WO2004111011A2 - Synthese d'amides d'acide 2-aryl pyrimidine 4-carboxylique - Google Patents

Synthese d'amides d'acide 2-aryl pyrimidine 4-carboxylique Download PDF

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Publication number
WO2004111011A2
WO2004111011A2 PCT/US2004/016859 US2004016859W WO2004111011A2 WO 2004111011 A2 WO2004111011 A2 WO 2004111011A2 US 2004016859 W US2004016859 W US 2004016859W WO 2004111011 A2 WO2004111011 A2 WO 2004111011A2
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compound
formula
group
hydrogen
alkyl
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PCT/US2004/016859
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WO2004111011A3 (fr
Inventor
Jeffrey M. Marra
R. Richard Goehring
Julio Perez
Linas R. Stasaitis
Yanbing Liu
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Euro-Celtique S.A.
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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

Definitions

  • the present invention is in the field of synthetic organic chemistry.
  • the invention relates to a method for preparing 2-aryl pyrimidine 4-carboxylic acid amides, especially 2-(p- phenoxyphenyl)-pyrimidine-4-carboxylic acid amides.
  • the invention also relates to the preparation of 4-substituted 2-oxo-3-butenoic esters.
  • Na + channel blockers prevent hypoxic damage to mammalian white matter (Stys et al, J. Neurosci. 72:430-439 (1992)). Thus, they may offer advantages for treating certain types of strokes or neuronal trauma where damage to white matter tracts is prominent.
  • neuropathic pain such as from trigeminal neurologia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trends Pharmacol. Sd.
  • 2-Aryl pyrimidine 4-carboxylic acid amides have been shown to block or modulate Na + channel activity, and thus are useful for treating disorders responsive to the blockade of sodium channels (Hogenkamp, DJ. et al, U.S. Pat. Appl. Publ. No. 2002/0040025 Al).
  • the usual method of manufacturing this type of compound involves creation of the pyrimidine ring by cyclizing an aryl carboxamidine with methyl 2,2-dimethoxyethyl ketone, followed by oxidation of the methyl group at the 4-position of the pyrimidine ring to a carboxyl group and subsequent conversion to an amide to generate the pyrimidine 4-carboxylic acid amide.
  • the present invention provides a novel synthesis of 2-aryl pyrimidine 4-carboxylic acid amides.
  • the present invention also provides a novel synthesis of 2-aryl 4-alkoxycarbonyl pyrimidines, which are thereafter converted to the corresponding 2-aryl pyrimidine 4-carboxylic acid amides by treatment with ammonia or an amine.
  • the present invention also provides a novel method of preparing 4-substituted 2-oxo-3-butenoic esters.
  • the present invention provides a method for synthesizing 2- aryl pyrimidine 4-carboxylic acid amides.
  • one aspect of the invention relates to a method for the preparation of 2-aryl pyrimidine 4-carboxylic acid amides comprising reacting an aryl carboxamidine with a 4-substituted 2-oxo-
  • the invention in a second aspect, relates to a method for the preparation of 2-aryl 4-alkoxycarbonyl pyrimidines comprising reacting an aryl carboxamidine with a 4-substituted 2-oxo-3-butenyl ester.
  • the resulting alkoxycarbonyl pyrimidines are thereafter converted to the corresponding pyrimidine carboxylic acid amides by reaction with a suitable reagent, such as a solution of ammonia or an amine.
  • a suitable reagent such as a solution of ammonia or an amine.
  • a polar protic solvent such as methanol or ethanol is employed.
  • the invention relates to novel compounds useful in the method of the present invention, and to methods of making these novel compounds.
  • the invention relates to a method for the preparation of 4-substituted 2-oxo-3-butenoic esters.
  • the method of the present invention proceeds in high yield and eliminates the need to employ toxic reagents such as selenium dioxide to oxidize the carbon atom attached to C-4 of the pyrimidine ring.
  • the method of the present invention is also suitable to large-scale employment.
  • the invention relates to a method for the preparation of a compound of Formula IA:
  • X is -O- or -S-;
  • Y is -NR c R d where R c and R d are independently hydrogen, alkyl or aryl, or R c and R d , together with the nitrogen atom to which they are attached, form a 3-12 membered aromatic or non-aromatic ring;
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino and cyano;
  • R w is selected from the group consisting of alkyloxy, dialkylamino and -NR a R b where R a and R b taken together with the nitrogen atom to which they are attached form a 3- to 8-membered ring, which ring optionally contains 1 or 2 additional heteroatoms selected from the group consisting of N, O and S; and Z is -CHO or -C(H)(0R z )(0R z' ) where R z and R z' are independently alkyl or aryl, or -OR Z and OR Z , together with the carbon atom to which they are attached, form a 5- to 8-menibered ring.
  • Preferred methods according to this first aspect of the present invention include those wherein X is -O- and wherein said compound selected from the group consisting of a compound of Formula HIA and a compound of Formula IVA is a compound of Formula HIA.
  • Preferred methods according to this first aspect of the present invention also include those wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, nitro, amino and cyano. More preferred include those wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl and nitro. Most preferred include those wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, chloro and fluoro.
  • Preferred methods according to this first aspect of the present invention also include those wherein R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl. More preferred include those wherein R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 haloalkyl. More preferred still include those wherein R 3 and R 4 are independently selected from the group consisting of hydrogen, chloro and fluoro. Most preferred include those wherein R 3 and R 4 are hydrogen.
  • Preferred methods according to this first aspect of the present invention also include those wherein R w is selected from the group consisting of C 1-4 alkyloxy, di(C 1-4 alkyl)amino, pyrrolidine, piperidine, piperazine and morpholine. More preferred include those wherein R w is selected from the group consisting of methoxy, ethoxy, dimethylamino, and diethylamino. Most preferred include those wherein R w is ethoxy or dimethylamino.
  • Preferred methods according to this first aspect of the present invention also include those wherein R z and R z have the same value. More preferred include those wherein R z and R z have the same value, and the value is of C 1-6 alkyl.
  • Preferred methods according to this first aspect of the present invention also include those wherein R c and R d are independently hydrogen or C 1-6 alkyl. More preferred include those wherein R c and R d are hydrogen.
  • Preferred methods according to this first aspect of the present invention also include those wherein the reaction is carried out in a polar solvent.
  • Suitable solvents include dimethylformamide (DMF), iV-methyl-2-pyrrolidone (NMP), isopropyl acetate, dimethylsulfoxide (DMSO) and ethers. More preferred solvents include ethers. Suitable ethers include dioxane, glyme and diglyme.
  • Preferred methods according to this first aspect of the present invention also include those wherein the reaction is carried out at a temperature between about 25 0 C and about 175 0 C. More preferred include those wherein the reaction is carried out at a temperature between about 85 0 C and about 115 0 C.
  • Preferred methods according to this first aspect of the present invention also include those wherein said compound selected from the group consisting of a compound of Formula HIA and a compound of Formula IVA is
  • the invention relates to a method for the preparation of a compound of Formula IB:
  • X is -O- or -S-;
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino and cyano;
  • R 10 is alkyl or optionally-substituted aryl
  • R w is selected from the group consisting of alkyloxy, dialkylamino and -NR a R b where R a and R b taken together with the nitrogen atom to which they are attached form a 3- to 8-membered ring, which ring optionally contains 1 or 2 additional heteroatoms selected from the group consisting of N, O and S; and
  • Preferred methods according to this second aspect of the present invention include those wherein X is -O- and wherein said compound selected from the group consisting of a compound of
  • Formula HIB and a compound of Formula /FJB is a compound of
  • Preferred methods according to this second aspect of the present invention also include those wherein R and R are as preferred in the first aspect, described above. [0032] Preferred methods according to this second aspect of the present invention also include those wherein R 3 and R 4 are as preferred in the first aspect, described above.
  • Preferred methods according to this second aspect of the present invention also include those wherein R w is as preferred in the first aspect, described above.
  • Preferred methods according to this second aspect of the present invention also include those wherein R z and R z are as preferred in the first aspect, described above.
  • Preferred methods according to this second aspect of the present invention also include those wherein the reaction is carried out in a solvent as preferred in the first aspect, described above.
  • Preferred methods according to this second aspect of the present invention also include those wherein the reaction is carried out in a temperature range as preferred in the first aspect, described above.
  • Preferred methods according to this second aspect of the present invention also include those wherein R 10 is C 1-6 alkyl. More preferred include those wherein R 10 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl. Most preferred include those wherein R 10 is ethyl.
  • Preferred methods according to this second aspect of the present invention also include those wherein said compound selected from the group consisting of a compound of Formula IUB and a compound of Formula IVB is
  • esters that can be prepared using this second aspect of the present invention include: ethyl 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4- carboxylate. [0040] Esters of Formula IB can be converted to the corresponding amides of Formula IA:
  • Y is -NR c R d wherein R c and R d are independently hydrogen, alkyl or aryl, or R c and R d , together with the nitrogen atom to which they are attached, form a 3-12 membered aromatic or non-aromatic ring.
  • R c and R d are independently hydrogen, alkyl or aryl, or R c and R d , together with the nitrogen atom to which they are attached, form a 3-12 membered aromatic or non-aromatic ring.
  • treatment of IB where R 10 is -OCH 2 CH 3 with methanolic ammonia produces IA where Y is -NH 2 .
  • Specific examples of amides that can be prepared using the present invention include:
  • 4-Dimethylamino-2-oxo-but-3-enoic acid amide can be produced by reacting ethyl pyruvate with ammonia, then reacting the product of this reaction with N,N-dimethylformamide dimethylacetal. This reaction is believed to proceed through an intermediate pyruvamide.
  • 4-dimethylamino-2-oxo-but-3-enoic acid amide can be produced by reacting ethyl pyruvate with N,N-dimethylformamide dimethylacetal, then reacting the product of this reaction with ammonia.
  • the ammonia can be provided as a gas or in solution.
  • the invention relates to the preparation of compounds of Formula V:
  • R' and R" are independently selected from the group consisting of alkyl, alkenyl, alkynyl and haloalkyl.
  • Suitable values of R' and R" include C 1-4 alkyl, C 2-4 alkenyl,
  • Suitable bases include amines, preferably tertiary amines. One preferred base is triethylarnine.
  • Suitable solvents according to this aspect of the present invention are aprotic solvents, such as ethyl acetate.
  • Preferred solvents are ethers, such as diethyl ether and 1 ⁇ 4-dioxane.
  • Formula V includes compounds of Formula IIIB in which R 10 is alkyl and R w is alkyloxy.
  • R 10 is alkyl and R w is alkyloxy
  • compounds of Formula IIIB in which R 10 is alkyl and R w is alkyloxy, useful in the second aspect of the present invention, are prepared according to this further aspect of the present invention.
  • alkyl refers to both straight and branched chain radicals of up to 12 carbons, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.
  • alkenyl is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is otherwise limited, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l- ⁇ ropenyl, 1-butenyl, 2- butenyl, and the like.
  • the alkenyl chain is 2 to 10 carbon atoms in length, more preferably 2 to 8 carbon atoms in length, most preferably 2 to 4 carbon atoms in length.
  • the unsaturated linkage i.e., the vinylene linkage, is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.
  • alkynyl is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is otherwise limited, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to > ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like.
  • the alkynyl chain is 2 to 10 carbon atoms in length, more preferably 2 to 8 carbon atoms in length, most preferably 2 to 4 carbon atoms in length.
  • alkoxy or "alkyloxy” as employed herein by itself or as part of another group refers to a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is otherwise limited, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, ⁇ -propoxy, isopropoxy, and the like.
  • the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
  • halogen or "halo" as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine, with chlorine being preferred.
  • dialkylamine or "dialkylamino” as employed herein by itself or as part of another group refers to an amino group substituted with two alkyl groups, each independently having from 1 to 6 carbon atoms.
  • aryl as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 14 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
  • heteroatom is used herein to mean an oxygen atom
  • Optional substituents on R 10 when R 10 is optionally-substituted aryl include alkyl, alkenyl, alkynyl, halo, haloalkyl, hydroxyalkyl,
  • R 10 when R 10 is optionally- substituted aryl include C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, halo(C 1-6 )alkyl, hydroxy(Ci -6 )alkyl, phenyl, (Ci -6 alkyl)phenyl, halophenyl, (Ci -6 alkoxy)phenyl, nitro, hydroxy, amino and cyano.
  • Preferred subtituents on R 10 when R 10 is optionally-substituted aryl include phenyl.
  • stable compound or “stable formula” is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.
  • Scheme 1 illustrates a first aspect of the present invention.
  • Scheme 2 illustrates a second aspect of the present invention.
  • Substituents R 1 -R 4 , X, R 10 , R w , Y and Z are defined as above, hi this aspect, aryl carboxamidine 1 is reacted with either cyclization reagent 5 or cyclization reagent 6 to form 2-aryl-pyrimidine 4-carboxylic acid ester 7. This ester is further reacted with ammonia or an amine, usually in a polar solvent such as methanol, ethanol DMF or NMP, to form 2-aryl pyrimidine 4-carboxylic acid amide 4.
  • a polar solvent such as methanol, ethanol DMF or NMP
  • a round bottom (RB) flask equipped with an agitator was nitrogen purged to remove oxygen. Added to the flask was 5.6 liters of N-methyl-2-pyrrolidone (NMP). Next, 1.2 kg (3.2 moles, 95% purity) 2-[4-(4-chloro-2-fluoro-phenoxy)-phenyl] pyrimidine-4-carboxylic acid ethyl ester (crude ethyl ester, Example 2) was added and dissolved. Under a nitrogen atmosphere, 230 g of activated powdered carbon was then added, and the solution was heated to 80-100°C, and held for approximately 1 hour to decolorize the solution. The carbon was then removed by filtration, and washed with 230 mL NMP to recover product trapped on the carbon.
  • NMP N-methyl-2-pyrrolidone
  • the NMP/product filtrate/wash was added to a second RB flask that was nitrogen purged to remove oxygen.
  • the flask was equipped with an agitator and gas dispersion tube. Under a nitrogen atmosphere, the NMP/product filtrate/wash was cooled to -20 to 0°C.
  • 700-800 g anhydrous ammonia was charged via the gas dispersion tube to the ethyl ester, forming the 2-[4-(4-chloro-2- fluoro-phenoxyl)-phenyl] pyrimidine-4-carboxylic acid amide.
  • the reaction was complete in approximately 2 hours, and then the reaction solution was heated to 80-100 0 C.
  • the desired fraction 2 was purified again through another short plug of silica gel column.
  • the gel column was washed with 90/10 methylene chloride/methanol.
  • Fraction 4 from the wash contained the title compound.
  • the brown oil (0.9 g) was used in the next reaction.
  • Ethyl pyruvate (1.16 g, 10 mmole) was dissolved in 10 mL absolute EtOH (200 proof). Ammonia gas was bubbled in through a dispersion tube with vigorous stirring. A precipitate soon ensued. The solid was filtered and washed with ethanol. HPLC analysis indicated a retention time of 1.020 minutes and the product was pyruvamide, as verified by the GC-mass spectrum, m/z 87 (M + ) with 43 % of sample (area %). Ethyl acetate was added to the filtrate and a second precipitate formed. This solid was filtered and washed with cold ethyl acetate.
  • This solid had a retention time of 0.886 minutes, GC-mass spectrum, m/z 112 (M + ) with 70 % of sample (area %) unknown and m/z 87 (M + ) with 13 % of sample (area %).
  • 1,4-dioxane (6.8 mL), triethylamine (2.96 g, 0.0293 mol) and ethyl vinyl ether (7.37 g, 0.102 mol).
  • the resulting solution was warmed to 3O 0 C under nitrogen.
  • Ethyl chlorooxoacetate (2.73 g, 0.02 mol) was added via syringe over 5 min., and the reaction was allowed to stir at 33-36 0 C for 2 h.
  • the reaction mixture was cooled to room temperature, and filtered to remove solid.
  • To the crude oil obtained by concentration was added water (15 mL).
  • the resultant mixture was extracted with ethyl acetate (15 mL).

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé pour préparer des amides d'acide 2-aryl pyrimidine 4-carboxylique comprenant la mise en réaction de l'aryle carboxamidine avec un amide 2-oxo-3-butényle substitué en position 4. L'invention concerne également un procédé pour préparer des amides d'acide 2-aryle pyrimidine 4-carboxylique comprenant la mise en réaction de l'aryle carboxamidine avec un ester de 2-oxo-3-butényle substitué en position 4 et la conversion de l'ester ainsi obtenu en un amide. L'invention concerne, de plus, un procédé pour préparer des esters 2 oxo-3 buténoïques substitués en position 4.
PCT/US2004/016859 2003-05-30 2004-05-28 Synthese d'amides d'acide 2-aryl pyrimidine 4-carboxylique WO2004111011A2 (fr)

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US60/474,221 2003-05-30

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102675215A (zh) * 2012-05-17 2012-09-19 盛世泰科生物医药技术(苏州)有限公司 一种2-甲基嘧啶-4-羧酸乙酯的合成方法
WO2014151393A2 (fr) * 2013-03-15 2014-09-25 Purdue Pharma L.P. Dérivés de carboxamide et leur utilisation
US9884865B2 (en) 2013-08-26 2018-02-06 Purdue Pharma L.P. Azaspiro[4.5] decane derivatives and use thereof
CN110615751A (zh) * 2018-06-19 2019-12-27 上海医药工业研究院 一种2-氧代硫代丙酰胺的制备方法

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102675215A (zh) * 2012-05-17 2012-09-19 盛世泰科生物医药技术(苏州)有限公司 一种2-甲基嘧啶-4-羧酸乙酯的合成方法
WO2014151393A2 (fr) * 2013-03-15 2014-09-25 Purdue Pharma L.P. Dérivés de carboxamide et leur utilisation
WO2014151393A3 (fr) * 2013-03-15 2014-12-18 Purdue Pharma L.P. Dérivés de carboxamide et leur utilisation
US9493449B2 (en) 2013-03-15 2016-11-15 Purdue Pharma L.P. Carboxamide derivatives and use thereof
US10005768B2 (en) 2013-03-15 2018-06-26 Purdue Pharma L.P. Carboxamide derivatives and use thereof
US9884865B2 (en) 2013-08-26 2018-02-06 Purdue Pharma L.P. Azaspiro[4.5] decane derivatives and use thereof
US11180502B2 (en) 2013-08-26 2021-11-23 Purdue Pharma L.P. Azaspiro[4.5]decane derivatives and use thereof
CN110615751A (zh) * 2018-06-19 2019-12-27 上海医药工业研究院 一种2-氧代硫代丙酰胺的制备方法
CN110615751B (zh) * 2018-06-19 2021-08-17 上海医药工业研究院 一种2-氧代硫代丙酰胺的制备方法

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