CA2014533A1 - Process for the production of 4 - hydroxy -6- polyfluoroalkylpyrimidines - Google Patents
Process for the production of 4 - hydroxy -6- polyfluoroalkylpyrimidinesInfo
- Publication number
- CA2014533A1 CA2014533A1 CA 2014533 CA2014533A CA2014533A1 CA 2014533 A1 CA2014533 A1 CA 2014533A1 CA 2014533 CA2014533 CA 2014533 CA 2014533 A CA2014533 A CA 2014533A CA 2014533 A1 CA2014533 A1 CA 2014533A1
- Authority
- CA
- Canada
- Prior art keywords
- process according
- reaction
- hydroxy
- alkali
- methanol
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 14
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical class NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 10
- 125000005907 alkyl ester group Chemical group 0.000 claims abstract description 7
- LXVMDQNWDBEYDC-UHFFFAOYSA-N 6-(1,1,2,2,2-pentafluoroethyl)-1h-pyrimidin-4-one Chemical compound OC1=CC(C(F)(F)C(F)(F)F)=NC=N1 LXVMDQNWDBEYDC-UHFFFAOYSA-N 0.000 claims abstract description 6
- SJBYLUUKNXJKAT-UHFFFAOYSA-N 2-(1,1,2,2,2-pentafluoroethyl)pyrimidine Chemical class FC(F)(F)C(F)(F)C1=NC=CC=N1 SJBYLUUKNXJKAT-UHFFFAOYSA-N 0.000 claims abstract description 5
- YDAGLPIQWWSUJT-UHFFFAOYSA-N 2-(trifluoromethyl)-7h-purine Chemical class FC(F)(F)C1=NC=C2NC=NC2=N1 YDAGLPIQWWSUJT-UHFFFAOYSA-N 0.000 claims abstract description 3
- BQDJLAWUTBCDHK-UHFFFAOYSA-N 2-(trifluoromethyl)pyrimidine Chemical class FC(F)(F)C1=NC=CC=N1 BQDJLAWUTBCDHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 239000003513 alkali Substances 0.000 claims description 12
- WYVJHLQPKOHCOS-UHFFFAOYSA-N 2,2,2-trifluoroethyl 3-oxobutanoate Chemical group CC(=O)CC(=O)OCC(F)(F)F WYVJHLQPKOHCOS-UHFFFAOYSA-N 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- LVOYSBZJJWPUBD-UHFFFAOYSA-N 6-(trifluoromethyl)-1h-pyrimidin-4-one Chemical compound OC1=CC(C(F)(F)F)=NC=N1 LVOYSBZJJWPUBD-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 7
- MWGSZQXKIYWSFS-UHFFFAOYSA-N ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)C(F)(F)F MWGSZQXKIYWSFS-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 5
- 150000001491 aromatic compounds Chemical class 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 3
- 239000001099 ammonium carbonate Substances 0.000 claims description 3
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical group C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical group [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 239000013067 intermediate product Substances 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 4
- YZAOETRYQWFEOY-UHFFFAOYSA-N 2-sulfanylidene-6-(trifluoromethyl)-1h-pyrimidin-4-one Chemical compound FC(F)(F)C1=CC(=O)NC(=S)N1 YZAOETRYQWFEOY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- TYSPDLZOMUDHQZ-UHFFFAOYSA-N 4-chloro-6-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CC(Cl)=NC=N1 TYSPDLZOMUDHQZ-UHFFFAOYSA-N 0.000 description 1
- FIAIKJQZLXLGCR-UHFFFAOYSA-N 6-(trifluoromethyl)pyrimidin-4-amine Chemical compound NC1=CC(C(F)(F)F)=NC=N1 FIAIKJQZLXLGCR-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A process is disclosed for the production of 4-hydroxy-6-polyfluoroalkylpyrimidines, starting from a polyfluoroalkylcarbonylacetic acid lower alkyl ester and a formamidine salt. 4-Hydroxy-6-pentafluoroethylpyrimidine is an intermediate product. The 4-hydroxy-6-polyfluoroalkylpyrimidines can be used for the production of trifluoromethylpyrimidines, trifluoromethylpurines and pentafluoroethylpyrimidines.
A process is disclosed for the production of 4-hydroxy-6-polyfluoroalkylpyrimidines, starting from a polyfluoroalkylcarbonylacetic acid lower alkyl ester and a formamidine salt. 4-Hydroxy-6-pentafluoroethylpyrimidine is an intermediate product. The 4-hydroxy-6-polyfluoroalkylpyrimidines can be used for the production of trifluoromethylpyrimidines, trifluoromethylpurines and pentafluoroethylpyrimidines.
Description
~0~ ~33 This invention relates to a process for the production of 4-hydroxy-6-polyfluoroalkylpyrimidines, as well as to a novel pyrimidine, namely 4-hydroxy-6-pentafluoroethylpyrimidine.
A process for the production of 4-hydroxy-6-trifluoromethylpyrimidine from 4-hydroxy-2-mercapto-6-trifluoromethylpyrimidine, starting from trifluoroethyl acetoacetate, is described in J. Am. Chem. Soc., Vol. 80, (1958), pp. 5744 to 5752. In the described production, thiourea and trifluoroethyl acetoacetate are reacted to form 4-hydroxy-2-mercapto-6-trifluoromethylpyrimidine, which is then converted in another step in the presence of hydrogen and Raney nickel into the desired product. Such a two-step process leads to a total yield of only about 48.4 percent, based on the trifluoroethyl acetoacetate used. A
drawback of such process lies in the fact that the -SH
group must be removed from the intermediate product, 4-hydroxy-2-mercapto-6-trifluoromethylpyrimidine, and thus the accumulating product is contaminated.
An object of the present invention is to provide an economical process for the production of 4-hydroxy-6-polyfluoroalkylpyrimidines, the process being characterized by high yields and purity. Another object of thè invention is to provide a novel product for use as an intermediate in the production of pentafluoroethylpyrimidines.
Accordingly, the invention provides a process for the production of a 4-hydroxy-6-polyfluoroalkylpyrimidine of the general formula:
R
` ~
N OH (1) wherein ~ is a trifluoromethyl or pentafluoroethyl group, which comprises reacting a polyfluoroalkylcarbonyl acetic acid lower alkyl ester of the general formula:
-.:: :: : : : ~: . ~ ::
-3~3 R - C - CH2 - COOR1 (2) wherein ~ has the above-mentioned meaning and Rl is a lower alkyl group having 1 to 4 carbon toms, with a formamidine salt of the general formula:
HC - NH2 HX (3) ll NH
wherein X is an acetate or chloride radical, either in the presence of an alkali alcoholate or in the presence of ammonium carbonate or an alkali carbonate.
Examples of the polyfluoroalkylcarbonylacetic acid lower alkyl ester of general formula (2) are polyfluoroalkylcarbonylacetic acid methyl, ethyl, propyl and butyl ester. Preferably 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester or trifluoroethylacetoacetate is used. Examples of the formamidine salt (3) are formamidine acetate and formamidine hydrochloride.
Preferably formamidine acetate is used. Examples of suitable alkali alcoholates are sodium and potassium alcoholate (e.g., methylate or ethylate). Preferably sodium methylate is used. Examples of the alkali carbonate include sodium and potassium carbonate. Preferably sodium carbonate is used.
The reaction of the polyfluoroalkylcarbonylacetic acid lower alkyl ester is advantageously performed with 1.0 to 2.0 equivalents of the formamidine salt. The reaction of the 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester is preferably performed with 1.0 to 1.5 equivalents of the formamidine salt, more preferably with 1.1 to 1.3 equivalents of the formamidine salt. The reaction of the trifluoroethyl acetoacetate is advantageously performed with 1.3 to 2.0 equivalents of the formamidine salt, 2 ~ 3 ~
preferably with 1.4 to 1.5 equivalents of the formamidine salt.
Either a low-boiling aliphatic alcohol or a mixture of a low-boiling aliphatic alcohol and an aromatic compound can be used as a solvent in the reaction.
Methanol, ethanol, propanol or butanol can be used as the aliphatic alcohol. Toluene, benzene, and xylene can be used as the aromatic compound, with toluene being preferably used. The reaction of the 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester is preferably performed in a solvent mixture of methanol and toluene.
The reaction of the 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester is advantageously performed at a temperature of 40C to reflux temperature, preferably at reflux temperature, with stirring, with a reaction time of 1 to 24 hours, preferably 2 to 5 hours. Then, the pH is adjusted to the range of 3 to 5, preferably to pH 3.5 to 4.5.
The reaction of the trifluoroethyl acetoacetate is preferably performed in methanol. The reaction of the trifluoroethyl acetoacetate is advantageously carried out at a temperature of 40 to 65C, preferably at 60 to 65C, with stirring, for a reaction time of 5 to 24 hours, preferably of about 5.5 hours. Then, the pH is adjusted to 25 a range of 2.0 to 4.0, preferably to pH 2.5 to 3.5.
Suitable acids for adjusting the pH, include non-oxidizing mineral acids, such as hydrochloric acid, sulfuric acid and phosphoric acid. Hydrochloric acid is preferred.
In the known prior art, a melting point of 160~
to 162C is indicated for 4-hydroxy-6-trifluoromethylpyrimidine. It may be assumed, therefore, that the product produced according to the invention which axhibits a higher melting point, in comparison with the product in the prior art, exhibits a substantially higher purity.
4-Hydroxy-6-trifluoromethylpyrimidine is a valuable intermediate product for the production of .
- -,, . . -:
.
trifluoromethylpyrimidines and trifluoromethylpurines. 4-Hydroxy-6-pentafluoroethylpyrimidine is not known from the literature, and is an important intermediate product ln the production of pentafluoroethylpyrimidines.
The following Examples illustrate the invention.
Example_l 4-Hydroxv-6-pentafluoroethylpyrimidine 5.2 g of 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester (0.020 mol), 2.3 g of formamidine acetate (0.022 mol), 1.2 g of sodium methylate (0.022 mol), 2.8 mg of methanol and 50 g of toluene were mixed together. The reaction mixture was refluxed, and the methanol, the water and a part of the toluene were distilled off by a condenser and water separator over 2 hours. Another 1.2 g (0.022 mol) of sodium methylate and 2.8 g of methanol were added and after 2 hours and 20 minutes, the reaction mixture was cooled to room temperature, diluted with water and adjusted to pH 4.5 with 10 percent hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the organic phase separated, dried (over Na2SO4) and concentrated by evaporation. The raw product was purified by bulb tube distillation. 2.5 g of a pale yellow crystalline product was obtained corresponding to a yield of 48 percent based on the 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester used. Data for the product was as follows:
H NMR (CDC13, 300 MHz): ~ 6.91 (lH, s) 8.42 (lH, s) 13.22 (lH, bs) Example 2 4-Hydroxy-6-trifluoromethylpyrimidine A mixture of 435.0 g t2.3 mol) of trifluoroethyl acetoacetate, 359.0 g (3.45 mol) of formamidine acetate and 304 g (2.83 mol) of sodium carbonate in 800 g of methanol was heated to about 60C with stirring. After a reaction time of 5.5 hours, the mixture was cooled to room temperature and adjusted to pH 3.0 with 689 g (6.9 mol) of concentrated hydrochloric acid. the methanol was partially distilled off under vacuum, and the residue suspended with , . ~ , .
:: :
5 3 ~
300 ml of water. After cooling to a temperature of 5 to 10C, the raw product was filtered off, washed twice with 200 ml of cold water and dried at 60C and at a pressure of 13332.2 Pa. 321.1 g of a white crystalline product was obtained, corresponding to a yield of 85 percent, based on the trifluoroethyl acetoacetate used. Data for the product were as follows:
Melting point: 164 to 165C
lH NMR: (DMSO-d6, 300 MHz) ~ 6.89 (s, lH) 8.40 (s, lH) 13.18 (bs, lH) MS: M+ 164 IR (KBr) cm~1 3417, 3348, 3286, 3165, 3120, 3082, 3048, 3001, 2932, 2892, 2707, 2684, 2657, 1823, 1687, 1618, 1558, 1482, 1438, 1348, 1275, 1205 W (MeOH) nm: 219, 279 Exam~le 3 4-Amino-6-trifluoromethylpyrimidine 8 ml of diethylaniline (0.05 mole) was added dropwise at 20 to 25C to a solution of 4 g (0.025 mole) of 4-hydroxy-6-trifluoromethylpyrimidine in 30 ml (0.32 mole) of phosphorus oxychloride. An additional amount of phosphorus oxychloride (15 ml, 0.16 mole) was poured into the mixture, which was stirred and refluxed for 1.5 hours.
About half of the phosphorus oxychloride was removed by distillation in vacuo. After cooling, the crude 4-chloro-6-trifluoromethylpyrimidine was poured onto 250 g of cracked ice. The greenish oil which formed was separated from the aqueous layer and, after washing with cold water, was poured into 30 ml of a saturated solution of ammonia in ethanol. The combined aqueous layers and washings were extracted with ether and the dried ether extracts were also treated with ethanolic ammonia. The ammoniacal solutions were combined and evaporated to dryness in vacuo. The residue was washed with water and dried to yield 2.3 g (58 percent) of yellow prisms, m.p. 165 to 170~C.
- . ~ , . .
2D 7 ~ r~33 Pentafluoroethylpyrimidines can be prepared from 4-hydroxy-6-pentafluoroethylpyrimidine in the same way or in an analogous way.
Further preparations of pyrimidines and purines from 4-hydroxy-6-trifluoromethylpyrimidine are described in J. Am. Chem. Soc., Vol. 80, 1958, ibid., p. 5750.
A process for the production of 4-hydroxy-6-trifluoromethylpyrimidine from 4-hydroxy-2-mercapto-6-trifluoromethylpyrimidine, starting from trifluoroethyl acetoacetate, is described in J. Am. Chem. Soc., Vol. 80, (1958), pp. 5744 to 5752. In the described production, thiourea and trifluoroethyl acetoacetate are reacted to form 4-hydroxy-2-mercapto-6-trifluoromethylpyrimidine, which is then converted in another step in the presence of hydrogen and Raney nickel into the desired product. Such a two-step process leads to a total yield of only about 48.4 percent, based on the trifluoroethyl acetoacetate used. A
drawback of such process lies in the fact that the -SH
group must be removed from the intermediate product, 4-hydroxy-2-mercapto-6-trifluoromethylpyrimidine, and thus the accumulating product is contaminated.
An object of the present invention is to provide an economical process for the production of 4-hydroxy-6-polyfluoroalkylpyrimidines, the process being characterized by high yields and purity. Another object of thè invention is to provide a novel product for use as an intermediate in the production of pentafluoroethylpyrimidines.
Accordingly, the invention provides a process for the production of a 4-hydroxy-6-polyfluoroalkylpyrimidine of the general formula:
R
` ~
N OH (1) wherein ~ is a trifluoromethyl or pentafluoroethyl group, which comprises reacting a polyfluoroalkylcarbonyl acetic acid lower alkyl ester of the general formula:
-.:: :: : : : ~: . ~ ::
-3~3 R - C - CH2 - COOR1 (2) wherein ~ has the above-mentioned meaning and Rl is a lower alkyl group having 1 to 4 carbon toms, with a formamidine salt of the general formula:
HC - NH2 HX (3) ll NH
wherein X is an acetate or chloride radical, either in the presence of an alkali alcoholate or in the presence of ammonium carbonate or an alkali carbonate.
Examples of the polyfluoroalkylcarbonylacetic acid lower alkyl ester of general formula (2) are polyfluoroalkylcarbonylacetic acid methyl, ethyl, propyl and butyl ester. Preferably 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester or trifluoroethylacetoacetate is used. Examples of the formamidine salt (3) are formamidine acetate and formamidine hydrochloride.
Preferably formamidine acetate is used. Examples of suitable alkali alcoholates are sodium and potassium alcoholate (e.g., methylate or ethylate). Preferably sodium methylate is used. Examples of the alkali carbonate include sodium and potassium carbonate. Preferably sodium carbonate is used.
The reaction of the polyfluoroalkylcarbonylacetic acid lower alkyl ester is advantageously performed with 1.0 to 2.0 equivalents of the formamidine salt. The reaction of the 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester is preferably performed with 1.0 to 1.5 equivalents of the formamidine salt, more preferably with 1.1 to 1.3 equivalents of the formamidine salt. The reaction of the trifluoroethyl acetoacetate is advantageously performed with 1.3 to 2.0 equivalents of the formamidine salt, 2 ~ 3 ~
preferably with 1.4 to 1.5 equivalents of the formamidine salt.
Either a low-boiling aliphatic alcohol or a mixture of a low-boiling aliphatic alcohol and an aromatic compound can be used as a solvent in the reaction.
Methanol, ethanol, propanol or butanol can be used as the aliphatic alcohol. Toluene, benzene, and xylene can be used as the aromatic compound, with toluene being preferably used. The reaction of the 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester is preferably performed in a solvent mixture of methanol and toluene.
The reaction of the 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester is advantageously performed at a temperature of 40C to reflux temperature, preferably at reflux temperature, with stirring, with a reaction time of 1 to 24 hours, preferably 2 to 5 hours. Then, the pH is adjusted to the range of 3 to 5, preferably to pH 3.5 to 4.5.
The reaction of the trifluoroethyl acetoacetate is preferably performed in methanol. The reaction of the trifluoroethyl acetoacetate is advantageously carried out at a temperature of 40 to 65C, preferably at 60 to 65C, with stirring, for a reaction time of 5 to 24 hours, preferably of about 5.5 hours. Then, the pH is adjusted to 25 a range of 2.0 to 4.0, preferably to pH 2.5 to 3.5.
Suitable acids for adjusting the pH, include non-oxidizing mineral acids, such as hydrochloric acid, sulfuric acid and phosphoric acid. Hydrochloric acid is preferred.
In the known prior art, a melting point of 160~
to 162C is indicated for 4-hydroxy-6-trifluoromethylpyrimidine. It may be assumed, therefore, that the product produced according to the invention which axhibits a higher melting point, in comparison with the product in the prior art, exhibits a substantially higher purity.
4-Hydroxy-6-trifluoromethylpyrimidine is a valuable intermediate product for the production of .
- -,, . . -:
.
trifluoromethylpyrimidines and trifluoromethylpurines. 4-Hydroxy-6-pentafluoroethylpyrimidine is not known from the literature, and is an important intermediate product ln the production of pentafluoroethylpyrimidines.
The following Examples illustrate the invention.
Example_l 4-Hydroxv-6-pentafluoroethylpyrimidine 5.2 g of 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester (0.020 mol), 2.3 g of formamidine acetate (0.022 mol), 1.2 g of sodium methylate (0.022 mol), 2.8 mg of methanol and 50 g of toluene were mixed together. The reaction mixture was refluxed, and the methanol, the water and a part of the toluene were distilled off by a condenser and water separator over 2 hours. Another 1.2 g (0.022 mol) of sodium methylate and 2.8 g of methanol were added and after 2 hours and 20 minutes, the reaction mixture was cooled to room temperature, diluted with water and adjusted to pH 4.5 with 10 percent hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the organic phase separated, dried (over Na2SO4) and concentrated by evaporation. The raw product was purified by bulb tube distillation. 2.5 g of a pale yellow crystalline product was obtained corresponding to a yield of 48 percent based on the 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester used. Data for the product was as follows:
H NMR (CDC13, 300 MHz): ~ 6.91 (lH, s) 8.42 (lH, s) 13.22 (lH, bs) Example 2 4-Hydroxy-6-trifluoromethylpyrimidine A mixture of 435.0 g t2.3 mol) of trifluoroethyl acetoacetate, 359.0 g (3.45 mol) of formamidine acetate and 304 g (2.83 mol) of sodium carbonate in 800 g of methanol was heated to about 60C with stirring. After a reaction time of 5.5 hours, the mixture was cooled to room temperature and adjusted to pH 3.0 with 689 g (6.9 mol) of concentrated hydrochloric acid. the methanol was partially distilled off under vacuum, and the residue suspended with , . ~ , .
:: :
5 3 ~
300 ml of water. After cooling to a temperature of 5 to 10C, the raw product was filtered off, washed twice with 200 ml of cold water and dried at 60C and at a pressure of 13332.2 Pa. 321.1 g of a white crystalline product was obtained, corresponding to a yield of 85 percent, based on the trifluoroethyl acetoacetate used. Data for the product were as follows:
Melting point: 164 to 165C
lH NMR: (DMSO-d6, 300 MHz) ~ 6.89 (s, lH) 8.40 (s, lH) 13.18 (bs, lH) MS: M+ 164 IR (KBr) cm~1 3417, 3348, 3286, 3165, 3120, 3082, 3048, 3001, 2932, 2892, 2707, 2684, 2657, 1823, 1687, 1618, 1558, 1482, 1438, 1348, 1275, 1205 W (MeOH) nm: 219, 279 Exam~le 3 4-Amino-6-trifluoromethylpyrimidine 8 ml of diethylaniline (0.05 mole) was added dropwise at 20 to 25C to a solution of 4 g (0.025 mole) of 4-hydroxy-6-trifluoromethylpyrimidine in 30 ml (0.32 mole) of phosphorus oxychloride. An additional amount of phosphorus oxychloride (15 ml, 0.16 mole) was poured into the mixture, which was stirred and refluxed for 1.5 hours.
About half of the phosphorus oxychloride was removed by distillation in vacuo. After cooling, the crude 4-chloro-6-trifluoromethylpyrimidine was poured onto 250 g of cracked ice. The greenish oil which formed was separated from the aqueous layer and, after washing with cold water, was poured into 30 ml of a saturated solution of ammonia in ethanol. The combined aqueous layers and washings were extracted with ether and the dried ether extracts were also treated with ethanolic ammonia. The ammoniacal solutions were combined and evaporated to dryness in vacuo. The residue was washed with water and dried to yield 2.3 g (58 percent) of yellow prisms, m.p. 165 to 170~C.
- . ~ , . .
2D 7 ~ r~33 Pentafluoroethylpyrimidines can be prepared from 4-hydroxy-6-pentafluoroethylpyrimidine in the same way or in an analogous way.
Further preparations of pyrimidines and purines from 4-hydroxy-6-trifluoromethylpyrimidine are described in J. Am. Chem. Soc., Vol. 80, 1958, ibid., p. 5750.
Claims (15)
1. A process for the production of a 4-hydroxy-6-polyfluoroalkylpyrimidine of the general formula:
(I) wherein R is a trifluoromethyl or pentafluoroethyl group, which comprises reacting a polyfluoroalkylcarbonylacetic acid lower alkyl ester of the general formula:
(2) wherein R has the above mentioned meaning and R1 is a lower alkyl group having 1 to 4 carbon atoms with a formamidine salt of the general formula:
(3) wherein X is acetate or chloride, ether in the presence of an alkali alcoholate or in the presence of ammonium carbonate or an alkali carbonate, to form the 4-hydroxy-6-polyfluoroalkylpyrimidine of formula (1).
(I) wherein R is a trifluoromethyl or pentafluoroethyl group, which comprises reacting a polyfluoroalkylcarbonylacetic acid lower alkyl ester of the general formula:
(2) wherein R has the above mentioned meaning and R1 is a lower alkyl group having 1 to 4 carbon atoms with a formamidine salt of the general formula:
(3) wherein X is acetate or chloride, ether in the presence of an alkali alcoholate or in the presence of ammonium carbonate or an alkali carbonate, to form the 4-hydroxy-6-polyfluoroalkylpyrimidine of formula (1).
2. A process according to claim 1, wherein the reaction is performed either in a low-boiling aliphatic alcohol or in a mixture of a low-boiling aliphatic alcohol and an aromatic compound.
3. A process according to claim 2, wherein the low-boiling aliphatic alcohol is methanol and the aromatic compound is toluene.
4. A process according to claim 1, 2 or 3, wherein the alkali alcoholate is sodium methylate.
5. A process according to claim 1, 2 or 3, wherein the alkali carbonate is sodium carbonate.
6. A process according to claim 1, 2 or 3, wherein the reaction is performed at a temperature of from 40°C to reflux temperature.
7. A process according to claim 1, 2 or 3, wherein the reaction is performed with 1.0 to 2.0 equivalents of the formamidine salt (3), based on the polyfluoroalkylcarbonylacetic acid ester (2).
8. A process according to claim 1, 2 or 3, wherein the polyfluoroalkylcarbonylacetic acid lower alkyl ester (2) is 4,4,5,5,5-pentafluoro-3-oxopentanoic acid ethyl ester and the reaction is performed with 1.0 to 1.5 equivalents of the formamidine salt in the presence of an alkali methylate, dissolved in a mixture of methanol and toluene, at a temperature of from 40°C to reflux temperature.
9. A process according to claim 1, 2 or 3, wherein the polyfluoroalkylcarbonylacetic acid lower alkyl ester is trifluoroethyl acetoacetate and the reaction is performed with 1.3 to 2.0 equivalents of the formamidine salt in the presence of an alkali carbonate, dissolved in methanol, at a temperature of from 40° to 65°C.
10. A process according to claim 1, wherein the reaction is conducted in a mixture of methanol and toluene.
11. A process according to claim 1, 2 or 3, wherein the reaction is conducted in the presence of an alkali alcoholate.
12. A process according to claim 1, 2 or 3, wherein the reaction is conducted in the presence of ammonium carbonate or an alkali carbonate.
13. 4-Hydroxy-6-pentafluoroethylpyrimidine.
14. A process for preparing a trifluoromethyl-pyrimidine and a trifluoromethylpurine, which comprises utilizing 4-hydroxy-6-trifluoromethylpyrimidine.
15. A process for preparing a pentafluoroethyl-pyrimidine, which comprises utilizing 4-hydroxy-6-pentafluoroethylpyrimidine.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH154289A CH682663A5 (en) | 1989-04-24 | 1989-04-24 | New and known 4-hydroxy-6-fluoroalkyl-pyrimidine cpds. |
| CH1542/89 | 1989-04-24 | ||
| CH428989A CH679044A5 (en) | 1989-11-30 | 1989-11-30 | New and known 4-hydroxy-6-fluoroalkyl-pyrimidine cpds. |
| CH4289/89 | 1989-11-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2014533A1 true CA2014533A1 (en) | 1990-10-24 |
Family
ID=25687952
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2014533 Abandoned CA2014533A1 (en) | 1989-04-24 | 1990-04-12 | Process for the production of 4 - hydroxy -6- polyfluoroalkylpyrimidines |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0395977A1 (en) |
| JP (1) | JPH02304066A (en) |
| CA (1) | CA2014533A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115043780B (en) * | 2022-07-11 | 2024-01-16 | 上海飞琰化工科技有限公司 | Synthesis method and application of 4-hydroxy-5-fluoro-6-ethylpyrimidine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH524617A (en) * | 1970-04-28 | 1972-06-30 | Lonza Ag | Process for the preparation of 4-hydroxy-6-halomethylpyrimidines |
| GB8906946D0 (en) * | 1988-04-22 | 1989-05-10 | Ici Plc | Novel compounds |
-
1990
- 1990-04-12 CA CA 2014533 patent/CA2014533A1/en not_active Abandoned
- 1990-04-19 JP JP10436490A patent/JPH02304066A/en active Pending
- 1990-04-23 EP EP90107670A patent/EP0395977A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02304066A (en) | 1990-12-17 |
| EP0395977A1 (en) | 1990-11-07 |
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