with 10% sodium carbonate solution, and combining water layer, is acidified to pH～4 with concentrated hydrochloric acid, then uses dichloromethane extraction, combining extraction liquid, anhydrous sodium sulfate drying, filters, revolve and steam except desolventizing, obtain 24g product compound V, yield: 93.75%.
1H-NMR(400MHz,CDCl3)δ:5.83(s，1H),4.46(q,J＝4.0Hz，4H)，1.38(t，J=4.0Hz，6H)。
(2) compounds Ⅳ is synthetic
Take rapidly 12g sodium Metal 99.5 and be dissolved in 480ml dehydrated alcohol, add 23g α-nitro diethyl malonate V and 11g thiocarbamide, under backflow, reaction vigorous stirring 2 hours, be cooled to room temperature, with concentrated hydrochloric acid, be acidified to acidity, now have a large amount of solids to separate out, filter, filter cake water and washing with alcohol, dry, weigh, obtain 20.5g product compound IV, yield: 96.70%.
1H-NMR(400MHz,DMSO-d6)δ:11.16(s，3H)。
(3) compound III is synthetic
Take 10g compounds Ⅳ and 80ml water is put into 250ml round-bottomed flask, then add the 20.8ml aqueous solution that contains 5.2g sodium hydroxide, stir half an hour, solid dissolves completely.Add 10ml NMP (N-Methyl pyrrolidone), then add 9.9g propyl iodide, reaction is stirred and is spent the night (approximately 18 hours), with hydrochloric acid, adjusts pH to 2, there are a large amount of solids to generate, filter water, washing with alcohol filter cake, solid drying, weigh, obtain 10.3g product compound III, yield: 84.43%.
1H-NMR(400MHz,DMSO-d6)δ:3.16(t，J=7.2Hz，2H),1.67(m，2H)，0.97(t，J=7.2Hz，3H)。
(4) compound ii is synthetic
Take 5g compound III and put into 100ml round-bottomed flask, add 20ml phosphorus oxychloride and 3ml DMA, 110 degree reactions 3 hours, cooling, revolve to steam and remove excessive phosphorus oxychloride, in resistates, slowly add appropriate water, ethyl acetate is got, and merges organic layer, anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separation obtains 4.7g product compound II, yield 81.03%.
1H-NMR(400MHz,CDCl3)δ:3.19(t，J＝7.2Hz，2H),1.84(m，2H)，0.92(t，J＝7.2Hz，3H)。
(5) chemical compounds I is synthetic
Take 2g compound ii, be dissolved in 30ml dehydrated alcohol, add the 0.2g palladium carbon that wets, under room temperature, pass into hydrogen, stir 3 hours, point board monitoring is until without compound ii, filter, use washing with alcohol solid, revolve to steam and remove the solvent in liquid, obtain 1.6g product compound I, yield: 90.40%.
1H-NMR(400MHz,DMSO-d6)δ:4.21(brs，2H)，3.12(t，J=7.2Hz，2H),1.77(m，2H)，1.06(t，J=7.2Hz，3H)。
Embodiment 2
(1) compound V is synthetic
Justice is got 20g diethyl malonate and is put into 250ml round-bottomed flask, slowly drips 5ml nitrosonitric acid under ice bath, controls temperature below 15 degree.Stirring at room 2 hours, pours mixture in frozen water into, then uses dichloromethane extraction twice, merges a month machine layer; Friend's machine layer is distinguished the aqueous solution of urea washing of water and 5%, until starch potassium iodide paper does not develop the color.Dichloromethane solution extracts with 10% sodium carbonate solution, and combining water layer, is acidified to pH2 with concentrated hydrochloric acid, then uses dichloromethane extraction, combining extraction liquid, anhydrous sodium sulfate drying, filters, revolve and steam except desolventizing, obtain 24g product compound V, yield: 93.75%.
1H-NMR(400MHz,CDCl3)δ:5.83(s，1H),4.46(q,J＝4.0Hz，4H)，1.38(t，J=4.0Hz，6H)。
(2) compounds Ⅳ is synthetic
Take rapidly 12g sodium Metal 99.5 and be dissolved in 120ml dehydrated alcohol, add 23g α-nitro diethyl malonate V and 9.2g thiocarbamide, under backflow, reaction vigorous stirring 2 hours, be cooled to room temperature, with concentrated hydrochloric acid, be acidified to acidity, now have a large amount of solids to separate out, filter, filter cake water and washing with alcohol, dry, weigh, obtain 20.5g product compound IV, yield: 96.70%.
1H-NMR(400MHz,DMSO-d6)δ:11.16(s，3H)。
(3) compound III is synthetic
Take 10g compounds Ⅳ and 10ml water is put into 250ml round-bottomed flask, then add the aqueous solution 46.8ml that contains 2.5g sodium hydroxide, stir half an hour, solid dissolves completely.Add 2ml NMP (N-Methyl pyrrolidone), then add 3.3g propyl iodide, reaction is stirred and is spent the night (approximately 18 hours), with hydrochloric acid, adjusts pH to 2, there are a large amount of solids to generate, filter water, washing with alcohol filter cake, solid drying, weigh, obtain 10.3g product compound III, yield: 84.43%.
1H-NMR(400MHz,DMSO-d6)δ:3.16(t，J=7.2Hz，2H),1.67(m，2H)，0.97(t，J=7.2Hz，3H)。
(4) compound ii is synthetic
Take 5g compound III and put into 100ml round-bottomed flask, add 7ml phosphorus oxychloride and 0.35ml DMA, 110 degree reactions 3 hours, cooling, revolve to steam and remove excessive phosphorus oxychloride, in resistates, slowly add appropriate water, ethyl acetate extraction, merges organic layer, anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separation obtains 4.7g product compound II, yield 81.03%.
1H-NMR(400MHz,CDCl3)δ:3.19(t，J＝7.2Hz，2H),1.84(m，2H)，0.92(t，J＝7.2Hz，3H)。
(5) chemical compounds I is synthetic
Take 2g compound ii, be dissolved in 200ml dehydrated alcohol, add the 0.02g palladium carbon that wets, under room temperature, pass into hydrogen, hydrogen flow rate is controlled at 0.1ml/min, stir 3 hours, some board monitoring is until without raw material, filter, use washing with alcohol solid, revolve to steam and remove the solvent in liquid, obtain 1.6g product compound I, yield: 90.40%.
1H-NMR(400MHz,DMSO-d6)δ:4.21(brs，2H)，3.12(t，J=7.2Hz，2H),1.77(m，2H)，1.06(t，J=7.2Hz，3H)。
Embodiment 3
(1) compound V is synthetic
Take 20g diethyl malonate and put into 250ml round-bottomed flask, under ice bath, slowly drip 80ml nitrosonitric acid, control temperature below 15 degree.Stirring at room 2 hours, pours mixture in frozen water into, then uses dichloromethane extraction twice, merges organic layer; Organic layer is distinguished the aqueous solution of urea washing of water and 5%, until starch potassium iodide paper does not develop the color.Dichloromethane solution extracts with 10% sodium carbonate solution, and combining water layer, is acidified to pH2 with concentrated hydrochloric acid, then uses dichloromethane extraction, combining extraction liquid, anhydrous sodium sulfate drying, filters, revolve and steam except desolventizing, obtain 24g product compound V, yield: 93.75%.
1H-NMR(400MHz,CDCl3)δ:5.83(s，1H),4.46(q,J＝4.0Hz，4H)，1.38(t，J=4.0Hz，6H)。
(2) compounds Ⅳ is synthetic
Take rapidly 12g sodium Metal 99.5 and be dissolved in 480ml dehydrated alcohol, add 23g α-nitro diethyl malonate V and 23g thiocarbamide, under backflow, reaction vigorous stirring 2 hours, be cooled to room temperature, with concentrated hydrochloric acid, be acidified to acidity, now have a large amount of solids to separate out, filter, filter cake water and washing with alcohol, dry, weigh, obtain 20.5g product compound IV, yield: 96.70%.
1H-NMR(400MHz,DMSO-d6)δ:11.16(s，3H)。
(3) compound III is synthetic
Take 10g compounds Ⅳ and 200ml water is put into 250ml round-bottomed flask, then add the aqueous solution 23ml that contains 10g sodium hydroxide, stir half an hour, solid dissolves completely.Add 20ml NMP (N-Methyl pyrrolidone), then add 20g n-propyl bromide, reaction is stirred and is spent the night (approximately 18 hours), with hydrochloric acid, adjusts pH to 2, there are a large amount of solids to generate, filter water, washing with alcohol filter cake, solid drying, weigh, obtain 10.3g product compound III, yield: 84.43%.
1H-NMR(400MHz,DMSO-d6)δ:3.16(t，J=7.2Hz，2H),1.67(m，2H)，0.97(t，J=7.2Hz，3H)。
(4) compound ii is synthetic
Take 5g compound III and put into 250ml round-bottomed flask, add 50ml phosphorus oxychloride and 50ml DMA, 110 degree reactions 3 hours, cooling, revolve to steam and remove excessive phosphorus oxychloride, in resistates, slowly add appropriate water, ethyl acetate extraction should be got merging organic layer, anhydrous sodium sulfate drying, filters, concentrated, silica gel column chromatography separation obtains 4.7g product compound II, yield 81.03%.
1H-NMR(400MHz,CDCl3)δ:3.19(t，J＝7.2Hz，2H),1.84(m，2H)，0.92(t，J＝7.2Hz，3H)。
(5) chemical compounds I is synthetic
Take 2g chemical compounds I I, be dissolved in 1ml dehydrated alcohol, add the 2g palladium carbon that wets, under room temperature, pass into hydrogen, hydrogen flow rate is controlled at 10ml/min, stir 3 hours, some board monitoring is until without raw material, filter, use washing with alcohol solid, revolve to steam and remove the solvent in liquid, obtain 1.6g product compound I, yield: 90.40%.
1H-NMR(400MHz,DMSO-d6)δ:4.21(brs，2H)，3.12(t，J=7.2Hz，2H),1.77(m，2H)，1.06(t，J=7.2Hz，3H)。
Claims (3)
1. 2-rosickyite base-4, the preparation method of 6-bis-chlorine-5-amido pyrimidines, is characterized in that, reactions steps is specific as follows;
1) take diethyl malonate and put into round-bottomed flask, under ice bath, slowly drip nitrosonitric acid, control temperature at 0-15 ℃, dropwise, under room temperature, stir 2 hours, mixture is poured in frozen water, then use dichloromethane extraction twice, merge organic layer; The aqueous solution of urea washing of organic layer difference water and concentration 5%; until test organic layer starch potassium iodide paper does not develop the color; the sodium carbonate solution extraction that organic layer is 10% by concentration, collects water layer, with concentrated hydrochloric acid, is acidified to pH2～5; then use dichloromethane extraction; collected organic layer, anhydrous sodium sulfate drying, filters; revolve and steam except desolventizing, obtain compound V;
Described, the mass volume ratio of diethyl malonate and nitrosonitric acid is 4:1～1:4g/ml;
2) take rapidly sodium Metal 99.5 and be dissolved in dehydrated alcohol, the compound V and the thiocarbamide that add step 1) to prepare, stir under reflux conditions 2 hours; be cooled to room temperature, with concentrated hydrochloric acid, be acidified to pH2～5, filter; filter cake water and washing with alcohol, dry, obtain compound IV;
Described, the mass volume ratio of sodium Metal 99.5 and dehydrated alcohol is 1:10～1:40g/ml;
Described, the mass ratio of compound V and thiocarbamide is 2.5:1～1:1;
3) take compound IV and water is put into round-bottomed flask, then add the alkaline solution that concentration is 10%～30%, under room temperature condition, stir half an hour; solid dissolves completely, adds NMP, then adds halo n-propane; under room temperature, stirring reaction is 18 hours; with acid, adjust pH to 2, filter water; washing with alcohol filter cake; filtration cakes torrefaction, weighs, and obtains chemical compounds I I I;
Described, the mass volume ratio of compound IV and water is 1:1～1:20g/ml;
Described, the mass ratio of compound IV and alkali is 4:1～1:1;
Described, the mass volume ratio of compound IV and NMP is 5:1～1:2g/ml;
Described, the mass ratio of compound IV and halo n-propane is 3:1～0.5:1;
Described, acid is selected from hydrochloric acid or formic acid or acetic acid or phosphoric acid or sulfuric acid;
Described halo n-propane is selected from n-propyl bromide or propyl iodide;
Described, alkali is selected from lithium hydroxide or sodium hydroxide or potassium hydroxide or salt of wormwood or cesium carbonate;
4) take compound III and put into round-bottomed flask, add trichlorine oxygen squama and DMA; 110 ℃ are reacted 3 hours, are cooled to room temperature, revolve and steam the phosphorus oxychloride of removing; in resistates, add water; ethyl acetate extraction, collects ethyl acetate layer, anhydrous sodium sulfate drying; filter; be spin-dried for, obtain crude product, crude product obtains chemical compounds I I with silica gel column chromatography separation;
Described, the mass volume ratio of compound III and phosphorus oxychloride is 0.7:1～1:10g/ml;
Described, the volume ratio of phosphorus oxychloride and DMA is 20:1～1:1;
5) take compound ii, be dissolved in dehydrated alcohol, add wet palladium carbon, under room temperature, pass into hydrogen, stir 3 hours, some board monitoring is until without compound ii, filtration, obtains palladium carbon and filtrate, and filtrate is spin-dried for,, obtain chemical compounds I;
Described, the mass volume ratio of Compound I I and dehydrated alcohol is 1:100～1:1g/ml;
Described, the mass ratio of Compound I I and palladium carbon is 100:1～1:1;
Described, the flow velocity of hydrogen is 0.1ml～10ml/min.
2. a kind of 2-rosickyite according to claim 1 and 2 base-4, the preparation method of 6-bis-chlorine-5-amido pyrimidines, is characterized in that, in step 3), described alkaline solution is that concentration is 20%.
3. a kind of 2-rosickyite according to claim 1 and 2 base-4, the preparation method of 6-bis-chlorine-5-amido pyrimidines, is characterized in that, in step 3), described alkali is sodium hydroxide.
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| CN105294573A (en) * | 2015-06-16 | 2016-02-03 | 厦门医学高等专科学校 | Method for synthesizing 4,6-dichloro-2-(propylthio)-5-aminopyrimidine |
| CN111205232A (en) * | 2020-02-26 | 2020-05-29 | 浙江天宇药业股份有限公司 | Synthesis method of ticagrelor intermediate |
| CN113024471A (en) * | 2019-12-25 | 2021-06-25 | 上海泓博智源医药股份有限公司 | Synthetic method of 4, 6-dichloro-2-propylmercapto-5-amino piperidine |
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| CN113024471A (en) * | 2019-12-25 | 2021-06-25 | 上海泓博智源医药股份有限公司 | Synthetic method of 4, 6-dichloro-2-propylmercapto-5-amino piperidine |
| CN111205232A (en) * | 2020-02-26 | 2020-05-29 | 浙江天宇药业股份有限公司 | Synthesis method of ticagrelor intermediate |
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