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WO2006126730A1 - Dérivés bicycliques de pyrimidine et procédé de synthèse desdits dérivés - Google Patents

Dérivés bicycliques de pyrimidine et procédé de synthèse desdits dérivés Download PDF

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Publication number
WO2006126730A1
WO2006126730A1 PCT/JP2006/310952 JP2006310952W WO2006126730A1 WO 2006126730 A1 WO2006126730 A1 WO 2006126730A1 JP 2006310952 W JP2006310952 W JP 2006310952W WO 2006126730 A1 WO2006126730 A1 WO 2006126730A1
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Prior art keywords
group
optionally substituted
carbon atoms
alkyl group
hydrogen atom
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PCT/JP2006/310952
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English (en)
Japanese (ja)
Inventor
Daisuke Takahashi
Kunisuke Izawa
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Ajinomoto Co., Inc.
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Publication date
Application filed by Ajinomoto Co., Inc. filed Critical Ajinomoto Co., Inc.
Priority to JP2007517937A priority Critical patent/JPWO2006126730A1/ja
Publication of WO2006126730A1 publication Critical patent/WO2006126730A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a bicyclic pyrimidine compound useful as a synthetic intermediate such as a hepatitis C virus inhibitor and a serine protease inhibitor, and a method for producing the same.
  • Bicyclic pyrimidine compounds represented by the following formula (a) have been reported to be useful as synthetic intermediates such as hepatitis C virus inhibitors, serine protease inhibitors, etc. 8 1 1 6 Panflate and international publication 0 4 0 0 2 4 0 6 pamphlet).
  • C b z represents a benzyloxycarbonyl group.
  • the present invention has been made in view of such circumstances, and the problem to be solved is a novel bicyclic pyrimidine useful as an industrially advantageous production method of a bicyclic pyrimidine compound and an intermediate of a pharmaceutical compound. It is to provide a compound.
  • a bicyclic pyrimidine compound can be industrially advantageously produced by using a pyrroline compound and an oxazolinone compound or a glycine derivative as a starting material.
  • the headline and this effort were completed.
  • the present invention has the following features.
  • R represents a hydrogen atom, an alkyl group or an aralkyl group
  • R 1 represents a hydrogen atom, a substituted or unsubstituted alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group
  • R 2 represents a hydrogen atom, an alkyl group, an aralkyl group or an alkali metal
  • R 3 represents an optionally substituted alkyl group or an optionally substituted aralkyl group
  • * represents an asymmetric group. Indicates carbon, and the wavy line indicates cis, trans, or a mixture thereof.
  • R force A production method according to the above [1], which is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, or an aralkyl group having 7 to 12 carbon atoms.
  • R 1 is a hydrogen atom, an optionally substituted alkyl group having 1 to 7 carbon atoms, an optionally substituted group, an aryl group having 6 to 14 carbon atoms, or an optionally substituted group.
  • R represents a hydrogen atom, an alkyl group or an aralkyl group
  • R 11 represents an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group
  • R 2 represents a hydrogen atom, an alkyl group, an aralkyl group, or an alkali metal
  • R 3 represents an optionally substituted alkyl group or an optionally substituted aralkyl group
  • * represents an asymmetric carbon.
  • the wavy line indicates that it is a cis isomer, a trans isomer or a mixture thereof.
  • R 11 force 'optionally substituted alkyl group having 1 to 7 carbon atoms, optionally substituted aryl group having 6 to 14 carbon atoms, or optionally substituted aralkyl having 7 to 12 carbon atoms
  • R represents a hydrogen atom, an alkyl group or an aralkyl group
  • R 1 represents a hydrogen atom, an alkyl group which may be substituted, an aryl group which may be substituted or an aralkyl group which may be substituted. * Indicates an asymmetric carbon.
  • R 1 is a hydrogen atom, an optionally substituted alkyl group having 1 to 7 carbon atoms, an optionally substituted aryl group having 6 to 14 carbon atoms, or an optionally substituted carbon atom.
  • bicyclic pyrimidine compounds having various substituents can be advantageously produced industrially without using expensive reagents or special production equipment.
  • the production method of the present invention has a great significance in overcoming conventional technical obstacles. That is, in the conventional production method using the Curtius rearrangement, the protective group for the carboxyl group could not be obtained as a bicyclic pyrimidine compound which is a bulky substituent such as tert-butyl. Therefore, a bicyclic pyrimidine compound having a desired substituent can be produced without being limited by the size of the substituent. As a result, the variety of intermediates becomes rich, and pharmaceutical compounds can be produced by various methods. Further, according to the present invention, a bicyclic pyrimidine compound useful as an intermediate of a pharmaceutical compound is provided in the same manner as the compound represented by the formula (a).
  • the alkyl group in R or R 2 is a linear or branched alkyl group having preferably 1 to 10 carbon atoms, more preferably 1 to 7 carbon atoms, and further preferably 1 to 4 carbon atoms.
  • Specific examples include a methinole group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isoptyl group, a sec-butinole group, a tert-butylene group, a pentyl group, a hexyl group, a heptyl group, and an octyl group.
  • R 1 or R 1 1 alkyl group which may be substituted in, a halogen atom (e.g., chlorine atom, bromine atom, fluorine atom), a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (e.g., methoxy group )
  • a halogen atom e.g., chlorine atom, bromine atom, fluorine atom
  • a hydroxyl group e.g., an alkoxy group having 1 to 6 carbon atoms (e.g., methoxy group )
  • the above alkyl group which may be substituted with one or more substituents selected from, for example, a trifluoromethyl group.
  • the aryl group of the optionally substituted aryl group in R 1 or R 11 is an aryl group having preferably 6 to 14 carbon atoms, more preferably 6 to 8 carbon atoms.
  • Specific examples include a phenylol group, a fluorenyl group, a trinole group, a xylinole group, a biphenol-linole group, a naphthinole group, an anthryl group, a phenanthryl group, and the like, among which a phenyl group and a tolyl group are preferable.
  • the optionally substituted aryl group in R 1 or R 11 is a halogen atom (for example, a chlorine atom, a bromine atom, a fluorine atom), a nitro group, a hydroxyl group, or an alkoxy group having 1 to 6 carbon atoms (for example, , A methoxy group), the above aryl group which may be substituted with one or more substituents selected from trifluoromethyl group, etc., for example, o-, 'm- or ⁇ And m- or p-methoxyphenyl group, o-, m- or p-trifluoromethylphenol group, A phenyl group is preferred.
  • the aralkyl group in R or R 2 refers to a monovalent group in which an aryl group is bonded to an alkyl group, and the alkyl group preferably has 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms.
  • the total carbon number of the aralkyl group is preferably 7-12, more preferably 7-9.
  • the optionally substituted aralkyl group in R 1 or R 11 is a halogen atom (eg, a chlorine atom, a bromine atom, a fluorine atom), a hydroxyl group, or an alkoxy group having 1 to 6 carbon atoms (eg, methoxy Group), the above-mentioned aralkyl group which may be substituted with one or more substituents selected from a trifluoromethyl group and the like, for example, the 3rd and 4th or 4th positions of the aromatic ring are chlorine atoms
  • the benzyl group substituted with is enumerated. '
  • Examples of the alkali gold in R 2 include sodium, potassium, and lithium, and sodium and potassium are preferable.
  • the alkyl group which may be substituted in R 3 refers to the same group as the alkyl group which may be substituted in R 1 or R 11 , and examples thereof include an alkyl group having 1 to 6 carbon atoms. Of these, a methinole group and an ethyl group are preferred.
  • the optionally substituted aralkyl group in R 3 refers to the same group as the optionally substituted aralkyl group in R 1 or R 11 , and examples thereof include a benzyl group.
  • R 3 is particularly preferably a methyl group or an ethyl group.
  • a salt with an inorganic base or a salt with an organic base can be used.
  • the salt with an inorganic base include sodium salt salts such as sodium salt and strong salt, ammonium salt and the like.
  • the salt with an organic base include salts with dicyclohexylamine, benzylamine and the like.
  • bicyclic pyrimidine compound (1) is a pyrroline polymer represented by the following general formula (2). Or a salt thereof (hereinafter simply referred to as “pyrroline compound (2) J”) and an oxazolinone compound represented by the following general formula (3) (hereinafter referred to as “oxazolinone compound (3) J”).
  • pyrroline compound (2) J a salt thereof
  • oxazolinone compound (3) J an oxazolinone compound represented by the following general formula (3)
  • the pyrroline compound (2) can be isolated in the form of a stable salt, it can be used as it is in the form of a salt or as a free form.
  • the salt of the pyrroline compound (2) include acid addition salts such as hydrochloride, sulfate, and trifluoroacetate.
  • the acid addition salt of the pyroline compound (2) may be neutralized with a base in a solvent and once converted into a free form, and then reacted with the oxazolinone compound (3).
  • the free form may not be formed once before the reaction, for example, the salt of the pyrroline compound (2) and the oxazolinone compound (3) may be dissolved in a solvent, and the reaction may be performed by adding a base.
  • the base used for neutralization is not particularly limited, and examples thereof include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, sodium methoxide, sodium ethoxide, and the like. Among these, sodium carbonate is preferable.
  • the amount of the base used is not particularly limited as long as it can convert the salt of the pyrroline compound (2) into a free form. Is preferred.
  • the pyrroline compound (2) any of R-form, S-form or a mixture thereof can be used, but if S-form is used, it is useful as a synthetic intermediate such as hepatitis C virus inhibitor.
  • S form of a bicyclic pyrimidine compound (1) can be obtained.
  • the pyrophosphorus compound (2) can be produced according to the description in the above-mentioned International Publication No. 04/002406 pamphlet using pyroglutamic acid as a starting material.
  • any compound having a substituent represented by R 1 and R 2 can be used without particular limitation.
  • R 2 is a hydrogen atom, sodium or ethynole group.
  • a compound is preferred.
  • the oxa / linone compound (3) has a cis isomer or a trans isomer. Any form of those mixtures may be sufficient.
  • (3) can be produced, for example, by the Erlenmeyer method using hippuric acid as a starting material.
  • any solvent that does not inhibit this reaction may be used.
  • acetate esters for example, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate
  • hydrocarbons For example, toluene, benzene, xylene
  • nitriles eg, acetonitrile
  • ethers eg, tetrahydrofuran
  • alcohols eg, ethanol, isopropyl alcohol, n- .
  • Butanol N, N-dimethylformamide, etc., among which nitriles such as acetonitryl are preferable, and these may be used alone or in admixture of two or more.
  • the amount of the oxazolinone compound (3) to be used is generally 0.7-3 equivalents, preferably 0.8-1.3 equivalents, relative to the pyrroline compound (2).
  • the reaction between the pyrroline compound (2) and the oxazolinone compound (3) is usually carried out within the range of the reflux temperature of the solvent used (preferably 60 to 130 ° C).
  • the reaction is usually completed within 2 to 30 hours (preferably 5 to 20 hours) within the above temperature range.
  • Isolation and purification of the bicyclic pyrimidine compound (1) can be performed by a conventional method. For example, after completion of the reaction, the solvent is distilled off, and the residue is washed by adding ethyl acetate and an acidic aqueous solution (for example, hydrochloric acid, sulfuric acid). Next, the organic layer obtained by liquid separation is concentrated and subjected to silica gel chromatography, whereby the bicyclic pyrimidine compound (1) can be isolated. In the case where an inorganic salt is precipitated, the bicyclic pyrimidine compound is obtained by filtering the reaction solution after completion of the reaction and subjecting the residue obtained by concentrating the filtrate to siri-gel gel chromatography. (1) can be isolated.
  • the carboxylic acid of the compound (1) can be obtained, for example, by hydrolysis under acidic conditions.
  • the regioisomer generated as an impurity can be removed by crystallization, filtration, washing, etc.
  • Crystallization solvents include etherols (eg, jetyl ether, tetrahydrofuran), acetone, acetonitrile, hydrocarbons (eg, toluene, benzene, hexane, heptane), halogenated hydrocarbons (eg, dichloromethanone). , Dichloroethane), alcoholones (for example, methanol, ethanol, isopropanol) ', water or a mixed solvent thereof.
  • bicyclic pyrimidine compound (1) is composed of the pyrroline compound (2) and the following formula:
  • glycine derivative (4) It can also be produced by reacting with a glycine derivative represented by (4) (hereinafter referred to as “glycine derivative (4)”).
  • the reaction scheme is shown below.
  • the above reaction is performed in a solvent. Specifically, a solvent is added to the pyrroline compound (2) and the glycine derivative (4), and the mixture is heated and stirred.
  • the order of adding the pyrroline compound (2) and the glycine derivative (4) is not particularly limited.
  • the glycine derivative (4) is preferably in the form of an alkali metal salt. Thereby, the reaction can be performed without neutralizing the acid addition salt of the pyrroline compound (2).
  • the acid addition salt of the pyrroline compound (2) for example, hydrochloride, sulfate, trifluoroacetate and the like can be used.
  • the pyrroline compound (2) is preferably in the S form, and its ester is preferably used.
  • the glycine derivative (4) can be produced, for example, according to the method described in EP 88395.
  • the amount of the pyrroline compound (2) used is usually 0.7 to 3.0 equivalents, preferably 0.8, based on the glycine derivative (4).
  • the reaction temperature is usually 10 ° C to within the range of the reflux temperature of the solvent used (preferably 20 to 80 ° C).
  • the reaction is completed within the above temperature range for 1 to 24 hours (preferably 2 to 8 hours).
  • the solvent used in the above reaction may be any solvent that does not inhibit this reaction.
  • water, alcohols for example, methanol, ethanol, isopropanol
  • acetic acid esters for example, ethyl acetate, isopropyl acetate.
  • the amount of the solvent used is usually 3 to 50 times the weight, preferably 5 to 20 times the weight of the pyrroline compound (2).
  • Isolation and purification of the bicyclic pyrimidine compound (1) can be performed by a conventional method. For example, after completion of the reaction, the solvent is distilled off, and the residue is washed by adding ethyl acetate and an acidic aqueous solution (for example, hydrochloric acid, sulfuric acid). The bicyclic pyrimidine compound (1) can then be isolated by concentrating the organic layer obtained by liquid separation and subjecting it to silica gel chromatography. In addition, in the same manner as described above, crystallization can be performed as necessary to remove impurities. As the crystallization solvent, the same solvents as described above can be used. Further, after isolating the ester of the bicyclic pyrimidine compound (1) in the same manner as described above, for example, hydrolysis / reponic acid of the compound (1) can be obtained by hydrolysis under acidic conditions.
  • an acidic aqueous solution for example, hydrochloric acid, sulfuric acid
  • bicyclic pyrimidine compound (6) a bicyclic pyrimidine compound represented by the following formula (6) or a salt thereof (hereinafter simply referred to as “bicyclic pyrimidine compound (6)”) will be described.
  • the bicyclic pyrimidine compound (6) is produced by reacting a pyrroline compound (2) with a glycine derivative represented by the following general formula (5) (hereinafter referred to as “glycine derivative (5)”). It is characterized by.
  • the reaction scheme is shown below.
  • the above reaction can be carried out by the same method as the above-mentioned production method of the bicyclic pyrimidine compound (1), and isolation and purification can also be carried out by the same method.
  • the group represented by RHOCO include tert-butyloxycarbonyl group (Bo c group), benzyloxycarbonyl group (Cb z group), methoxycarbonyl group (Mo c group) or 9-fluorenyl.
  • a methoxycarbonyl group (Fmo c group) is preferably used.
  • the Dari "sin derivative (5) is prepared by first reacting a glycine compound represented by the formula (I) with tert-butoxybisdimethylaminomethane, dimethylformamide dimethylacetal or dimethylformamide jetylacetal. A dialkylaminomethylene compound represented by the formula (II) is obtained, then treated with an acid, then reacted with an alkali metal compound such as sodium methoxide, and alkylated or aralkylated as necessary. can do.
  • a glycine compound represented by the formula (I) with tert-butoxybisdimethylaminomethane, dimethylformamide dimethylacetal or dimethylformamide jetylacetal.
  • a dialkylaminomethylene compound represented by the formula (II) is obtained, then treated with an acid, then reacted with an alkali metal compound such as sodium methoxide, and alkylated or aralkylated as necessary. can do.
  • X 1 and X 2 each independently represent a methyl group or an ethyl group, and other symbols have the same meanings as described above.
  • bicyclic pyrimidine compounds having various substituents can be advantageously produced in an industrial manner.
  • the bicyclic pyrimidine compound of the present invention
  • (1) can be used as an intermediate for the synthesis of a pharmaceutical compound in the same manner as the compound represented by the formula (a).
  • a bicyclic pyrimidine compound having various substituents useful as an intermediate of a pharmaceutical compound can be advantageously produced industrially without using an expensive reagent or a special production apparatus. It can.
  • This application is based on Japanese Patent Application No. 20 0 5 _ 1 5 4 4 6 6 filed in Japan, the contents of which are incorporated in full herein.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un procédé industriellement avantageux pour la synthèse de dérivés bicycliques de pyrimidine, spécifiquement un procédé de synthèse de dérivés bicycliques de pyrimidine de formule générale (1) ou de sels desdits dérivés, caractérisé par la réaction entre un dérivé de pyrroline de formule générale (2) ou un sel dudit dérivé avec un dérivé d'oxazolinone de formule générale (3) ou un dérivé de glycine de formule générale (4).
PCT/JP2006/310952 2005-05-26 2006-05-25 Dérivés bicycliques de pyrimidine et procédé de synthèse desdits dérivés WO2006126730A1 (fr)

Priority Applications (1)

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JP2007517937A JPWO2006126730A1 (ja) 2005-05-26 2006-05-25 二環式ピリミジン化合物及びその製造方法

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JP2005154466 2005-05-26
JP2005-154466 2005-05-26

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10504285A (ja) * 1994-06-17 1998-04-28 バーテクス ファーマシューティカルズ インコーポレイテッド インターロイキン−１β変換酵素のインヒビター
WO2002048116A2 (fr) * 2000-12-13 2002-06-20 Bristol-Myers Squibb Pharma Company Inhibiteurs de la protease ns3 du virus de l'hepatite c

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10504285A (ja) * 1994-06-17 1998-04-28 バーテクス ファーマシューティカルズ インコーポレイテッド インターロイキン−１β変換酵素のインヒビター
WO2002048116A2 (fr) * 2000-12-13 2002-06-20 Bristol-Myers Squibb Pharma Company Inhibiteurs de la protease ns3 du virus de l'hepatite c

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