WO1987000527A1 - Composes antibacteriens, leur utilisation et procede de preparation - Google Patents

Composes antibacteriens, leur utilisation et procede de preparation Download PDF

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Publication number
WO1987000527A1
WO1987000527A1 PCT/JP1985/000394 JP8500394W WO8700527A1 WO 1987000527 A1 WO1987000527 A1 WO 1987000527A1 JP 8500394 W JP8500394 W JP 8500394W WO 8700527 A1 WO8700527 A1 WO 8700527A1
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Prior art keywords
compound
group
hydrogen
reaction
formula
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PCT/JP1985/000394
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English (en)
Japanese (ja)
Inventor
Hideaki Natsugari
Yasuhiko Kawano
Akira Morimoto
Kouichi Yoshioka
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Takeda Chemical Industries, Ltd.
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Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to PCT/JP1985/000394 priority Critical patent/WO1987000527A1/fr
Priority to AT86302819T priority patent/ATE80163T1/de
Priority to EP86302819A priority patent/EP0219923B1/fr
Priority to DE8686302819T priority patent/DE3686632T2/de
Priority to HU861788A priority patent/HU197742B/hu
Priority to DK195986A priority patent/DK195986A/da
Priority to KR1019860003319A priority patent/KR930005174B1/ko
Priority to CA000507875A priority patent/CA1285950C/fr
Priority to ES554495A priority patent/ES8802317A1/es
Priority to US06/857,834 priority patent/US4851422A/en
Priority to CN198686102923A priority patent/CN86102923A/zh
Publication of WO1987000527A1 publication Critical patent/WO1987000527A1/fr
Priority to ES557661A priority patent/ES8801650A1/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • Antimicrobial compounds their uses and their production methods, technical fields
  • the present invention relates to a novel 2- (4-substituted amino-3,5-oxo-2, -isoxazolidinyl) -1-5-oxo1-2-te-h.
  • TAN-5 8 8 A new antibiotic, which has antibacterial activity against a new bacterial species belonging to the genus Pseudorhizobacteria, a gram-positive bacterium and a gram-negative bacterium recently isolated from soil. 5 8 8 (hereinafter sometimes abbreviated as “TAN-5 8 8”) was found. ' ⁇
  • the antibiotic TAN-588 a 3-oxoisoxazolidin ring with a nitrogen atom bonded to 5-oxo-iso-2-tetrahydrofuran-carponic acid. ⁇ Has a completely new skeleton. Thus, when a derivative of TAN-58815 was synthesized, it was found that the derivative had excellent antibacterial activity and could be used as an antibacterial agent.
  • the inventors of the present invention further added the time of examination, and found that they have 25 substituents at the 5-position of the 3-oxosoxazolidin ring, the 3- and 4-positions of the 5-oxotetrahydrofuran ring, and the like.
  • a method that can be manufactured chemically has been found.
  • the inventors have found that the compound obtained by this method has an excellent antibacterial activity, and as a result of further research, completed the present invention.
  • the present invention relates to (1)
  • R 1 represents an amino residue or an organic residue via nitrogen.
  • R 2 represents a carboxyl group or a group derivable therefrom.
  • R 3 , R 4 , R 5 , R 8 , R 7, R 8 are the same or different and each represent hydrogen or an organic residue, and R 5 ⁇ is R 6 and R 7 ⁇ R 8 includes a bond forming a chemical bond.
  • X represents hydrogen, methoxy or formylamino.
  • R 3, R, R 5 , R 6, R 7 Oyopi R 8 is Nai simultaneously hydrogen. Or a salt thereof,
  • R 5 , R 8 , R 7 and R 8 are as defined above.
  • 11 5 , 11 6 , 11 7 and 11 8 include hydrogen at the same time. And reacting with a compound represented by the formula (1) or a reactive derivative thereof, and subjecting the compound, if necessary, to a conversion reaction of R compound and / or 'R 2 '.
  • RR 2, R 3, R +, R 5, Il s .R 7 Oyobi R 8 is that having a as defined above. This includes the case where R 3 , R + , R 5 , R e , R 7 and R 8 are simultaneously hydrogen.
  • R 2 ′, 0 5 [wherein, Y represents a leaving group.
  • R 2 ′, R 5 , R S , R 7 and R 8 have the same meaning as described above. This includes the case where R 5 , R 8 , R 7 and R 8 are simultaneously hydrogen.
  • R 2 ′, R 5 .R 6 , R 7 and R 8 have the same meaning as described above.
  • R 5 , R e , and R 7 include the case where R 8 is simultaneously hydrogen.
  • R 2 ′ is not ethoxycarbonyl.
  • R 1 is an example of an organic residue via nitrogen represented by R 1 ′, for example, phenylamino, alkamino substituted by carbon, alkenylamino, thioamino, silylamino. , Phosphinoamino, and groups represented by the formula —CO—C 0 —NH—.
  • acyl used in the above acylamino examples include an acyl group obtained by substituting the amino group at the 6-position of a conventionally known penicillin derivative and an amino group substituted at the 7-position of a cephalosporin derivative. And the like.
  • acylamino group examples include, for example,
  • R 13 is hydrogen, alkyl 3 ⁇ (in the description of each group in this specification, The attached group indicates a case where the group has a substituent. ), Alkenyl 58 , cycloalkyl « ⁇ , aralkyl ⁇ heterocycle, alkoxy ⁇ aralkyloxy «, R represents hydrogen, aralkyl *, acyl ', and R 13 forms a ring with R ".
  • R 18 represents an alkyl ⁇ ', an aryl *, a cycloalkenyl or a heterocyclic ring', respectively.
  • R 18 is a formula R 2 . - C in one ⁇ formula, R 2.
  • R 21 is hydrogen, aralkyl *, alkenyl *, arylcarbonyl, cycloalkyl, heterocycle * or the formula R 22 — R 23 (wherein R 22 is aralkylene, cycloalkylene or arkenylene, R 23 Represents aryl, carboxy, or its ester, or mono- or dialkyl amide, respectively.
  • R 19 is a chemical bond or a compound represented by the formula —C 0 —NH—C ⁇ — (formula
  • R 2 represents alkyl 5 ⁇ , aryl 5 * or a heterocyclic ring.
  • the groups represented by parentheses) are shown respectively.
  • R 25 represents aryl, heterocycle 58 or cycloalkenyl
  • R 28 represents hydroxy, carboxy ⁇ , sulfamoyl, sulfo, sulfoxy, aryloxycarbonyl ⁇ 'or acyloxy «, respectively.
  • R 27 -R 28 -CH 2 -C O-H- [wherein, R 27 is alkyl, ⁇ ,, cyano, aryl, ⁇ ,, aryloxy 5 , alkenylene J heterocycle *, aramino * or R 27 ′ — C ( S) — (wherein, R 27 ′ represents alkoxy.), And R 28 represents a chemical compound or —S—.
  • R 29 ⁇ R 3 Represents the same or different and represents hydrogen, aralkyl *, aryl 58 , heterocycle, cycloalkyl, and ⁇ ⁇ represents 0 or S, respectively. ], Respectively.
  • R 1 is an example of an amino group substituted via a carbon atom as an example of an organic residue via a nitrogen represented by R.
  • R 31 represents alkir *, aryl ⁇ 1 ⁇ , alkenyl 58 or heterocycle 5 *.
  • R 32 and R 33 are the same or different and represent alkyl *, aryl 5 ⁇ , and alkenyl *, respectively, wherein R 32 and R 33 form a heterocyclic ring with an adjacent nitrogen atom. A group represented by].
  • R 34 , R 35 and R 36 are the same or different, and represent alkyl 5 ⁇ , aryl *, and alkenyl *, respectively, and R 34 and R 35 are both R 36 This includes the case where a heterocyclic ring is formed together with an adjacent nitrogen atom.
  • R 37 and R 38 are the same or different and represent hydrogen, alkyl 5 ⁇ , aryl «cycloalkyl, amino or heterocycle ⁇ R 37 and R 38 Form a cycloalkyl * or heterocycle 5 * with an adjacent carbon atom. ].
  • R 1 is an example of an organic residue via nitrogen represented by R.
  • thioamino As an example of thioamino,
  • R 1 is an example of silylamino as an example of an organic residue via nitrogen represented by R 1 ′.
  • R ′ 1 is an example of an amino acid phosphate as an example of an organic residue via nitrogen represented by R 1 ′.
  • R "and R +5 are the same or different and represent an alkyl * .aryl 56 , an alkoxy 55 or an aryloxy ⁇ ', and R ++ and R +5 represent a heterocyclic ring And a group represented by the following formula:
  • R 1 is preferably an organic residue via nitrogen represented by R, for example, one having a molecular weight of up to 500.
  • R 2 is an example of a group that can be derived from a carboxyl group represented by
  • R 7 represents alkaryl 3 *, alkenyl 85 , aryl * .cycloalkyl, heterocycle or silyl.
  • R + e and R * a are the same or different and represent hydrogen.
  • Aralkyl, aryl *, cycloalkyl «, alkenyl or heterocycle *, and R 8 and R 49 are adjacent This includes the case where a heterocycle * is formed together with the nitrogen atom.
  • the group which can be derived from the carboxyl group represented by R 2 is preferably, for example, one having a molecular weight of up to 500.
  • Alkyl in the group in the above formula is preferably, for example, one having 1 to 6 carbon atoms, such as methyl, ethyl, ⁇ -propyl, isopropyl, ⁇ -butyl, isobuti. 1, sec-butyl, t-butyl. 1, 1-Dimethylpropyl, n-pentyl, isopentyl, n-hexyl, isohexyl and the like.
  • substituents which the alkyl group has include, for example, halogen, nitro, and amino (which may have an alkyl, alkenyl, cycloalkyl, or aryl as a substituent), Sulfo, cyano, hydroxy, carboxy, cycloalkyl, alkoxy (amino, hydroxy, carboxynologen, aryl, cycloalkyl, alkoxy may be substituted), aryl (halogen, halogen) Arkir, Arkoxy, Arkiramino, Arkir Mino, carbamoyl, sulfo, aralkylsulfonyl, cyano, hydroxy, ka
  • Heterocyclic aryloxy Heterocycles (nitro, oxo, aryl, arke)
  • Aminosulfonyl Alkylsulfinyl, Arylsulfonyl, Alkyls
  • heterocycle cyano, hydroxy, amino, alkamino, alkyne
  • Aryl carbonyl (Asiloxy nitrogen, Amino, Hydroxy, Al
  • the cycloalkyl in the group in the above formula is preferably a cycloalkyl having 3 to 8 carbon atoms which forms a ring, for example, cyclopropyl, cyclobutyl, cyclopentyl. . Cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • Examples of the substituent which the cycloalkyl group has include, for example, halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, oxo and the like.
  • Examples of the cycloalkylene in the group in the above formula include those in which the above cycloalkyl further has a strong bond.
  • aryl (ary 1), arylcarbonyl, aryloxycarbonyl), aryloxy or aryloxy in the above formula include, for example, phenyl, naphthyl, biphenyl, biphenyl, anthril, and inyl. Denenyl and the like.
  • the aryl group may have a substituent such as halogen.
  • 1 Alkoxy in the above formula is preferably one having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, ⁇ -pentyloxy, ⁇ -hexyloxy and the like.
  • substituents possessed by the alkoxy group include, for example, halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, aryl (nitro, amino, hydroxy, aralkyloxy). :), and silyl (alkyl, aryl, and aralkyl may be used as substituents).
  • the alkirchio in the group in the above formula is preferably one having 1 to 6 carbon atoms, such as methylthio, ethylthio, ⁇ -propylthio, i-propylthio, n-butylthio, i- Spotted Retio, ⁇ -pentylcho, ⁇ -hexylcho, etc.
  • substituent having an aralkyl group include the same substituents as those described above for the alkoxy.
  • the alkenyl in the group in the above formula is preferably an alkenylene having, for example, 1 to 4 carbon atoms, such as, for example, methylene, vinyl, allyl, Isoprolidone, 1-propenyl, 2-butenyl, 1,3-butadenyl, ethylidene, isopropylidene, propylenylene,
  • substituents which the alkenyl group has include, for example, halogen, nitro, amino (which may have acryl as a substituent :), sulfo, cyano, and hydroxy. , Carboxy, carbamoyl, sulfamoyl, aryl (ary L), and acyl.
  • the heterocyclic ring represented by the group in the above formula contains, for example, one sulfur atom, nitrogen atom or oxygen atom as a heterocyclic ring formed by these groups. ⁇ 13—
  • 5- to 7-membered heterocyclic group 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms. 1 to 2 nitrogen atoms and 5- or 6-membered heteroatom containing one sulfur or oxygen atom
  • These heterocyclic groups may be fused with a 6-membered ring group containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring group containing one sulfur atom.
  • heterocyclic group examples include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, thiazolyl, isotizazolyl.
  • Reel (halogen, nitro, alkir, alkoxy, amino, sulfo, hydro It has xy and cyano as substituents. :!, Oxo, thioxo, amino acid residue-thio (Examples of amino acid residues include those similar to those described below. :), C. Alkyl-thiol [arylalkyl, amino, hydroxy, carboxy, alkoxy, alkyrsul "honifre, dialkylamino, phosphoric acid (substituted with alkyl as a substituent). Yes City be Yoi.], heterocyclic (Arukiru, Arukokishino, androgenic, nitro.
  • examples of the acyl represented by R 1 * include, for example, phthaloyl, succinyl, maleol, citraconyl, glutaryl, adipoyl and the like which are cyclic with R 13 .
  • substituent which the acyl group may have include, for example, halogen, nitroamino, hydroxy, sulfo, cyano, carboxy and the like.
  • the acyl group in the acyloxy group and the acyl group in R 3 -8 ' 1 °' 11 are, for example, preferably those having 1 to 4 carbon atoms.
  • Examples include formyl, acetyl. Propionyl, butyryl, isobutyryl, and the like, and the substituents include, for example, aralkyl (amino, halogen, cyano, alkoxy. Carboxy, and hydroxy as substituents). ).
  • the amino acid residue represented by R 15 may be, for example, glycyl, aranyl nokril, roysyl, isoloicyl, seryl, threonyl, cystinyl, cistyl, methionyl, ⁇ - or approximately / 3-asparagyl. ⁇ - or ⁇ -glutamyl, lysyl, arginyl, phenylaralanyl, phenylglycyl, -15-Tyrosyl, histidyl, tryptophanyl, prolyl and the like.
  • substituents possessed by the amino acid residue include, for example, halogen, hydroxy, sulfo, carboxy, cyano, alkarylamino, aralkyloxycarbonyl, aralkyloxy, guanidino and the like.
  • protecting group for the amino group represented by R 15 for example, those used for this purpose in the field of 8-lactam peptide synthesis are conveniently employed.
  • Aromatic acyl groups such as phthaloyl, 4-nitrobenzoyl, 4-tert-butylbenzoyl, 4-tert-butylbenzenesulfonyl, benzenesulfonyl, and toluenesulfonyl;
  • Aliphatic acyl groups such as cetyl, propionyl, dichloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, trifluoroacetyl, malonyl, succinyl, etc., for example, methoxycarbonyl, ethoxy Carbonyl, t-nibutoxycarbonyl, isopropoxycarbonyl, 2-cyanoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, Esterified carboxyl groups such as diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, etc.
  • Kisaki draw 1 H Methylene groups such as azepin-1-yl) methylene; sulfonyl groups such as 2-amino-2-carboxyethylsulfonyl; and, for example, trityl, 2-nitrophenylylthio, benzylidene, 4-nitrobenzylidene, di- or tri-methyl.
  • Protecting groups for amino groups other than acyl groups such as alkenylsilyl benzyl and 4-nitrobenzyl. The choice of the protecting group is particularly important in the present invention. Although not limited, in particular, monochloroacetyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzene [Roxycarbonyl is preferred.
  • the consequent Arukeniru is Table pictmap in R 1 8 '2 5, another a tut if cyclohexene consequent sigma, Kisajen cyclohexane, heptene cyclohexane, cyclo Bae integrators down, Shikurookuten the like.
  • substituent on the carboxy group having the substituent in the above-mentioned formula include, for example, aralkyl (having halogen, cyano, or hydroxy as the substituent).
  • Aryl (aralkyl.alkoxy, halogen, hydroxy, acyloxy, sulfo, cyano, sulfa.yl) as substituents :), silyl (aralkyl, Aryl, aralkyl may be substituted as a substituent. :), and heterocyclic ring (amino, aralkylamino, sulfamoyl. Carbamoylnoperogen, cyano.nitro) may be substituted. ), Amino (aralkyl, aryl, cycloalkyl, sulfo, or aralkyl) as a substituent. Also, a nitrogen atom in the amino group may be substituted with a 5- to 6-membered heterocyclic ring. May form ) And the like behavior up.
  • Substituents in the above formula which have substituents in the above groups include, for example, amidine, iminomethyl, imino (aryl) Substitution) Methyl guanidyl carbonyl, heterocycle (having the same substitution * as the above-mentioned heterocycle), imino (heterocycle-substituted) methyl, aralkylcarbonyl, arylcarbonyl, Droxylkill. '
  • Substituents in the silyl group having a substituent in the above formula include, for example, aralkyl, aryl, aralkyl and the like.
  • R 13 and R 1 + form a cyclic group, for example, 2,2-dimethyl-5-oxo-4—phenylimidazazolidin And the like.
  • R * °, R 4 1, R 4 2 are also form a R + 3 and cyclic groups consentration, Hatateba as its example, 2, and 5-disilyl ⁇
  • the cycloalkyl pentyl is These may have substituents such as aralkyl and aryl. Examples of the halogen in the description of the above substituent include chlorine, bromine, fluorine and iodine.
  • Alkyl in the description of the above substituents preferably has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and 1 to 4 carbon atoms.
  • methyl, ethyl, n Provided by Alkyl, a Chemical Vapor, a Chemical Vapor, a Chemical Vapor, a Chemical Vapor, a Chemical Vapor, a Chemical Vapor, a Chemical Vapor, methyl, ethyl, n —Propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, heptyl, octyl, nonyl, Decyl and the like.
  • cycloalkyl those having 3 to 6 carbon atoms are preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Alkoxy as the above substituent is preferably one having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, i-butoxy, n-butoxy, i-butoxy, t Butoxy and the like.
  • aryl as the substituent include, for example, phenyl, naphthyl and the like.
  • heterocyclic ring as the substituent examples include those similar to the above-described heterocyclic ring.
  • acyl as the above substituent, those having 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms are preferable, and examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl phenol, isovaleryl, pivaloyl, and hexanoyl.
  • Examples of the above aralkyl as a substituent include benzyl and phenyl. [R, phenyl-propyl and the like.
  • the alkenyl as the substituent may be the same as the alkenenyl as the alkenylene.
  • Examples of the 5- or 6-membered complex ring formed together with the nitrogen in the amino group as the substituent include, for example, pyrididine, virolidine, imidazolidine, perolin, piperazine and the like.
  • the number of substituents in each of the above groups is preferably 1 to 3.
  • amino group examples include, for example, 3- (2,6-dichlorophenyl) -5-methylisoxazoyl 4-ylcarbonylamino, 4-ethyl-23-dioxo.1-piradizino Carbonylamino, 3-phenyl-5-methylisoxazole-4-ylcarbonylamino, 3- (2-chlorophenyl) -5-methylisoxazolu-4-ylcarbonylamino, 3- (2-chloro-6-fluorophenyl) -5-methylisoxazol-4-ylcarbonylamino, nicotinylamino, benzoylamino, 4-bromobenzylamino, 2,6-dimethoxybenzoylamino, formylamino, acetylamino, Propionylamino, butyrylamino, isobutyrylamino, pivaloylamino, methoxycarbonylamino, benzene
  • Examples include D-alanylamino.
  • Benzyl N “—carbobenzoxy 7-D-glutamiru D-araranamino, D-phenylglycirol D-araranylamino, N-carbobenzoxy-D— N-Carbobenzoxy-D-Phenylglycylamino, D-Aranilhu D-Phenylglycylamino, A-D-Glutamyl-D-Aranylamino, 2- (4-Ethyru-2 , 3-dioxo-1-perazinocarboxamido)-2-phenylacetylamino, 2-(4-cyclohexyl-2, ⁇ 3-dioxo-1-perazinocarboxamide)-1-2-phenylacetylamido Bruno, 2- (4 one Echiru one 2.3- Jiokiso one 1 over pin piperazino carbonitrile Kisami de) Single 2- (4-sulphoxide phen
  • a specific example of the acylamino group represented by the formula R 18 — R 13 — C 0 — NH— is, for example, N— [2 -— (2-amino-4-thiazolyl) -1 2— Methoxyminoacetyl] —D—alanilamino, ⁇ — “2— (2—amino4 -Thiazolyl ') -1 2-Methoxyiminoacetyl]-D-Phenylglycylamino, 2- (2-Amino-4-thiazolyl) -1 2- [2- (2-Aminothiazolyl ⁇ )-2 —Methoxyiminoacetamido] acetylamino, 2— (2-chloroacetamido-4-thiazolyl) -1-2 methoxymininoacetylamine, 2 -— (2-amino-4-thiazolyl) -1-2-methoxyminoacetylami No, 2- (2-a
  • acylamino group represented by the formula R 27 — R 28 — CH 2 —C 0 —NH— examples include, for example, cyanoacetamino, phenylacetylamino, and phenoxyacetylamino.
  • Trifluoromethylthioacetyla Mino Trifluoromethylthioacetyla Mino, cyanomethylthiocetylamino, difluo ⁇ methylthioacetylamino, 1 ⁇ -tetrazolyl-1-acetylamino, chenylacetylamino, 2- (2-amino4-1thiazolyl ) Acetylamino, 4-pyridylthioacetylamino, 2-Chenylthioacetylamic, 3,5-dichloro-1,4-dihydro 4-oxopyridin-1-acetylamino, ⁇ -Carboxyvinylthioacetylamino No, 2- (2-aminomethylphenyl) acetylamino, 2-chloroacetylamino, 3-aminopropionylamino, (2-amino-2-carboxy) ethylthio Cetylamino, 4-amino-3, hydroxy
  • carbamoylamino methylaminocarbonylamino, ethylaminocarbonylamino, t-butylaminocarbonylamino, isobutylaminocarbonylamino, dimethylaminocarbonylamino, 2-methylphenylaminocarbonyl, 2-methylphenylaminoaminocarbonyl , 3-chlorophenylamino carbonylamino, 41-nitrophenylamino carbonylamino, 4-bromophenylaminocarbonylamino, thiocarbamoylamino, methylaminothiocarbonylamino, ethylaminotin Carbonylamino, phenylaminothiocarbonylamino, dimethylaminocarbonylamino, and 3-fluoroaminocarbonylamino.
  • R 3 1 Examples of groups NH- Table pictmap, Teba Mechirua; Mino, Echiruamino, Ariruamino, Kishiruamino cyclohexane, xylene Rumechiruamino cyclohexane, base Njiruamino, 4 Kuro port base Njiruamino, phenyl Amino , 2-imidazolylamino, 1-methyl-2-imidazolylamino, 2- (2-aminobutyralyl) -2- (methyximinothioacetylamino), 1-benzoylamine, 4-pyridinylamino Mino, 2-acetyl-1r-methylvinylamino and the like.
  • alkamino group represented by the formula ( 3 )>! ⁇ 1- include, for example, dimethylamino, getylamino, dipropylamino, dibenzylamino, dicyclohexylamino, N-benzyl. N-methylamino, diarylamino, N-phenyl-N-methylamino, pyrrolidinyl, pyridinyl, piperazinyl, morpholinyl and the like.
  • dimethylaminomethyleneamino 1-dimethylaminoethylideneamino, hexahydro 1H-azepin-1-ylmethyleneamino And 1,1- (N-benzyl-1N-methylamino): ethylideneamino, 4-dimethylaminobenzylideneamino, (P-nitro) benzylideneamino, benzylidylideamino, and the like.
  • thioamino group represented by the formula R 3 a — SO n — NH— include, for example, benzenesulfonylamino, 4-methylbenzenesulfonylamino, and 4-methoxybenzenesulfonylamina.
  • silylamino groups represented by N— include, for example, trimethylsilylamino, triethylsilylamino, t-butyldimethylsilylamino, and t-butyldiphenylsilylamino.
  • R * 5 examples include dimethylaminophosphate, aminoethylethylamine, aminoaminodiphenylphosphate, aminoaminedibenzylphosphate, aminoaminodi-4-chlorophenylphosphate, and the like. '
  • R * e —C 0— C 0—NH— examples include, for example, methoxalylamino, ethoxylylamino, phenoxalylamino, benzyloxalylamino , Pilvoylamino, etyloxalylamino, oxilylamino, benzylaminooxalylamino, chenyloxilarylamino, 2-amino 4- thiazolyluoxalylamino, ethylaminoxolylamino Mino and the like.
  • Specific examples of the group represented by the formula —C 0 R 47 include, for example, methylester, ethylester, ⁇ -propylester, isopropylester, t-butylester, t-amylester, benzylester, 4 '-Brobenzylbenzene, 4-Nitrobenzylester, 2-Nitrobenzylester.
  • 3.5-Dinitrobenzylester 4-Methoxybenzylester, Benzhydrylester, Fenacilester, 4-Brofenenacilester, Phenylester Methoxymethylester, methoxymethylester, methoxymethylester, ethoxymethylester, benzyloxymethylester, acetoxymethylester, piperoyloxymethylester, 2-methyl Sulfonyluchester, 2-tri Tylsilylester, methylthiomethylester.
  • Tritylester 2,2,2-trichloroethylester, 2-dodoethylester, cyclohexylester, cyclopentylester, Arylester, cinnamylle Stell, 41-picolylester, 2-tetrahydropyranylester, 2-tetrahydrofuranylester, trimethylsilylester, t-butyldimethylsilylester, t-butyldiphenylsilylester.acetylmethylester, 4-nitrobenzyl Nzylmethyle Stel, 4-methylsilvenzylmethylester, phthalimidmethylester, sigma-pyonyoxymethylester, 1,1-dimethylpropylester, 3-methyl-3-butenylester, succini Midmethylester, 3,5-di-tert-butyl-4-hydroxybenzylester, mesylmethylester, benzenesulfonylmethylester, phenylthiomethyl
  • Methyl amide getyl amide, dipropyl amide, dibenzyl amide. Dicyclohexyl amide. ⁇ -benzyl ⁇ —methyl amide, diaryl amide, ⁇ -phenyl ⁇ -methyl amide, pyrrolidine amide, pyridine Examples include lysinamide, piperazine amide, morpholine amide, carboxymethyl amide, and 1-carboxyethyl amide.
  • examples of the organic residue represented by R 3 and R + include, for example, an organic residue bonded to a carbon atom.
  • organic residues bonded to the carbon atom include, for example, —30—
  • cycloalkyl, alkenyl 58 , aryl *, acyl, cyano or esterified is preferably amidated, preferably carboxyl.
  • Organic residues linked through 5 atoms organic residues linked through oxygen, nitrogen or sulfur atoms; or halogens.
  • R 1 (5 and R "are the same or different and represent hydrogen, alkyl, aryl or acyl.).
  • Examples of the organic residue bonded through the sulfur atom include a compound represented by the formula —S (O) n—R 12 wherein R 12 represents hydrogen, alkyl *, aryl *, heterocycle *, or amino *; Represents 0, 1 or 2. ] Is preferable.
  • the 1 3, 11 4, 1 5, 11 6, 1 7 Oyobi 11 The 8 Yoi group optionally substituted City Okeru Arukiru group and the other a Ebahi Dorokishi, Ashiruokishi, Karubamoiru Okishi, Amino Alkenylamino, alkylamino, alkylamino, alkirchio, heterocyclic thio, carboxy, alkoxycarbonyl, carbamoyl, cyano, azide, arylnoperogen and the like.
  • molybdenum group examples include, for example, halogen, alkoxy, and alkyl.
  • the Yoi group optionally substituted City Okeru Amino above R 12, the other a Eba Monoarukiru, Jiarukiru, Monoariru and the like.
  • Examples of the 11 3, 11 4, 11 5, 1 6, 11 7 Oyopi 11 8 Okeru Esuteru reduction is tee be 0 Yoi carboxyl other and Eba carboxy, etc. Arukiruokishi carbonyl and the like .
  • the 1 3.11 4, & 5, 1 8, 11 7 to Oyobi 1 8 Examples of Okeru ⁇ Mi de reduction is Yo I carboxyl be tee, the other a Eba expression.
  • R +3 ' is the same or different and represents hydrogen or alkyl, and may form a heterocyclic ring with an adjacent nitrogen atom.
  • alkyl including the alkyl in the group
  • those having 1 to 6 carbon atoms are preferable.
  • cycloalkyl those having 3 to 6 carbon atoms are preferable.
  • the above alkenyl is preferably one having 1 to 4 carbon atoms.
  • acyl including the case of the acyl in the group
  • those having 1 to 6 carbon atoms and arylcarbonyl are preferable.
  • Specific examples of halogen are the same as those described above for R 1 and the like.
  • the heterocyclic ring is preferably a 5- to 6-membered ring, and specific examples thereof include, for example, pyrrolyl, pyrrolidinyl, pyridinyl, and pyridinyl. Radinyl and the like.
  • Preferred examples of the group represented by R 3 and R 4 include, for example, methyl, ethyl, isopropyl, vinyl, allyl, cyclopropyl, cyclohexyl, cyclohexyl. , Phenylphenylchlorophenyl, paramethoxyphenyl, acetyl, propionyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, dimethylaminocarbonyl, cyano, carboxyl, t-droxymethyl, acetomethyl, carbamoyloxymethyl, chloromethyl, methyl Thiomethyl, 1-methyl-1H-5-tetrazolylthiomethyl, azidomethyl, acetamidomethyl, cyanomethyl, methoxycarbonylmethyl.hydroxyxethyl, acetooxyhydroxyxethyl, carbamoyloxethyl, chloroethyl, methylthio Eth
  • R 5 .R S .R 7 and R 8 above include, for example, methyl, ethyl, cyclopropyl, cyclopentyl, cyclohexyl, vinyl, and aryl.
  • any leaving group represented by ⁇ may be substituted with water at the 2-position of compound ( ⁇ ).
  • examples thereof include sulfonylo having, for example, a halogen (eg, bromo, chloro), a substituent (eg, alkyl, aryl) (alkyl and aryl include the same as the above-mentioned substituents).
  • Xy for example, ⁇ -toluenesulfonyloxy, ⁇ -nitrophenylsulfonyloxy, methanesulfonyloxy
  • disubstituted phosphoryloxy eg, diphenylphosphoryloxy, diethylphosphoryl
  • R, R 2 ', R 3 .R 4 , R 5 .R 6 , R 7 , R 8 and X have the same meanings as above. Have. R 3 , R 4 , R 5 , R 8 , R 7 hopping R 8 is simultaneously hydrogen.
  • a compound (I-2) represented by the general formula (I-2) is then subjecting the compound (I-2) to a conversion reaction of R 1 ' ⁇ Z or R 2 ' as necessary.
  • R 1 represents an amino residue or an organic residue via nitrogen.
  • R 2 represents a carboxyl group or a group which can be derived therefrom.
  • R 3 , R 4 , R 5 , R S , R 7, R 8 are the same or different and represent hydrogen or an organic residue, and R 5 is R 6 and R 7 is This includes the case where R 8 forms a chemical association.
  • R 3 , RR 5 , R S , R 7 and R 8 include the case where hydrogen is simultaneously applied.
  • X ' represents hydrogen, methoxy or pormyramino. Are obtained.
  • the reaction between the compound (E) and the compound (EO) can be carried out in a solvent in the presence of a lysic acid as a condensing agent.
  • the reaction between the reactive derivative of the compound ( ⁇ ) and the compound ( ⁇ ) The reaction is performed in a solvent.
  • condensing agent used herein include, for example, —, ⁇ '—di-six ⁇ -hexylcarbodiimide (DCC), and DC-hydroxysuccinimide Benzotriazole added; ⁇ -ethyl-N '-[3- (dimethylamino) pyralpyl] carbopimid; carbonyldiimidazole; ⁇ -ethyl-5-isoxazolidumu 3'-sulfonate; 2-Ethyl-1-7-hydroxybenzodioxazolum dimethyl trifluorophosphate; 1-ethoxycarbonyl-2-ethoxy-i, 2-dihydroxyquinoline; 2,2'-dipyridyl disulfide and Combination of rifinylphosphine: Combination of carbon tetrachloride and triphenylphosphine; for example, 2-chloro-1-methyl-pyridinium, 2-fluoro-1-methyl-pyr
  • Salts of azarene such as chillenbenzoxazolidium tetrafluoroborate and 2-fluoro-3-methyl-benzothiazolum fluorosulfate [anggebante hemi-interta] National eddy i / 3 (see Angewandte Chemie, International Edition), 18 and 0707 (19779).
  • lysic acid used in this reaction include, for example, boron trifluoride etherate, zinc chloride, tin tetrachloride, aluminum chloride, titanium tetrachloride, and boron trisalt.
  • a reactive derivative used in the c-terminal activation method in peptide synthesis can be applied.
  • the reactive derivative used here can be prepared in a solvent without particular hindrance, and used as it is for the condensation reaction.
  • Specific examples of the reactive derivative of the carboxylic acid used herein include acid halides such as acid chloride and acid bromide; acid azide; mixed anhydrides with monoalkylester carbonate; Tibaba chew acid, Pival
  • Acids valeric acid.
  • Isovaleric acid Mixed acid anhydrides composed of aliphatic carboxylic acids such as trichloroflic acid, acids such as diphenyl phosphinic acid, phosphinic acid such as getyl phosphonic acid, and sulfuric acid.
  • Mixed acid anhydride consisting of, for example, benzoic acid, etc .; symmetrical acid anhydride; for example, pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole Amide compounds in which an acyl group is bonded to the nitrogen in the ring, such as le-benzotriazole, thiazolidin-2-thione, etc .; for example, 4-nitrophenyl, 2,4-dinitrophenyl.
  • Trichlorophenyl Pentachlorophenyl, pentafluorophenyl, cyanomethyl, ⁇ -hydroxysuccinimide, ⁇ -hydroxyphthalimide, etc .
  • an active ester for example, 2-pyridylthiol
  • an equivalent amount of the compound ( ⁇ ) is equivalent to a small excess of the compound ( ⁇ )
  • an equivalent amount is an excess amount of the condensing agent or a catalytic amount of lysic acid
  • an equivalent amount is equivalent to the compound ( ⁇ ).
  • the compound can be reacted with a small excess of a reactive derivative of the compound (II) in a solvent.
  • Solvents that do not affect the reaction can be any problem, but examples include dichloromethane, chloroform, tetrahydrofuran, dioxane, getylether, ethyl sulphate, benzene, tren, Normal solvents such as ⁇ -hexane, acetonitrile, dimethylformamide and the like are used.
  • the reaction is carried out in the presence of a base (for example, if the condensing agent is 2-chloro-1-methylpyridinium, .2,2'-dipyridyldisulfide-triphenylphosphine) , Carbon tetrachloride-triphenylphosphine, etc.), and the bases used here include, for example, triethylamine, diisopropylethylamine, and —Methylmorpholine, 3, 4 —Dihydro-1 22-pyrido [1,2—a] pyrimidin-2-one, among which 3,4—dihydro-1 2H—pyrido [ 1,2-a] pyrimidine-2-one is preferred.
  • a base for example, if the condensing agent is 2-chloro-1-methylpyridinium, .2,2'-dipyridyldisulfide-triphenylphosphine) , Carbon tetrachloride-triphen
  • the reaction temperature is not particularly limited as long as the reaction proceeds, but is usually about ⁇ 50 ° C. to 150 ° C., preferably about ⁇ 10 ° C. to 100 °. (The reaction time depends on the starting materials, reagents, solvents used, reaction temperature, etc. It usually takes about 5 minutes to 30 hours. When condensation is carried out using a naphthalic acid as a catalyst, a dehydrating agent such as a molecular sieve may be coexisted in the reaction system.
  • the reaction between the compound (EO and the compound (RO) is carried out by reacting both in the presence of a base in a solvent.
  • a base for example, triethylamine, tripropylamine , Tri-n-butylamine, diisopropylethylamine, triethylendiamine (DAB CO), 1,8-diazabicyclo [5. 4.
  • DBU 7-indene
  • ⁇ Methylpyridine, ⁇ -methylpyrrolidine, 3,4-dihydro1-2-pyrido [1,2—a] pyrimidine-12-one, 4-ditylaminopyridine, pyridyl Organic amines such as gin, lutidine, y-collidine, etc., for example, alkali metals such as sodium, calcium, and cesium, and alkali metals such as, for example, magnesium and calcium.
  • the earth metal pulp is composed of these hydrides,
  • the carbonates used are alcoholates, etc.
  • Solvents are, for example, dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, toluene-acetonitrile, Normal solvents such as dimethylacetamide and dimethylformamide are used, etc.
  • liquid ones can be used also as solvents.
  • the compound (] y) and the base are usually used in an equivalent amount, but may be used in excess as long as the reaction is not hindered. The reaction is carried out at 00 ° C, and the reaction time is usually about 5 minutes to 30 hours.
  • the compound (I-I) obtained in this manner is further required by R ⁇
  • Compound (I ′) can be produced by subjecting the compound to the conversion reaction of R 2 ′.
  • the conversion reaction includes, for example, a deprotection group reaction, an acylation reaction, a peridation (thiolation) reaction, an alkylation reaction, an alkenylation reaction, a thiolation reaction, a silylation reaction, a phosphorylation reaction, Examples include esterification and amidation reactions.
  • an appropriate method such as a method using an acid, a method using a base, a method using hydrazine, a method using reduction, etc. is appropriately selected according to the type of the protecting group. You can do it.
  • the method using an acid it differs depending on the type of the protecting group and other conditions.
  • the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, formic acid, formic acid, trifluoroacetic acid and the like.
  • organic acids such as acetic acid and propionic acid, acidic ion exchange resins are used.
  • a base for example, water of an alkali metal such as sodium or potassium or an alkaline earth metal such as calcium or magnesium is used.
  • inorganic bases such as oxides and carbonates, metal alkoxides, organic amines, organic bases such as quaternary ammonium salts, basic ion exchange resins and the like are used.
  • a solvent is used in the above-mentioned method based on an acid or a base, a hydrophilic organic solvent, water or a mixed solvent is often used.
  • metals having different types of protecting groups such as tin and zinc, and metal compounds such as chromium dichloride and chromium acetate
  • a method of using an acid such as an organic or inorganic acid such as propion or hydrochloric acid, a method of reducing in the presence of a metal catalyst for catalytic reduction, and the like are used, and here, the catalytic reduction is used.
  • the medium include platinum catalysts such as platinum wire, platinum sponge, platinum black, platinum oxide, and colloidal platinum, palladium sponge, palladium black, palladium oxide, palladium sulfate, palladium carbonate, palladium carbon, palladium carbon.
  • Silica gel, Koroi Examples include palladium catalysts such as dopalladium, reduced nickel, nickel oxide. Raneyni, sokel, and Urushibara nickel.
  • a metal such as iron or chromium and an inorganic acid such as hydrochloric acid or an organic acid such as formic acid or acetic acid or propionic acid are used.
  • the reduction is usually carried out in a solvent, for example, the methods of catalytic reduction include alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, etc. Oxyethyl and the like are frequently used. Water, acetone, etc. are commonly used in the method using metal and acid, but when the acid is liquid, the acid itself can be used as a solvent.
  • the reaction temperature in the method using an acid, the method using a base, and the method using a reduction can be generally performed by heating a little under cooling.
  • the compound (I-2) By subjecting the compound (I-2) to a reaction with a deprotecting group, the compound ((a compound wherein R 1 is an amino group and R 2 is a group which can be derived from a carboxyl group) ( ⁇ -3) or a compound (I-4) wherein R 2 is a carboxyl group and R 1 is an organic residue via nitrogen. Is further subjected to a deprotection reaction to produce a compound (I-15) in which R 1 is an amino group and R 2 is a carboxyl group in the compound (I ′). be able to.
  • compound (I-2) can be subjected to a deprotection reaction to give compound (I-5) at once.
  • Te Oi compound (1 ') when R 5 Arui is R 8 and R 7 Arui is to obtain compound when forming Shitiru mosquitoes chemical bond and R 8 is,
  • the compound (5-oxo-2,5-dihydro-2-furancarboxylic acid derivative) can be hydrogenated as necessary, if necessary.
  • the hydrogenation For example, a method similar to the above-described reduction method used for deprotection of a protecting group can be employed. Incidentally, by performing the reduction reaction, hydrogenation of the double polymerization and deprotection of the protecting group can be simultaneously performed.
  • the compound (1-3) is subjected to reactions such as acylation, elimination (thiolation), alkylation, alkenylation, thiolation, silylation, and phosphorylation.
  • Compound (I-2) can also be converted. Next, the reaction will be described in detail.
  • Ashiru of ⁇ Mi amino group in a solvent and the starting compound, Ashiru agent containing T sill group in group R 1, this and Nyori rows Na reacting a reactive derivative of the other and Eba carboxylic acid Can be.
  • the reactive derivative of the carboxylic acid for example, acid halides, acid anhydrides, amide compounds, active esters, active esters, etc. are used. The next step. .
  • acid halide for example, acid chloride, acid bromide and the like are used.
  • the acid anhydride is, for example, a mixed acid anhydride composed of, for example, monoalkyl carbonate mixed acid anhydride and aliphatic carboxylic acid (for example, acetic acid, pivalic acid, valeric acid, izovaleric acid, trichloroacetic acid, etc.).
  • Acid anhydrides, symmetrical acid anhydrides, etc. composed of aromatic acids, aromatic carboxylic acids (for example, benzoic acid, etc.).
  • amide compound for example, a compound in which an acyl group is bonded to nitrogen in a ring, such as pyrazole, imidazole.4-substituted imidazole, dimethylpyrazole, and benzotriazole, is used.
  • active ester a compound in which an acyl group is bonded to nitrogen in a ring, such as pyrazole, imidazole.4-substituted imidazole, dimethylpyrazole, and benzotriazole.
  • the active ester may be, for example, methylester, ethylester, methoxymethylester, propargylester, 4-nitrophenylester, 2,4-dinitrophenylester, succinylester, pentachlorophe.
  • esters such as peni-ester and mesylphenyl ester, etc., esters with 1-hydroxy-1 1 ⁇ —2-zelidone, ⁇ -hydroxysuccinimide, ⁇ -hydroxyphthalimide, etc. Used.
  • the active chaoester for example, a chaoester with a heterocyclic thiol such as 2-pyridylthiol or 2-benzthiazolylthiol is used.
  • the reaction is often carried out in the presence of a base, and the base to be used is, for example, an aliphatic tertiary amine (eg, trimethylamine, triethylamine, tripropylamine, or the like).
  • a base for example, an aliphatic tertiary amine (eg, trimethylamine, triethylamine, tripropylamine, or the like).
  • Tert-amines such as tri- ⁇ -butylamine), -methylpiperidine, ⁇ -methylpyrrolidine, cyclohexyldimethylamine, ⁇ -methylmorpholine, etc., for example, di- ⁇ -butylamine.
  • a reactive derivative of a carboxylic acid is generally used in an amount equivalent to about about the compound (I-3), but an excess may be used as long as the reaction is not hindered. it can.
  • the amount of the base used depends on the starting compound used.
  • (1-3) a carboxylic acid which varies depending on the type of the reactive derivative thereof, other reaction conditions, usually about an equivalent to 30 equivalents, preferably about an equivalent, relative to the compound (I-3). Add 10 equivalents.
  • This reaction is usually performed in a solvent.
  • the solvent include ethers such as dioxane tetrahydrofuran, getyl ether, diisopropyl ether, propylene oxide and butylene oxide, and esters such as ethyl ethyl sulphate and ethyl formate.
  • halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1.1-trichloroethane, hydrocarbons such as benzene, toluene, ⁇ -hexane, etc.
  • Ordinary organic solvents such as amides such as ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide and nitriles such as acetonitrile are used alone or in combination.
  • a liquid of the above-mentioned bases can also be used as a solvent.
  • the reaction temperature is not particularly limited as long as the reaction proceeds, but is usually not about -50 to 150 ° C, preferably not about -30.
  • reaction is usually completed within tens of minutes to several tens of hours, but sometimes takes several tens of days, although it differs depending on the used raw material, base, reaction temperature and type of solvent.
  • R 2 3, R 3 ° Oyobi Z has the same meaning as defined above.
  • the substitution isocyanate containing a group represented by ()) can be carried out by reacting the substitution isocyanate.
  • the substituted isocyanate include methyl isocyanate, ethyl isocyanate, vinylisocyanate, and P-butyrate.
  • Lomophenyl isocyanate and the like are used as substituted isotiosinates, for example, methyl isotsionate and phenyl isotsionate.
  • the substituted isocyanate or the substituted isocyanate is generally used in an excess amount with respect to the compound (I-13), but an excessive amount is used as long as the reaction is not hindered.
  • reaction temperature can be set at about ⁇ 20 ° C. to about 50 ° C.
  • reaction time is usually set at about 1.0 minute to about 5 hours.
  • the reaction for coupling a group bonded via carbon to an amino group of compound (I-3) is described below as alkylation.
  • the alkylation of the compound (I-3) is carried out by reacting the compound (I-3) with an alkylating agent containing a group bonded to the nitrogen of the group R 1 via carbon. can do.
  • the alkylating agent include propyl chloride, butyl chloride, benzyl chloride, butyl bromide, benzyl bromide, aryl bromide, methyl iodide, ethyl iodide, and propyl iodide.
  • Halogenated alkyl compounds such as dimethyl sulfate and getyl sulfate; substituted sulfonic acid ester compounds such as methyl mesylate, ethyl mesylate, methyl tosylate and ethyl sylate; dihalogenated Alkyl compounds (eg, 1,5-dichloropentane, 1,4-dichlorobutane, etc.) are used.
  • This reaction is usually carried out in a solvent.
  • the solvent used include water, methanol, ethanol, benzyl alcohol, benzene, ⁇ , ⁇ -dimethylformamide, tetrahydrofuran, and acetonitrile. Is raised.
  • the temperature of this reaction ranges from about 20 ° C to 200 ° C, and the reaction time ranges from about 30 minutes to 50 hours.
  • This reaction is carried out under the reaction conditions, for example, By changing the molar ratio between the compound (I-3) and the alkylating agent, the ninth and third tertiary compounds are selectively produced as quaternary amide compounds; Can be built. Further, by performing the reaction stepwise, it is possible to introduce a different substituent into nitrogen.
  • the reaction for introducing a group bonded via carbons other than alkyl can also be performed in the same manner as described above.
  • the alkylation can also be carried out by combining the compound (I-3) with a carbonyl compound in the presence of a reducing agent.
  • a reducing agent used in this reaction include hydrogen peroxide, sodium cyanoborohydride, sodium hydrogen borohydride, sodium, sodium sodium, a combination of zinc and an acid. And so on. Catalytic reduction using palladium, platinum, rhodium, etc. as a catalyst can also be performed.
  • the conversion of a group to an imino-substituted alkamino group or an alkamino group is carried out by dioxane, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, chloroform, aceton, acetonitrile, water In a solvent such as, for example, by reacting with imidesters.
  • Suitable imidoesters include, for example, methylformimidate, ethylformimidate, benzylformimidate, methylaseimidate, methylaseimidate, methylfurimidate.
  • imide, ethyl-formimidate, methyl-ethylformimidate, methyl-isopropylformimidate are used.
  • the reaction temperature ranges from 0 ° C. to about 25, and the reaction time usually ranges from 1 hour to 6 hours.
  • the conversion reaction of the amino group to the guanidino group is carried out using a solvent such as water, N, N-dimethylformamide, hexamethylenephosphoramide.
  • the middle for example, it can be performed by reacting with 0-alkyl or, 0-aryl pseudourea or S-alkyl or S-aryl pseudo urea.
  • pseudoureas include 0-methylpseudourea, S-methylpseudourea, 0-2,4-dichlorophenylpseudourea, 0-N.N-trimethylpseudourea, and the like.
  • S—p-nitrophenylpseudothiourea and the like are used.
  • the reaction temperature ranges from 0 ° C to around 40 ° C, and the reaction time usually ranges from 1 hour to 2 hours.
  • Alkynylation (iminolation) of compound (I-13) can be carried out by dehydration condensation of compound (1-3) with a carbonyl compound. This reaction proceeds without a solvent, but can be carried out in a solvent. 'The acid may use a base as a catalyst. In the presence of a dehydrating agent, the compound (I-3) and the carbonyl compound can be produced by subjecting the dehydration apparatus to a dehydration apparatus such as Dean Stark, followed by ripening and reflux.
  • the solvent used in this reaction is, for example, benzene, toluene, dichloromethane, ethanol, etc., the reaction temperature is about 0 ° C to 200 ° C, and the reaction time is about 1 hour.
  • Examples of the acid used as a catalyst include fresh benzene sulfonic acid, methanesulfonic acid, sulfuric acid, boron trifluoride, and zinc chloride, and bases such as potassium hydroxide and sodium carbonate. I can do it.
  • Examples of the dehydrating agent used in this reaction include molecular sieves, silica gel, magnesium sulfate anhydrous, and anhydrous sodium sulfate.
  • the thiolation reaction of the compound ( ⁇ -3) is usually carried out by reacting the compound (I-13) with a compound represented by the formula
  • R 3 3 - SO n- (.
  • R 3 3 Oyobi n is of the same meaning as defined above) with a halogenating Chio compounds containing group table Wasa (eg, halogenated Suruhoniruno ⁇ Rogge (Sulfinyl halide, sulfonyl halide) in the presence of a base in a solvent.
  • halogenating Chio compounds containing group table eg, halogenated Suruhoniruno ⁇ Rogge (Sulfinyl halide, sulfonyl halide) in the presence of a base in a solvent.
  • the solvent used in this reaction include, for example, water, acetone, dioxane, ⁇ , ⁇ -dimethylformamide, benzene, tetrahydrofuran, dichloromethane, puru, and a mixture of these solvents.
  • the base examples include many organic bases such as pyridine, picolin, triethylamine, diisopropylethylamine, and methyl morpholine.
  • An inorganic base such as potassium is used.
  • This reaction usually uses about 1 equivalent of the halogenated thio compound, about 1 equivalent to 10 equivalents of the base to the compound (I-3), and the reaction temperature is about ⁇ 20 to 80 ° C. The reaction time is between 15 minutes and 10 hours.
  • This reaction can also be performed using a thioic anhydride (eg, toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.) instead of a halogenated thio compound.
  • a thioic anhydride eg, toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.
  • ⁇ -sulfonyl-1-methylpyrrolidinium, ⁇ -sulfonylimidazolide is ⁇ -sulfonyl-1 ⁇ ⁇ -1,
  • It can also be performed by reacting with a thiolating reagent such as 2.4-triazolide.
  • the silylation reaction of the compound (I_3) is usually carried out by combining the compound (1-3) with ⁇
  • R + 1 —Si— ⁇ is R + 3 (wherein R + °- + 3 has the same meaning as described above)
  • silyl halide compound eg, silyl chloride compound, silyl bromide compound
  • bases include, for example, pyridine, picolin, triethylamine, diisopropylethylamine, N-methylphenol
  • Organic bases such as phosphorus are exemplified.
  • the reaction is preferably carried out in a solvent.
  • the solvent include acetone, dioxane, ⁇ , ⁇ -dimethylformamide, benzene and tetrahydrofuran, and dichloromethane.
  • the reaction temperature ranges from about -20 ° C to the boiling point of the solvent, from about -20 ° C to 80, and the reaction time ranges from about 15 minutes to 20 hours.
  • the phosphorylation reaction of compound (I-3) is usually carried out at about equivalent amount of 0 to compound (I-3).
  • Organic bases such as pyridine, picolin, triethylamine, N-methylmorpholine, and the like include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate, and the like.
  • reaction temperature is about -20 ° C. C
  • reaction time is 15 minutes to 15 hours.
  • the compound (I-5) is subjected to a reaction such as, for example, acylation, peridation (thiolation), alkylation, alkenylation, thiolation, silylation, or phosphorylation to give the compound (I-5). Can be converted to I-4).
  • This conversion reaction can be carried out in the same manner as the above-mentioned conversion reaction from compound (I-3) to compound (I-2).
  • the compound (I-4) can be converted to the compound (I-2) by subjecting it, for example, to an esterification reaction of carboxylic acid or an amide reaction of carboxylic acid. Next, the reaction will be described.
  • the esterification of a carboxylic acid can be performed, for example, by the following method.
  • the starting compound is a diazoalkane, for example, diazomethane, phenyldiazomethane, diphenyldiazomethane, etc., and a solvent, for example, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, etc., at about 0 ° C. React at reflux temperature for about 2 minutes to 2 hours.
  • a diazoalkane for example, diazomethane, phenyldiazomethane, diphenyldiazomethane, etc.
  • a solvent for example, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, etc.
  • alkali metal salt of an alkali metal halide for example, alkydhalide, for example, sodium chloride methyl, benzyl bromide, ⁇ -nitro-benzyl bromide, m-phenoxybenzyl bromide, ⁇ -t-butyl benzyl bromide, React with pivaloyloxymethyl chloride.
  • alkydhalide for example, sodium chloride methyl, benzyl bromide, ⁇ -nitro-benzyl bromide, m-phenoxybenzyl bromide, ⁇ -t-butyl benzyl bromide, React with pivaloyloxymethyl chloride.
  • Appropriate reaction conditions include the use of a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoramide at about 0 ° C. Incubate at 60 ° C for about 2 minutes to 4 hours. Even if triethylamine and the like co
  • the acid anhydrides of the starting compounds obtained by reacting the starting compounds with acid chlorides are alcohols, for example, those listed in 3). And under the reaction conditions described in 3).
  • acid chlorides such as, for example, ethyl chlorocarbonate and benzyl chlorocarbonate
  • This anhydride is obtained by converting the starting compound into an acid chloride and a solvent, for example, tetrahydrochloride. 25 in furan. Dichloromethane, etc. It can be obtained by reacting at C-reflux temperature for about 15 minutes for 10 hours.
  • Amidation of carboxylic acid is carried out by converting the starting compound to an acid chloride, for example, ethyl chloride or benzyl carbonate or an acid anhydride, for example, acetic anhydride, trifluoroacetic anhydride, or the like.
  • An anhydride may be synthesized and reacted with the ammonia or the selected amine, for example, the alkyl, dialkyl, aralkyl or heterocyclic amines described above.
  • the reaction can also be carried out by reacting a carboxylic acid with the above-mentioned amines in the presence of a condensing agent such as DCC.N-3-dimethylaminopropyl N-ethylcarbodiimide. .
  • the above reaction should be carried out in a solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, etc. at a reflux temperature of about 0 ° C for about 15 minutes or 16 hours. I can do it.
  • a solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, etc.
  • the compound (a compound in which X can be methoxy) can also be produced by subjecting a compound (in which X is hydrogen to methoxylation reaction).
  • meth- oxylation is carried out in the fields of nisililine and cephalosporin, and the meth- oxylation method at the 6th position and the 7th position can be applied.
  • meth- oxylation method at the 6th position and the 7th position can be applied.
  • E.M.G.Gordon, R.B.S.ykes, and other chemists, and Bayolo are involved in the methoximation of cephalosporins. 1991 (1982), Academic Press, Chemistry and Biology of ⁇ L actam Antibiotics, vol. 1, 1991.
  • the methoxylation reaction is carried out by reacting the starting compound in the presence of methanol with an alkali metal salt of methanol and a halogenating agent.
  • an alkali metal salt of methanol lithium methoxide, sodium methoxide, potassium methoxide and the like are used.
  • the halogenating agent include, for example, t-butylpipochloride, ⁇ -chlorosuccinimide, ⁇ -bromosuccinimide, ⁇ -chloracetamide, ⁇ -bromoacetamide, and ⁇ -chlorbemid. Notwithstandingfonamide, chlorine, bromine, etc. are used.
  • This reaction is carried out in a solvent, for example, tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, methanol, ⁇ , ⁇ -dimethylformamide, etc. are used as the solvent.
  • a solvent for example, tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, methanol, ⁇ , ⁇ -dimethylformamide, etc.
  • the solvent for example, tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, methanol, ⁇ , ⁇ -dimethylformamide, etc. are used as the solvent.
  • the reaction proceeds not at about ⁇ 80 but at about 30, and the reaction is stopped by making the reaction system acidic.
  • Suitable acids for terminating the reaction include, for example, formic acid, citric acid, trichloroacetic acid and the like.
  • the excess halogenating agent is, for example, sodium thiosulfate, triol of phosphorous acid. It is removed by treatment with a reducing agent such as lukirester.
  • a compound (a compound in which X is formylamino can be produced by subjecting a compound (a compound in which X is hydrogen to formylamino reaction).
  • the formylamino is obtained by converting a compound in which X is formylamino to the compound (I ') with a general formula
  • R 1 represents a moiety other than nitrogen in an organic residue via nitrogen
  • R 2 , R 3 , R, R 5 , R 6 , R 7 and R 8 have the same meanings as described above.
  • R 3 , R + , R 5 , • R S , R 7, and R 8 simultaneously contain hydrogen sulphate.
  • the nucleophilic derivatives of formamide include, for example, N-silyl, N-stanyl and N-phosphorylformamide conductors. Among them, preferred is N, N-bis (trimethylsilyl) formamide, which is usually carried out in a solvent under an inert atmosphere such as nitrogen and argon. The reaction temperature is about 100 ° C.
  • the reaction time is about 10 minutes. And it takes 8 hours, It is preferably about 15 minutes to 2 hours, and the solvent used is preferably a non-protonic solvent, for example, tetrahydrofuran, N, N-dimethylformamide.
  • the acid is hydrolyzed with a base, or the mercury, silver, and tallum are copper.
  • Formylamide groups can be formed by treatment with metal ions.
  • the production of an imine body composed of a natural compound is carried out by the above-mentioned meth- oxylation.
  • the target compound thus obtained (I is a method known per se such as concentration, liquid conversion, phase transfer, solvent extraction, freeze drying, crystallization, recrystallization, fractionation, chromatography, etc.). Can be isolated and purified.
  • the target compound (I has two or more asymmetric carbons in the basic skeleton, so there are theoretically four or more stereoisomers. Each of these isomers and mixtures thereof are also used in this book. In the case where the group represented by R 1 ⁇ R 2 has an asymmetric carbon, stereoisomers are also produced, but each of these isomers, and mixtures thereof are also included in the present invention. In the case where these isomers are mixedly produced in the above reaction, the respective isomers can be isolated by various methods such as chromatography and recrystallization as necessary.
  • the compound of the present invention (I can act with a base to form a salt. Examples of the base include inorganic bases such as sodium, potassium, lithium, calcium, magnesium, and ammonium. , For example, pyridine, kolysin. And organic bases such as triethanolamine.
  • the compound of the present invention (I When the compound of the present invention (I is obtained in free form, it may be used to form a salt using conventional means, and the compound obtained as a salt may be used in free form using conventional means. As well.
  • the compound (I) may form an inner salt, which is also included in the present invention.
  • stereoisomers of the compound (I) can be used as a medicament alone, and any of the mixtures can be used as a medicine.
  • the compounds used as starting compounds in the method of the present invention are as follows: It can be manufactured according to the following method.
  • R 2 ′, R 5 , R 8 , R 7 and R 8 in the formula have the same meaning as described above.
  • the compound (II) is converted into the compound (iy).
  • This reaction is usually carried out by reacting with an activator in a solvent without a solvent.
  • the activator used here include, for example, thionyl chloride, thionyl bromide, sulfuryl chloride, oxylin chloride, oxalyl chloride, chlorine, and bromine.
  • Halogenating agents such as phenylphosphine, for example, P-toluenesulfonic anhydride, p-nitto ⁇ -benzenebenzenesulfonic anhydride, 2,4,6, anhydride, triisopropylphenylsulfonic acid, methanesulfonic anhydride
  • Sulfonylating agents such as acids, ⁇ -toluenesulfonyl chloride, ⁇ -chlorobenzenesulfonyl chloride, and phosphoryls such as, for example, diphenylphosphoryl chloride, dimethylphosphoric chloride JJdo, and getyl phosphoric chloride. Agents and the like.
  • This reaction is carried out by reacting the compound ( ⁇ ) with an approximately equivalent to excess amount of the above-mentioned activator in a solvent or without a solvent.
  • a base such as triethylamine, disopropylethylamine, pyridine, or 4-dimethylaminopyridine may be used.
  • Solvents include dichloromethane. Chloroform, carbon tetrachloride, 1,2-dichloroethane, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, acetonitrile, tetrahydrofuran, benzene , Tolwen etc. are used.
  • the reaction temperature is usually about ⁇ 20 to about 100, and the reaction time is about 30 minutes to about 50 hours.
  • Compound ( ⁇ ) ⁇ Compound (iy):- ⁇ f is the formula Is reacted with a halogenating agent to give a compound (iy) (here, in general formula (17), when R 6 and R 8 form a chemical bond, Will be described in the case of indicating halogen.)
  • halogenating agent chlorine, bromine and the like are suitable.
  • solvent chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane-benzene, acetonitrile and the like are used.
  • the reaction temperature is about Q ° C to about 80, and the reaction time is about 10 minutes to about 10 hours.
  • Compound (IY) is an esterification of a carboxylic acid that converts a starting compound in which R of the compound (] y) corresponds to a carboxyl group, for example, from the above-mentioned compound (I-4) to a compound ( ⁇ -2). Reaction. It can also be produced by subjecting it to a reaction similar to the carboxylic acid amidation reaction.
  • the compound (II) used as a starting compound in the method of the present invention can be produced, for example, by the following method.
  • R 2 ′ .R 5 , R 8 , R 7 and R 8 have the same meaning as described above.
  • esterifying agent used herein examples include methyl bromide, benzizolebromide, p-nitrobenzyl bromide, m-phenoxybenzyl bromide, p-t-butylbenzyl bromide, and diphenylmethyl bromide.
  • examples include halides such as mid and piperoyloxymethyl chloride, and dialkyl sulfates such as dimethyl sulfate and getyl sulfate.
  • the base include, for example, diisopropylamine, dicyclohexylamine. Cyclohexylypropylamine, triethylamine, tripropylamine, tri-n-butylamine, diisopropylethyl. Amin, DABCO, DBU, N—Methylmorpholine, N—Methylpyridine, N—Methylpyrrolidine, 3,4—Dihydro-1 2H—Pyrido [1,2—a] Pyrimidine
  • N, N-dimethylformamide, ⁇ -dimethylacetamide, hexamethylphosphoramide, dimethylsulfoxide, dichloromethane, acetonitrile, tetrahydrofuran and the like are used as the solvent.
  • reaction The temperature is usually about ⁇ 20 to about 100 ° C., and the reaction time is about 5 minutes to about 30 hours.
  • a compound (VI) represented by the following formula is produced, and is subjected to an esterification reaction in the next step.
  • the compound (n) is converted into the compound (vr) represented by, and then subjected to an acid treatment to produce the compound (n).
  • benzyl carbamate is used in an amount equivalent to a little in excess of the compound (V), usually by heating under reduced pressure without a solvent to effect dehydration condensation.
  • the degree of pressure reduction is about 0.1 Hg or about 5 OmmHg.
  • the reaction temperature is usually about 50 ° C. to about 120, and the reaction time is about 30 minutes to about 20 hours.
  • Compound (VI) is subjected to an esterification reaction with a copper to convert to compound (VT).
  • the esterification reaction is carried out by applying the same conditions as in the above-mentioned esterification of compound (V) ⁇ compound ( ⁇ ).
  • esterification is carried out in the presence of, for example, methanol ethanol, benzyl alcohol, and a carbodiimide condensing agent such as DCC.
  • the method of esterification is appropriately selected depending on the desired ester, but the ester used here is selected from those which are stable to the target acid since an acid is used in the next reaction.
  • the compound is converted to compound (II) by acid treatment.
  • the acid used here include, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, perchloric acid, periodic acid, formic acid, acetic acid, trifluoroacetic acid, and -toluenesulphonic acid.
  • the compound (II) represented by the formula (II) is then decarboxylated to produce the compound (II).
  • ethyl chlorocarbonate decarboxylation with lip
  • conversion of 2-oxoglutaric acid Examples of synthesizing 1-ethylester are known in the literature. [J. M. Domagala., Tetrahedron Letters, 21: 4997, 1989].
  • compound (V) is reacted with halogenocarbonate ester in a solvent in the presence of a base, and decarboxylation is carried out with lip to produce compound (II).
  • halogenocarbonic acid esters include, for example, methyl chlorocarbonate and chlorocarbonate. Ethyl. Benzyl chlorocarbonate, 2.2, 2-trichloroethyl chlorocarbonate.
  • the base and solvent used herein include those described in the production method in the step of compound (iy) ⁇ compound (I-2). This reaction uses about an equivalent of a base and about an equivalent of a halogenocarbonate based on compound (V). The reaction temperature is usually about -30 ° C
  • reaction time is about 1 minute to about 2 hours.
  • Compound 01) does not need to be particularly isolated, and the decarboxylation reaction continues to proceed under the above reaction conditions, whereby compound ( ⁇ ) can be obtained at once.
  • a compound (IX) represented by the following formula is produced, and alcohol is reacted with the mixture to produce a compound (H).
  • the dehydrating agent used in S include halogen compounds such as phosphorus oxychloride, thionyl chloride and chlorosulfonic acid, and acids of lower fatty acids such as acetic anhydride and trifluoroacetic anhydride. Acid anhydrides, such as acetyl chloride,
  • Imidazole derivatives such as ⁇ , ⁇ '-carbonyldiimidazole and ⁇ -trifluoroacetylimidazole; and DCC.
  • an organic base such as pyridine or triethylamine may be used in combination.
  • This reaction is carried out in a solvent using about an equivalent or an excess of the dehydrating agent with respect to compound (V), or in a solvent if the dehydrating agent is a liquid.
  • a solvent for example, Romethane. Wensen, Tolwen, Acetonitrile, etc. are used.
  • the reaction temperature is usually about 0 to 100, and the reaction time is about 15 minutes to about 30 hours.
  • a compound (CO with about an equivalent or an excess of alcohol a compound (II) is obtained.
  • Specific examples of the alcohol include, for example, methyl alcohol, ethyl alcohol, and vinyl alcohol.
  • reaction temperature is about 0 to 100, and the reaction time is about 10 minutes to about 4 days.
  • compound (V) is converted into a gestelle to form
  • R 5 Q in the above formulas (X), (3 ⁇ 4), and (3 ⁇ 4 [) is, for example, 0-alkyl groups such as methyl and ethyl, and benzyl, p-bromobenzyl, and p-nitrobenzyl. And aralkyl groups such as benzyl.
  • the reaction of compound (V) ⁇ compound (X) ′ is carried out according to the method described earlier in the preparation of compound (V) ⁇ compound ( ⁇ ), and the esterification agent and the base are converted to compound (V). In each case, about 2 equivalents or more are used.
  • the hydrolysis of compound (X) ⁇ compound (XI) is usually carried out with alkali metal hydroxides such as lithium, sodium, potassium and cesium, and bases such as carbonates and alcoholates. In a solvent.
  • the solvent water, methanol, ethanol, tetrahydrofuran, dimethyl sulfoxide or the like is used alone or as a mixed solvent.
  • This hydrolysis reaction can be carried out using a base in an amount equivalent to the compound (X).
  • the reaction temperature is usually about
  • the reaction is carried out at about 0 ° C for about 80 minutes, and the reaction time is about 10 minutes for about 20 hours.
  • the esterification reaction of compound ⁇ ) ⁇ compound (3 ⁇ 40 can be produced according to the method described in the production method of compound ( ⁇ ) ⁇ compound ( ⁇ ). Further, compound (a) is acid-catalyzed.
  • the reaction of compound (M) ⁇ compound ( ⁇ ) can be carried out in the presence of isobutene to produce t-butyl ester, where the ester group at position 1 is stable to the base and the ester at position 5 Group --1
  • the reduction method is usually carried out in a solvent, for example, water, methanol, ethanol, ethyl acetylacetone, or the above-mentioned acids.
  • a solvent for example, water, methanol, ethanol, ethyl acetylacetone, or the above-mentioned acids.
  • the reaction temperature is usually about 0 ° C to about 60 ° C, and the reaction time is about 10 minutes to 20 hours.
  • a compound represented by the formula (XYD is converted to a compound (3 ⁇ 40 (described above)) by further oxidizing the hydroxyl group, which is subjected to the reaction of the compound ( ⁇ ) described above,
  • the esterification of compound (XV) ⁇ compound (XVI) is carried out according to the above-mentioned method of compound (V! I) ⁇ compound (VF).
  • the oxidation reaction of compound (XYI) ⁇ compound (II) can be performed by treating compound (XVI) with an oxidizing agent in a solvent.
  • oxidizing agents include potassium permanganate, manganese dioxide, and dimethyl sulfoxide.
  • the above-mentioned method for amidating a carboxylic acid is applied to the compound (XI). However, it can be carried out according to the method described in the method for producing the compound (II) from the compound 030.
  • Compound (V) which is a raw material compound used in the present invention, can be produced by various methods already reported.
  • the compounds themselves are known according to the documents listed below, or compound (V) can be obtained according to the method described in these documents.
  • R 2 ′, R 8 , R 7 and R 8 have the same meaning as described above.
  • ⁇ Conversion of compound (Xil) ⁇ compound (XO is a reaction known as Claisen condensation, in which compound (XVI) and compound (XVI) are condensed in a solvent in the presence of a base.
  • the “base” used in this reaction is, for example, alkali metal such as lithium, sodium, and potassium, and alkaline earth metal such as magnesium, calcium, and the like.
  • Rur is a hydride, alkoxide, amide, aralkyl metal, etc.
  • ⁇ is a quaternary ammonium salt (eg, tetra-n-butylammonium hydroxide).
  • solvents examples include alcohols such as methanol and ethanol (when alcohol is used, alcohols which are the same as the alcoholic group of the ester) and ethers.
  • alcohols such as methanol and ethanol (when alcohol is used, alcohols which are the same as the alcoholic group of the ester) and ethers.
  • Tet hydrofuran, Joki'san, N, N-dimethylform Mi de, 1, Jime Tokishetan, dichloromethane, downy benzene, such as torque E down is use Ira.
  • the reaction temperature is usually about 0 to about 80 ° C, and the reaction time is about 10 minutes to about 10 hours.
  • the conversion of compound (II) ⁇ compound (V) is carried out in the process of producing compound (V) through reduction treatment of acid and alkali. This reaction can be carried out in the same manner as described above, for example, from the compound ( ⁇ ) to the compound (a), according to the method for producing the compound (D—compound ( ⁇ )).
  • the compound (m), which is the starting compound used in the present invention can be produced by various known methods.
  • the compounds themselves are known according to the literatures listed in the literature and the like, or compound (IE) can be obtained according to the method described therein.
  • the esterification of compound (XX) ⁇ compound (XXI) can be achieved by various known esterifications generally used. For example, it can be produced according to the above-mentioned esterification production method. Among them, a method of treating with thionyl chloride in alcohol is preferably used. At this time, the amino group may form a salt as a hydrochloride, but the reaction is not hindered at all.
  • Compound (XXO ⁇ compound (X3 ⁇ 40 is a process for converting a hydroxyl group to a leaving group Y.
  • the method for converting a hydroxyl group to a leaving group is, for example, the above-mentioned compound (11) ⁇
  • Compound (IV) can be produced according to a method similar to that of compound (IV) Compound ( ⁇ 3 ⁇ 4 ⁇ ) ⁇ Compound (xxm) ⁇
  • Compound (XXRO is a compound Product (XXtt) with hydroxyamine in the presence of a base
  • (X X) is manufactured.
  • the compound (XX ⁇ ) can be isolated, but it is also possible to convert the compound (XXRO) into a compound (XXRO) without singularity.
  • the reaction is carried out by reacting the compound (about an equivalent or a small excess with respect to X3 ⁇ 40) in the presence of about an equivalent or a small excess of a hydroxylamine.
  • Alkali metals such as lithium, sodium, potassium and cesium, and hydroxides and carbonates such as alkaline earth metals such as magnesium and calcium, etc.
  • the reaction temperature is usually ⁇ 20 ° C or less.
  • the reaction is carried out at about 60 ° C, and the reaction time is about 10 minutes for about 10 minutes.
  • Compound (XXIV) can be used in the next reaction step without isolation and purification.
  • Compound ( ⁇ ⁇ ) ⁇ is a process in which the amino group of compound (xx jy) is converted to an organic residue via nitrogen to produce compound (m.). Can be carried out in the same manner as in the method for converting the compound (I-3) into the compound (1-2) described above.
  • the methoxylation reaction and the formylamination reaction are the same as those described above for the compound (I ′) in which X is hydrogen and subjected to the methoxylation reaction or the formylamination reaction. You can do it.
  • the compound (no is converted to a compound represented by the general formula
  • R pro represents a protecting group.
  • a nucleophilic derivative of formamide acts on the imine body.
  • the protecting group represented by R pro include those similar to the above-mentioned protecting group for an amino group.
  • the reaction can be carried out in the same manner as in the above-mentioned reaction of subjecting a compound (a compound in which X is hydrogen in the formula I to hydrogenation) to a formylamination reaction.
  • Each of the intermediate compounds thus obtained can be subjected to concentration, liquid transformation, phase transfer, solvent extraction, freeze-drying, crystallization, recrystallization, fractional distillation, chromatography, etc. by a method known per se. Can be released.
  • -The compounds ( ⁇ ) and (IE) and (IV ') obtained in this way are useful as raw materials for producing, for example, a compound (I).
  • the compound (I ′) obtained by the above method is useful as a medicine and has antibacterial activity against various kinds of Gram-positive bacteria and Gram-negative bacteria.
  • the antibacterial spectrum of typical compounds among various compounds is shown in Table 1 below. Table l
  • Inoculum volume 1 0 8 CF U / ml '
  • Compound (25) refers to compound (25) produced in Example 25 described later.
  • the compound (I ') or a salt thereof of the present invention exhibits antibacterial activity against various Gram-positive bacteria and Gram-negative bacteria, so that mammals infected with bacteria (eg, bacterial infections in mice, rats, dogs, pigs, cows, humans, etc. (eg, respiratory infections, urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, obstetrics and gynecology infections) For treating bacterial infections and surgical infections) can be used as an antibacterial agent.
  • mammals infected with bacteria for example, bacterial infections in mice, rats, dogs, pigs, cows, humans, etc. (eg, respiratory infections, urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, obstetrics and gynecology infections)
  • bacterial infections and surgical infections can be used as an antibacterial agent.
  • the daily dose of the compound (1 ′) or a salt thereof is in an amount of about 2 to 10 mg ZKg, more preferably about 5 to 40 mg / Kg of the compound (I ′).
  • the available salts are mixed with the appropriate pharmacologically acceptable carriers, excipients, and diluents by conventional means to form tablets, granules, capsules, drops, etc. It can be administered parenterally, or can be formed into an injection according to conventional means, manufactured by conventional means, blended into a sterile carrier, and administered non-parenterally. .
  • a binder eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, etc.
  • disintegrant eg, Methylcellulose calcium, excipients (eg, lactose, starch, etc.), lubricants (eg, magnesium stearate, talc, etc.) can be added as appropriate.
  • parenteral preparations such as injections, use isotonic agents (eg, budousugar, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (eg, benzylalkonil) , Chlorobutanol, methyl para-oxybenzoate, propyl para-oxybenzoate, etc.), and buffering agents (eg, phosphate buffer, sodium acetate buffer, etc.) can be appropriately compounded.
  • isotonic agents eg, budousugar, D-sorbitol, D-mannitol, sodium chloride, etc.
  • preservatives eg, benzylalkonil
  • Chlorobutanol methyl para-oxybenzoate
  • propyl para-oxybenzoate e.g, etc.
  • buffering agents eg, phosphate buffer, sodium acetate buffer, etc.
  • H P-20 Dyayon H P-20 (Mitsubishi Kasei Corporation, Japan)
  • X AD-2 Amber Lite X AD-2 (Roam ⁇ Hand ⁇ Company, USA).
  • s is a singlet
  • d is a doublet
  • dd is a double
  • t is a triplet
  • m is a multiplete
  • b is a broadband.
  • the reaction solution was subjected to pH 3.0.Qi by adding ethyl acetate, and the organic layer was separated and concentrated.
  • the residue was dissolved in ethyl acetate, extracted with aqueous solution of sodium carbonate (1.6 g) in 303 ⁇ 4 £ (divided into two portions), and the aqueous layer was adjusted to pH 2.5 with 5 N hydrochloric acid, and then extracted with ethyl acetate. Extracted (twice).
  • the organic layer was washed with a saturated saline solution, dried (MgSO 4 O, concentrated under reduced pressure with a zipper.
  • the residue was treated with ether, and the precipitated crystals were collected by filtration to give 1.16 g of the title compound. Obtained.
  • IR ⁇ ⁇ ⁇ ⁇ cm -1 3300, 1710, 169.5. 1680, 1545, 1330, 1250
  • Example 2 185 mg of the compound (2) obtained in Example 2 was dissolved in a mixed solution of 5% of ethyl sulphate and 5% of water, and 20 mg of 5% radiocarbon was added, followed by stirring at room temperature for 50 minutes in a hydrogen stream. did.
  • the catalyst was removed by filtration, and after the water method, the filtrate and the washing solution were combined, the aqueous layer was taken out, and 53 ⁇ 4 of tetrahydrofuran was heated and stirred under ice-cooling, and 67- ⁇ 2 of 2-phenylphenyl chloride and carbonic acid were added. An aqueous solution of sodium hydrogen was added thereto, and the reaction was carried out for 30 minutes while maintaining the temperature at around 7.0.
  • Example 5 Using 65 mg of the compound (5) obtained in Example 5, the reaction and post-treatment were carried out in the same manner as in the method of Example 3, to obtain 162 mg of the title compound (6) as a colorless powder.
  • IR ⁇ max at cm -1 1815, 1760, 1520, 1340, 1160, 1080.
  • Example 17 60 mg of (4R) —4-benzyloxycarbonylamino-3-isoxazolidinone was dissolved in dichloromethane 42, and the mixture was dissolved in ice-cooled diisopropylethylamine 0.08 » ⁇ and Example 1.
  • Example 17 60 mg of (4R) —4-benzyloxycarbonylamino-3-isoxazolidinone was dissolved in dichloromethane 42, and the mixture
  • Example 8 22 mg of the compound (8) obtained in Example 8 was dissolved in a mixture of ethyl acetate and PH7.0 phosphoric acid buffer 7.5; ⁇ , and 10% palladium carbon 220 g was added thereto. The mixture was stirred for 90 minutes under ice cooling. After removing the catalyst by filtration and washing with water, the filtrate and the washing liquid were combined, and the aqueous layer was separated. Tetrahydrofuran was added to the aqueous layer, and the mixture was cooled on ice and stirred with sodium bicarbonate. 11 Omg. 2- (2-octane rosacetamide 1-4-thiazolyl) 1- ( ⁇ )-2-methoxyoximino 195 mg of acid chloride hydrochloride was added.
  • Example 4 118 mg of (4S) -4-benzyloxycarbonylaminosoxosazolidinone obtained in Reference Example 4 was dissolved in 53 ⁇ 4 of dichloromethane, and 0.143 ⁇ 4 £ of triethylamine was added under ice cooling and stirring. 60 mg of the compound (1) obtained in 1 was added to a solution of 1 ⁇ ⁇ ⁇ ⁇ in dichloromethane. The reaction solution was washed at room temperature for 30 minutes, washed with water and dried (Na 2 S 0 + ), and the solvent was distilled off.
  • Example 23 25 mg of the compound (23) obtained in Example 23 was dissolved in 5- ⁇ -ethyl acetate and pH 7.0 phosphate buffer 7.5-JZ, and 25 mg of 10% palladium carbon was added, followed by hydrogenation. The mixture was stirred in an air stream for 75 minutes under ice cooling. After removing the catalyst by filtration and washing with water, the filtrate and the washing liquid were combined, and the aqueous layer was separated. Add tetrahydrofuran 5 ⁇ ⁇ to the aqueous layer, and ice ..
  • IR ⁇ iaxv at cm ' 1 1810, 1760, 1260, 1210, 1100, 1060, 880
  • Example 30 The compound (30) 30 mg obtained in Example 30 was dissolved in tetrahydrofuran 3 ⁇ 3, and 30 mg of 10% palladium-carbon was stirred at room temperature for 30 minutes in a heated air current. did. After removing the catalyst by filtration and washing with tetrahydrofuran, the filtrate and the washing solution were combined, and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (2: 3) to give the title compound (31) mg as a colorless oil.
  • IR ⁇ at cnT l 3300. 1800, 1760, 1660, 1530, 1260, 1080, 1035,
  • Example 32 68 mg of the compound (32) obtained in Example 32 was dissolved in a mixture of ethyl acetate and pH 7.0 phosphate buffer, and 10% palladium-carbon 7 Omg was added thereto. The mixture was stirred for 2 hours under ice cooling. After removing the catalyst by filtration and washing with water, the filtrate and the washing solution were combined, and the aqueous layer was separated. The aqueous layer is concentrated, and the concentrate is purified using an HP-20 column. Made. The fraction eluted with .5% ethanol is freeze-dried to give the title compound.
  • IRV i B r cm- 1 3400, 1775, 1720, 1650, 1530, 1370. 1185, 1110, max
  • IRV N " 301 cm” 1 1745, 1720, 1700. 1530. 1350, 1255
  • Example 39 To a solution of the compound (3-9) obtained in Example 39, 170 mg of sodium 2-dichloroethane (4.2%) was added thionyl chloride (0.30-6), and the mixture was ripened and refluxed for 3.5 hours. The solvent was distilled off, and the residue was subjected to column chromatography using florisil. Elution with hexane and hexane-ethyl acetate (3: 1) gave 79 mg of the title compound (40) as a colorless oil.
  • IR ⁇ m ilax at ci _1 1730, 1370, 1295, 1260, 1200, 1160, 1080
  • Example 2 Using the same method as in Example 1 (a) using 2.93 g of 2-oxoglutaric acid, 4.75 g of diphenylmethylbutamide and 3.63 g of dicyclohexylamine, 3.2 g of the title compound (42) were crystallized. As obtained. ⁇ Melting point: 107 °-109 ° C
  • Example 43-Tablets are prepared in a conventional manner using the following ingredients. 'Compound (4) obtained in Example 4' 30 Omg
  • the following components are used to produce disintegrants in a conventional manner.
  • Example 45 60 mg of the compound (45) obtained in Example 45 was dissolved in a mixture of ethyl acetate 5 ⁇ and PH 7.0 phosphate buffer (5 mL), and 10% paradigm carbon 15 Omg was added thereto. The mixture was stirred in a hydrogen stream under ice cooling for 4 hours. After removing the catalyst by filtration and washing with water, the filtrate and the washing liquid were combined to separate an aqueous layer. Add 33 ⁇ 4 of tetrahydrofuran to the aqueous layer, cool with ice, and stir with 3 Omg of sodium bicarbonate and 2- (2-chloroacetamide-4-1-thiazolyl)-(Z) -2-methoxyamino acid. 4 Omg of chloride hydrochloride was added.
  • IR K r cm “ 1 1780, 1720, 1660, 1530,1380,1030.
  • IRV 1 cm “ l 1820, 1760, 1380, 1080.
  • Stele [Compound (50)]: (a), 110 mg of (4S) -4-phenylacetylamino-1-3-isoxazolidinone and the compound obtained in Example 47 ( 47) DCC (15 mg) was added to 25 mg of dichloromethane (1 suspension), and the mixture was stirred at room temperature for 2 hours. The deposited crystals were removed by filtration and washed with dichloromethane.
  • IR cm- 1 3330, 1810, 1750.1670.
  • IR ⁇ I maIx 01 001 _1 3300, 1800, 1750, 1670, 1250.
  • Toxicarbonyl-3-isoxazolidino was dissolved in 103 ⁇ 4 of water and 103 ⁇ 4 of tetrahydrofuran, and benzyloxycarbonyl chloride 0.5713 ⁇ 4fi was added thereto while stirring under ice-cooling, followed by stirring for 1 hour.
  • the reaction solution was maintained at about 7.0 with sodium bicarbonate water.
  • the reaction solution was extracted twice with ethyl acetate, washed with brine, dried (MgS 0 + ), and concentrated under reduced pressure.
  • IRV cm- l 3340-, 1765,1730,1695,1535, 1290,1245,1225.
  • Example 52 104 mg of the compound (52) obtained in Example 52 was dissolved in ethyl acetate 3 ⁇ and water 3 ⁇ , 100 mg of 5% palladium carbon was added, and the mixture was heated at room temperature for 45 minutes in a hydrogen stream. I stirred it. The catalyst is removed by filtration, washed with water, and the filtrate and washing solution are combined to form an aqueous layer. Take tetrahydrofuran, add 103 ⁇ 4 3 ⁇ 4, add 2— (2-chloro ⁇ acetamido-4 4thiazolyl) -1- ( ⁇ ) —- 2-methoximinoacetic acid chloride hydrochloride 8 1 mg under ice-cooling and stirring.
  • IR T cm -1 1780, 1760-1730, 1665, 1530, 1040.
  • I R ( ⁇ : 3300.1750, 1710 (shoulder), 1690, 1540, 1255, 1225.
  • Example 54 Using 114 mg of the compound (54) obtained in Example 54, the reaction was carried out in the same manner as in Example 53 to obtain 50 mg of the title compound (55).
  • Compound ( ⁇ ′) or a salt thereof has an excellent antibacterial activity, and is an antibacterial agent. Is used as a therapeutic agent for bacterial infections

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Abstract

Composés représentés par la formule générale (I) (où R1 représente un groupe amino ou un résidu organique lié via un atome d'azote, R1 représente un groupe carboxyle ou un groupe dérivé de celui-ci, R3, R4, R5, R6, R7 et R8 peuvent être identiques ou différents et représentent chacun H ou un résidu organique, y compris dans le cas où R5 ou R6 forment une liaison chimique avec R7 ou R8, et X représente H, méthoxy ou formylamino). Ces composés présentent un excellent effet antibactérien et peuvent être utilisés comme agents antibactériens.
PCT/JP1985/000394 1985-04-30 1985-07-12 Composes antibacteriens, leur utilisation et procede de preparation WO1987000527A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
PCT/JP1985/000394 WO1987000527A1 (fr) 1985-07-12 1985-07-12 Composes antibacteriens, leur utilisation et procede de preparation
AT86302819T ATE80163T1 (de) 1985-04-30 1986-04-16 Antibiotische derivate, ihre herstellung und verwendung.
EP86302819A EP0219923B1 (fr) 1985-04-30 1986-04-16 Dérivés antibiotiques, leur préparation et leur application
DE8686302819T DE3686632T2 (de) 1985-04-30 1986-04-16 Antibiotische derivate, ihre herstellung und verwendung.
DK195986A DK195986A (da) 1985-04-30 1986-04-29 2-(4-substituerede amino-3-oxo-2-isoxazolidinyl)-5-oxo-2-tetrahydrofurankarboxylsyrederivater og fremgangsmaade og anvendelse deraf
HU861788A HU197742B (hu) 1985-04-30 1986-04-29 Eljárás izoxazolidinil-tetrahidrofurán-kárbonsav antibiotikum-származékok, és hatóanyagként e vegyületeket tartalmazó gyógyszerkészítmények előállítására
KR1019860003319A KR930005174B1 (ko) 1985-04-30 1986-04-29 항생물질 유도체의 제조방법
CA000507875A CA1285950C (fr) 1985-04-30 1986-04-29 Derives de l'acide 2-(amino-3-oxo-2-isoxazolidinyl substitue en 4)-5-oxo-2-tetrahydrofuranecarboxylique, leur production et leur utilisation
ES554495A ES8802317A1 (es) 1985-04-30 1986-04-29 Un procedimiento para preparar derivados de acido (2-aminosustituido-3-oxo-2-isoxazolidinil)-5-oxo-2-tetrahidrofuran-carboxilico
US06/857,834 US4851422A (en) 1985-04-30 1986-04-30 Antibiotic 2-(3-oxo-2-isoxazolidinyl)-5-oxo-2-tetrahydrofuran-carboxylates
CN198686102923A CN86102923A (zh) 1985-04-30 1986-04-30 制备抗菌素衍生物的方法
ES557661A ES8801650A1 (es) 1985-04-30 1987-08-13 Un metodo para preparar derivados de acido (2-amino sustutuido-3-oxo-2-isoxazolidinil)-5-oxo-2-tetrahidrofuran-carboxilico.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1985/000394 WO1987000527A1 (fr) 1985-07-12 1985-07-12 Composes antibacteriens, leur utilisation et procede de preparation

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WO1987000527A1 true WO1987000527A1 (fr) 1987-01-29

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PCT/JP1985/000394 WO1987000527A1 (fr) 1985-04-30 1985-07-12 Composes antibacteriens, leur utilisation et procede de preparation

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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No relevant documents disclosed. *

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