WO2022090101A1 - Process for synthesis of 2,4-dichloro-5-aminopyrimidine - Google Patents

Process for synthesis of 2,4-dichloro-5-aminopyrimidine Download PDF

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WO2022090101A1
WO2022090101A1 PCT/EP2021/079442 EP2021079442W WO2022090101A1 WO 2022090101 A1 WO2022090101 A1 WO 2022090101A1 EP 2021079442 W EP2021079442 W EP 2021079442W WO 2022090101 A1 WO2022090101 A1 WO 2022090101A1
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dichloro
nitropyrimidine
reactor
reaction
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PCT/EP2021/079442
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French (fr)
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Klaus GROLL
Michael PANGERL
Yanling Wang
Lidong Xing
Jianping Xu
Pinjie ZHANG
Yongsheng Zhang
Zhibin Zhu
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Boehringer Ingelheim International Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • the invention is directed to the commercially synthetic process of 2,4-Dichloro-5-amino- pyrimidine, starting from 5-nitrouracil.
  • 2,4-Dichloro-5-aminopyrimidine 1 is an important intermediate for drug substances and other industrial intermediate preparation. Although the molecule seems quite simple, there are not much references describing the synthesis of it, among those, the most popular way is to reduce the nitro group of 5-nitrouracil with metals such as iron or zinc (WO 2010 026121, WO 2011 106168, WO 2015 148344, CN 103864792). The metal reduction is accommodated by the heavy environmental pollution and low yield due to the product being trapped inside the metal residue. Other ways are including direct chlorination of 5-amino- pyrimidine or 5-aminouracil which always lead to quite low yields, combined with low selectivity. No metal catalytical hydrogenation had ever being reported applied in the synthesis of this compound.
  • 5-nitrouracil 3 is converted to 2,4-dichloro-5-nitro- pyrimidine 2 by chlorination reaction with phosphorus oxychloride in high yield following a workup in a finely controlled process.
  • 2,4-dichloro-5-nitropyrimidine 2 due to the electronic absorption effect of both, the pyrimidine ring and the nitro group, is very easily decomposed by water or at high temperature e.g. according to a conventional procedure mentioned in WO 2004 110343, more than half of the product is lost in a workup process at commercial scale. Mainly caused by decomposition in water, furthermore the resulting emulsion of the process was hard to be handled. Furthermore J. Org. Chem.
  • the resulting mixture is concentrated to remove excessive phosphorus oxychloride and then quenched in a biphasic mixture of toluene and water between 0-10°C. After phase separation and discoloration e.g. with activated carbon, the mixture or the toluene solution could be used into the next step with or without purification. At a 100 kg scale, the yield was around 84%, which is 14% higher than the lab scale shown in WO 2004 110343.
  • crude 2,4-dichloro-5-aminopyrimidine 2 can be directly reduced by catalytically hydrogenation, to give high quality of 2,4-dichloro-5-aminopyrimidine 1.
  • Pd/C could catalyse the hydrogenation with the pre-requisition that the reaction is separated into two stages.
  • First stage from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5- hydroxylaminopyrimidine.
  • Second stage from 2,4-dichloro-5-hydroxylaminopyrimidine to 2 ,4-dichloro- 5 - aminopyrimidine .
  • a lab scale process with Pd/C (Evonik PMPC SP1020 W, 10% Pd) could be conducted like following: React purified 2,4-dichloro-5-nitropyrimidine with hydrogen under catalytic Pd/C in ethyl acetate at 5 bar and 25-30°C until completion of the first stage reaction from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5-hydroxylaminopyrimidine. Charge methanol and continue to react at 5 bar and 38-43 °C until completion of the second stage reaction from 2,4-dichloro-5-hydroxylaminopyrimidine to 2,4-dichloro-5-aminopy- rimidine. After filtration and concentration, purify the product with methanol and water.
  • an upscaled process with Pd/C (Evonik PMPC SP1020 W, 10% Pd) could be conducted like following: React the 2,4-dichloro-5-nitropyrimidine toluene solution from the preceding step with hydrogen under catalytic Pd/C and acetic acid in ethyl acetate at 4-5 bar and 20-25°C for 3 ⁇ 4 hours. Raise the temperature to 35-40°C and continue to react at 4-5 bar until completion of the reaction. After workup with sodium carbonate and water, filter the reaction mixture and concentrate. Purify the product with methanol and water firstly and toluene and ethyl acetate secondly to get high purity 2,4-dichloro-5-ami- nopyrimidine.
  • the two stages reaction mentioned above need a strategy to be pushed into completion.
  • the first stage needs high pressure, but low temperature to push the completion of the 2,4- dichloro-5-nitropyrimidine as fast as possible, while avoid the reaction between 2,4-di- chloro-5-nitropyrimidine and 2,4-dichloro-5-aminopyrimidine.
  • the second stage needs higher temperature to push the completion of the 2,4-dichloro-5-hydroxylaminopyrimidine.
  • a Pt/C catalyst poisoned with V or Fe can be understood as 1% Pt/C poisoned with 5% V2O5 or 1% Pt/C poisoned with 5% Fe).
  • the invention is an improved process for the manufacturing of wherein in step a) a compound of formula 3 is chlorinated and without purification in step b) the resulting compound of formula 2 is reduced by catalytically hydrogenation in presence of a metal catalyst.
  • the metal catalyst is selected from Pd/C, Pt/C poisoned with V or Pt/C poisoned with Fe.
  • step b) 2,4-dichloro-5-nitropyrimidine 2 is reacted with hydrogen and Pd/C as catalyst in ethyl acetate at 5 bar and 25-30°C until completion of the first stage reaction from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5-hydroxyla- minopyrimidine, thereafter methanol is charged and the reaction is continued at 5 bar and 38-43°C until completion of the second stage reaction from 2,4-dichloro-5-hydroxylamino- pyrimidine to 2,4-dichloro-5-aminopyrimidine.
  • step b) 2,4-dichloro-5-nitropyrimidine 2 in the toluene solution from step a) is reacted with hydrogen and Pd/C as catalyst and acetic acid in ethyl acetate at 4-5 bar and 20-25°C for 3-4 hours, thereafter the temperature is raised to 35- 40°C and the reaction continues at 4-5 bar until completion.
  • step b) 2,4-dichloro-5-nitropyrimidine 2 in the toluene solution from step a) or pure 2,4-dichloro-5-nitropyrimidine 2 is reacted with hydrogen and Pt/C poisoned with V or Pt/C poisoned with Fe as catalyst in ethyl acetate at 5-10 bar and 20-32°C until completion of the first stage reaction from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5-hydroxylaminopyrimidine, thereafter the temperature is raised to 45-52°C and continue to react at 9-10 bar until completion of the reaction.
  • step b) Pt/C poisoned with V is 1% Pt/C poisoned with 5% V2O5.
  • step b) Pt/C poisoned with Fe is 1% Pt/C poisoned with 5% Fe.
  • step a) the chlorination from compound of formula 3 to a compound of formula 2 is done with phosphorus oxychloride in presence of N,N-di- ethylaniline at 60-65 °C.
  • step a) the chlorination from compound of formula 3 to a compound of formula 2 is done with phosphorus oxychloride in presence of N,N-di- ethylaniline at 60-65 °C in toluene.
  • Example 1 Upscaled process for nitration: To 1 1 reactor #1 charge 656 g cone. H2SO4, 300 g Uracil was charged into reactor #1 at 50-70°C with stirring. Charge 202 g fuming HNO3 into reactor #1 at 50-60°C in Ih. After addition, keep stirring at 50-60°C for 2 h. Complete conversion was indicated by HPLC. The reaction mixture was quenched into 1.2 1 Water at 20-30°C in reactor #2. 300 ml water was charged to rinse reactor #1 and then transferred to reactor #2. The resulting suspension was stirred at 20-30°C for 1 h, and then filtered. The wet cake was washed with 600 ml water in two portions. Dry the solid under 30-50 mbar at 55-60°C until KF NMT 0.8%. Product 5-Nitrouracil was obtained as white solid in 92% yield. B. PREPARATION OF 2,4-DICHLORO-5-NITROPYRIMIDINE
  • Example 1 Upscaled process for chlorination with 2.5eq. Phosphorus oxychloride
  • To 2 1 reactor #1 charge 100 g 5-Nitrouracil, 200 ml Toluene and 244 g Phosphorus oxychloride. The mixture was heat to 55-65°C. 209 g N,N-Diethylaniline was charged into at 55-65°C in at least 3 h. The reaction was stirred at same temperature for 1 h. Complete conversion was indicated by HPLC. The solvent was removed by evaporation under 65 mbar and at ⁇ 60°C. Charge 200 ml Toluene into reactor #1. The reaction mixture was cooled to 0-10°C.
  • Example 2 Upscaled process for chlorination with 3.0eq. Phosphorus oxychloride
  • To 2 1 reactor #1 charge 200 g 5-Nitrouracil, 400 ml Toluene and 600 g phosphorus oxychloride. The mixture was heat to 55-65°C. 436 g N,N-Diethylaniline was charged into at 55-65°C in at least 3 h. The reaction was stirred at same temperature for 1 h. Complete conversion was indicated by HPLC. The solvent was removed by evaporation under 65 mbar and at ⁇ 60°C. Charge 400 ml Toluene into reactor #1. The reaction mixture was cooled to 0-10 °C.
  • reactor #1 charge 103 g (corrected by weight assay) 2,4-Dichloro-5-nitropyrimidine, 927 ml Ethyl acetate and 5 g Activated carbon. The mixture was stirred at 20-30°C for 1 h. Filter the mixture in reactor #1 and transfer to hydrogenation reactor #2. 103 ml Ethyl acetate was charged to rinse the cake and transferred to reactor #2. Reactor #2 was purged with Nitrogen for three times. 10 g Pt/C (wet, LOD 69%, Evonik P8078) was charged into reactor #2. The internal temperature was adjusted to 15-25°C. Reactor #2 was purged with Hydrogen for three times. Then start the agitation.
  • reaction was run under Hydrogen pressure 7-10 bars at 20-32°C until hydrogen absorption slow down. Then reactor #2 was heated to 45-52°C. The reaction was run under Hydrogen pressure 9-10 bars at 45-52°C until Hydrogen absorption ceased. Complete conversion was given by HPLC. Relieve Hydrogen and purge with Nitrogen for three times. The reaction mixture was cooled to 15- 25°C and filtered into reactor #3. 21 ml Ethyl acetate was charged to rinse reactor #2, wet cake and then transferred to reactor #3. 206 ml Water was charged into reactor #3. The resulting mixture was stirred at 15-25°C for 15-30 min and then standed at same temperature for 20-30 min.
  • the upper organic layer was concentrated under 60-100 mbar at ⁇ 50°C until a residual volume of 200-300 ml.
  • 206 ml Water was charged into reactor #3.
  • the mixture was concentrated under 120-150 mbar at ⁇ 60°C to a residual volume of 150-250 ml.
  • 206 ml Methanol was charged to reactor #3. Heat the suspension to 45-55°C until a clear solution.
  • 206 ml Water was charged into reactor #3 at 45-55°C for 30 min.
  • the resulting suspension was concentrated under 120-150 mbar at ⁇ 60°C to a residual volume of 250- 350 ml.
  • the mixture was stirred at 45-55°C for NLT 30 min and then cooled to 0-10°C for NLT 3 h.
  • reactor #1 To 500 ml reactor #1 charge 15 g (corrected by weight assay) 2,4-Dichloro-5-nitropyrimi- dine, 160 ml Ethyl acetate and 2.5 g Pt/C (wet, LOD 69%, SinoCompound SC8711) was charged into reactor #1. The internal temperature was adjusted to 30°C. Reactor #1 was purged with Hydrogen for three times. Then start the agitation. The reaction was run under Hydrogen pressure 7-10 bars at 30°C for 15 h. Complete conversion was given by HPLC. Relieve Hydrogen and purge with Nitrogen for three times. The reaction mixture was filtered into reactor #2.
  • the filtrate was washed with 40 ml Water and concentrated under 60- 100 mbar at ⁇ 50°C until a residual volume of 60 ml.
  • 60 ml Toluene was charged into reactor #2.
  • the mixture was concentrated under 60-100 mbar at ⁇ 60°C to a residual volume of 60 ml.
  • 60 ml Toluene was charged to reactor #2.
  • the mixture was concentrated under 60- 100 mbar at ⁇ 60°C to a residual volume of 60 ml.
  • the mixture was stirred at 50°C for NLT 30 min and then cooled to 0-10°C for NLT 2 h. After stirring at 5°C for NLT 1 h, the suspension was filtered. Dry the product in vacuum oven at 55-60°C for 16 h. The product was obtained as cream solid in 90.7 % yield.
  • reactor #1 To 1 1 1 reactor #1 charge 50 g (corrected by weight assay) 2,4-Dichloro-5-nitropyrimidine, 400 ml Ethyl acetate and 2.5 g Activated carbon. The mixture was stirred at 20-30°C for 1 h. Filter the mixture in reactor #1 and transfer to hydrogenation reactor #2. 50 ml Ethyl acetate was charged to rinse the cake and transferred to reactor #2. Reactor #2 was purged with Nitrogen for three times. 50 ml Acetic acid and 5 g Pd/C (wet, LOD 50%, Evonik PMPC SP1020 W) was charged into reactor #2. The internal temperature was adjusted to 25-30°C. Reactor #2 was purged with Hydrogen for three times.
  • the upper organic layer was concentrated under 60-100 mbar at ⁇ 60°C until a residual volume of 100 ml.
  • 150 ml Water was charged into reactor #3.
  • the mixture was concentrated under 60-100 mbar at ⁇ 60°C to a residual volume of 100 ml.
  • 150 ml Methanol was charged to reactor #3.
  • 150 ml Water was charged into reactor #3. 4 g activated carbon was charged.
  • the mixture was stirred at 45-50°C for 1 h, and then filtered.
  • the filtrate was concentrated under 60-100 mbar at ⁇ 60°C until a residual volume of 150 ml.
  • 50 ml Water was charged at 45- 55°C. Concentrate the mixture under 60-100 mbar at ⁇ 60°C until a residual volume of 150 ml.
  • the content in reactor #4 was concentrated under 60-100 mbar at ⁇ 60°C until a residual volume of 100 ml. The resulting mixture was then cooled to 0-10°C for NLT 3 h. After stirring at 0-10°C for NLT 1 h, the suspension was filtered. Dry the product in vacuum oven at 55°C for 16 h. Purified product was obtained as light brown solid in 69.3 % yield.
  • the dried reactor was exchanged with Nitrogen for three times. 2299.9 kg Acetic acid and 230.0 kg 2,4-Dichloro-5-nitropyrimidine were charged into the reactor at 20-35°C. 229.4 kg Iron powder was charged slowly in portions. The reaction mixture was stirred at 20- 35°C for 2-4 h. Complete conversion was given by HPLC. The reaction mixture was centrifuged, and the cake was washed with 1380.5 kg Acetic acid. The obtained filtrate was concentrated under vacuum at ⁇ 60°C until no distillate come out. Charge 1382.8 kg Ethyl acetate. The mixture was stirred at 55-65°C for 2-3 h, cooled to 15-25°C and stirred at 15- 25°C for 1-2 h.
  • the mixture was centrifuged.
  • the first filtrate was obtained.
  • the centrifugal cake was stirred with 919.9 kg Ethyl acetate at 55-65°C for 2-3 h, cooled to 15-25°C and stirred at 15-25 °C for 1-2 h.
  • the mixture was centrifuged, and the cake was washed with 230.1 kg Ethyl acetate.
  • the second filtrate was obtained.
  • the combined filtrate was neutralized with 10% Na2COs aqueous solution at 10-15°C until pH 7-8.
  • the resulting two phases were stirred at 10-15°C for 10-20 min and stood for 1-2 h. Phase separation and the organic layer was obtained.
  • the dried autoclave was exchanged with Nitrogen for three times.
  • 97.0 kg 2,4-Dichloro-5- nitropyrimidine solution (90.2 kg corrected by assay) and 806 kg Ethyl acetate were charged into the reactor at 20-30°C.
  • 9.43 kg wet Pt/C (3.66 kg corrected by assay) was charged into reactor.
  • the reactor was exchanged with Nitrogen three times and Hydrogen three times. Cool the internal temperature to 20-25°C and feed Hydrogen gas until pressure
  • the resulting mixture was concentrated under vacuum at 30-50°C until a residual of 2.0-3.0 volume. Adjust internal temperature to 45-50°C, stir at same temperature for 0.5- Ih, cool to 0-10°C in 3 h, and then stir at same temperature for 0.5-1 h. The suspension was centrifuged and the cake was washed with 45 kg Toluene. The obtained 70 kg crude 2,4-Dichloro-5-aminepyrimi- dine was charged into reactor. 245 kg Ethyl acetate and 3.5 kg Activated carbon were added into reactor at 15-25°C. Stir the mixture at 15-25°C for 1-2 h, and then filtered. The filtrate was concentrated under vacuum at 30-50°C until a residual of 2.0-3.0 volume.
  • Toluene was charged into the reactor. Concentrate the mixture under vacuum at 30-50°C until a residual of 2.0-3.0 volume. Adjust internal temperature to 45-50°C, stir at same temperature for 0.5-lh, cool to 0-10°C in 3 h, and then stir at same temperature for 0.5-1 h. The suspension was centrifuged and the cake was washed with 45 kg Toluene. The wet cake was dried under vacuum by double cone at 50-60°C for 20-24 h. The product was obtained as brown solid in 80.7 % yield.

Abstract

The invention is directed to the commercially synthetic process of 2,4-Dichloro-5-amino- pyrimidine, starting from 5-nitrouracil.

Description

PROCESS FOR SYNTHESIS OF 2,4-DICHLORO-5-AMINOPYRIMIDINE
The invention is directed to the commercially synthetic process of 2,4-Dichloro-5-amino- pyrimidine, starting from 5-nitrouracil.
BACKGROUND OF THE INVENTION
2,4-Dichloro-5-aminopyrimidine 1 is an important intermediate for drug substances and other industrial intermediate preparation. Although the molecule seems quite simple, there are not much references describing the synthesis of it, among those, the most popular way is to reduce the nitro group of 5-nitrouracil with metals such as iron or zinc (WO 2010 026121, WO 2011 106168, WO 2015 148344, CN 103864792). The metal reduction is companied by the heavy environmental pollution and low yield due to the product being trapped inside the metal residue. Other ways are including direct chlorination of 5-amino- pyrimidine or 5-aminouracil which always lead to quite low yields, combined with low selectivity. No metal catalytical hydrogenation had ever being reported applied in the synthesis of this compound.
DESCRIPTION OF THE INVENTION
In detail, according to the invention 5-nitrouracil 3 is converted to 2,4-dichloro-5-nitro- pyrimidine 2 by chlorination reaction with phosphorus oxychloride in high yield following a workup in a finely controlled process.
Figure imgf000002_0001
2,4-dichloro-5-nitropyrimidine 2, due to the electronic absorption effect of both, the pyrimidine ring and the nitro group, is very easily decomposed by water or at high temperature e.g. according to a conventional procedure mentioned in WO 2004 110343, more than half of the product is lost in a workup process at commercial scale. Mainly caused by decomposition in water, furthermore the resulting emulsion of the process was hard to be handled. Furthermore J. Org. Chem. 2015, 80, 7757-7763 disclosed that substituted amine catalyst, like N-methylpiperidine, N,N‘ -dimethylethylamine, triethylamine causes a large amount of amine substituted side products, which consequently cause a huge loss of yield and creates a difficult purification process. Although N,N‘ -diethylaniline had been used in WO 2004 110343, the impurity control of this base had never been disclosed at lower temperature. Thus, the carefully controlled process according to the invention requires to control the decomposition in reaction and is done with phosphorus oxychloride in presence of a base (N,N-diethylaniline) in toluene at 60-65°C.
After completion of the reaction, the resulting mixture is concentrated to remove excessive phosphorus oxychloride and then quenched in a biphasic mixture of toluene and water between 0-10°C. After phase separation and discoloration e.g. with activated carbon, the mixture or the toluene solution could be used into the next step with or without purification. At a 100 kg scale, the yield was around 84%, which is 14% higher than the lab scale shown in WO 2004 110343.
As said, crude 2,4-dichloro-5-aminopyrimidine 2 can be directly reduced by catalytically hydrogenation, to give high quality of 2,4-dichloro-5-aminopyrimidine 1.
Figure imgf000003_0001
The reduction of 2,4-dichloro-5-nitropyrimidine 2 has rarely been reported by metal catalytic hydrogenation. According to Journal of Organic Chemistry (1962), 27, 2170-73, only 18% yield was obtained by Pd/C catalytical hydrogenation, since 2,4-dichloro-5-nitro- pyrimidine 2 is too reactive and usually forms a lot of side-products which are catalysts poisons and stop the reaction. Surprisingly, it has been found that according to the invention, Pd/C, Pt/C poisoned with V or Pt/C poisoned with Fe show good selectivity under the control of the inventive process parameters.
Pd/C could catalyse the hydrogenation with the pre-requisition that the reaction is separated into two stages. First stage, from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5- hydroxylaminopyrimidine. Second stage, from 2,4-dichloro-5-hydroxylaminopyrimidine to 2 ,4-dichloro- 5 - aminopyrimidine .
Following that, a lab scale process with Pd/C (Evonik PMPC SP1020 W, 10% Pd) could be conducted like following: React purified 2,4-dichloro-5-nitropyrimidine with hydrogen under catalytic Pd/C in ethyl acetate at 5 bar and 25-30°C until completion of the first stage reaction from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5-hydroxylaminopyrimidine. Charge methanol and continue to react at 5 bar and 38-43 °C until completion of the second stage reaction from 2,4-dichloro-5-hydroxylaminopyrimidine to 2,4-dichloro-5-aminopy- rimidine. After filtration and concentration, purify the product with methanol and water.
If conversion is applied directly from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5- aminopyrimidine, the unreacted 2,4-dichloro-5-nitropyrimidine will react with the formed product and cause low solubility side products (dimer or trimer), which stick to the surface of the catalyst and stop the reaction.
The lab procedure shown above needs to stop the reaction and add methanol to start the second stage reaction, while, according to the invention an upscaled Pd/C process could overcame this shortage by adding acetic acid to improve the reactivity of the catalyst to complete the reaction without additional solvent.
Following that, an upscaled process with Pd/C (Evonik PMPC SP1020 W, 10% Pd) could be conducted like following: React the 2,4-dichloro-5-nitropyrimidine toluene solution from the preceding step with hydrogen under catalytic Pd/C and acetic acid in ethyl acetate at 4-5 bar and 20-25°C for 3~4 hours. Raise the temperature to 35-40°C and continue to react at 4-5 bar until completion of the reaction. After workup with sodium carbonate and water, filter the reaction mixture and concentrate. Purify the product with methanol and water firstly and toluene and ethyl acetate secondly to get high purity 2,4-dichloro-5-ami- nopyrimidine.
The two stages reaction mentioned above need a strategy to be pushed into completion. The first stage needs high pressure, but low temperature to push the completion of the 2,4- dichloro-5-nitropyrimidine as fast as possible, while avoid the reaction between 2,4-di- chloro-5-nitropyrimidine and 2,4-dichloro-5-aminopyrimidine. The second stage needs higher temperature to push the completion of the 2,4-dichloro-5-hydroxylaminopyrimidine.
But, an upscaled process based on 1% Pt/C poisoned with 5% V2O5 shows higher selectivity and different reactivity compared to Pd/C catalyst (In the context of this invention a Pt/C catalyst poisoned with V or Fe can be understood as 1% Pt/C poisoned with 5% V2O5 or 1% Pt/C poisoned with 5% Fe). Following that, an upscaled process with Pt/C poisoned with V (Evonik P8078, 1% Pt & 5% V2O5) or Pt/C poisoned with Fe (SinoCompound SC8711, 1% Pt & 5% Fe) could be conducted like following: React 2,4-dichloro-5-nitro- pyrimidine toluene solution from last step or pure 2,4-dichloro-5-nitropyrimidine with hydrogen under catalytic Pt/C in ethyl acetate at 5-10 bar and 20-32°C until completion of the first stage reaction from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5-hydroxylamino- pyrimidine. Raise the temperature to 45-52°C and continue to react at 9-10 bar until completion of the reaction. After filtration and concentration, purify the product with methanol and water firstly and toluene and ethyl acetate secondly to get high purity 2,4-dichloro-5- aminopyrimidine. The Pt/C catalyst gives 10-20% higher yield and better quality than Pd/C catalyst.
Thus, the invention is an improved process for the manufacturing of
Figure imgf000005_0001
wherein in step a) a compound of formula 3
Figure imgf000006_0001
is chlorinated and without purification in step b) the resulting compound of formula 2
Figure imgf000006_0002
is reduced by catalytically hydrogenation in presence of a metal catalyst.
In one aspect of the invention in step b) the metal catalyst is selected from Pd/C, Pt/C poisoned with V or Pt/C poisoned with Fe.
In another aspect of the invention in step b) 2,4-dichloro-5-nitropyrimidine 2 is reacted with hydrogen and Pd/C as catalyst in ethyl acetate at 5 bar and 25-30°C until completion of the first stage reaction from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5-hydroxyla- minopyrimidine, thereafter methanol is charged and the reaction is continued at 5 bar and 38-43°C until completion of the second stage reaction from 2,4-dichloro-5-hydroxylamino- pyrimidine to 2,4-dichloro-5-aminopyrimidine.
In another aspect of the invention in step b) 2,4-dichloro-5-nitropyrimidine 2 in the toluene solution from step a) is reacted with hydrogen and Pd/C as catalyst and acetic acid in ethyl acetate at 4-5 bar and 20-25°C for 3-4 hours, thereafter the temperature is raised to 35- 40°C and the reaction continues at 4-5 bar until completion.
In another aspect of the invention in step b) 2,4-dichloro-5-nitropyrimidine 2 in the toluene solution from step a) or pure 2,4-dichloro-5-nitropyrimidine 2 is reacted with hydrogen and Pt/C poisoned with V or Pt/C poisoned with Fe as catalyst in ethyl acetate at 5-10 bar and 20-32°C until completion of the first stage reaction from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5-hydroxylaminopyrimidine, thereafter the temperature is raised to 45-52°C and continue to react at 9-10 bar until completion of the reaction.
In another aspect of the invention in step b) Pt/C poisoned with V is 1% Pt/C poisoned with 5% V2O5.
In another aspect of the invention in step b) Pt/C poisoned with Fe is 1% Pt/C poisoned with 5% Fe.
In another aspect of the invention in step a) the chlorination from compound of formula 3 to a compound of formula 2 is done with phosphorus oxychloride in presence of N,N-di- ethylaniline at 60-65 °C.
In another aspect of the invention in step a) the chlorination from compound of formula 3 to a compound of formula 2 is done with phosphorus oxychloride in presence of N,N-di- ethylaniline at 60-65 °C in toluene.
EXPERIMENTAL PART
A. PREPARATION OF 5-NITROURACIL
Example 1. Upscaled process for nitration: To 1 1 reactor #1 charge 656 g cone. H2SO4, 300 g Uracil was charged into reactor #1 at 50-70°C with stirring. Charge 202 g fuming HNO3 into reactor #1 at 50-60°C in Ih. After addition, keep stirring at 50-60°C for 2 h. Complete conversion was indicated by HPLC. The reaction mixture was quenched into 1.2 1 Water at 20-30°C in reactor #2. 300 ml water was charged to rinse reactor #1 and then transferred to reactor #2. The resulting suspension was stirred at 20-30°C for 1 h, and then filtered. The wet cake was washed with 600 ml water in two portions. Dry the solid under 30-50 mbar at 55-60°C until KF NMT 0.8%. Product 5-Nitrouracil was obtained as white solid in 92% yield. B. PREPARATION OF 2,4-DICHLORO-5-NITROPYRIMIDINE
Figure imgf000008_0001
Example 1. Upscaled process for chlorination with 2.5eq. Phosphorus oxychloride To 2 1 reactor #1 charge 100 g 5-Nitrouracil, 200 ml Toluene and 244 g Phosphorus oxychloride. The mixture was heat to 55-65°C. 209 g N,N-Diethylaniline was charged into at 55-65°C in at least 3 h. The reaction was stirred at same temperature for 1 h. Complete conversion was indicated by HPLC. The solvent was removed by evaporation under 65 mbar and at < 60°C. Charge 200 ml Toluene into reactor #1. The reaction mixture was cooled to 0-10°C. Charge 500 ml Water and 350 ml Toluene into reactor #2 and cool to 0- 5°C. Quench reaction mixture in reactor #1 into reactor #2 at 0-10°C in l-2h. The resulting mixture was stirred at 0-10°C for 20-40 min and then standed at same temperature for 20- 40 min. The bottom aqueous layer was extracted with 100 ml Toluene. The two organic layers were combined and concentrated under 65 mbar at < 60°C until dryness. Product 2,4-Dichloro-5-nitropyrimidine was obtained as brown oil in 84% assay yield.
Example 2. Upscaled process for chlorination with 3.0eq. Phosphorus oxychloride To 2 1 reactor #1 charge 200 g 5-Nitrouracil, 400 ml Toluene and 600 g phosphorus oxychloride. The mixture was heat to 55-65°C. 436 g N,N-Diethylaniline was charged into at 55-65°C in at least 3 h. The reaction was stirred at same temperature for 1 h. Complete conversion was indicated by HPLC. The solvent was removed by evaporation under 65 mbar and at < 60°C. Charge 400 ml Toluene into reactor #1. The reaction mixture was cooled to 0-10 °C. Charge 1000 ml Water and 700 ml Toluene into reactor #2 and cool to 0- 5°C. Quench reaction mixture in reactor #1 into reactor #2 at 0-10°C in l-2h. The resulting mixture was stirred at 0-10°C for 20-40 min and then standed at same temperature for 20- 40 min. The bottom aqueous layer was extracted with 100 ml Toluene. The two organic layers were combined and concentrated under 65 mbar at < 60°C until dryness. Product 2,4-Dichloro-5-nitropyrimidine was obtained as brown oil in 90.7% assay yield. Example 3. Lab procedure for chlorination with 2.9 eq. Phosphorus oxychloride
To 500 ml reactor #1 charge 20 g 5-Nitrouracil, 40 ml Toluene and 56 g phosphorus oxychloride. The mixture was heat to 55-65°C. 35 g N,N-Dimethylaniline was charged into at 55-65°C in at least 3 h. The reaction was stirred at same temperature for 1 h. 8% starting materials was indicated by HPLC and couldn’t be further consumed. The solvent was removed by evaporation under 65 mbar and at < 60°C. Charge 40 ml Toluene into reactor #1. The reaction mixture was cooled to 0-10°C. Charge 100 ml Water and 70 ml Toluene into reactor #2 and cool to 0-5°C. Quench reaction mixture in reactor #1 into reactor #2 at 0- 10°C in l-2h. The resulting mixture was stirred at 0-10°C for 20-40 min and then standed at same temperature for 20-40 min. The bottom aqueous layer was extracted with 20 ml Toluene. The two organic layers were combined and concentrated under 65 mbar at < 60°C until dryness. Product 2,4-Dichloro-5-nitropyrimidine was obtained as brown oil in 57% assay yield, this crude product was purified by distillation at 120-140°C under 9-10 mbar
Figure imgf000009_0001
Example 1. Lab process with Pt/C poisoned with V2O5
To 2 1 reactor #1 charge 103 g (corrected by weight assay) 2,4-Dichloro-5-nitropyrimidine, 927 ml Ethyl acetate and 5 g Activated carbon. The mixture was stirred at 20-30°C for 1 h. Filter the mixture in reactor #1 and transfer to hydrogenation reactor #2. 103 ml Ethyl acetate was charged to rinse the cake and transferred to reactor #2. Reactor #2 was purged with Nitrogen for three times. 10 g Pt/C (wet, LOD 69%, Evonik P8078) was charged into reactor #2. The internal temperature was adjusted to 15-25°C. Reactor #2 was purged with Hydrogen for three times. Then start the agitation. The reaction was run under Hydrogen pressure 7-10 bars at 20-32°C until hydrogen absorption slow down. Then reactor #2 was heated to 45-52°C. The reaction was run under Hydrogen pressure 9-10 bars at 45-52°C until Hydrogen absorption ceased. Complete conversion was given by HPLC. Relieve Hydrogen and purge with Nitrogen for three times. The reaction mixture was cooled to 15- 25°C and filtered into reactor #3. 21 ml Ethyl acetate was charged to rinse reactor #2, wet cake and then transferred to reactor #3. 206 ml Water was charged into reactor #3. The resulting mixture was stirred at 15-25°C for 15-30 min and then standed at same temperature for 20-30 min. The upper organic layer was concentrated under 60-100 mbar at < 50°C until a residual volume of 200-300 ml. 206 ml Water was charged into reactor #3. The mixture was concentrated under 120-150 mbar at < 60°C to a residual volume of 150-250 ml. 206 ml Methanol was charged to reactor #3. Heat the suspension to 45-55°C until a clear solution. 206 ml Water was charged into reactor #3 at 45-55°C for 30 min. The resulting suspension was concentrated under 120-150 mbar at < 60°C to a residual volume of 250- 350 ml. The mixture was stirred at 45-55°C for NLT 30 min and then cooled to 0-10°C for NLT 3 h. After stirring at 0-10°C for NLT 1 h, the suspension was filtered. Crude product was obtained as cream solid. Dissolve the crude product in 316 ml Ethyl acetate at 15- 25°C. Discard bottom aqueous layer. 4 g activated carbon was charged. The mixture was stirred at 15-25°C for 1 h, and then filtered. 40 ml Ethyl acetate was charged to rinse the cake and transferred to the filtrate. The combined organic layer was concentrated under 60- 100 mbar at < 55°C until a residual volume of 160-240 ml. 316 ml Toluene was charged at 45-55°C in 30 min. Concentrate the mixture under 60-100 mbar at < 55°C until a residual volume of 160-240 ml. 316 ml Toluene was charged at 45-55°C in 30 min. Concentrate the mixture under 60-100 mbar at < 55 °C until a residual volume of 160-240 ml. The mixture was stirred at 45-55°C for NLT 30 min and then cooled to 0-10°C for NLT 3 h. After stirring at 0-10°C for NLT 1 h, the suspension was filtered. Dry the product in vacuum oven at 55-60°C for 16 h. The product was obtained as cream solid in 80.9 % yield.
Example 2. Lab process with Pt/C poisoned with Fe
To 500 ml reactor #1 charge 15 g (corrected by weight assay) 2,4-Dichloro-5-nitropyrimi- dine, 160 ml Ethyl acetate and 2.5 g Pt/C (wet, LOD 69%, SinoCompound SC8711) was charged into reactor #1. The internal temperature was adjusted to 30°C. Reactor #1 was purged with Hydrogen for three times. Then start the agitation. The reaction was run under Hydrogen pressure 7-10 bars at 30°C for 15 h. Complete conversion was given by HPLC. Relieve Hydrogen and purge with Nitrogen for three times. The reaction mixture was filtered into reactor #2. The filtrate was washed with 40 ml Water and concentrated under 60- 100 mbar at < 50°C until a residual volume of 60 ml. 60 ml Toluene was charged into reactor #2. The mixture was concentrated under 60-100 mbar at < 60°C to a residual volume of 60 ml. 60 ml Toluene was charged to reactor #2. The mixture was concentrated under 60- 100 mbar at < 60°C to a residual volume of 60 ml. The mixture was stirred at 50°C for NLT 30 min and then cooled to 0-10°C for NLT 2 h. After stirring at 5°C for NLT 1 h, the suspension was filtered. Dry the product in vacuum oven at 55-60°C for 16 h. The product was obtained as cream solid in 90.7 % yield.
Example 3. Lab process with Pd/C, Evonik PMPC SP1020 W
To 1 1 reactor #1 charge 50 g (corrected by weight assay) 2,4-Dichloro-5-nitropyrimidine, 400 ml Ethyl acetate and 2.5 g Activated carbon. The mixture was stirred at 20-30°C for 1 h. Filter the mixture in reactor #1 and transfer to hydrogenation reactor #2. 50 ml Ethyl acetate was charged to rinse the cake and transferred to reactor #2. Reactor #2 was purged with Nitrogen for three times. 50 ml Acetic acid and 5 g Pd/C (wet, LOD 50%, Evonik PMPC SP1020 W) was charged into reactor #2. The internal temperature was adjusted to 25-30°C. Reactor #2 was purged with Hydrogen for three times. Then start the agitation. The reaction was run under Hydrogen pressure 5 bars at 25-30°C for 3 h. Then reactor #2 was heated to 35-40°C in 1 h. The reaction was run under Hydrogen pressure 5 bars at 35- 40°C for 12 h. Complete conversion was given by HPLC. Relieve Hydrogen and purge with Nitrogen for three times. The reaction mixture was cooled to 20-30°C and filtered into 465 g 10% Na2COs in reactor #3 at 20-30°C. 50 ml Ethyl acetate was charged to rinse reactor #2, wet cake and then transferred to reactor #3. The resulting mixture was stirred at 20-30°C for 30 min and then standed at same temperature for 30 min. The upper organic layer was concentrated under 60-100 mbar at < 60°C until a residual volume of 100 ml. 150 ml Water was charged into reactor #3. The mixture was concentrated under 60-100 mbar at < 60°C to a residual volume of 100 ml. 150 ml Methanol was charged to reactor #3. 150 ml Water was charged into reactor #3. 4 g activated carbon was charged. The mixture was stirred at 45-50°C for 1 h, and then filtered. The filtrate was concentrated under 60-100 mbar at < 60°C until a residual volume of 150 ml. 50 ml Water was charged at 45- 55°C. Concentrate the mixture under 60-100 mbar at < 60°C until a residual volume of 150 ml. The resulting mixture was then cooled to 0-10°C for NLT 3 h. After stirring at 0-10°C for NLT 1 h, the suspension was filtered. Dry the product in vacuum oven at 55°C for 16 h. Crude product was obtained as light brown solid in 75.2 % yield. The crude product and 150 ml Ethyl acetate was charged into reactor #3. Heat reactor #3 to 45-50°C and stir at same temperature for 1 h. The mixture was filtered and transferred into reactor #4. 150 ml Toluene was charged into reactor #4. The content in reactor #4 was concentrated under 60- 100 mbar at < 60°C until a residual volume of 100 ml. 50 ml Toluene was charged into reactor #4. The content in reactor #4 was concentrated under 60-100 mbar at < 60°C until a residual volume of 100 ml. The resulting mixture was then cooled to 0-10°C for NLT 3 h. After stirring at 0-10°C for NLT 1 h, the suspension was filtered. Dry the product in vacuum oven at 55°C for 16 h. Purified product was obtained as light brown solid in 69.3 % yield.
Example 4. Upscaled process with Iron Powder
The dried reactor was exchanged with Nitrogen for three times. 2299.9 kg Acetic acid and 230.0 kg 2,4-Dichloro-5-nitropyrimidine were charged into the reactor at 20-35°C. 229.4 kg Iron powder was charged slowly in portions. The reaction mixture was stirred at 20- 35°C for 2-4 h. Complete conversion was given by HPLC. The reaction mixture was centrifuged, and the cake was washed with 1380.5 kg Acetic acid. The obtained filtrate was concentrated under vacuum at < 60°C until no distillate come out. Charge 1382.8 kg Ethyl acetate. The mixture was stirred at 55-65°C for 2-3 h, cooled to 15-25°C and stirred at 15- 25°C for 1-2 h. The mixture was centrifuged. The first filtrate was obtained. The centrifugal cake was stirred with 919.9 kg Ethyl acetate at 55-65°C for 2-3 h, cooled to 15-25°C and stirred at 15-25 °C for 1-2 h. The mixture was centrifuged, and the cake was washed with 230.1 kg Ethyl acetate. The second filtrate was obtained. The combined filtrate was neutralized with 10% Na2COs aqueous solution at 10-15°C until pH 7-8. The resulting two phases were stirred at 10-15°C for 10-20 min and stood for 1-2 h. Phase separation and the organic layer was obtained. The resulting organic layer was further washed with 456.4 kg Water, 231.2 kg Water and then concentrated under vacuum at < 55°C until no distillate come out. 625.5 kg n-Heptane and 1324.3 kg Ethyl acetate were charged into the residue. The mixture was heated to 40-50°C and stirred for 0.5-1 h. 23.0 kg Activated carbon was charged into the mixture. Discoloration was carried out at 40-50°C for 3-5 h and then 0- 10°C for 1-2 h. Filter off the activated carbon, and the filtrate was concentrated under vacuum at 40-50°C. 230.4 kg Toluene was charged into the mixture and concentrated under vacuum at < 55°C until no distillate come out. 1039.4 kg Toluene was charged into the residue. The resulting suspension was stirred at 40-50°C for 3-5 h, cooled to 5-10°C, and stirred at 5-10°C for 3-5 h. The suspension was centrifuged, and the cake was washed with 229.9 kg Toluene. The wet cake was dried under vacuum by double cone at 50-60°C for 6-
8 h. The product was obtained as brown solid in 49.5 % yield.
Example 5. Upscaled process with Pt/C poisoned with V2O5
The dried autoclave was exchanged with Nitrogen for three times. 97.0 kg 2,4-Dichloro-5- nitropyrimidine solution (90.2 kg corrected by assay) and 806 kg Ethyl acetate were charged into the reactor at 20-30°C. 9.43 kg wet Pt/C (3.66 kg corrected by assay) was charged into reactor. The reactor was exchanged with Nitrogen three times and Hydrogen three times. Cool the internal temperature to 20-25°C and feed Hydrogen gas until pressure
9 ~ 10 bar. Keep stirring at 20-32°C for NLT 5 h, and take sample to check conversion of 2,4-Dichloro-5-nitropyrimidine. Warm the internal temperature to 45-52°C and keep stirring for 18-24 h. Take sample to check conversion of 2,4-Dichloro-5-hydroxylaminepyrim- idine. The reaction mixture was cooled to 15-25°C, exchanged with Nitrogen, and filtered. The filter cake was washed with 20 kg Ethyl acetate. The combined filtrate was washed with 180 kg Water at 20-30°C, and concentrated under vacuum at 30-50°C until a residual of 2.0-3.0 volume. 234.5 kg Toluene was charged into the residual. The resulting mixture was concentrated under vacuum at 30-50°C until a residual of 2.0-3.0 volume. Adjust internal temperature to 45-50°C, stir at same temperature for 0.5- Ih, cool to 0-10°C in 3 h, and then stir at same temperature for 0.5-1 h. The suspension was centrifuged and the cake was washed with 45 kg Toluene. The obtained 70 kg crude 2,4-Dichloro-5-aminepyrimi- dine was charged into reactor. 245 kg Ethyl acetate and 3.5 kg Activated carbon were added into reactor at 15-25°C. Stir the mixture at 15-25°C for 1-2 h, and then filtered. The filtrate was concentrated under vacuum at 30-50°C until a residual of 2.0-3.0 volume.
238.5 kg Toluene was charged into the reactor. Concentrate the mixture under vacuum at 30-50°C until a residual of 2.0-3.0 volume. Adjust internal temperature to 45-50°C, stir at same temperature for 0.5-lh, cool to 0-10°C in 3 h, and then stir at same temperature for 0.5-1 h. The suspension was centrifuged and the cake was washed with 45 kg Toluene. The wet cake was dried under vacuum by double cone at 50-60°C for 20-24 h. The product was obtained as brown solid in 80.7 % yield.

Claims

WHAT WE CLAIM
1. A process for the manufacturing of a compound of formula 1
Figure imgf000014_0001
wherein in step a) a compound of formula 3
Figure imgf000014_0003
is chlorinated and without purification in step b) the resulting compound of formula 2
Figure imgf000014_0002
is reduced by catalytically hydrogenation in presence of a metal catalyst.
2. A process according to claim 1 wherein in step b) the metal catalyst is selected from Pd/C, Pt/C poisoned with V or Pt/C poisoned with Fe.
3. A process according to claim 1 wherein in step b) 2,4-dichloro-5-nitropyrimidine 2 is reacted with hydrogen and Pd/C as catalyst in ethyl acetate at 5 bar and 25-30°C until completion of the first stage reaction from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5-hy- droxylaminopyrimidine, thereafter methanol is charged and the reaction is continued at 5 bar and 38-43°C until completion of the second stage reaction from 2,4-dichloro-5-hydrox- ylaminopyrimidine to 2,4-dichloro-5-aminopyrimidine.
4. A process according to claim 1 wherein in step b) 2,4-dichloro-5-nitropyrimidine 2 in the toluene solution from step a) is reacted with hydrogen and Pd/C as catalyst and acetic acid in ethyl acetate at 4-5 bar and 20-25°C for 3-4 hours, thereafter the temperature is raised to 35-40°C and the reaction continues at 4-5 bar until completion.
5. A process according to claim 1 wherein in step b) 2,4-dichloro-5-nitropyrimidine 2 in the toluene solution from step a) or pure 2,4-dichloro-5-nitropyrimidine 2 is reacted with hydrogen and Pt/C poisoned with V or Pt/C poisoned with Fe as catalyst in ethyl acetate at 5-10 bar and 20-32°C until completion of the first stage reaction from 2,4-dichloro-5-nitro- pyrimidine to 2,4-dichloro-5-hydroxylaminopyrimidine, thereafter the temperature is raised to 45-52°C and continue to react at 9-10 bar until completion of the reaction.
6. A process according to claim 1 wherein in step b) 2,4-dichloro-5-nitropyrimidine 2 in the toluene solution from step a) or pure 2,4-dichloro-5-nitropyrimidine 2 is reacted with hydrogen and 1% Pt/C poisoned with 5% V2O5 as catalyst in ethyl acetate at 5-10 bar and 20-32°C until completion of the first stage reaction from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5-hydroxylaminopyrimidine, thereafter the temperature is raised to 45-52°C and continue to react at 9-10 bar until completion of the reaction.
7. A process according to claim 1 wherein in step b) 2,4-dichloro-5-nitropyrimidine 2 in the toluene solution from step a) or pure 2,4-dichloro-5-nitropyrimidine 2 is reacted with hydrogen and 1% Pt/C poisoned with 5% Fe as catalyst in ethyl acetate at 5-10 bar and 20- 32°C until completion of the first stage reaction from 2,4-dichloro-5-nitropyrimidine to 2,4-dichloro-5-hydroxylaminopyrimidine, thereafter the temperature is raised to 45-52°C and continue to react at 9-10 bar until completion of the reaction.
8. A process according to one of the claims 1 to 7 wherein in step a) the chlorination from compound of formula 3 to a compound of formula 2 is done with phosphorus oxychloride in presence of N,N-diethylaniline at 60-65°C.
9. A process according to one of the claims 1 to 7 wherein in step a) the chlorination is done in toluene.
-15-
PCT/EP2021/079442 2020-10-26 2021-10-25 Process for synthesis of 2,4-dichloro-5-aminopyrimidine WO2022090101A1 (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004110343A2 (en) 2003-06-13 2004-12-23 Kyungdong Pharm. Co., Ltd. 2-amino-9-(2-substituted ethyl)purines and preparing methods for 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]- 2- aminopurine using the same
WO2010026121A1 (en) 2008-09-02 2010-03-11 Novartis Ag Bicyclic kinase inhibitors
WO2011106168A1 (en) 2010-02-24 2011-09-01 Dcam Pharma Inc Purine compounds for treating autoimmune and demyelinating diseases
CN103864792A (en) 2012-12-12 2014-06-18 山东亨利医药科技有限责任公司 Heterocyclic nitrogen compound acting as tyrosine kinase inhibitor
WO2015148344A2 (en) 2014-03-26 2015-10-01 Merck Sharp & Dohme Corp. Trka kinase inhibitors, compositions and methods thereof
CN105906621A (en) * 2015-04-06 2016-08-31 四川百利药业有限责任公司 Ethanol compound used as FGFR inhibitor
CN109293578A (en) * 2018-10-29 2019-02-01 淮安万邦香料工业有限公司 A kind of preparation method of the chloro- 5- nitro-pyrimidine of 2,4- bis-

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004110343A2 (en) 2003-06-13 2004-12-23 Kyungdong Pharm. Co., Ltd. 2-amino-9-(2-substituted ethyl)purines and preparing methods for 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]- 2- aminopurine using the same
WO2010026121A1 (en) 2008-09-02 2010-03-11 Novartis Ag Bicyclic kinase inhibitors
WO2011106168A1 (en) 2010-02-24 2011-09-01 Dcam Pharma Inc Purine compounds for treating autoimmune and demyelinating diseases
CN103864792A (en) 2012-12-12 2014-06-18 山东亨利医药科技有限责任公司 Heterocyclic nitrogen compound acting as tyrosine kinase inhibitor
WO2015148344A2 (en) 2014-03-26 2015-10-01 Merck Sharp & Dohme Corp. Trka kinase inhibitors, compositions and methods thereof
CN105906621A (en) * 2015-04-06 2016-08-31 四川百利药业有限责任公司 Ethanol compound used as FGFR inhibitor
CN109293578A (en) * 2018-10-29 2019-02-01 淮安万邦香料工业有限公司 A kind of preparation method of the chloro- 5- nitro-pyrimidine of 2,4- bis-

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ISTANBULLU HUSEYIN ET AL: "Design, synthesis, and in vitro biological evaluation of novel thiazolopyrimidine derivatives as antileishmanial compounds", ARCHIV DER PHARMAZIE, vol. 353, no. 8, 2 June 2020 (2020-06-02), Weinheim, pages 1900325, XP055878175, ISSN: 0365-6233, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ardp.201900325> DOI: 10.1002/ardp.201900325 *
J. ORG. CHEM., vol. 80, 2015, pages 7757 - 7763
JOURNAL OF ORGANIC CHEMISTRY, vol. 27, 1962, pages 2170 - 73

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