CN105294573A - Method for synthesizing 4,6-dichloro-2-(propylthio)-5-aminopyrimidine - Google Patents
Method for synthesizing 4,6-dichloro-2-(propylthio)-5-aminopyrimidine Download PDFInfo
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Abstract
The invention discloses a novel method for synthesizing 4,6-dichloro-2-(propylthio)-5-aminopyrimidine (I), namely an important intermediate of ticagrelor. The method comprises the following steps: carrying out a condensation reaction between substituted aminomalonic acid diethyl ester (III) and urea to generate 2,4,6-trihydroxy-5-substituted aminopyrimidine (IV); conducting chlorination on the obtained compound 2,4,6-trihydroxy-5-substituted aminopyrimidine (IV), to obtain 2,4,6-trichloro-5-aminopyrimidine (V); carrying out a reaction between the obtained compound 2,4,6-trichloro-5-aminopyrimidine (V), and propanethiol to generate 4,6-dichloro-2-(propylthio)-5-aminopyrimidine (I). The synthetic route adopted in the method is low in cost, simple to operate, and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of method of synthesis 4,6-bis-chloro-2-(rosickyite base)-5-aminopyrimidine.
Background technology
ADZ6140 (II), chemistry (1S, 2S by name, 3R, 5S)-3-[7-[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl] is amino]-5-(rosickyite base)-3H-[1,2,3] triazole also [4,5-D]-3-pyrimidyl]-5-(2-hydroxy ethoxy) pentamethylene-1,2-ethanol, developed by Astrazeneca AB of Britain, be a kind of novel, there is optionally small molecules anticoagulant.This medicine can purine 2 acceptor (purinoceptor2 reversibly on vasoactive smooth muscle cell (VSMC), P2) hypotype P2Y12, obvious restraining effect is had to the platelet aggregation that ADP causes, and oral rear onset is rapid, therefore effectively can improve the symptom of acute coronary patient.
The chloro-2-of 4,6-bis-(rosickyite base)-5-aminopyrimidine (I) is an important fragment intermediate of synthesis ADZ6140.The method of current this intermediate of synthesis is all reported by Britain's AstraZeneca.Wherein, patent US5654285, depicts Article 1 route.
This route for initial feed, after alkyl replaces, obtains 4,6-dihydroxyl-2-(rosickyite base) pyrimidine with 4,6-dihydroxyl-2-mercaptopyrimidine.Subsequently under the effect of nitrosonitric acid, there is nitration reaction and obtain 4,6-dihydroxyl-5-nitro-2-(rosickyite base) pyrimidine.Then, under the effect of phosphorus oxychloride, there is chlorination and obtain the chloro-5-nitro of 4,6-bis--2-(rosickyite base) pyrimidine.The chloro-2-of 4,6-bis-(rosickyite base)-5-aminopyrimidine (I) is obtained finally by iron powder reducing.
This route also exists following defect: first employ nitric acid and carry out nitration reaction, can produce a large amount of spent acid waste water, both cause high risks to environment, large to equipment corrosion again; Secondly, chlorination have employed column chromatography and purifies, and is unfavorable for amplifying producing; Whole piece route is containing four-step reaction, and total recovery only has 25%.In addition, reduction nitro uses the method for acid lower iron powder reducing, and aftertreatment can produce a large amount of iron mud and cause operational difficulty.These defects limit its scale operation significantly.
Although AstraZeneca is reported in the patents such as WO2005095358, WO2010030224, by the method reduction nitro of platinum carbon pressure hydration, platinum carbon price is very expensive, limits its suitability for industrialized production equally.
Britain's AstraZeneca develops again a variation route afterwards, as patent WO0192263 describes:
This route still with 4,6-dihydroxyl-2-mercaptopyrimidine for initial feed, through alkyl replace after obtain 4,6-dihydroxyl-2-(rosickyite base) pyrimidine.Subsequently, 4,6-dihydroxyl-2-(rosickyite base)-5-(p-methylphenyl azo) pyrimidine is obtained by reacting with the para-totuidine diazonium salt of fresh preparation.Then, under the effect of phosphorus oxychloride, there is chlorination and obtain the chloro-2-of 4,6-bis-(rosickyite base)-5-(p-methylphenyl azo) pyrimidine.Finally, hydrogenation under the effect of platinum carbon, obtains the chloro-2-of 4,6-bis-(rosickyite base)-5-aminopyrimidine (I).
This route has some superiority compared to Article 1 route, avoid and use a large amount of nitric acid, and yield improves.But also there is following defect in this route: first in route, utilize diazonium salt to prepare 4,6-dihydroxyl-2-(rosickyite base)-5-(p-methylphenyl azo) pyrimidine, not only complex operation, severe reaction conditions, need strictly to control temperature of reaction, and the preparation of diazonium salt needs a large amount of acid equally; Secondly, make catalyzer with expensive 50% platinum carbon in route, and usage quantity large (substrate 1.1kg, 50% platinum carbon 0.81kg), therefore route cost is high.
Patent WO2007093368 reduces this step to azo and improves, and azo-compound is first first reduced into hydrazine with zinc powder/ammonium formiate by it, and under Raney-Ni effect, hydrazine is reduced into amine by hydrogenation more subsequently.Use expensive platinum carbon although avoid, the method not only increases single step reaction, and due to Raney-Ni inflammable, in preparation and use procedure, security is lower, therefore the method is not suitable for suitability for industrialized production equally.
Summary of the invention
Instant invention overcomes the defect of above-mentioned prior art, provide the novel method that one prepares the chloro-2-of ADZ6140 important intermediate 4,6-bis-(rosickyite base)-5-aminopyrimidine (I).Present method has the features such as route is short, cost is low, easy and simple to handle.
The present invention specifically comprises the steps:
(1) substituted-amino diethyl malonate (III) and urea condensation react generation 2,4,6-trihydroxy--5-substituted-amino pyrimidine (IV);
(2) compound (IV) generates 2,4,6-tri-chlorine-5-amido pyrimidine (V) after chloro;
(3) compound (V) and propylmercaptan react the chloro-2-of generation 4,6-bis-(rosickyite base)-5-aminopyrimidine (I).
Involved in the present invention to reaction can represent with following reaction formula:
In formula, R is hydrogen, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl, and wherein alkyl-carbonyl is selected from ethanoyl, propionyl; Aryl carbonyl is selected from benzoyl, p-nitrophenyl formyl radical; Alkoxy carbonyl is selected from tert-butoxycarbonyl, benzyloxycarbonyl.
Of the present inventionly prepare 2 from substituted-amino diethyl malonate (III) and urea, 4, the reaction of 6-trihydroxy--5-substituted-amino pyrimidine (IV) carries out under suitable alkali effect, and alkali used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide.
Of the present inventionly prepare 2 from substituted-amino diethyl malonate (III) and urea, 4, the reaction of 6-trihydroxy--5-substituted-amino pyrimidine (IV) carries out under suitable solvent, solvent used is selected from tetrahydrofuran (THF), acetone, espeleton, methylene dichloride, chloroform, toluene, acetonitrile, methyl alcohol, ethanol, DMF.
It is above-mentioned that to prepare the operating process of the reaction of 2,4,6-trihydroxy--5-substituted-amino pyrimidine (IV) from substituted-amino diethyl malonate (III) and urea roughly as follows:
Add substituted-amino diethyl malonate (III), urea, alkali and solvent in reaction flask after, react 1-48 hour at a suitable temperature.If have solid to separate out after reaction terminates, filter, collect filter cake.Solid is not had to separate out then except desolventizing.By the compound water dissolution of gained, regulate pH to neutral, if there is solid to separate out, filter, collect filter cake.Do not have solid to separate out and then remove desolventizing subsequently with organic solvent extraction.Namely obtain 2,4,6-trihydroxy--5-substituted-amino pyrimidine (IV) after abundant drying, directly carry out next step reaction.
Of the present invention from 2,4,6-trihydroxy--5-substituted-amino pyrimidine (IV) prepares 2,4, the reaction needed of 6-tri-chlorine-5-amido pyrimidine (V) uses chlorinating agent, and chlorinating agent used is selected from phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, dichloride sulfone.
Of the present inventionly prepare 2 from 2,4,6-trihydroxy--5-substituted-amino pyrimidine (IV), 4, the reaction of 6-tri-chlorine-5-amido pyrimidine (V) carries out under suitable alkali effect, and alkali used is selected from diisopropyl ethyl amine, DMA, triethylamine, pyridine.
Of the present invention from 2,4,6-trihydroxy--5-substituted-amino pyrimidine (IV) prepares 2,4, the reaction of 6-tri-chlorine-5-amido pyrimidine (V) carries out under suitable solvent, solvent used is selected from toluene, DMF, methyl-sulphoxide, dimethylbenzene, benzene, trichloromethane, methylene dichloride.
The above-mentioned operating process preparing the reaction of 2,4,6-tri-chlorine-5-amido pyrimidine (V) from 2,4,6-trihydroxy--5-substituted-amino pyrimidine (IV) is roughly as follows:
In reaction flask, add 2,4,6-trihydroxy--5-substituted-amino pyrimidine (IV), alkali, chlorinating agent and solvent, react 1-48 hour at a suitable temperature subsequently.After reacting completely, the most of chlorinating agent of concentrated removing.Residual solution is poured in frozen water, add solvent extraction, after concentrated, namely obtain 2,4,6-tri-chlorine-5-amido pyrimidine (V).
Of the present invention from 2,4,6-tri-chlorine-5-amido pyrimidine (V) and propylmercaptan prepare 4, the reaction of the chloro-2-of 6-bis-(rosickyite base)-5-aminopyrimidine (I) is carried out under alkali effect, and alkali used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium methylate, sodium ethylate, sodium tert-butoxide, triethylamine, diisopropyl ethyl amine, pyridine.
Of the present invention from 2,4,6-tri-chlorine-5-amido pyrimidine (V) and propylmercaptan prepare 4, the reaction of the chloro-2-of 6-bis-(rosickyite base)-5-aminopyrimidine (I) carries out under suitable solvent, solvent used is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), toluene, chlorinated benzene, DMF, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone, water.
Of the present invention from 2,4,6-tri-chlorine-5-amido pyrimidine (V) and propylmercaptan prepare 4, the reaction of the chloro-2-of 6-bis-(rosickyite base)-5-aminopyrimidine (I) is carried out under transition-metal catalyst effect, and transition-metal catalyst used is selected from cuprous iodide, cupric iodide, cuprous bromide, cupric bromide, nickelous bromide, nickelous chloride, Palladous chloride, palladium.
Of the present invention from 2, 4, 6-tri-chlorine-5-amido pyrimidine (V) and propylmercaptan prepare 4, the reaction needed of the chloro-2-of 6-bis-(rosickyite base)-5-aminopyrimidine (I) adds part makes catalyst stabilization, part used is selected from 2, 2 '-dipyridyl (bipy), proline(Pro), triphenylphosphine, tri-n-butyl phosphine, two (diphenylphosphine) methane (dppm), two (diphenylphosphine) ethane (dppe), 1, two (diphenylphosphine) propane (dppp) of 3-, 1, two (diphenylphosphine) butane (dppb) of 4-, 1, two (diphenylphosphine) ferrocene (dppf) of 1'-.
Of the present invention from 2,4,6-tri-chlorine-5-amido pyrimidine (V) prepares 4, the reaction needed of the chloro-2-of 6-bis-(rosickyite base)-5-aminopyrimidine (I) uses additive, selected additive is selected from tetra-alkyl ammonium chloride, tetraalkyl brometo de amonio, tetralkyl ammonium fluorides, tetraalkylammonium iodides, tetraalkyl monoammonium sulfate, tetra-alkyl ammonium hydroxide, sodium iodide, Sodium Bromide, and alkyl is selected from: ethyl, propyl group, butyl.
The above-mentioned operating process preparing the reaction of the chloro-2-of 4,6-bis-(rosickyite base)-5-aminopyrimidine (I) from 2,4,6-tri-chlorine-5-amido pyrimidine (V) is roughly as follows:
2,4,6-tri-chlorine-5-amido pyrimidine (V), alkali, catalyzer, part, additive and solvent is added in reaction flask.Add propylmercaptan subsequently, and react 1-48 hour at a suitable temperature.Namely the chloro-2-of 4,6-bis-(rosickyite base)-5-aminopyrimidine (I) is obtained through suitable purification after reaction terminates.
The invention has the advantages that by brief route, simple operation, prepared the chloro-2-of important intermediate 4,6-bis-(rosickyite the base)-5-aminopyrimidine (I) of ADZ6140 with high yield and high purity.Particularly, the intermediate of whole piece route, all without the need to carrying out purification operations, directly can carry out next step reaction, enormously simplify operation.Compared to other route, this route is not only with low cost, simple to operate, is applicable to suitability for industrialized production.
Embodiment
Further illustrate technical scheme of the present invention with specific embodiment below, but protection scope of the present invention is not limited thereto:
(IV synthesis a) of embodiment 12,4,6-trihydroxy--5-kharophen pyrimidine
Under room temperature, 50.0g acetamino diethyl malonate (III), 28.8g urea, 77.0g sodium ethylate are mixed mutually with 750mL ethanol, back flow reaction 15 hours.After reaction terminates, filter, filter cake 50mL washing with alcohol, collect filter cake.By the solid of gained 1L water dissolution, with salt acid for adjusting pH to neutral, have solid to separate out, namely separate solid also obtains 39.3g2 after abundant drying, and (IV a), directly carries out next step reaction for 4,6-trihydroxy--5-kharophen pyrimidine.ESI-MSm/z:186[M+H]
+；
1HNMR(400MHz，D
2O)δ2.13(s,3H)。
(IV synthesis b) of embodiment 22,4,6-trihydroxy--5-benzene carbon amide yl pyrimidines
Under room temperature, 6.43g benzamido diethyl malonate (III), 2.9g urea, 7.7g sodium ethylate are mixed mutually with 75mL ethanol, back flow reaction 13 hours.After reaction terminates, removal of solvent under reduced pressure, adds 100mL water.With salt acid for adjusting pH to neutral, aqueous solution 200mL chloroform extraction, repeats 3 times, combined chloroform layer.After drying except desolventizing, (IV oily matter b), directly carries out next step reaction containing 2,4,6-trihydroxy--5-benzene carbon amide yl pyrimidines to obtain 5g.ESI-MSm/z:248[M+H]
+。
The synthesis of embodiment 32,4,6-tri-chlorine-5-amido pyrimidine (V)
By the compound of gained in embodiment one (IV a) crude product 33.0g, 21.2g pyridine mutually mix with 500mL toluene, add 62.2g phosphorus oxychloride subsequently, heating reflux reaction 24h.After reaction terminates, the concentrated phosphorus oxychloride removing desolventizing and most of surplus.Residual solution is poured in frozen water, extracts at twice by 500mL ethyl acetate.After organic phase merges, wash once with 300mL saturated sodium bicarbonate solution.Organic phase is dry, and concentrated 35.1g comprises the oily matter of 2,4,6-tri-chlorine-5-amido pyrimidine (V).ESI-MSm/z:199[M+H]
+。
The synthesis of embodiment 42,4,6-tri-chlorine-5-amido pyrimidine (V)
By the compound of gained in embodiment two (IV b) crude product 5.0g, 3.5g triethylamine mutually mix with 80mL toluene, add 7.0g phosphorus oxychloride subsequently, heating reflux reaction 24h.After reaction terminates, the concentrated phosphorus oxychloride removing desolventizing and most of surplus.Residual solution is poured in frozen water, extracts at twice by 100mL ethyl acetate.After organic phase merges, wash once with 50mL saturated sodium bicarbonate solution.Organic phase is dry, concentrates and obtain the oily matter that 3.9g comprises 2,4,6-tri-chlorine-5-amido pyrimidine (V), directly drops into next step reaction.
The synthesis of the chloro-2-of embodiment 54,6-bis-(rosickyite base)-5-aminopyrimidine (I)
By oily matter 28.5g, 1.8g nickelous chloride of the inclusion compound (V) in embodiment three under room temperature; 5.8g two (diphenylphosphine) ethane, 21g sodium iodide and 8gNaOH are blended in 500mL toluene; under protection of inert gas; slowly add 10g propylmercaptan, and stir 24h.After reaction terminates, add 500mL water extracting and separating and obtain toluene layer.After toluene layer anhydrous sodium sulfate drying, except desolventizing obtains oily matter.In oily matter, add 150mL isopropyl ether, stir 5h at 50 DEG C, be slowly cooled to-10 degree, suction filtration obtains 21.2g4, the chloro-2-of 6-bis-(rosickyite base)-5-aminopyrimidine (I).ESI-MSm/z:239[M+H]
+；
1HNMR(400MHz，CDCl
3)δ1.03(t,J＝7.2Hz,3H),1.70-1.78(m,2H)，3.07(t,J＝7.0Hz,2H)，4.20(s,2H)。
The synthesis of the chloro-2-of embodiment 64,6-bis-(rosickyite base)-5-aminopyrimidine (I)
By oily matter 1g, 0.1g cuprous iodide of the inclusion compound (V) in embodiment four under room temperature; 0.1g2; 2 '-dipyridyl, 0.16g Tetrabutyl amonium bromide and 1g pyridine are blended in 20mLN; in dinethylformamide; under protection of inert gas; slowly add 0.3g propylmercaptan, and stir 24h.After reaction terminates, add 30mL water and 50mL toluene extracting and separating obtains toluene layer.After toluene layer anhydrous sodium sulfate drying, except desolventizing obtains oily matter.This oily matter obtains 0.42g4 by column chromatography for separation, the chloro-2-of 6-bis-(rosickyite base)-5-aminopyrimidine (I).
Those skilled in the art are known, when technical scheme of the present invention changes in following parameter area, still can obtain excessively close technique effect same as the previously described embodiments:
A kind of method of synthesis 4,6-bis-chloro-2-(rosickyite base)-5-aminopyrimidine, its structure is as follows:
Comprise following steps:
A () substituted-amino diethyl malonate (III) and urea condensation generate 2,4,6-trihydroxy--5-substituted-amino pyrimidine (IV),
B () compound (IV) generates 2,4,6-tri-chlorine-5-amido pyrimidine (V) after chloro,
C () compound (V) and propylmercaptan react the chloro-2-of generation 4,6-bis-(rosickyite base)-5-aminopyrimidine (I),
In formula, R is hydrogen, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl, and wherein alkyl-carbonyl is selected from ethanoyl, propionyl; Aryl carbonyl is selected from benzoyl, p-nitrophenyl formyl radical; Alkoxy carbonyl is selected from tert-butoxycarbonyl, benzyloxycarbonyl.
The reaction of described step (a) is carried out in the basic conditions, and the alkali used is selected from: sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide.
The reaction of described step (a) carries out under suitable solvent, and solvent used is selected from tetrahydrofuran (THF), acetone, espeleton, methylene dichloride, chloroform, toluene, acetonitrile, methyl alcohol, ethanol, DMF.
The reaction needed of described step (b) uses chlorinating agent, and chlorinating agent used is selected from phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, dichloride sulfone.
The reaction of described step (b) is carried out under alkali effect, and alkali used is selected from: diisopropyl ethyl amine, DMA, triethylamine, pyridine.
The reaction of described step (c) is carried out under alkali effect, and alkali used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium methylate, sodium ethylate, sodium tert-butoxide, triethylamine, diisopropyl ethyl amine, pyridine.
The reaction of described step (c) carries out under suitable solvent, and solvent used is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), toluene, chlorinated benzene, DMF, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone, water.
The reaction of described step (c) is carried out under transition-metal catalyst effect, and transition-metal catalyst used is selected from cuprous iodide, cupric iodide, cuprous bromide, cupric bromide, nickelous bromide, nickelous chloride, Palladous chloride, palladium.
The reaction needed of described step (c) adds part makes catalyst stabilization, part used is selected from 2,2 '-dipyridyl (bipy), proline(Pro), triphenylphosphine, tri-n-butyl phosphine, two (diphenylphosphine) methane (dppm), two (diphenylphosphine) ethane (dppe), 1, two (diphenylphosphine) propane (dppp), 1 of 3-, two (diphenylphosphine) butane (dppb) of 4-, 1,1'-two (diphenylphosphine) ferrocene (dppf).
The reaction needed of described step (c) uses additive, selected additive is selected from tetra-alkyl ammonium chloride, tetraalkyl brometo de amonio, tetralkyl ammonium fluorides, tetraalkylammonium iodides, tetraalkyl monoammonium sulfate, tetra-alkyl ammonium hydroxide, sodium iodide, Sodium Bromide, and alkyl is selected from: ethyl, propyl group, butyl.
Claims (10)
1. the method for synthesis 4,6-bis-chloro-2-(rosickyite base)-5-aminopyrimidine, its structure is as follows:
It is characterized in that: comprise following steps:
A () substituted-amino diethyl malonate (III) and urea condensation generate 2,4,6-trihydroxy--5-substituted-amino pyrimidine (IV),
B () compound (IV) generates 2,4,6-tri-chlorine-5-amido pyrimidine (V) after chloro,
C () compound (V) and propylmercaptan react the chloro-2-of generation 4,6-bis-(rosickyite base)-5-aminopyrimidine (I),
In formula, R is hydrogen, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl, and wherein alkyl-carbonyl is selected from ethanoyl, propionyl; Aryl carbonyl is selected from benzoyl, p-nitrophenyl formyl radical; Alkoxy carbonyl is selected from tert-butoxycarbonyl, benzyloxycarbonyl.
2. method according to claim 1, it is characterized in that: the reaction of described step (a) is carried out in the basic conditions, and the alkali used is selected from: sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide.
3. preparation method according to claim 1, it is characterized in that: the reaction of described step (a) carries out under suitable solvent, solvent used is selected from tetrahydrofuran (THF), acetone, espeleton, methylene dichloride, chloroform, toluene, acetonitrile, methyl alcohol, ethanol, DMF.
4. preparation method according to claim 1, is characterized in that: the reaction needed of described step (b) uses chlorinating agent, and chlorinating agent used is selected from phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, dichloride sulfone.
5. preparation method according to claim 1, is characterized in that: the reaction of described step (b) is carried out under alkali effect, and alkali used is selected from: diisopropyl ethyl amine, DMA, triethylamine, pyridine.
6. preparation method according to claim 1, it is characterized in that: the reaction of described step (c) is carried out under alkali effect, and alkali used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium methylate, sodium ethylate, sodium tert-butoxide, triethylamine, diisopropyl ethyl amine, pyridine.
7. preparation method according to claim 1, it is characterized in that: the reaction of described step (c) carries out under suitable solvent, solvent used is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), toluene, chlorinated benzene, DMF, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone, water.
8. preparation method according to claim 1, it is characterized in that: the reaction of described step (c) is carried out under transition-metal catalyst effect, and transition-metal catalyst used is selected from cuprous iodide, cupric iodide, cuprous bromide, cupric bromide, nickelous bromide, nickelous chloride, Palladous chloride, palladium.
9. preparation method according to claim 1, it is characterized in that: the reaction needed of described step (c) adds part makes catalyst stabilization, part used is selected from 2,2 '-dipyridyl (bipy), proline(Pro), triphenylphosphine, tri-n-butyl phosphine, two (diphenylphosphine) methane (dppm), two (diphenylphosphine) ethane (dppe), 1, two (diphenylphosphine) propane (dppp), 1 of 3-, two (diphenylphosphine) butane (dppb) of 4-, 1,1'-two (diphenylphosphine) ferrocene (dppf).
10. preparation method according to claim 1, it is characterized in that: the reaction needed of described step (c) uses additive, selected additive is selected from tetra-alkyl ammonium chloride, tetraalkyl brometo de amonio, tetralkyl ammonium fluorides, tetraalkylammonium iodides, tetraalkyl monoammonium sulfate, tetra-alkyl ammonium hydroxide, sodium iodide, Sodium Bromide, and alkyl is selected from: ethyl, propyl group, butyl.
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| CN108640870A (en) * | 2018-04-12 | 2018-10-12 | 常州大学 | A method of synthesis 6- bromomethyl -3- methoxyl group -2- nitropyridines |
| 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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