EP1097143A1 - Verfahren zur herstellung von 5-(1-methylethyl) 6-(phenylmethyl)pyrimidin-2,4(1h,3h)-dione - Google Patents

Verfahren zur herstellung von 5-(1-methylethyl) 6-(phenylmethyl)pyrimidin-2,4(1h,3h)-dione

Info

Publication number
EP1097143A1
EP1097143A1 EP99929485A EP99929485A EP1097143A1 EP 1097143 A1 EP1097143 A1 EP 1097143A1 EP 99929485 A EP99929485 A EP 99929485A EP 99929485 A EP99929485 A EP 99929485A EP 1097143 A1 EP1097143 A1 EP 1097143A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
preparation
group
methylethyl
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Withdrawn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
EP99929485A
Other languages
English (en)
French (fr)
Inventor
Guy Adrian
Sylviane Mignonac
François LECOUTTEUX
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.)
Finorga SAS
Original Assignee
Sanofi Synthelabo SA
Finorga SAS
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 Sanofi Synthelabo SA, Finorga SAS filed Critical Sanofi Synthelabo SA
Publication of EP1097143A1 publication Critical patent/EP1097143A1/de
Withdrawn legal-status Critical Current

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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
    • C07D239/30—Halogen atoms or nitro radicals
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals

Definitions

  • the subject of the present invention is a process for the preparation of 5- (1-methylethyl) -6- (phenylmethyl) pyrimidine-2,4, (1H, 3H) -dione of formula (I):
  • the compound of formula (I) is known in itself. It can in particular be used as an intermediate for the synthesis of active compounds which inhibit HIV reverse transcriptase (Human Immunodeficiency Virus) of general formula:
  • A represents a RaOCH (Rb) - group, where Ra is a (C 1 _ 6 ) al yl group and Rb is a (C 1 _) alkyl group or a hydrogen atom.
  • a first object of the present invention consists of a new process for the preparation of the compounds of formula (I) defined above, as well as all of its variants.
  • Another subject of the invention consists of new compounds, useful in particular as synthesis intermediates.
  • M represents, an alkali metal or any other metal of the class II and III of the periodic table. More particularly, M represents a manganese, tin, zinc, iron, magnesium or copper atom.
  • X represents a halogen atom such as chlorine, bromine or iodine,
  • R ] _ represents a halogen atom or a group -OR 2 , where R 2 represents a (C 1-4 ) alkyl group, R 3 represents a (C 1 _) alkyl group.
  • the method according to the invention consists in reacting a compound of formula (VI) in which R ] _ is as defined above by coupling of an organometallic compound of formula (V), in which M and X are as defined above , in the presence of a homogeneous metal catalyst to obtain the compound of formula (IV), in which R x is defined as above.
  • this compound of formula (IV) it is possible either to hydrolyze this compound of formula (IV) directly with a strong acid, in an aqueous medium, in an alcoholic solvent such as ethanol or isopropanol, or, when R x represents a halogen atom , carry out a dialkoxylation by the conventional methods known to those skilled in the art before proceeding to the hydrolysis of this compound obtained of formula (III) under the same hydrolysis conditions as above.
  • This dialkoxylation can for example be carried out by the action of alcoholates of formula R 3 ONa, according to methods known to those skilled in the art or by the action of alcohols of formula R 3 OH in the presence of a strong base in aqueous solution such as diluted soda.
  • the organometallic compound of formula (V) can for example be chosen from: a benzylmagnesium halide or a benzylzinc halide. Benzylmagnesium halide and more particularly benzylmagnesium chloride are preferred. According to another particular embodiment of the coupling of the compound of formula (VI) with a compound of formula (V), the latter can be carried out under the conditions of the Barbier reaction (Barbier P., CR, 1899, 128- 110), that is to say addition of a benzyl halide on the compound of formula (VI) in the presence of magnesium turn, in an appropriate solvent. Within the scope of the present invention, benzyl chloride is preferred as the benzyl halide. This suitable solvent can be an ether such as ethyl ether, tetrahydrofuran or an acetal such as methylal or ethylal.
  • the catalyst is a derivative of either nickel or palladium. It can be chosen from homogeneous metallic catalysts derived either from nickel or from palladium complexed with ligands such as acetylacetone, triarylphosphines, l, n-bis (diarylphosphino) alkanes, of structural formula Ni (Acac) 2 , NiCl 2 [PR 3 ] 2 , NiBr 2 [PR 3 ] 2 , NiCl 2 [R 2 P (CH 2 ) n PR 2 ], Pd [P (R) 3 ] 4 , PdCl 2 [PR 3 ] 2 etc ...
  • ligands such as acetylacetone, triarylphosphines, l, n-bis (diarylphosphino) alkanes
  • Acac is the acetylacetonate group and R is a ⁇ C 1 _ 6 ) alkyl, aryl or heteroaryl group.
  • aryl group is meant a carbon aromatic nucleus, for example phenyl, naphthyl or anthracenyl
  • heteroaryl group is meant an aromatic heterocycle such as, for example, pyridine or thiophene.
  • the reaction according to the invention can be carried out in a polar aprotic solvent (such as tetrahydrofuran, isopropyl ether, diethoxymethane) or in a mixture of polar solvents as defined above and non-polar solvents such as aromatic hydrocarbons (toluene, l 'heptane etc ).
  • a polar aprotic solvent such as tetrahydrofuran, isopropyl ether, diethoxymethane
  • non-polar solvents such as aromatic hydrocarbons (toluene, l 'heptane etc .
  • the coupling step can be carried out at a temperature between -80 and + 110 ° C.
  • the molar ratio between the compound of formula (VI) and the organometallic compound of formula (V) is between 0.5 and 1.5, preferably between 0.9 and 1.2.
  • the molar ratio between the compound of formula (VI) and the benzyl halide is between 1 and 3, preferably between 1.1 and 1.5 and the molar ratio between magnesium and benzyl halide is between 1 and 5, preferably between 1 and
  • the molar ratio between the compound of formula (VI) and the catalyst can be between lS ⁇ 0 and 30% by weight relative to the compound of formula (VI).
  • the strong acid used during the hydrolysis can be chosen from hydrochloric acid, hydrobromic acid, sulfuric acid, alkanesulfonic acids such as methanesulfonic acid. To a lesser extent, acetic acid can also be used.
  • urea is reacted with diethyl isopropylmalonate (which can be prepared according to conventional methods known to those skilled in the art or which is commercially available), in a solvent of type alcohol, at a temperature which may be between 20 ° C. and the reflux temperature of the solvent, to obtain 5- (1-methylethyl) pyrimidine- 2,4,6 (1H, 3H, 5H) -trione of formula ( VII).
  • This compound of formula (VII) is then reacted with phosphorus oxychloride under the conditions described in J. Badiley et al., J. Chem. Soc, 678 (1944), I. empen et al., J. Med.
  • the crude products can be used in the successive synthesis stages from the stage involving the compound of formula (VII) until the compound of formula (I) is obtained.
  • This last alkylation reaction can be carried out in an aprotic solvent, that is to say either in a halogenated solvent such as dichloromethane, chloroform, chlorobutane, or in a polar solvent such as tetrahydrofuran, diethoxymethane, dioxane ... etc.
  • a halogenated solvent such as dichloromethane, chloroform, chlorobutane
  • a polar solvent such as tetrahydrofuran, diethoxymethane, dioxane ... etc.
  • This alkylation reaction with an alkoxyalkane halide can also be carried out according to the procedure described in patent application O95 / 18109, while in this patent application R is an allyl and propargyl group.
  • This reaction is carried out in polar solvents such as dimethylformamide or dimethylsulfoxide, in the presence of a base such as potassium carbonate.
  • a third subject of the invention therefore consists of a process for the preparation of the compounds of formula (II), starting from the compound of formula (I) prepared according to the new process described above.
  • the reaction medium at the end of the reaction is a thick white suspension, it is brought to dryness by evaporation of methanol under vacuum.
  • the residue is taken up in 1370 ml of water and then filtered after cooling to 20 ° C.
  • the fluid medium obtained is poured onto a two-phase mixture stirred with water (800 ml) and isopropyl ether (1070 ml), controlling the temperature rise so as not to exceed 35 ° C.
  • the upper biphasic organic phase is separated, washed with 270 ml of water, adding sodium hydroxide solution until the pH of the aqueous phase is equal to 7.
  • the organic phase is concentrated under vacuum. and the residue taken up in 530 ml of isopropyl alcohol and water.
  • the mixture is brought to 50 ° C. for dissolution, 400 ml of water are added and the mixture is cooled to 0 ° C.
  • the reaction medium is treated by adding 60 ml of a 9% solution of ammonium chloride, the upper organic phase is separated, washed with an additional 60 ml of a 9% solution. of ammonium chloride, the organic phase evaporates to dryness which is taken up in isopropyl ether and washed successively with a solution diluted to 10% of citric acid, then with water.
  • the product obtained can be crystallized from ethanol as in Example 4. Melting point: 61-63 ° C
  • the fine suspension obtained is carried by mixing 40 g (0.177 mole) of the compound of Example 2, with 200 ml of toluene and 2 g of nickel NiCl 2 catalyst. dppe at 0 ° C. and treated by adding 97.6 ml (0.195 mole) of a 2M benzylmagnesium chloride solution in tetrahydrofuran without exceeding 10 ° C.
  • the reaction medium is treated by adding 120 ml of a 10% solution of ammonium chloride, separating the upper organic phase, washing 10% aqueous ammonium chloride up to discoloration, evaporates the organic phase to dryness under vacuum.
  • Ni (Acac) 2 In a 0.25 liter three-necked Erlenmeyer flask inert with nitrogen, 0.15 g of nickel catalyst with the structural formula Ni (Acac) 2 is added at once to the mixture in solution of 15 g (0.07 mole) of the compound of Example 8, 150 ml of tetrahydrofuran and 34.6 ml (0.07 mole) of a solution of 2M benzylmagnesium chloride in tetrahydrofuran. The medium is brought to ambient temperature and, at the end of the coupling evolution, treated by adding 50 ml of a 10% solution of ammonium chloride.
  • the oily residue is crystallized from a mixture of isopropanol and water to obtain 5.2 g of 1- (ethoxymethyl) -5- (1- methylethyl) -6- (phenylmethyl) pyrimidine-2, 4 (1ff, 3 H) -dione dry.
  • the toluene solution of the previous example is placed with 0.55 g of NiCl 2 -dppe in a 0.5 liter reactor inert with nitrogen and equipped with an ink stirrer.
  • the suspension obtained is brought to 0 ° C and 268.3 g (0.356 mole) of benzylmagnesium chloride 20% w / w in tetrahydrofuran is added thereto without exceeding 5 ° C.
  • reaction medium is treated with a 10% solution of ammonium chloride, then the organic phase is washed successively with 10% solutions of ammonium chloride, then with water until pH neutral.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP99929485A 1998-07-16 1999-07-15 Verfahren zur herstellung von 5-(1-methylethyl) 6-(phenylmethyl)pyrimidin-2,4(1h,3h)-dione Withdrawn EP1097143A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9809085 1998-07-16
FR9809085A FR2781219B1 (fr) 1998-07-16 1998-07-16 Procede pour la preparation de 5-(1-methylethyl)-6-(phenylmethyl)pyrimidine-2,4 (1h, 3h) -dione
PCT/FR1999/001723 WO2000003999A1 (fr) 1998-07-16 1999-07-15 Procede pour la preparation de 5-(1-methylethyl) -6-(phenylmethyl)pyrimidine-2,4(1h,3h)-dione

Publications (1)

Publication Number Publication Date
EP1097143A1 true EP1097143A1 (de) 2001-05-09

Family

ID=9528671

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99929485A Withdrawn EP1097143A1 (de) 1998-07-16 1999-07-15 Verfahren zur herstellung von 5-(1-methylethyl) 6-(phenylmethyl)pyrimidin-2,4(1h,3h)-dione

Country Status (8)

Country Link
US (1) US6452006B1 (de)
EP (1) EP1097143A1 (de)
JP (1) JP2002520400A (de)
KR (1) KR20010092262A (de)
AU (1) AU764168B2 (de)
CA (1) CA2337243A1 (de)
FR (1) FR2781219B1 (de)
WO (1) WO2000003999A1 (de)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU205917B (en) 1989-09-29 1992-07-28 Mitsubishi Chem Ind Process for producing 6-substituted pyrimidine derivatives and antiviral pharmaceutical compositions containing them as active components
FR2676734B1 (fr) 1991-05-23 1995-05-19 Roussel Uclaf Nouveaux derives de la pyrimidine, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0003999A1 *

Also Published As

Publication number Publication date
JP2002520400A (ja) 2002-07-09
CA2337243A1 (en) 2000-01-27
US6452006B1 (en) 2002-09-17
FR2781219B1 (fr) 2000-08-25
WO2000003999A1 (fr) 2000-01-27
AU764168B2 (en) 2003-08-14
AU4628699A (en) 2000-02-07
KR20010092262A (ko) 2001-10-24
FR2781219A1 (fr) 2000-01-21

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