WO2022090101A1 - Procédé de synthèse de 2,4-dichloro-5-aminopyrimidine - Google Patents

Procédé de synthèse de 2,4-dichloro-5-aminopyrimidine Download PDF

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Publication number
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
bar
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PCT/EP2021/079442
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English (en)
Inventor
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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Publication of WO2022090101A1 publication Critical patent/WO2022090101A1/fr

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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

L'invention concerne un procédé de synthèse commerciale de 2,4-dichloro-5-amino-pyrimidine à partir de 5-nitrouracile.
PCT/EP2021/079442 2020-10-26 2021-10-25 Procédé de synthèse de 2,4-dichloro-5-aminopyrimidine WO2022090101A1 (fr)

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Citations (7)

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Publication number Priority date Publication date Assignee Title
WO2004110343A2 (fr) 2003-06-13 2004-12-23 Kyungdong Pharm. Co., Ltd. 2-amino-9-(2-substitue ethyl)purines et procedes de preparation de 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]- 2- aminopurine au moyen de celles-ci
WO2010026121A1 (fr) 2008-09-02 2010-03-11 Novartis Ag Inhibiteurs bicycliques des kinases
WO2011106168A1 (fr) 2010-02-24 2011-09-01 Dcam Pharma Inc Composés de purine pour le traitement de maladies auto-immunes et démyélinisantes
CN103864792A (zh) 2012-12-12 2014-06-18 山东亨利医药科技有限责任公司 作为酪氨酸激酶抑制剂的含氮并环类化合物
WO2015148344A2 (fr) 2014-03-26 2015-10-01 Merck Sharp & Dohme Corp. Inhibiteurs de la kinase trka, compositions en contenant et méthodes associées
CN105906621A (zh) * 2015-04-06 2016-08-31 四川百利药业有限责任公司 用作fgfr抑制剂的乙醇类化合物
CN109293578A (zh) * 2018-10-29 2019-02-01 淮安万邦香料工业有限公司 一种2,4-二氯-5-硝基嘧啶的制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004110343A2 (fr) 2003-06-13 2004-12-23 Kyungdong Pharm. Co., Ltd. 2-amino-9-(2-substitue ethyl)purines et procedes de preparation de 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]- 2- aminopurine au moyen de celles-ci
WO2010026121A1 (fr) 2008-09-02 2010-03-11 Novartis Ag Inhibiteurs bicycliques des kinases
WO2011106168A1 (fr) 2010-02-24 2011-09-01 Dcam Pharma Inc Composés de purine pour le traitement de maladies auto-immunes et démyélinisantes
CN103864792A (zh) 2012-12-12 2014-06-18 山东亨利医药科技有限责任公司 作为酪氨酸激酶抑制剂的含氮并环类化合物
WO2015148344A2 (fr) 2014-03-26 2015-10-01 Merck Sharp & Dohme Corp. Inhibiteurs de la kinase trka, compositions en contenant et méthodes associées
CN105906621A (zh) * 2015-04-06 2016-08-31 四川百利药业有限责任公司 用作fgfr抑制剂的乙醇类化合物
CN109293578A (zh) * 2018-10-29 2019-02-01 淮安万邦香料工业有限公司 一种2,4-二氯-5-硝基嘧啶的制备方法

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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 *
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JOURNAL OF ORGANIC CHEMISTRY, vol. 27, 1962, pages 2170 - 73

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