EP2922824A1 - New process for the synthesis of trichloropyrimidine-amine derivatives - Google Patents

New process for the synthesis of trichloropyrimidine-amine derivatives

Info

Publication number
EP2922824A1
EP2922824A1 EP13805592.6A EP13805592A EP2922824A1 EP 2922824 A1 EP2922824 A1 EP 2922824A1 EP 13805592 A EP13805592 A EP 13805592A EP 2922824 A1 EP2922824 A1 EP 2922824A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
synthesis
amino
trichloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13805592.6A
Other languages
German (de)
French (fr)
Inventor
László Czibula
László Dobay
Krisztina SZAVICSKÓ
Dorottya Kiss-Bartos
Judit NAGYNÉ BAGDY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Nyrt
Original Assignee
Richter Gedeon Nyrt
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richter Gedeon Nyrt filed Critical Richter Gedeon Nyrt
Publication of EP2922824A1 publication Critical patent/EP2922824A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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 relates to a new process for the synthesis of 2-(N-methyl)-amino-4,5,6- trichloro-l,3-pyrimidine of formula (I), as well as the new compounds of formula (II) and (III) synthesized as intermediates in the process.
  • 2-(N-methyl)-amino-4,5,6-trichloro-l,3-pyrimidine of formula (I) can preferably be used in the synthesis of drug substances, for example in the synthesis of compounds described in the Hungarian patent application HU20070000269 of Richter.
  • the compound of formula (I) can be obtained the following way: methyl guanidine hydrochloride and diethylmalonate are condensed in the presence of sodium ethoxide in ethanol, then the obtained product is transformed into the desired compound with phosphorous(V) oxychloride.
  • the invention relates to the process for the synthesis of compound of formula (I) which consist of the following steps:
  • the chlorination reaction is preferably carried out between 25 and 105°C, more preferably between 75 and 80°C.
  • apolar solvents can preferably be used.
  • solvents are for example: toluene, xylene or chlorobenzene.
  • the chlorination reaction is preferably carried out in the presence of equimolar (1-1.2 mol/mol) dimethyl formamide.
  • the invention relates to the compound of formula (II), obtained in the chlorination reaction carried out in the presence of dimethyl formamide, the chemical name of which is 2-(N N'-dimethylamino-methylene)-amino-4,5,6-trichloro-l,3-pyrirnidine.
  • the invention relates to the observation that depending on the quality of the acidic hydrolysis compound of formula (III) or compound of formula (IV) is formed from compound of formula (II):
  • the acidic hydrolysis can be carried out with an acid, preferably with a strong mineral acid or an organic sulfonic acid, such as for example hydrochloric acid, sulfuric acid, phosphoric acid, p-toluene sulfonic acid.
  • a strong mineral acid or an organic sulfonic acid such as for example hydrochloric acid, sulfuric acid, phosphoric acid, p-toluene sulfonic acid.
  • the mild acidic hydrolysis is typically carried out with a small excess of acid, preferably 2.5- 3.5 equivalent of hydrochloric acid calculated on the amount of compound of formula (II).
  • the strong acidic hydrolysis is typically carried out with a large excess of acid, preferably 9- 10 equivalent of hydrochloric acid.
  • the invention relates to the new compound of formula (III) obtained from the compound of formula (II) under mild acidic conditions.
  • This reaction is preferably carried out in a C C 4 alcohol type solvent.
  • the reaction is most preferably carried out in isopropanol, because in this case the compound of formula (III) precipitates in good yield.
  • the invention relates to the surprising observation that during the alkylation reaction of the compound of formula (IV) the monoalkylated product can only be synthesized under phase transfer conditions.
  • the compound of formula (IV) can be transformed into the desired compound of formula (I) in good yield by using generally applied methylating agents, for example: methyl halogenides, dimethyl sulfate, under phase transfer conditions.
  • methylating agents for example: methyl halogenides, dimethyl sulfate
  • organic ammonium salts as phase transfer catalysts, such as for example benzyltriethylammonium chloride, benzyltriethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulfate.
  • the alkylation is preferably carried out between 0 and 20°C, more preferably between 0 and 5°C.
  • the alkylation can be carried out in the presence of methyl iodide, but for industrial scale the most applicable solution is the use of dimethyl sulfate. Structure elucidation of the compounds was carried out by NM R spectroscopy.
  • Example 1 The invention is illustrated by the following not limiting examples.
  • Example 1 The invention is illustrated by the following not limiting examples.
  • the reaction mixture was stirred at 40-42 °C for 30 min, then at 20-22 °C for 1 h.
  • the precipitated almost white product was filtered and washed with 150 ml of ion exchanged water in three portions.
  • the product was dried at maximum 60 °C in a vacuum oven for 3 h, then at 100-102 °C for further 5 h till constant weight.
  • the mixture was warmed to 75-78 °C and stirred at this temperature for 7 h.
  • the reaction was monitored by thin layer chromatography.
  • the mixture was cooled to 20-22 °C, stirring was stopped, the lower phase containing the product was separated and added to a mixture of 300 ml of concentrated NH 3 and 300 g of ice.
  • the obtained two- phase mixture was separated: the aqueous phase was extracted with 50 ml of toluene, the combined organic phases were washed with a solution of 25 g of sodium chloride and 130 ml of water.
  • the reaction was monitored by thin layer chromatography. After completion of the reaction the mixture was cooled to 20- 22 °C and 700 ml of ion exchanged water was added. The mixture was stirred at this temperature for 30 min, then cooled to 10-15°C and stirred at this temperature for 1 h. The precipitated crystals were filtered, washed with 3x100 ml of water and dried at maximum 30 °C till constant weight.
  • the reaction was monitored by thin layer chromatography. After completion of the reaction the mixture was cooled to 20- 22 °C and 700 ml of ion exchanged water was added. The mixture was stirred at this temperature for 30 min, then cooled to 10-15°C and stirred at this temperature for 1 h. The precipitated crystals were filtered, washed with 3x100 ml of water and dried at maximum 30 °C till constant weight.
  • the mixture was stirred at this temperature for 30 min, then cooled to 10- 15°C and stirred at this temperature for 1 h.
  • the precipitated crystals were filtered, washed with 3x100 ml of water and dried at maximum 30 °C till constant weight.
  • the reaction was monitored by thin layer chromatography. After completion of the reaction 120 ml of water and 40 ml of dichloromethane were added keeping the temperature below 20 °C. The phases were separated, the organic phase was extracted with 120 ml of water in two portions, then a solution of 6 g of sodium chloride and 34 ml of water. The organic phase was concentrated in vacuum, the residue was refluxed in 80 ml of isopropanol for 2 h, then cooled to 20-25 °C and stirred at this temperature for 2 h. The crystals were filtered and washed with 40 ml of isopropanol (20-25 °C) in two portions.
  • the precipitated crystals were filtered, washed with 3x50 I of water and dried at maximum 30 °C till constant weight.
  • the reaction was monitored by thin layer chromatography (samples were taken in every hour). After completion of the reaction 100 I of water and 33.3 I of dichloromethane were added keeping the temperature below 20 °C. The phases were separated, the organic phase was extracted with 100 I of water in two portions, then a solution of 5 kg of sodium chloride and 28 I of water. The organic phase was concentrated in vacuum, the residue was dissolved in 66.7 I of isopropanol in a 250 I autoclave and it was refluxed for 2 h, then cooled to 20-25 °C and stirred at this temperature for 2 h. The crystals were filtered and washed with 33 I of isopropanol (20-25 °C) in two portions.
  • the wet (with isopropanol) 2-(N-methyl)-amino-4,5,6-trichloro-l,3-pyrimidine was refluxed in 17 I of methanol for 1 h, then cooled to 20-25 "and stirred at this temperature for further 1 h. The crystals were filtered, washed with 17 I of methanol in two portions and dried at maximum 50 °C till constant weight.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a new process for the synthesis of 2-(N-methyl)-amino-4,5,6- trichloro-l,3-pyrimidine, which is more economical than the known process, as well as the new compounds synthesized as intermediates in the process: 2-(N',N'-dimethylamino- methylene)-amino-4,5,6-trichloro-l,3-pyrimidine and 2-(N-formyl)-amino-4,5,6-trichloro-l,3- pyrimidine.

Description

New process for the synthesis of trichloropyrimidine-amine derivatives
Summary of the invention
The invention relates to a new process for the synthesis of 2-(N-methyl)-amino-4,5,6- trichloro-l,3-pyrimidine of formula (I), as well as the new compounds of formula (II) and (III) synthesized as intermediates in the process.
I II III
Bachground of the invention
2-(N-methyl)-amino-4,5,6-trichloro-l,3-pyrimidine of formula (I) can preferably be used in the synthesis of drug substances, for example in the synthesis of compounds described in the Hungarian patent application HU20070000269 of Richter.
The synthesis of compound of formula (I) is described in the Journal of Medicinal Chemistry 25 (1982) 1459-1465. Although there is no particular example for the synthesis of this compound an analogous compound is obtained in a yield of only 25%.
According to the synthesis of the analogous compound the compound of formula (I) can be obtained the following way: methyl guanidine hydrochloride and diethylmalonate are condensed in the presence of sodium ethoxide in ethanol, then the obtained product is transformed into the desired compound with phosphorous(V) oxychloride.
The invention
Our aim was to elaborate a new process for the synthesis of compound of formula (I), which is more economical than the known process and the yield of the product is higher. Surprisingly it was found that if 2-amino-5-chloro-lH-pyrimidin-4,6-dione of formula (V) is reacted with phosphorous(V) oxychloride in the presence of equimolar dimethyl formamide, then a new trichloropyrimidine derivative of formula (II) is obtained, the chemical name of which is 2-(N N'-dimethylamino-methylene)-amino-4,5,6-trichloro-l,3-pyrirnidine.
V
The acidic hydrolysis of compound of formula (II) under mild conditions results in a new "N- formyl" derivative, the compound of formula (III), the chemical name of which is 2-(N- formyl)-amino-4,5,6-trichloro-l,3-pyrimidine. if the reaction is carried out under strong acidic conditions 2-amino-4,5,6-trichloro-l,3-pynrmdine 0f formula (IV) is obtained via compound of formula (III).
The yield was high in both cases, under mild or under strong acidic conditions.
IV
During our experiments surprisingly it was found that compound of formula (IV) can be transformed into the desired compound of formula (I) in good yield by using generally applied methylating agents (for example: methyl halogenides, dimethyl sulfate) under phase transfer conditions. Detailed description of the invention
The invention relates to the process for the synthesis of compound of formula (I) which consist of the following steps:
a) reaction of 2-amino-5-chloro-lH-pyrimidin-4,6-dione of formula (V) with phosphorous(V) oxychloride in the presence of dimethyl formamide, b) acidic hydrolysis of the obtained compound of formula (II),
c) reaction of the obtained compound of formula (IV) with alkyl halogenides or dimethyl sulfate under phase transfer conditions. During our experiments surprisingly it was found that if 2-amino-5-chloro-lH-pyrimidin-4,6- dione of formula (V) is reacted with phosphorous(V) oxychloride in the presence of equimolar dimethyl formamide, then a new trichloropyrimidine derivative of formula (II) is obtained, the chemical name of which is 2-(N',N'-dimethylamino-methylene)-amino-4,5,6- trichloro-l,3-pyrimidine.
The chlorination reaction is preferably carried out between 25 and 105°C, more preferably between 75 and 80°C.
In the chlorination reaction apolar solvents can preferably be used. Such solvents are for example: toluene, xylene or chlorobenzene.
The chlorination reaction is preferably carried out in the presence of equimolar (1-1.2 mol/mol) dimethyl formamide.
Furthermore, the invention relates to the compound of formula (II), obtained in the chlorination reaction carried out in the presence of dimethyl formamide, the chemical name of which is 2-(N N'-dimethylamino-methylene)-amino-4,5,6-trichloro-l,3-pyrirnidine. The invention relates to the observation that depending on the quality of the acidic hydrolysis compound of formula (III) or compound of formula (IV) is formed from compound of formula (II):
- under strong acidic conditions compound of formula (IV) is formed via compound of formula (III);
- under mild acidic conditions compound of formula (III) is obtained.
The acidic hydrolysis can be carried out with an acid, preferably with a strong mineral acid or an organic sulfonic acid, such as for example hydrochloric acid, sulfuric acid, phosphoric acid, p-toluene sulfonic acid.
The mild acidic hydrolysis is typically carried out with a small excess of acid, preferably 2.5- 3.5 equivalent of hydrochloric acid calculated on the amount of compound of formula (II). The strong acidic hydrolysis is typically carried out with a large excess of acid, preferably 9- 10 equivalent of hydrochloric acid.
Furthermore the invention relates to the new compound of formula (III) obtained from the compound of formula (II) under mild acidic conditions. This reaction is preferably carried out in a C C4 alcohol type solvent. The reaction is most preferably carried out in isopropanol, because in this case the compound of formula (III) precipitates in good yield.
If the amount of the acid is increased during the hydrolysis of the compound of formula (II) then the percentage of compound of formula (IV) is increased as compared to compound of formula (III). For example using 9-10 mol/mol hydrochloric acid results in the formation of compound of formula (IV) quantitatively.
Furthermore the invention relates to the surprising observation that during the alkylation reaction of the compound of formula (IV) the monoalkylated product can only be synthesized under phase transfer conditions. The compound of formula (IV) can be transformed into the desired compound of formula (I) in good yield by using generally applied methylating agents, for example: methyl halogenides, dimethyl sulfate, under phase transfer conditions. During our experiments it was found that if the reaction is carried out in non-aqueous medium the disubstituted product is formed almost exclusively. The phase transfer process elaborated by us overcomes this difficulty and makes the synthesis of monosubstituted derivative possible. During the process preferably concentrated alkaline solutions (preferably sodium hydroxide or potassium hydroxide) and organic solvents can be used as immiscible phases. The reaction is carried out in the presence of known organic ammonium salts as phase transfer catalysts, such as for example benzyltriethylammonium chloride, benzyltriethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulfate.
The alkylation is preferably carried out between 0 and 20°C, more preferably between 0 and 5°C.
The alkylation can be carried out in the presence of methyl iodide, but for industrial scale the most applicable solution is the use of dimethyl sulfate. Structure elucidation of the compounds was carried out by NM R spectroscopy.
Examples
The invention is illustrated by the following not limiting examples. Example 1
Synthesis of 2-amino-5-chloro-lH-pyrimidine-4,6-dione (starting material) (V)
Under nitrogen 625 ml of methanol and 45 g (0.833 mol) of sodium methoxide were charged into a 3 liter four-neck round bottom flask, which was degassed with nitrogen prior to use. After complete dissolution 36.25 g (0.38 mol) of guanidine hydrochloride was added and the mixture was stirred for 15 min. then 62.5 g (0.375 mol) of dimethyl chloromalonate was added. The obtained mixture was stirred at 62-64 °C for 1 h, the reaction was monitored by gas chromatography. After completion of the reaction the mixture was cooled to 40-42 °C and a solution of 27.5 ml of glacial acetic acid and 1500 ml of ion exchanged water was added over a period of 1 h at this temperature.
The reaction mixture was stirred at 40-42 °C for 30 min, then at 20-22 °C for 1 h. The precipitated almost white product was filtered and washed with 150 ml of ion exchanged water in three portions.
Wet weight: 112 g
The product was dried at maximum 60 °C in a vacuum oven for 3 h, then at 100-102 °C for further 5 h till constant weight.
Yield: 54.6 g (89 %)
H NMR 6.82 br s (2H) [H-7]; 10.94 br s (2H) [H-8, H-10]
13C NMR 84.2 [C-5]; 151.3 [C-2]; 169.7 [C-4, C-6] Example 2
"Trichloropyrimidine derivative"
Synthesis of 2-(N N'-dimethylamino-methylene)-amino-4,5,6-trichloro-1 -pyriiTiidine (II)
Under nitrogen 120 ml of toluene and 30 ml (28.5 g) of Ν,Ν-dimethylformamide were charged into a 500 ml four-neck round bottom flask equipped with a condenser and a stirrer, which was degassed with nitrogen prior to use, then 12 g (0.0738 mol) of 2-amino- 5-chloro-lH-pyrimidine-4,6-dione and 1.2 ml (0.0095 mol) of Ν,Ν-dimethylaniline were added. The reaction mixture was cooled to 0-5 °C and 112.8 g (0.738 mol, 69 ml) of phosphorous(V) oxychloride was added. After completion of the addition the mixture was warmed to 75-78 °C and stirred at this temperature for 7 h. The reaction was monitored by thin layer chromatography. After completion of the reaction the mixture was cooled to 20-22 °C, stirring was stopped, the lower phase containing the product was separated and added to a mixture of 300 ml of concentrated NH3 and 300 g of ice. The obtained two- phase mixture was separated: the aqueous phase was extracted with 50 ml of toluene, the combined organic phases were washed with a solution of 25 g of sodium chloride and 130 ml of water. The organic phase was concentrated in vacuum, the residue (about 18 g) was treated with 20 ml (13.18 g) of hexane, stirred about 30 min, the product was filtered and washed with 2x5 ml of cold (8-10 °C) hexane.
Wet weight: 15.5 g The product was dried at maximum 30 °C till constant weight.
Yield: 15.1 g (80.71 %)
XH NMR 3.07 s (3H) [H-14]; 3.21 s (3H) [H-10];8.60 s (1H) [H-8]
13C NMR 35.5 [C-14]; 41.4 [C-10]; 117.0 [C-5]; 158.5 [C-4, C-6] 160.1 [C-8]; 163.5 [C-2]
Example 3
Synthesis of 2-amino-4,5,6-trichloro-l,3-pyrimidine (IV)
20.2 g (purity minimum 90 w%, about 18 g, 0.0717 mol) of 2-(N',N'-dimethylamino- methylene)-amino-4,5,6-trichloro-l,3-pyrimidine obtained as evaporation residue in example 2 was dissolved in 140 ml of isopropanol, then poured into a 500 ml four-neck round bottom flask equipped with a condenser and a stirrer and a mixture of 45 ml (53.55 g) of concentrated HCI and 90 ml of ion exchanged water was added. The reaction mixture was warmed to 40-42 °C and stirred at this temperature for 2 h. The reaction was monitored by thin layer chromatography. After completion of the reaction the mixture was cooled to 20- 22 °C and 700 ml of ion exchanged water was added. The mixture was stirred at this temperature for 30 min, then cooled to 10-15°C and stirred at this temperature for 1 h. The precipitated crystals were filtered, washed with 3x100 ml of water and dried at maximum 30 °C till constant weight.
Wet weight: 24.6 g
Yield: 11.1 g (71 %)
XH NMR 7.70 s (2H) [NH2-7]
13C NMR 111.8 [C-5]; 158.7 [C-2]; 160.4 [C-6, C-4]
Example 4
"N-formyl"
Synthesis of 2-(N-formyl)-amino-4,5,6-trichloro-l,3-pyrimidine (III)
20.2 g (purity minimum 90 w%, about 18.2 g, 0.0717 mol) of 2-(N',N'-dimethylamino- methylene)-amino-4,5,6-trichloro-l,3-pyrimidine obtained as evaporation residue in example 2 was dissolved in 140 ml of isopropanol, then poured into a 500 ml four-neck round bottom flask equipped with a condenser and a stirrer and a mixture of 15 ml (17.85 g) of concentrated HCI and 90 ml of ion exchanged water was added. The reaction mixture was warmed to 40-42 °C and stirred at this temperature for 2 h. The reaction was monitored by thin layer chromatography. After completion of the reaction the mixture was cooled to 20- 22 °C and 700 ml of ion exchanged water was added. The mixture was stirred at this temperature for 30 min, then cooled to 10-15°C and stirred at this temperature for 1 h. The precipitated crystals were filtered, washed with 3x100 ml of water and dried at maximum 30 °C till constant weight.
Wet weight: 26.5 g
Yield: 13.8 g (71 %) Example 5
Synthesis of 2-amino-4,5,6-trichloro-l,3-pyrimidine (IV)
13.8 g of "N-formyl" compound obtained in example 4 was dissolved in 140 ml of isopropanol, then poured into a 500 ml four-neck round bottom flask equipped with a condenser and a stirrer and a mixture of 30 ml (35.7 g) of concentrated HCI and 90 ml of ion exchanged water was added. The reaction mixture was warmed to 40-42 °C and stirred at this temperature for 2 h. The reaction was monitored by thin layer chromatography. After completion of the reaction the mixture was cooled to 20-22 °C and 700 ml of ion exchanged water was added. The mixture was stirred at this temperature for 30 min, then cooled to 10- 15°C and stirred at this temperature for 1 h. The precipitated crystals were filtered, washed with 3x100 ml of water and dried at maximum 30 °C till constant weight.
Wet weight: 21.6 g
Yield: 11.2 g (98 %)
H NMR 7.70 s (2H) [NH2-7]
13C NMR 111.8 [C-5]; 158.7 [C-2]; 160.4 [C-6, C-4]
Example 6
Synthesis of 2-(N-methyl)-amino-4,5, 6-trichloro-l,3-pyrimidine ( I)
120 ml of chlorobenzene, 120 ml of sec-butanol and a solution of 12.8 g of sodium hydroxide and 19.2 g of water were charged into a 1 I round bottom flask. 0.8 g (0.00375 mol) of benzyltriethylammonium chloride and 6 g (0.03 mol) of 2-amino-4,5,6-trichloro-l,3- pyrimidine were added to the so obtained mixture. The heterogeneous mixture was stirred and cooled to 0-5 °C then 19.1 g (0.152 mol; 14.4 ml) of dimethyl sulfate was added at this temperature. The reaction mixture was stirred at 0-5 °C for 3 h. The reaction was monitored by thin layer chromatography. After completion of the reaction 120 ml of water and 40 ml of dichloromethane were added keeping the temperature below 20 °C. The phases were separated, the organic phase was extracted with 120 ml of water in two portions, then a solution of 6 g of sodium chloride and 34 ml of water. The organic phase was concentrated in vacuum, the residue was refluxed in 80 ml of isopropanol for 2 h, then cooled to 20-25 °C and stirred at this temperature for 2 h. The crystals were filtered and washed with 40 ml of isopropanol (20-25 °C) in two portions.
Wet weight: about 6.3 g (after drying: 4.0 g. (62.9%))
If required 15.8 g (wet with isopropanol) of 2-(N-methyl)-amino-4,5,6-trichloro-l,3- pyrimidine was refluxed in 20 ml of methanol for 1 h, then cooled to 20-25 "and stirred at this temperature for further 1 h. The crystals were filtered, washed with 20 ml of methanol in two portions and dried at maximum 50 °C till constant weight.
Wet weight: 4.2 g
Yield: 3.6 g (56.6 %)
H NMR 2.78 d (3H) [8CH3]; 8.16 d (1H) [NH-7]
13C NMR 28.5 [C-8 CH3]; 111.5 [C-5]; 158.8 [C-2]; 159.4 [C-4, C-6] Example 7
Synthesis of 2-amino-4,5,6-trichloro-l,3-pyrimidine (IV)
Under nitrogen 80 I of toluene, 20 I of N,N-dimethylformamide, 8 kg (49.53 mol) of 2-amino- 5-chloro-lH-pyrimidine-4,6-dione and 800 ml (6.3 mol) of Ν,Ν-dimethylaniline were charged into a 250 I enamelled reactor. The reaction mixture was cooled to 0-5 °C and 80 kg (522 mol, 46 I) of phosphorous(V) oxychloride was added. After the addition the reaction mixture was warmed to 75-78 °C and stirred at this temperature for 7 h. The reaction was monitored by gas chromatography. After completion of the reaction the mixture was cooled to 20-22 °C, stirring was stopped and the reaction mixture was added to a mixture of 200 I of concentrated NH3, 200 kg of ice and 33 I of toluene keeping the temperature below 2 °C. The obtained two-phase reaction mixture was separated, the water phase was extracted with 33 I of toluene, the organic phase was filtered through Celite, then the combined organic phases were washed with a solution of 16.6 kg of sodium chloride and 86.5 I of water. The organic phase was concentrated in vacuum, the residue was 13.4 kg (purity: 90 w%, yield: about 95 %).
13.5 kg (purity minimum 90 w%, about 12 kg, 48 mol) of 2-(N',N'-dimethylamino- methylene)-amino-4,5,6-trichloro-l,3-pyrimidine obtained as evaporation residue above was dissolved in 93 I of isopropanol, then pumped into a 630 I enamelled autoclave and a mixture of 30 I of concentrated HCI and 36 I of ion exchanged water was added. The reaction mixture was warmed to 40-42 °C and stirred at this temperature for 2 h. The reaction was monitored by thin layer chromatography. After completion of the reaction the reaction mixture was cooled to 20-22 °C and 450 I of ion exchanged water was added. The mixture was stirred at this temperature for 30 min, then cooled to 10-15 °C and stirred at this temperature for 1 h.
The precipitated crystals were filtered, washed with 3x50 I of water and dried at maximum 30 °C till constant weight.
Wet weight: 16.4 kg
Yield: 7.4 kg (70 %)
Η NMR 7.70 s (2H) [NH2-7]
13C NMR 111.8 [C-5]; 158.7 [C-2]; 160.4 [C-6, C-4] Example 8
Synthesis of 2-(N-methyl)-amino-4,5, 6-trichloro-l,3-pyrimidine ( I)
100 I of chlorobenzene, 100 I of sec-butanol and a solution of 10.7 kg of sodium hydroxide and 16 kg of water were charged into a 630 I autoclave. 670 g (3.1 mol) of benzyltriethylammonium chloride (Botak) and 5 kg (25 mol) of 2-amino-4,5,6-trichloror-l,3- pyrimidine were added to the so obtained mixture. The heterogeneous mixture was stirred and cooled to 0-5 °C then 15.9 kg (126.7 mol; 12 I) of dimethyl sulfate was added at this temperature. The reaction mixture was stirred at 0-5 °C for 3 h. The reaction was monitored by thin layer chromatography (samples were taken in every hour). After completion of the reaction 100 I of water and 33.3 I of dichloromethane were added keeping the temperature below 20 °C. The phases were separated, the organic phase was extracted with 100 I of water in two portions, then a solution of 5 kg of sodium chloride and 28 I of water. The organic phase was concentrated in vacuum, the residue was dissolved in 66.7 I of isopropanol in a 250 I autoclave and it was refluxed for 2 h, then cooled to 20-25 °C and stirred at this temperature for 2 h. The crystals were filtered and washed with 33 I of isopropanol (20-25 °C) in two portions.
Wet weight: about 5 kg (after drying: 3.33 kg. (62%))
If required the wet (with isopropanol) 2-(N-methyl)-amino-4,5,6-trichloro-l,3-pyrimidine was refluxed in 17 I of methanol for 1 h, then cooled to 20-25 "and stirred at this temperature for further 1 h. The crystals were filtered, washed with 17 I of methanol in two portions and dried at maximum 50 °C till constant weight.
Wet weight: 3.5 kg
Yield: 3 kg (56 %)
H NMR 2.78 d (3H) [8CH3]; 8.16 d (1H) [NH-7]
13C NMR 28.5 [C-8 CH3]; 111.5 [C-5]; 158.8 [C-2]; 159.4 [C-4, C-6]

Claims

Claims
2-(N N'-dimethylamino-methylene)-amino-4,5,6-trichloro-1 -pyrirnidine of form
(ID
Process for the synthesis of compound of formula (II) defined in claim 1 characterized by chlorinating the compound of formula (V) with phosphorous(V) oxychloride in the presence of dimethyl formamide.
V
3. 2-(N-formyl)-amino-4,5,6-trichloro-l,3-pyrimidine of formula (III)
III Process for the synthesis of 2-(N-formyl)-amino-4,5,6-trichloro-l,3-pyrimidine of formula (III) defined in claim 3 characterized by hydrolyzing of compound of formula (II) defined in claim 1 under mild acidic conditions using small excess of acid.
The process according to claim 4 characterized by carrying out the hydrolysis with 2.5-3.5 equivalent of hydrochloric acid.
Process for the synthesis of compound of formula (IV) characterized by
IV a) hydrolyzing the compound of formula (II) defined in claim 1 under mild acidic conditions via isolation of compound of formula (III), then increasing the amount of the applied acid gradually raising the percentage of compound of formula (IV) as compared to compound of formula (III). b) hydrolyzing the compound of formula (II) defined in claim 1 under strong acidic conditions using large excess of acid without isolating the intermediate compound of formula (III).
7. The process according to point b) of claim 6 characterized by carrying out the hydrolysis with 9-10 equivalent of hydrochloric acid.
8. Process for the synthesis of compound of formula (I) characterized by alkylating the compound of formula (IV) using phase transfer catalysis.
I
9. The process according to claim 8 for the synthesis of compound of formula (I) characterized by alkylating the compound of formula (IV) with methyl halogenide using phase transfer catalysis.
10. The process according to claim 8 for the synthesis of compound of formula (I) characterized by alkylating the compound of formula (IV) with dimethyl sulfate using phase transfer catalysis.
EP13805592.6A 2012-11-21 2013-11-20 New process for the synthesis of trichloropyrimidine-amine derivatives Withdrawn EP2922824A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU1200674A HU230149B1 (en) 2012-11-21 2012-11-21 Process for the production of trichloro-pyrimidine amine derivatives
PCT/IB2013/060264 WO2014080341A1 (en) 2012-11-21 2013-11-20 New process for the synthesis of trichloropyrimidine-amine derivatives

Publications (1)

Publication Number Publication Date
EP2922824A1 true EP2922824A1 (en) 2015-09-30

Family

ID=89990948

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13805592.6A Withdrawn EP2922824A1 (en) 2012-11-21 2013-11-20 New process for the synthesis of trichloropyrimidine-amine derivatives

Country Status (3)

Country Link
EP (1) EP2922824A1 (en)
HU (1) HU230149B1 (en)
WO (1) WO2014080341A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109485608B (en) * 2018-12-24 2020-09-22 大连大学 Industrial production method of 4, 6-dichloro-5-fluoro-2-aminopyrimidine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU651630B2 (en) * 1990-11-14 1994-07-28 Pharmacia & Upjohn Company 5-fluoro-2,4,6-pyrimidinetriamine compounds
US5958930A (en) * 1991-04-08 1999-09-28 Duquesne University Of The Holy Ghost Pyrrolo pyrimidine and furo pyrimidine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2014080341A1 *

Also Published As

Publication number Publication date
WO2014080341A1 (en) 2014-05-30
HU230149B1 (en) 2015-09-28
HUP1200674A2 (en) 2014-05-28

Similar Documents

Publication Publication Date Title
US9758469B2 (en) Process for the preparation of 2-substituted-1,4-benzenediamines and salts thereof
TWI808347B (en) Process for preparing 5-fluoro-4-imino-3-methyl-1-tosyl-3,4 dihydropyrimidine-2(1h)-one and derivatives of the compound
EP2878595A1 (en) Method of producing 4-[5-(pyridin-4-yl)-1h-1,2,4-triazole-3-yl]pyridin-2-carbonitrile, and intermediary thereof
KR20170026444A (en) Process for the preparation of 3-hydroxypicolinic acids
US11512062B2 (en) Process for the synthesis of piperazinyl-ethoxy-bromophenyl derivates and their application in the production of compounds containing them
EP2674420B1 (en) Method for producing aminophenyl pyrimidinyl alcohol derivative, and synthesis intermediate thereof
EP2922824A1 (en) New process for the synthesis of trichloropyrimidine-amine derivatives
SK285993B6 (en) Process for producing derivatives of pyrimidine substituted by amino group
EP1873145B1 (en) Method for producing nicotinic acid derivative or salt thereof
US6462218B1 (en) Method for preparing 3-cyano-2,4-dihalogeno-5-fluoro-Benzoic acid
WO2013059572A1 (en) Process for the preparation of etravirine and intermediates in the synthesis thereof
EP2895486B1 (en) Process for the preparation of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine from 4-chloro-2,5-dimethoxypyrimidine
US20040199002A1 (en) Process for producing(2-nitrophenyl)acetonitrile derivative and intermediate therefor
KR20170108080A (en) Methods for the preparation of compounds such as 3-arylbutanal which are useful in the synthesis of medetomidine
AU2003242638A1 (en) Method for the production of 1,2,4-triazolylmethyl-oxiranes
EP2463277B1 (en) Method for producing 4,6-dialkoxy-2-cyanomethylpyrimidine and synthetic intermediate thereof
US7094914B2 (en) Process for producing chromone compound
US20120178931A1 (en) Process for preparation of pyrimidinylacetonitrile derivatives and intermediates for synthesis thereof
JP2003171359A (en) Method for producing 2-nitrophenylacetonitrile derivative, and its synthetic intermediate
US5973189A (en) Monoesters of carboxymethylene anthranilic acids and process for preparing the same
WO2007086559A1 (en) Method for producing tetrahydropyran compound
JP2002193914A (en) Nitrile compound and its producing method
EA043537B1 (en) METHOD FOR SYNTHESIS OF PIPERAZINIL-ETHOXY-BROMOPHENYL DERIVATIVES AND THEIR APPLICATION IN OBTAINING COMPOUNDS CONTAINING THEM
JPS626706B2 (en)
PL208977B1 (en) The manner of obtaining of o-hydroxybenzyloamines

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20150522

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20160513