WO2002026719A1 - Procede servant a preparer des quinazolines 1-substituees - Google Patents

Procede servant a preparer des quinazolines 1-substituees Download PDF

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Publication number
WO2002026719A1
WO2002026719A1 PCT/JP2001/008076 JP0108076W WO0226719A1 WO 2002026719 A1 WO2002026719 A1 WO 2002026719A1 JP 0108076 W JP0108076 W JP 0108076W WO 0226719 A1 WO0226719 A1 WO 0226719A1
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WO
WIPO (PCT)
Prior art keywords
reaction
salt
added
quinazolines
mixture
Prior art date
Application number
PCT/JP2001/008076
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English (en)
Japanese (ja)
Inventor
Kentaro Kawazoe
Nobuo Takefuji
Masanori Nishiwaki
Hiroyuki Tsuboi
Ryoichi Uematsu
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
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 Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU2001288057A priority Critical patent/AU2001288057A1/en
Publication of WO2002026719A1 publication Critical patent/WO2002026719A1/fr

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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
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms

Definitions

  • the present invention relates to a process for producing a mono-substituted quinazoline (I), an intermediate for producing a 1,3-disubstituted quinazoline useful as an anti-inflammatory agent or a therapeutic agent for diabetic complications.
  • R3 is a hydrogen atom or a halogen atom
  • R 4 is or carboxy group means a protected force Rupokishi group
  • X means an acid residue
  • Q is meant a lower alkylene emissions group ]
  • R 3 , R 4 and Q have the same meanings as above, Qi represents a lower alkylene group, and R5 represents a carboxy group or a protected carboxy group.
  • Qi represents a lower alkylene group
  • R5 represents a carboxy group or a protected carboxy group.
  • R 1 represents a hydrogen atom or a hapogen atom
  • R 2 represents a carboxy group or a protected carboxy group
  • A represents a lower alkylene group
  • lower refers to having from 1 to 6 carbon atoms unless otherwise specified.
  • halogen atom represented by Ri above examples include fluorine, chlorine, bromine and iodine.
  • Examples of the protected carboxy group represented by R2 include esterified carboxyls, for example, lower alkoxycarbonyl (for example, methoxycarboxy / ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, putoxycarbonyl, tert-butoxycarboxy).
  • esterified carboxyls for example, lower alkoxycarbonyl (for example, methoxycarboxy / ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, putoxycarbonyl, tert-butoxycarboxy).
  • Mono (or di- or tri-) phenyl (lower) alkoxycarbonyl which may have a nitro group (for example, benzinoleoxy force / reponinole, 412-trobenzinoleoxycarbinole) , Fuenechi / Reoki aryloxycarbonyl, benzhydryl Ruo alkoxycarbonyl, trityl O alkoxycarbonyl, etc.) and the like, preferred among these are C i ⁇ C 4 alkoxycarbonyl two Le, most preferred are the ethoxycarbonyl .
  • the lower alkylene group represented by A is, for example, a linear or branched chain such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methynolemethylene, ethylethylene, and propylene.
  • a linear or branched chain such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methynolemethylene, ethylethylene, and propylene.
  • C i ⁇ alkylene groups preferred is methylene or methylmethylene.
  • Examples of the salt of the mono-substituted quinazoline (I) obtained in the present invention include, for example, alkali metal salts such as lithium salt, sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; Salts with inorganic bases such as ammonium salts, etc.
  • Salts with bases such as salts with organic bases such as liethylamine salt, pyridine salt, picoline salt, ethanolamine salt, dicyclohexylamine salt, N, ⁇ '-dibenzylethylenediamine salt, hydrochloride, bromide Salts with inorganic acids such as hydrates, sulfates, phosphates, etc., Formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, toluenesulfonates, etc. Salts with acids such as salts with organic acids and the like can be mentioned.
  • silylated derivatives of quinazolines (II) can be obtained by reacting quinazolines (II) with a silylating agent in the presence of a catalytic amount of sulfuric acid.
  • the reaction temperature of the siliridani reaction is not particularly limited, it is usually carried out at a temperature ranging from room temperature to the reflux temperature of the solvent.
  • Examples of the silinolelating agent include hexamethyldisilazane, trimethylchlorosilane, ⁇ , ⁇ -bis (trimethylsilyl) acetamide, hexamethyldisiloxane, ⁇ -trimethylsilylacetamide, and ⁇ -methyl-1-trimethylsilylacetate.
  • Examples include amide, ⁇ -trimethylsilyldimethylamine, ⁇ -trimethylsilylethylamine, ⁇ -trimethylsilyl tert-butylamine, and N-trimethylsilylimidazole.
  • the amount of the silylating agent is preferably 0.6 to 1.0 equivalent, more preferably 0.7 to 0.9 equivalent, per equivalent of the silylated derivative of the quinazoline (II).
  • Examples of the solvent used for the silylation reaction include conventional solvents that do not adversely affect the reaction.
  • Specific examples include aromatic hydrocarbons such as benzene, xylene, and toluene, ethers such as tetrahydrofuran and dioxane, and dichloromethane.
  • Halogenated hydrocarbons such as benzene, o-dichlorobenzene, and benzene, and esters such as ethyl acetate, methyl acetate, and chloroethyl acetate can be used. Of these, toluene is most preferred.
  • These solvents may be used alone or in combination of two or more.
  • Salts of chloroalkanoic acids (III) and corresponding salts of promoalkanoic acids (IV) include salts with bases as exemplified for the salts of 1-substituted quinazolines (I).
  • chloroalnic acid (III) and the corresponding promoalkanoic acid (IV) to be reacted with the silylated derivative of quinazoline (II) are not particularly limited. ⁇ One equivalent of the silylido derivative of quinazoline (II)
  • chloroalkanoic acids (III) are preferably 0.8 to: L. 5 equivalents, more preferably 1.0 to 1.2 equivalents
  • the corresponding promoalkanoic acids (IV) are preferably 0.05 to 0 equivalents. It is used in an amount of 0.4 equivalent, more preferably 0.1 to 0.3 equivalent.
  • Examples of the solvent used in the method of the present invention include conventional solvents that do not adversely affect the reaction, and solvents having a large relative permittivity (preferably having a relative permittivity ⁇ of 5 or more) (specifically, ⁇ —Dichlorobenzene, nitrobenzene, 'propylene carbonate, etc.) are preferred, of which propylene carbonate is most preferred. These solvents may be used alone or in combination of two or more.
  • reaction temperature of the present invention is not particularly limited, it is usually preferable to heat or heat it.
  • the reaction is preferably carried out at about 80 ° C or higher, more preferably at about 90 to 160 ° C, most preferably at about 100 to 150 ° C.
  • Low-boiling substances present in the reaction mixture according to the invention are removed during the reaction.
  • Methods for removing low-boiling substances include evaporation under normal pressure or reduced pressure, and evaporation under a nitrogen stream.
  • the removal of low-boiling substances may be carried out continuously throughout the reaction, or may be carried out intermittently by suspending the reaction. It is presumed that the low-boiling substances removed are compounds derived from silylating agents such as ichtrimethylsilyl salt. If this low-boiling substance is present in the reaction mixture, it is considered that the boiling point of the reaction system as a whole decreases, leading to a decrease in the yield of the mono-substituted quinazolines (I) or an increase in the reaction time.
  • the desilylation reaction of a silylated derivative of a 1-substituted quinazoline (I) or a salt thereof is carried out by a conventional method such as hydrolysis, alcoholysis, etc., and the mono-substituted quinazoline (I) or a salt thereof is used. can get.
  • the mono-substituted quinazolines (I) or salts thereof obtained as described above can be used, for example, as the final target 1,3-disubstituted quinazolines or salts thereof by the method described in JP-A-64-25767. It is led to.
  • Example 1 During the reaction, the same operation as in Example 1 was carried out except that the generated low-boiling substances were not removed, and the mixture was heated under reflux for 18 hours. Table 1 shows the yield, yield, and purity of the obtained 2_ (7-chloro-1,2,3,4-tetrahydroquinazoline-1-yl-2,4-dione) ethyl acetate. T / C / 08076
  • the present invention was carried out by a two-step reaction in which the low-boiling substances formed in the reaction mixture were removed during the reaction and a catalytic amount of a promoalkanoic acid or a salt thereof was added.
  • a higher conversion rate of quinazolines (II) to 1-substituted quinazoline bodies 0 (I) could be achieved in a shorter time than in Comparative Examples in which the removal of low-boiling substances and the two-step reaction were not performed.
  • Example 7 The same operation as in Example 7 was performed, except that the amount of ortho-dichlorobenzene (o-DCB) was changed as shown in Table 2.
  • o-DCB ortho-dichlorobenzene
  • Table 2 The ratio of the added amount of ethyl acetate bromoacetate added to the first and second times (and sometimes the third time), the ratio of the added amount of ethyl acetoacetate added to the first and second times, and the reflux heating time before and after removal.
  • the same operation as in Example 7 was performed, except that the conditions were changed as shown in Table 2. 108076
  • Example 8 and 10 the generated low-boiling substances were instead removed under reduced pressure to remove low-boiling substances in a stream of N 2.
  • Example 10 to 15 120 to 150 ° C. was used as the reflux heating temperature.
  • Table 2 shows the conversion rate to ethyl acetate. Comparative Examples 3-4
  • Example 7 The same operation as in Example 7 was performed without removing the low-boiling substances generated during the reaction.
  • Table 2 shows the conversion of the obtained 2- (7-chloro-1,1,2,3,4-tetrahydroquinazoline-1-yl-2,4-dione) ethyl acetate.
  • the method of the present invention uses inexpensive chloroalkanoic acids as the main raw material, completes the reaction in a short time, and stably achieves high yields of anti-inflammatory drugs or diabetic complications.
  • An intermediate for producing 1,3-disubstituted quinazolines useful as an agent, a method for efficiently producing mono-substituted quinazolines (I) or a salt thereof is provided.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé servant à préparer des quinazolines 1-substituées (I) ou leurs sels au moyen de la réaction d'un dérivé silylé d'une quinazoline (II) avec un chloroalcane (III) ou un de ses sels en présence d'une quantité catalytique du bromoalcane correspondant (IV) ou d'un de ses sels. Cette réaction est exécutée en deux étapes dont la première consiste en la réaction elle-même, pendant laquelle on supprime les substances à point d'ébullition bas, puis on ajoute une quantité catalytique de bromoalcane (IV) ou un de ses sels au mélange réactionnel et on effectue la désilylation du produit obtenu. Ce procédé permet d'exécuter la réaction en un temps limité et de préparer des quinazolines 1-substituées (I) à partir de chloroalcanes économiques utilisés comme matière première principale selon une productivité et une efficacité élevées.
PCT/JP2001/008076 2000-09-26 2001-09-17 Procede servant a preparer des quinazolines 1-substituees WO2002026719A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001288057A AU2001288057A1 (en) 2000-09-26 2001-09-17 Process for the preparation of 1-substituted quinazolines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000292336 2000-09-26
JP2000-292336 2000-09-26

Publications (1)

Publication Number Publication Date
WO2002026719A1 true WO2002026719A1 (fr) 2002-04-04

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PCT/JP2001/008076 WO2002026719A1 (fr) 2000-09-26 2001-09-17 Procede servant a preparer des quinazolines 1-substituees

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AU (1) AU2001288057A1 (fr)
WO (1) WO2002026719A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998041514A1 (fr) * 1997-03-17 1998-09-24 Fujisawa Pharmaceutical Co., Ltd. Procede de production de derives de quinazoline

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998041514A1 (fr) * 1997-03-17 1998-09-24 Fujisawa Pharmaceutical Co., Ltd. Procede de production de derives de quinazoline

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