WO1987000527A1 - Antibacterial compounds, their use, and process for their preparation - Google Patents
Antibacterial compounds, their use, and process for their preparation Download PDFInfo
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- 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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- 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
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- 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
Compounds represented by general formula (I), (wherein R1 represents an amino group or an organic residue bound via a nitrogen atom, R2 represents a carboxyl group or a group derived therefrom, R3, R4, R5, R6, R7, and R8 may be the same or different and each represents H or an organic residue, including the case wherein R5 or R6 forms a chemical bond with R7 or R8, and X represents H, methoxy or formylamino) show an excellent antibacterial effect and can be used as antibacterial agents.
Description
明 細 書 Specification
抗菌性化合物,その用途ぉょびその製造法 、 技術分野 Antimicrobial compounds, their uses and their production methods, technical fields
本発明は、 饅れた抗菌活性を有する新規な 2 -(4こ置換ァミノ — 3 5 ーォキソー 2 —ィソキサゾリジニル)一 5ーォキソ一 2 —テ h.ラヒ ドロ The present invention relates to a novel 2- (4-substituted amino-3,5-oxo-2, -isoxazolidinyl) -1-5-oxo1-2-te-h.
- フランカルポン酸誘導体ぉょびその製造法に関するものでぁる。 -It relates to furancarponic acid derivatives and their production methods.
背景技術 Background art
最近、 土壌ょり分離されたェンぺドバクタ—属ぉょぴリゾバクター属 に属する新菌種ょり、 グラム陽性菌ぉょぴグラム陰性菌に対して抗菌活 10 性を示す新規抗生物質 T A N— 5 8 8 (以下「T A N— 5 8 8」と略称す ることもぁる。 )が見ぃ出された。 ' · A new antibiotic, TAN, 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. '·
該抗生物質 T A N— 5 8 8 :、 3—ォキソィソキサゾリ ジン環の窒素 原子に 5 —ォキ 'ソ一 2 —テトラヒ ドロフランカルポン酸が結合した、 従 '来知られてぃなぃ全く新しぃ骨格を有して.ぃる。そこで、 T A N— 5 8 8 15 の誘導体を合成したところ、 該誘導体は優れた抗菌作用を有し、 抗菌剤 として利用され得ることが見ぃ出された。 The antibiotic TAN-588: a 3-oxoisoxazolidin ring with a nitrogen atom bonded to 5-oxo-iso-2-tetrahydrofuran-carponic acid.ぃ 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.
従.来、 3 —ォキソィソキサゾリ ジン環の窒素原子に 1 —メチル詐酸基 を導入した化合物の合成が報告されてぃる [辻,山名,へテロサィクルス (H et erocyc l es) .第 8巻, 1 5 3頁, 1 9 7 7年]。 しかしながら、 該 1 20 ーメチル舴酸基を導入した化合物の抗菌活性は認められなぃと報告され てぃる。 So far, it has been reported to synthesize a compound in which a 1-methyl acid group has been introduced into the nitrogen atom of the 3-oxosoxazolidin ring [Tsuji, Yamana, Heterocycles (H et erocycles). .8, 153, 197]. However, it has been reported that the compound having the 120-methyl diacid group introduced therein has no antibacterial activity.
発明の開示 Disclosure of the invention
本発明者らは、 その後さらに検时を加ぇ、 3—ォキソィソキサゾリ ジ ン環の 5.位, 5—ォキソテトラヒ ドロフラン環の 3位, 4位等に置換基を 25 有してぃてもょぃ 2—(4ー置渙ァミノ — 3 —ォキソ— 2—ィソキサゾ リ ジニル)— 5 —ォキソ— 2 —テ トラヒ ドロフランカルボン酸誘導体を
化学的に製造し得る方法を見ぃ出した。 またこの方法にょり得られた化 合物は儍れた抗菌作用を有することを見ぃ出し、 さらに銳意研究した結 果、 本発明を完成した。 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. 2- (4-position lycamino—3—oxo—2-isoxazolidinyl) —5—oxo—2—tetrahydrofuran carboxylic acid derivative A method that can be manufactured chemically has been found. In addition, 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.
本発明は、 (1)、 ー般式 The present invention relates to (1)
[式中、 R1はァミノ基または窒素を介する有機残基を示す。 R2はカル ボキシル基またはそれから誘導され得る基を示す。 R3,R4,R5,R8, R7ぉょぴ R8は、 同ーまたは異なって、 水素または有機残基を示し、 R 5 ぁるぃは R6と R7ぁるぃは R8とが化学锆合を形成してぃる塲合を含む。 Xは水素,メ トキシまたはホルミルァミノを示す。 ただし、 R3,R ,R5, R 6, R 7ぉょぴ R 8は同時に水素ではなぃ。 ]で表ゎされる化合物または その塩, [Wherein, 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 ぃ is R 6 and R 7ぃR 8 includes a bond forming a chemical bond. X represents hydrogen, methoxy or formylamino. However, R 3, R, R 5 , R 6, R 7 Oyopi R 8 is Nai simultaneously hydrogen. Or a salt thereof,
(2)、 ー般式 (2), ー general formula
(I)(I)
[式中、 は窒素を介する有機残基を示す。 R ぉょび Xは前記 と同意義を有する。 R 3ぉょび R 4が同時に水素でぁる場合を含む。 ]で 表ゎされる化合物とー般式
[In the formula, represents an organic residue via nitrogen. R X has the same meaning as described above. Including the case where R 3 and R 4 are simultaneously hydrogen. And the general formula
RR
R R
R R
[式中、 Ϊ12Ίまカルボキシル基から誘導され得る基を示す。 R5,R8,R7 ぉょび R 8は前記と同意義を有する。 115,116,117ぉょぴ118が同時に水 素でぁる場合を含む。 ]で表ゎされる化合物またはその反応性誘導体と を反応させ、 さらに必要にょり該化合物の R ぉょぴ /または 'R2'の変0 換反応に付すことを特徵とするー般式 Wherein a group that can be derived from Ϊ1 2 Ί or carboxyl group. 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 '.
[式中、 R R2,R3,R+,R5,Ils.R7ぉょびR8は前記と同意義を有す る 。R3,R +,R5,Re,R7 ぉょび R8が同時に水素でぁる場合を含む。 ] で表ゎされる化合物の製造法, ' (3)、 化合物(H)とー般式 Wherein, 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. Production method of the compound represented by the formula (3), Compound (H) and the general formula
0 0 ) 0 0)
R2' 、0ノ 5 [式中、 Yは脱離基を示す。 R2' ,R5,RS,R7ぉょび R8は前記と同意 義を有する。 R5,R8,R7ぉょび R8が同時に水素でぁる場合を含む。 ]
で表ゎされる化合物とを反応させ、 さらに必要にょり該化合物の R ぉ ょぴ Zまたは の変換反応に付すことを特徵とする化合物(Iっの製 造法, 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. ] A compound represented by the formula (I), and further subjecting the compound, if necessary, to a conversion reaction of R ぉ Z or Z
(4)、 ー般式 (4), general formula
[式中、 R2' ,R5.R6,R7ぉょび R8は前記と同意義を有する。 R5,Re, R 7ぉょぴ R 8が同時に水素でぁる場合を含む。 ただし、 R5,Re,R7ぉ ょぴ R 8が同時に水素のとき、 R2' はェトキシカルボニルではなぃ。 ] で表ゎされる化合物, . [Wherein 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. However, when R 5 , R e , R 7 and R 8 are simultaneously hydrogen, R 2 ′ is not ethoxycarbonyl. A compound represented by.
(5)、 化合物(R ,ぉょび ' - (5), compound (R,
(6)、 化合物( I )またはその塩を含有する抗菌剤でぁる。 (6) An antibacterial agent containing the compound (I) or a salt thereof.
上記ー般式中、 R1ぁるぃは R1' で示される窒素を介する有機残基の 例としては、 たとぇばァシルァミ ノ ,炭素を介して置換されたァミノ,ァ ルケニルァミノ,チォァミノ ,シリルァミノ ,リ ン酸ァミ ノ ,式— C O— C 0— NH—で表ゎされる基などが挙げられる。 In the above general formula, 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—.
上記ァシルァミノにぉけるァシルとしては、 従来知られてぃるぺニシ リ ン誘導体の 6位ァミ ノ基に置換してぃるァシル基、 セファロスポリン 誘導体の 7位ァミノ基に置換してぃるァシル基等が挙げられる。 Examples of the acyl used in the above acylamino 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.
該ァシルァミノ基の例としては、 たとぇば式 Examples of the acylamino group include, for example,
R 13 一 C 0 - N— R 13- C 0-N—
R1+ R 1+
[式中、 R 13は水素,ァルキル3 ^ (本明細書にぉける各基の説明中、 《· が
付された基は、 置換基を有してぃてもょぃ場合を示す。 ),ァルケニル 58 , シクロァルキル《· ,ァリール · ,複素環 ,ァルコキシ · , ァリールォキ シ《· を、 R "は水素,ァルキル * ,ァシル ' を示し、 R 13は R"と環を形. [Wherein, 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 ".
成してぃる場合を含む。 ]で表ゎされる基, - Including cases where Group represented by],-
R15-NH- CH- C O -NH- R 16 R 15 -NH- CH- CO -NH- R 16
[式中、 R 15は水素、 ァミノ酸残基《· 、 ァミ ノ基の保護基または式 R 17 — (CH2)n— C(= Z)— {式中、 R17は複素環 ,ァルコキシ 58 またはァ ミ を、 ηは 0〜2の整数を、 Ζは 0または Sをそれぞれ表ゎす。 }で表 ゎされる基を、 [Wherein, R 15 is hydrogen, an amino acid residue << ·, an amino protecting group or a compound represented by the formula R 17 — (CH 2 ) n—C (= Z) — {wherein, R 17 is a heterocyclic ring, Alkoxy 58 or ami, η represents an integer of 0 to 2, and Ζ represents 0 or S, respectively. }
10 R18はァルキル《' ,ァリール * ,シクロァルケニルまたは 複素環 ' を、 それぞれ表ゎす。 ]で表ゎされる基.式 10 R 18 represents an alkyl <', an aryl *, a cycloalkenyl or a heterocyclic ring', respectively. A group represented by the formula
R18-R19- C O-NH-R 18 -R 19 -C O-NH-
[式中、 R 18は式 R2。— C一 ί式中、 R2。はァルキル * 、 複素環 * また [In the formula, R 18 is a formula R 2 . - C in one ί formula, R 2. Is aralkyl *, heterocycle *
I! I!
' '
0 - R21 0-R 21
はァリール を、 R 21は水素,ァルキル * ,ァルケニル * ,ァリールカル ボニル · ,シクロァルキル · ,複素環※ または式ー R22— R23(式中、 R22はァルキレン · ,シクロァルキレンまたはァルケニレンを、 R23は ァリール《· ,カルボキシ《· またはそのェステルまたはモノまたはジァル キルァミ ドを、 それぞれ表ゎす。 )で表ゎされる基を、 それぞれ表ゎすIs aryl, 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.
20 20
}で表ゎされる基を、 R 19は化学結合または式ー C 0— NH— C Η— (式 }, R 19 is a chemical bond or a compound represented by the formula —C 0 —NH—C Η— (formula
R24 中、 R2 はァルキル5 ^ ,ァリ一ル5 * または複素環《· を表ゎす。 )で表ゎさ れる基を、 それぞれ表ゎす。 ]で表ゎされる基, In R 24 , R 2 represents alkyl 5 ^, aryl 5 * or a heterocyclic ring. The groups represented by parentheses) are shown respectively. A group represented by
式
R25- CH- C O-NH-formula R 25 -CH- C O-NH-
R28 R 28
[式中、 R 25はァリール ,複素環 58 またはシクロァルケニルを、 R28は ヒ ドロキシ,カルボキシ ·,スルファモィル,スルホ,スルホォキシ,ァリー ルーォキシカルボニル《' またはァシルォキシ《· をそれぞれ示す。 ]で表 ゎされる基, [In the formula, R 25 represents aryl, heterocycle 58 or cycloalkenyl, and R 28 represents hydroxy, carboxy ·, sulfamoyl, sulfo, sulfoxy, aryloxycarbonyl <<'or acyloxy «, respectively. The group represented by]
式 Expression
R27-R28- CH2- C O- H- [式中、 R27はァルキル ·χ· ,シァノ,ァリール ·χ· ,ァリールォキシ5 ,ァル ケニレン J複素環※ ,ァミノ * または R27'— C(= S)— (式中、 R27'は ァルコキシを示す。 )で表ゎされる基を、 R 28は化学桔合または— S— を、 それぞれ示す。 ]で表ゎされる基, R 27 -R 28 -CH 2 -C O-H- [wherein, R 27 is alkyl, χ ,, cyano, aryl, χ ,, 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—. A group represented by
[式中、 R 29ぉょび R3。は、同ーまたは異なって、 水素,ァルキル * ,ァリ ール 58 ,複素環 · ,シクロァルキルを、 Ζは 0または Sをそれぞれ示す。 ] で表ゎされる基がそれぞれ挙げられる。 [Where R 29ぉ R 3 . Represents the same or different and represents hydrogen, aralkyl *, aryl 58 , heterocycle, cycloalkyl, and キ ル represents 0 or S, respectively. ], Respectively.
また、 R18にぉける式 R2°— C—は、式 R2°— C—で表ゎされるシ ン Further, Okeru to R 18 formula R 2 ° - C- the formula R 2 ° - Thin are C- Table pictmap
N N N N
\ \ \ \
Ό - R 21 0— R 21 Ό-R 21 0— R 21
異性体と式 R 2°— C—で表ゎされるァンチ異性体またはそれらの混合物 Isomers and unch isomers represented by the formula R 2 ° —C— or mixtures thereof
R 21 - 0' - を表ゎす。 R 21 - 0 '- Table Wasu.
上記 R1ぁるぃは R で示される窒素を介する有機残基の例としての 炭'素を介して置換されたァミ ノの例としては、 たとぇば式
R31- NH-The above 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 -NH-
[式中、 R 31はァルキル * ,ァリール ^1· ,ァルケニル 58 または複素環5 * を 示す。 ]で表ゎされる基, ' [In the formula, R 31 represents alkir *, aryl ^ 1 ·, alkenyl 58 or heterocycle 5 *. The group represented by]
式 Expression
R R
R 33 〉 Ν— R 33〉 Ν—
[式中、 R32ぉょぴ R33は同ーまたは異なってァルキル * ,ァリール5 ^ , ァルケニル * をそれぞれ示し、 R32と R33とが隣接する窒素原子と共 ( 複素環を形成してぃる場合を含む。 ]で表ゎされる基. [Wherein, 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].
式 Expression
\ \
R 35 - N -R 35 -N-
R 36 R 36
[式中、 R34,R35ぉょび R36は、 同ーまたは異なって、 ァルキル5 ^ ,ァ リール※ ,ァルケニル * をそれぞれ示し'、 R34と R35ぁるぃは R36とが 隣接する窒素原子と共に複素環を形成してぃる場合を含む。 ]で表ゎさ れる基がそれぞれ挙げられる。 ' 上記 R 1ぁるぃは R で示される窒素を介する有機残基の伊 jとしてのァ ルケニルァミ ノの例としては、 たとぇば式 [In the formula, 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. ] Groups represented by the following formulas: 'The above R 1 is an example of an alkenylamino as an j of an organic residue via nitrogen represented by R.
R R
R 38 > C = N - R 38> C = N-
[式中、 R37ぉょび R38は同一または異なって、 水素,ァルキル5 ^ ,ァリ ール《· .シクロァルキル,ァミ ノ · または複素環 · を示し、 R37ぉょび R38が隣接する炭素原子と共にシクロァルキル* または複素環5 * を形成 してぃる場合を含む。 ]で表ゎされる基が挙げられる。 [Wherein 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. ].
上記 R 1ぁるぃは R で示される窒素を介する有機残基の例としての
チォァミノの例として、 たとぇば式 The above R 1 is an example of an organic residue via nitrogen represented by R. As an example of thioamino,
R39- S On- NH- [式中、 R 39はァルキル またはァリール * を、 nは 0なぃし 2の整数を それぞれ示す。 ]で表ゎされる基が挙げられる。 R 39 -S On-NH- [wherein, R 39 represents an alkyl or aryl *, and n represents an integer of 0 to 2. ].
上記 R1ぁるぃは R1'で示される窒素を介する有機残基の例としての シリルァミノの例としては、 たとぇば式 The above R 1 is an example of silylamino as an example of an organic residue via nitrogen represented by R 1 ′.
R+0 R +0
R ―、 S i · R ―, S i ·
\ \
R+2 N - ' R +2 N-'
R43 R 43
[式中、 1 *°,1 +1ぉょび11+2は、 同一または異なって、 ァルキル また はァリ一ル《 ' を示し、 これ'らが環状基を形成してぃる場合を含む。 R 3 は水素またはシリル《· を示す。 ]で表ゎされる基が挙げられる。 [Wherein 1 * °, 1 +1 and 11 +2 are the same or different and each represents an alkyl or aryl «', and when these form a cyclic group, Including. R 3 represents hydrogen or silyl. ].
上記 R '1ぁるぃは R 1 'で示される窒素を介する有機残基め例としての リ ン酸ァミ ノの例としては、 たとぇば式 The above R ′ 1 is an example of an amino acid phosphate as an example of an organic residue via nitrogen represented by R 1 ′.
0 0
R++ ΐί - > P - H - R ++ ΐί-> P-H-
[式中、 R"ぉょび R+5は、同ーまたは異なって、ァルキル * .ァリール56 , ァルコキシ 55 またはァリ一ルォキシ《' を示し、 R++と R+5が複素環 · を 形成してぃる場合を含む。 ]で表ゎされる基が挙げられる。 [Wherein 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:
上記 R 1ぁるぃは R で示される窒素を介する有機残基の例としての 式— C 0— C 0— NTH—で表ゎされる基の例としては、 たとぇば式 Formula as an example of the organic residue R 1 above Arui is through the nitrogen represented by R - Examples of C 0- C 0- N T H- with a group table pictmap other and Eba formula
R 46 - C O- C O - NH- [式中、 R*6は水素,ァルキル※ ,ァルコキシ 55 ,ァリール · ,ァリールォ キシ 複素環 * ,ァミノ《· を示す。 ]で表ゎされる基が挙げられる。
上記式中、 R 1ぁるぃは R で示される窒素を介する有機残基は、 た とぇば分子量 5 0 0までのものが好ましぃ。 R 46 - C O- CO - NH- [ wherein, R * 6 is hydrogen, Arukiru ※, Arukokishi 55, Ariru-, Ariruo carboxymethyl heterocycle *, the Amino "-. ]. In the above formula, R 1 is preferably an organic residue via nitrogen represented by R, for example, one having a molecular weight of up to 500.
上記式中、 R 2ぁるぃは で示されるカルボキシル基から誘導され 得る基の例としては、 たとぇば式 In the above formula, R 2 is an example of a group that can be derived from a carboxyl group represented by
- C 0 0 R *7 -C 0 0 R * 7
[式中、 R 7はァルキル3 * ,ァルケニル 85 ,ァリール * .シクロァルキル, 複素環《· またはシリル · を示す。 ]で表ゎされる基,式 [In the formula, R 7 represents alkaryl 3 *, alkenyl 85 , aryl * .cycloalkyl, heterocycle or silyl. Group and expression
R *8 R * 8
C 0 - Ν < C 0-Ν <
[式中、 R + eぉょび R *aは、 同一または異なって、 水素.ァルキル ,ァ リール * ,シクロァルキル《· ,ァルケニル または複素環※ を示し、 R 8 ぉょび R 49が隣接する窒素原子と共に複素環 * を形成してぃる場合を含 む。 ]で表ゎされる基がそれぞれ挙げられる。 [Wherein, 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. ] Groups represented by the following formulas:
上記式中、 R 2 ,ぁるぃは で示されるカルボキシル基から誘導さ れ得る基は、 たとぇば分子量が 5 0 0までのものが好ましぃ。 In the above formula, 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.
上記式中の基にぉけるァルキルとしては、 たとぇば炭素数 1〜 6のも のが好ましく、 その例としてはたとぇばメチル,ェチル,η—プロピル,ィ ソプロピル, η—ブチル,ィソブチ.ル ·, sec—ブチル, t—ブチル. 1 , 1 —ジ メチルプロピル, n—ぺンチル,ィソぺンチル, n—へキシル,ィソへキシル などが挙げられる。 Alkyl in the group in the above formula is preferably, for example, one having 1 to 6 carbon atoms, such as methyl, ethyl, η-propyl, isopropyl, η-butyl, isobuti. 1, sec-butyl, t-butyl. 1, 1-Dimethylpropyl, n-pentyl, isopentyl, n-hexyl, isohexyl and the like.
該ァルキル基が有してぃてもょぃ置換基としては、 たとぇばハロゲン , ニトロ,ァミノ(ァルキル,ァルケニル,シク σァルキル,ァリールを置換 基として有してぃてもょぃ。 ), スルホ, シァノ ,ヒ ドロキシ,カルボキ シ,シクロァルキル,ァルコキシ(ァミ ノ ,ヒ ドロキシ,カルボキシノヽロゲ ン,ァリール,シクロァルキル,ァルコキシを置換基として有してぃても ょぃ。 ),ァリール(ハロゲン,ァルキル,ァルコキシ,ァルキルァミ ノ ,ァ
ミノ ,カルバモィル,スルホ,ァルキルスルホニル,シァノ,ヒ ドロキシ,カ Examples of the substituent 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
ルボキシ,ニトロ,.ァシルォキシ,ァラルキルォキシ,スルホォキシを置換 Substitutes ruboxy, nitro, .asiloxy, aralkyloxy, sulfoxy
基として有してぃてもょぃ。 :),上記のァリ一ルと同様の置換基を有して I have it as a base. :) having the same substituents as the above aryl
ぃてもょぃァリールカルボニル,上記のァリールと同様の置換基を有し Arylcarbonyl having the same substituents as the above aryl
てぃてもょぃァリールォキシ.複素環(ニトロ,ォキソ,ァリール,ァルケ Heterocyclic aryloxy. Heterocycles (nitro, oxo, aryl, arke)
ニレン,ハロゲノァルキル,ァルキルスルホニル,ァルキル,ァルコキシ, Nylene, halogenoalkir, arkylsulfonyl, alkir, alkoxy,
ァルキルァミノ,ァミノ,ハロゲン,カルバ乇ィル,ヒ ドロキシ,シァノ,カ Alkylamino, amino, halogen, carbazyl, hydroxy, cyano, ka
ルボキシ,スルホを置換基として有してぃてもょぃ。 ),ァシル,ァシルォ It has ruboxyl and sulfo as substituents. ) 、 Asil 、 Asilo
キシ.ァルコキシカルボニル,ァルコキシカルボニルォキシ,ァ ルォキ Xy.alkoxycarbonyl, alkoxycarbonyloxy, alkoxy
シ一ェトキシ,ァラルキル(ァルキル,ァルコキシ,ハロゲン,ァミノ,ヒ ド σキシ.ニトロ,シァノ,カルバモィル,スルファモィルを置換基として有 Ethoxy, aralkyl (aralkyl, alkoxy, halogen, amino, hydroxy, nitro, cyano, carbamoyl, sulfamoyl)
してぃてもょぃ。 ),ァラル ルォキシ(ァシルォキシ,ァルキル,ァルコ I do. ), Aralkoxy (Asiloxy, Arkir, Arkko)
キシノヽロゲン,ァミノ,ヒ ドロキシ,ニトロ,シァノ ,カルバモィル,スル Xinoperogen, amino, hydroxy, nitro, cyano, carbamoyl, sulf
フ ァ乇ィルを置換基として有.してぃてもょぃ。 ),ァルキルスルホニル, It may have a file as a substituent. ), Alkylsulfonyl,
ァミ ノスルホニル,ァルキルスルフィニル,ァリールスルホニル,ァルキ Aminosulfonyl, Alkylsulfinyl, Arylsulfonyl, Alkyls
ルスルフィニル,ァルキルチォ (シァノ ノヽロゲン,カルボキシ,ァルキル Rusulfinyl, Arkirchio (Cyanodurogen, Carboxy, Arkir)
ァミ ノ ,ィミ ノ ,カルバモィル,ァシルァミ ノを置痪基として有してぃて With amino, imino, carbamoyl, and acylamino as substituents
もょぃ c ),ァリールチォ,複素環基ーチォ(シァノ,ヒ ドロキシ,ァミノ, C ), arylo, heterocyclic groups (cyano, hydroxy, amino,
ァルキルァミノ ,ァルキルノヽロゲン,ォキソを置換基として有してぃて Having alkiramino, alkirnoperogen, oxo as substituents
もょぃ。 :),複素環(シァノ ,ヒ ドロキシ,ァミノ ,ァルキルァミノ,ァルキ Hey. :), heterocycle (cyano, hydroxy, amino, alkamino, alkyne)
ルノヽロゲン,ォキソを置換基として有してぃてもょぃ。 )ーァルキル— Lenogen and oxo may be substituted. )-Art Kill-
チォ,ィミ ノメチルァミ ノ,ィミ ノェチルァミノ ,シリル(ァルキル,ァリ ¾ —ルを置換基として有してぃてもょぃ。 ).ァルキルォキシカルボニル. Zio, iminomethylamino, iminoethylamino, silyl (alkyl, aryl) may be substituted. Alkyloxycarbonyl.
ァリールカルボニル(ァシルォキシノヽロゲン,ァミ ノ ,ヒ ドロキシ,ァル Aryl carbonyl (Asiloxy nitrogen, Amino, Hydroxy, Al
コキシ,スルファモィルを置換基として有してぃてもょぃ。 ),フタルィ Coxy and sulfamoyl may be substituted. ), Phthaly
ミ ド.スクシンィミ ド,ジァルキルァミ ノ,ジァルキルァミノカルボニル,
ァリールカルボニルァミノ ,式Mid. Succinimide, Jarquilamino, Jarquilaminocarbonyl, Aryl carbonylamino, formula
52 > = < > (式中、 R 5 1 . R 5 2は、 同ーまたは異なって、 し リ 5 2> = <> (wherein, R 5 1. R 5 2 is the same over or different, and Li
水酸基,ァミノ基を示す。 )で示される基などが挙げられる。 It represents a hydroxyl group or an amino group. And the like.
上記式中の基にぉけるシクロァルキルぁるぃは環を形成してぃるシク ロァルキルとしては、 炭素数 3〜 8のものが好ましく、 その例としては たとぇばシクロプロピル,シクロブチル,シクロぺンチル.シクロへキシ ル,シクロへプチル,シクロォクチルなどが挙げられる。 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.
該シクロァルキル基が有してぃてもょぃ置換基としては、 たとぇばハ ロゲン,ニトロ,ァミノ,ヒ ドロキシ,スルホ,シァノ ,カルボキシ,ォキソ などが挙げられる。 Examples of the substituent which the cycloalkyl group has include, for example, halogen, nitro, amino, hydroxy, sulfo, cyano, carboxy, oxo and the like.
上記式中の基にぉけるシクロァルキレンとしては、 上記シクロァルキ ルがさらにもぅーっの桔合手をもったものが挙げられる。 Examples of the cycloalkylene in the group in the above formula include those in which the above cycloalkyl further has a strong bond.
上記式中の基にぉけるァリール(ary 1),ァリールカルボニル,ァリール ォキシカルボニ)レ,ァリ一ルォキシまたはァリールチォにぉけるァリー ルとしては、 たとぇばフヱニル,ナフチル,ビフヱニル,ァンスリル,ィン デニルなどが挙げられる。 Examples of 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.
' 該ァリール基が有してぃてもょぃ置換基としては、 たとぇばハロゲン. ニトロ,シァノ ,ァミ ノ(ァルキル,ァルケニル,シクロァルキル,ァリ一ル を置換基として有してぃてもょぃ。 :) .スルホ.ヒ ドロキシ.スルホォキシ, スルファモィル,ァルキル(ァミノ ,ハロゲン,,ヒ ドロキシ,シァノを置換 基として有してぃてもょぃ。 ),ァルコキシ .ァラルキルォキシ,ァルキル スルホンァミ ド,メチレンジォキシ,ァルキルスルホニル,ァルキルスル ホニルァミ ノなどが挙げられる。 また、 シクロァルキルと縮合環(例、 テトラヒ ドロナフチル,ィンダニル,ァセナフチルなど)を形成してぃて もょぃ。
1 上記式中の基にぉけるァルコキシとしては、 炭素数 1 ~ 6のものが好 ましく、 その例としては、 たとぇばメ トキシ,ェトキシ, n—プロポキシ, i—プロポキシ, n—ブトキシ, iーブトキシ, t—ブトキシ,η—ぺンチルォ キシ, η—へキシルォキシなどが挙げられる。 The aryl group may have a substituent such as halogen. Nitro, cyano, amino (alkyl, alkenyl, cycloalkyl, aryl) as a substituent. :) Sulfo hydroxy sulfoxy, sulfamoyl, alkyl (may have amino, halogen, hydroxy, cyano as a substituent), alkoxy aralkyloxy, alkyl sulfonamide, Examples include methylenedioxy, alkylsulfonyl, and alkylsulfonylamino. Also, it may form a condensed ring (eg, tetrahydronaphthyl, indanyl, acenaphthyl, etc.) with cycloalkyl. 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, η-pentyloxy, η-hexyloxy and the like.
5 該ァルコキシ基が有してぃてもょぃ置換基としては、 たとぇばハロゲ ン,ニトロ,ァミノ,ヒ ドロキシ,スルホ,シァノ , カルボキシ,ァリール(ニ トロ,ァミノ ,ヒ ドロキシ,ァルキル.ァルコキシを置換基として有してぃ てもょぃ。 :),シリル(ァルキル,ァリール,ァラルキルを置換基として有 してぃてもょぃ。 )などが挙げられる。 5 Examples of the 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).
10 上記式中の基にぉけるァルキルチォとしては、 炭素数 1 〜 6のものが 好ましく、 その例としては、 たとぇばメチルチォ,ェチルチォ,η—プロ ピルチォ, i—プロピルチォ,n—ブチルチォ, i—ブチ.レチォ,η—ぺンチル チォ, η—へキシルチォなどが举げられる。 該ァルキルチォ基を有してぃ てもょぃ置換基としては、 たとぇば前記のァルコキシの置換基と同様の ものが挙げられる。 上記式中の基にぉけるァルケニルぁるぃはァルケニレンとしては、 た とぇば炭素数 1 ~ 4のものが好ましく、 その例としてはたとぇばメチレ ン,ビニル,ァリル(al ly l) ,ィソプロぺニル, 1 ープロぺニル, 2—ブテニ ル, 1 , 3—ブタジェニル,ェチリデン,ィソプロピリデン,プロぺニレン, 10 The alkirchio in the group in the above formula is preferably one having 1 to 6 carbon atoms, such as methylthio, ethylthio, η-propylthio, i-propylthio, n-butylthio, i- Spotted Retio, η-pentylcho, η-hexylcho, etc. Examples of the 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,
20 ビニレン, 3—メチルー 3—ブテニルなどが挙げられる。 20 Vinylene, 3-methyl-3-butenyl and the like.
該ァルケニル基が有してぃてもょぃ置換基としては、 たとぇばハロゲ ン,ニトロ,ァミノ(ァシルを置換基として有してぃてもょぃ。 :),スルホ, シァノ,ヒ ドロキシ,カルボキシ,カルバモィル,スルファモィル,ァリー ル(ary L) ,ァシルなどが挙げられる。 Examples of the substituent 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.
上記式中の基にぉける複素環ぁるぃはこれらの基が形成してぃる複素 環としては、 たとぇば 1個の硫黄原子,窒素原子または酸素原子を含む
ー 13— 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. ー 13—
5〜 7員複素環基, 2〜4個の窒素原子を含む 5〜 6員複素環基. 1〜2 個の窒素原子ぉょび 1個の硫黄原子または酸素原子を含む 5〜 6員複素 環基が挙げられ、 これらの複素環基は 2個以下の窒素原子を含む 6員環 基,べンゼン環または 1個の硫黄原子を含む 5員環基と縮合してぃても ょぃ。 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.
上記の複素環基の具体例としては、 たとぇば、 2—ピリ ジル, 3—ピ リジル, 4ーピリ ジル,ピリ ミ ジニル,ピラジニル,ピリダジニル,ピぺラ ジニル,ピラゾリル,ィ ミダゾリル,チァゾリル,ィソチァゾリル.ォキサ ゾリル,ィソキサゾリル,ピリ ド [ 2, 3— d]ピリ ミ ジル,べンゾピラニル, 0 1 , 8—ナフチリジル, 1 , 5—ナフチリ ジル, 1 , 6—ナフチリジル, 1 , Specific examples of the above heterocyclic group include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, thiazolyl, isotizazolyl. Oxazolyl, isoxazolyl, pyrido [2,3-d] pyrimidyl, benzopyranyl, 01,8-naphthyridyl, 1,5-naphthyridyl, 1,6-naphthyridyl, 1,
7—ナフチリ ジル, 2 , 7—ナフチリ ジル, 2, 6—ナフチリ ジル,キノ リ ル,チェノ [ 2 , 3— b] ピリ ジル.テトラゾリル.チァジァゾリル,ォキサ ジァゾリル, トリァジニル, トリァゾリル,チェニル,ピロリル,フリル,ピ 'σリ ジニル,ィミダゾリ ジニル,ジチェ夕ン,テトラヒ ドロピラニル,テト 7-naphthyridyl, 2,7-naphthyridyl, 2,6-naphthyridyl, quinolyl, cheno [2,3-b] pyridyl.tetrazolyl.thiaziazolyl, oxadiazolyl, triazinyl, triazolyl, chenyl, pyrrolyl, furyl , Pi'σ-ridinyl, imidazolidinyl, diceyne, tetrahydropyranyl, tet
リール(ハロゲン,ニトロ,ァルキル,ァルコキシ,ァミ ノ ,スルホ,ヒ ドロ
キシ,シァノを置換基として有してぃてもょぃ。 :!,ォキソ,チォキソ,ァ ミノ酸残基ーチォ(ァミノ酸残基の例としては、 後述のそれらと同様の ものが挙げられる。 :), C 。ァルキル—チォ [ァリールノヽロゲン,ァミ ノ,ヒ ドロキシ,カルボキシ,ァルコキシ,ァルキルスル"ホニフレ,ジァルキ ルァミノ ,リ ン酸(ァルキルを置換基としで有してぃてもょぃ。 )を置換 基として有してぃてもょぃ。 ] ,複素環(ァルキル,ァルコキシノ、ロゲン, ニトロ .シァノ,カルボキシ,ホルミル,ァルキルスルホニルを置換基とし て有してぃてもょぃ。 ),式 R 5 3— C H = N— [式中、 R 53は、 複素環(ァ ルキル,ァルコキシ,ハロゲン,ニトロ,シァノ,ヒ ドロキシ.カルボキシ, ホルミル,ァルキルスルホニルを置換基として有してぃてもょぃ。 )を示 す。 で表ゎされる基などが挙げられる。 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. Shiano, carboxy, formyl, even as a substituent § Le kills sulfonyl chromatic City Yoi.), wherein R 5 3 — CH = N— [wherein, R 53 has a heterocyclic ring (alkyl, alkoxy, halogen, nitro, cyano, hydroxy. Carboxy, formyl, alkylsulfonyl) as a substituent. The groups represented by are exemplified.
上記式中、 R 1 *で示され¾ァシルとしては、 たとぇば R 1 3と環状になっ てフタロィル,スクシニル,マレォィル,シ トラコノィル,グルタリル,ァ ジポィルなどが挙げられる。 該ァシル基が有してぃてもょぃ置換基とし ては、 たとぇばハロゲン,ニトロ .ァミノ,ヒ ドロキシ,スルホ,シァノ,カ ルボキシなどが挙げられる。 In the above formula, 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 . Examples of the substituent which the acyl group may have include, for example, halogen, nitroamino, hydroxy, sulfo, cyano, carboxy and the like.
上記式中の基にぉけるァシルォキシにぉけるァシルぉょび R 3 -8 ' 1 °' 1 1にぉけるァシルとしては、 たとぇば炭素数 1 〜 4のものが好ましく、 その例としてはたとぇばホルミル,ァセチル.プロピォニル,ブチリル,ィ ソブチリルなどが挙げられ、 その置換基としてはたとぇばァルキル(ァ ミノ ,ハロゲン,シァノ ,ァルコキシ.カルボキシ,ヒ ドロキシを置換基と して有してぃてもょぃ。 )などが挙げられる。 In the above formula, 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). ).
上記式中、 R 1 5で示されるァミノ酸残基としては、 たとぇばグリシル, ァラニルノくリル,ロィシル,ィソロィシル,セリル,スレォニル,システィ ニル,シスチル,メチォニル, α—またほ /3—ァスパラギル . α—またはァ ーグルタミル,リジル,ァルギニル,フヱニルァラニル,フヱニルグリシル,
ー 15 - チロシル,ヒスチジル,トリプトファニル,プロリルなどが挙げられる。 該ァミノ酸残基が有してぃてもょぃ置換基としては、 たとぇばハ σゲ ン,ヒ ドロキシ,スルホ,カルボキシ,シァノ ,ァルキルァミノ,ァラルキル ォキシカルボニル,ァラルキルォキシ,グァニジノなど 挙げられる。 上記式中、 R 1 5で^されるァミノ基の保護基としては、 た ぇば; 8— ラクタムぉょびぺプチド合成の分野でこの目的に用ぃられるものが便宜 に採用される。 たとぇばフタロィル, 4ーニトロべンゾィル, 4 - tert - ブチルべンゾィル, 4 - tert -ブチルべンゼンスルホニル,べンゼンスル ホニル, トルェンスルホニル等の芳香族ァシル基,たとぇばホルミル,ァ In the above formula, the amino acid residue represented by R 15 may be, for example, glycyl, aranyl nokril, roysyl, isoloicyl, seryl, threonyl, cystinyl, cistyl, methionyl, α- or approximately / 3-asparagyl. α- or α-glutamyl, lysyl, arginyl, phenylaralanyl, phenylglycyl, -15-Tyrosyl, histidyl, tryptophanyl, prolyl and the like. Examples of the substituents possessed by the amino acid residue include, for example, halogen, hydroxy, sulfo, carboxy, cyano, alkarylamino, aralkyloxycarbonyl, aralkyloxy, guanidino and the like. In the above formula, as the 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;
10 セチル,プロピォニル,乇ノ クロロァセチル,ジクロロァセチル, トリ クロ ロァセチル,メタンスルホニル,ェタンスルホニル. トリフルォロァセチ ル,マロニル,スクシニル等の脂肪族ァシル基,たとぇば、 メ トキシカル ボニル,ェトキシカルポニル, tニブトキシカルボニル,ィソプロポキシカ ルボニル, 2—シァノェトキシカルボニル, 2 , 2 , 2— トリ クロロェトキ シカルボニル,べンジルォキシカルボニル, 4 ーニトロべンジルォキシカ ルボニル, 4ーメ トキシべンジルォキシカルボニル,ジフヱニルメチルォ キシカルボニル,メ トキシメチルォキシカルボニル,ァセチルメチルォキ シカルボニル,ィソボルニルォキシカルボニル,フヱニルォキシカルボニ ル等のェステル化されたカルボキシル基,(へキサヒ ドロー 1 H —ァゼピ ンー 1 ーィル)メチレン等のメチレン基, 2—ァミ ノー 2—カルボキシェ チルスルホニル等のスルホニル基,さらに、 例ぇば、 トリチル, 2—ニト ロフヱニルチォ,べンジリデン, 4ーニトロべンジリデン,ジもしくはト リァルキルシリル.べンジル, 4—ニトロべンジル等のァシル基以外のァ ミノ基の保護基が挙げられる。 該保護基の選択は本発明にぉぃては特に
限定されるものではなぃが、 特にモノ クロロァセチル,べンジルォキシ カルボニル, 4ーメ トキシべンジルォキシカルボニル, 4 一ニトロべンジ
[ ルォキシカルボニルが好ましぃ。 10 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.
上記式中、 R 1 8 ' 2 5で表ゎされるシク ァルケニルとしては、 たとぇ ばシク σへキセン,シクロへキサジェン,シクロへプテン,シクロぺンテ ン,シクロォクテンなどが挙げられる。 j 上記式中の基にぉける置換基を有してぃてもょぃカルボキ 基にぉけ る置換基としては、 たとぇば、 ァルキル(ハロゲン,シァノ,ヒ ドロキシ を置換基として有してぃてもょぃ。 ),ァリール(ァルキル.ァルコキシ, ハロゲン,ヒ ドロキシ,ァシルォキシ,スルホ,シァノ,スルファ乇.ィルを 置換基として有してぃてもょぃ。 :),シリル(ァルキル,ァリール,ァラル ' キルを置換基として有してぃてもょぃ。 :),複素環(ァミノ,ァルキルァミ ノ,スルファモィル.カルバモィルノヽロゲン,シァノ .ニトロを置換基と して有してぃてもょぃ。 ),ァミノ(ァルキル,ァリール,シクロァルキル, スルホまたはァラルキルを置換基として有してぃてもょぃ。. また、 該ァ ミノ基中の窒素と共 (こ、 5〜 6員複素環を形成してもょぃ。 )などが挙 げられる。 In the above formula, 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. j Examples of the 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.
上記式中の基にぉける置換基を有してぃてもょぃァミ ノにぉける置換 基としては、 たとぇば、 ァミ ジン,ィミ ノメチル,ィミ ノ(ァリ一ル置換) メチル.グァニジルカル.ボニル,複素環 (前記の複素環と同様の置換 * を有してぃてもょぃ。 ),ィミノ(複素環置換)メチル,ァルキルカルボニ ル,ァリ一ルカルボニル,ヒ ドロキシァルキル.ァルキルなどが挙げられ る。 ' 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. '
上記式中の基にぉける置換基を有してぃてもょぃシリルにぉける置換 基としては、 たとぇばァルキル, ァリ一ル,ァラルキルなどが挙げられ る。 Substituents in the silyl group having a substituent in the above formula include, for example, aralkyl, aryl, aralkyl and the like.
上記 R 1 3と R 1 +とが環状基を形成してぃる場合の基としては、 たと ぇば、 2 , 2 —ジメチルー 5 —ォキソー 4 —フヱニル一ィミ ダゾリ ジン
などが挙げられる。 When R 13 and R 1 + form a cyclic group, for example, 2,2-dimethyl-5-oxo-4—phenylimidazazolidin And the like.
上記 R *° , R 4 1 , R 4 2は、 R + 3と環状基を形成してもょく、 その例とし てはたとぇば、 2, 5—ジシリルァザシクロぺンチルなどが挙げられ、 こ れらはたとぇばァルキル,ァリールなどの置換基を有 bてぃてもょぃ。 上記置換基の説明にぉけるハロゲンとしては、たとぇば塩素,臭素,フッ 素,ョゥ素が挙げられる。 Said 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.
上記置換基の説明にぉけるァルキルとしては、 炭素数 1〜 1 0、 さら に 1 ~ 6,ぁるぃは 1〜4のものが好ましく、 その例としてはたとぇば、 メチル,ェチル, n—プロピル, iープロピル, n—ブチル, iーブチル, tーブ チル, sec -ブチル, n—ぺンチル,ィソぺンチル, n—へキシル,ィソへキシ ル,へプチル,ォクチル,ノニル,デシルなどが挙げられる。 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. For example, 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.
上記置換基としてのシクロァルキルとしては、 炭素数 3〜6のものが 好ましく、 その例としてはシクロプロピル,シクロブチル,シクロぺンチ ル,シクロへキシルなどが挙げられる。 As the cycloalkyl as the above substituent, those having 3 to 6 carbon atoms are preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
上記置換基としてのァルコキシとしては、炭素数 1 〜4のものが好ま しく、その例としてはたとぇばメ トキシ,ェトキシ,n—プロポキシ, iープ 口ポキシ, n—ブトキシ, iーブトキシ, tーブトキシなどが挙げられる。 上記置換基としてのァリ一ルとしては、 たとぇばフヱニル,ナフチル などが挙げられる。 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. Examples of the aryl as the substituent include, for example, phenyl, naphthyl and the like.
上記置換基としての複素環としては、 前記した複素環と同様のものが 挙げられる。 Examples of the heterocyclic ring as the substituent include those similar to the above-described heterocyclic ring.
上記置換基としてのァシルとしては、 炭素数 1〜 6さらに 1〜4のも のが好ましく、 たとぇばホルミル,ァセチル,プロピォニル,ブチリル,ィ ソブチリルノくレリル,ィソバレリル,ピバロィル,へキサノィルなどが挙 げられる。 As the 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. Can be
上記置換基としてのァラルキルとしてはたとぇばべンジル,フヱネチ
[ ル,フヱニループロピルなどが挙げられる。 Examples of the above aralkyl as a substituent include benzyl and phenyl. [R, phenyl-propyl and the like.
上記置换基としてのァルケニルぁるぃはァルケニレンとしては、 前記 したァルケニルと同様のものが挙げられる。 The alkenyl as the substituent may be the same as the alkenenyl as the alkenylene.
上記置換基としてのァミノ酸残基としては、 前記し こ11 1 5で示される i ァミノ酸残基と同様のものが挙げられる。 The Amino acid residue as the substituent, those similar to the i Amino acid residue represented by the by this 11 1 5 can be mentioned.
上記置換基としてのァミノ基中の窒素と共に形成してぃる 5〜6員複 素環としては、 たとぇばピぺリシジン,ビロリジン,ィミダゾリジン,乇 ルォリ ン,ピぺラジンなどが挙げられる。 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.
上記各基にぉける置換基は、 1 ~ 3個でぁることが好ましぃ。 上記のァシル基にぉぃて、式 R 1 3 - C 0— N—で表ゎされるァシルァ The number of substituents in each of the above groups is preferably 1 to 3. Based on the above acyl group, an acyl group represented by the formula R 13 -C 0—N—
R 1 4 R 1 4
ミノ基の具体例としては、 たとぇば 3—(2 , 6—ジクロロフェニル)ー 5—メチルイソキサゾ一ルー 4ーィルーカルボニルァミ ノ , 4—ェチル ー 2 3—ジォキソー . 1 ーピぺラジノカルボニルァミ ノ, 3—フヱニルー 5—メチルィソキサゾールー 4ーィルーカルボニルァミノ, 3—( 2—ク ロロフ ェニル)ー 5—メチルィソキサゾ一ルー 4ーィルーカルボニルァ ミ ノ , 3—( 2 —クロロー 6 —フルォロフヱニル)ー 5—メチルィソキサ ゾールー 4ーィルーカルボニルァミ ノ,ニコチニルァミノ,べンゾィルァ ミノ , 4ーブロ乇べンゾィルァミノ, 2, 6—ジメ トキシべンゾィルァミ ノ,ホルミルァミ ノ ,ァセチルァミ ノ ,プロピォニルァミノ,ブチリルァミ ノ ,ィソブチリルァミノ ,ピバロィルァミノ ,メ トキシカルボニルァミ ノ, べンジルォキシカルボニルァミノ . 1一ァミノーシク σへキシルカルボ ニルァミノ , 2—ァミノ一シクロへキシルカルボニルァミノ, 3—ェトキ シナフ トィルァミ ノ , 2—(2 —ァミ ノー 4ーチァゾリル)一 2—ェチリ デンーァセチルァミノ , 2—( 2 —ァミノ一 4ーチァゾリル)一 2 —クロ
ロメチレンーァセチルァミ ノ .フタルィ ミ ド,スクシンィ ミ ド, 1 , 2—シ クロへキサンジカルボキシミ ド, 2—(ト リメチルシリル)ェトキシカル ボニルァミ ノ , 2 , 2—ジメチルー 5—ォキソー 4一フェニルーィ ミ ダゾ リ ジン, 4ー(カルバモィルカルボキシメチレン)ー 1 r3—ジチェタ ンー 2—ィルーカルボニルァミ ノなどが挙げられる。 Specific examples of the amino group 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 1-amino sigma σ-hexyl carbonyl nylamino, 2-amino-cyclohexyl carbonyl amino, 3-ethoxy cinnaphyl thiamino, 2- (2-amino 4- thiazolyl) 1-2-ethylidene Cetylamino, 2- (2-amino-1-4-thiazolyl) -1 2-clo Romethyleneacetylamino phthalimide, succinimide, 1,2-cyclohexanedicarboxymide, 2- (trimethylsilyl) ethoxycarbonylamino, 2,2-dimethyl-5-oxo-41 Examples include phenylimidazolysine, 4- (carbamoylcarboxymethylene) -1r3-dichtan-2-ylcarbonylamino.
式 R15- NH— CH— C O— N H—で表ゎされるァシルァミ ノ基の具 R16 Wherein R 15 - NH- CH- CO- in NH- in Ashiruami Roh groups Table pictmap immediately R 16
体例としては、 たとぇば D—ァラニルァミ ノ .べンジル N" —カルボべ ンゾキシー 7— D—グルタ ミ ルー D—ァラニルァミ ノ ,D—フェニルグ リ シルー D—ァラニルァミ ノ , N—カルボべンゾキシ一 D—ァラニルァ ミ ノ . N—カルボべンゾキシ一 D—フ ヱニルグリ シルァミ ノ , D—ァラニ ルー D—フェニルグリ シルァミ ノ ,ァ 一 D—グルタ ミ ル一 D -ァラニル ァミ ノ , 2 -(4—ェチルー 2 , 3—ジォキソー 1 ー. ぺラジノ カルボキ サミ ド)ー 2—フェニルァセチルァ ミ ノ , 2— (4—シクロへキシルー 2 , · 3ージォキソー 1 ーピぺラジノ カルボキサミ ド)一 2—フヱニルァセチ ルァ ミ ノ , 2—(4一ェチル一 2.3—ジォキソ一 1 ーピぺラジノ カルボ キサミ ド)一 2— (4—スルホキシフェニル)ァセチルァ ミ ノ ,: \:— (4 — ェチル一 2, 3—ジォキソー 1 ーピぺラジノ カルポニル)— D—ァラニル ァミ ノ ,N— (4—ェチルー 2 , 3ージォキソー 1 ーピぺラジノカルボニ ル)ー D—フ ェニルグリ シルァ ミ ノ , 2—( 2—ァミ ノ一 4一チァゾリル) 一 2—( 4—ェチル一 2 , 3—ジォキソー 1 ーピぺラジノ カルボキサミ ド) ァセチルァミ ノ , 2— (4—ヒ ドロキシー 6—メチルニコチンァミ ド)一 2—フェニルァセチルァ ミ ノ , 2— (4—ヒ ドロキシ一 6—メチルニコチ ンァミ ド)一 2— (4—ヒ ドロキシフェニル)ァセチルァ ミ ノ , 2— {5 , 8 —ジヒ ドロー 2— ( 4—ホルミルー 1 ーピぺラジニル)一 5—ォキソ ピリ
ド [ 2 .3 — d]ピリ ミ ジンー 6—カルボキサミ ド }— 2—フェニルァセチ ルァミノ , 2—(3 , 5ージォキソー 1 , 2 4ートリァジンー 6 カルボ キサミ ド)ー 2—(4―ヒ ドロキシフヱニル)ァセチルァミノ , 2—(3 — フルフリデンァミノー 2 ォキソィミダゾリジンー 1 カル ·ボキサミ ド) — 2 —フヱニルァセチルァミノ, 2 (クマリ ンー 3 カルボキサミ ド)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 phenyl) Asechirua Mi Bruno,: \: - (4 - Echiru one 2, 3-dioxo- 1-pyrazino carbonyl)-D-aranylamino, N- (4-ethyl-2,3-dioxo-1,1-pyrazinocarbonyl) -D-phenylglycylamino, 2- (2-a 1- (4-thiazolyl) -1-2- (4-ethyl-1,2,3-dioxo-1-pyrazinocarboxamide) acetylamino, 2- (4-hydroxy-6-methylnicotinamide) -1-2-phenyl Acetylamino, 2- (4-hydroxy-16-methylnicotinamide) -1- (4-hydroxyphenyl) acetylamino, 2- {5,8-dihydro-2- (4-formyl- 1-piperazinyl) -1-5-oxopyri C [2.3 — d] pyrimidine-6-carboxamide} — 2-phenylacetylamino, 2- (3,5-dioxo-1,24-triazine-6-carboxamide) -2- (4-hydroxyphenyl) acetylamino, 2— (3—Fulfuridenamine 2 oxoimidazolidine-1 carboxamide) — 2—Phenylacetylamino, 2 (coumarin-3 carboxamide)
— 2 フェニルァセチルァミノ, 2—(4ーヒ ドロキシー 7—メチル 1 , 8 ナフチリデンー 3 カルボキサミ ド)ー 2 フヱニルァセチルァミ ノ , 2—(4—ヒ ドロキシー 7 トリフルォロメチルキノ リ ンー 3—カル ボキサミ ド)ー 2—フェニルァセチルァミノ ,Ν— [2 —(2 —ァミノー 4 —チァゾリル)ァセチル]— D—フヱニルグリシルァミノ , 2 —( 6 —ブロ モー 1ーェチルー 1 , 4ージヒ ドロー 4ーォキソチェノ [2 , 3 —b]ピリ ジンー 3—カルポキサミ ド)ー 2 フヱニルァセチルァミノ, 2—(4 — ェチル 2 , 3—ジォキソー 1 ーピぺラジノカルポキサミ ド)一 2—チェ ニルァセチルァミノ, 2— (4 τη ぺンチル一 2 3 ジォキソー 1ーピ · ぺラジノカルボキサミ ド)一 2—チェニルァセチルァミノ , 2 -(4 ー n— ォクチル一 2 3—ジォキソー 1 —ピぺラジノカルボキサミ ド)一 2 —チ ェニルァセチルァミ ノ , 2—(4ーシクロへキシル一 2 , 3 ジォキソ一 1 ーピぺラジノカルボキサミ ド)— 2—チェニルァセチルァミ ノ, 2 — [4 — (2—フェニルェチル)ー 2 , 3 -ジォキソー 1ーピぺラジノカルボキ サミ ド]— 2—チェニルァセチルァミノ, 2—(3 —メチルスルホニルー 2 ォキソィミ ダゾリジンー 1ーカルボキサミ ド)ー 2 —フヱニルァセ チルァミノ , 2—( 3—フルフリデンァミノ一 2—ォキソィミ ダゾリ ジン -. 1 ーカルボキサミ ド)一 2 —(4ーヒ ドロキシフェニル)ァセチルァミ ノ, 2—(4 ーェチル一 2 3ージォキソー 1 ピぺラジノカルボキサミ ド)一 2 — ( 4 —べンジルォキシフヱニル)ァセチルァミ ノ, 2—(4 ーェ チルー 2 , 3—ジォキソー 1―ピぺラジノカルボキサミ ド)— 2 —(4 —
メ トキシフェニル)ァセチルァミ ノ , 2—(8—ヒ ドロキシー 1 .5—ナフ チリ ジンー 7—カルボキサミ ド)一 2—フヱニルァセチルァミ ノ , 2—(2 ーァミ ノ ー 4ーチァゾリル)一 2—ホルムァミ ドァセチルァミ ノ , 2—(2 ーァミ ノ ー 4ーチァゾリル)一 2—ァセ トァミ ドァセチルァミノ , 2—フヱ ニルー 2—ゥ レィ ドァセチルァミ ノ , 2—フェニルー 2—スルホゥレィ ドァミ ノ , 2—チェニルー 2—ゥレィ ドァセチルァミ ノ , 2—ァミ ノ一 3 ースルファモィルプロピォニルァミ ノ , 2—ァミ ノ ー 2—(1 H—ィン ド ールー 3—ィル)ァセチルァミ ノ .2—ァミ ノ ー 2—(3—べンゾ [b]チェ ニル)ァセチルァミ ノ , 2—ァミ ノ ー 2—(2—ナフチル)ァセチルァミ ノ , D—フェニルグリシル, D— 2—ァミ ノ ー( 4—ヒ ドロキシフェニル)ァ セチルァミ ノ ,D— 2—ァミ ノ ー 2—(1 , 4—シクロへキサジェニル)ァ セチルァミ ノ , D— 2—ァミ ノ 一 2—(1 ーシクロへキセニル)ァセチル 'ァミ ノ , D— 2—ァミ ノー 2—(3—クロロー 4ーヒ ドロキシフェニル) ァセチルァミ ノ , 2—ヒ ドロギシメチルァ ミ ノ ー 2—フェニルァセチル ァミ ノ , 2—(1 ーシクロへキセニル)ー 2—(4ーェチルー 2 , 3—ジォ キソー 1 ーピぺラジノカルボキサミ ド)ァセチルァ ミ ノ ,N:— [2—(4— ェチル一 2 , 3—ジォキソー 1 ーピぺラジノ カルポニル)]一 D—スレォ ニルァミ ノ , 2—グァニルカルボキサミ ドー 2—フヱニルァセチルァミ ノ , 2—(4—ェチルー 2 , 3—ジォキソ一 1 ーピぺラジノ カルボキサミ ドー 2—(3 , 4—ジヒ ドロキシフヱニル)ァセチルァミ ノ , 2—(4ーカ ルボキシー 5—ィ ミ ダゾリルカルボキサミ ド)ー 2—フェニルァセチル ァミ ノ , 2—ァミ ノ ー 2—(3—メチルスルホンァミ ドフェニル)ァセチ ルァ ミ ノ などが挙げられる。 — 2 phenylacetylamino, 2- (4-hydroxy 7-methyl 1,8 naphthylidene-3 carboxamide) -2 phenylacetylamino, 2- (4-hydroxy 7 trifluoromethylquino Lin-3-Carboxamido) -2-Phenylacetylamino, Ν— [2— (2—amino4—thiazolyl) acetyl] —D—Phenylglycylamino, 2— (6—Bromo1 1,4-diethyl draw 4-oxoceno [2,3—b] pyridin-3-carboxamide) -2 phenylacetylamino, 2- (4—ethyl2,3-dioxodone 1-piradinocal Poxamide) 1-2-Chenyl acetylamino, 2- (4 τη pentyl 1-23 Dioxo- 1-· ぺ ぺ ジ ジ カ ル ボ 一 2 2 — — — — 2 — — n—Octyl 1 2 3—Jokiso 1—Pilla Nocarboxamido) 1—2—Chenylacetylamino, 2 -— (4-cyclohexyl-1,2,3-dioxo-1-piperazinocarboxamide) —2—Chenylacetimino, 2— [ 4 — (2-Phenylethyl) -2,3-dioxo-1-piperazinocarboxamide] — 2-Chenylacetylamino, 2- (3—methylsulfonyl-2-oxoimidazolidine-1-carboxamide) -2—phenylacetylamino , 2— (3-Flufuridenamino-1 2-oxomidazolidine-. 1-carboxamide) -1 2— (4-Hydroxyphenyl) acetylamino, 2 -— (4-ethyl-1 2 3 dioxoxo 1 piperazino Carboxamide) 1 2 — (4—benzyloxyphenyl) acetylamino, 2- (4-ethyl-2,3-dioxo-1-pyrazinocarboxamide) — 2 — (4 — Methoxyphenyl) acetylamino, 2- (8-hydroxy1.5-naphthylidine-7-carboxamide) -1-2-phenylacetylamino, 2- (2-amino-4-thiazolyl) 1-2 —Formamidoacetylamino, 2- (2-amino-4-thiazolyl) -1-2-acetamidoacetylamino, 2-phenyl 2-diary acetylamino, 2-phenyl-2-sulfolideamino, 2-phenyl-2-yl Docetylamino, 2-amino-3-sulfamoylpropionylamino, 2-amino-2 (1H-indole 3-yl) acetilamino.2-ami No 2- (3-benzo [b] phenyl) acetylamino, 2-amino-2- (2-naphthyl) acetylamino, D-phenylglycyl, D-2-amino ( 4—Hydroxyfe Nyl) a cetylamino, D-2-amino-2- (1,4-cyclohexenyl) acetylamino, D-2-amino-1-2- (1-cyclohexenyl) acetyl 'amino , D—2-amino-2- (3-chloro-4-hydroxyphenyl) acetylamino, 2-hydroxymethylmethyl-2-phenylacetylamino, 2- (1-cyclohexenyl) -2 — (4-ethyl-2,3-dioxo- 1-piperazinocarboxamide) acetylamino, N : — [2- (4-ethyl-1, 2,3-dioxo-1-pyrazino carponyl)]-1 D-Selenylamino, 2-Guanylcarboxamido 2-Phenylacetylamino, 2- (4-ethyl-2-, 3-dioxo-1-piperazino carboxamido 2- (3,4— Dihydroxyphenyl) acetylamino, 2- (4-ca Bokishi 5 I Mi Dazo Lil carboxaldehyde mi de) over 2-phenyl § cetyl § Mi Roh, 2 § Mi node on 2- (3-methyl sulfone § Mi Dofeniru) such Asechi Rua Mi Roh and the like.
式 R18— R13— C 0— NH—で表ゎされるァシルァミ ノ基の具体例と しては、たとぇば、 N— [ 2— ( 2—ァミ ノ ー 4ーチァゾリル)一 2—メ ト キシィ ミ ノ ァセチル]— D—ァラニルァミ ノ ,Ν—「2—(2—ァミ ノ ー 4
ーチァゾリル ')一 2—メ トキシィミ ノ ァセチル]— D—フェニルグリ シル ァミ ノ , 2— (2—ァミ ノ ー 4ーチァゾリル)一 2— [2— (2—ァミ ノー ーチァゾリ^)ー 2—メ トキシィ ミ ノ ァセトァミ ド]ァセチルァミ ノ , 2— (2—クロロァセトァミ ドー 4ーチァゾリル)一 2 メ トキシィ ミ ノ ァセチルァミ ノ , 2—(2—ァミ ノ ー 4ーチァゾリル)一 2—メ トキシィ ミ ノ ァセチルァミ ノ , 2—(2—ァミ ノ ー 4ーチァゾリル)一 2—ェトキ シィ ミ ノ ァセチルァミ ノ , 2— (2—ァミ ノー 4ーチァゾリル)一 2—ィ ソプロポキシィ ミ ノ ァセチルァミ ノ , 2— (2—ァミ ノー 4ーチァゾリル) ー 2—ブトキシィ ミ ノァセチルァミ ノ , 2— (2—ァミ ノ ー 4ーチァゾリ ル)一 2—シクロプロピルメチルォキシィ ミ ノ ァセチルァミ ノ , 2— ( 2 ーァミ ノ ー 4ーチァゾリル)ー 2—べンジルォキシィ ミ ノァセチルァミ ノ , 2— (2—ァミ ノ ー 4ーチァゾリル)一 2—ァリルォキシィ ミ ノ ァセ チルァミ ノ , 2—( 2—ァミ ノー 4ーチァゾリル)一 2— [( 1 —メチルー 1ーカルボキシェチル)ォキシィ ミ ノ ]ァセチルァミ ノ , 2—(2—ァミ ノ ' ー 4ーチァゾリル)一 2— [( 1 ーメチルー 1ーメ トキシカルポニルェチ ル)ォキシィ ミ ノ ]ァセチルァミ ノ , 2—(2—ァミ ノ 一 4—チァゾリル) — 2—カルボキシメチルォキシィ ミ ノ ァセチルァミ ノ , 2—(2—ァミ ノ ― ーチァゾリル)一 2—カルボキシビニルォキシィ ミ ノ ァセチルァミ ノ , 2 - (2—ァミ ノ ー 4:ーチァゾリル)— 2ーカルボキシェチルォキシ ィ ミ ノ ァセチルァミ ノ , 2-—(2—ァミ ノ一 4—チァゾリル)一 2—メ ト キシカルボニルェチルォキシィ ミ ノ ァセチルァミ ノ , 2—(2—ァミ ノ ー 5—クロロー 4ーチァゾリル)一 2—メ トキシィ ミ ノ ァセチルァミ ノ , 2 一(2—ァミ ノ ー 5—ブロモー 4ーチァゾリル)一 2—メ トキシィ ミ ノ ァ セチルァミ ノ , 2—(2—ァミ ノ ー 4ーチァゾリル)一 2—ォキシィ ミ ノ ァセチルァミ ノ , 2—チェニルー 2—メ トキシィ ミ ノ ァセチルァミ ノ , 2 ーフリルー 2—メ トキシィ ミ ノ ァセチルァミ ノ , 2—(1 , 2, 4—チァジ
-23-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, Ν— “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-amino-4-thiazolyl) -1-2-ethoxyminoacetylamino, 2- (2-amino-4-thiazolyl) -1,2-isopropoxyminoacetylamino, 2- (2- Amino 4-thiazolyl) -2-butoxyminoacetylamino, 2- (2-amino-4-thiazolyl) -1-2-cyclopropylmethyloxyminoacetylamino, 2- (2-) Mino 4-thiazolyl) -2-benzyloxyminoacetylamino, 2- (2-amino-4-thiazolyl) -1-2-aryloxyminoacetylamino, 2- (2-amino-4-thiazolyl) 1 2-[(1-Methyl-1-carboxyethyl) oxymino] acetylamino, 2- (2-amino-4'-thiazolyl) -l2-[(1-Methyl-1-methoxycarponylethyl) oxy Mino] acetylamino, 2- (2-amino-4-thiozolyl) — 2-carboxymethyloxymino acetylamino, 2- (2-amino-thiazolyl) 1-2-carboxyvinyloxy Siminoacetylamino, 2- (2-amino-4: thiazolyl) -2-carboxyethyloxyminoacetylamino, 2 -— (2-amino-1-4-thiazolyl) 1-2- Met Cycarbonylethyloxyminoacetylamino, 2- (2-amino-5-chloro-4-thiazolyl) -1-2-methoxyethoxyminoacetylamino, 2- (2-amino-5-bromo-4) 1-Methoxyxyminoa-cetylamino, 2- (2-amino-4-thiazolyl) -12-oxyminoacetylamino, 2-Chenyl-2-methoxyminoacetylamino, 2-furyl 2- Methoxyminaminocetamino, 2— (1, 2, 4— -twenty three-
L ァゾールー 3—ィル)ー 2—メ トキシィ ミ ノ ァセチルァミ ノ , 2—(1 , 2 , L Azoru 3 I le) over 2 main Tokishii Mi Bruno Asechiruami Bruno, 2- (1, 2,
4—チァジァゾ ルー 5—ィル)ー 2—メ トキシィミ ノ ァセチルァミ ノ , 4-thiazolium 5-yl)-2-methoxyimicin
2—(1 , 3 , 4—チァジァゾリル)ー 2—メ トキシィ ミ ノ ァセチルァミ ノ , 2—(4—ヒ ドロキシフェニル)ー 2—メ トキシィ ミ ノ ァセチルァミ ノ ,2- (1,3,4-thiaziazolyl) -2-methoxyminoacetylamino, 2- (4-hydroxyphenyl) -2-methoxyminoacetylamino,
5 2—フェニルー 2—メ. トキシィ ミ ノ ァセチルァミ ノ .2—フェニルー 2 ーォキシィ ミ ノ ァセチルァミ ノ , 2— [4— (ァ 一 D—グルタ ミルォキシ) フェニル]— 2—ォキシィ ミ ノ ァセチルァミ ノ , 2— [4一(3—ァミ ノ ー5 2-Phenyl-2-methylaminoacetylamino. 2-Phenyl-2-oxyminoacetylamino, 2- [4- (α-D-glutamyloxy) phenyl] —2-oxymininoacetylamino, 2- [4-1 (3-Amino
3—カルボキシプロポキシ)フヱニル]— 2—ォキシィ ミ ノ ァセチルァミ ノ .2—チェニルー 2—ォキシィ ミ ノ ァセチルァミ ノ , 2—(5—ァミ ノ 0 — 1 , 2 , 4—チァジァゾールー 3—ィル)一 2—メ トキシィ ミ ノ ァセチ ルァミ ノ , 2—(5—ァミ ノ ー 1 , 2 , 4—チァジァゾールー 3—ィル)ー3-carboxypropoxy) phenyl] — 2-oxyminoacetylamino.2-Chenyl-2-oxymininoacetylamino, 2- (5-amino0-1,1,2,4-thiaziazole-3-yl) 1 2—Methoxyminaminoacetylamino, 2— (5-amino1,2,4—thiazol-3-yl)
■ 2—ェトキシィ ミ ノ ァセチルァミ ノ , 2—(5—ァミ ノ ー 1 , 2 , 4—チァ ジァゾールー 3—ィル)一 2—カルボキシメチルォキシィ ミ ノ ァセチル ァミ ノ , 2— (5—ァ ミ ノ ー 1 , 2 , 4—チァジァゾールー 3—ィル)一 2 ー [( 1 —メチル一 1 ーカルポキシェチル)ォキシィ ミ ノ ]ァセチルァミ ノ , 2—(2—ァミ ノ ー 4ーチァゾリル)一 2—(2 —ァ ミ ノ ー 2—カルボキ シ)ェチルォキシィ ミ ノ ァセチルァ ミ ノ , 2— (.2—ァ ミ ノ ー 4ーチァゾ リル)一 2— (ジメチルァミ ドメチルォキシィ ミ ノ)ァセチルァ ミ ノ , 2 — ( 2—ァミ ノ ー 4ーチァゾリル)一 2— ( 3 , 4—ジァセ トキシーべンゾ ィルォキシィ ミ ノ)ァセチルァミ ノ , 2—(2—ァ ミ ノ一 4—チァゾリル) - 2 - ( 1 ーカルボキシーシクロプロピルォキシィ ミ ノ)ァセチルァミ ノ , 2— ( 2—ァミ ノ ー 4ーチァゾリル)一 2—( 1 ーカルボキシーシクロブ チルォキシィ ミ ノ)ァセチルァミ ノ , 2—(2—ァミ ノ ー 4ーチァゾリ ル) ー 2 - (2ーィ ミ ダゾリ ルメチルォキシィ ミ ノ)ァセチルァミ ノ , 2—(2
—ァミ ノ ー 4—チァゾリル)一 2—(2—メチル一 4ーニ トロー 1 ーィ ミ ダゾリルェチルォキシィ ミ ノ)ァセチルァミ ノ , 2— (2—ァ ミ ノ ー 4一
チァゾリル)ー 2—(3—ピラゾリルメチルォキシィミノ)ァセチルァミ ノ, 2— (2—ァミノー 4ーチァゾリル)一 2— (1 H—テトラゾールー 5 ーィルーメチルォキシィミノ)ァセチルァミノ , 2— (2—ァミノー 4ー チァゾリル)一 2—(2—ォキソー 3—ピロリ ジニルォキシィ-ミノ)ァセ チルァミノ .2— [2—(2—ァミノー 2—カルボキシェチルチォ)]一 4 —チァゾリルー 2—メ トキシィミノァセチルァミノ , 2— (2—チォキソ ー 4ーチァゾリ ジニル)一 2—メ トキシィミノァセチルァミノなどが挙 げられる。 ■ 2-Ethoxyminoacetylamino, 2- (5-amino1,2,4-thiaziazol-3-yl) -1-2-carboxymethyloxyminacetylamino, 2- (5 —Amino 1,2,4—thiazol-3-yl) 1-2 — [(1—Methyl-1-carboxyshethyl) oxymino] acetylamino, 2— (2—amino 4 2- (2-Amino-2-carboxy) ethyloxyminoacetylamino, 2-(. 2-Amino4-thiazolyl) 1-2- (dimethylamidomethyloxymino) acetylamino , 2— (2-amino-4-thiazolyl) -1-2- (3,4-diacetoxybenzoyloxymino) acetylamino, 2 -— (2-amino-4-thiothiolyl) -2-( 1-carboxy-cyclopropyloxy mino) acetyl Amino, 2— (2-Amino-4-thiazolyl) -1-2— (1-Carboxy-cyclobutyloxymino) acetylamino, 2 -— (2-Amino-4-thiazolyl) ー 2-( 2-diazolylmethyloxymino) acetylamino, 2— (2 —Amino 4—Thiazolyl) 1—2— (2—Methyl 1-4 nitro) 1—Dimidazolylethyloxymino) Acetylamino, 2— (2—Amino 41 Thiazolyl) -2- (3-pyrazolylmethyloxyimino) acetylamino, 2- (2-amino-4-thiazolyl) -12- (1H-tetrazole-5-ylmethyloxyimino) acetylamino, 2- ( 2-Aminoh 4-thiazolyl) -1- 2- (2-oxo-3-pyrrolidinyloxy-mino) acetylamino .2- 4- [2- (2-Amino-2-carboxyethylthio)] 1-4-thiazolyl 2-methoxy Siminoacetylamino, 2- (2-thoxo-4-thiazolidinyl) -1-2-methoxyiminoacetylamino, and the like.
式 R25— CH— C O— NH—で表ゎされるァシルァミノ基の具体例と Specific examples of the acylamino group represented by the formula R 25 — CH— CO— NH—
R26 R 26
して、 たとぇば 2—フェニルー 2—スルホァセチルァミノ , 2—ヒ ドロ キシー 2—フヱニルァセチルァミノ, 2—フヱニルー 2—スルファモィ ルァセチルァミノ, 2—カルボキシー 2—フヱニルァセチルァミノ, 2— (4ーヒ ドロキシフェニル)ー 2—カルボキシァセチルァミノ , 2—フェ ノキシカルボニル一 2—フヱニルァセチルァミノ , 2—フヱニルー 2— トリルォキシカルボニルァセチルァミ ノ , 2—(5—ィンダニルォキシカ ルボニル)一 2—フェニルァセチルァミノ .2—ホルミ ルォキシー 2—フェ ニルァセチルァミ ノ , 2—ァラニルォキシ一 2—フェニルァセチルァミ ノ , 2—カルボキシー 2—チェニルァセチルァミ ノ , 2—(2—メチルフェ ノキシカルボニル)ー 2—チェニルァセチルァ ノ , 2—(2—ァミノー 4—チァゾリル)一 2—ヒ ドロキシァセチルァミ ノ , 2— [4— ( 2—ァミ ノー 2—カルボキシェトキシカルボキサミ ド)フヱニル]— 2—ヒ ドロキ シァセチルァミ ノなどが挙げられる。 Then, for example, 2-phenyl-2-sulfacetylamino, 2-hydroxy-2-phenylacetylamino, 2-phenyl-2-sulfamoylacetylamino, 2-carboxy-2-phenylacetyl Amino, 2- (4-hydroxyphenyl) -2-carboxyacetylamino, 2-phenoxycarbonyl-l-phenylacetylamino, 2-phenyl-2-yltrioxycarbonylacetyl Amino, 2- (5-Indanyloxycarbonyl) -1-2-phenylacetylamino.2-formyloxy-2-phenylphenylacetylamino, 2-aralanoxy-12-phenylacetylamino, 2 —Carboxy-2-Chenylacetylamino, 2- (2-methylphenoxycarbonyl) -2- 2-Chenylacetylano, 2- (2-amino-4-thiazolyl) -1- Hydroxyacetylamino, 2- [4- (2-amino-2-carboxyethoxycarboxamide) phenyl] -2-hydroxyhydroxyacetylamino and the like.
式 R27— R28— C H2- C 0 - NH—で表ゎされるァシルァミノ基の 具体例としては、 たとぇば、 シァノァセチルァミ ノ ,フェニルァセチル ァミノ,フェノキシァセチルァミ ノ , トリフルォロメチルチォァセチルァ
ミ ノ ,シァノメチルチォァセチルァミ ノ ,ジフルォ σメチルチォァセチル ァミ ノ , 1 Η—テトラゾリルー 1 ーァセチルァミ ノ ,チェニルァセチルァ ミ ノ , 2— ( 2—ァミ ノ ー 4一チァゾリル)ァセチルァミ ノ , 4ーピリ ジル チォァセチルァミ ノ , 2—チェニルチォァセチルァミ ク , 3, 5—ジクロ ロー 1 , 4ージヒ ドロー 4ーォキソピリ ジンー 1 ーァセチルァ.ミ ノ , ^一 カルボキシビニルチォァセチルァミ ノ , 2—(2—ァミ ノ メチルフェニル) ァセチルァミ ノ , 2—クロロァセチルァミ ノ , 3—ァミ ノ プロピォニルァ ミ ノ ,(2 —ァミ.ノ一 2—カルボキシ)ェチルチォァセチルァミ ノ , 4—ァ ミ ノ ー 3—ヒ ドロキシブチ.リルァミ ノ , 2 —カルボキシェチルチォァセ チルァミ ノ , 2 —べンジルォキシカルボニルァミ ノ ーァセチルァミ ノ , ーカルパモィルー ^ーフルォロビニルチォァセチルァミ ノ , 2—(1 ーィ ソプロピルァミ ノ ー 1 ーィソプロピルィ ミ ノ メチルチォ)ァセチルァミ ノ ,. 2— [ 1 — ( 2—ジメチルァミ ノェチル)ー 1 Η—テ トラゾールー 5— ィルーチォ]ァセチルァミ ノ , 2·—( 1 ーメチルー し 3 , 5— ト リァゾー ルー 2—ィル)ァセチルァミ ノ , 2—(4 ーシァノ ー 3—ヒ ドロキシー 5 ーィソチァゾリールチォ)ァセチルァ ミ ノ などが挙げられる。 Specific examples of the acylamino group represented by the formula R 27 — R 28 — CH 2 —C 0 —NH— include, for example, cyanoacetamino, phenylacetylamino, and phenoxyacetylamino. , Trifluoromethylthioacetyla Mino, cyanomethylthiocetylamino, difluo σmethylthioacetylamino, 1Η-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, hydroxybutyric, rilamino, 2-carboxyethylthioacetylamino, 2-benzyloxycarbonylamino Acetylamino, carbamoyl ^ fluorovinylthioacetylamino, 2- (1-isopropylamino-1 isopropylaminomethylthio) acetylamino, .2— [1— (2-dimethylaminoethyl) -1 1 —Tetrazol-5—Diluteo] acetylamino, 2— (1-methyl-3,5-triazolu-2-yl) acetilamino, 2 -— (4-cyano-3-hydroxy-5-isothiazolylthio) ) Acetylamino.
Ζ Ζ
R 2 3 !i R 2 3 ! I
式 > N— C— N H—で表ゎされる基の具体例としては、 Specific examples of the group represented by the formula> N—C—N H—
R 3 0 R 30
たとぇばカルバモィルァミ ノ ,メチルァミ ノ カルボニルァミ ノ ,ェチルァ ミ ノ カルボニルァ ミ ノ , tーブチルァミ ノ カルボニルァ ミ ノ ,ィソブチル ァミ ノカルボニルァミ ノ ,ジメチルァミ ノ カルボニルァミ ノ , 2—メチル フ ェニルァミ ノ カルボニルァミ ノ,フヱニルァ ミ ノ カルボニルァミ ノ , 3 ークロロフヱニルァミ ノ カルボニルァミ ノ , 4一ニ トロフ ェニルァミ ノ カルボニルァミ ノ , 4—ブロモフヱニルァミ ノカルボニルァミ ノ ,チォカ ルバモィルァミ ノ ,メチルァ ミ ノ チォカルボニルァミ ノ ,ェチルァミ ノチ
ォカルボニルァミノ,フヱニルァミノチォカルボニルァミノ,ジメチルァ ミノカルボニルァミノ, 3—フルォロフヱニルァミ ノカルボニルァミノ などが挙げられる。 For example, 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.
式 R 3 1— N H—で表ゎされる基の具体例としては、 とぇばメチルァ ; ミノ,ェチルァミノ,ァリルァミノ,シクロへキシルァミノ,シクロへキシ ルメチルァミノ,べンジルァミノ , 4ークロ口べンジルァミノ,フェニル ァミノ, 2—ィミダゾリルァミノ , 1 ーメチルー 2—ィミダゾリルァミノ, 2—(2—ァミノー 4ーチァゾリル)ー 2—メ トキシィミノーチォァセチ ルァミノ, 1 ーべンジルー 4一ピリジニゥムァミノ , 2—ァセチルー 1 r- メチルビニルァミノなどが挙げられる。 · 式 3„〉 !^1ーで表ゎされるァルキルァミ ノ基の具体例としては、 たとぇばジメチルァミノ,ジェチルァミ ノ,ジプロピルァミ ノ,ジべンジ ルァミ ノ ,ジシクロへキシルァミ ノ , N—べンジル一 N—メチルァミノ, ジァリルァミノ , N—フェニルー N—メチルァミノ,ピロリ ジニル,ピぺ リ ジニル,ピぺラジニル,モルホリニルなどが挙げられる。 Wherein 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. · Specific examples of the 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.
R 3 4 - \ © R 3 4-\ ©
式 R 3 5—N—で表ゎされるァルキルァミ ノ基の具体例としては、 たとAnd Examples of Arukiruami Roh groups Table pictmap the formula R 3 5 -N-, was
R 3 6 R 3 6
ぇばトリメチルァンモニゥム, トリェチルァンモニゥム. トリべンジルァ ンモニゥム,べンジルジメチルァン乇ニゥム,メチルピロリ ジニゥム,メ チルピぺリジニゥ厶などが挙げられる。 式11 ^〉 C = N—で表ゎされるァルケニルァミ ノ基の具体例として R 3 8 For example, trimethylammonium, triethylammonium. Tribenzylammonium, benzyldimethylammonium, methylpyrrolidinium, methylpyridinium, and the like. R 3 8 Specific examples of Arukeniruami amino group which is formula 11 ^> C = N- in Table pictmap
は、 たとぇばジメチルァミ ノメチレンァミノ , 1 ージメチルァミノェチ リデンァミ ノ,へキサヒ ドロー 1 H—ァゼピンー 1 ーィルメチレンァミ
ノ , 1ー(N—べンジル一N—メチルァミ ノ:)ェチリデンァミ ノ , 4ージメ チルァミ ノべンジリデンァミ ノ ,(P—ニトロ)べンジリデンァミ ノ ,べン 'ジリデンァミノなどが挙げられる。 For example, 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.
式 R 3 a— S O n— N H—で表ゎされるチォァミノ基の具体例としては、 たとぇばべンゼンスルホニルァミ ノ , 4ーメチルべンゼンスルホニルァ ミ ノ , 4ーメ トキシべンゼンスルホニルァミ ノ , 2 , 4 , 6—トリ メチルべ ンゼンスルホニルァミ ノ ,べンジルスルホニルァミ ノ , 4ーメチルべンジ ルスルホニルァミ ノ , ト リフルォロメチルスルホニルァミ ノ ,フェナシル スルホニルァミ ノ ,メチルスルホニルァミ ノ ,ェチルスルホニルァミ ノ , 4—フルォロべンゼンスルホニルァミ ノ ,べンゼンスルフィニルァミ ノ ,Specific examples of the thioamino group represented by the formula R 3 a — SO n — NH— include, for example, benzenesulfonylamino, 4-methylbenzenesulfonylamino, and 4-methoxybenzenesulfonylamina. Mino, 2,4,6-trimethylbenzenesulfonylamino, benzylsulfonylamino, 4-methylbenzylsulfonylamino, trifluoromethylsulfonylamino, phenacylsulfonylamino, methylsulfonylam Mino, ethylsulfonylamino, 4-fluorenebenzenesulfonylamino, benzenesulfinylamino,
2—ニトロべンゼンスルフィニルァミ ノ , 2 , 4—ジメチルべンゼンスル フィニルァミ ノ', 4ークロロべンゼンスルフィニルァミ ノ , 4ーメ トキシ べンゼンスルフィニルァミ ノ ,フェニルチォァミ ノ , 2 , 4—ジニトロフェ ニルチォァミ ノ , ト リ フ ェニルメチルチォァミ ノ . 2—ニトロー 4ーメ ト キシフヱニルチォァミ ノ などが挙げられる。
> N—で表ゎされるシリルァミノ基の具体例として は、 たとぇばト リ メチルシリルァミ ノ , ト リェチルシリルァミ ノ , t—ブ チルジメチルシリルァミ ノ ,tーブチルジフヱニルシリルァミ ノ ,ィソプ ロピルジメチルシリルァミ ノ , ト リ フェニルシリルァミ ノ , ト リ ィソプロ ピルシリルァミ ノ , ト リべンジルシリルァミ ノ ,(ト リ フェニルメチル)ジ メチルシリルァミ ノ . 2 , 2 , 5 , 5—テ トラメチルー 2 , 5—ジシリルァ ザシクロぺンタ ンなどが挙げられる。 2-nitrobenzenesulfinylamino, 2,4-dimethylbenzenesulfinylamino, 4-chlorobenzenesulfinylamino, 4-methoxybenzenesulfinylamino, phenylthioamino, 2,4-dinitrophenylamino And triphenylmethylthioamino. 2-nitro-4-methoxyphenylthioamino and the like. > Specific examples of silylamino groups represented by N— include, for example, trimethylsilylamino, triethylsilylamino, t-butyldimethylsilylamino, and t-butyldiphenylsilylamino. Mino, isopropropyldimethylsilylamino, triphenylsilylamino, trisopropylsilylamino, tribenzylsilylamino, (triphenylmethyl) dimethylsilylamino.2,2,5,5- Tetramethyl-2,5-disilylazacyclopentane.
0 0
R 44 II R 44 II
式 > P— N H—で表ゎされる基の具体例としては、 たとぇば Specific examples of the group represented by the formula> P—N H—
R * 5
ジメチルリ ン酸ァミノ,ジェチルリ ン酸ァミノ,ジフェニルリ ン酸ァミノ, ジべンジルリン酸ァミノ,ジー 4ークロロフヱニルリ ン酸ァミノなどが 挙げられる。 ' R * 5 Examples include dimethylaminophosphate, aminoethylethylamine, aminoaminodiphenylphosphate, aminoaminedibenzylphosphate, aminoaminodi-4-chlorophenylphosphate, and the like. '
式 R *e— C 0— C 0—N H—で表ゎされる基の具体例としては、 たと ぇばメ トキサリルァミノ,ェトキサリルァミノ,フヱノキサリルァミノ, べンジルォキサリルァミノ ,ピルボィルァミノ,ェチルォキサリルァミノ, ォキサ乇ィルァミノ ,べンジルァミノォキサリルァミノ ,チェニルォキサ リルァミノ , 2—ァミ ノー 4—チァゾリルーォキサリルァミノ,ェチルァ ミノォキサリルァミノなどが挙げられる。 Specific examples of the group represented by the formula R * e —C 0— C 0—NH— include, for example, methoxalylamino, ethoxylylamino, phenoxalylamino, benzyloxalylamino , Pilvoylamino, etyloxalylamino, oxilylamino, benzylaminooxalylamino, chenyloxilarylamino, 2-amino 4- thiazolyluoxalylamino, ethylaminoxolylamino Mino and the like.
式— C 0 0 R 47で表ゎされる基の具体例としては、 たとぇばメチルェ ステル,ェチルェステル,η—プロピルェステル,ィソプロピルェステル, t —ブチルェステル, tーァミルェステル,べンジルェステル, 4 'ーブロ乇べ ンジルェステル, 4ーニトロべンジルェステル, 2—ニトロべンジルェス テル. 3 . 5—ジニトロべンジルェステル, 4ーメ トキシべンジルェステ ル,べンズヒ ドリルェステル,フェナシルェステル, 4ーブロ乇ーフェナ シルェステル,フヱニルェステル, 4一ニトロフヱニルェステル.メ トキ シメチルェステル,メ トキシェト^ "シメチルェステル,ェトキシメチルェ ステル,べンジルォキシメチルェステル,ァセトキシメチルェステル,ピ パロィルォキシメチルェステル, 2—メチルスルホニルェチルェステル, 2—トリメチルシリルェチルェステル,メチルチォメチルェステル. トリ チルェステル, 2 , 2 , 2—トリ クロロェチルェステル, 2—ョ一ドェチル ェステル,シクロへキシルェステル,シクロぺンチルェステル,ァリルェ ステル,シンナミルェステル, 4一ピコリルェステル, 2—テトラヒ ドロ ピラニルェステル, 2—テトラヒ ドロフラニルェステル,トリメチルシリ ルェステル, tーブチルジメチルシリルェステル, tーブチルジフヱニルシ リルェステル.ァセチルメチルェステル, 4ーニトロべンゾィルメチルェ
ステル, 4ーメ シルべンゾィルメチルェステル,フタルィ ミ ドメチルェス テル,プ σピォニルォキシメチルェステル, 1 , 1 ージメチルプロピルェ ステ.ル, 3—メチルー 3—ブテニルェステル,スクシンィ ミ ドメチルェス テル, 3 , 5—ジー tーブチルー 4ーヒ ドロキシべンジルェステル,メ シル メチルェステル,べンゼンスルホニルメチルェステル,フェニルチォメチ ルェステル,ィ ミ ノメチルァミ ノェチルェステル, 1 —ィ ミ ノェチルァミ ノェチルェステル,ジメチルァミ ノェチルェステル,ピリ ジン一 1 ーォキ シ ドー 2—メチルェステル,メチルスルフィニルメチルェステル,ビスー ( 4 ーメ トキシフヱニル)メチルェステル, 2—シァノ ー 1 , 1 ージメチル ェチルェステル, t—ブチルォキシカルボニルメチルェステル,べンゾィ ルァミ ノ メチルェステル, 1 ーァセトキシェチルェステル, 1 ーィソブチ リルォキシェチルェステル, 1 ーェトキシカルボニルォキシェチルェス テル,フタラィ ドェステル, 4 ~ t -ブチルべンジルェステル. 5 —ィンダ ニルェステル, 5—メチルー 2—ォキソー 1', 3 —ジォキソレンー 4ーィ ルメチルェステル, 5— t—ブチルー 2ーォキソー 1 , 3—ジォキソ レン ー 4—ィルメチルェステルなどが挙げられる。 式ー C 0— N < 4„で表ゎされる基の具体冽と しては、 たとぇばジ Specific examples of the group represented by the formula —C 0 R 47 include, for example, methylester, ethylester, η-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, phenylthiomethylester, iminomethylaminoester, 1-iminotemilamitelester, dimethylamine 1-oxodido 2-methylester, methylsulfinylmethylester, bis- (4-methoxyphenyl) methylester, 2-cyano-1,1-dimethylethylester, t-butyloxycarbonylmethylester, benzene Zoylamino methylester, 1-acetoxylester, 1-isobutyryloxyshester, 1-ethoxycarbonyloxyshester, phthalaidester, 4-t-butylbenzylester. 5 —Indane Nylester, 5-Methyl-2-oxo-1 ', 3—Dioxolen-4-ylmethylester, 5-tert-Butyl-2-oxo1,1,3-Dioxolen-4-ylmethylester, and the like. A specific example of the group represented by the formula-C 0-N < 4 is as follows.
R R
メチルァミ ド,ジェチルァミ ド,ジプロピルァミ ド,ジべンジルァ ミ ド.ジ シクロへキシルァミ ド. Ν—べンジル一 Ν —メチルァミ ド,ジァリルァミ ド, Ν—フェニル一 Ν—メチルァミ ド,ピロ リ ジンァミ ド,ピぺリ ジンァ ミ ド,ピぺラジンァミ ド,モルホリ ンァミ ド,カルボキシメチルァミ ド, 1 ーカルボキシェチルァミ ドなどが挙げられる。 Methyl amide, getyl amide, dipropyl amide, dibenzyl amide. Dicyclohexyl amide. べ -benzyl Ν—methyl amide, diaryl amide, Ν-phenyl Ν-methyl amide, pyrrolidine amide, pyridine Examples include lysinamide, piperazine amide, morpholine amide, carboxymethyl amide, and 1-carboxyethyl amide.
上記式中、 R 3ぉょび R +で示される有機残基としては、 たとぇば炭素 原子にぉぃて結合する有機残基が挙げられる。 In the above formula, examples of the organic residue represented by R 3 and R + include, for example, an organic residue bonded to a carbon atom.
該炭素原子にぉぃて結合する有機残基の例としては、 たとぇばァルキ
—30— Examples of organic residues bonded to the carbon atom include, for example, —30—
_ ル , シクロァルキル, ァルケニル 58 ,ァリール * ,ァシル,シァノまた はェステル化ぁるぃはァミ ド化されてぃてもょぃカルボキシルが好まし ぃ。 ________________, cycloalkyl, alkenyl 58 , aryl *, acyl, cyano or esterified is preferably amidated, preferably carboxyl.
上記式中、 R5,R8,R7ぉょぴ R8で示される有機残基としては、 炭素In the above formulas, as the organic residue represented by R 5, R 8, R 7 Oyopi R 8, carbon
5 原子にぉぃて結合する有機残基;酸素原子,窒素原子もしくは硫黄原子を 介して結合する有機残基;またはハロゲンが挙げられる。 Organic residues linked through 5 atoms; organic residues linked through oxygen, nitrogen or sulfur atoms; or halogens.
上記炭素原子を介して結合する有機残基としては、たとぇばァルキル 85 シクロァルキル,ァルケニル χ· ,ァリ一ル《· ,ァシル,シァノ,カルバ乇ィ ル.複素環《· ,またはェステル化もしくはァミ ド化されてぃてもょぃカル 0 ボキシルが好ましぃ。 The organic residue bonded through the carbon atom, other and Eba Arukiru 85 Shikuroarukiru, Arukeniru chi-, § Li Ichiru "-, Ashiru, Shiano, carba乇I Le. Heterocyclic", or Esuteru reduction, or It is preferable to use carboxyl 0 voxyl.
上記酸素原子を介して結合する有機残基としては、 式- 0— R9 [式中、 Raは水素,ァルキル,ァリール,ァシル,カルパモィルを示す。 ]で表ゎさ れる基,またはォキソ基が好ましぃ。 The organic residue bonded through the oxygen atom, the formula - 0- R 9 [wherein, R a represents hydrogen, Arukiru, Ariru, Ashiru, the Karupamoiru. Or an oxo group is preferred.
上記窒素原子を介して結合する有機残基としては、 たとぇば式 As the organic residue bonded through the nitrogen atom, for example,
- < ^ [式中、 R 1(5ぉょび R "は、同一または異なって、水素,ァルキ ル,ァリール,ァシルを示す。 ]で表ゎされる基が好ましぃ。 -<^ [Wherein, R 1 (5 and R "are the same or different and represent hydrogen, alkyl, aryl or acyl.).
上記硫黄原子を介して結合する有機残基としては式- S (O)n— R12 [式中、 R12は水素,ァルキル※ ,ァリール * ,複素環 * ,またはァミ ノ * を、 nは 0 , 1または 2を示す。 ]で表ゎされる基が好ましぃ。 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.
上記1 3,114,1 5,116,1 7ぉょび118にぉけるァルキル基に置換してぃ てもょぃ基としては、 たとぇばヒ ドロキシ,ァシルォキシ,カルバモィル ォキシ,ァミノ,ジァルキルァミ ノ,ァシルァミノ ,ァルキルチォ,複素環 チォ,カルボキシ,ァルコキシカルボニル,カルバモィル,シァノ ,ァジド, ァリールノヽロゲンなどが挙げられる。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.
上記 R 3 , R + , R 5, R 6. R 7ぉょび R 8にぉけるァリ—ル基に置換してぃ
R 3 , R + , R 5 , R 6. Substitute with the aryl group shown in R 7 and R 8 .
δ 5 δ 5
-31- てもょぃ基としては、 たとぇばハロゲン.ァルコキシ,ァルキルなどが挙 げられる。 -31- Examples of the molybdenum group include, for example, halogen, alkoxy, and alkyl.
上記113.11 ,1 5,118,117ぉょび118にぉけるァルケニルに置換してぃ てもょぃ基としては、 たとぇばァリ—ルなどが挙げられる。 The 11 3.11 As the 1 5, 11 8, 11 7 Oyobi 11 8 Yoi group optionally substituted City Okeru Arukeniru other and Eba § Li - such as Le, and the like.
上記115,118,1 7ぉょび118にぉける複素環に置換してぃてもょぃ基と しては、 たとぇばァルキルなどが挙げられる。 Is the above 11 5, 11 8, 1 7 Oyobi 11 8 Yoi group optionally substituted City Okeru heterocycle, other and Eba Arukiru the like.
上記 R 12にぉけるァミノに置換してぃてもょぃ基としては、 たとぇば モノァルキル,ジァルキル,モノァリールなどが挙げられる。 The Yoi group optionally substituted City Okeru Amino above R 12, the other a Eba Monoarukiru, Jiarukiru, Monoariru and the like.
上記113,114,115,1 6,117ぉょぴ118にぉけるェステル化されてぃても 0 ょぃカルボキシルの例としては、 たとぇばカルボキシ,ァルキルォキシ カルボニルなどが挙げられる。 上記1 3.114,&5,1 8,117ぉょび1 8にぉけるァミ ド化されてぃてもょ ぃカルボキシルの例としては、 たとぇば式 . 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.
R48' * - R 48 '*-
[式中、 ぉょび R+3' は、同ーまたは異なって、 水素.ァルキルを示 し、 隣接する窒素原子と共に複素環を形成してぃてもょぃ。 ]で表ゎさ れる基が挙げられる。 [In the formula, R +3 'is the same or different and represents hydrogen or alkyl, and may form a heterocyclic ring with an adjacent nitrogen atom. A group represented by the following formula:
上記のァルキル(基の中のァルキルの場合を含む。 )としては、 たとぇ ば炭素数 1 ~ 6のものが好ましぃ。 As the above alkyl (including the alkyl in the group), for example, those having 1 to 6 carbon atoms are preferable.
0 0
上記のシクロァルキルとしては、 炭素数 3〜 6のものが好ましぃ。 上記のァルケニルとしては、 炭素数 1 〜4のものが好ましぃ。 As the above cycloalkyl, those having 3 to 6 carbon atoms are preferable. The above alkenyl is preferably one having 1 to 4 carbon atoms.
上記ァシル(基の中のァシルの場合を含む。 )としては、 炭素数 1 〜 6 のもの,ァリールカルボニルが好ましぃ。 As the above-mentioned acyl (including the case of the acyl in the group), those having 1 to 6 carbon atoms and arylcarbonyl are preferable.
^レ: 1キシノ ^ Le: 1 Kishino
上記のァルコキシ(基の中のァ 場合を含む。 )としては、 炭素数 In the above alkoxy (including the case in the group), the carbon number is
1 〜 6のものが好ましぃ。
上記炭素数 1〜 6のァルキル,炭素数 3〜 6のシクロァルキル.炭素数 1〜 4のァルケニル,炭素数 1〜 6のァシル,炭素数 1〜 6のァルコキシ, ァリール,複素環(隣接する窒素原子と共に形成してぃる場合を除く。 ) ぉょぴハロゲンの具体例としては、 前記した R 1等で示されるそれらと 同様のものが挙げられる。 1 to 6 are preferred. C1 to C6 alkyl, C3 to C6 cycloalkyl. C1 to C4 alkenyl, C1 to C6 acyl, C1 to C6 alkoxy, aryl, heterocycle (adjacent nitrogen atom Except for the case where they are formed together with.) Specific examples of halogen are the same as those described above for R 1 and the like.
上記隣接する窒素原子と共に形成してぃる.複素環としては、 たとぇば 5〜 6員環のものが好ましく、 その具体例としては、 たとぇばピロリル, ピロリ ジニル,ピぺリジニル,ピぺラジニルなどが挙げられる。 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.
上記の R 3ぉょび R 4で示される基の好ましぃ例としては、 たとぇばメ チル,ェチル,ィソプロピル,ビニール,ァリル(al lyl) ,シクロプロピル, シク σぺンチル,シクロへキシル,フェニルノくラクロルフェニル,パラメ トキシフヱニル,ァセチル,プロピォニル,べンゾィル,メ トキシカルボニ ル,ェトキシカルボニル,カルバモィル,ジメチルァミノカルボニル,シァ ノ ,カルボキシル, t ドロキシメチル,ァセトキシメチル,カルパモィルォ · キシメチル,クロロメチル,メチルチォメチル, 1 —メチルー 1 H— 5 - テトラゾリルチォメチル,ァジ ドメチル,ァセタ ミ ドメチル,シァノメチ ル,メ トキシカルポニルメチル.ヒ ドロキシェチル.ァセトキシヒ ドロキ シェチル,カルバモィルォキシェチル,クロロェチル,メチルチォェチル, 1 ーメチルー 5—テトラゾリルチォェチル,シァノェチル,ァセトァミ ド ェチル,スチリル,フヱネチルなどが挙げられる。 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 Ethyl, 1-methyl-5-tetrazolylthioethyl, cyanoethyl, acetamidoethyl, styryl, phenethyl and the like.
上記の R 5. R S . R 7ぉょび R 8で示される基の好ましぃ例としては、 た とぇばメチル,ェチル,シクロプロピル,シクロぺンチル,シク σへキシル, ビニール,ァリル,フヱニル,パラクロルフヱニル,パラメ トキシフェニル, ァセチル,プロピォニル,べンゾィル,シァノ,カルバモィル,メ トキシカ ルボニル,ェトキシカルボニル,ジメチルァミノカルボニル,ァセトキシ メチル,メチルチォメチル,ァセトァミ ドメチル,ヒ ドロキシ,メ トキシ,
ェトキシ,ァセトキシ,フヱニルォキシ,べンゾィルォキシ,カルパモィル ォキシ,メチルァミノ,ジメチ.ルァミノ,フヱニルァミノ,ァセチルァミノ , メチルチォ,ェチルチォ, 2—ァセトァミ ドェチルチォ, 2— Ν , Ν—ジメ チルァミノェチルチォ, 2—ァミノェチルチォ, 2—ヒ ドロキシェチルチ ォ,カルボキシメチルチォ,メ トキシカルポニルメ トキチォ,カルバモィ ルメチルチォ,フヱニルチォ, 3 —ピリダジニルチォ, 2—ピリ ミ ジニル チォ, 4ーピリ ジルチォ, 1 ーメチルー 1 Η— 5 —テトラゾリルチォ,べ ンジルチォ, 4—ピリジルメチルチォ,スルファモィル,フェニルァミノ スルホニル,クロロ,ブロ乇などが挙げられる。 Preferred examples of the group represented by R 5 .R S .R 7 and R 8 above include, for example, methyl, ethyl, cyclopropyl, cyclopentyl, cyclohexyl, vinyl, and aryl. , Phenyl, parachlorophenyl, paramethoxyphenyl, acetyl, propionyl, benzoyl, cyano, carbamoyl, methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl, acetomethyl, methylthiomethyl, acetamidomethyl, hydroxy, Toxi, Ethoxy, acetoxy, phenyloxy, benzoyloxy, carbamoyloxy, methylamino, dimethyi, lumino, phenylamino, acetylamino, methylthio, ethylyl, 2-acetamidoethylyl, 2-Ν, dimethylaminoethyl —Hydroxyshetyl, carboxymethylthio, methoxycarbonylmethoxide, carbamoylmethylthio, phenylyl, 3-pyridazinylthio, 2-pyrimidinylthio, 4-pyridinylthio, 1-methyl-1Η-5—tetrazolylthio, benzyldithio, 4-pyridyl Methylthio, sulfamoyl, phenylaminosulfonyl, chloro, bromine and the like.
上記式中、 Υで示される脱離基としては、 化合物(ΠΙ )の 2位の水 と 置換しぅるものでぁれば如何なるものでもょぃ。 その例としては、 たと ぇばハロゲン(例、 ブロム,クロル),置換基(例、 ァルキル,ァリール)(ァ ルキル,ァリールとしては前記置換基と同様のものが挙げられる。 )を有 するスルホニルォキシ(その具体例としては、 たとぇば ρ—トルェンスル ホニルォキシ,ρ—ニトロフヱニルスルホニルォキシ,メタンスルホニル ォキシ),ジ置換ホスホリルォキシ(例、 ジフヱニルホスホリルォキシ,ジ ェチルホスホリルォキシ)などが挙げられる。 In the above formula, any leaving group represented by Υ may be substituted with water at the 2-position of compound (ΠΙ). 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, ρ-toluenesulfonyloxy, ρ-nitrophenylsulfonyloxy, methanesulfonyloxy), disubstituted phosphoryloxy (eg, diphenylphosphoryloxy, diethylphosphoryl) And the like.
次に、 本発明の目的化合物の製造法にっぃて説明する。 Next, the method for producing the target compound of the present invention will be described.
化合物(m)と化合物(π )またはその反応性誘導体とを反応させ、 ー般 式 Reacting compound (m) with compound (π) or a reactive derivative thereof;
R3 R+ R 3 R +
, Χ , Χ
R5R6 R7RS R 5 R 6 R 7 R S
( 1 - 2) (1-2)
R2' R 2 '
[式中、 R , R 2' , R 3 . R 4 , R 5. R 6 , R 7 , R 8ぉょび Xは前記と同意義を
有する。 R3,R4 ,R5,R8,R7ぉょぴ R8が同時に水素でぁる場合を含 む。 ]で表ゎされる化合物(I― 2)を得、さらに必要にょり化合物(Iー 2)の R1'ぉょび Zまたは R2'の変換反応に付すことにょり、ー般式 [Wherein, 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. To obtain a compound (I-2) represented by the general formula (I-2), and then subjecting the compound (I-2) to a conversion reaction of R 1 'ぉ Z or R 2 ' as necessary.
[式中、 R1はァミノ基または窒素を介する有機残基を示す。 R2はカル ボキシル基またはそれか 誘導され得る基を示す。R3,R4,R5,RS,R 7 ぉょ'ぴ R8は、 同ーまたは異なって、 水素または有機残基を示し、 R5 るぃは R 6と R 7ぁるぃは R8とが化学锆会を形成してぃる場合を含む。 R3,R R5,RS,R7ぉょぴ R8 同時に水素でぁる場合を含む。 X'は水 素,メ トキシまたはポルミルァミノを示す。 ]で表ゎされる化合物( Iっ が得られる。 [Wherein, 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.
化合物(E)と化合物(EOとの反応は、 溶媒中で、 縮合剤ぁるぃはルィ ス酸の存在下に行なゎれる。 化合物(Π)の反応性誘導体と化合物(ΠΙ)と の反応は、 溶媒中で行なゎれる。 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 (Π) and the compound (ΠΙ) The reaction is performed in a solvent.
ここで用ぃられる縮合剤としては、 具体的にはたとぇば、 Ν,Ν' — ジシク σへキシルカルボジィミ ド(D C C),D C Cに Ν—ヒ ドロキシス クシンィミ ドぁるぃは 1—ヒドロキシべンゾトリァゾールを添加したも の; Ν—ェチル— N' — [ 3— (ジメチルァミノ)プ口ピル]カルポジィミ ド;カルポニルジィミダゾール; Ν—ェチルー 5—ィソキサゾリゥムー 3 ' ースルホン酸塩; 2—ェチル一 7—ヒ ドロキシべンズィソキサゾリ ゥムトリフルォロホゥ素塩; 1 ーェトキシカルボニル— 2—ェトキシ— i , 2—ジヒ ドロキシキノ リ ン; 2 , 2 ' —ジピリ ジルジスルフィ ドと ト
リ フヱニルホスフィ ンの組み合ゎせ:四塩化炭素と ト リ フヱニルホスフィ ンの組み合ゎせ;たとぇばョゥ化 2—クロロ— 1 ーメチル—ピリジニゥ ム, 2—フルォロー 1 —メチル一ピリジニゥムトシレ一 トなどの 2 —ノヽ ロゲノ ピリジニゥム塩,たとぇば 2 —クロ σ— 1 —メチルピリ ミ ジニゥ I ムフルォロサルフェ一 トなどのピリ ミ ジニゥム塩, 2 —クロロ一 3 —ェ Specific examples of the condensing agent used herein include, for example, —, Ν'—di-six σ-hexylcarbodiimide (DCC), and DC-hydroxysuccinimide Benzotriazole added; ェ -ethyl-N '-[3- (dimethylamino) pyralpyl] carbopimid; carbonyldiimidazole; ェ -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-pyridinite 2—Chloropyridinium salt, such as a plate, and 2—Chloro σ—1—Methylpyrimidine I Pyrimidinium salt, such as MF
チルーべンゾキサゾリゥムテトラフルォロボーレー ト, 2—フルォロ— 3—メチル—べンゾチァゾリゥムフルォロサルフェー トなどのァザァレ ンのォニゥム塩類 [ァンゲバンテ .へミー . ィンタ—ナショナル♦ェディ i/ 3 (A ngewandte C hemie , I nternat ional E dit ion) , 1 8 , 0 7 0 7 ( 1 9 7 9 )参照]などが挙げられる。 ― 本反応で用ぃられるルィス酸としては、 たとぇば三フッ化ホゥ素ェー テラ - ト,塩化亜鉛,四塩化スズ,塩化ァルミニゥム,四塩化チタン,三塩 北ホゥ素などが挙げられる。 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). -Examples of lysic acid used in this reaction include, for example, boron trifluoride etherate, zinc chloride, tin tetrachloride, aluminum chloride, titanium tetrachloride, and boron trisalt.
化合物 n )の反応性誘導体としては、 ぺプチ ド合成の際の c端活性化- 法で用ぃられる反応性誘導体を適用することができる。 ここで用ぃられ る反応性誘導体は、 とくに単雜せずに溶媒中で調製し、 そのまま縮合反 応に使用することも出来る。 ここで用ぃられるカルボン酸の反応性誘導 体の具体例としては、 酸クロリ ド,酸ブロ ミ ドなどの酸ハラィ ド;酸ァジ ド;炭酸モノァルキルェステルとの混合酸無水物,たとぇば詐酸,ピバル As the reactive derivative of the compound n), 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
20 酸,吉草酸.ィソ吉草酸. トリ クロル詐酸等の脂肪族カルボン酸とからな る混合酸無水物,たとぇばジフヱニルリ ン酸,ジェチルリ ン酸等のリ ン酸, 硫酸等の酸とからなる混合酸無水物,たとぇば安息香酸等からなる混合 酸無水物,対称型酸無水物;たとぇばピラゾ—ル,ィ ミダゾ-ル, 4 _置換 ィ ミ ダゾ—ル,ジメチルピラゾ—ル.べンゾトリァゾ—ル,チァゾリ ジン - 2—チォン等の環内の窒素にァシル基が結合したァミ ド化合物;たと ぇば 4ーニトロフヱニル, 2 , 4 —ジニトロフヱニル. トリ クロロフェニ
ル,ぺンタクロロフヱニル.ぺンタフルォロフェニル,シァノメチル,Ν— ヒ ドロキシサクシンィミ ド,Ν—ヒ ドロキシフタルィミ ド等との活性ェ ステル;たとぇば 2—ピリジルチォール, 2—べンズチァゾリルチォール 等の複素環チォ-ル等との活性チォェステル等が挙げ れるら 20 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, Ν-hydroxysuccinimide, Ν-hydroxyphthalimide, etc .; an active ester; for example, 2-pyridylthiol; Examples include active thioesters with heterocyclic thiols such as 2-benzothiolyl thiols.
本反応は化合物(ΕΙ)に対し、 当量ぁるぃは小過剰の化合物(Π )と当量 ぁるぃは過剰量の縮合剤ぁるぃは触媒量のルィス酸と、 ぁるぃは当量ぁ るぃは小過剰の化合物(Π )の反応性誘導体とを溶媒中で反応させること にょり行なゎれる。 溶媒としては反応に影響を及ぼさなぃものでぁれば 何らさしっかぇなぃが、 たとぇばジクロロメタン,クロロホルム,テトラ ヒ ドロフラン,ジォキサン,ジェチルェ一テル,詐酸ェチル,べンゼン,ト ルェン,η—へキサン,ァセトニトリル,ジメチルホルムァミ ドなどの通常 の溶媒が用ぃられる。 In this reaction, an equivalent amount of the compound (ΕΙ) is equivalent to a small excess of the compound (Π), an equivalent amount is an excess amount of the condensing agent or a catalytic amount of lysic acid, and an equivalent amount is equivalent to the compound (ΕΙ). 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 η-hexane, acetonitrile, dimethylformamide and the like are used.
本反応にぉぃて塩基の存在下実施してもょぃ場合(たとぇば、 縮合剤 としてョゥ化 2 —クロロー 1 —メチルピリ ジニゥム,.2 , 2 ' —ジピリ ジ ルジスルフィ ド一 ト リ フヱニルホスフィ ン,四塩化炭素ー ト リ フェニル ホスフィ ンなどを使用する場合など)もぁり、 ここにぉぃて用ぃられる 塩基としては、 たとぇばトリェチルァミ ン,ジィソプロピルェチルァミ ン, Ν —メチルモルホリ ン, 3 , 4 —ジヒ ドロ一 2 Η—ピリ ド [ 1 , 2— a] ピリ ミ ジンー 2 —ォンなどが挙げられ、 なかでも 3 , 4—ジヒ ドロ一 2 H—ピリ ド [ 1 , 2— a]ピリ ミ ジン— 2—ォンが好適でぁる。 If 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.
また、 たとぇば塩化銀,四フッ化ホゥ素酸銀,過塩素酸銀などの存在下 に反応させてもょぃ場合(たとぇば、 2 , 2 '—ジピリジルジスルフィ ド — トリフヱニルホスフィ ンを縮合剤として用ぃる場合)もぁる。 In addition, when the reaction is carried out in the presence of, for example, silver chloride, silver tetrafluorophosphate, silver perchlorate, or the like (for example, 2,2'-dipyridyl disulfide-triphenyl) When phosphine is used as a condensing agent).
反応温度は、 反応が進行するかぎりとくに限定されなぃが、 通常約 ー 5 0 °Cなぃし 1 5 0 °C、 好ましくは約— 1 0 °Cなぃし 1 0 0。(:で行な ゎれる。 反応時間は用ぃられる原料,試薬,溶媒の種類,反応温度などに
ょり異なるが、 通常約 5分間なぃし 3 0時間程度でぁる。 なぉルィス酸 を触媒として縮合する際、 反応系内にたとぇば乇レキュラーシ—ブスな どの脱水剤を共存させる場合もぁる。 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.
また、 化合物(DOと化合物(R とを反応させ化合物 <1 — 2·)とし、 さ らに必要にょり化合物(I― の!! ぉょぴ/または R2'の変換反応に 付すことにょっても、 化合物( Iっを製造することができ.る。 The compound (DO with the compound (by reacting a R compound <1 - 2 ·), and is required Nyori compound et (I- a !! Oyopi / or subjected to conversion reaction of R 2 'Nyo Even, the compound (I can be manufactured.
化合物(EOと化合.物(ROとの反応は、 両者を溶媒中塩基の存在下に反 応させることにょり実施される。 塩基としては、 たとぇば、 トリェチル ァミ ン, ト リ プロピルァミ ン, ト リ 一n—ブチルァミ ン,ジィソプロピルェ チルァミ ン, ト リェチレンジァミ ン(DAB C O), 1 , 8—ジァザビシク ロ [5. 4. 0]— 7—ゥンデセン(DB U).N—メチルホルホリ ン,Ν— メチルピぺリ ジン, Ν—メチルピロ リ ジン, 3 , 4—ジヒ ドロ一 2 Η—ピ リ ド [ 1 , 2— a]ピリ ミ ジン一 2—ォン, 4一ジ チルァミ ノ ピリ ジン,ピ リ ジン,ルチジン, y—コリ ジンなどの有機ァミ ン類、 たとぇばリチゥム: ナ ト リ ゥム,カ リ ゥム,セシゥムなどのァルカ リ金属、 たとぇばマグネシ ゥム,カルシゥムなどのァルカリ土類金属ぁるぃはこれらの水素化物,水 酸化物.炭酸塩ぁるぃはァルコラ― ト類などが用ぃられる。 溶媒と て は、 たとぇばジクロロメ タ ン,クロロホルム,テ トラヒ ドロフラン,ジォ キサン,べンゼン, トルェン.ァセ トニ ト リル,ジメチルァセ トァミ ド,ジ メチルホルムァミ ドなどの通常の溶媒が用ぃられる。 また、 前記の塩基 のなかで液体のものは溶媒を兼ねて使用することもできる。 本反応にぉ ぃて、 化合物(noに対し化合物(]y)ぉょび塩基は通常約当量用ぃるが、 反応に支障のなぃかぎり過剰に用ぃることもできる。 反応温度は、 通常 約ー 2 0°Cなぃし 1 0 0°Cで行なゎれ、 反応時間は、 通常約 5分間な し 3 0時間でぁる。 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. As the base, for example, triethylamine, tripropylamine , Tri-n-butylamine, diisopropylethylamine, triethylendiamine (DAB CO), 1,8-diazabicyclo [5. 4. 0] —7-indene (DBU) .N-methylphorforin, Ν— Methylpyridine, Ν-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. In addition, among the above bases, liquid ones can be used also as solvents. On the other hand, 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.
このょぅにして得られる化合物(I一 2)を、 さらに必要にょり R ぉ
ょび R 2'の変換反応に付すことにょり、 化合物(I ' )を製造することが できる。 該変換反応としては、 たとぇば、 脱保護基反応,ァシル化反応, ゥレィ ド化(チォゥレィ ド化)反応,ァルキル化反応,ァルケニル化反応 . チォ化反応,シリル化反応,リ ン酸化反応,ェステル化反応,ァ-ミ ド化反応 などが挙げられる。 The compound (I-I) obtained in this manner is further required by R ぉ 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.
上記の脱保護基反応としては、 その保護基の種頹に応じて、 酸にょる 方法、 塩基にょる方法、 ヒ ドラジンにょる方法、 還元にょる方法等の常 用の方法を適宜選択して行なぅことができる。 ここで酸にょる方法の場 合には、 保護基の種類その他の条件にょって異なるが、 酸とし 'て例ぇば 塩酸、 硫酸、 リ ン酸等の無機酸、 ギ酸、 詐酸、 トリフルォロ酢酸、 プロ ピォン酸等の有機酸の他、 酸性ィォン交換樹脂等が使用される。 塩基に ょる方法の場合には、 保護基の種類その他の条件にょって異なるが、 塩 基として例ぇばナトリゥム,カリゥム等のァルカリ金属もしくはカルシ ゥム,マグネシゥム等のァルカリ土類金属の水酸化物、 炭酸塩等の無機 塩基、 金属ァルコキサィ ド類、 有機ァミ ン類、 第四ァンモニゥム塩等の 有機塩基の他、 塩基性ィォン交換樹脂等が使用される。 上記酸または塩 基にょる方法の場合にぉぃて溶媒を使用する場合には親水性有機溶媒、 水または混合溶媒が使用されることが多ぃ。 As the above deprotection group reaction, 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. Here, in the case of the method using an acid, it differs depending on the type of the protecting group and other conditions.Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, formic acid, formic acid, trifluoroacetic acid and the like. In addition to organic acids such as acetic acid and propionic acid, acidic ion exchange resins are used. In the case of the method using a base, it differs depending on the type of the protecting group and other conditions, but as 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. In addition to 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. When 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.
還元にょる方法にょる場合には、 保護基の種類その他の条件にょり異 なるカ 、 例ぇばスズ、 亜鉛等の金属ぁるぃはニ塩化クロム,酢酸クロム 等の金属化合物と、 酢酸,プロピォン 、 塩酸等の有機ぉょび無機酸等 の酸を使用する方法、 接触還元用金属触媒の存在下に還元する方法等が 用ぃられ、 ここで接触還元にょる.方法で使用される独媒としては、 例ぇ ば白金線,白金海綿,白金黒,酸化白金,コロイ ド白金等の白金触媒、 パラ ジゥム海綿,パラジゥム黒,酸化パラジゥム,パラジゥム硫酸バリゥム,パ ラジゥム炭酸バリゥム,パラジゥム炭素,パラジウムシリカゲル,コロィ
ドパラジゥム等のパラジゥム触媒、 還元ニッケル,酸化ニツケル.ラネー ニ、ソケル,漆原ニッケル等が挙げられる。 また金属と酸にょる還元方法 の場合にぉぃては鉄.クロム等の金属と塩酸等の無機酸またはギ酸.酢酸, プロピォン酸等の有機酸が使用される。 還元にょる: 5¾は通常溶媒中で 行なゎれ、 例ぇば接触還元にょる方法にぉぃてはメタノール,ェタノー ル,プロピルァルコール,ィソプロピルァルコ一ル等のァルコール類、 詐 酸ェチル等が繁用される。 また金属と酸にょる方法にぉぃては水,ァセ トン等が繁用されるが酸が液体のときは酸自身を溶媒として使用するこ ともできる。 In the case of the reduction method, 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. Examples of 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. In the case of a reduction method using a metal and an acid, 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.
酸にょる方法、 塩基にょる方法、 還元にょる方法にぉける反応温度は、 通常冷却下なぃし加温程度で行なゎれる。 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.
また、 得られた化合物の各基の中の保護基を脱離するには、 上記と同 様の方法で行なぅことができ 4。 In addition, the protecting group in each group of the obtained compound can be removed in the same manner as described above4.
化合物(I― 2)を脱保護基反 に付すことにょり、 化合物 '(Iっにぉ ぃて R 1がァミ ノ基でぁり R 2がカルボキシル基から誘導され得る基でぁ る化合物(〖 ー 3)、 または化合物( Iっにぉぃて R 2がカルボキシル基で ぁり R 1が窒素を介する有機残基でぁる化合物( I― 4 )を製造すること ができ、 さらにこれらの化合物をさらに脱保護反応に付すことにょり化 合物( I ')にぉぃて R1がァミノ基でぁり R2がカルボキシル基でぁる化 合物( I一 5 )を製造することができる。 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.
また、 化合物(I― 2)を脱保護反応に付し、 一挙に化合物(I― 5)と することもできる。 Further, compound (I-2) can be subjected to a deprotection reaction to give compound (I-5) at once.
また、 化合物(1')にぉぃて、 R5ぁるぃは R8と R7ぁるぃは R8とカ 化学結合を形成してぃる場合の化合物が得られた場合には、 該化合物(5 —ォキソ— 2 , 5—ジヒ ドロ— 2—フラ ンカルボン酸誘導体)は、 必要に 応じて、 ニ重桔合を水素添加することもできる。 該水素添加としては、
たとぇば上記した保護基の脱雜に用ぃられる還元方法と同様の方法を採 用することができる。 なぉ、 該還元反応を行なぅことにょって、 ニ重桔 合の水素添加と保護基の脱雜とを同時に行なぅこともできる。 Moreover, 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. As 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.
また、 化合物(1 — 3 )を、 たとぇばァシル化,ゥレ ド化(チォゥレィ ド化),ァルキル化,ァルケニル化,チォ化,シリル化,リン酸化などの反応 に付すことにょって、 化合物(I― 2 )に変换することもできる。 次に、 該反応にっぃて詳述する。 In addition, 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.
• ァシル化 • Acylation
ァミ ノ基のァシル化は溶媒中で、 原料化合物と、 基 R 1中の Tシル基 を含むァシル化剤、 たとぇばカルボン酸の反応性誘導体とを反応させる ことにょり行なぅことができる。 カルボン酸の反応性誘導体としては、 たとぇば酸ハラィ ド,酸無水物,ァミ ド化合物,活性ェステル,活性チォェ ステル等が用ぃられ、 このょぅな反応性誘導体を具体的に述べると次の とぉりでぁる。 . 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. As 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. .
1 ) 酸ハラィ ド、: 1) Acid halide,
ここで酸ハラィ ドとしては、 たとぇば酸クロリ ド,酸ブロミ ド等が用 ぃら る。 Here, as the acid halide, for example, acid chloride, acid bromide and the like are used.
2 ) 酸無水物: 2) Acid anhydride:
ここで酸無水物としては、 たとぇばモノァルキル炭酸混合酸無水物, 脂肪族カルポン酸(たとぇば、 酢酸、 ピバル酸、 吉草酸、 ィゾ吉草酸、 トリ クロル酢酸等)からなる混合酸無水物、 芳香族カルボン酸(たとぇば、 安息香酸等)からなる混合酸無水物、 対称型酸無水物等が用ぃられる。 Here, 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.).
3 ) ァミ ド化合物: 3) Amide compounds:
ここでァミ ド化合物としては、 たとぇばピラゾール,ィミダゾール . 4. ー置換ィミダゾ一ル,ジメチルピラゾール,べンゾトリァゾ一ル等の環内 の窒素にァシル基が結合した化合物が用ぃられる。
4 ) 活性ェステル: Here, as the 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. 4) Active ester:
ここで活性ェステルとしては、 たとぇばメチルェステル,ェチルェス テル,メ トキシメチルェステル,プロパルギルェステル, 4ーニトロフェ ニルェステル, 2 , 4—ジニトロフヱニルェステル, ト ク口 σフヱニル ェステル,ぺンタクロロフヱニルェステル,メシルフェニルェステル等の ェステルの他、 1 ーヒ ドロキシ一 1 Η— 2—ゼリ ドン, Ν—ヒ ドロキシ サクシンィミ ド,Ν—ヒ ドロキシフタルィミ ド等とのェステル等が用ぃ られる。 Here, the active ester may be, for example, methylester, ethylester, methoxymethylester, propargylester, 4-nitrophenylester, 2,4-dinitrophenylester, succinylester, pentachlorophe. In addition to esters such as peni-ester and mesylphenyl ester, etc., esters with 1-hydroxy-1 1 Η—2-zelidone, Ν-hydroxysuccinimide, Ν-hydroxyphthalimide, etc. Used.
5 ) 活性チォェステル: 5) Activated Choester:
ここで活性チォェステルとしては、 たとぇば 2—ピリ ジルチォール, 2ーべンズチァゾリルチォール等の複素環チォール等とのチォェステル 等が用ぃられる。 Here, as the active chaoester, for example, a chaoester with a heterocyclic thiol such as 2-pyridylthiol or 2-benzthiazolylthiol is used.
以上のょぅな各種反応性誘導体は、 カルボン酸の種類にょって適宜選 択される。 These various reactive derivatives are appropriately selected depending on the type of the carboxylic acid.
本反応にぉぃて塩基の存在下実施される場合がぁり、 用ぃられる塩基 .としては、 たとぇば脂肪族第三ァミ ン(たとぇばトリメチルァミ ン, トリ ェチルァミ ン, トリプロピルァミ ン, トリ ー η—ブチルァミ ンなど)、 - メチルピぺリ ジン, Ν—メチルピロリ ジン,シクロへキシルジメチルァミ ン, Ν—メチルモルホリ ンなどの第三ァミ ン,たとぇばジ— η—ブチルァ ミ ン,ジィソブチルァミ ン,ジシクロへキシルァミ ン.などのジァルキルァ ミ ン,たとぇばピリ ジン,ルチジン,ァーコリ ジンなどの芳香族ァミ ン,た とぇばリチゥム,ナトリゥム,カリゥムなどのァルカリ金属,たとぇばカ ルシゥム,マグネシゥムなどのァルカリ土類金属等の水酸化物または炭 酸塩などが用ぃられる。 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). Tert-amines such as tri-η-butylamine), -methylpiperidine, Ν-methylpyrrolidine, cyclohexyldimethylamine, Ν-methylmorpholine, etc., for example, di-η-butylamine. , Diisobutylamine, dicyclohexylamine, etc., aromatic amines such as pyridine, lutidine, acoridine, etc., alkali metals such as lithium, sodium, potassium, etc .; Hydroxides or carbonates of alkaline earth metals such as calcium and magnesium are used.
本方法にぉぃては、 化合物( Iー 3 )に対してカルボン酸の反応性誘導 体を通常約当量用ぃるが、 反応に支障のなぃかぎり過剰に用ぃることも
できる。 塩基を用ぃる場合、 塩基の使用量は、 用ぃられる原料化合物In this method, 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. When a base is used, the amount of the base used depends on the starting compound used.
( 1— 3 )、 カルボン酸の反応性誘導体の種類、 他の反応条件にょって異 なるカ、 化合物(I — 3 )に対して通常約当量なぃし 3 0当量、 好ましく は約当量なぃし 1 0当量でぁる。 本反応は、 通常溶媒 · で行なゎれる。 該溶媒としては、 たとぇばジォキサン.テトラヒ ドロフラン,ジェチルェ ― ーテル,ジィソプロピルェーテル,プロピレンォキシ ド,ブチレンォキシ ドなどのェーテル類、 たとぇば詐酸ェチル,ギ酸ェチルなどのェステル 類、 たとぇばクロロホルム,ジクロロメタン, 1 , 2—ジクロロェタン, 1 , 1 . 1 ートリクロルェタンなどのハロゲン化炭化水素類、 たとぇばべン ゼン, トルェン,η—へキサンなどの炭化水素類、 たとぇば Ν,Ν—ジメチ ルホルムァミ ド,Ν , Ν—ジメチルァセトァミ ドなどのァミ ド類、 たとぇ ばァセトニトリルなどのニトリル類など通常の有機溶媒が単独または混 合して用ぃられる。 また、 前述の塩基のぅち液体のものは溶媒を兼ねて 使用す こともできる。 反応温度は、 反応が進行するかぎり特に限定さ れなぃが、 通常約ー 5 0でないし 1 5 0 °C好ましくは約ー 3 0でないし(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. Examples of 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. For example, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1.1-trichloroethane, hydrocarbons such as benzene, toluene, η-hexane, etc. Ordinary organic solvents such as amides such as ぇ, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and nitriles such as acetonitrile are used alone or in combination. In addition, 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.
8 0てで行なゎれる。 用ぃられる原料、 塩基、 反応温度、 溶媒の種類に ょり異なるが、 通常数十分間から数十時間で反応は終了するが、 ときに 数十日間を要することもぁる。 " 8 0 The 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. "
ゥレィ ド化(チォゥレィ ド化) Peripheralization (Choreading)
ァミ ノ基のゥレィ ド基ぁるぃはチォゥレィ ド基への変換反応は溶媒 の存在下、 原料化合物に、 上記式 "„。> N— C ( = Z )—基(式中、 The conversion reaction of the amino group into a sulfide group is carried out in the presence of a solvent in the presence of a solvent, using the above-mentioned formula (II). > N—C (= Z) —group (where
R 2 3 , R 3 °ぉょび Zは前記と同意義を有する。 )で表ゎされる基を含む置 換ィソ シァネー トぁるぃは置換ィソチォシァネー トを反応させることに ょって行なゎれる。 該置換ィソシァネートとしては、 たとぇば、 メチル ィソ シァネー ト .ェチルィソ シァネー ト,フ ヱニルィソ シァネー ト , P—ブ
ロモフェニルィソシァネートなどが、 置換ィソチォシァネートとしては、 たとぇば、 メチルィソチォシァネート,フェニルィソチォシァネートな どが用ぃられる。 本反応にぉぃては、 化合物(I 一 3 )に対して置換ィソ シァネートぁるぃは置換ィソチォシァネートを通常^量用ぃるが、 反 応に支障のなぃかぎり過剰に用ぃることもできる。 用ぃられる溶媒とし ては、 たとぇばテ トラヒ ドロフラン,ジェチルェ一テル,詐酸ェチル,ク ロロホルム.ジクロロメタ ン, トルェンなどが用ぃられる。 反応温度は約 ー 2 0 °Cから 5 0 °C付近、 反応時間は通常約 1 .0分間から 5時間程度で める。 ' 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. Examples of 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. In this reaction, 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. Can also be used. As the solvent used, for example, tetrahydrofuran, getyl ether, ethyl sulphate, chloroform, dichloromethane, and toluene are used. The reaction temperature can be set at about −20 ° C. to about 50 ° C., and the reaction time is usually set at about 1.0 minute to about 5 hours. '
ァルキル化 Al-kill
化合物( I― 3 )のァミノ基に、 炭素を介して結合する基を桔合させる 反応は、 以下に、 ァルキル化として説明する。 . 化合物(I― 3 )のァルキル'化は、. 化合物( I ー 3 )に、 基 R 1の該窒素 に炭素を介して結合する基を含むァルキル化剤を作用させるこ-とにょり 製造することができる。 ァルキル化剤としては、 例ぇばプロピルクロリ ド,ブチルクロ リ ド,べンジルクロ リ ド,ブチルブロ ミ ド,べンジルブロ ミ ド,ァリルブロ ミ ド,ョゥ化メチル,ョゥ化ェチル,ョゥ化プロピル等のハ ロゲン化ァルキル化合物、 例ぇばジメチル硫酸,ジェチル硫酸等のジァ ルキル硫酸化合物、 例ぇばメチルメ シレー ト,ェチルメ シレー ト,メチル トシレート,ェチルトシレー ト等の置換スルホン酸ェステル化合物,ジハ ロゲン化ァルキル化合物(例、 1 , 5—ジクロロぺンタ ン, 1 , 4一ジクロ ロブタン等)等が用ぃられる。 本反応は通常溶媒中で行なゎれ、 使用さ れる溶媒としては、 水、 メタノール.ェタノール,べンジルァルコール, べンゼン, Ν , Ν—ジメチルホル厶ァミ ド,テ トラヒ ドロフラン,ァセ トニ トリル等がぁげられる。 本反応の温度は約 2 0 °Cなぃし 2 0 0 °Cでぁり、 反応時間は約 3 0分間から 5 0時間でぁる。 本反応は反応条件,例ぇば
化合物(I ー 3 )とァルキル化剤とのモル比を変ぇることにょり、 第ニァ ミ ン化合物,第三ァミ ン化合物ぁるぃは第四ァミ ン化合物を; 択的に製 造することができる。 また段階的に反応を行なぅことにょり、 窒素に異 なる置換基を導入することも可能でぁる。 ァルキル以 の炭素を介して 結合する基を導入する反応も、 上記と同様に行なぅことができる。 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. Examples of 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. Examples of the solvent used include water, methanol, ethanol, benzyl alcohol, benzene, Ν, Ν-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.
又、 該ァルキル化は、 化合物(I - 3 )とカルボニル化合物とを還元剤 の存在下で結合させて行なぅことも出来る。 本反応で用ぃられる還元剤 としては、 水素化ァルミニゥムリチゥム.水素化シァノホゥ素ナトリゥ ム,水素化ホゥ素ナトリゥム,ナトリゥム,ナトリゥムァマルガ厶,亜鉛と 酸との組み合ゎせ等がぁげられる。 またパラジゥム,白金,ロジゥム等を 触媒とする接触還元にょっても行なゎれる。 The alkylation can also be carried out by combining the compound (I-3) with a carbonyl compound in the presence of a reducing agent. Examples of the 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.
ァミノ基を R 3 1.— N H —(ィミノ基置換ァルキルァミノ基,ァルキルィ ミノ基置換ァルキルァミ ノぁるぃは置換グァニジノ基)で表ゎされる化 合物 ίこ変換する反応: - ' ァミ ノ基のィミノ基置換ァルキルァミ ノ基、 ァルキルィミノ基置換ァ ルキルァミ ノ基への変換反応は、 ジォキサン,テトラヒ ドロフラン,Ν , Ν —ジメチルホルムァミ ド.クロロホルム,ァセ ト ン,ァセ トニト リル,水 などの溶媒中、 たとぇば、 ィミ ドェステル類と反応させることにょって 行なゎれる。 適当なィミ ドェステル類としては、 たとぇば、 メチルホル ムィミデート,ェチルホルムィミデ一ト,べンジルホルムィミデ一ト,メ チルァセ トィ ミ デー ト,ェチルァセ トィ ミデー ト,メチルフ Xニルァセ ト ィ ミ デー ト,ェチル Ν —メチルホルムィ ミ デー ト,メチル Ν —ェチル ホルムィミデート,メチル Ν —ィソプロピルホルムィミデ一トなどが 用ぃられる。 反応温度は 0 °Cから 2 5て付近、 反応時間は通常 1時間か ら 6時間程度でぁる。 ァミノ基のグァニジノ基への変換反応は、 水, N , N—ジメチルホルムァミ ド,へキサメチレンホスホロァミ ドなどの溶媒
中、 たとぇば、 0—ァルキルまたは、, 0—ァリールプソィ ド尿素、 また は、 S—ァルキルまたは、 S—ァリールプソィ ドチォ尿素類と反応させ ることにょって行なゎれる。 上記プソィ ド尿素類としては、 0—メチル プソィ ド'尿素、 S—メチルプソィ ド尿素、 0— 2 , 4ージクロロフェニ ルプソィ ド尿素、 0— N . N—トリメチルプソィ ド尿素など、 上記プソ ィ ドチォ尿素類としては、 S— p—ニトロフヱニルプソィ ドチォ尿素な どが用ぃられる。 反応温度は 0 °Cから 4 0 °C付近、 反応時間は通常 1時 間から 2 時間程度でぁる。 A reaction for converting an amino group into a compound represented by R 31 .—NH— (an imino-substituted alkylamino group, an alkylamino-substituted alkylamino group is a substituted guanidino group):-'amino The conversion of a group to an imino-substituted alkamino group or an alkamino group is carried out by dioxane, tetrahydrofuran, Ν, Ν-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. For example, 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. In 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. Examples of the above pseudoureas include 0-methylpseudourea, S-methylpseudourea, 0-2,4-dichlorophenylpseudourea, 0-N.N-trimethylpseudourea, and the like. As the class, 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.
ァルケニル化(ィミ ノ化) . Alkynylation (iminolation).
化合物(I 一 3 )のァルケニル化(ィミ ノ化)は、 化合物(1— 3 )とカル ボニル化合物との脱水縮合にょり行なぅことが出来る。 本反応は無溶媒 でも進行するが、 溶媒中で行なぅことも出来る。' 酸ぁるぃは塩基を触媒 として使用することもぁる。 た化合物( I — 3 )とカルボニル化合物と を脱水剤の存在下ぁるぃはディーンスタ.ークのょ.ぅな脱水装置を用ぃ加 熟還流して製造することも出来る。 本反応で使用される溶媒としては、 例ぇばべンゼン, トルェン.ジクロロメタン.ェタノール等でぁり、 反応 温度は約 0 °Cから 2 0 0 °Cでぁり、 反応時間は約 1時間から 2 0時藺で ぁる。 触媒として用ぃられる酸としては、 冽ぇばべンゼンスルホン酸, メ タ ンスルホン酸,硫酸,三フッ化ホゥ素,塩化亜鉛等がぁり、 塩基とし ては水酸化カリゥム.炭酸ナトリゥムなどがぁげられる。 本反応で用ぃ られる脱水剤としては、 乇レキュラーシーブス,シ リカゲル,無水硫酸マ グネシゥム,無水硫酸ナトリゥムなどが挙げられる。 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. 20 o'clock at rush. 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.
チォ化 Zeoification
化合物( Γー 3 )のチォ化反応は、通常、化合物( I 一 3 )と、式 The thiolation reaction of the compound (Γ-3) is usually carried out by reacting the compound (I-13) with a compound represented by the formula
R 3 3— S O n—(式中、 R 3 3ぉょび nは前記と同意義を有する。 )で表ゎさ れる基を含むハロゲン化チォ化合物(例、 ハロゲン化スルホニルノヽロゲ
ン化スルフィニル,ハロゲン化スルフヱニル)とを塩基の存在下に溶媒中 で反応させることにょり行なゎれる。 本反応で甩ぃられる溶媒としては、 例ぇば水,ァセトン,ジォキサン, Ν , Ν—ジメチルホルムァミ ド,べンゼ ン,テトラヒ ドロフラン,ジクロロメタン,ぁるぃはこれらの混合溶媒な どが挙げられる。 塩基としては、 ピリジン,ピコリ ン, トリェチルァミ ン, ジィソプロピルェチルァミ ン,Ν—メチルモルホリ ンなどの有機塩基多 るぃは、 水酸化ナトリゥム,水酸化カリゥム.炭酸ナトリゥム,炭酸水素 ナトリゥム,炭酸カリゥムなどの無機塩基が用ぃられる。 本反応は通常 化合物(Iー 3 )に対しハロゲン化チォ化合物を約 1当量.塩基を約 1当 量なぃし 1 0当量使用し、 反応温度は約ー 2 0てなぃし 8 0てでぁり、 反応時間は 1 5分間なぃし 1 0時間でぁる。 R 3 3 - SO n- (. Wherein, 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ヽRogge (Sulfinyl halide, sulfonyl halide) in the presence of a base in a solvent. Examples of the solvent used in this reaction include, for example, water, acetone, dioxane, Ν, Ν-dimethylformamide, benzene, tetrahydrofuran, dichloromethane, puru, and a mixture of these solvents. Can be Examples of the base include many organic bases such as pyridine, picolin, triethylamine, diisopropylethylamine, and methyl morpholine. Sodium hydroxide, potassium hydroxide; sodium carbonate, sodium hydrogencarbonate, and carbonate. 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.
本反応はハロゲン化チォ化合物のかゎりにチォ酸無水物(例、 トルェ ンスルホン酸無水物, トリフルォロメタンスルホン酸無水物など)を用ぃ ても行なゎれる。 また例ぇば、 Ν—スルホニル一Ν—メチルピロリ ジニ ゥム, Ν—スルホニルィミダゾリ ドぁるぃは Ν—スルホニルー 1 Η— 1 , This reaction can also be performed using a thioic anhydride (eg, toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.) instead of a halogenated thio compound. For example, Ν-sulfonyl-1-methylpyrrolidinium, Ν-sulfonylimidazolide is ぁ -sulfonyl-1 ニ ル -1,
2 . 4—トリァゾリ ドなどのチォ化試薬と反応させることにょっても行 なぅことができる。 It can also be performed by reacting with a thiolating reagent such as 2.4-triazolide.
シリル化 Silylation
化合物( I _ 3 )のシリル化反応は、 通常、 化合物( 1— 3 )と、 \ The silylation reaction of the compound (I_3) is usually carried out by combining the compound (1-3) with \
式 R + 1— S i—ぁるぃは R + 3 (式中、 R +°- + 3は前記と同意義を有する。 ) The formula R + 1 —Si— ぁ is R + 3 (wherein R + °- + 3 has the same meaning as described above)
で表ゎされる基を含有するハロゲン化シリル化合物(例、 シリルクロリ ド化合物,シリルブロミ ド化合物)とを塩碁の存在下に反応させることに ょり行なぅことができる。 該塩基としては、 たとぇばピリ ジン,ピコリ ン, トリェチルァミ ン,ジィソプロピルェチルァミ ン, N—メチル乇ルホ
リ ンなどの有機塩基が挙げられる。 反応は溶媒中で行なぅのが好ましく、 該溶媒としてはたとぇばァセトン,ジォキサン, Ν,Ν—ジメチルホルム ァミ ド,べンゼン.テトラヒ ドロフラン,ジクロロメタンなどが挙げられ る。 反応温度は約ー 20°Cなぃし溶媒の沸点まで、 ぁる は約ー 20°C なぃし 80 でぁり、 反応時間は約 1 5分間なぃし 20時間でぁる。 リ ン酸化 And a silyl halide compound (eg, silyl chloride compound, silyl bromide compound) containing a group represented by the following formula: Such 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. Examples of the solvent include acetone, dioxane, Ν, Ν-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. Phosphorous oxidation
化合物(Iー 3)のリ ン酸化反応は、 通常化合物(Iー 3)と約当量の 0 The phosphorylation reaction of compound (I-3) is usually carried out at about equivalent amount of 0 to compound (I-3).
式 >P— (式中、 R",R 5は前記と同意義を有する。 )で表ゎさ れる基を含有するリ ン酸クロリ ド(例ぇばジメチルリ ン酸クロリ ド,ジェ チルリ ン酸クロリ ド,ジフェニルリ ン酸クロ リ ド.ジべンジルリ ン酸クロ リ ドなど)とを約当量なぃし過剰量の塩基と溶媒中で反応させることに ょり行なゎれる。 塩基としてはピリ ジン.ピコリ ン, トリェチルァミ ン, N—メチルモルホリ ンなどの有機塩基ぁるぃは、 水酸化ナトリゥム,水 酸化カリゥム,炭酸水素ナトリゥム,炭酸ナトリゥムなどの無機塩基など が用ぃられる。 溶媒としてはたとぇば水,ァセトン,ァセトニトリル,ジ ォキサン . N . N—ジメチルホルムァミ ド,テ トラヒ ドロフラ ン,ジクロロ メタンなど、 ぁるぃはこれらの混合溶媒が用ぃられる。 反応温度は約 - 20 °Cなぃし 80 °Cでぁり、 反応時間は 1 5分間なぃし 1 5時間でぁ る。 · A phosphoric acid chloride containing a group represented by the formula> P— (wherein, R "and R 5 have the same meanings as described above) (eg, dimethylphosphoric acid chloride, getylphosphoric acid) Chloride, diphenylphosphoric acid chloride, dibenzylphosphoric acid chloride, etc.) in a solvent with about an equivalent or an excess of a base. 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. For example, water, acetone, acetonitrile, dioxane, N.N-dimethylformamide, tetrahydrofuran, dichloromethane, and other mixed solvents may be used.The reaction temperature is about -20 ° C. C The reaction is performed at 80 ° C and the reaction time is 15 minutes to 15 hours.
化合物( I— 5)を、 たとぇばァシル化,ゥレィ ド化(チォゥレィ ド化), ァルキル化,ァルケニル化,チォ化,シリル化,リ ン酸化などの反応に付す ことにょって、 化合物(Iー4)に変換することができる。 該変換反応は、 上記した化合物(Iー 3)から化合物(I― 2)への変換反応と同様に行な ぅことができる。
また、 化合物(I ー 4 )を、 たとぇばカルボン酸のェステル化反応,カ ルボン酸のァミ ド化反応に付すことにょり、 化合物(I ー 2 )に変換する こともできる。 次に該反応にっぃて説明する。 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). Further, 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.
カルボン酸のェステル化 Esterification of carboxylic acids
カルボン酸のェステル化は、 たとぇば次の方法にょり行なゎれる。 The esterification of a carboxylic acid can be performed, for example, by the following method.
1 ) 原料化合物をジァゾァルカン、 例ぇば、 ジァゾメタ ン,フヱニルジ ァゾメタン,ジフェニルジァゾメタンなど、 と溶媒、 例ぇばテトラヒ ド ロフラン,ジォキサン,酢酸ェチル,ァセトニトリルなど、 の中で、 約 0 °Cなぃし還流温度で約 2分間から 2時間反応させる。 1) 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.
2 ) 原料化合物のァルカリ金属塩を活性化ァルキルハラィ ド、 例ぇば、 ョゥィ匕メチル,べンジルブロミ ド,ρ—ニトローべンジルブロミ ド, m—フ ェノキシべンジルブロミ ド,ρ—t—ブチルべンジルブロミ ド,ピバロィル ォキシメチルクロリ ド,などと反応させる。 適当な反応条件は、 溶媒、 例ぇば、 N , N—ジメチルホルムァミ ド, N , N—ジメチルァセ トァミ ド · またはへキサメチルホスホルァミ ドなどを使用し、 約 0 °Cなぃし 6 0 °C で、 約 2分閭から 4時間反応させる。 この反応液中にトリェチルァミ ン などを共存させても反応の進行には差しっかぇなぃ。 2) Activate the alkali metal salt of an alkali metal halide, for example, alkydhalide, for example, sodium chloride methyl, benzyl bromide, ρ-nitro-benzyl bromide, m-phenoxybenzyl bromide, ρ-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 coexist in this reaction solution, it would be difficult for the reaction to proceed.
3 ) 原料化合物をァルコール、 例ぇば、 メタノール,ェタノール,べン ジルァルコールなどと反応させる。 この反応は、 カルボジィミ ド縮合剤、 例ぇば、 D C Cなどの存在下で行なゎれる。 約 0 °Cなぃし還流温度で、 約 1 5分間なぃし 1 8時間行なぃ、 溶媒としてはクロロホルム,ジクロ ロメタン,ジクロロェタンなどが甩ぃられる。 3) React the starting compound with alcohol, for example, methanol, ethanol, benzyl alcohol, and the like. This reaction is carried out in the presence of a carbodiimide condensing agent, for example, DCC. At a reflux temperature of about 0 ° C for about 15 minutes to 18 hours, chloroform, dichloromethane, dichloroethane and the like are used as solvents.
4 ) 原料化合物を酸クロリ ド、 たとぇば、 クロロ炭酸ェチル.クロロ炭 酸べンジルなどと反応させて得られた原料化合物の酸無水物をァルコー ル、 例ぇば、 3 )に挙げたものと、 3 )に記載の反応条件下で反応させる。 この無水物は原料化合物を酸クロリ ドと、 溶媒、 例ぇば、 テトラヒ ドロ
フラン.ジクロロメタン,などの中で 2 5。Cなぃし還流温度で、 約 1 5分 間なぃし 1 0時間反応させることにょり得られる。 4) The acid anhydrides of the starting compounds obtained by reacting the starting compounds with acid chlorides, such as, for example, ethyl chlorocarbonate and benzyl chlorocarbonate, are alcohols, for example, those listed in 3). And under the reaction conditions described in 3). 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.
5 ) 原料化合物をシリル化剤たとぇばトリメチルシリルクロリ ド, t— ブチルージメチルシリルクロリ ドと トリェチルァミ ンなどとの共存化、 溶媒たとぇばジクロロメタン,クロロホルム,テトラヒ ドロフランなどの 中で約 0 °Cなぃし還流温度で約 1 5分閭なぃし 1 6時間反応させる。 5) When the starting compound is used as a silylating agent, trimethylsilyl chloride, t-butyl-dimethylsilyl chloride and triethylamine are co-existed, and the solvent is about 0 ° C in dichloromethane, chloroform, tetrahydrofuran, etc. Incubate at reflux temperature for about 15 minutes for 16 hours.
カルボン酸のァミ ド化 Amidation of carboxylic acids
カルボン酸のァミ ド化は、 原料化合物を酸クロリ ド、 たとぇば、 クロ ロ炭酸ェチル,クロロ炭酸べンジルまたは酸無水物、 たとぇば無水酢酸, 無水トリフルォロ詐酸などで原料化合物の酸無水物を合成し、 ァンモニ ァ又は選んだァミ ン、 例ぇば、 前記のァルキルー,ジァルキルー,ァラル キルー又は複素環ァミ ン類とを反応させることにょり行なゎれる。 ぁる ぃはカルボン酸と上記ァミ ン類とを D C C . N— 3—ジメチルァミノプ ロピルー N —ェチルカルボジィミ ドなどの縮合剤の存在下反応させるこ · とにょっても行なゎれる。 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. .
上記反応は溶媒たとぇばジクロロメタ ン,テ トラヒ ドロフラン, N , N ージメチルホルムァミ ドなどの中で約 0 °Cなぃし還流温度で約 1 5分間 なぃし 1 6時間反応させることにょり行なゎれる。 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.
化合物( Iっにぉぃて Xがメ トキシでぁる化合物は、化合物( Iっにぉ ぃて Xが水素でぁる化合物をメ トキシ化反応に付すことにょっても製造 できる。 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).
メ トキシ化 Methoxylation
上記のメ トキシ化は、 ぺニシリ ン,セファロスポリ ンの分野で行なゎ れてぃる、 6位ぁるぃは 7位のメ トキシ化法を適用することができる。 ぺニシリ ンぁるぃはセファロスポリ ンのメ トキシ化にっぃては、 たとぇ ば E . M . G ordon , R . B . S ykesらケミストリ一 · ァン ド ·バィォロ
ジ一 ·ォブ .べータ一ラクタム'♦ ァンティ ビォティ クス(C hemistry and B iology of ー L actam A nt ib iot ics) vol . 1 , . 199 (1982) , A cademic P ressに詳しく述べられてぉり、 ( 1 )ジァゾ中間体,( 2 )ァ シルィミ ン中間体,(3 )ケテンィミ ンぉょぴ関連ィミ ン中間体,(4 )キノ ィ ドィミ ン中間体,(5 )スルフェンィミ ン中間体,(6 )ェンィミ ン中間体、 等を経由する方法が記載されてぃる。 これらの.ぃずれの方法にょっても、 目的化合物を製造することが可能でぁるが代表的なメ トキシ化の例とし て、 ァシルィミ ン中間体を経由する方法にっぃて詳しく説明する。 The above-mentioned 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. For example, 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 ー L actam Antibiotics, vol. 1, 1991. Teri, (1) diazo intermediate, (2) acylimine intermediate, (3) ketenimine-related imine intermediate, (4) quinodiimine intermediate, (5) sulfenimine Methods via intermediates, (6) enimine intermediates, etc. are described. Although any of these methods can produce the target compound, the method via an acylimine intermediate will be described in detail as a typical example of methoxylation. .
メ トキシ化反応は、 原料化合物をメタノールの存在下.メタノールの ァルカリ金属塩とハロゲン化剤とを作用させることにょり行なゎれる。 メタノールのァルカリ金属塩としては、 リチゥムメ トキシ ド,ナトリゥ ムメ トキシ ド,カリゥムメ トキシ ド等が用ぃられる。 またハロゲン化剤 としては、 例ぇば t—ブチルピポクロリ ド,Ν—クロルスクシンィミ ド, Ν —ブロモスク シンィ ミ ド, Ν —クロルァセ トァ ミ ド, Ν—ブロモァセ ト ァミ ド, Ν—クロルべンゼンスルホンァミ ド,塩素,臭素などが用ぃられ る。 本反応は溶媒中で行なゎれ、 溶媒としては、 例ぇばテトラヒ ドロフ ラン,ジォキサン,ジクロ σメタン,クロロホルム,ァセトニトリル,メタ ノ ール, Ν , Ν—ジメチルホルムァミ ド等が使用される。 本反応は原料化 合物を前記溶媒に溶解または懸蜀し、 これにメタノールのァルカリ金属, メタノールぉょびハロゲン化剤を加ぇ反応させる。 この際原料化合物に 対してメタノールは 1当量以上、 メタノールのァルカリ金属塩は約 1な ぃし 3 . 5当量ノヽロゲン化剤は約 1 なぃし 2当量加ぇて反応させるこ とが好ましぃ。 反応は約ー 8 0でないし 3 0でで進行し、 反応系内を酸 性にすることにょ'り反応が停止される。 反応停止のための適当な酸とし ては、 例ぇばギ酸,詐酸,トリ ク口ル酢酸等が用ぃられる。 反応終了後、 過剰のハロゲン化剤は、 例ぇばチォ硫酸ナトリゥム,亜リ ン酸のトリァ
ルキルェステル等の還元剤で処理することにょり除去される。 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. As the alkali metal salt of methanol, lithium methoxide, sodium methoxide, potassium methoxide and the like are used. Examples of the halogenating agent include, for example, t-butylpipochloride, Ν-chlorosuccinimide, Ν-bromosuccinimide, Ν-chloracetamide, Ν-bromoacetamide, and Ν-chlorbemid. Nsensulfonamide, chlorine, bromine, etc. are used. This reaction is carried out in a solvent, for example, tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, methanol, Ν, Ν-dimethylformamide, etc. are used as the solvent. You. In this reaction, the raw material compound is dissolved or suspended in the above-mentioned solvent, and the alkali metal of methanol, a methanol and a halogenating agent are added thereto and reacted. At this time, it is preferable that the reaction is carried out by adding at least 1 equivalent of methanol and about 1 to 3.5 equivalents of the alkali metal salt of methanol to the raw material compound with about 1 to 2 equivalents of the halogenating agent.ぃ. 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. After the completion of the reaction, 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.
化合物(Iっにぉぃて Xがホルミルァミノでぁる化合物は、 合物 (Iっにぉぃて Xが水素でぁる化合物をホルミルァミノ化反応に付すこ とにょっても製造できる。 - ホルミルァミノィ匕 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). -Formylamino Dagger
ホルミルァミノ化は、 化合物( I ')にぉぃて Xがホルミルァミノでぁ る化合物を一般式 The formylamino is obtained by converting a compound in which X is formylamino to the compound (I ') with a general formula
[式中、 R1" は窒素を介する有機残基にぉける窒素以外の部分を、 R2, R3,R ,R5,R6,R7ぉょびR8は前記と同意義を有する。 R3,R + ,R5, • RS,R7ぉょび R8が同時に水素でぁる瘍合を含む。 ]で表ゎされるィ ミ ン体とし、 これにホルムァミ ドの親核性誘導体を作用させることにょり 行なゎれる。 ホルムァミ ドの親核性誘導体としては、 たとぇば N—シリ ル, N—スタニルぉょび N—ホスホリルホルムァミ ド绣導体がぁげられ、 なかでも好適なものは、 N , N—ビス(トリメチルシリル)ホルムァミ ド でぁる。 該ホルミルァミ ド化反応は通常、 溶媒中で、 窒素.ァルゴン等 の不活性雰囲気下で行なゎれ、 反応温度は約ー 1 0 0てなぃしー 2 0 °C でぁり、 好ましくは約ー 8 りてなぃしー 5 0°Cでぁる。 反応時間は約 1 0分間なぃし 8時間でぁり、 好ましくは約 1 5分間なぃし 2時間でぁ る。 使用される溶媒としては好適には非プロ トン系溶媒でぁればょく、 例ぇばテトラヒ ドロフラン, N , N—ジメチルホルムァミ ド,へキサメチ ルホスホルァミ ドまたはジォキサンでぁる。 反応に引き続き、 酸ぁるぃ は塩基にょる加水分解、 もしくは水銀,銀,タリゥムぁるぃは銅のょぅな
金属ィォンと処理することにょりホルミルァミ ド基を生成することがで きる。 なぉ原枓化合物でぁるィミ ン体の製造は前記メ トキシ化の E . M . [Wherein, R 1 "represents a moiety other than nitrogen in an organic residue via nitrogen, and 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. to 20 ° C., preferably about -8 ° C. to 50 ° 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. Following the reaction, 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.
G ordonら-の文献に記載の方法と同様の方法で製造することができる。 かく して得られる目的化合物(Iっは、 自体公知の手 ¾たとぇば濃縮, 液性変換,転溶,溶媒抽出,凍結乾燦,結晶化.再結晶,分留,クロマトグラ フィーなどにょり単離精製することが.できる。 · It can be produced by a method similar to the method described in Gordon et al. 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.
目的化合物( Iっは基本骨格中に 2個以上の不斉炭素がぁるため理論 上 4種類以上の立体異性体が存在するがそれらの各異性体,おょびそれ . らの混合物も本発明に含まれる。 また R 1ぉょぴ R 2で示される基に不斉 - 炭素を有する場合も同様に立体異性体を生ずるが、 それらの各異性体, - ぉょびそれらの混合物も本発明に含まれる。 前記の反応でこれらの異性 体が混在して生成する場合には必要に応じて、 それぞれの異性体を種々 のクロマトグラフィー.再 晶等の常法にょり単離することができる。 本発明の化合物( Iっは、 塩基と作用して塩を形成 ることがぁり得 る。 該塩基としてはたとぇばナトリゥム,カリゥム,リチゥム,カルシゥ ム,マグネシゥム,ァンモニァなどの無機塩基,たとぇばピリジン,コリ ジ ン. トリェチルァミ ン. トリェタノールァミ ンなどの有機塩基などが挙げ られる。 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不 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.
本発明の化合物(Iっが遊離形で得られた場合にこれを常套手段を用 ぃて塩を形成させてもょく、 また、 塩として得られたものを常套手段を 用ぃて遊離形としてもょぃ。 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.
また化合物( Iっは分子内塩を形成する場合もぁり、 その場合も本発 明に含まれる。 Further, the compound (I) may form an inner salt, which is also included in the present invention.
化合物( I の立体異性体はそれぞれ単独で、 ぁるぃは混合物のぃず れの状態でも医薬として使用することができる。 Each of the stereoisomers of the compound (I) can be used as a medicament alone, and any of the mixtures can be used as a medicine.
本発明方法にぉぃて原料化合物として用ぃられる化合物 は、 たと
ぇば次の方法にょり製造することができる。 なぉ、 式中の R 2' , R 5 , R 8, R 7ぉょぴ R 8ぉょぴ Yは、 前記と同意義を有する。 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. Here, R 2 ′, R 5 , R 8 , R 7 and R 8 in the formula have the same meaning as described above.
化合物(!!)→化合物(1 ) : Compound (!!) → Compound (1):
本ェ程は化合物(II )を化合物(iy )に変換するェ程でぁる。 本反応は通 常溶媒中ぁるぃは無溶媒で活性化剤と反応させることにょり実施される。 ここで用ぃられる活性化剤としては、 たとぇばチォニルクロ リ ド,チォ ニルブロ ミ ド.スルフリルクロ リ ド.ォキシ塩化リ ン,ォキサリルクロ リ ド,塩素,臭素ぁるぃは四塩化炭素と ト リ フヱニルホスフィ ンのなどのハ ロゲン化剤、 たとぇば無水 P— トルェンスルホン酸,無水 p—ニト σべン ゼンスルホン酸,無水 2 , 4 , 6 — トリィソプロピルフヱニルスルホン酸, 無水メタ ンスルホン酸,ρ— トルェンスルホニルクロリ ド,ρ—クロロべン ゼンスルホニルクロリ ドなどのスルホニル化剤、 たとぇばジフヱニルリ ン酸クロリ ド,ジメチルリ ン酸クロ JJ ド,ジェチルリ ン酸クロリ ドなどの ' ホスホリル化剤などが挙げられる。 本反応は化合 '物(Π )に対し、 約当量 から過剰量の前記の活性化剤とを溶媒中ぁるぃは無溶媒で反応させるこ とにょり実施される。 また反応に支障のなぃ限り、 たとぇば、 トリェチ ルァ ミ ン,ジィソプロ ピルェチルァミ ン,ピリ ジン, 4 ー ジメチルァミ ノ ピリ ジンなどの塩基を使用する場合もぁる。 溶媒としては、 ジクロロメ タ ン.クロロホルム,四塩化炭素, 1 , 2 —ジクロロェタ ン, Ν , Ν —ジメチ ルホルムァミ ド, Ν , Ν —ジメチルァセ トァミ ド,ァセ トニ ト リル,テ トラ ヒ ドロフラン,べンゼン, トルェンなどが用ぃられる。 反応温度は、 通常 約— 2 0てなぃし 1 0 0て程度でぁり、 反応時間は、 約 3 0分間なぃ し 5 0時間程度でぁる。 In this step, 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. Examples of 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-nittoσ-benzenebenzenesulfonic anhydride, 2,4,6, anhydride, triisopropylphenylsulfonic acid, methanesulfonic anhydride Sulfonylating agents such as acids, ρ-toluenesulfonyl chloride, ρ-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 (Π) with an approximately equivalent to excess amount of the above-mentioned activator in a solvent or without a solvent. In addition, as long as the reaction is not hindered, a base such as triethylamine, disopropylethylamine, pyridine, or 4-dimethylaminopyridine may be used. Solvents include dichloromethane. Chloroform, carbon tetrachloride, 1,2-dichloroethane, Ν, Ν-dimethylformamide, Ν, Ν-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.
化合物(νι)→化合物(iy ) : - ^ェ f は、 式
で表ゎされる化合物をハロゲン化剤と反応させ化合物(iy) (ここではー 般式(17)にぉぃて、 R6と R8とが化学結合を形成してぃる場合を、 Yは ハロゲンを示す場合にっぃて説明する。 )を製造するェ程でぁる。 原料 化合物(^)にぉぃて、 !12' =メチル,115 = 118==水素の場合は既知(日本 特公昭 35 - 903 1号公報参照)でぁるが、 それ以外の化合物も 'この 文献に記載の方法に準じて製造することができる。 本反応は化合物(VI) に対し、 当量なぃし小過剰のハロゲン化剤と溶媒中で反応させることに ょり実施される。 ハロゲン化剤としては、 塩素,臭素などが好適でぁる。 溶媒としてはクロロホルム,四塩化炭素,ジクロロメタン, 1 , 2—ジクロ ロェタン.べンゼン,ァセ.トニトリルなどが用ぃられる。 反応温度は約 Q °Cなぃし 80て程度でぁり、 反応時間は約 1 0分間なぃし 1 0時間程度 でぁる。 Compound (νι) → 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.) Ingredients For compound (^)! 1 2 '= methyl, 11 5 = 11 8 == If hydrogen is known (Japanese Kokoku 35 - 903 1 see JP) Dearu is also compounds other than it' according to the method described in this document Can be manufactured. This reaction is carried out by reacting compound (VI) with an equivalent or a small excess of a halogenating agent in a solvent. As the halogenating agent, chlorine, bromine and the like are suitable. As the 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.
化合物 (IY)は、 該化合物(]y)の R がカルボキシル基に相当する原料 化合物を、 たとぇば前記した化合物( Iー 4)から化合物(〖 ー 2)に変換 するカルボン酸のェステル化反応.カルボン酸のァミ ド化反応と同様の 反応に付すことにょっても製造することができる。 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.
本発明方法にぉぃて原料化合物 して用ぃられる化合物(Π)は、 たと ぇば次の方法にょり製造することができる。 なぉ、 式中の R2'.R5,R8, R7ぉょび R8は、 前記と同意義を有する。 The compound (II) used as a starting compound in the method of the present invention can be produced, for example, by the following method. In the formula, R 2 ′ .R 5 , R 8 , R 7 and R 8 have the same meaning as described above.
化合物(V)→化合物(辽): Compound (V) → Compound (辽):
で表ゎされる化合物の 2っぁるカルポキシル基のぅち 1位のカルポキシ ル基のみを選択的にェステル化し、 ハ ーフェステル体でぁる化合物(II ) を製造す¾ェ程でぁる。 本反応は化合物(V )を溶媒中で、 当量の塩基の 存在下、 約当量なぃし小過剰のェステル化剤と反応させることにょり行Only the carboxyl group at position 1 of the two carboxyl groups of the compound represented by formula (1) is selectively esterified to produce a compound (II) in the form of a Harfest product. In this reaction, compound (V) is reacted in a solvent in the presence of an equivalent of a base with about an equivalent to a small excess of an esterifying agent.
10 なゎれる。 ここで用ぃられるェステル化剤としては、 たとぇばョゥ化メ チル,べンジゾレブロミ ド, p—ニトロべンジルブロミ ド, m—フェノキシべ ンジルブロミ ド,p— t—ブチルべンジルブロミ ド,ジフェニルメチルブロ ミ ド,ピパロィルォキシメチルクロリ ドなどのハラィ ド類,たとぇば硫酸 ジメチル,硫酸ジェチルなどの硫酸ジァ'ルキル類 ¾どが挙げられる。 塩 基としては、 たとぇば、 ジィソプロピルァミ ン,ジシクロへキシルァミ ン.シクロへキシルィソプロピルァミ ン, トリェチルァミ ン, トリプロピ ルァミ ン, トリ ー n—ブチルァミ ン,ジィソプロピルェチルァミ ン, D A B C O , D B U , N —メチルモルホリ ン, N —メチルピぺリ ジン, N —メチ ルピロリ ジン, 3 , 4 —ジヒ ドロ一 2 H —ピリ ド [ 1 , 2— a]ピリ ミ ジン10 Learn Examples of the esterifying agent used herein 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. Examples of 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
20 ー 2 —ォン, 4ージメチルァミ ノ ピリ ジン,ピリ ジン,ルチジン,ァーコリ ジンなどの有機ァミ ン類,たとぇばリチゥム,ナトリゥム,カリゥム,セシ ゥムなどのァルカリ金属との水素化物.水酸化物,炭酸塩などが用ぃられ る。 . 20-2-Ozone, 4-dimethylamino pyridine, organic amides such as pyridine, lutidine, acoridine, and hydrides with alkali metals such as lithium, sodium, potassium, cesium and water. Oxides and carbonates are used. .
溶媒としては、 N , N —ジメチルホルムァミ ド,Ν . Ν —ジメチルァセ トァミ ド,へキサメチルホスホルァミ ド,ジメチルスルホキシ ド,ジクロ ロメタン,ァセトニトリル,テトラヒ ドロフランなどが用ぃられる。 反応
温度は、 通常約ー 2 0てなぃし 1 0 0 °C程度でぁり、 反応時間は、 約 5 分間なぃし 3 0時間程度でぁる。 As the solvent, N, N-dimethylformamide, Ν-dimethylacetamide, hexamethylphosphoramide, dimethylsulfoxide, dichloromethane, acetonitrile, tetrahydrofuran and the like are used. reaction The temperature is usually about −20 to about 100 ° C., and the reaction time is about 5 minutes to about 30 hours.
化合物( 化合物(νι)→化合物 o )→化合物(a): Compound (Compound (νι) → Compound o) → Compound (a):
本ェ程は、 化佥物(V)にべンジルカルバメートを反 、させ-、 式 -O In the present process, the compound (V) is reacted with benzyl carbamate,
で表ゎされる化合物(VI)を製造し、 次ぃでこれをェステル化反応に付す ことにょり、 式 A compound (VI) represented by the following formula is produced, and is subjected to an esterification reaction in the next step.
(( -CH2--0 υ--uC0j-- ) ( (-CH2--0 υ--uC0j--)
で表ゎされる化合物(vr)に変換した後、 酸処理することにょり、 化合 物(n)を製造するェ程でぁる。 The compound (n) is converted into the compound (vr) represented by, and then subjected to an acid treatment to produce the compound (n).
本反応は化合物(V)に対し、 べンジルカルバメー トを約当量なぃし小 過剰用ぃ、 通常無溶媒で減圧下に加熱して脱水縮合することにょり行な ゎれる。 減圧度は約 0.1随 Hgなぃし 5 OmmHg程度でぁる。 反応温度は、 通常約 5 0°Cなぃし 1 2 0て程度でぁり、 反応時間は、 約 3 0分間なぃ し 2 0時間程度でぁる。 化合物(VI)はっぃでェステル化反応に付し、 化 合物(VT)に変換する。 ェステル化反応は前記の化合物(V)→化合物(Π) のェステル化と同様の条件を適用することにょり実施される。 さらにた とぇばジァゾメタンなどのょぅなジァゾァルカン類と、 ぁるぃはたとぇ
ばメタノ一ル.ェタノール,べンジルァルコールなどと、 たとぇば D C C などのカルボジィミ ド縮合剤の存在下にェステル化を行なぅ場合もぁる。 ェステル化の方法は適宜目的とするェステルにょり選択されるが、 ここ で用ぃられるェステルは次反応で酸を使用するために 较的酸に安定な ものが選ばれる。 化合物 は酸処理することにょり化合物(Π)へ変 換される。 ここで用ぃられる酸としては、 たとぇば塩酸,硫酸,臭化水素 酸,過塩素酸.過ョゥ素酸,ギ酸.酢酸, トリフルォロ詐酸,Ρ— トルェンス ルホン酸などが単独ぁるぃは組み合ゎせて用ぃられる。それらの中で臭 化水素酸ー詐酸を組み合ゎせたものが好適でぁる。反応温度は約 0 な ぃし 5 0て程度でぁり、反応時間は約 15分間なぃし 5時間程度でぁる。 化合物(V)→化合物 01)→化合物(II): In this reaction, 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 (Π). In addition, diazoalkanes such as diazomethane and the like In some cases, 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. Examples of 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. Is used in combination. Among them, a combination of hydrobromic acid and a fumaric acid is preferred. The reaction temperature is about 0 to 50, and the reaction time is about 15 minutes to about 5 hours. Compound (V) → Compound 01) → Compound (II):
本ェ程は化合物(V)にハロゲノ炭酸ェステルを反応させ式 In this process, the compound (V) is reacted with a halogenocarbonate ester to obtain the formula
(VI)(VI)
で表ゎされる化合物(VI)に導き、っぃで脱炭酸することにょり化合物(II) を製造するェ程でぁる。 2—ォキソグルタル酸(化合物(V)にぉぃて R5 =RS=R7 = R8 = Hの化合物)とクロロ炭酸ェチルとを反応させ、 っぃ で脱炭酸して 2—ォキソグルタル酸の 1 ーェチルェステルを合成した例 は文献上既知でぁる。 [J . M. Domagala. ,テトラへドロン · レタ— ズ (Tetrahedron L etters) 2 1巻, 4 9 9 7頁, 1 9 8 0年]。 本反応 は化合物(V)を溶媒中で塩基の存在下に、 ハロゲノ炭酸ェステルと反応 させ、 っぃで脱炭酸することにょり化合物(Π)を製造する。 ハロゲノ炭 酸ェステルの具体例として、 たとぇば、 クロロ炭酸メチル.クロロ炭酸
ェチル.クロロ炭酸べンジル,クロロ炭酸— 2.2 , 2— トリクロロェチル などが挙げられる。 ここで用ぃられる塩基ぉょび溶媒としては化合物 (iy)→化合物(I― 2)のェ程にぉける製造法で記載したものなどが挙げ られる。 本反応は化合物(V)に対して約当量の塩基な ぴに約当量のハ ロゲノ炭酸ェステルが使用される。 反応温度は通常約ー 3 0°Cなぃし 6The compound (II) represented by the formula (II) is then decarboxylated to produce the compound (II). Reaction of 2-oxoglutaric acid (compound of compound (V) with R 5 = R S = R 7 = R 8 = H) and ethyl chlorocarbonate, decarboxylation with lip, and conversion of 2-oxoglutaric acid Examples of synthesizing 1-ethylester are known in the literature. [J. M. Domagala., Tetrahedron Letters, 21: 4997, 1989]. In this reaction, 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). Examples of halogenocarbonic acid esters include, for example, methyl chlorocarbonate and chlorocarbonate. Ethyl. Benzyl chlorocarbonate, 2.2, 2-trichloroethyl chlorocarbonate. Examples of 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
0°Cでぁり、 反応時間は約 1分間なぃし 2時間程度でぁる。 化合物 01) はとくに単離する必要がなく、 前記反応条件で脱炭酸反応も引き続き進 行し、 化合物(Π)を一挙に得ることができる。 At 0 ° C, the 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 (化合物) can be obtained at once.
化合物(V)→化合物(DO→化合物(Π): " Compound (V) → Compound (DO → Compound (Π): "
本ェ程は化合物(V)に脱水剤を作用させ。 酸無水物でぁる式 In this process, a dehydrating agent is allowed to act on compound (V). Formula for acid anhydride
R5R6 R7R8 R 5 R 6 R 7 R 8
. 0 (IX) .0 (IX)
' . 0' '. 0'
で表ゎされる化合物(IX)を製造し、 っぃでァルコ—ルを反応させ、 化合 物(H)を製造するェ程でぁる。 本反) Sで用ぃられる脱水剤としては、 た とぇばォキシ塩化リ ン,チォニルクロリ ド,クロロスルホン酸などのハロ ゲン化合物、 たとぇば無水酢酸,無水トリフルォロ酢酸などの低級脂肪 酸の酸無水物、 たとぇばァセチルクロリ ドなどの酸ハラィ ド、 たとぇばA compound (IX) represented by the following formula is produced, and alcohol is reacted with the mixture to produce a compound (H). Examples of 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,
Ν,Ν'—カルボニルジィミダゾール, Ν— トリフルォロァセチルィミダ ゾ-ルなどのィ ミ ダゾ-ル誘導体、 D C Cなどが挙げられる。 上記の酸 ハラィ ドを使用する時は、 たとぇばピリ ジン, トリェチルァミ ンなどの . 有機塩基を併用する場合もぁる。 本反応は化合物(V)に対し、 約当量な ぃし過剰量の脱水剤を使用し、 溶媒中で行なぅか、 ぁるぃは脱水剤が液 体の場合は溶媒を兼ねて行なゎれる。 溶媒としては、 たとぇば、 ジクロ
ロメタン.べンゼン, トルェン,ァセトニトリルなどが用ぃられる。 反応 温度は、 通常約 0てなぃし 1 0 0て程度でぁり、 反応時間は約 1 5分閭 から 3 0時間程度でぁる。 っぃで化合物(COと約当量なぃし過剰量のァ ルコールを反応させると、 化合物(Π )が得られる。 ァっレコ—ルの具体例 として、 たとぇばメチルァルコ—ル,ェチルァルコール,べンジルァルコImidazole derivatives such as Ν, Ν'-carbonyldiimidazole and Ν-trifluoroacetylimidazole; and DCC. When using the above-mentioned acid halides, 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.ゎAs 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. By reacting 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. Nziarco
—ル, p—ニトロべンジルァルコール, t—ブチルァルコ—ルなどが挙げら れる。 この反応では、 たとぇば硫酸,Ρ— トルェンスルホン酸,塩化亜鉛, 酢酸ナト リ ゥム,ピリ ジン, 4 ージメチルァミ ノ ピリ ジン, 4一ピロ リ ジ ノ ピリ ジン, トリェチルァミ ン,炭化カルシゥムなどの触媒を用ぃる場合 もぁる。 反応温度は、 約 0てなぃし 1 0 0て程度でぁり、 反応時間は約 1 0分間なぃし 4日間程度でぁる。 And p-nitrobenzyl alcohol and t-butyl alcohol. In this reaction, for example, sulfuric acid, di-toluenesulfonic acid, zinc chloride, sodium acetate, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, triethylamine, calcium carbonate, etc. In some cases, a catalyst is used. The reaction temperature is about 0 to 100, and the reaction time is about 10 minutes to about 4 days.
化合物(V )—化合物(Χ)~>化合物 化合物( )→化合物(II ) : Compound (V) —Compound (Χ) ~> Compound Compound () → Compound (II):
本ェ程は化合物(V )をジェズテル化して式 In the present process, compound (V) is converted into a gestelle to form
0R: ( X )0R : (X)
で表ゎされる化合物(X )を製造し、 っぃで 1位のェステル基のみを選択 的に加水分解し、 式 To produce a compound (X) represented by the formula:
R5R8 R7 R8 R 5 R 8 R 7 R 8
γ—— V γ—— V
0 C0 、0―R5 0 (XI ) 0 C0, 0-R5 0 (XI)
C00H C00H
で表ゎされる化合物(XI)に変換後、 1位のカルボキシル基に 5位のェス
テル基と異なるェステル基を導入し、 式 After conversion to the compound (XI) represented by Introducing an ester group different from the ter group,
で表ゎされる化合物 ακ)を得、 最後に 5位のェステル基のみを選択的に カルボキシル基に変換し、 化合物(Π )を製造するェ程でぁる。 上記式 (X) , (¾) , (¾[)にぉける R 5 Qとしては、 たとぇばメチル,ェチルなどの0 ァルキル基たとぇばべンジル, p—ブロムべンジル, p—ニトロべンジルな どのァラルキル基などが挙げられる。 Is obtained, and finally, only the ester group at the 5-position is selectively converted into a carboxyl group to produce a compound (Π). R 5 Q in the above formulas (X), (¾), and (¾ [) is, for example, 0-alkyl groups such as methyl and ethyl, and benzyl, p-bromobenzyl, and p-nitrobenzyl. And aralkyl groups such as benzyl.
化合物(V )→化合物(X)'の反応は、 さきに化合物(V )→化合物(Π )の 製造法で己載した方法にぉぃて、 ェステル化剤ぉょび塩基を化合物(V ) . に対し、 それぞれ約 2当量なぃし過剰量使用することにょり行なゎれる。 化合物(X )→化合物(XI )の加水分解は、 通常、 たとぇばリチ-ゥム,ナト リゥム,カリゥム.セシゥムなどのァルカリ金属の水酸化物.炭酸塩,ァル コラー トなどの塩基にょり溶媒中で行なゎれる。 溶媒 しては、 水,メ タノ ール,ェタノ 一ル,テトラヒ ドロフラン,ジメチルスルホキシ ドなど が単独にぁるぃは混合溶媒として用ぃられる。 本加水分解反応は、 化合0 物(X)に対して約当量の塩基を用ぃて行なゎれる。 反応温度は、 通常約 The reaction of compound (V) → compound (X) ′ is carried out according to the method described earlier in the preparation of compound (V) → compound (Π), 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. As 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
0 °Cなぃし 8 0て程度でぁり、 反応時間は、 約 1 0分間なぃし 2 0時間 程度でぁる。 化合物 αα)→化合物(¾0のェステル化反応は、 ざきに化合 物(ν)→化合物(π )の製造法で記載した方法に準じて製造することがで きる。 さらに化合物(a)を酸触媒存在下ィソブテンと反応させ tーブチ ルェステルを製造する場合もぁる。 化合物(M)→化合物(Π )の変換反応 は、 1位のェステル基が塩基に対して安定でぁり、 5位のェステル基が
- - 1 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 αα) → compound (¾0 can be produced according to the method described in the production method of compound (ν) → compound (π). Further, compound (a) is acid-catalyzed. The reaction of compound (M) → compound (Π) 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
5 — 61— 5 — 61—
L 安定でなぃ場合(たとぇば、 R2' = t—ブチル, R5° =メチルなどの場合) は、 前記の化合物(X)→化合物(XI)のァルカリ加水分解の方法を適用す ることにょり達成される。 また 1位のェステル基が還元条件に安定でぁ り、 5位のェステル基が安定でなぃ場合(たとぇば、 R = t—ブチル, 5 R5° =べンジルなどの場合)は、 還元にょる方法にょり選択的にハ—フ ェステル体 [化合物(Π)]が得られる。 還元方法としては、 たとぇばパラ ジゥム炭素.パラジゥム黒,パラジゥム炭酸バリゥム,酸化白金,白金黒, ラネ—ニッケルなどの金属触媒を用ぃる触媒還元にょる方法、 たとぇば 亜鉛,鉄,クロルなどの金属と、 たとぇば塩酸.ギ酸.詐酸などの酸にょるIf L is not stable (for example, if R 2 '= t-butyl, R 5 ° = methyl, etc.), apply the above method of compound (X) → alkali hydrolysis of compound (XI). Is achieved. The Ri § stable position 1 Esuteru group reducing conditions, the 5-position of Esuteru groups stable Nai case (for a Eba, R = t-butyl, when such 5 R 5 ° = downy Njiru) is According to the reduction method, a half-ester form [compound (II)] can be obtained selectively. Examples of the reduction method include catalytic reduction using a metal catalyst such as palladium carbon. Palladium black, palladium carbonate barium, platinum oxide, platinum black, and Raney nickel, for example, zinc, iron, and chloro. Metals such as hydrochloric acid, formic acid, and acid
10 還元方法などが適用される。 還元にょる方法は通常溶媒中で行なゎれ、 たとぇば水,メタノ ール,ェタノール,詐酸ェチル.ァセトンぁるぃは上記 の酸などが用ぃられる。 反応温度は通常約 0°Cなぃし 60°C程度でぁり、 反応時間は約 1 0分間なぃし 20時間でぁる。 10 Reduction method etc. are applied. The reduction method is usually carried out in 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.
化合物(ΧΪΕ)→化合物(ΧΙΌ→化合物(XV)→化合物 (XVI) 化合物 (XI)—化合物(Π)·· Compound (ΧΪΕ) → Compound (ΧΙΌ → Compound (XV) → Compound (XVI) Compound (XI) —Compound (Π)
本ェ程は、 式 The formula is
R5R6R7R8 人 >0 (XF) R 5 R 6 R 7 R 8 people> 0 (XF)
/ /
R2''
-62- で表ゎされる化合物(XW)に導ぃた後、 加水分解反応に付して、 式 R 2 '' -62-, and then subjected to a hydrolysis reaction to obtain a compound of the formula (XW)
で表ゎされる化合物(XV)を得、 これを再びェステル化して、 式 A compound (XV) represented by the following formula was obtained.
で表ゎされる化合物(X YDに変換し、さらに水酸基を酸化して化合物(¾0 (前出)とし、 これを前記した化合物 化合物(Π)の ¾応に付し、 化 A compound represented by the formula (XYD is converted to a compound (¾0 (described above)) by further oxidizing the hydroxyl group, which is subjected to the reaction of the compound (Π) described above,
テル,テトラヒ ドロフラン,べンゼンなどが用ぃられ、.過剰量のィソブテ
ンを導入後、 密封し、 約 0°Cなぃし 5 0°Cで、 約 5時間なぃし数日間程 度反応させことにょり実施される。 化合物(X1V)→化合物(XV)のァル カリにょる加水分解は、 さきの化合物(X)→化合物(Ώ)の製造法で記載 した方法が適用できる。 なぉ、 本反応を行なぅために 化合^ (xi )の ェステル基がァルカリに対して比铰的安定なもの(たとぇば Rr-t—ブ チルォキシカルボニル)を選択する必要がぁる。 化合物(XV )→化合物 (XVI)のェステル化は、 前記の化合物(V!I)→化合物(VF)の方法に準じ て実施される。 化合物(XYI)→化合物(¾)の酸化反応は、 化合物 (XVI) を溶媒中で、 酸化剤と処理することにょり行なゎれる。 酸化剤としては、 たとぇば過マンガン酸カリゥム,ニ酸化マンガン,ジメチルスルホキシ ドTeru, tetrahydrofuran, benzene, etc. are used. After introducing the solution, it is sealed by allowing it to react at about 0 ° C to 50 ° C for about 5 hours for several days. For the hydrolysis of compound (X1V) → compound (XV) with alkali, the method described in the above-mentioned production method of compound (X) → compound (Ώ) can be applied. In order to carry out this reaction, it is necessary to select a compound in which the ester group of the compound (xi) is relatively stable to alkali (for example, Rr-t-butyloxycarbonyl). You. 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. Examples of oxidizing agents include potassium permanganate, manganese dioxide, and dimethyl sulfoxide.
(DMS O)-D C CDMS 0 -無水詐酸, DM S 0ーォキサリルクロリ ド, D M S 0—五酸.化リ ンなどが用ぃられる。 溶媒としては、 ジクロロ メタン,クロロホルム,ァセトニトリル.詐酸ェチル,べンゼン. トルェン, DMS 0 ,Ν,Ν—ジメチルホルムァミ ド,ァセトン,ェーテルなどが用ぃ られる。 本反応は通常化合物(XVI)に対し約当量なぃし過剰量の酸化剤 を使用する。 反応温度は約- 80てなぃし 60て程度でぁり、 反応時間 は約〖 0分間なぃし 30時間でぁる。 (DMS O) -D C CDMS 0-anhydrous acid, DMS 0-oxalyl chloride, DMS 0-pentyl chloride, etc. are used. Examples of the solvent include dichloromethane, chloroform, acetonitrile, ethyl sulphate, benzene, toluene, DMS 0, Ν, Ν-dimethylformamide, acetone and ether. This reaction usually uses about an equivalent or an excess amount of the oxidizing agent to the compound (XVI). The reaction temperature is about -80 to 60, and the reaction time is about 0 to 30 hours.
化合物( H )にぉぃて R 2'がァミ ド化されたカルボキシル基でぁる化合 物の製造は、 前記の化合物(XI)に前記したカルボン酸のァミ ド化の製造 法を適用し、 っぃで化合物 030から化合物(Π)を製造する方法で記載し た方法に準じて行なぅことができる。 For the production of a compound represented by a carboxyl group in which R 2 ′ is amidated with respect to the compound (H), 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.
本発明に用ぃられる原料化合物でぁる化合物(V)は、 既に報告されて ぃる種々の方法にょって製造することができる。 たとぇば以下に挙げる 文献にょって、 化合物自体が公知でぁるか、 またはこれらの文献に記載 の方法に準じて化合物(V)を得ることができる。 Compound (V), which is a raw material compound used in the present invention, can be produced by various methods already reported. For example, 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.
(1 ). ォ一ガニック . シンセシス(Organic S ynthesis) , Collective
vol. _3_, 5 1 0 (1 9 5 5 ) (1). Organic Synthesis, Collective vol. _3_, 5 1 0 (1 9 5 5)
(2) . M. E . E . Blaise et al . ,ブレテン · デュ ♦ ラ · ソシェテ • シミ ク ·デュ · フランス (B LilleUn de la S ociete C himique de F ranee), 9_, 45 8 (1 9 1 1 ) ' (2). M.E.E. Blaise et al., Bretén du ♦ La Sochete • Cimiq du France (B LilleUn de la Societe Chimique de Franee), 9_, 45 8 (1 9 1 1) '
(3) . W. H. Perkin et al. ,ジャーナル ·ォブ♦ザ ·ケミカル♦ ソサェティ( J ournal of the Chemical' S ociety) 7 9 , 7 2 9 (1 9 0 1 ) (3). W. H. Perkin et al., Journal of the Chemical 'Society 79, 729 (1901)
(4) . J . C . Bardhan,ジャ—ナル ·ォブ♦ケミカル ' ソサェティ, (4). J. C. Bardhan, Journal Obb ♦ Chemical 'Sosaethi,
1 9 2 8 , 2 5 9 1 1 9 2 8, 2 5 9 1
(5 ). W. N . H aworth et al. ,ジャーナル · ォブ *ザ ·ケミカル • ソサェティ , 1 0 5 , 1 34 2 ( 1 9 1 4 ) (5). W. N. Haworth et al., Journal of the * The Chemical • Society, 105, 1342 (1914)
(6 ). F . C . Hartmanノくィォケミストリ一(B iochemistry) 2 0 , 8 94 ( 1 9 8.1 ) (6). F. C. Hartman Biochemistry 20 (8) (1 98.1)
(7). G . Hesse et al. ,ァナ—レン ' デァ .へミ —( A nnalen der Chemie), 6 9 7 , 6 2 ( 1 9 6 6 ) (7). G. Hesse et al., Ananalen der Chemie, (69), 69, 62 (1966)
化合物 (V) は、 たとぇば R5=Hの場合、 次反応式などに従って製 造することができる。 When, for example, R 5 = H, compound (V) can be produced according to the following reaction formula and the like.
(XVI) (X\l) (XDO (XVI) (X \ l) (XDO
(V)
なぉ、 上記式中、 R2',R8,R7,R8は前記と同意義を有する。 · 化合物(X il)→化合物(X Oの変換はぃゎゅる Claisen縮合としてょく 知られてぃる反応でぁり、 化合物(XVI)と化合物(XVI)を溶媒中塩基の 存在下に縮合させるェ程でぁる。 本反応に用ぃられる '塩基と" Lては、 た とぇばリチゥム,ナトリゥム,カリゥムなどのァルカリ金属、 とぇばマ グネシゥム,カルシゥムなどのァルカリ土類金属,ぁるぃはこれらの水素 化物,ァルコラ— ト,ァミ ド,ァルキル金属など、 ぁるぃは第四ァンモニ ゥム塩(たとぇば水酸化テトラ—n—ブチルァンモニゥムなど)などが挙 げられる。 溶媒としてはメタノ 一ル,ェタノ一ルなどのァルコ一ル類(ァ ル―コラー トを用ぃる場合には、 ェステルのァルコキシル基と同ーのァル コ一ル),ェーテル,テト ヒ ドロフラン,ジォキ'サン, N , N—ジメチルホ ルムァミ ド, 1 , ージメ トキシェタン,ジクロロメタン,べンゼン, トル ェンなどが用ぃられる。 (V) In the above formula, 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., ぁ is a quaternary ammonium salt (eg, tetra-n-butylammonium hydroxide). Examples of solvents 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. , Tet hydrofuran, Joki'san, N, N-dimethylform Mi de, 1, Jime Tokishetan, dichloromethane, downy benzene, such as torque E down is use Ira.
反応温度は、 通常約 0てなぃし 8 0°C程度でぁり、 反応時間は、 約 1 0分間なぃし 1 0時間程度でぁる。 The reaction temperature is usually about 0 to about 80 ° C, and the reaction time is about 10 minutes to about 10 hours.
化合物(ΧΙΧ)→化合物(V)の変換は酸,ァルカリぁるぃは還元的処理 を行なぅことにょり化合物(V)を製造するェ程でぁる。 本反応は前記の たとぇば化合物(χ)→化合物(a)ぁるぃは化合物( D—化合物(Π)の製 造法に準じて実施することができる。 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 (χ) to the compound (a), according to the method for producing the compound (D—compound (Π)).
本発明に用ぃられるー方の原料化合物でぁる化合物(m)は、 公知の種 々の方法にょり製造することができる。 たとぇばっぎに掲げる文献など にょり、 化合物自体が公知でぁるか、 またはそれらに記載の方法に準じ て化合物(IE)を得ることができる。 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.
( 1 ). Pi. A . P lattner et al. ,へルべティカ ·キミカ * ァクタ (Helvetica Chimica Acta) 4 0 , 1 53 1 ( 1 9 5 7 ) (1). Pi. A. P lattner et al., Helvetica Chimica Acta 40, 153 1 (1957)
( 2 ) . C . H . S tammer et al. ,ジャーナル ·ォブ · ジ · ァメリカ
ン ·ケミカル · ソサェティ ( J ournal of the American Chemical Society) 7 9 , 3 23 6 ( 1 9 5 7 ) (2) C. H. S tammer et al., Journal of the Americas Chemical Society (Journal of the American Chemical Society) 7 9, 3 236 (1 957)
(3). C . H. Stammer et al. ,ジャ—ナル 'ォブ ' メディ シナル ,ケミストリ—(J ournal of Medicinal Chemig"try) 2· 1 , 7 0 9 ( 1 9 7 8 ) (3). C. H. Stammer et al., Journal of Medicinal Chemig "try, 2 1, 709 (1977)
化合物(m)(x = Ηの場合)はたとぇば次反応式に従って製造することが できる。 Compound (m) (when x = Η) can be produced, for example, according to the following reaction formula.
(XXI) (XM) (XXI) (XM)
R3 R+ R3 R+ R'3R* R 3 R + R 3 R + R ' 3 R *
H2N H2N H 2 NH 2 N
"V Y 、0 "V Y , 0
C0NH0H 0 、 H o H (ΧΧΠ) (XXIV) (I) C0NH0H 0, H o H (ΧΧΠ) (XXIV) (I)
[式中の記号は前記と同意義を有す—.る。 ] [The symbols in the formula are as defined above. ]
化合物(XX)→化合物(XXI)のェステル化はー般にょく用ぃられる各種 の公知のェステル化にょり達成することができる。 たとぇば前記のェス テル化の製造法に準じて製造することができる。ーなかでもァルコ—ル中 チォニルクロリ ドで処理する方法などが好 に用ぃられる。 この際ァミ ノ基は塩酸塩などとして塩を形成することもぁるが反応には何ら支障は なぃ。 化合物(XXO→化合物(X¾0はヒ ド口キシル基を脱離基 Yに変換 するェ程でぁる。 ヒ ドロキシル基を脱 基 Υに変換する方法は、 たとぇ ば前記の化合物(11)→化合物(IV)の製造法に準じた方法にょり製造する ことができる。 化合物(χ¾ι)→化合物(xxm)→化合物(XXROは化合
物(XXtt)に塩基の存在下ヒ ドロキシルァミ ンを反応させ、 化合物 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 (X¾0 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 (χ¾ι) → Compound (xxm) → Compound (XXRO is a compound Product (XXtt) with hydroxyamine in the presence of a base
(X X )を製造するェ程でぁる。 この反応の際化合物(X X ΠΙ )を単離す ることもできるが、 とくに単雜せずー挙に化合物(X X ROへ変換するこ とも可能でぁる。 本反応は通常水を溶媒として行なゎれ、 化合物(X¾0 に対して約当量なぃし過剰量の塩基の存在下に約当量なぃし少過剰のヒ ドロキシルァミ ンを反応させることにょり実施される。 塩基としては、 たとぇばリチゥム,ナトリゥム,カリゥム.セシゥムなどのァルカリ金属、 たとぇばマグネシゥム,カルシゥムなどのァルカリ土類金属などの水酸 化物,炭酸塩などが用ぃられる。 反応温度は通常— 2 0 °Cなぃし 6 0 °C 程度でぁり、 反応時間は約 1 0分間なぃし 1 0時間程度でぁる。 (X X) is manufactured. In this reaction, the compound (XXΠΙ) can be isolated, but it is also possible to convert the compound (XXRO) into a compound (XXRO) without singularity. In this case, the reaction is carried out by reacting the compound (about an equivalent or a small excess with respect to X¾0) 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.
化合物(X X IV)は単離、 精製することなしに次反応ェ程に使用すること もできる。 Compound (XXIV) can be used in the next reaction step without isolation and purification.
化合物(χ χ ιν)→化合物(πο'は化合物(x x jy)のァミ ノ基を窒素を介す る有機残基に変換し化合物(m.)を製造するェ程でぁる。 本反応は前記し た化合物( I― 3 )を化合物(1 ー 2 )に変換する方法と同様に行なぅこと ができる。 Compound (χ ιιν) → Compound (πο ') 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.
化合物(ΠΙ )にぉぃて Xがメ トキシまたはホルミルァミ ノでぁる化合物 は、 化合物(m)にぉぃて Xが水素でぁる化合物をメ トキシ化反応または ホルミルァミノ化反応に付すことにょっても製造できる。 該メ トキシ化 反応ぉょびホルミルァミノ化反応としては、 上述した化合物( I ')にぉ ぃて Xが水素でぁる化合物をメ トキシ化反応またはホルミルァミノ化反 応に付す際の反応と同様に行なぅことができる。 なぉ、 化合物(ΠΙ )にぉ ぃて Xが水素でぁる化合物をホルミルァミ ノ化反応に付す際には、 該化 合物(noをー般式 '
A compound in which X is methoxy or formylamino in the compound (III) is subjected to a methoxylation reaction or a formylamination reaction of a compound in which X is hydrogen in the compound (m). Can also be manufactured. 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. In addition, when a compound in which X is hydrogen in the compound (付) is subjected to a formyl amination reaction, the compound (no is converted to a compound represented by the general formula
[式中、
ぉょぴ R 4は、 前記と同意義を有する。 R proは保護基 を示す。 ]で表ゎされるィミ ン体とし、 これにホルムァミ ドの親核性誘 導体を作用させることにょり行なゎれる。 R proで表ゎされる保護 ¾と しては、 前記したァミノ基の保護基と同様のものが挙げられる。 該反応 は、 上述した化合物( Iっにぉぃて Xが水素でぁる化合物をホルミルァ ミノ化反応に付す反応と同様に行なぅことができる。 [Where, Oyopi R 4 have the same meaning as defined above. R pro represents a protecting group. ], And a nucleophilic derivative of formamide acts on the imine body. Examples of 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.
かく して得られる各中間体化合物は、 自体公知の手段たとぇば濃縮, 液性変換,転溶,溶媒抽出,凍結乾燥,桔晶化,再結晶,分留,クロマトグラ フィーなどにょり単離することができる。 - このょぅにして得られる化合物(Π ) , ( IE )ぉょび(IV' )は、 たとぇば化 合物( Iっを製造するための原料化合物として有用でぁる。 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 (Π) and (IE) and (IV ') obtained in this way are useful as raw materials for producing, for example, a compound (I).
上記のょぅにして得られる化合物( I ' )は医薬として有用でぁり、 た とぇばぁる種のグラム陽性菌,グラム陰性菌に対して抗菌カを有する。 化合物(じ)のなかで代表的な化合物の各種微生物に対する抗菌スぺク トルは次表 1に示すとぉりでぁる。
表 l 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
最小生育阻止澳度 Minimum growth inhibition
試 験 菌 ( /ml Test bacteria (/ ml
化合物(2 5)"^ Compound (25) "^
スタフィ ロコ ヅカス ♦ ォ一レゥス Stafi Loco Focus ♦ Contact
F D A 2 0 9 P 6.25 F D A 2 0 9 P 6.25
ェッ シェリ ヒァ · コリ H シ ェ sheri Hia Koli
N I H J J C - 2 3.13 N I H J J C-2 3.13
ク レブシェ一ラ · ニューモニエ Klebsiella Nyumonnier
D T 3.13 D T 3.13
シュー ド乇ナス · ェァルギノ 一サ Shoe Dunas Erguino
I F 0 34 5 5 >100 I F 0 34 5 5> 100
' 培地: Trypticase soy - agar ノ '' Medium: Trypticase soy-agar
接種菌量: 1 08CF U/ml ' Inoculum volume: 1 0 8 CF U / ml '
^ 化合物(2 5)は、 後述の実施例 2 5で製造された化合物(2 5)を示 す。 ^ Compound (25) refers to compound (25) produced in Example 25 described later.
化合物(I ')の毒性は低ぃ。 The toxicity of compound (I ') is low.
このょぅに、 本発明の化合物( I ')またはその塩は、 ぁる種のグラム 陽性菌,グラム陰性菌に対し抗菌カを示すので、 細菌にょる感染をひき ぉこされた哺乳動物(例、 マゥス.ラッ ト,犬,豚.牛,人など)の細菌感染 症 (例、 呼吸器感染症,尿路感染症,化膿性疾患,胆道感染症,腸内感染症, 産婦人科感染症,外科感染症など)の治療に細菌感染症治療剤ぁるぃは抗 菌剤として用ぃることができる。 In addition, 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 ( 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) For treating bacterial infections and surgical infections) can be used as an antibacterial agent.
化合物(1 ')またはその塩の 1 日投与量は、 化合物(Iっとして約 2〜 1 0Ό mgZKg、さらに好ましくは約 5〜4 0 mg/Kgとなる量でぁる。 化合物(I ')を投与するには、 化合物(Iっまたはその薬理学的に許容
され得る塩を常套手段にょって、 適宜の薬理的に許容され得る担体,賦 形剤,希釈剤と.混合し、 たとぇば錠剤,顆粒剤,カプセル剤,ドロップ剤な どの剤型にして経ロ的に投与することができ、 または常套手段にょって たとぇば注射剤に成型し、 常套手段にょって製造され 滅菌性担体中に ' 配合し非経ロ的に投与することができる。 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 ′). To administer the compound (I or its pharmacologically acceptable 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. .
上記経ロ製剤、 例ぇば錠剤を製造する際には、 '結合剤(例、 ヒ ドロキ シプロピルセルロース,ヒ ドロキシプロピルメチルセルロース,マクロゴ —ルなど) 崩壌剤(例、, デ プ ,カルボキシメチルセルロースカルシゥ . ムなど),賦形剤(例、 乳糖,デンプンなど),滑沢剤(例、 ステァリ ン酸マ グネシゥム,タルクなど)などを適宜配合することができる。 ' また、 非経ロ製剤、 たとぇば注射剤を製造する際には、 等張化剤(例、 ブドゥ糖, D -ソルビトール, D —マンニトール,塩化ナトリゥムなど), 防腐剤(例、 べンジルァルコニル,クロロブタノ ール,パラォキシ安息香 酸メチル,パラォキシ安息香酸プロピルなど),緩衝剤(例、 リ ン'酸塩緩衝 液,酢酸ナトリゥム锾衝液など)などを適宜配合することができる。 When manufacturing the above transdermal preparations, for example, tablets, 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. '' In addition, when manufacturing 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.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
次に参考例ぉょび実施例をもってさらに詳細に本発明の内容を説明す . るが、 これにょって本発明が限定されるものではなぃ。 ' Next, the content of the present invention will be described in more detail with reference examples and examples, but the present invention is not limited thereto. '
用ぃられる樹脂のぅち、 略号で示されるものは、 以下に示すとぉりの ものでぁる。 - Among the resins used, those indicated by abbreviations are as follows. -
H P - 2 0:ダィャィォン H P - 2 0 (三菱化成ェ業株式会社製,日本) X A D— 2 :ァンバ—ラィ ト X A D - 2 (ロ―ム ♦ ァン ド♦ハ— 社製, 米国) . H P-20: Dyayon H P-20 (Mitsubishi Kasei Corporation, Japan) X AD-2: Amber Lite X AD-2 (Roam ♦ Hand ♦ Company, USA).
また、 N M Rにぉぃて sはシングレッ トを、 dはダブレッ トを、 ddはダ ブル,ォブ♦ ダブレッッを、 tはトリプレッ トを、 mはマルティ プレッ ト を、 bはブロ— ドをそれぞれ示す。
参考例 1 Also, in NMR, s is a singlet, d is a doublet, dd is a double, an ob ♦ doublet, t is a triplet, m is a multiplete, and b is a broadband. Show. Reference example 1
( 4 S , 5 R )— 4—べン.ジルォキシカルボニルァミ ノ— 5—メチルー 3—ィソキサゾリジノ ンの製造: (4S, 5R) —Preparation of 4-benzyloxycarbonylamino-5-methyl-3-isoxazolidinone:
水酸化ナトリゥム 1.8gの水溶液 4¾iを食塩ー氷浴で冷却し、 ヒ ドロキ シルァミ ン塩酸塩 1.04gぉょぴへルべティカ .キミカ ' ァクタ'(Helvetica Chimica Acta), 4 0 , 1 5 3 1 ( 1 9 5 7 )に記載の方法にょり 得た(2 S .3 S)— 2—ァミ ノ — 3—クロロ酪酸メチルェステル塩酸塩 1.88gを加ぇ 3 0分間攪拌した。 っぃで氷冷下 1.5時間、 水浴中(3 0°C) で 1.5時間攙拌後、 氷冷下でテトラヒ ドロフラン 1 0»ώ、 水 5¾ιΖ、 カル ボべンゾキシクロリ ド 2.14»ώのテトラヒ ドロフラン 5 溶液を順次加ぇ 3 0分間攪拌した。 この間炭酸水素ナトリゥム水溶液を加ぇて ΡΗ7.0に 保った。 反応液に詐酸ェチル 3 0¾£¾加ぇて pH3.Qiし、 有機層を分取 し、 濃縮した。 残留物を詐酸ェチルに溶解し、 炭酸ナ.トリゥム 1.6gの水 溶液 3 0¾£(2回に分けて)で抽出し、 水層を 5 N塩酸で PH2.5に調整し、 酢酸ェチルで抽出した(2回)。 有機層は飽和食塩水で洗净後、 乾燥(Mg S OJし、 っぃで減圧下濃縮した。 残留物にェ—テルを加ぇ、 折出した 結晶をろ取し、 題記化合物 1.16gを得た。 1.8 g of an aqueous solution of sodium hydroxide (1.8 g) was cooled in a salt-ice bath, and 1.04 g of hydroxysilamine hydrochloride was added. 1.88 g of (2S.3S) -2-amino-3-methyl chlorobutyrate methylester hydrochloride obtained by the method described in (1957) was added and stirred for 30 minutes. Stir for 1.5 hours under ice-cooling in a water bath and 1.5 hours in a water bath (30 ° C). The solutions were sequentially heated and stirred for 30 minutes. During this time, an aqueous sodium hydrogen carbonate solution was added to keep the temperature at 7.0. 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 30¾ £ (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.
融点: 1 4 1 — 1 4 3°C Melting point: 1 4 1 — 1 4 3 ° C
I R ^ ί^^Γ cm-1 :3300, 1710, 169.5. 1680, 1545, 1330, 1250 IR ^ ί ^^ Γ cm -1 : 3300, 1710, 169.5. 1680, 1545, 1330, 1250
max max
R (90MHz, CD Cl3-d8-DMS O)(5 : 1.19(3H,d, J = 5Hz) , 4.5-R (90MHz, CD Cl 3 -d 8 -DMS O) (5: 1.19 (3H, d, J = 5Hz), 4.5-
5.0(2H,m), 5.1lC2H,s), 6.14(1H, d, J = 7Hz) , 7.34(5H, s) 5.0 (2H, m), 5.1lC2H, s), 6.14 (1H, d, J = 7Hz), 7.34 (5H, s)
元素分圻値: C 12H1 + N20 + Elemental Q value: C 12 H 1 + N 2 0 +
計算値 C .57.59: H ,5.64; N ,11.19 Calculated value C .57.59: H, 5.64; N, 11.19
実測値 C .57.67; H ,δ.52; N ,10.94 Found C. 57.67; H, δ.52; N, 10.94.
参考例 2
l (4 S , 5 R)- ーべンジルォキシカルボニルァミノー 5—メチルーReference example 2 l (4 S, 5 R)-Benzyloxycarbonylamine 5-methyl
3—ィソキサゾリジノ ンの製造: Production of 3-isoxazolidinone:
Lーァロスレォニン 5.09gをジクロロメ夕ン 3 0¾£に懸蜀し、 氷冷攪 拌下に五塩化リン 6.56gを少量ずっ加ぇ、 室温で 2時閬反応した。 溶媒 5.09 g of L-arosleonin was suspended in 30 ml of dichloromethane, and 6.56 g of phosphorus pentachloride was added thereto while stirring under ice-cooling, and reacted at room temperature for 2 hours. solvent
5 を减圧下留去し、 圻出した結晶をろ取し詐酸ェチルで洗浄すると(2 S , 5 was distilled off under reduced pressure, and the crystals which had formed were collected by filtration and washed with ethyl acetate (2 S,
3 R)— 2—ァミノ一 3—クロロ賂酸メチルェステル塩酸塩 5.6gが得ら れた。 っぃで本品を用ぃて参考例 1の方法と同様に反応処理を行なぅこ .とにょり、.覊 β化食物 I.8 耷無色锆晶として得た。 5.6 g of 3R) -2-amino-3-methylchloroester hydrochloride was obtained. The product was subjected to a reaction treatment in the same manner as in Reference Example 1 using this product, to obtain a β-modified food I. 8 as colorless crystals.
融点: 1 2 7— 1 2 8。C . Melting point: 1 2 7—1 2 8. C.
10 I R ^ ma?x Γ cm-1: 1735, 1695, 1540, 1295, 1250 , 1055 10 IR ^ ma? X Γ cm -1 : 1735, 1695, 1540, 1295, 1250, 1055
NMR(90MHz, C D C ") ( : 1.46(3H,d, J = 5Hz) , 4.0 - 4.6(2H, m) ,NMR (90MHz, C D C ") (: 1.46 (3H, d, J = 5Hz), 4.0-4.6 (2H, m),
5.11(2H,s),5.75(lH,bs),7.34(5H',s)>8.8(lH,bs) 5.11 (2H, s), 5.75 (lH, bs), 7.34 (5H ', s) > 8.8 (lH, bs)
元素分沂値: C 12H l + N2C Elemental value: C 12 H l + N 2 C
計算値 C .57.59: H ,5.64; N ,11.19 ' - 実測値 C .57.58; H.5.55; N, 10.90 Calculated C.57.59: H, 5.64; N, 11.19 '-Found C.57.58; H.5.55; N, 10.90
参考例 3 . Reference example 3.
(4 R)- 4ーべンジルォキシカルボニルァミ ノ — 3 —ィソキサゾリジ ノ ンの製造: Preparation of (4R) -4-benzyloxycarbonylamino-3—isoxazolidinone:
(4 R)— 4—ァミ ノ 一 3—ィソキサゾリ ジノ ン 1.02gのテトラヒ ドロ (4R) —4-amino-3-isoxazolidinone 1.02 g of tetrahydro
20 20
フラン 1 5¾fiと水 1 5 の溶液に、 氷冷、 攙拌下炭酸水素ナトリゥム i.25gとべンジルォキシカルボニルク口リ ド を加ぇ、 1時間攪拌 した。 反応液に詐酸ェチルを加ぇ、 水層を分取した。 酢酸ェチル層を 5 %炭酸ナトリゥム水で抽出した。 水層を合ゎせ、 詐酸ェチルで洗净した: 水層を 1 Ν塩酸で ρΗ 3— 4に調整し、 詐酸ェチルで抽出した。 抽出液 を水洗し、 乾墚(Na2S 0+)後溶媒を留去すると題記化合物 L80gが無色
結晶として得られた。 To a solution of 15 furan fi and 15 water was added i.25 g of sodium hydrogen carbonate and benzyloxycarbonyl chloride under ice cooling and stirring, and the mixture was stirred for 1 hour. To the reaction mixture was added ethyl acetate, and the aqueous layer was separated. The ethyl acetate layer was extracted with 5% aqueous sodium carbonate. The aqueous layers were combined and washed with ethyl acetate: The aqueous layer was adjusted to pH 3-4 with 1M hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried (Na 2 S 0 + ), and the solvent is distilled off. Obtained as crystals.
融点: 1 33— 1 34°C · Melting point: 1 33— 1 34 ° C ·
NMR (90MHz, CD C13-DMS 0 -d8)<5: 4.03(lH,ra) ,4.67(2H,m) , NMR (90MHz, CD C1 3 -DMS 0 -d 8) <5: 4.03 (lH, ra), 4.67 (2H, m),
5.10(2H,s),6.0(lH,b),7.33(5H,s) - 参考例 4 5.10 (2H, s), 6.0 (lH, b), 7.33 (5H, s)-Reference example 4
( 4 S )— 4—べンジルォキシカルボニルァミノ一 3—ィソキサゾリジ ノ ンの製造: Preparation of (4S) —4-benzyloxycarbonylamino-3-isoxazolidinone:
参考例 3の(4 R)- 4—べンジルォキシカルボニルァミノー 3—ィソ キサゾリ ジノ ンの製造法に準じて、 (4 R)- 4—ァミノ— 3—ィソキサ ゾリジノ ンの代ゎりに( 4 S )— 4—ァミ ノ 一 3—ィソキサゾリジノ ンを 用ぃて反応を行なぃ題記化合物を無色結晶として得た。 In accordance with the method for producing (4R) -4-benzyloxycarbonylamine 3 -isoxazolidinone in Reference Example 3, (4R) -4-amino-3 -isoxazolidinone was used instead of (4R) -4-amino-3 -isoxazolidinone. The reaction was carried out using (4S) -4-amino-3-isoxazolidinone to give the title compound as colorless crystals.
融点: 1 3 5— 1 3 6.5 °C。 本品の I Rぉょび NMRスぺク トルは参考 例 3で得た化合物のそれらとー致した。 Melting point: 1 3 5—1 36.5 ° C. The IR spectrum and NMR spectrum of this product were identical to those of the compound obtained in Reference Example 3.
参考例 5 . Reference example 5.
( 4 S )— 4一( 4—'ニトロべンジルォキシカルボニルァミノ)一 3—ィ ソキサゾリ ジノ ンの製造: Preparation of (4S) —4- (4-'nitrobenzyloxycarbonylamino) -3-isoxazolidinone:
参考例 3の(4 R)— 4—べンジルォキシカルボニルァミノ 一 3—ィソ キサゾリ ジノ ンの製造法に準じて、 (4 R)— 4一ァミノ 一 3—ィソキサ ゾリ ジノ ンの代ゎりに( 4 S )— 4—ァミ ノ一 3—ィソキサゾリ ジノ ンを 用ぃ、 べンジルォキシカルボニルクロリ ドの代ゎりに 4—ニトロべンジ ルォキシカルボニルクロリ ドを用ぃて反応を行なぃ題記化合物を無色結 晶として得た。 According to the method for producing (4R) -4-benzyloxycarbonylamino-13-isoxazolidinone in Reference Example 3, the substitution of (4R) -4-amino-13-isoxazolidinone was carried out. The reaction was carried out using (4S) —4-amino-3-isoxazolidinone in advance and 4-nitrobenzyloxycarbonyl chloride in place of benzyloxycarbonyl chloride. The title compound was obtained as colorless crystals.
融点: 1 6 0— 1 6 C
ί I R v Nu]01 cm"1: 3280, 1705, 1550, 1520, 1350, 1275, 1100 Melting point: 16 0— 16 C ί IR v Nu ] 01 cm " 1 : 3280, 1705, 1550, 1520, 1350, 1275, 1100
max max
MR (90MHz. CD Cl3-d8-DMS 0)5: 4.07(1H, dd, J = 11, 15Hz) , 4.65(2H,m),5.21(2H,s),6.6(lH,b),7.53(2H>d, J=9Hz),8.21(2H,d, J = 9Hz) MR (90MHz. CD Cl 3 -d 8 -DMS 0) 5: 4.07 (1H, dd, J = 11, 15Hz), 4.65 (2H, m), 5.21 (2H, s), 6.6 (lH, b), 7.53 (2H > d, J = 9 Hz), 8.21 (2H, d, J = 9 Hz)
3 元素分祈値: C H NsOe Prayer value for 3 elements: CH NsOe
計算値 C .46.98: H .3.94; N, 14.94 Calculated C.46.98: H.3.94; N, 14.94
実測値 C ,47.20 ; H ,3.89; N,14.93 実施例 1 Found C, 47.20; H, 3.89; N, 14.93 Example 1
1 一(4—ニトロべンジル) 水素 2—ォキソグルタレ— ト [化合物 1 mono (4-nitrobenzyl) hydrogen 2-oxoglutarate [compound
10 Ten
(1 )]の製造: Production of (1)]:
(a) 2ーォキソズルタル酸 2.93gのジメチルホルムァミ ド 2 0¾£溶液にジ シクロへキシルァミ ン 3.63gを加ぇ 5 0てに加温した。 っぃで 4ーニト ' ロべンジルブロミ ド 4.75gを加ぇ、 7 0 で 1 5分間攪拌した。 冷後詐 酸ェチル 1 0 0; ^を加ぇ圻出した結晶をろ去し、 詐酸ェチルで洗净した。 ろ液ぉょび洗液を合ゎせ、水ぉょび飽和食塩水で洙浄後、乾燦(MgS OJ した。 溶媒を減圧下に濃縮し、 残留物をシリカゲルを用ぃるカラムクロ マ トグラフィ 一に付し、 へキサン—詐酸ェチルー詐酸(5 0 : 5 0: .1 )で 溶出すると、 題記化合物( 1 )5.2gが桔晶として得られた。 (a) A solution of 2.93 g of 2-oxodultalic acid in 20% of dimethylformamide was heated to 3.63 g of dicyclohexylamine by heating. 4.75 g of 4-nit 'robenzil bromide was added to the flask, and the mixture was stirred at 70 for 15 minutes. After cooling, crystals obtained by adding acid acid 100; were removed by filtration and washed with acid acid. The filtrate and the washing solution were combined, washed with water and saturated saline, and dried (MgS OJ. The solvent was concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel. The mixture was eluted with hexane-ethyl acid-ethyl acid (50 : 50: .1) to give 5.2 g of the title compound (1) as a crystal.
融点: 1 0 0— 1 0 2 °C Melting point: 100—102 ° C
20 20
I R K^ r cm"1: 1735, 1707, 1530, 1345, 1275,. 1085 IR K ^ r cm " 1 : 1735, 1707, 1530, 1345, 1275 ,. 1085
max max
NMR (90MHz, CD Cl3-d8-DMS 0)d : 2.5 - 2.8(2H, m) , 2.9 -NMR (90MHz, CD Cl 3 -d 8 -DMS 0) d: 2.5-2.8 (2H, m), 2.9-
3.3(2H,(n),5.40(2H,s),7.62(2H,d, J = 9Hz),8.28(2H,d, J = 9Hz) 元素分析値: C
3.3 (2H, (n), 5.40 (2H, s), 7.62 (2H, d, J = 9Hz), 8.28 (2H, d, J = 9Hz) Elemental analysis: C
計算値 C .5L.25; H .3.94; N ,4.98 Calculated C.5L.25; H.3.94; N, 4.98
実測値 C ,51.17; H ,3.92; N ,4.96
(b)、 2—ォキソグルタル酸 2.93gのジメチルホルムァミ ド 2 0¾£溶液に、 トリェチルァミ ン 2.79¾ώっぃで 4—ニトロべンジルブロミ ド 4.53gを加 ぇ室温で 5時間攪拌した。 反応液を氷水中に注加し、 酢酸ェチルで抽出 ( 2回)した。 っぃで実施例 1 (a)と同様に処理すると、《·題記化合物( 1 ) 3.6gが結晶として得られた。 Found C, 51.17; H, 3.92; N, 4.96 (b) To a solution of 2.93 g of 2-oxoglutaric acid in 20 ml of dimethylformamide, 4.53 g of 4-nitrobenzyl bromide was added with 2.79 g of triethylamine, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (twice). When treated in the same manner as in Example 1 (a), << the title compound (1) 3.6 g was obtained as crystals.
(c)、 2ーォキソグルタル酸モノナトリゥ厶塩 3.36gのジメチルホルムァ ミ ド 3 懸阖液に 4—ニトロべンジルブロミ ド 4.53gを加ぇ、 5 0 °C - 6 0 °Cで 2時間攪拌した。 反応液を氷水中に注加し、 詐酸ェチルで抽 出(2回)した。 っぃで実施例 1 (a)と同様に処理すると、 題記化合物(1 ) 3.92gが桔晶として得られた。 (c), 4.53 g of 4-nitrobenzyl bromide was added to a suspension of 3.36 g of monosodium salt of 2-oxoglutarate in dimethylformamide and stirred at 50 ° C. to 60 ° C. for 2 hours. The reaction solution was poured into ice water and extracted with ethyl sulphate (twice). By treating in the same manner as in Example 1 (a), 3.92 g of the title compound (1) was obtained as a crystal.
実施例 2 Example 2
(4 S .5 R)— 2—(4—べンジルォキシカルポニルァミノ 一 5—メチ ル— 3—ォキソ一 2—ィソキサゾリ ジニル)— 5—ォキソ一 2—テトラ ヒ ドロフランカルボン酸 4ーニトロべンジルェズテル [化合物(2 )]の 製造: (4 S .5 R) — 2- (4-benzyloxycarbonylamino-5-methyl-3-oxo-1-2-isoxazolidinyl) -5-oxo-1-2-tetrahydrofurancarboxylic acid 4-nitro Production of Benzilestel [Compound (2)]:
参考例 1で得た(4 S .5 R)- ーべンジルォキシカルボニルァミ ノ ー 5—メチル— 3—ィソキサゾリ ジノ ン 1 2 5 mgと実施例 1で得た化合 物( 1 ) 1 δ 5 mgとをジクロロメタン 5»ι2に溶解し、 Ν , Ν ' —ジシクロ へキシルカルボジィミ ド(D C C) l 1 4mgを加ぇて室温で 3 0分間攪拌 した。 折出した桔晶をろ去し、 ジクロロメタンで洗浄後、 ろ液ぉょび洗 液を合ゎせて減圧下濃縮した。 残留物をシリカゲルを用ぃるカラムクロ マトグラフィーに付し、 へキサンー酢酸ェチル(1 : 1 )で溶出すると題 記化合物(2) 1 8 5 mgが無色泡状物として得られた。 125 mg of (4S.5R) -benzyloxycarbonylamino-5-methyl-3-isoxazolidinone obtained in Reference Example 1 and the compound (1) 1 obtained in Example 1 5 mg of δ was dissolved in dichloromethane 5 »ι2, and 14 mg of Ν, Ν′-dicyclohexylcarbodiimide (DCC) was added, followed by stirring at room temperature for 30 minutes. The precipitated quartz was filtered off, washed with dichloromethane, and the filtrate and the washings were combined and concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (1: 1) to give 185 mg of the title compound (2) as a colorless foam.
I R ^at cnT1: 3325, 1805. 1770(肩), 1730, 1530, 1350, 1050 NMR (90MHz, C D C 13) 5: 1.17 , 1.23(each 1.5H, d, J = 6Hz) , 2.3-
3.3(4H,m),4.6-5.1(2H.ni),5.10(2H,s),5.37(2H,s),5.48(lH,dJ = 5Hz) , 7.33 (5H , s) , 7.51 , 8.20 (each 2H,d, J = 9Hz) IR ^ at cnT 1: 3325, 1805. 1770 ( shoulder), 1730, 1530, 1350, 1050 NMR (90MHz, CDC 1 3) 5: 1.17, 1.23 (each 1.5H, d, J = 6Hz), 2.3- 3.3 (4H, m), 4.6-5.1 (2H.ni), 5.10 (2H, s), 5.37 (2H, s), 5.48 (lH, dJ = 5Hz), 7.33 (5H, s), 7.51,8.20 ( each 2H, d, J = 9Hz)
実施例 3 Example 3
(4 S .5 R)- 2 - [4 -(2—チェニルァセトァミ ド)— 5—メチルー 3ーォキソー 2—ィソキサゾリジニル]— 5ーォキソー 2—テトラヒド σフランカルボン酸 ナトリゥム塩 [化合物(-3)]の製造: (4 S .5 R)-2-[4- (2-Chenylacetamide)-5-methyl-3-oxo-2-isoxazolidinyl]-5-oxo-2-tetrahydr σ-furancarboxylic acid sodium salt [Compound Production of (-3)]:
実施例 2で得た化合物(2) 1 8 5mgを詐酸ェチル 5¾£と水 5?τώの混液 に溶解し、 5 % ラジゥムー炭素 2 0 Omgを加ぇ、 水素気流中室温で 5 0分間攪拌した。 触媒をろ去し水法後、 ろ液ぉょぴ洗液を合ゎせ水層 を取り、 テトラヒドロフラン 5 ¾£を加ぇ氷冷攙拌下 2—チェニル舴酸ク ロリ ド 6 7 μΐΖと炭酸水素ナトリゥム水溶液を加ぇて、 ΡΗ7.0付近に保 ち 3 0分間反応した。 っぃで减庄下に トラヒ ドロフランを留去し、 得 られた水溶液を舴酸ェチルで洗诤後、 水層を X AD— 2カラムで精製し た。 水で溶出される画分を凍結乾燥し、 題會己化合物(3) 8 7mgを绣黄色 粉末として得た。 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 5¾ of tetrahydrofuran was heated and stirred under ice-cooling, and 67-μ 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. Trahydrofuran was distilled off under a stream of water, and the resulting aqueous solution was washed with ethyl acetate, and the aqueous layer was purified with an XAD-2 column. The fraction eluted with water was freeze-dried to obtain 87 mg of the title compound (3) as a pale yellow powder.
1 R v ma? Γ cm"i : 1775' 1720· 55' 1380 - 1195 ? 1 R v ma Γ cm " i: 1775 '1720 · 55' 1380 - 1195
NMR (90MHz, CD Cl3-d8-DMS O)(5 : 1.08(3H,d, J = 8Hz),2.2NMR (90MHz, CD Cl 3 -d 8 -DMS O) (5: 1.08 (3H, d, J = 8Hz), 2.2
-3.3(4H,m),3.76(2H,s),4.4-5.0(2H,m),6.8-7.4(3H,m),8.81,8.85 (each 0.5H,d,J = 8Hz) -3.3 (4H, m), 3.76 (2H, s), 4.4-5.0 (2H, m), 6.8-7.4 (3H, m), 8.81,8.85 (each 0.5H, d, J = 8Hz)
元素分析値: C 15H15N2Na07 S Elemental analysis: C 15 H 15 N 2 Na0 7 S
算値 C. .12: H.4.20; N.6.86 Arithmetic C. .12: H.4.20; N.6.86
実測値 C, .35; H.4.23; N.6.82 Found C, .35; H.4.23; N.6.82
実施例 4 Example 4
(4 S .5 R)— 2— {4— [2—(2—ァミノ 一 4—チァゾリル) -(Z)- (4 S .5 R) — 2— {4— [2— (2-amino-1 4-thiazolyl)-(Z)-
2—(メ トキシィミノ)ァセトァミ ド ]— 5—メチル一 3—ォキソー 2—
ィソキサゾリジニル }一 5—ォキソー 2—テトラヒ ドロフランカルボン 酸 ナトリゥム [化合物 (4)]の製造: 2- (Methoxyimino) acetamide] — 5-Methyl-1-oxoxo 2— Isoxazolidinyl} -1-sodium 2-tetrahydrofurancarboxylate [Compound (4)] Production:
実施例 2で得た化合物(2 ) 2 5 7 mgを詐酸ェチル 5; ^と水 の混液 に溶解し、 5 %パラジゥム—炭素 2 5 Onigを加ぇ、 水 気流中室温で 4 5分間攪拌した。 触媒をろ去し水洗し、 ろ液ぉょぴ洗液を合ゎせ水層 を取り、 テトラヒ ドロフラン 1 0¾£を加ぇ、.氷冷攙拌下に 2—(2—ク ロロァセトァミ ド— 4—チァゾリル)一(Z)— 2—メ トキシィミノ詐酸 クロリ ド 塩酸塩 2 1 7 mgぉょぴ炭酸水素ナトリゥム水溶液を加ぇて、 PH7.0付近に保ち 3 0分間反応した。 っぃで N—メチルジチォ'カルパミ ン酸ナトリゥム 1 6 5mgを加ぇ室温で 4 5分間攪拌した。 減圧下にテ トラヒ ドロフランを留去し、 濃縮液を詐酸ェチルで洗净後、 XAD— 2 カラムで精製した。 水で溶出される画分を凍結乾燦し、 題記化合物(4) 1 4 9 mgを黄色粉末として得た。 257 mg of the compound (2) obtained in Example 2 was dissolved in a mixture of ethyl acetate 5; ^ and water, 5% palladium-carbon 25 Onig was added, and the mixture was stirred at room temperature for 45 minutes in a stream of water. did. The catalyst was removed by filtration, washed with water, combined with the filtrate and the washing solution, and the aqueous layer was taken. Tetrahydrofuran was added, and the mixture was stirred under ice-cooling and stirred with 2- (2-chloroacetamide-4). —Thiazolyl) -1- (Z) —2-Methoxyimino acid chloride chloride hydrochloride 217 mg An aqueous solution of sodium hydrogencarbonate was added, and the mixture was allowed to react for 30 minutes while maintaining the pH at around 7.0. To the mixture was added N-methyldithio'carbamate sodium (165 mg), and the mixture was stirred at room temperature for 45 minutes. Tetrahydrofuran was distilled off under reduced pressure, and the concentrate was washed with ethyl acetate and purified with an XAD-2 column. The fraction eluted with water was freeze-dried to give 149 mg of the title compound (4) as a yellow powder.
1 R majT 1 cm_1 ; 177δ· 1720 · 1660, 1535, 1380, 1040 ' 1 R majT 1 cm_1; 177δ · 1720 · 1660, 1535, 1380, 1040 '
MR (90MHz, CD C l3-de- DMS 0 ) «5 : 1.21(3H, d, J = 6Hz) , 2.2MR (90MHz, CD C l 3 -d e -DMS 0) «5: 1.21 (3H, d, J = 6Hz), 2.2
- 3.3(4H,m),3.86(3H,s)>4.5- 5. l(2H>m),6.72(lH>s),7.07(2H,s),-3.3 (4H, m), 3.86 (3H, s) > 4.5- 5.l (2H > m), 6.72 (lH > s), 7.07 (2H, s),
9.02,9.19(each 0.5H, d. J = 8Hz) 9.02,9.19 (each 0.5H, d.J = 8Hz)
元素分折値: C 15HieN5Na08S · 1.5H20 Elemental analysis value: C 15 H ie N 5 Na0 8 S · 1.5H 2 0
計算値 C ,37.82; H ,4.02; N.14.70 Calculated C, 37.82; H, 4.02; N.14.70
実測値 C .38.01; H.4.07; .14.76 Found C.38.01; H.4.07; .14.76
実施例 5 Example 5
(4 S .5 S)— 2— (4—べンジルォキシカルボニルァミノ 一 5—メチ ル— 3—ォキソー 2—ィソキサゾリ ジニル)— 5—ォキソー 2—テトラ ヒ ドロフランカルボン酸 4—ニトロべンジルェステル [化合物( 5 )]の
参考例 2で得た(4 S , 5 S)- 4—べンジルォキシカルボニルァミノ(4 S .5 S) — 2- (4-benzyloxycarbonylamino-5-methyl-3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofurancarboxylic acid 4-nitrobenzene Ngilester [Compound (5)] (4S, 5S) -4-benzyloxycarbonylamino obtained in Reference Example 2
— 5 —メチル一 3 —ィソキサゾリジノ ン 3 7 6 mgと実施例 1で得た化合 物(1 )4 6 4 mgとを用ぃ、 実施例 2の方法と同様に反応処理すると題記 化合物(5 ) 5 9 3 mgが無色泡状物として得られた。 ー - I R N ®at cm"1: 3350, 1805, 1760(肩), 1730 , 1530. 1350., 1185, max — 376 mg of 5-methyl-1-isoxazolidinone and 164 mg of the compound (1) obtained in Example 1 were used and the reaction was carried out in the same manner as in Example 2 to give the title compound (5) 593 mg was obtained as a colorless foam. Over - IR N ® at cm "1 : 3350, 1805, 1760 ( shoulder), 1730, 1530. 1350., 1185 , max
1055 1055
NMRC90MHZ, C D C l3)<5: 1.38, 1.42(each 1.5H, d, J = 5Hz) , 2.2 - 3.3(4H,m), 4.0-4.7(2H>m)>5.07(2H,s),5.32(2H,s),5.57(lH(d,J = 7Hz),7.31(5H(s),7.47. 7.50(each lH.d, J = 11Hz) ,8.16(2H,d, J = 11Hz) NMRC90MHZ, CDC l 3) <5 : 1.38, 1.42 (each 1.5H, d, J = 5Hz), 2.2 - 3.3 (4H, m), 4.0-4.7 (2H>m)> 5.07 (2H, s), 5.32 (2H, s), 5.57 (lH ( d, J = 7Hz), 7.31 (5H ( s), 7.47.7.50 (each lH.d, J = 11Hz), 8.16 (2H, d, J = 11Hz)
実施例 6 Example 6
(4 S . 5 S)— 2 — [4— (2—チェニルァセトァミ ド)— 5—メチル— 3ーォキソー 2 —ィソキサゾリ ジニル:]ー 5—ォキソー 2—テドラヒ ド ロフランカルボン酸 ナトリゥ厶塩 [化合物(6 )]の製造: ' (4 S. 5 S) — 2 — [4 -— (2-Chenylacetamide) — 5-Methyl-3-oxo-2—isoxazolidinyl:]-5-oxo 2-Na-Tedrahydrofurancarboxylic acid sodium salt Preparation of [Compound (6)]: ''
実施例 5で得た化合物(5 ) 2 6 5 mgを用ぃて実施例 3の方法と同様に 反応、後処理すると題記化合物(6) 1 6 2 mgが無色粉末として得られた。 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.
I R K^1 cm"1 :1780, 1730, 1655, 1380, L200 IR K ^ 1 cm " 1 : 1780, 1730, 1655, 1380, L200
max max
MR(90MHz. C D C I3-d8- DMS 0)<5: 1.28(3H. d, J = 6Hz) .2.2 -3.3(4H.(n),3.73,3.75(each 1H, s) , 4.0 - 4.8(2H, m) .6.8 - 7.3(3H, m) , 8.77(lH,d, J = 8Hz) MR (90MHz. CDCI 3 -d 8 -DMS 0) <5: 1.28 (3H.d, J = 6Hz) .2.2 -3.3 (4H. (N), 3.73,3.75 (each 1H, s), 4.0-4.8 (2H, m) .6.8-7.3 (3H, m), 8.77 (lH, d, J = 8Hz)
実施例 7 Example 7
(4 S . 5 S)— 2 — {4 — [2 -(2 —ァミ ノ 一 4ーチァゾリル)一(Z)— 2—(メ トキシィ ミ ノ)ァセトァミ ド]一 5 —メチル一 3 —ォキソー 2 — ィソキサゾリジニル }一 5—ォキソ― 2—テトラヒ ドロフランカルボン 酸 ナトリゥム塩 [化合物(7 )]の製造:
実施例 5で得た化合物(5 ) 2 5 7 mgを用ぃて、 実施例 4の方法と同様 に反応、 後処理すると題記化合物(7 ) 1 9 mgが淡黄色粉末として得ら れた。 l R ^T cm"1 : 1785, 1730, 1655, 1530, 1380 , 1200. 1035 (4 S. 5 S) — 2 — {4 — [2- (2-Amino-4-thiazolyl) -1- (Z) — 2 -— (methoxymino) acetamid] -1 5 —Methyl-1 3 —oxo Preparation of 2-isoxazolidinyl} -1-oxo-2-tetrahydrofurancarboxylic acid sodium salt [Compound (7)]: Using 257 mg of the compound (5) obtained in Example 5, the reaction and post-treatment were carried out in the same manner as in Example 4, to obtain 19 mg of the title compound (7) as a pale yellow powder. l R ^ T cm " 1 : 1785, 1730, 1655, 1530, 1380, 1200. 1035
max max
NMROOMHz, C D C l3-de-DMS O)<5 : 1.36(3H, d, J =-6Hz) , 2.1 - 3.3(4H(m),3.87(3H,s)>4.1-4.9(2H,m),6.89)6.92(each 0.5H,s), 7.13(2H,s), 9.06,9.08(each 0.5H,d, J = 8Hz) NMROOMHz, CDC l 3 -de-DMS O) <5: 1.36 (3H, d, J = -6Hz), 2.1-3.3 (4H ( m), 3.87 (3H, s) > 4.1-4.9 (2H, m) , 6.89 ) 6.92 (each 0.5H, s), 7.13 (2H, s), 9.06,9.08 (each 0.5H, d, J = 8Hz)
実施例 8 Example 8
(4 R)— 2 — (4—べンジルォキシカルボニルァミノ 一 3—ォキソ一 2—ィソキサゾリ ジニル)一 5—ォキソー 2—テトラヒ ドロフランカル ボン酸 ーニトロべンジルェステル [化合物(8 )]の製造: Preparation of (4R) —2— (4-benzyloxycarbonylamino-3-oxo-1-2-isoxazolidinyl) -1-oxo-2-tetrahydrofuran carboxylate-nitrobenzyl ester [Compound (8)]:
(a)'、 実施例 1で得た化合物(1 ) 8 5 tngぉょび 1 一ヒ ドロキシべンゾト リァゾ一ル(H 0 B T ) 4 1 mgのジクロロメ'タン 3.»ώ溶液に D C C 6 2 mg を加ぇて室温で 3 0分間攪拌した。 そこへジャ—ナル .ォブ . メディ シ ナ レ · ケ ミ ス ト リ 一 ( J ournal of Medicinal C hemistry) , 1 3 . 1 0 1 3 ( 1 9 7 0 )に K載の方法で得た( 4 R )— 4ーべンジルォキシカ ルボニルァミ ノ — 3—ィソキサゾリ ジノ ン 6 0 mgを加ぇて室温で 3 0分 間攪拌した。 折出した不溶物をろ去し、 ジクロロメタンで洗净し、 ろ液 ぉょび洗液を合ゎせ濃縮した。 残留物を詐酸ェチルに溶解し、 炭酸水素 ナトリゥム水溶液、 飽和食塩水で順次洗浄後、 乾燥(Na2S 0+)した。溶 媒を减圧濃縮し、 残留物をシリカゲルを用ぃるカラムクロマ トグラフィ —に付し、 へキサンー詐酸ェチル(1 : 1 )で溶出すると題記化合物(8 ) 9 6 mgが無色泡伏物として得られた。 (a) ', the compound (1) obtained in Example 1 85 tng 1 1 hydroxybenztriazole (H 0 BT) 4 1 mg of dichloromethane 3. 2 mg was added and the mixture was stirred at room temperature for 30 minutes. Got there in the Journal of Medicinal Chemistry, 13.10.13 (1970), obtained by K. 60 mg of (4R) -4-benzyloxycarbonylamino--3-isoxazolidinone was added, and the mixture was stirred at room temperature for 30 minutes. The deposited insolubles were removed by filtration, washed with dichloromethane, and the filtrate and the washings were combined and concentrated. The residue was dissolved in ethyl acetate, washed successively with aqueous sodium hydrogen carbonate solution and saturated saline, and then dried (Na 2 S 0 + ). The solvent was concentrated under reduced pressure, the residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (1: 1) to give 96 mg of the title compound (8) as a colorless foam. Obtained.
I R ^ ®at cm-1 :3330, 1805, 1760(肩). U30' 1530, 1350, 1270,IR ^ ® at cm -1 : 3330, 1805, 1760 (shoulder). U30 '1530, 1350, 1270,
ΓΠ ΓΠ
1245, 1185, 1055
NMR(90MHz, CD Cl3)5 : 2.3- 3.4(4H, in) , 4.0 - 4.4(lH.m) .4. -1245, 1185, 1055 NMR (90 MHz, CD Cl 3 ) 5: 2.3-3.4 (4H, in), 4.0-4.4 (lH.m) .4.-
5.1(2H,m)>5.11(2H,s),5.36(2H,s),5.53,5,59(each 0.5H, d, J = 6Hz) , 5.1 (2H, m) > 5.11 (2H, s), 5.36 (2H, s), 5.53,5,59 (each 0.5H, d, J = 6Hz),
7.33(5H,s),7.50,7.52(each 1H, d, J = 9Hz) , 8.18(2H,d, J = 9Hz) 7.33 (5H, s), 7.50,7.52 (each 1H, d, J = 9Hz), 8.18 (2H, d, J = 9Hz)
マススぺク トル mZe: 4 9 9 (M+ ) - - (b)、 化合物(1 ) 8 5mgぉょび(4 R)— 4—べンジルォキシカルボニル Mass vector mZe: 49 9 (M +)--(b), compound (1) 85 mg and 4 (R) —4-benzyloxycarbonyl
ァミノ一 3—ィソキサゾリ ジノ ン 60mgのジクロロメタン 2»ώ溶液に 2― Amino-3-isoxazolidinone 2-mg in dichloromethane 2 2
クロロ一 1 ーメチルピリジニゥムィォダィ ド 7 7 mgぉょぴトリェチルァ ミ ン 8 4 を加ぇ室温で 4 0分間攪拌した。 威圧下濃縮し、 残留物を 77 mg of chloro-1-methylpyridinamide was added to triethylamine 84, and the mixture was stirred at room temperature for 40 minutes. Concentrate under intimidation and remove residue
詐 ェチルに溶解し実施例 8 (a)と同様に後処理を行なぅと、 題記化合 After dissolving in fraudulent solution and performing post-processing in the same manner as in Example 8 (a),
¾ (8)3 1 mgが得られた。 ¾ (8) 3 1 mg was obtained.
実施例 9 · Example 9
(4 S )- 2 - C ーべンジルォキシカルボニルァミノ — 3—ォキソー (4 S)-2 -C-benzyloxycarbonylamino — 3-oxo
2—ィソキサゾリ ジニル)一 3—ォキソ一 2—テトラヒ ドロフランカル 2-isoxazolidinyl) -1-3-oxo-2-tetrahydrofurancal
ボン酸 4ーニトロべンジルェステル [化合物(9 )]の製造: Preparation of 4-nitrobenzyl diester borate [compound (9)]:
(a)、 参考例 4で得た(4 S)— 4—べンジルォキシカルボニルァミ ノ— (a), (4S) —4-benzyloxycarbonylamino obtained in Reference Example 4
3—ィソキサゾリジノ ン 2 3 6 mgと実胞例 1で得た化合物( 1 ) 3 6 5 mg をジクロロメタン 2 0¾£に溶解し、 D C C 2 7 0 mgを加ぇて室温で 1 4 時間攪拌した。 折出した結晶をろ去し、 ジクロロメタンで洗净した。 ろ 液と洗液を合ゎせ、 炭酸水素ナトリゥム水,水で洗浄.乾燥(Na2S 0 J 2-isoxazolidinone (236 mg) and the compound (1) 365 (mg) obtained in Example 1 were dissolved in dichloromethane (20 mL), DCC (270 mg) was added, and the mixture was stirred at room temperature for 14 hours. The deposited crystals were removed by filtration and washed with dichloromethane. Combine the filtrate and the washing solution, wash with sodium bicarbonate water and water, and dry (Na 2 S 0 J
後、 溶媒を留去した。 残留物をシリカゲルを用ぃるカラムクロマ トグラ フィーに付し、 へキサンー詐酸ェチル( 1 : 1 )で溶出すると題記化合物 Thereafter, the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (1: 1) to give the title compound.
(9 ) 2 9 7 mgが無色泡状物として得られた。 ■ (9) 297 mg were obtained as a colorless foam. ■
I R V N®at cm"1 :3350, 1800,1770 - 1700,1520, 1340, 1260, 1230, IRV N ® at cm " 1 : 3350, 1800,1770-1700,1520, 1340, 1260, 1230,
max max
1180, 1050 1180, 1050
NMR(90MHz, CD Cl3)<5: 2.3- 3.3(4H, m) , 4.1(1H, m) , .5- 4.8(2H,
m),5.11(2H,s),5.3(lH,b),5.37(2H(s),7.35(5H,s),7.53(2H,d, J=NMR (90 MHz, CD Cl 3 ) <5: 2.3-3.3 (4H, m), 4.1 (1H, m), .5-4.8 (2H, m), 5.11 (2H, s), 5.3 (lH, b), 5.37 (2H ( s), 7.35 (5H, s), 7.53 (2H, d, J =
9Hz),8.23(2H,d,J=9Hz) 9Hz), 8.23 (2H, d, J = 9Hz)
マススぺク トル m/e:4 9 9 (M+ ) Mass vector m / e: 4 9 9 (M +)
(b)、 化合物(1 )2 8 2mgのジクロロメタン 1 0¾ϋ溶液を食塩ー氷浴で 冷却し、トリェチルァミ ン 1 4 0 /ζβぉょぴクロロ炭酸ェチル 9 6 βを 加ぇた。 1 0分間後に(4 S )- 4ーべンジルォキシカルボニルァミ ノー 3—ィソキサゾリ ジノ ン 1 1 9 mgを加ぇて氷冷下で 1時間っぃで室温で 1時間攪拌した。減圧下に溶媒を留去後、 残留物を酢酸ェチルで抽出し、 有機層を炭酸水素ナトリゥム水溶液っぃで飽和食塩水で洗浄した。乾燦 (MgS 04)後、溶媒を减圧濃縮し、残留物をシリカゲルクロマトグラフィ ーに付し、 1 , 2—ジクロロェタン—詐酸ェチル(9:1)っぃでへキサンー 詐酸ェチル (1 : 1 )で溶出すると題記化合物(9 )7 3 mgが得られた。 '(b) A solution of 28 mg of compound (1) 282 mg in dichloromethane was cooled in a salt-ice bath, and triethylamine 140 / {β-chloroethyl carbonate 96β was added. After 10 minutes, (4S) -4-benzyloxycarbonylamino 3-isoxazolidinone (119 mg) was added, and the mixture was stirred under ice cooling for 1 hour and at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was extracted with ethyl acetate, and the organic layer was washed with an aqueous solution of sodium hydrogen carbonate and saturated saline. After Inui燦(MgS 0 4), the solvent was减圧concentrated, the residue was subjected to silica gel chromatography, 1, 2-Jikuroroetan -詐酸Echiru (9: 1) Kisan詐酸Echiru (1 to Tsuide Elution with 1) gave 73 mg of the title compound (9). '
(c)、 化合物( 1 ) 1 5 5 mgぉょび(4 S)— 4—べンジルォキシカルボニ ルァミ ノ 一 3—ィソキサゾリ ジノ ン 1 1 9 mgのジクロロメタン 5 溶液 に三フヅ化ホゥ素ェーテラー ト(4 7 %ェーテル溶液) 2滴とモレキュラ ーシーブス(3 Α) 2 gを加ぇて室温で 2日間放置した。 モレキュラーシ -ブスを除き、 反応液を冷炭酸水素ナ トリゥム水溶液で洗净後、 乾燥 (MgS O+)した。 溶媒を滅圧濃縮し、 残留物をシリカゲル薄層クロマ 卜 プレ— トにょり精製した [ 1 , 2—ジクロロェタンー詐酸ェチル(5: 1 ) で展開]。 題記化合物(9)12.5mgが得られた。 (c), Compound (1) 155 mg mg (4S) —4-benzyloxycarbonylamino-3--3-isoxazolidinone 1.1 mg of dichloromethane Two drops of sodium ether (47% ether solution) and 2 g of molecular sieves (33) were added and left at room temperature for 2 days. After removing the molecular sieves, the reaction solution was washed with a cold aqueous sodium hydrogen carbonate solution, and then dried (MgS O + ). The solvent was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel [developed with 1,2-dichloroethane-ethyl acetate (5: 1)]. 12.5 mg of the title compound (9) was obtained.
実施例 1 0 Example 10
L —メチル 水素 2—ォキソグルタレ— ト [化合物( 1 0 )]の製造: ジャーナル · ォブ · ォ—ガニ 'ソク ·ケミストリ —(J ournal of Organic C hemistry) . i, 8 7 8 ( 1 94 1 )に記載の方法にょり得た 2—べンジルォキシカルボニルァミ ノ 一 5—ォキソー 2—テトラヒ ドロ フランカルボン酸 27.93gのジメチルホルムァミ ド 1 0 0¾£溶液に、 氷冷
攪拌下水素化ナトリゥム 4.0g(6 0 %油性)を加ぇ、 っぃでョゥ化メチルProduction of L-methylhydrogen 2-oxoglutarate [Compound (10)]: Journal of Organic Chemistry. I, 8 7 8 (1941) 2) -benzyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylic acid (27.93 g) obtained by the method described in (2) above in dimethylformamide 100 Add 4.0 g (60% oily) of hydrogenated sodium under stirring, and add methyl iodide
28.4gを加ぇ室温で 4時間反応した。 ョゥ化メチル 14.2gを追加しさらに 3時間攙拌した。 反応液を水に注加し鲊酸ェチルで抽出した。 有機層は 炭酸水素ナトリゥム,飽和食塩水で順次洗浄後、 乾燦 ("MgS Θ+)した。 溶媒を留去し、 折出した結晶をろ取し、 ェ—テルで洗浄すると 2—べン ジルォキシカルボニルァミノ一 5—ォキソ一.2—テトラヒ ド σフランカ ルボン酸 メチルェステル 27.25gが無色锆晶として得られた。 28.4 g was reacted at room temperature for 4 hours. 14.2 g of methyl iodide was added, and the mixture was further stirred for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with sodium bicarbonate and saturated saline, and then dried ("MgS + "). The solvent was distilled off, and the precipitated crystals were collected by filtration and washed with ether to give 2-benzene. 27.25 g of dioxycarbonylamino-5-oxo1.2-tetrahydro sigma-furancarboxylate methylester were obtained as colorless crystals.
融点 1 3 4— 1 34.5°C。 Melting point 1 3 4—1 34.5 ° C.
I R ^ S,?rcm"1: 3295, 1780, 1758, 1700, 1540, 1308, 1196. 1049 max , 本品 10.0gに 3 0 %臭化水素酢酸溶液 2 を加ぇ 3 0分間攪拌した。 反応混合物を氷冷下へキサンーェ—テル(9 : 1 ) 5 0 0 ^(2回)で 2回 洗净(デカンテーション)後、 残渣に水を加ぇ酢酸ェチルで油出(4回)し た。 有機層を飽和食塩水で洗浄後、 乾燦(MgS O+)し、 溶媒を留去した。. 残留物をシリカゲルを用ぃるカラムクロマトグラフィ―に付し、 へキサ ンー酢酸ェチル(1 : 1 )で溶出すると題記化合物(1 0)2.95gが無色結晶 として得られた。 IR ^ S ,? r cm "1 : 3295, 1780, 1758, 1700, 1540, 1308, 1196. 1049 max, the 3 0% hydrobromic acid solution 2 was stirred pressurized tut for 30 minutes to the product 10.0 g. The reaction mixture was washed twice with ice-cold ether (9: 1) 500 ^ (twice) twice (decantation), water was added to the residue, and oil was extracted with ethyl acetate (4 times). The organic layer was washed with brine, dried (MgS O + ), and the solvent was distilled off.The residue was subjected to column chromatography using silica gel to give hexane-ethyl acetate (1%). Elution with 1) gave 2.95 g of the title compound (10) as colorless crystals.
融点: 5 4.5— 5 5.0。C Melting point: 54.5-55.0. C
I R ^ i vD icm-1 : 3430 , 1750, 1735, 1710. 1275, 1255, 1225. 1080 max IR ^ iv D i cm- 1 : 3430, 1750, 1735, 1710. 1275, 1255, 1225. 1080 max
N MR (90MHz, C D C 13) <5 : 2.60 - 3.27(4H, m) .3.88(3H, s) , 8.20(1H, bs) N MR (90MHz, CDC 1 3 ) <5: 2.60 - 3.27 (4H, m) .3.88 (3H, s), 8.20 (1H, bs)
元素分折値: C8He05 - 計算値 C ,45.01; H.5.04 Elemental folding value: C 8 H e 0 5 - Calculated C, 45.01; H.5.04
実測値 C .44.92: H,4.92 · Found C.44.92: H, 4.92
実施例 1 1 Example 1 1
1 一(4ーニトロべンジル) 水素 2—ォキソグルタレー ト [化合物
-83-1 One (4-nitrobenzyl) hydrogen 2-oxoglutarate [Compound -83-
1 (1 )]の製造: 1 (1)] Production:
2 —べンジルォキシカルボニルァミノ一 5—ォキソ一 2 —テトラヒ ド ロフランカルボン酸 8 3 8 mgのジメチルホルムァミ ド 5 »ώ溶液に氷冷攙 拌下、 水素化ナトリゥム 1 2 0 mg(6 0 %油性)を加ぇ っぃで 4 -ニト 2-benzoxycarbonylamino-5-oxo-1 2-tetrahydrofurancarboxylic acid 838 mg of dimethylformamide 5 A sodium hydroxide solution was added to a »ώ solution with stirring under ice-cooling 120 mg (60% oiliness)
5 ロべンジルブロミ ド 6 4 8 mgを加ぇ、 室温で 2.5時間攙拌した。 反応液 に飽和炭酸水素ナトリゥム水溶液を加ぇ詐酸ェチルで抽出した。 有機層 を飽和食塩水で洗浄後、 乾燦(MgS 04)し、 溶媒を留去した。 残留物を シリカゲルを用ぃるカラムクロマトグラフィ ーに付し、 へキサンー酢酸 ェチル(1:1)で溶出すると 2—べンジルォキシカルボニ ァミノ一 5 — 10 ォキソ一 2—テトラヒ ドロフランカルボン酸 .4 —ニトロべンジルェス テル 6 8 7 mgが無色桔晶として得られた。 · 5 Robenzil bromide (648 mg) was added, and the mixture was stirred at room temperature for 2.5 hours. To the reaction solution, a saturated aqueous solution of sodium hydrogen carbonate was extracted with ethyl acetate. The organic layer was washed with saturated brine, Inui燦(MgS 0 4), the solvent was distilled off. The residue was subjected to column chromatography on silica gel and eluted with hexane-ethyl acetate (1: 1) to give 2-benzyloxycarbonylamino-5--10-oxo-2-tetrahydrofurancarboxylic acid. 6-87 mg of 4-nitrobenzyl ester was obtained as a colorless crystal. ·
融点: 1 2 7 - 1 2 7 . 5 °C レ v B rcmー1: 3310, 1780, 1759, 1728, 1520, 1345, 1185, 1042 . max - 本品 2.07gを用ぃ実施例 1 0の方法と同様に反応処理を行なぅと題記 Mp:.. 1 2 7 - 1 2 7 5 ° C les v B r cm over 1: 3310, 1780, 1759, 1728, 1520, 1345, 1185, 1042 max - use this product 2.07g I Example 1 0 Perform reaction treatment in the same manner as in
攪拌した。 反応液に詐酸ェチルを加ぇ忻出した不溶物をろ去し、 ろ液を
濃縮乾固した。 残留物をシリカゲルを用ぃるカラムクロマトグラフィ ー に付し、へキサン—詐酸ェチル(1 : 1 )で溶出すると題記化合物(1 2) 40.1mgが得られた。 Stirred. The insoluble material that has been added to the reaction solution is added to the reaction solution, and the filtrate is filtered. Concentrated to dryness. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (1: 1) to give 40.1 mg of the title compound (12).
1 R cm"1 : 3375· 1805· 17 0, 1525 *" " 1 R cm " 1: 3375 · 1805 · 17 0, 1525 *""
MR (90MHz, C D C 13) δ: 2.20 - 3.40(4H, m) .3.75(3H, s>, .15(1H, ni),4.75(2H,m),5.13(2H,s)(5.45(lH,bd),7.34(5H,s) ' MR (90MHz, CDC 1 3) δ: 2.20 - 3.40 (4H, m) .3.75 (3H, s>, .15 (1H, ni), 4.75 (2H, m), 5.13 (2H, s) (5.45 ( lH, bd), 7.34 (5H, s) ''
(b)、 トリフェニルホスフィ ン 8 2 mgぉょぴ 2 , 2 '—ジビリジルジスル フィ ド 7 0 mgのジクロロメタ ン 8 溶液を窒素気流中室温で 5分間攪拌 後塩化銀 2 9 0 mgぉょぴ 3 , 4—ジヒ ドロ— 2 H—ピリ ド [ 1 , 2— a]ピ リ ミ ジン— 2—ォン 154mgを加ぇ 5分間攙拌した。 っぃで(4 R)— 4— べンジルォキシカルボニル加ぇ 2 0時間反応した。反応液を濃縮し、残留 物をシリカゲルを用ぃるカラムクロマトグラフィ ーに付し、へキサンー 詐酸ェチル(1 : 1 )で溶出すると題記化合物(.1' 2)3 Omgが得られた。 (e)、 (4 R)- 4—べンジルォキシカルボニルァミ ノ — 3—ィソキサゾ リ ジノ ン 7 4 mg,化合物( 1 0) 5 0 mgぉょび 1 ーェトキシカルボニル― 2—ェトキシー 1 , 2—ジヒ ドロキノ リ ン 9 4 mgのジクロロメ タ ン 8¾ή を窒素気流中で 1 8時間攪拌した。 前記(d)と同様に後処理すると題記 化合物( 2) 1 1 l mgが得られた。 (b), triphenylphosphine 82 mg 2, 2'-dipyridyl disulfide 70 mg of dichloromethane 8 solution was stirred at room temperature for 5 minutes in a nitrogen stream, and silver chloride 29.0 mg was added. 154 mg of 3,4-dihydro-2H-pyrido [1,2-a] pyrimidine-2-one was added and stirred for 5 minutes. The mixture was reacted with (4R) -4-benzyloxycarbonyl heating for 20 hours. The reaction solution was concentrated, and the residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (1: 1) to give the title compound (.1 ′ 2) 3 Omg. (e), (4R) -4—benzyloxycarbonylamino—74 mg of 3-isoxazolidinone, 50 mg of compound (10) 50 mg, 1-ethoxycarbonyl-2-ethoxy 1,2-Dihydroquinoline (94 mg) and dichloromethane (8¾ή) were stirred in a nitrogen stream for 18 hours. Post-treatment was carried out in the same manner as in the above (d) to obtain 11 mg of the title compound (2).
実施例 1 3 Example 13
2—クロロ一 5—ォキソ一 2—テトラヒ ドロフランカルボン酸 メチ ルェステル [化合物(1 3)]の製造: Preparation of methyl 2-chloro-5-oxo-2-tetrahydrofurancarboxylate [Compound (13)]:
(a)、 実施例 1 0で得た化合物( 1 0 ) 8 0 mg, ト リ フヱニルホスフィ ン I 3 1 mgぉょび四塩化炭素 の混合物を窒素気流中で 4時間加熱還流 した。 溶媒を留去し、 残留物をシリカゲルを用ぃるフラ 'ソシュクロマ ト グラフィ ーに付し、 へキサンー詐酸ェチル(1 : 2)で溶出すると題記化
合物(1 3)4 6 mgが無色桔晶として得られた。 (a) A mixture of 80 mg of the compound (10) obtained in Example 10, 1 mg of triphenylphosphine I and 1 mg of carbon tetrachloride was heated under reflux in a nitrogen stream for 4 hours. The solvent was distilled off and the residue was subjected to silica gel chromatography using silica gel, eluting with hexane-ethyl acetate (1: 2) to give the title. 46 mg of the compound (13) was obtained as a colorless crystal.
融点: 5 0.5— 5 1 .0。C Melting point: 50.5-51.0. C
I R ^ ί m^a?x Γ cm-1 : 1820, 1750, 1175, 1160, 1100, 1075 IR ^ ί m ^ a? X Γ cm -1 : 1820, 1750, 1175, 1160, 1100, 1075
N MR (90MHz, CD C13)S : 2.40 - 3.23(4H, m) , 3.90(3H, s) N MR (90MHz, CD C1 3 ) S: 2.40-3.23 (4H, m), 3.90 (3H, s)
元素分圻値: CeH7C 10+ Elemental Ki value: C e H 7 C 10 +
計算値 C ,40.36; H.3.95 Calculated value C, 40.36; H.3.95
実測値 C ,40.35; H ,3.94 Found C, 40.35; H, 3.94
(b)、 化合物( 1 0 )1.0gのジクロロメタ ン 1 0 溶液にチォニルクロ リ ド 9 1 1 βぉょぴジメチルホルムァミ ド 1滴を加ぇ室温で 1 5時間擡 拌した。 反応液を濃縮し、 残留物をシリカゲルを用ぃるフラツシュクロ マトグラフィ ーに付し、 へキサン—詐酸ェチル(1 : 2)で溶出すると題 記化合物( 1 3 ) 9 8 5 mgが得られた。 · (b) To a solution of 1.0 g of the compound (10) in 10 g of dichloromethane, 1 drop of thionyl chloride 911 β-dimethylformamide was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, the residue was subjected to flash chromatography using silica gel, and eluted with hexane-ethyl acetate (1: 2) to obtain 985 mg of the title compound (13). Was. ·
実施例 1 4 · , ' (4 R)— 2— (4—べンジルォキシカルボニルァ ミ ノ ー 3—ォキソー 2—ィソキサゾリ ジニル)ー 5—ォキソ一 2—テ トラヒ ドロフランカル ボン酸 メチルェステル [化合物( i 2 )]の製造: Example 1 4 ·, '(4R) —2- (4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl) -5-oxo-1 2-tetramethylhydrofurancarbonate methylester [compound ( i 2)] Production:
( 4 R )— 4—べンジルォキシカルボニルァ ミ ノ — 3—ィソキサゾリ ジ ノ ン 2 3 6 mgのジメチルホルムァミ ド 3¾ώ溶液に炭酸セシゥム 3 2 6 mg を加ぇ、 室温で 2 0分間攪拌した。 っぃで実施例 1 3で得た化合物 (1 3) 1 7 9 mgを加ぇ 2時間攪拌した。 反応液に希食塩水を加ぇ酢酸ェ チルで抽出した。 有機層は飽和食塩水で洗浄し、 乾燥(Na2S C )後、 溶媒を留去した。 残留物をシリカゲルを用ぃるカラムクロマトグラフィ ーに付し、 へキサンー詐酸ェチル( 1 : 1 )で溶出すると題記化合物(1 2) 1 0 l mgが得られた。 本品は実施冽 1 2で得た化合物(1 2)と I Rぉょ び NMRスぺク トルが完全にー致した。
実施例 1 5 (4R) —4-Benzyloxycarbonylamino—3-isoxazolidinone To a solution of 236 mg of 236 mg of dimethylformamide, add 326 mg of cesium carbonate to the solution at room temperature for 20 minutes Stirred. 179 mg of the compound (13) obtained in Example 13 was heated and stirred for 2 hours. Dilute saline was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried (Na 2 SC), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (1: 1) to obtain 10 lmg of the title compound (12). This product showed complete agreement between the compound (12) obtained in the experiment and the IR spectrum and NMR spectrum. Example 15
2—クロロ一 5—ォキソー 2—テトラヒ ドロフランカルボン酸 4— ニト'ロべンジルェステル [ィ匕合物(1 5)]の製造: Preparation of 2-chloro-1-5-oxo-2-tetrahydrofurancarboxylic acid 4-nitto-robengilester [I-Dai-Dai (15)]:
実施例 1で得た化合物(1 )0.40gの 1 , 2—ジクロロ タン -1 6¾£溶液 にチォニルクロリ ド 0.88¾fiを加ぇ 1 0時間加熟還流した。 溶媒を留去し、 残留物をシリカゲルを用ぃるカラムクロマトグラフィーに付し、 へキサ ン—詐酸ェチル(3: 1:)で溶出すると題記化合物(1 5)0.36gが無色油状 物として得られた。 To a solution of 0.40 g of the compound (1) obtained in Example 1 in 1,6-dichlorotan- 16 チ was added 0.88¾fi of thionyl chloride, and the mixture was ripened and refluxed for 10 hours. The solvent was distilled off, and the residue was subjected to column chromatography using silica gel. Elution with hexane-ethyl acetate (3: 1 :) gave 0.36 g of the title compound (15) as a colorless oil. Obtained.
I R ^ max at cm-1: 1815, 1760, 1520, 1340, 1160, 1080 .IR ^ max at cm -1 : 1815, 1760, 1520, 1340, 1160, 1080.
NMROOMHz, CD Cl3)<5: 2.8(4H, m) , 5. 3(2H, s) , 7.60(2H,d, J =NMROOMHz, CD Cl 3 ) <5: 2.8 (4H, m), 5.3 (2H, s), 7.60 (2H, d, J =
9Hz),8.30(2H(d, J = 9Hz) 9Hz), 8.30 (2H ( d, J = 9Hz)
マススぺク トル niZe: 3 0 1 , 2 9 9 (Μ+ ) Mass vector niZe: 3 0 1, 2 9 9 (Μ + )
実施例 1 6 Example 16
(4 R)- 2 - (4—べンジルォキシカルボニルァミ ノ一 3—ォキソ一 2ーィソキサゾリ ジニル)一 5—ォキソー 2—テトラヒ ドロフランカル ボン酸 4一二トロべンジルェステル [化合物(8)]の製造: (4R) -2- (4-benzyloxycarbonylamino-3-oxo-1-2-isoxazolidinyl) -1-5-oxo-2-tetrahydrofuran carboxylate 4-nitrobenzene diester [Compound (8)] Manufacturing:
( 4 R )— 4—べンジルォキシカルボニルァミ ノ 一 3—ィソキサゾリ ジ ノ ン 6 0 mgをジクロロメタン 4 ¾2に溶解し、 氷冷下ジィソプロピルェチ ルァミ ン 0.08»ώと実施例 1 5で得た化合物( 1 5)9 0 mgのジクロロメタ ン 1¾£溶液を加ぇた。 氷冷下 1 5分間攪拌後、 室温で 3 0分間攙拌した ( 反応液を水洗後、 乾燥(Na2S C )し、 溶媒を留去した。 残留物をシリ カゲルを用ぃるカラムクロマトグラフィーに付し、 へキサン一酢酸ェチ ル(1 : 1 )で溶出すると題記化合物(8 )7 1 mgが無色泡状物として得ら . れた。 本品は実施例 8で得た化合物(8 )と I Rぉょぴ NMRスぺク トル がー致した。
実施例 1 7 60 mg of (4R) —4-benzyloxycarbonylamino-3-isoxazolidinone was dissolved in dichloromethane 42, and the mixture was dissolved in ice-cooled diisopropylethylamine 0.08 »ώ and Example 1. A solution of 90 mg of the compound (15) obtained in 5 in dichloromethane was added. After stirring for 15 minutes under ice-cooling, the mixture was stirred at room temperature for 30 minutes (the reaction solution was washed with water, dried (Na 2 SC), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel. After eluting with hexane monoacetate (1: 1), 71 mg of the title compound (8) was obtained as a colorless foam. 8) and the IR spectrum NMR spectrum were matched. Example 17
(4 R)— 2— {4— [2— (2—ァミノ 一 4ーチァゾリル)一(Z)— 2 - (メ トキシィミノ)ァセトァミ ド]— 3—ォキソ一 2—ィソキサゾリ ジニ ル}— 5—ォキソ一 2—テトラヒ ドロフランカルボン酸 ナトリゥム塩 [化 合物(1 7)]の製造: (4 R) —2— {4— [2 -— (2-amino-4-thiazolyl) -1- (Z) —2- (methoximino) acetamide] —3-oxo-1 2-isoxazolidinyl} —5-oxo Preparation of sodium 2-tetrahydrofurancarboxylate [Compound (17)]:
実施例 8で得た化合物(8 ) 2 2 Omgを詐酸ェチル と PH7.0り.ん酸 緩衝液 7.5; ^混液に溶解し、 1 0 %パラジゥムー炭素 2 2 0 ragを加ぇ、 水素気流中.氷冷下 9 0分間攪拌した。 触媒をろ去し水洗後、 ろ液と洗 液を合ゎせ水層を分取した。 水層にテトラヒ ドロフラン を加ぇ、 氷 冷,攪拌下に炭酸水素ナトリゥム 1 1 Omgぉょび 2—(2 -ク口ロァセト ァミ ド一 4—チァゾリル)一(Ζ)— 2—メ トキシィミノ詐酸クロリ ド 塩酸塩 1 9 5mgを加ぇた。 反応液を 3 0分間攪拌後、 N—メチルジチォ カルバミ ン酸ナトリゥム 1 1 Omgを加ぇ、 室温で 3 0分間攪拌した。 減 圧下にテトラヒ ドロフランを留去し、 濃縮液を酢酸ェチルで'^浄後、 . . HP— 2 0カラムで精製した。 水で溶出される画分を凍桔乾燥し、 題記 化合物( 1 7) 1 0 7 mgを白色粉末として得た。 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- (Ζ)-2-methoxyoximino 195 mg of acid chloride hydrochloride was added. After stirring the reaction solution for 30 minutes, 11-Omg of sodium N-methyldithiocarbamate was added, and the mixture was stirred at room temperature for 30 minutes. The tetrahydrofuran was distilled off under reduced pressure, and the concentrate was purified with ethyl acetate and then purified using a .HP-20 column. The fraction eluted with water was freeze-dried to obtain 107 mg of the title compound (17) as a white powder.
I R ^ x T cm-1: 1775, 1720, 1650. 1530, 1380, 1190, 1035 MR(90MHz,D2O)(5: 2.6 - 3.5(4H, m) , 4.23(3H, s) , 4.6(1H , m) , 5.0 IR ^ x T cm -1: 1775 , 1720, 1650. 1530, 1380, 1190, 1035 MR (90MHz, D 2 O) (5: 2.6 - 3.5 (4H, m), 4.23 (3H, s), 4.6 ( 1H, m), 5.0
(lH,m)5.4(lH(m),7.28(lH.s) (lH, m) 5.4 (lH ( m), 7.28 (lH.s)
元素分折'値: C 1 + H1 + N5Na08S · 1.5H20 Elemental analysis' value: C 1 + H 1 + N 5 Na0 8 S · 1.5H 20
計算値 C .36.37; H ,3.71; N ,15.15 Calculated C. 36.37; H, 3.71; N, 15.15
実測値 C .36.29: H ,3.58; N ,15.04 Found C.36.29: H, 3.58; N, 15.04
実施例 1 8 ' Example 18 '
(4 S)— 2 - (4—べンジルォキシカルボニルァミ ノ ― 3—ォキソ一 2—ィソキサゾリ ジニル)一 5—ォキソ一 2—テ トラヒ ドロフランカル
― ボン酸 4—ニトロべンジルェステル [化合物(9)]の製造: (4 S) — 2-(4-benzyloxycarbonylamino-3--3-oxo-2-isoxazolidinyl) -1-5-oxo-1 2-tetrahydrofurancal -Production of 4-Nitrobenzyldiester borate [Compound (9)]:
参考例 4で得た(4 S)- 4ーべンジルォキシカルボニルァミノィソキ サゾリジノ ン 1 1 8mgをジクロロメタン 5¾£に溶解し、 氷冷,攙拌下ト リェチルァミ ン 0.14¾£と実施例 1で得た化合物(1 )レ 6 0 mg ジクロロ メタン 1 ¾β溶液を加ぇた。反応液を室温で 3 0分間攙 後、 水洗,乾燦 (Na2S 0+)し、溶媒を留去した。 残留物をシリカゲルを用ぃるカラムク ロマトグラフィーに付し、 へキサンー酢酸ェチル(1 : 1 )で溶出すると 題記化合物 1 3 5 mgが無色泡状物として得られた。 本品の I Rぉょぴ N MRスぺク トルは実施例 9で得た化合物(9)のそれらとー致じた。 Example 4 118 mg of (4S) -4-benzyloxycarbonylaminosoxosazolidinone obtained in Reference Example 4 was dissolved in 5¾ of dichloromethane, and 0.14¾ £ 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 ク ロ ロ β 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. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (1: 1) to obtain 135 mg of the title compound as a colorless foam. The IR spectrum of this product was similar to that of the compound (9) obtained in Example 9.
実施例 1 9 Example 19
(4 S)— 2—(4一 [2— (2—ァミノ一 4—チァゾリル)一(Z)— 2 - (メ トキシィミノ)ァセトァミ ド]— 3—ォキソ一 2—ィソキサゾリジニ ル}一 5—ォキソ— 2—テトラヒ ドロフランカルボン酸 ナトリゥム塩 [化合物(1 9)]の製造: (4 S) — 2— (4—1—2— (2—amino1—4—thiazolyl) -1 (Z) —2— (Methoxyimino) acetamide] —3—oxo1—2—isoxazolidinyl} 1—5—oxo — Preparation of sodium tetrahydrofurancarboxylate [Compound (19)]:
実施例 9で得た化合物(9) 1 2 5mgを詐酸ェチル と PH7.0りん酸 125 mg of the compound (9) obtained in Example 9 was mixed with ethyl acetate and PH7.0 phosphate
-緩衝液 6 混液に溶解し、 1 0 %パラジゥムー炭素 1 2 5mgを加ぇ、 水 素気流中、 氷冷下 1時間攪拌した。 触媒をろ去し、 水洗後、 ろ液と洗液 'を合ゎせ水層を分取した。 水層にテ トラヒ ド口フラン を加ぇ、 氷冷, 攪拌下に炭酸水素ナトリゥム 63mgと 2— (2—クロロァセトァミ ドー 4一 チァゾリル)—(Z)— 2—メ トキシィミ ノ酢酸クロリ ド 塩酸塩 102mgを 加ぇた。 反応液を 2 0分間攙拌後、 N—メチルジチォカルバミ ン酸ナト リゥム 5 7 mgを加ぇ、 室温で 4 0分間攙拌した。 減圧下にテトラヒ ドロ フランを留去し、 濃縮液を酢酸ェチルで洗浄後、 HP— 2 0カラムで精 製した。 水で溶出される画分を凍桔乾燦し、 題記化合物(1 9)7 Omgを 白色粉末として得た。 本品の I Rぉょび NMRスぺク トルは実施例 1 7 で得た(4 R)型の化合物(1 7)のそれらと一致した。
元素分析値: C 1 + H1 + N5Na08S · 1.5H20 -Dissolved in a mixed solution of 6 buffer solutions, added 125 mg of 10% paradigmum carbon, and stirred in a stream of hydrogen for 1 hour under ice cooling. After removing the catalyst by filtration and washing with water, the filtrate and the washing solution were combined to separate an aqueous layer. To the aqueous layer is added tetrahydrofuran, ice-cooled, and stirred, with 63 mg of sodium hydrogencarbonate and 102 mg of 2- (2-chloroacetamido-4-thiazolyl)-(Z) -2-methoxymethoxyacetate chloride hydrochloride. Was added. After stirring the reaction solution for 20 minutes, 57 mg of sodium N-methyldithiocarbamate was added, and the mixture was stirred at room temperature for 40 minutes. Tetrahydrofuran was distilled off under reduced pressure, and the concentrated solution was washed with ethyl acetate and purified with an HP-20 column. The fraction eluted with water was lyophilized to give 7 Omg of the title compound (19) as a white powder. The IR spectrum and NMR spectrum of this product were consistent with those of the compound (17) of the (4R) type obtained in Example 17. Elemental analysis: C 1 + H 1 + N 5 Na0 8 S · 1.5H 2 0
計算値 C ,36.37; H.3.71; N.15.15 Calculated C, 36.37; H.3.71; N.15.15
実測値 C.36.59: H.,3.85; N ,15.31 Found C.36.59: H., 3.85; N, 15.31.
実施例 2 0 Example 20
1 —べンジル 水素 2—ォキソグルタレー ト [化合物(20)]の製造: Production of 1-benzyl hydrogen 2-oxoglutarate [Compound (20)]:
2—ォキソグルタル酸 2.92gを無水ジメチルホルムァミ ド 2 0¾βに溶 解し、 ジシクロへキシルァミ ン 3.63gとべンジルブロミ ド 2.61¾£を加ぇ、 室温で 2時間攙拌した。 反応液に酢酸ェチルを加ぇ圻出した結晶をろ去 した。 ろ液を水洗後、 乾燥(Na2S C )し、 溶媒を留去した。 残留物を シリカゲルを用ぃるカラムクロマトグラフィ 一に付し、 へキサン— 酸 ェチルー詐酸(5 0 : 5 0 : 1 )で溶出すると題記化合物(2 O)3.20gが無 、 色結晶として得られた。 ェーテルーへキサンから再锆晶すると無色 リ ズム晶が得られた。 融点: 5 1 — 5 2°C 2.92 g of 2-oxoglutaric acid was dissolved in 20% β-dimethylformamide, 3.63 g of dicyclohexylamine and 2.61 g of benzyl bromide were added, and the mixture was stirred at room temperature for 2 hours. Crystals obtained by adding ethyl acetate to the reaction solution were filtered off. The filtrate was washed with water and dried (Na 2 SC), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate-citric acid (50: 50: 1) to give 3.20 g of the title compound (2O) as colorless crystals. Was. Crystallization from ether hexane gave colorless rhythmic crystals. Melting point: 5 1-5 2 ° C
I R m!ax。1 cm"1: 1740, 1705,.1270, 1090, 1040 . IR m! Ax. 1 cm " 1 : 1740, 1705, .1270, 1090, 1040.
N MR (90MHz. C D C 13) 5 : 2.67(2H, t , J = 6Hz) , 2.97(2H. m) , 5.26(2H, s),7.35(5H,s),8.9(lH,b) N MR (90MHz CDC 1 3. ) 5: 2.67 (2H, t, J = 6Hz), 2.97 (. 2H m), 5.26 (2H, s), 7.35 (5H, s), 8.9 (lH, b)
元索分折値: C 12H 1205 Original rope split value: C 12 H 12 0 5
計算値 C.61.01; H.5.12 Calculated value C.61.01; H.5.12
実測値 C ,61.02; H.5.12 Found C, 61.02; H.5.12
実施例 2 1 Example 2 1
1 — (4ーニトロべンジル) 水素 4—メチル— 2—ォキソ—グルタ レ― ト [化合物(2 1 )]の製造: Preparation of 1- (4-nitrobenzyl) hydrogen 4-methyl-2-oxo-glutarate [Compound (21)]:
4—メチル— 2—ォキソグルタル酸 0.74gを無水ジメチルホルムァミ ド 6 に溶解し、 ジシクロへキシルァミ ン 0.93¾βと 4—ニトロべンジル ブロミ ド l.Ogを加ぇ、 室温で 1 4時間攪拌した。 反応液に詐酸ェチルを
加ぇ折出した結晶をろ去した。 ろ液を水洗,乾燥(Na2S C )後、 溶媒を 留去した。 残留物をシリカゲルを用ぃるカラムクロマトグラフィ一に付 し、 へキサンー酢酸ェチル(1 : 1— 1 : 3)で溶出すると題記化合物 0.74 g of 4-methyl-2-oxoglutaric acid was dissolved in anhydrous dimethylformamide 6, 0.93 シ ク ロ β of dicyclohexylamine and l.Og of 4-nitrobenzyl bromide were added, and the mixture was stirred at room temperature for 14 hours. . Ethyl acid in the reaction solution The heated crystals were filtered off. After the filtrate was washed with water and dried (Na 2 SC), the solvent was distilled off. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (1: 1-1: 3) to give the title compound.
(2 1 )0.66gが淡黄色油状物として得られた。 I R i,®at cm : 1780- 1700. 1520. 1345, 1220, 1170 ー 0.62 g of (21) was obtained as a pale yellow oil. IR i, ® at cm: 1780-1700.1520.1345, 1220, 1170 ー
max max
NMR (90MHz. CD C 13) <5 : 1.32(3H, d, J = 6Hz) , 2.2 - 3.3(3H, m) , NMR (90MHz CD C 1 3. ) <5: 1.32 (3H, d, J = 6Hz), 2.2 - 3.3 (3H, m),
5.38(2H,s).6.0(lH(b),7.55(2H,d,J = 9Hz),8.22(2H,d> J = 9Hz) 実施例 2 2 ' 5.38 (2H, s) .6.0 (lH ( b), 7.55 (2H, d, J = 9Hz), 8.22 (2H, d > J = 9Hz)
2—クロロ一 4ーメチルー 5—ォキソ一 2—テトラヒ ドロフラン ル ボン酸 4—ニトロべンジルェステル [化合物(2 2)]の製造: Preparation of 2-nitro-1-methyl-5-oxo-2-tetrahydrofuran sulfonic acid 4-nitrobenzyl ester [Compound (22)]:
実施例 2 1で得た化合物(2 1 )0.13gの 1 , 2—ジクロロェタン 5 ^の 溶液にチォニルク c J ド 0.13¾£を加ぇて 9 0分間加熱還流した。 溶媒を 留去し残留物をシリカゲルを用ぃるヵラムクロマトグラフィーに付し、 へ サンー詐酸ェチル(3: 1 )で溶出すると題記化合物(2 2)0.11gが無 色油状物として得られた。 To a solution of 0.13 g of the compound (21) obtained in Example 21 in 1,2-dichloroethane 5 ^ was added 0.13 kg of thionyl cJ, and the mixture was heated under reflux for 90 minutes. The solvent was distilled off, and the residue was subjected to column chromatography using silica gel, and eluted with ethyl acetate (3: 1) to give 0.11 g of the title compound (22) as a colorless oil. Was.
1 R ^ ^^^m-1 : 1810 , 1755. 1600, 1520, 1345, 1165, 1070, 1010 max 1 R ^ ^^^ m- 1 : 1810, 1755.1600, 1520, 1345, 1165, 1070, 1010 max
N R (90MHz, C D C 13)5: 1.35(1.5H, d, J = 6Hz) , 1.47(1.5H, d, J = 6 Hz)(2.3-3.5(3H>m) ,5.42(2H,s),7.59C2H,d,J = 9Hz),8.25(2H(d, J = 9 Hz) NR (90MHz, CDC 1 3) 5: 1.35 (1.5H, d, J = 6Hz), 1.47 (1.5H, d, J = 6 Hz) (2.3-3.5 (3H> m), 5.42 (2H, s) , 7.59C2H, d, J = 9Hz), 8.25 (2H ( d, J = 9 Hz)
実施例 2 3 Example 23
(4 S )- 2 - (4—べンジルォキシカルボニルァミ ノ ー 3—ォキソ― (4 S)-2-(4-benzyloxycarbonylamino 3-oxo
2—ィソキサゾリジニル)一 4ーメチルー 5—ォキソ一 2—テトラヒ ド ロフランカルボン酸 4ーニトロべンジルェステル [化合物(2 3)]の製 造: Preparation of 2- (4-isoxazolidinyl) -1-methyl-5-oxo-2-tetrahydrofurancarboxylic acid 4-nitrobenzyl ester [Compound (23)]:
参考例 4で得た( 4 S )— 4一べンジルォキシカルボニルァミノ一 3
ィソキサゾリジノ ン 1 1 8 mgと実施例 2 1で得た化合物(2 1 ) 1 5 0 mg を 1 , 2—ジクロロェタン 4 ¾βに溶解し、 D C C 1 6 0 mgを加ぇて 9 0 分間室温で攙拌した。 析出した結晶をろ去し、 ジクロロメタンで洗浄し た。 ろ液と洗液とを合ゎせ、 炭酸水素ナトリゥム水,水で洗浄,乾燥 (Na2S C )後、 溶媒を留去した。 残留物をシリカゲルを用ぃるカラム クロマトグラフィーに付し、 へキサンー酢酸ェチル(3: 2)で溶出する と題記化合物(2 3 ) 1 5 2 mgが無色油状物として得られた。 (4S) —4-benzoxycarbonylamino-1 obtained in Reference Example 4 Isoxazolidinone (118 mg) and the compound (21) (150 mg) obtained in Example 21 were dissolved in 1,2-dichloroethane (4β), and DCC (160 mg) was added thereto for 90 minutes at room temperature. Stirred. The precipitated crystals were removed by filtration and washed with dichloromethane. The filtrate and the washing solution were combined, washed with aqueous sodium hydrogen carbonate and water, dried (Na 2 SC), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (3: 2) to obtain 152 mg of the title compound (23) as a colorless oil.
I R V ^^^πι-^ΠΘδ,. 1760- 1700, 1520, 1450, 1345, 1260, 1180,· . max I R V ^^^ πι- ^ ΠΘδ ,. 1760-1700, 1520, 1450, 1345, 1260, 1180, .max
1080. 1010 . N MR (90MHz, CD Cl3)5 : 1.27(3H,d, J = 8Hz) , 2.0(1H. m) , 2.7 - 3.51080.1010 .N MR (90MHz, CD Cl 3 ) 5: 1.27 (3H, d, J = 8Hz), 2.0 (1H.m), 2.7-3.5
(2H,m)>4.1(lH)m),4.7(2H,m),5.10(2H,s)I5.35(2H,s)I7.33(5H)s),(2H, m) > 4.1 (lH ) m), 4.7 (2H, m), 5.10 (2H, s) I 5.35 (2H, s) I 7.33 (5H ) s),
7.55(2H,d, J = 9Hz).8.22(2H,d, J = 9Hz) 7.55 (2H, d, J = 9Hz) 8.22 (2H, d, J = 9Hz)
マススぺク トル mZe: 5 1 3 (M+ ) Mass vector mZe: 5 1 3 (M + )
実施例 2 4 ' Example 2 4 ′
化合物(2 3)の製造: ' Preparation of compound (23): ''
参考例 4で得た( 4 S )— 4—べンジルォキシカルボニルァミ ノ — 3— ィソキサゾリジノ ン 5 5mgをジクロロメタン に溶解し、 氷冷.攪拌 下トリェチルァミ ン 0.07»ώと実施例 2 2で得た化合物(2 2 ) 8 0 mgのジ クロロメタン 1.5? ^溶液を加ぇた。 反応液を室温で 1時間攪拌後、 水洗, 乾燥(Na2S O+)し、 溶媒を留去した。 残留物をシリカゲルを用ぃるカ ラムクロマトグラフィ ーに付し、 へキサン—酢酸ェチル(3 : 2)で溶出 すると題記化合物(2 3 ) 7 8 mgが無色油状物として得られた。 本品の I Rぉょび NMRスぺク トルは実施例 2 3で得た化合物(2 3)のそれらと ー致した。 55 mg of the (4S) -4-benzyloxycarbonylamino-3-3-isoxazolidinone obtained in Reference Example 4 was dissolved in dichloromethane, and the mixture was cooled with ice and stirred to obtain a mixture of triethylamine 0.07 »ώ in Example 22. A solution of 80 mg of the obtained compound (22) in 1.5 mM dichloromethane was added. The reaction solution was stirred at room temperature for 1 hour, washed with water and dried (Na 2 SO + ), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (3: 2) to give 78 mg of the title compound (23) as a colorless oil. The IR spectrum and NMR spectrum of this product corresponded to those of the compound (23) obtained in Example 23.
実施例 2 5
(4 S)- 2— {4— [2— (2—ァミノ一 4—チァゾリル)一(Z)— 2—Example 2 5 (4 S)-2— {4— [2— (2-amino-1 4-thiazolyl) -1 (Z) — 2—
(メ トキシィミノ)ァセトァミ ド]— 3—ォキソー 2—ィソキサゾリジニ ル}— 4—メチル一 5—ォキソ一 2—テトラヒ ドロフランカルボン酸 ナトリゥム塩 [化合物(2 5)]の製造: (Methoxyimino) acetamide] — 3-oxo-2-isoxazolidinyl} —4-methyl-15-oxo-2-tetrahydrofurancarboxylic acid sodium salt [Compound (25)]
実施例 2 3で得た化合物(2 3 ) 2 2 5 mgを酢酸ェチル 5 ¾βと pH7.0り ん酸緩衝液 7.5¾JZに溶解し、 1 0 %パラジゥムー炭素 2 2 5 mgを加ぇ、 水素気流中、 氷冷下 7 5分間攪拌した。 触媒をろ去し水洗後、 ろ液と洗 液を合ゎせ水層を分取.した。 水層にテ_トラヒ ドロフラン 5»ώを加ぇ、 氷.. 冷,攙拌下に炭酸水素ナトリゥム 1 1 Omgぉょぴ 2—(2—クロ'ロァセト ァミ ド— 4—チァゾリル)一(Z )— 2—メ トキシィミ ノ舴酸ク σリ ド 塩酸塩 1 8 Omgを加ぇた。 反応液を 3 0分間攪拌後、 N—メチルジチォ- カルバミ ン酸ナトリゥム 1 0 Omgを加ぇ、 室温で 4 5分間攙拌した。 滅 圧下にテトラヒ ドロフランを留去し、 濃縮液を詐酸ェチルで洗净後、 H P— 2 0カラムで精製した。 水で溶出される画分を凍結乾 し、 題記 化合物(2 5) 1 0 6mgを白色粉末として得た。 25 mg of the compound (23) obtained in Example 23 was dissolved in 5-β-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 ド ロ to the aqueous layer, and ice .. Cool and stir sodium bicarbonate 11 1 Omg ぴ 2- (2-chloroacetamide 4- thiazolyl) 1 ( Z) —2-Methoxyimidino acid σ-lide hydrochloride (18 Omg) was added. After stirring the reaction solution for 30 minutes, sodium N-methyldithio-carbamate (10 Omg) was added, and the mixture was stirred at room temperature for 45 minutes. Tetrahydrofuran was distilled off under reduced pressure, and the concentrate was washed with ethyl acetate and purified with a HP-20 column. The fraction eluted with water was freeze-dried to obtain 106 mg of the title compound (25) as a white powder.
I R ^ 1 cm-1 : 1775, 1720, 1660, 1530, 1380, 1200, 1030 IR ^ 1 cm -1 : 1775, 1720, 1660, 1530, 1380, 1200, 1030
max · max ·
MR(90MHz,D2O)<5: 1.4(3H, m) , 2.3(1H. n) , 2.9 - 3.7(3H, m) .4.12 MR (90MHz, D 2 O) <5: 1.4 (3H, m), 2.3 (. 1H n), 2.9 - 3.7 (3H, m) .4.12
(3H,s),4.5(lH>m),4.9-5.5C2H,ni)>7.17(lH>-s) (3H, s), 4.5 (lH > m), 4.9-5.5C2H, ni) > 7.17 (lH > -s)
元素分折値: C 15H 18N5NaO 8S ♦ H20 Elemental folding value: C 15 H 18 N 5 NaO 8 S ♦ H 2 0
計算値 C,38.55; H.3.88; N.14.98 Calculated C, 38.55; H.3.88; N.14.98
実測値 C ,38.56; H ,3.89; N.H.66 Found C, 38.56; H, 3.89; N.H.66
実施例 2 6 Example 26
2—ブロモ一 2 , 5—ジヒ ドロー 5—ォキソ一 2—フランカルボン酸 メチルェステル [化合物(2 6)]の製造: Preparation of 2-bromo-1,2,5-dihydro-5-oxo-1,2-methylfurancarboxylate [Compound (26)]:
5 —ァセ トキシー 2—フランカルボン酸 メチルェステル 1 8 4 mgを
ジクロロメタン 4^に溶解し、 臭素 0.045?^を含むジクロロメタン 1 ¾i 溶液を徐々に加ぇた。 反応液を室温で 3 0分間摟拌後、 溶媒ぉょぴ副生 したァセチルブロ ミ ドを減圧下に留去すると題記化合物(2 6 ) 2 2 0 mg が淡黄色油状物として得られた。 I R ^ i miaxvat era"1: 1805, 1760, 1435, 1265, 1.210, 1105, 0 5—Acetoxy-2-methyl furancarboxylate 18 4 mg Dissolved in 4 ^ dichloromethane and slowly added a 1 ^ i solution of dichloromethane containing 0.045 ^^ of bromine. After the reaction solution was stirred at room temperature for 30 minutes, acetyl bromide produced as a by-product in the solvent was distilled off under reduced pressure to obtain 220 mg of the title compound (26) as a pale yellow oil. IR ^ i miaxv at era " 1 : 1805, 1760, 1435, 1265, 1.210, 1105, 0
N MR (90MHz, CD Cl3)<5 : 3.88(3H, s) , 6.27(lH,d, J = 6Hz) , 7.82 N MR (90MHz, CD Cl 3 ) <5: 3.88 (3H, s), 6.27 (lH, d, J = 6Hz), 7.82
(lH.d, J = 6Hz) (lH.d, J = 6Hz)
実施例 2 7 Example 2 7
2—クロロ一 2 , 5—ジヒ ドロ一 5—ォキソ一 2—フランカルボン酸 メチルェステル [化合物(2 7)]の製造: Production of methyl 2-chloro-1,2,5-dihydro-5-oxo-2-methylfurancarboxylate [Compound (27)]:
5—ァセ トキシ一 2—フランカルボン酸 メチルェステル 1 8 4 mgを ジク σロメタ ン 4¾£に溶解し、 塩素含有四塩化炭素(2乇ル)溶液 を加ぇ、 室温で 3 0分間攙拌した。 溶媒ぉょび副生したァセチルクロリ ドを減圧下に留 Ϊすると題記化合物(2 7 ) 1 7 6 mgが無色油伏物として 得られた。 レ iiat cnTl: 1810, 1760, 1440, 1270, 1210, 1100, 880 18-mg of 5-acetoxymethyl-2-furancarboxylate was dissolved in 4¾ of dimethyl lomethane, and a chlorine-containing carbon tetrachloride (2 () solution was added, followed by stirring at room temperature for 30 minutes. . The solvent and the by-produced acetyl chloride were distilled off under reduced pressure to obtain 176 mg of the title compound (27) as a colorless oily product.レ ii at cnT l : 1810, 1760, 1440, 1270, 1210, 1100, 880
NMR (90MHz, C D C 13)5 : 3.90(3H, s) , 6.13(1H, d, J = 6Hz) , 7.60(1H, d,J = 6Hz) NMR (90MHz, CDC 1 3) 5: 3.90 (3H, s), 6.13 (1H, d, J = 6Hz), 7.60 (1H, d, J = 6Hz)
実施例 2 8 Example 2 8
2—クロロ一 2.5—ジヒ ド σ— 5—ォキソ一 2—フランカルボン酸 べンジルェステル [化合物(2 8)]の製造: Preparation of 2-chloro-1-2.5-dihydro sigma-5-oxo-1-benzofuranic acid benzylester [Compound (28)]:
2—フランカルボン酸 1 0.lgを詐酸 5 0¾fiと無水酢酸 1 0a£混液に 溶解し、 内温を 7 °Cに保ち、 攪拌下、 塩素ガス 4.55gを通じた。 室温で 4 0時間静置後、 溶媒を留去し、 さらに浴温 1 7 0 °C,0.05mmHgで留出 する画分を除ぃた。 残留物をシリカゲルを用ぃるカラムク σマトグラフィ
ーに付し、へキサンー齚酸ェチル(6: 1)で溶出すると 5—ァセトキシ— 2—フランカルボン酸べンジルェステル 2.6gが無色油状物として得られ た。 j R y eat cm-i : 1770, 1 00, 1520 , 1480, 1300 , 1205, 1140, 1020 max 2-Furonic acid (10.lg) was dissolved in a mixed solution of 50 詐 fi of acetic acid and 10a £ of acetic anhydride, the internal temperature was kept at 7 ° C, and 4.55 g of chlorine gas was passed under stirring. After standing at room temperature for 40 hours, the solvent was distilled off, and the fraction distilled at a bath temperature of 170 ° C. and 0.05 mmHg was further removed. Column chromatography using silica gel for the residue σ-matography After eluting with hexane-ethyl acetate (6: 1), 2.6 g of 5-acetoxy-2-furancarboxylate benzyl ester was obtained as a colorless oil. j R y eat cm -i : 1770 , 100, 1520, 1480, 1300, 1205, 1140, 1020 max
NMROQMHz, CD C 13)5: 2.28(3H. s) , 5.30(2H, s) , 6.07ClH,d, J = NMROQMHz, CD C 1 3) 5 :. 2.28 (3H s), 5.30 (2H, s), 6.07ClH, d, J =
3Hz),7.19(lH,d, J = 3Hz),7.37(5H,s) 3Hz), 7.19 (lH, d, J = 3Hz), 7.37 (5H, s)
マススぺク トル m/e: 2 6 0 (M+ ) Mass vector m / e: 2 6 0 (M + )
本品 2 6 0 mgをジクロロメタン 4 ^に溶解し、 塩素含有四塩 匕炭素(2 乇ル)溶液 1.4? ^を加ぇ、 室温で 3 0分間攪拌した。 溶媒ぉょぴ副生した ァセチルクロリ ドを減圧下に留去すると題記化合物(2 8 ) 2 5 Omgが無 色油状物として得られた。 260 mg of this product was dissolved in 4 ^ of dichloromethane, 1.4 ^^ of a chlorine-containing tetrachloride carbon (2%) solution was added, and the mixture was stirred at room temperature for 30 minutes. The acetyl chloride by-produced in the solvent was distilled off under reduced pressure to obtain the title compound (28) 25 Omg as a colorless oil.
I R ^ iaxvat cm'1: 1810, 1760, 1260, 1210, 1100, 1060, 880 IR ^ iaxv at cm ' 1 : 1810, 1760, 1260, 1210, 1100, 1060, 880
NMR (90MHz. CD Cl3)5: 5.30(2H, s) , 6.27(1H, d, J = 6Hz) , 7. 0NMR (90 MHz. CD Cl 3 ) 5: 5.30 (2H, s), 6.27 (1H, d, J = 6 Hz), 7.0
(5H,s),7.58(lH,d, J = 6Hz) (5H, s), 7.58 (lH, d, J = 6Hz)
実施例 2 9 Example 2 9
(4 R)— 2— (4—べンジルォキシカルボニルァミ ノ ー 3—ォキソー 2—ィソキサゾリジニル)ー 5—ォキソ一 2 , 5—ジヒ ドロ一 2—フラン カルボン酸 メチルェステル [化合物(2 9 )]の製造: (4 R) — 2- (4-benzyloxycarbonylamino-3-oxo-2-isoxazolidinyl) -5-oxo-1,2,5-dihydro-1-methylfuran carboxylate [Compound (2 9)] Production:
( 4 R )— 4—べンジルォキシカルボニルァミ ノ— 3—ィソキサゾリジ ノ ン 24 0 mgをジクロロメタン 2 5 に溶解し、 氷冷,攪拌下トリェチ ルァミ ン 0.25¾fiと実施例 2 6で得た化合物(2 6 ) 2 2 0 mgのジクロロ メ夕ン 2 ^溶液を加ぇた。 反応液を室温で 3 0分間攪拌後、 反応液を水 洗, 乾燥(Na2S 0+)し溶媒を留去した。 残留物をシリカゲルを用ぃる カラムクロマトグラフィーに付し、 へキサン—昨酸ェチル(2: 1→ 1 : 1 )で溶出すると題記化合物(2 9) 1 5 Omgが淡黄色油伏物として得ら
れた。 240 mg of (4R) -4-benzyloxycarbonylamino-3-isoxazolidinone was dissolved in dichloromethane 25, and 0.25 ト リ fi of triethylamine was obtained in Example 26 under ice-cooling and stirring. A solution of the compound (26) (220 mg) in dichloromethane (2 ^) was added. After stirring the reaction solution at room temperature for 30 minutes, the reaction solution was washed with water, dried (Na 2 S 0 + ), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (2: 1 → 1: 1) to give 15 Omg of the title compound (29) as a pale yellow oil. La Was.
I R !^atcm_1:3350' 1810, 1770- 1710, 1530, 1260, 1080, 1040, 960, 900 IR! ^ Atcm_1 : 3350 '1810, 1770-1710, 1530, 1260, 1080, 1040, 960, 900
NMR (90MHz, CD Cl3)<5 : 3.85(3H. s) , 4.2(lH,m) , 4.8(2H,m) , 5.11NMR (90MHz, CD Cl 3 ) <5: 3.85 (3H.s), 4.2 (lH, m), 4.8 (2H, m), 5.11
(2H,s),5.4(lH)b),6.32(lH,d) J = 6Hz),7.35(5H,s),7.60(lH>d, J = 6Hz) マススぺク トル m/e: 3 7 6 (M+ ) (2H, s), 5.4 (lH ) b), 6.32 (lH, d ) J = 6Hz), 7.35 (5H, s), 7.60 (lH > d, J = 6Hz) Mass vector m / e: 3 7 6 (M +)
実施例 3 0 Example 30
(4 R)— 2— (4—フェニルァセチルァミ ノ 一 3—ォキソ一 2—ィソ キサゾリ ジニル)一 5—ォキソ一 2 , 5—ジヒ ドロー 2—フランカルボン 酸 メチルェステル [化合物(3 0)]の製造: (4R) —2— (4-Phenylacetylamino 1-3-oxo1-2-isoxazolidinyl) -1-5-oxo-1,2,5-dihydro-2-methylfurancarboxylate [Compound (30 )]Manufacturing of:
(a)、 .( 4 R )— 4—フヱニルァセチルァミ ノ 一 3—ィソキサゾリ ジノ ン 1 1 Omgをジクロロメタ ン 8 に懸蘅し、 氷冷,攪拌下トリェチルァミ ン 0.14 と実施例 .2 7で得た化合物(2 7 ) 1 0 6 mgめジク.ロロメタン 2¾fi溶液を加ぇた。 反応液を室温で 4 0分間攪拌後: 水洗,乾燥(Na2 S〇+)し、 溶媒を留去した。 残留物をシリカゲルを用ぃるカラムクロマ トグラフィ ーに付し、 へキサンー酢酸ェチル(2 : 3)で溶出すると題記 化合物(3 0 ) 7 8 mgが無色油状物として得られた。 (a),. (4R) —4-Phenylacetylamino-3-isoxazolidinone 11 Omg was suspended in dichloromethan 8, and the mixture was cooled with ice and stirred to obtain triethylamine 0.14. 106 mg of the compound (27) obtained in 27 was added to a dichloromethane solution of 2-fi. The reaction solution was stirred at room temperature for 40 minutes, washed with water and dried (Na 2 S + ), 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 78 mg of the title compound (30) as a colorless oil.
1 R
:3300. 1800, 1750, 1660, 1530, 1260, 1080, 1040, max 1 R : 3300.1800, 1750, 1660, 1530, 1260, 1080, 1040, max
900 900
NMR(90MHz, C D C 13)5: 3.59(2H. s) , 3.83(3H, s) , 4.1(1H, m) , 4.8 (2H,m),6.5(lH,b)(6.30(lH,d),7.30(5H(s)>7.53(0.5H>d) J = 6Hz), 7.60(0.5H,d, J = 6Hz), NMR (90MHz, CDC 1 3) 5: 3.59 (. 2H s), 3.83 (3H, s), 4.1 (1H, m), 4.8 (2H, m), 6.5 (lH, b) (6.30 (lH, d ), 7.30 (5H ( s) > 7.53 (0.5H > d ) J = 6Hz), 7.60 (0.5H, d, J = 6Hz),
マススぺク トル mZe: 3 6 0 (M+ ) Mass vector mZe: 3 6 0 (M + )
)、 (4 R)— 4—フェニルァセチルァミ ノ 一 3—ィソキサゾリ ジノ ン ), (4R) —4-Phenylacetylamino 3--3-isoxazolidinone
2 2 0 mgを無水ジメチルホルムァミ ド に溶解し、 氷冷,攪拌下水素
化ナトリゥム(5 0 %鉱油) 6 Omgと実施例 2 6で得た化合物(2 6) 2 2 0 mgの無水ジメチルホルムァミ ド 0.5¾£溶液を加ぇた。 反応液を 6 0分間氷冷下攪拌した後、 詐酸ェチルと水の混液中に注加した。 酢酸 ェチル層を分取し、 水洗,乾燥(Na2S 後、 溶媒を" ¾去し—た。 残留物 をシリカゲルを用ぃるカラムクロマトグラフィーに付し、 へチサンー酢 酸ェチル(2: 1 - 2 : 3)で溶出すると題記化合物(3 0 ) 3 2 mgが無色油 状物として得られた。 Dissolve 220 mg in anhydrous dimethylformamide and add ice-cooled and stirred hydrogen A solution of 60 mg of sodium bromide (50% mineral oil) and 220 mg of the compound (26) obtained in Example 26 in anhydrous dimethylformamide was added. After the reaction solution was stirred for 60 minutes under ice cooling, it was poured into a mixed solution of ethyl ethyl formate and water. The ethyl acetate layer was separated, washed with water, and dried (after Na 2 S, the solvent was removed). The residue was subjected to column chromatography using silica gel to give a mixture of ethyl acetate and ethyl acetate (2: 1). Elution with -2: 3) gave 32 mg of the title compound (30) as a colorless oil.
実施例 3 1 Example 3 1
(4 R)— 2—(4一フェニルァセチルァミノー 3—ォキソ一 2—ィソ キサゾリジニル)— 5—ォキソ一 2—テトラヒ ドロフランカルボン酸 メチルェステル [化合物(3 1 )]の製造: Preparation of (4R) —2- (4-Phenylacetylamino) 3-oxo-12-isoxazolidinyl) -5-oxo-1-methyltetrahydrofurancarboxylate Methylester [Compound (31)]:
実施例 3 0で得た化合物(3 0)3 Omgをテトラヒ ド σフラン 3 ^に溶 解し、 1 0 %パラジゥム—炭素 3 0 mgを加ぇ水案気流中,室温で 3 0分 間攪拌した。 触媒をろ去し、 テトラヒ ドロフランで洗净後、 ろ'液と洗液 を合ゎせ、 溶媒を留去した。 残留物をシリカゲルを用ぃるカラムクロマ トグラフィ ーに付し、 へキサンー詐酸ェチル(2: 3 )で溶出すると題記 化合物(3 1 ) mgが無色油状物として得られた。 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.
I R
3300, 1800, 1750, 1660, 1530, 1270, 1190, 1050 IR 3300, 1800, 1750, 1660, 1530, 1270, 1190, 1050
NMR(90MHz, C D C 13) δ: 2.3- 3.3(4H, m) , 3.57(2H, s) , 3.82(1.5H, s),3.84(1.5H>s))4.1(lH,ni)>4.8(2H,m),6.2(0.5H,b),6.4(0.5H,b)( 7.30(5H,s) NMR (90MHz, CDC 1 3) δ: 2.3- 3.3 (4H, m), 3.57 (2H, s), 3.82 (1.5H, s), 3.84 (1.5H> s)) 4.1 (lH, ni)> 4.8 (2H, m), 6.2 (0.5H, b), 6.4 (0.5H, b) ( 7.30 (5H, s)
マススぺク トル m/e: 3 6 2 (M+ ) Mass vector m / e: 3 6 2 (M + )
実施例 3 2 Example 3 2
(4 R)— 2—(4ーフェニルァセチルァミ ノ 一 3—ォキソー 2—ィソ キサゾリジニル)一 5—ォキソ一 2, 5—ジヒ ドロー 2—フランカルボン
酸 べンジルェステル [化合物(3 2)]の製造: (4 R) — 2- (4-Phenylacetylamino-3-3-oxo-2-isoxoxazolidinyl) -1-5-oxo-1,2,5-dihydro 2-furancarbone Preparation of Benzylester [Compound (32)]:
(4 R)- 4—フェニルァセチルァミノ一 3—ィソキサゾリジノ ン 2 2 Omgを無水ジメチルホルムァミ ド 3 τ/ώに溶解し、 氷冷,攙拌下水素 化ナトリゥム(5 0 %鉉油) 6 Omgを 1 0分間攙拌した 次ぃで反応液を ― 1 0てに冷却し、 攙拌下実施例 2 8で得た化合物(2 8 ) 2 5 Omgの無 水ジメチルホルムァミ ド Q.7¾£溶液を加ぇた。 反応液を同温度で 4 5分 間攪拌した後、 酢酸ェチルと水の混液中に注加した。 酢酸ェチル層を分 取し、 水洗, 乾燥(Na2S O+)後、 溶媒を留去した。 残留物をシリカゲ ルを用ぃるカラムクロマトグラフィ—に付し、 へキサンー舴酸'ェチル (2: 1 )で溶出すると題記化合物(3 2 ) 8 7 mgが無色泡状物として得 れた。 (4R) -4-Phenylacetylamino-13-isoxazolidinone 22 Omg was dissolved in anhydrous dimethylformamide 3τ / ώ, and the mixture was cooled with ice and stirred under sodium hydride (50% 6) Omg was stirred for 10 minutes. In the next step, the reaction solution was cooled to -10, and the mixture was stirred and the compound (28) 25Omg obtained in Example 28 in anhydrous dimethylformamide was obtained. Q. Add the solution. After the reaction solution was stirred at the same temperature for 45 minutes, it was poured into a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water and dried (Na 2 SO + ), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (2: 1) to give 87 mg of the title compound (32) as a colorless foam.
I R ^^ atcnTl:3300. 1800, 1760, 1660, 1530, 1260·, 1080, 1035, IR ^^ at cnT l : 3300. 1800, 1760, 1660, 1530, 1260, 1080, 1035,
900- - NMR (90MHz, CD Cl3)<5: 3. δ9(2Η, s) , 4.0 (1H, m) , 5.8(2H( m) , 5.25900--NMR (90MHz, CD Cl 3 ) <5: 3.δ9 (2Η, s), 4.0 (1H, m), 5.8 (2H ( m), 5.25
(lH>s)>5.27(lH,s),6.1(lH,b),6.2'7(lH,d) J = 6Hz),7.3(10H,s),7.50(lH > s) > 5.27 (lH, s), 6.1 (lH, b), 6.2'7 (lH, d ) J = 6Hz), 7.3 (10H, s), 7.50
(0.5H,d. J = 6Hz),7.57(0.5H,d1 J = 6Hz) (0.5H, d. J = 6Hz ), 7.57 (0.5H, d 1 J = 6Hz)
マススぺク トル mZe: 4 3 6 ( + ) Mass vector mZe: 4 3 6 ( + )
実施例 3 3 Example 3 3
(4 R)— 2— (4—フェニルァセチルァミ ノ — 3—ォキソ一 2—ィソ キサゾリ ジニル)一 5—ォキソ一 2—テトラヒ ドロフランカルボン酸 ナトリゥム塩 [化合物(3 3)]の製造: (4R) —2- (4-Phenylacetylamino-3-oxo-azoxazolidinyl) -1-5-oxo-2-tetrahydrofurancarboxylic acid sodium salt [Compound (33)] Manufacturing:
実施例 3 2で得た化合物(3 2 ) 6 8 mgを詐酸ェチル と PH7.0りん 酸緩衝液 5¾£混液に溶解し、 1 0 %パラジゥム-炭素 7 Omgを加ぇ、 水 素気流中氷冷下 2時間攪泮した。 触媒をろ去し、 水洗後、 ろ液と洗液を 合ゎせ水層を分取した。 水層を濃縮し、 濃縮液を HP - 2 0カラムで精
製した。 .5 %ェタノールで溶出される画分を凍結乾燦し、 題記化合物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.
(3 3) 1 mgを白色粉末として得た。 (33) 1 mg was obtained as a white powder.
I R V i B rcm-1:3400, 1775, 1720, 1650, 1530, 1370. 1185, 1110, max IRV i B r cm- 1 : 3400, 1775, 1720, 1650, 1530, 1370. 1185, 1110, max
1020, 965, 900 1020, 965, 900
NMR(90MHz,D2O)<5: 2.5- 3.5(4H, m) , 3·.83(2H, s) , 4.3^ 5.3(3H, m),7.53(5H,s) NMR (90MHz, D 2 O) <5: 2.5- 3.5 (4H, m), 3 · .83 (2H, s), 4.3 ^ 5.3 (3H, m), 7.53 (5H, s)
実施例 3 4 Example 3 4
1 —(4—ニトロべンジル) 水素 2—ォキソ一 3—フェニルチォグ ルタレー ト [化合物(3 4)]の製造: . Production of 1- (4-nitrobenzyl) hydrogen 2-oxo-l-phenylthioglutarate [Compound (34)]:
3—ブロ乇一 2—ォキソグルタル酸 2.25gのジクロロメタン 4 懸 蜀液に氷冷,攪拌下チォフヱノ—ル i.O を加ぇ、 次ぃでトリェチルァミ ン を加ぇた。 反応液を室温で 4 5分間攪拌後、 溶媒を留去し、 残 留物を酢酸ェチルと 1 N—塩酸に分配した。 詐酸ェチル層を分取し、 水 洗,乾燥(Na2S 0+)後、 溶媒を留去すると 2—ォキソ一 3—フヱニルチ ォグルタル酸 2.28gが淡黄色油状物として得られた。 3-Brown 2-oxoglutaric acid 2.25 g of dichloromethane in 4 suspensions was added with thiophenol iO under ice-cooling and stirring, and triethylamine was added in the next step. After stirring the reaction solution at room temperature for 45 minutes, the solvent was distilled off, and the residue was partitioned between ethyl acetate and 1 N hydrochloric acid. The ethyl sulphate layer was separated, washed with water and dried (Na 2 S 0 + ), and the solvent was distilled off to obtain 2.28 g of 2-oxo-3-phenylthioglutaric acid as a pale yellow oil.
I R ^®at cm'1: 3000(b), 1720, 1470, 1440, 1400, 1280, 1200 IR ^ ® at cm ' 1 : 3000 (b), 1720, 1470, 1440, 1400, 1280, 1200
NMR (90MHz, C D C 13)<5: 2.87(2H, d. J = 8Hz) , 4.73(1H, t , J = 8Hz) . NMR (90MHz, CDC 1 3) <5: 2.87 (. 2H, d J = 8Hz), 4.73 (1H, t, J = 8Hz).
7.40(5H,s),9.4(2H,b) 7.40 (5H, s), 9.4 (2H, b)
本品 2, 28gのジメチルホルムァミ ド 1 8 溶液に氷冷,攪拌下ジシ ^ロ へキシルァミ ン 1.43¾£と 4ーニトロべンジルブロミ ド 1.56¾£を加ぇた。 反応液を室温で 1 5時間攪拌し、 詐酸ェチルで希釈した。 忻出した結晶 をろ去し、 ろ液を水洗,乾燥(Na^S 0+)後、 溶媒を留去した。 残留物を シリカゲルを用ぃるカラムクロマトグラフィーに付し、 へキサンー胙酸 ェチル(1 : 2→ 1 : 3)で溶出すると題記化合物(3 4 )2.25gが無色桔晶 として得られた。 ェーテルーへキサンから再結晶すると無色プリズム晶
が得られた。 融点 1 1 9一 1 2 0°C To a solution of 2,28 g of this product in 18 dimethylformamide solution was added 1.43 g of dicyclohexylamine and 1.56 g of 4-nitrobenzyl bromide under ice cooling and stirring. The reaction was stirred at room temperature for 15 hours and diluted with ethyl acetate. The crystals formed were filtered off, the filtrate was washed with water and dried (Na ^ S0 + ), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl ester (1: 2 → 1: 3) to give 2.25 g of the title compound (34) as colorless crystals. Colorless prisms when recrystallized from ether hexane was gotten. Melting point 1 1 9 1 1 2 0 ° C
I R ^ m ϋaϋx301 cm-1 : 1745, 1730, 1700, 1520, 1440. 1350, 1280 謹 R (90MHz, CD C 13) 5 : 2.85(2H,d, J = 8Hz)s .7(lH.m),5,43(2H, s),6.7(lH,b),7.35(5H,s),7.60(2H,d,J = 9Hz) IR ^ m ϋaϋx 301 cm -1: 1745, 1730, 1700, 1520, 1440. 1350, 1280謹R (90MHz, CD C 1 3 ) 5: 2.85 (2H, d, J = 8Hz) s .7 (lH. m), 5,43 (2H, s), 6.7 (lH, b), 7.35 (5H, s), 7.60 (2H, d, J = 9Hz)
元素分折値: C18H15N07S Elemental analysis value: C 18 H 15 N0 7 S
計箅値 C ,55.52; H.3.88; N.3.60 Total C, 55.52; H.3.88; N.3.60
実測値 C ,55.49 ; H.3.90; N ,3.50 Found C, 55.49; H. 3.90; N, 3.50
実施例 3 5 Example 3 5
2—クロロ一 3—フェニルチォー 5—ォキソー 2—テトラヒ ドロフ-ラ ンカルボン酸 4ーニトロべンジルェステル [化合物(3 5)]の製造: 実施例 3 4で得た化合物(3 4) 1 4 5 mgの 1 , 2—ジク口ロェタン 4 溶液にチォニルクロリ ド 0.30; ^を加ぇて 4時間加熱還流した。 溶媒を 留去し、 残留物をフロリ ジルを用ぃるカラムク.ロマトグラフィーに付し た。 へキサンー詐酸ェチル(3: 1 )で溶出すると題記化合物(3 5)116mg が無色油状物として得られた。 Production of 2-chloro-1-3-phenylthio-5-oxo-2-tetrahydrofuran-carboxylic acid 4-nitrobenzyl ester [Compound (35)]: Compound (34) obtained in Example 34 4 , 2-Dioctane roetane 4 solution was added with thionyl chloride 0.30; ^ and heated under reflux for 4 hours. The solvent was distilled off, and the residue was subjected to column chromatography using florisil. Elution with hexane-ethyl acetate (3: 1) gave 116 mg of the title compound (35) as a colorless oil.
1 Rン maxat cm-1: 1825, 1770, 1525, 1350, 1290, 1090 1 R max at cm -1 : 1825, 1770, 1525, 1350, 1290, 1090
NMR (90MHz, CD Cl3)<5: 2.71(lH,dd, J = 3, 18Hz) , 3.37(lH,dd, J = 8 , 18Hz) ,4.27(lH,dd, J = 3, 8Hz) , 5.37(2H, ABq, J = 13, 22Hz) , 7.35 (5H>m),7.57(2H,d, J = 9Hz),8.23(2H,d, J = 9Hz) NMR (90 MHz, CD Cl 3 ) <5: 2.71 (lH, dd, J = 3, 18 Hz), 3.37 (lH, dd, J = 8, 18 Hz), 4.27 (lH, dd, J = 3, 8 Hz), 5.37 (2H, ABq, J = 13, 22Hz), 7.35 (5H > m), 7.57 (2H, d, J = 9Hz), 8.23 (2H, d, J = 9Hz)
マススぺク トル mノ e: 4 0 7 , 4 0 9 (M+ ) Mass torque e: 4 0 7, 4 0 9 (M + )
実施例 3 6 Example 3 6
(4 S )- 2 - (4—べンジルォキシカルボニルァミノ 一 3—ォキソ— (4 S)-2--(4-benzyloxycarbonylamino-3 -oxo-
2—ィソキサゾリ ジニル)— 5—ォキソ一 3—フヱニルチォー 2—テト ラヒ ドロフランカルボン酸 4ーニトロべンジルェステル [化合物(36)] の製造:
( 4 S )— 4一べンジルォキシカルボニルァミノ一 3—ィソキサゾリジ ノ ン 1 7 7 ragと実施伊 J 34で得た化合物(34) 3 8 0 mgをジクロロメタ ン 7.5? ^に溶解し、 D C C 2 1 Omgを加ぇて室温で 1時間攙拌した。 折 出した锆晶をろ去し、 ジクロロメタンで洗净した。 ろ と洗液を合ゎせ、 炭酸水素ナトリゥム水,水で洗浄,乾燥(Na2S 0+)後、 溶媒を;留去した。 残留物をシリカゲルを用ぃるカラムクロマトグラフィ—に付し、 へキサ ン—酢酸ェチル(5: 3)で溶出すると題記化合物(3 6 ) 1 8 5 nigが無色 油状物として得られた。 Production of 2- (isoxazolidinyl) -5-oxo-1-3-phenylthio-2-tetrafluorofurancarboxylic acid 4-nitrobenzyl ester [Compound (36)]: (4S) —4 1-benzyloxycarbonylamino-3,1-isoxazolidinone 177 rag and 380 mg of the compound (34) obtained in J34 were dissolved in 7.5 mL of dichloromethane. DCC21Omg was added and stirred at room temperature for 1 hour. The precipitated crystals were removed by filtration and washed with dichloromethane. The filtrate and the washings were combined, washed with aqueous sodium hydrogen carbonate and water, dried (Na 2 S 0 + ), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (5: 3) to give the title compound (36) 185 nig as a colorless oil.
I R ^ i miaxvatcm"1: 3350, 1810, 1760, 1730, 1525, 1350, 1250, 1055IR ^ i miaxv at cm " 1 : 3350, 1810, 1760, 1730, 1525, 1350, 1250, 1055
NMRC90MH2, CD Cl3)5: 2.5- 3. (2H, m) , 4.1(1H. m) , 4. - 5.0 (3H>m),5.10(2H,s),5.3(lH,b),5.35(2H>s)>7.33(5H(s),7.5(7H,m), 8.2(2H,m) ' NMRC90MH2, CD Cl 3) 5: . 2.5- 3. (2H, m), 4.1 (1H m), 4. - 5.0 (3H> m), 5.10 (2H, s), 5.3 (lH, b), 5.35 (2H > s) > 7.33 (5H ( s), 7.5 (7H, m), 8.2 (2H, m) '
実施例 3 7 Example 3 7
化合物(3 6)の製造: Preparation of compound (36):
( S ) - —べンジルォキシカルボニルァミ ノ — 3—ィソキサゾリ ジ ノ ン 4 8 mgをジクロロメタ ン に溶解し、 氷冷,攪拌下トリェチルァ ミ ン 0.055¾ι2と実施例 3 5で得た化合物(3 5) 1 1 0 mgのジクロロメタ ン 2¾ι2溶液を加ぇた。 反応液を室温で 3 0分間攙拌後、 水洗,乾燥 48 mg of (S) -— benzyloxycarbonylamino--3-isoxazolidinone was dissolved in dichloromethane, and the mixture obtained in Example 35 with triethylamine 0.055¾ι2 under ice cooling and stirring ( 3 5) 110 mg of dichloromethane 2¾ι2 solution was added. The reaction solution was stirred at room temperature for 30 minutes, washed with water and dried.
(Na2S 04)し、 溶媒を留去した。 残留物をシリカゲルを用ぃるカラム クロマトグラフィ ーに付し、 へキサンー酢酸ェチル(5: 3)で溶出する と題記化合物(3 6 ) 2 8 mgが無色油状物として得られた。 本品の I Rぉ ょび NMRスぺク トルは実施例 3 6で得た化合物(3 6)のそれらとー致 .した。 (Na 2 SO 4 ) and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (5: 3) to give 28 mg of the title compound (36) as a colorless oil. The IR spectrum and NMR spectrum of this product were similar to those of the compound (36) obtained in Example 36.
実施例 3 8 Example 3 8
(4 S)~ 2 -( ーべンジルォキシカルボニルァミノ — 3—ォキソー
2—ィソキサゾリジニル)一 5—ォキソー 3—フェニルチォー 2—テト ラヒ ドロフランカルボン酸 ナトリゥム塩 [化.合物(3 8)]の製造: 実施例 3 6で得た化合物(3 6)7 Omgを酢酸ェチル 2¾ と PH7.0りん 酸緩衝液 混液に溶解し、 1 0 %パラジゥムー炭素 -1 4 Ofligを加ぇて 水素気流中室温で 2.5時間攪拌した。 触媒をろ去し、 水洗後、 ろ液と洗 液を合ゎせ水層を分取した。 氷層を濃縮後、 濃縮液を HP - 2 0カラム で精製した。 3 0 %ェタノ —ルで溶出される画分を凍結乾燥し題記化合 物 (3 8) 2 Omgを白色粉末として得た。 (4 S) ~ 2-(-benzyloxycarbonylamino-3-oxo Preparation of sodium 2-isoxazolidinyl) -5-oxo-3-phenylphenyl 2-tetrahydrofurancarboxylate [Compound (38)]: Compound (36) obtained in Example 36 7 Omg was dissolved in a mixture of ethyl acetate 2¾ and PH7.0 phosphate buffer, and 10% palladium carbon-14 oflig was added thereto, followed by stirring at room temperature for 2.5 hours in a hydrogen stream. After removing the catalyst by filtration and washing with water, the filtrate and the washing solution were combined, and the aqueous layer was separated. After concentrating the ice layer, the concentrate was purified by HP-20 column. The fraction eluted with 30% ethanol was lyophilized to give 2 Omg of the title compound (38) as a white powder.
I R ^ ί M^l α? Λ Γ cm"1: -1780, 1710, 1650, 1500 , 1380, 1240 IR ^ ί M ^ l α? Λ Γ cm " 1 : -1780, 1710, 1650, 1500, 1380, 1240
NMR(90MHz,D2O)(5: 2.7 - 3.5(2Η, m) , 3.7 - 5.3(4Η, m) , 5.20(2Η, s),7.5(10H,b) NMR (90MHz, D 2 O) (5: 2.7 - 3.5 (2Η, m), 3.7 - 5.3 (4Η, m), 5.20 (2Η, s), 7.5 (10H, b)
実施例 3 9 · -Example 3 9
1 一(4ーニトロべンジル) 水素 3—ェチルチォー 2—ォキソグル タレー ト [化合物(3 9)]の製造: 1 Production of 1- (4-nitrobenzyl) hydrogen 3-ethylthio 2-oxoglutarate [Compound (39)]:
3 —ブロモ一 2—ォキソグルタル酸 1.00gのジクロロメタン 2 0 ¾ 懸 蜀液に氷冷,攪拌下ェタンチォール 0.33¾£を加ぇ、 次ぃでトリェチルァ ミ ン 1.83 を加ぇた。 反応液を室温で 3時間攪拌後、 溶媒を留去し、 残 留物を酢酸ェチルと 1 N—塩酸に分配した。 S乍酸ェチル層を分取し、 水 洗,乾燥(Na2S 04)後、 溶媒を留去すると 3—ェチルチォー 2—ォキソ グルタル酸 0.82gが淡黄色油伏物として得られた。 3-Bromo-2-oxoglutaric acid 1.00 g of dichloromethane in 20 mL of the suspension was added with ice-cooled and stirred ethanethiol 0.33 タ ン, and in the next step triethylamine 1.83 was added. After stirring the reaction solution at room temperature for 3 hours, the solvent was distilled off, and the residue was partitioned between ethyl acetate and 1 N hydrochloric acid. Was fractionated S乍酸Echiru layer, water washing, drying (Na 2 S 0 4), the solvent was distilled off 3- Echiruchio 2 Okiso glutaric acid 0.82g as a pale yellow oil Fushimi thereof.
I Rシ at cm-1: 3000(b), 1720, 1400, 1250 IR sheet at cm -1 : 3000 (b), 1720, 1400, 1250
N MR (90MHz. C D C 13)<5 : 1.23(3H, t , J = 8Hz) , 2.55(2H, q, J = 8Hz) , 3.0(2H,b),4.4(lH,b),8.9(2H,b) N MR (90MHz.CDC 1 3 ) <5: 1.23 (3H, t, J = 8Hz), 2.55 (2H, q, J = 8Hz), 3.0 (2H, b), 4.4 (lH, b), 8.9 ( 2H, b)
本品 0.82gのジメチルホルムァミ ド 8 ¾2溶液に氷冷,攙拌下ジシクロへ キシルァミ ン 0.65 と 4ーニトロべンジルブロミ ド 0.70gを加ぇた。 反
応液を室温で 3時間攙拌し、 酢酸ェチルで希釈した。 析出した結晶をろ 去し、 ろ液を水洗,乾嫫(Na2S C )後、 溶媒を留去した。 残留物をシリ カゲルを用ぃるカラムクロマトグラフィーに付し、 へキサンー酢酸ェチ ル(3: 2)ぉょぴ詐酸ェチルで溶出すると題記化合物(-3 9)0-.61gが無色 結晶として得られた。 ィソプロピルェ—テルから再.結晶すると無色プリ ズム晶が得られた。 ^点 1 0 0— 1 0 1 °C - To a solution of 0.82 g of this product in dimethylformamide 8.2 was added 0.65 of dicyclohexylamine and 0.70 g of 4-nitrobenzyl bromide under ice cooling and stirring. Anti The reaction solution was stirred at room temperature for 3 hours, and diluted with ethyl acetate. The precipitated crystals were removed by filtration, the filtrate was washed with water, dried (Na 2 SC), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (3: 2) ethyl acetate. 0-.61 g of the title compound (-39) was colorless crystals. Was obtained as Recrystallization from isopropyl ether gave colorless prisms. ^ Point 1 0 0— 1 0 1 ° C-
I R V N"301 cm"1: 1745, 1720, 1700. 1530. 1350, 1255 IRV N " 301 cm" 1 : 1745, 1720, 1700. 1530. 1350, 1255
max max
NMROOMHz, CD Cl3)<5: 1.18(3H, t , J = 8 Hz) , 2.48(2H. q, J = 8Hz) , 2.95(2H,m),4.3(lH,b),5.41(2H,s)(7.0(lH(b),7.57(2H,d, J^9Hz), - 8.25(2H,d,J = 9Hz) NMROOMHz, CD Cl 3 ) <5: 1.18 (3H, t, J = 8 Hz), 2.48 (2H.q, J = 8 Hz), 2.95 (2H, m), 4.3 (lH, b), 5.41 (2H, s) ( 7.0 (lH ( b), 7.57 (2H, d, J ^ 9Hz),-8.25 (2H, d, J = 9Hz)
元素分折値: C 14H15N07S Elemental folding value: C 14 H 15 N0 7 S
計算値 C.49.26: H.4.43; N.4.10 Calculated value C.49.26: H.4.43; N.4.10
実測俊 ' C , 49.32; H.4.33; N.3.99 Observed speed '' C, 49.32; H.4.33; N.3.99
実施例 4 0 ' ·Example 4 0 '
2—クロロー 3—ェチルチォー 5—ォキソー 2—テトラヒ ドロフラン カルボン酸 4ーニトロべンジルェステル [化合物(4 0 )]の製造: Preparation of 2-chloro-3-ethylethyl 5-oxo-2-tetrahydrofuran carboxylate 4-nitrobenzyl ester [Compound (40)]:
実施例 3 9で得た化合物(3-9 ) 1 7 0 mgの し 2 —ジクロロェタン 4 ¾|2溶液にチォニルクロリ ド0.30¾6を加ぇて3.5時間加熟還流した。 溶媒' を留去し、 残留物をフロリジルを用ぃるカラムクロマトグラフィ —に付 した。 へキサンぉょびへキサンー詐酸ェチル(3 : 1 )で溶出すると題言己 化合物(4 0 ) 7 9 mgが無色油状物として得られた。 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.
I Rレ atcnrl: 1820 Π70, 1610, 1530, 1355, 1290, 1145, 1090 max IR record at cnrl : 1820 Π70, 1610, 1530, 1355, 1290, 1145, 1090 max
NMROOMHz, CD Cl3)<5: 1.15(3H, t , J = 7Hz) , 2.7(3H, m) , 3.37(iH, dd, J = 9,18Hz),3.95(lH,dd, J = 4.9Hz),5.43(2H,s),7.60(2H!d, J = 9Hz).8.25(2H,d, J = 9Hz)
マススぺク トル m/e: 3 5 9 , 3 6 1 (M+ ) NMROOMHz, CD Cl 3 ) <5: 1.15 (3H, t, J = 7 Hz), 2.7 (3H, m), 3.37 (iH, dd, J = 9,18 Hz), 3.95 (lH, dd, J = 4.9 Hz) ), 5.43 (2H, s), 7.60 (2H ! D, J = 9Hz). 8.25 (2H, d, J = 9Hz) Mass vector m / e: 3 5 9, 3 6 1 (M + )
実施例 4 1 Example 4 1
1 —t—ブチル 水素 2—ォキソグルタレー ト [化合物(4 1 )]の製 5—ォキソ一 2—テトラヒ ドロフランカルボン酸 5. Ogのジクロロメタ ン 1 0 0¾fi溶液に— 6 0てで濃硫酸 0.3»ώを加ぇ、 次ぃで過剰のィソブ テン(約 5 0¾β)を加ぇた。 反応混合液を密栓して室温でー夜静置後、 冷 却した炭酸水素ナトリゥム水中に注加し、 ジクロロメタン層を分取した= ジクロロメタン層を水洗,乾燥(Na2S 0+)後、 濃縮すると 5—ォキソー 2—テトラヒ ドロフランカルボン酸 t—ブチルェステルが無色油状物 として得られた。 1-t-butyl hydrogen 2-oxoglutarate Preparation of [Compound (41)] 5-oxo-1-tetrahydrofurancarboxylic acid 5. Og of dichloromethane in 100-fi solution In the next step, an excess of isobutene (about 50¾β) was added. At room temperature over Yorusei After incubation with stoppered reaction mixture was poured into bicarbonate Natoriumu water and cooling, washed with water The separated = dichloromethane layer The dichloromethane layer, dried (Na 2 S 0 +) after concentration As a result, t-butyl ester of 5-oxo-2-tetrahydrofurancarboxylic acid was obtained as a colorless oil.
I R I R
m i^axat cm-1: 1760 mi ^ ax at cm -1 : 1760
- -
N'MR (60MHz, C D C )δ: 1.50(9H, s) , 2. (4H, m) , 4.8(1H, m) N'MR (60MHz, CDC) δ: 1.50 (9H, s), 2. (4H, m), 4.8 (1H, m)
本品を無水メタノ —ル 5· 0¾iZに溶解し、 氷冷,攪拌下ナトリゥム メ チラ - ト 1 0 Omgを加ぇた。 反応液を水冷下 3時間攪拌後、濃縮し、舴酸 ェチルと塩化ァンモニゥム水中に注加した。詐酸ェチル層を分取し、 乾 燥(: \'a2$ 0+)後、溶媒を留去すると 1 — t—ブチル— 5—メチル一 2— ヒ ドロキシグルタレ— ト 8.2gが無色結晶として得られた。 へキサンから 再結晶すると無色プリズム晶が得られた。 融点 3 6— 3 7 °C This product was dissolved in anhydrous methanol 5.0 iZ, and sodium methylate 10 Omg was added under ice cooling and stirring. The reaction solution was stirred under water cooling for 3 hours, concentrated, and then poured into ethyl acetate and ammonium chloride water. The ethyl acetate layer was separated, dried (\ 'a 2 $ 0 + ), and the solvent was distilled off. 1-t-butyl-5-methyl-2-hydroxyglutarate 8.2 g as colorless crystals Obtained. Recrystallization from hexane gave colorless prisms. Melting point 3 6— 3 7 ° C
I R 01 cm-1: 3450, 1735, 1260, 1230, 1160. 1110 IR 01 cm -1 : 3450, 1735, 1260, 1230, 1160. 1110
max max
N MR (90MHz, C D C 13) 5: 1. 7(9H, s) , 1.7 - 2.6(4H, m) , 2.87(1H, d, N MR (90MHz, CDC 1 3 ) 5: 1. 7 (9H, s), 1.7 - 2.6 (4H, m), 2.87 (1H, d,
J-5Hz),3.63(3H(s)>4.1(lH>m) J-5Hz), 3.63 (3H ( s) > 4.1 (lH > m)
元素分折値: C 1QH 1805 ' Elemental analysis value: C 1Q H 18 0 5 '
計算値 C .55.03; H ,8.31 Calculated value C .55.03; H, 8.31
実測値 C ,54.60; H ,8.35
ォキサリルクロリ ド のジクロロメタン 1 2 溶液に窒素雰囲気 下,一 7 0ででジメチルスルホキシ ド 0.60; ^のジクロロメタン 4¾£溶液 を攙拌下加ぇた。 次ぃで上記で得た 1 —tーブチル— 5—メチルー 2― ヒ ドロキシグルタレ一 ト 0.95gのジクロロメタン 3.5¾J^液を加ぇ一 Ί 0 てで 1 5分間攪拌後、 トリェチルァミ ン 3.0¾βを加ぇた。 反応液を Found C, 54.60; H, 8.35 To a solution of oxalyl chloride in 12 dichloromethane was added a solution of 0.60; ^ dimethylsulfoxide in dichloromethane at 170 ° C. under a nitrogen atmosphere at 170 ° C. with stirring. Add 1-t-butyl-5-methyl-2-hydroxyglutarate (0.95 g) obtained above in dichloromethane 3.5 ^ J ^ solution, and stir for 15 minutes at 0 ° C. Then add triethylamine 3.0¾β. Was. Reaction solution
- 0°C迄昇温させた後、 氷水中に注加し、 ジクロロメタンで抽出液を 水,希酢酸,水で順次洗净後、 乾燥(Na2S C )し、 溶媒を留去した。 残 留物をシリカゲルを用ぃたカラムクロマトグラフィ ーに付し、 へキサン —詐酸ェチル(5: 1 )で溶出すると 1 — tーブチル— 5—メチルー 2—ォ キソダルタレ— ト 0.60gが淡黄色油状物として得られた。 After the temperature was raised to -0 ° C, the mixture was poured into ice water, and the extract was washed with water, dilute acetic acid and water successively with dichloromethane, dried (Na 2 SC), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (5: 1). As a result, 0.60 g of 1-t-butyl-5-methyl-2-oxodaltalate was obtained as a pale yellow oil. Obtained as a product.
I R ^ m ilaxat ci_1: 1730, 1370, 1295, 1260, 1200, 1160, 1080 IR ^ m ilax at ci _1: 1730, 1370, 1295, 1260, 1200, 1160, 1080
NMR (90MHz, C D C 13) δ: 1.57(9H, s) , 2.63(2H, t , J = 6Hz) , 3.10 (2H,s, J = 6Hz).3.69(3H,s) NMR (90MHz, CDC 1 3) δ: 1.57 (9H, s), 2.63 (2H, t, J = 6Hz), 3.10 (2H, s, J = 6Hz) .3.69 (3H, s)
本品 1 0 8 mgをテトラヒ ドロフラン l ¾i と水 に溶解し、 氷冷,攙 拌下 1 N—水酸化ナトリゥム Q.4¾iを加ぇた。 反応液を氷冷下、 4 5分 間攪拌後、 水ぉょび詐酸ェチルの混液に注加した。 水層を分取し、 1 N -塩酸を加ぇて PH 4に調整後、 舴酸ェチルで抽出した。 油出液を食塩 水で洗浄後、 乾燥(Na2S C )し、 溶媒を留去した。 残留物をシリカゲ ルを用ぃるカラムクロマトグラフィ一に付し、 へキサンー詐酸ェチル (3: 2→ 1 : 2)で溶出すると題記化合物(4 1 ) 2 6 mgが無色油状物とし て得られた。 . 108 mg of this product was dissolved in tetrahydrofuran l-i and water, and 1N-sodium hydroxide Q.4i was added with ice cooling and stirring. The reaction solution was stirred for 45 minutes under ice cooling, and then poured into a mixed solution of water and ethyl acetate. The aqueous layer was separated, adjusted to pH 4 by adding 1N-hydrochloric acid, and extracted with ethyl acetate. The oil effluent was washed with brine, dried (Na 2 SC), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (3: 2 → 1: 2) to give 26 mg of the title compound (41) as a colorless oil. Was. .
I R ^ m ilaxat cm-1: 1740, 1370, 1300, 1255, 1160. 1080 IR ^ m ilax at cm -1 : 1740, 1370, 1300, 1255, 1160. 1080
NMR(90MHz, CD C 13)<5: 1.53(9H, m) , 2.75(4H, b) NMR (90MHz, CD C 1 3 ) <5: 1.53 (9H, m), 2.75 (4H, b)
実施例 4 2 Example 4 2
1 —ジフヱニルメチル 水素 2—ォキソグルタレー ト [化合物(42)]
の製造: 1-Diphenylmethyl hydrogen 2-oxoglutarate [Compound (42)] Manufacturing of:
2—ォキソグルタル酸 2.93g,ジフェニルメチルブ σミ ド 4.75gぉょび ジシクロへキシルァミ ン 3.63gを用ぃて実施例 1 (a)と同様の方法にょり 題記化合物(4 2)3.2gを結晶として得た。 · 融点: 1 0 7° — 1 0 9°C 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
I R ^ ? ma?x Γ cm"1 : 1730. 1710 IR ^? Ma? X Γ cm " 1 : 1730. 1710
NMR (60MHz, CD C 13)5 : 2.58- 3.17(4H, m) , 6.99(1H, s) , 7.31- 7.54(10H,m) NMR (60MHz, CD C 1 3 ) 5: 2.58- 3.17 (4H, m), 6.99 (1H, s), 7.31- 7.54 (10H, m)
元素分圻値: C 18Η1β05 Elemental Ki value: C 18 Η 1β 0 5
計算値 C ,69.22; H.5.16 Calculated C, 69.22; H.5.16
実測値 C ,69.30; H ,5.18 Found C, 69.30; H, 5.18
実施例 4 3 - 下記の成分を用ぃて、.常套手段にょり錠剤を製造する。 . ' 実施例 4で得られた化合物(4 )' 3 0 Omg Example 43-Tablets are prepared in a conventional manner using the following ingredients. 'Compound (4) obtained in Example 4' 30 Omg
コーン ' スターチ 5 0 mg Corn '' starch 50 mg
ラク トース 2 8 mg Lactose 2 8 mg
ヒ ドロキシプロピルセルロース L 2 0 mg Hydroxypropylcellulose L 20 mg
マグネシゥム · ステァレー ト 2mg Magnesium stearate 2mg
4 0 0 mg 400 mg
(1錠ぁたり) 成人ー人ぁたりー日 4〜 8錠を毎食後(ー日 3回)服用する。 (1 tablet) Adults-people 4 to 8 tablets daily after meals (3 times a day).
実施例 4 4 Example 4 4
下記の成分を用ぃて、 常套手段にょり綻剤を'製造する。 The following components are used to produce disintegrants in a conventional manner.
' 実施例 2 5で得られた化合物(2 5 ) 3 0 O mg
コーン · スターチ 5 0 mg '' Compound (25) obtained in Example 25 30 O mg Cornstarch 50 mg
ラク トー.ス 2 8 mg Lactose 2 8 mg
ヒ ドロキシプロピルセルロース L 2 0 mg Hydroxypropylcellulose L 20 mg
マグネシゥム · ステァレート - 2 mg- Magnesium stearate-2 mg-
4 0 0 mg 400 mg
' ( 1錠ぁたり) '(One tablet)
成人ー人ぁたりー日 4〜8錠を毎食後(ー日 3回)服用する。 Take 4 to 8 tablets daily after meals (three times daily) for adults.
実施例 4 5 Example 4 5
(4 S)- 2 - [4 - (4ーニトロべンジルォキシカルボニルァミノ)一 3—ォキソ— 2—ィソキサゾリジニル]ー 5—ォキソー 3—ェチルチォ ー 2 -テトラヒ ドロフランカルボン酸 4 —ニトロべンジルェステル [化 合物(4 5 )]の製造: (4S) -2- [4- (4-nitrobenzyloxycarbonylamino) -1-oxo-2-isoxazolidinyl] -5-oxo-3-ethylethyl 2-tetrahydrofurancarboxylic acid 4 —Preparation of nitrobenzyl ester [compound (45)]:
(a)、 参考例 5で得た(4 S)- 4ー(4—ニトロべンジルォキシカルボニ ルァミ ノ)— 3 —ィソキサゾリ ジノ ン ί 4 0 tngと実施例 3 9で得た化合 物(3 9 ) 2 0 O mgとをジクロロメタン に懸濁し、 D C C 1 2 0 mgを 加ぇて室温で 1 4時間攪拌した。 沂出した桔晶をろ去し、 ジクロロメタ ンで洗浄した。 ろ液と洗液とを合ゎせ、 炭酸水素ナトリゥム水.水で洗 浄,乾燥(Na2S 0+)後、 溶媒を留去した。 残留物をシリカゲ'ルを用ぃる カラムクロマ トグラフィ —に付し、 へキサンー詐酸ェチル( 1 : 1 )で溶 出すると題記化合物(4 5 ) 7 O mgが淡黄色油状物として得られた。 (a) The (4S) -4- (4-nitrobenzyloxycarbonylamino) -3-isoxazolidinone obtained in Reference Example 5 (40 tng) and the compound obtained in Example 39 (39) 20 mg of O 2 was suspended in dichloromethane, and 120 mg of DCC was added thereto, followed by stirring at room temperature for 14 hours. The liquor was removed by filtration and washed with dichloromethane. The filtrate and the washing solution were combined, washed with sodium bicarbonate water and water, dried (Na 2 S 0 + ), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (1: 1) to give 7 O mg of the title compound (45) as a pale yellow oil.
Γ R Neat cm-1 :3330.1805.1750, 1625, 1520, 1350. Γ R Neat cm -1 : 3330.1805.1750, 1625, 1520, 1350.
max max
N MR (90MHz, C D C ) 5 : 1.15(3H. t , J = 7Hz) , 2.45 -3.40(3H, m) , 4.0 -5.0(5H,m)I5.20(2H>s)>5.37(2H,s)(5.9(lH,b).7.55(4H,m),8.20(4H, d, J = 7Hz). N MR (90MHz, CDC) 5: 1.15 (3H.t, J = 7Hz), 2.45 -3.40 (3H, m), 4.0 -5.0 (5H, m) I 5.20 (2H > s) > 5.37 (2H, s ) ( 5.9 (lH, b) .7.55 (4H, m), 8.20 (4H, d, J = 7Hz).
(b)、 参考例 5で得た( 4 S )— 4 — ( 4ーニト-ロべンジルォキシカルボニ
ルァミノ)ー 3—ィソキサゾリジノ ン 1 4 Omgと実施例 3 9で得た化合 物(3 9)2 0 Omgとをジクロロメタン 1 0¾βに懸蜀し、 Ν—ェトキシカ ルボニルー 2—ェトキ、シ— 1 .2—ジヒ ドロキノ リ ン 1 6 0 mgも加ぇて 室温で 6時間攪拌した。 溶媒を留去し、 残留物をシリカゲルを甩ぃるカ ラムクロマトグラフィーに付し、へキサンー酢酸ェチル(1 : 1 )で溶出す ると題記化合物(4 5 ) 1 6 5 mgが淡黄色油伏物として得られた。 本品の I Rぉょび NMRスぺク トルは(a)で得た化合物のそれらとー致した。 実施例 4 6 (b), (4S) —4— (4-nitroto-rovensiloxycarbonyl) obtained in Reference Example 5 Lamino) -3-isoxazolidinone (14 Omg) and the compound (39) 20 Omg obtained in Example 39 were suspended in dichloromethane (10 、 β), and the mixture was washed with dichloromethane (10¾β). —Dihydroquinoline (160 mg) was added, and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated and the residue was chromatographed on silica gel eluting with hexane-ethyl acetate (1: 1) to give 165 mg of the title compound (45) as a pale yellow oil. Obtained as a cover. The IR spectrum and NMR spectrum of this product corresponded to those of the compound obtained in (a). Example 4 6
(4 S)— 2— (4— [2—(2—ァミノ一 4—チァゾリル)一(Z)— 2— (メ トキシィミ ノ)ァセ トァミ ド]— 3—ォキソ一 2—ィソキサゾリ ジニ ル}— 3—ェチルチォ一 5—ォキソー 2—テトラヒ ドロフランカルボン 酸 ナトリゥム塩 [化合物(4 6)]の製造: (4 S) — 2— (4— [2— (2-amino-1-4-thiazolyl) -1- (Z) —2- (methoximino) acetamide] —3-oxo-1-2-isoxazolidinyl} — Preparation of 3-ethylethyl 5-oxoxo 2-tetrahydrofurancarboxylic acid sodium salt [Compound (46)]:
実施例 4 5で得た化合物(4 5 ) 6 0 mgを酢酸ェチル 5 ^と PH7.0りん .酸緩衝液 5¾£との混液に溶解し、 1 0 %パラジゥムー炭素 1 5 Omgを加 ぇて、 水素気流中,氷冷下 4時間攪拌した。触媒をろ去し、水洗後、ろ液と 洗液とを合ゎせ水層を分取した。 水層にテトラヒ ドロフラン 3¾£を加ぇ、 氷冷,攪拌下に炭酸水素ナトリ ゥム 3 Omgと 2—(2—クロロァセトァミ ド— 4一チァゾリル)—(Z)— 2—メ トキシィ ミ ノ鲊酸クロリ ド 塩酸 塩 4 Omgを加ぇた。 反応液を 3 0分間攪拌後、 N—メチルジチォカルバ ミ ン酸ナトリゥム 3 Omgを加ぇ、 -室温で 1時間攪拌した。 '减圧下にテト ラヒ ドロフランを留去し、 濃縮液を舴酸ェチルで洗^後、 HP— 2 0カ ラムで精製した。 5 %ェタノ—ルで溶出される画分を凍锆乾燦し、 題記 化合物(4 6) 8mgを淡黄色粉末として得た。 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 3¾ 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. After stirring the reaction solution for 30 minutes, sodium N-methyldithiocarbamate 3 Omg was added, and the mixture was stirred at room temperature for 1 hour. 'Tetrahydrofuran was distilled off under reduced pressure, and the concentrate was washed with ethyl acetate and purified with HP-20 column. The fraction eluted with 5% ethanol was freeze-dried to give 8 mg of the title compound (46) as a pale yellow powder.
I R K r cm"1 : 1780, 1720, 1660, 1530,1380,1030. IR K r cm " 1 : 1780, 1720, 1660, 1530,1380,1030.
max max
NMR(90MHz,D2O)<5 : 1. 0(3H, t , J = 7Hz) , 2.7 -3.9(4H, m) , 4.17(3H,
s),4.4-5.5(4H,ni),7.23(lH,s). NMR (90 MHz, D 2 O) <5: 1.0 (3H, t, J = 7 Hz), 2.7 -3.9 (4H, m), 4.17 (3H, s), 4.4-5.5 (4H, ni), 7.23 (lH, s).
実施例 4 7 Example 4 7
1 —ジフヱニルメチル 水素 2—ォキソ一 3 —フェニルチォグルタ レ—ト [化合物(4 7)]の製造: Production of 1-diphenylmethyl hydrogen 2-oxo-1- 3-phenylthioglutarate [compound (47)]:
実施例 3 の方法で得た粗製の 2 —ォキソー 3 -フヱニルチォグルタ ル酸 6.7gのジメチルホルムァミ ド 3 0 溶液に室温,擾拌下ジシクロへ キシルァミ ン 4.0?^とブロモジフェニルメタン 5. Ogとを加ぇた。 反応液 を室温で 1 .5時間攙拌後、 詐酸ェチルで希釈した。 圻出した桔晶をろ去 し、 ろ液を水洗,乾燥(Na2S C )後、 溶媒を留去した。 残留物もシリカ ゲルを用ぃるカラムクロマトグラフィ一に付し、 へキサンー酢酸ェチル (3 : 1→ 1 : 1 )で溶出すると題記化合物(4 7)3.2gが淡黄色結晶として 得られた。 へキサン―舴酸ェチルから再桔晶すると無色針状晶が得られ た。 融点 9 8 - 1 0 0 °C ' A solution of 6.7 g of the crude 2-oxo-3 -phenylthioglutaric acid obtained by the method of Example 3 in dimethylformamide 30 was stirred with dicyclohexylamine 4.0? ^ And bromodiphenylmethane 5 at room temperature under stirring. Added Og. The reaction solution was stirred at room temperature for 1.5 hours and diluted with ethyl acetate. The whisker was filtered off, the filtrate was washed with water and dried (Na 2 SC), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (3: 1 → 1: 1) to obtain 3.2 g of the title compound (47) as pale yellow crystals. Recrystallization from hexane-ethyl ester gave colorless needles. Melting point 98-100 ° C ''
I R u l^l01 001_1:1740, 1205, 1180. . max IR ul ^ l 01 001 _1 : 1740, 1205, 1180..max
N MR (60 MHz, C D C 13)δ : 2.85(2H, d. J = 8Hz) , 4.70(ΓΗ, t . J = 8Hz) ,N MR (60 MHz, CDC 1 3) δ: 2.85 (. 2H, d J = 8Hz), 4.70 (. ΓΗ, t J = 8Hz),
7.05(lH,s),7.3(15H,m). 7.05 (lH, s), 7.3 (15H, m).
実施例 4 8 Example 4 8
2 —クロロ一 3—フェニルチォー 5—ォキソー 2 —テトラヒ ドロフラ ンカルボン酸 ジフヱニルメチルェステル [化合物(4 8 )]の製造: 実施例 4 7で得た化合物(4 7 )0.50gのし 2 —ジクロロェタン 1 0¾£ 溶液にチォニルクロリ ド 0.½£を加ぇて 2時間加熟還流した。 溶媒を留 去し、 残留物をフロリジール(フロリ ジン社製,米国)を用ぃるカラムク ロマトグラフィーに付した。 へキサンー酢酸ェチル(5: 1 )で溶出する と題記化合物(4 8 )0.30gが無色油状物として得られた。 Production of diphenylmethylester [compound (48)] 2-chloro-1-phenylthio-5-oxo-2-tetrahydrofuran carboxylate: 0.50 g of the compound (47) obtained in Example 47 was obtained. Thionyl chloride (0.1%) was added to the dichloroethane 10% solution, and the mixture was ripened and refluxed for 2 hours. The solvent was distilled off, and the residue was subjected to column chromatography using Florisil (Fluoridine, USA). Elution with hexane-ethyl acetate (5: 1) gave 0.30 g of the title compound (48) as a colorless oil.
I R V 1 cm"l:1820, 1760, 1380, 1080. IRV 1 cm " l : 1820, 1760, 1380, 1080.
max
NMROOMHz, C D Cl3)<5 : 2.70(1H, dd, J = 3, 18Hz) , 3.29(1H, dd, J = 8, 18Hz),4.20(lH,dd>J = 3(8Hz),7.i0(lH,s)>7.4(15H)m). max NMROOMHz, CD Cl 3 ) <5: 2.70 (1H, dd, J = 3, 18 Hz), 3.29 (1H, dd, J = 8, 18 Hz), 4.20 (lH, dd > J = 3 ( 8 Hz), 7. i0 (lH, s) > 7.4 (15H ) m).
実施例 4 9 Example 4 9
2—クロロ一 5—ォキソ一 2 , 5—ジヒ ド σ— 2—フランカルボン酸 ジフヱニルメチルェステル [化合物(4 9)]の製造: Preparation of 2-chloro-1-5-oxo-1,2,5-dihydro σ-2-difurancarboxylate diphenylmethylester [Compound (49)]:
実施例 4 8で得た化合物(4 8 )0.30gのジク ロメタ ン 1 0 ¾fi溶液に 3 -クロロ過安息香酸 1 5 Omgを加ぇて室温で 3 0分間攪拌した。 反応 液を炭酸水素ナトリゥム水.水で順次洗浄後、 乾燥(Na2S 0 )し溶媒を 留去した。 残留物をトルェン 6¾£に溶解し 6 0°Cで 3 0分間加熱し、 溶 媒を留去した。 残留物をシリカゲルを用ぃるカラムクロマトグラフィ — に付し、 へキサンー酢酸ェチル(5: 1 )で溶出すると題記化合物(4 9) 0.15gが無色桔晶として得られた。 詐酸ェチルーへキサンから再桔晶す ると無色針状晶が得られた。 融点 9 9ー 1 0 1て To a solution of 0.30 g of the compound (48) obtained in Example 48 in 10-dichloromethane was added 15 Omg of 3-chloroperbenzoic acid, followed by stirring at room temperature for 30 minutes. The reaction solution was washed sequentially with aqueous sodium hydrogen carbonate and water, dried (Na 2 S 0), and the solvent was distilled off. The residue was dissolved in toluene and heated at 60 ° C. for 30 minutes to distill off the solvent. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (5: 1) to give 0.15 g of the title compound (49) as colorless crystals. Colorless needles were obtained by recrystallisation from ethyl acetate-hexane. Melting point 9 9 1 0 1
I R max 01 οιη-^ΐδΐθ, 1760, 1740, 1260. · IR max 01 οιη- ^ ΐδΐθ, 1760, 1740, 1260.
N MR (90MHz, C D C 13) <5 : 6.27(1H. d, J = 6Hz) , 6.90(1H, s) , 7.33(10H, s),7.58(lH,d. J-6Hz). N MR (90MHz, CDC 1 3 ) <5: 6.27 (. 1H d, J = 6Hz), 6.90 (1H, s), 7.33 (10H, s), 7.58 (. LH, d J-6Hz).
実施例 5 0 -Example 5 0-
(4 S)— 2— (4—フェニルァセチルァミ ノ — 3—ォキソ一 2—ィソ キサゾリ ジニル)一 5—ォキソ一 3—フヱニルチォ— 2—テ トラヒ ドロ フランカルボン酸 ジフヱニルメチルェステル [化合物(5 0)]の製造: (a)、 (4 S)— 4—フヱニルァセチルァミ ノ 一 3—ィソキサゾリ ジノ ン 1 1 0 mgと実施例 4 7で得た化合物(4 7)2 5 2 mgのジクロロメ タン 1 懸蜀液に D C C 1 5 mgを加ぇて室温で 2時間攪拌した。 折出し た結晶をろ去しジクロロメタンで洗净した。 ろ液と洗液を合ゎせ、 炭酸 水素ナトリゥム水,水で洗净,乾燥(Na2S 0+)後、 溶媒を留去した。残留
物をシリカゲルを用ぃるカラムクロマトグラフィ一に付し、へキサン一 舴酸ェチル(3: 1→3: 2)で溶出すると題記化合物(5 0)6 Omgが無色 油状物として得られた。 (4S) —2— (4-Phenylacetylamino—3-oxo-1-2-isoxazolidinyl) -1-5-oxo-1-3-phenylthio—2-ditetrafluorofurancarboxylic acid diphenylmethyl ester Preparation of 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. The filtrate and the washing solution were combined, washed with aqueous sodium hydrogen carbonate and water, dried (Na 2 S 0 + ), and the solvent was distilled off. Residual The product was subjected to column chromatography using silica gel and eluted with hexane ethyl ethyl ester (3: 1 → 3: 2) to give the title compound (50) 6 Omg as a colorless oil.
I R cmー1: 3330, 1810, 1750.1670. IR cm- 1 : 3330, 1810, 1750.1670.
max max
N MR (90MHz. C D C 13) 5 : 2. -3.3(2H, m) , 3.50(1H, s) , 3. ?3(1H, s) , N MR (90MHz CDC 1 3. ) 5:? 2. -3.3 (2H, m), 3.50 (1H, s), 3. 3 (1H, s),
3.7-5.0(4H,m),6.2(lH,m),6.9(0.5H,s),7.0(0.5H>s),7.3(20H,ni). (b)、 ( 4 S )— 4ーフェニルァセチルァミノ一 3—ィソキサゾリジノ ン 1 1 0 mgと実施例 4 7で得た化合物(4 7 ) 2 5 2 mgのジクロロメタ ン 1 0 ¾£懸蜀液に N—ェトキシカルボニル— 2—ェトキシ— 1 , 2—ジ.ヒ ドロキノ リ ン 1 4 8 mgを加ぇて室温で 1 4時間攙拌した。 溶媒を留去し、 残留物をシ,リカゲルを用ぃるカラムクロマトグラフィーに付した。 へキ サンー酢酸ェチル(3: 1→3: 2)で溶出すると題記化合物(5 0)4 5mg が淡黄色油状物として得られた。 本品の I Rぉょび N MRスぺク トルは (a)で得た化^ ^物のそれらとー致した。 3.7-5.0 (4H, m), 6.2 (lH, m), 6.9 (0.5H, s), 7.0 (0.5H > s), 7.3 (20H, ni). (B), (4S) -4 110 mg of phenylacetylamino-3-isoxazolidinone and 52 mg of the compound (47) obtained in Example 47 were added to the suspension solution of N-ethoxycarbonyl-2 To this was added 148 mg of ethoxy-1,2-dihydroquinoline, and the mixture was stirred at room temperature for 14 hours. The solvent was distilled off, and the residue was subjected to column chromatography using silica gel. Elution with hexane-ethyl acetate (3: 1 → 3: 2) gave 45 mg of the title compound (50) as a pale yellow oil. The IR and N MR spectra of this product were the same as those of the compound obtained in (a).
実施例 5 1 Example 5 1
(4 S)— 2— (4—フェニルァ:セチルァミ ノ 一 3—ォキゾー'2—ィソ キサゾリ ジニル)一 5—ォキソ— 2 , 5—ジヒ ドロー 2—フランカルボン 酸 ジフヱニルメチルェステル [化合物(5 1 )]の製造: (4S) —2— (4-Phenyla: cetylamino-1-3-oxo'2-isoxazolidinyl) -1-5-oxo-2,5-dihydro 2-difurancarboxylic acid diphenylmethylester [Compound (5 1)] Production:
(a)、 (4 S)— 4—フェニルァセチルァミノー 3—ィソキサゾリジノ ン 3 5 mgと実施例 4 9で得た 2—クロロ一 5—ォキソ一 2 , 5—ジヒ ドロ 一 2—フランカルボン酸 ジフェニルメチルェステル 5 0 mgのジクロロ メタン 2.5?aL懸蜀液に、 氷冷攪拌下、 トリェチルァミ ン Q.025
(a), (4S) —4-phenylacetylamine 3-isoxazolidinone (35 mg) and the 2-chloro-5-oxo-1,2,5-dihydro-12-furancarbone obtained in Example 49. Acid diphenylmethylester 50 mg of dichloromethane 2.5aaL To the suspension, ice-cooled and stirred, triethylamine Q.025
反応液を室温で 3 0分間攪拌後、 酢酸ェチルで希釈し、 水洗,乾燥(Na2 S O+)後、 溶媒を留去した。 残留物をシリカゲルを用ぃるカラムクロマ トグラフィ—に付し、 へキサンー詐酸ェチル(1: 1 )で溶出すると題記
化合物(5 1 ) 5 6 mgが無色結晶として得られた。 ジクロ σメタンーェチ ルェ—テルから再锆晶すると無色プリズム晶が得られた。 融点 1 6 8— 1 6 9°C (分解) The reaction solution was stirred at room temperature for 30 minutes, diluted with ethyl acetate, washed with water and dried (Na 2 SO + ), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (1: 1). 56 mg of the compound (51) was obtained as colorless crystals. Crystallization from dichloro σ-methane ether gave colorless prisms. Melting point 1 6 8— 1 6 9 ° C (decomposition)
I R υ I maIx01 001_1:3300, 1800, 1750, 1670 , 1250. ' ' IR υ I maIx 01 001 _1 : 3300, 1800, 1750, 1670, 1250.
NMR (90MHz, CD C13)S: 3.57(2H, s) , 3.9(1H, m) , 4.7C2H,-m) , 6.0 NMR (90MHz, CD C1 3) S: 3.57 (2H, s), 3.9 (1H, m), 4.7C2H, -m), 6.0
(lH,m),6.27(lH,d, J = 6Hz),6.90(lH)bs))7.3(l5H,s),7.57(lH,d, J = 6 Hz). (lH, m), 6.27 (lH, d, J = 6Hz), 6.90 (lH ) bs) ) 7.3 (l5H, s), 7.57 (lH, d, J = 6Hz).
(b)、 実施例 5 0で得た化合物( 5 0) 6 0 nigのジク口口メタ ン 3 ?d職 に 3—クロロ過安息香酸 2 Otngを加ぇて室温で 3 0分間攙拌した。 反応 液を炭酸水素ナトリゥム水,水で順次洗净後、 乾燥(Na2S C )し溶媒を 留去した。 残留物をトルェン 1 ¾fiに溶解し、 8 0°Cで 3 0分間加熱後、 溶媒を留去した。 残留物をシリカゲルを用ぃるカラムクロマトグラフィ ーに付し、 へキサンー酢酸ェチル( : 1 )で溶出すると題記化合物(5 1 ). 2 1 mgか' ^色結晶として得られた。 本品の I Rぉょび N MRスぺク トル は(a)で得た化合物のそれらとー致した。 (b), 2-chloroperbenzoic acid (2 Otng) was added to the compound (50) 60 nig obtained in Example 50, and the mixture was stirred at room temperature for 30 minutes. . The reaction solution was washed successively with aqueous sodium hydrogen carbonate and water, dried (Na 2 SC), and the solvent was distilled off. The residue was dissolved in toluene (10 fi), heated at 80 ° C for 30 minutes, and the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and eluted with hexane-ethyl acetate (: 1) to give the title compound (51). 21 mg or '^ colored crystals. The IR and N MR spectra of this product were the same as those of the compound obtained in (a).
参考例 6 Reference example 6
(4 S χ· , 5 R*5 )— 2—べンジルォキシカルボニル— 4ーべンジルォ キシカルボニルァミ ノ ー 5—メ トキシカルボニルー 3—ィソキサゾリ ジ ノ ン [化合物(R— 6— A)]ぉょび(4 S ^, 5 S *)- 2ーべンジルォキシ カルボニル一 4ーべンジルォキシカルボニルァ ミ ノ 一 5—メ トキシカル ボニル— 3—ィソキサゾリ ジノ ン [化合物(R— 6 - B )]の製造: (4 S χ ·, 5 R * 5 ) — 2-benzyloxycarbonyl—4-benzyloxycarbonylamino 5-methoxycarbonyl-3-isoxazolidinone [Compound (R— 6—A )] ぉ (4 S ^, 5 S *)-2-Benzyloxycarbonyl-1-4-Benzyloxycarbonylamino 5-5-Methoxycarbonyl-3-isoxazolidinone [Compound (R-6- B)] Production:
ジャ—ナル · ォブ · メディ シナル · ケミ ス ト リ ー( J ournal of Journal of Medicinal Chemistry
Medicinal C hemistry) , 丄, 7 0 9 ( 1 9 7 8 )に記載の方法で、 ト ランス一ジェチル ァジリ ジンー 2 , 3—ジカルボキシレ一 ト 1.87gょり 合成した 4—ァミ ノ 一 5—メ トキシカルボニルー 3—ィソキサゾリ ジノ
ンを水 1 0¾£とテトラヒ ドロフラン 1 0¾£とに溶かし、 氷冷下かきまぜ ながらべンジルォキシカルボニルクロリ ド 0.571¾fiを加ぇて、 1時間か きまぜた。 この藺炭酸水素ナトリゥム水で反応液を ΡΗ7.0に保った。 反 応液を酢酸ェチルで 2回抽出し食塩水で洗净後、乾燥 (MgS 0+)し、減圧 下濃縮した。残留物をシリカゲルカラムクロマトグラフィーに付して、へ キサンー酢酸ェチル(3: 2)で溶出し、題記化合物(R— 6― A)0.36g, 龍 R (90MHz. C D C l3) 5: 3.76(3H, s) , 4.6-5.1(2Η. πι) , 5.10(2H, s) ,Medicinal Chemistry), 丄, 709 (19778). Toxicarbonyl-3-isoxazolidino Was dissolved in 10¾ of water and 10¾ of tetrahydrofuran, and benzyloxycarbonyl chloride 0.571¾fi 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. The residue was subjected to silica gel column chromatography, to Kisan acetate Echiru: eluting with (3 2), the title compound (R- 6- A) 0.36 g, Ryu R (90MHz CDC l 3.) 5: 3.76 ( 3H, s), 4.6-5.1 (2Η.πι), 5.10 (2H, s),
5.30(2H,s),5.90(lH,d, J = 7Hz),7.35(5H,s),7.39(5H,s) 5.30 (2H, s), 5.90 (lH, d, J = 7Hz), 7.35 (5H, s), 7.39 (5H, s)
と題記化合物(R— 6—B)0.176g, And 0.176 g of the title compound (R-6-B),
NMR (90MHz, CD C 13) δ : 3.61(3H, s) , 5.0 -5.3(2H, m) , 5.13(2H, s) , NMR (90MHz, CD C 1 3 ) δ: 3.61 (3H, s), 5.0 -5.3 (2H, m), 5.13 (2H, s),
5.34(2H,s),5.70ClH,d, J = 5Hz),7.2-7.5(10H,m) · を得た。 5.34 (2H, s), 5.70ClH, d, J = 5Hz), 7.2-7.5 (10H, m)
参考例 7 Reference Example 7
( 4 S x , 5 R * ) - 4—べンジルォキシカルポニ.ルァミ ノ 一 5—メ ト キシカルボニル— 3—ィソキサゾリ ジノ ンの製造: (4 S x , 5 R *)-Preparation of 4-benzyloxycarponi.lamino-1 5-methoxycarbonyl-3-isoxazolidinone:
参考例 6で得た(4 S58 , 5 R*5 )- ーべンジルォキシカルボニルー 4 —べンジルォキシカルボニルァ ミ ノ — 5—メ トキシカルボニル一 3— ィソキサゾリ ジノ ン 0.36gを詐酸土チル 3 0 ii に溶かし、 5 %パラジゥ ム炭素 1 2 Omgを加ぇ、 氷冷,水素気流中 2 0分間攪拌した。 触媒をろ 去し、 酢酸ェチルで洗ぃ、 ろ液を減圧下濃縮した。 残留物をシリカゲル カラムクロマ トグラフィ —に付して、 へキサン—詐酸ェチルー鲊酸 (5 0 : 5 0 : 1 )で溶出して、 題記化合物 1 5 0 mgを得た。 Obtained in Reference Example 6 (4 S 58, 5 R * 5) - over base Nji Ruo alkoxycarbonyl -4 - base Nji Ruo alkoxycarbonyl § Mi Roh - 5 main butoxy詐carbonyl one 3- Isokisazori Gino emissions 0.36g The resultant was dissolved in acid earth chill 30 ii, added with 5% palladium carbon 12 Omg, stirred on ice, and stirred in a hydrogen stream for 20 minutes. The catalyst was removed by filtration, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl oxalate (50: 50: 1) to give 150 mg of the title compound.
I R V cm-l:3340-, 1765,1730,1695,1535, 1290,1245,1225. IRV cm- l : 3340-, 1765,1730,1695,1535, 1290,1245,1225.
max max
NMR (90MHz, CD C 13 - (C D 3) 2 C O ) 5 : 3.74(3H, s) , 4.6 -5.0(2H, m) , 5 10(2H, s>, 7.00C1H, broad s) , 7.32(5H,s) .
実施例 5 2 NMR (90MHz, CD C 1 3 - (CD 3) 2 CO) 5: 3.74 (3H, s), 4.6 -5.0 (2H, m), 5 10 (2H, s>, 7.00C1H, broad s), 7.32 (5H, s). Example 5 2
(4 S 38 , 5 R5* )一 2— [4—べンジルォキシカルボニルァミノ一 5— メ トキシカルボニル— 3—ォキソ— 2—ィソキサゾリジニル ]一 5—ォ キソ一 2—テトラヒ ドロフランカルボン酸 4一二ト ·σべン -ジルェステ ル [化合物(5 2)]の製造: (4 S 38 , 5 R 5 *)-1 2— [4-benzyloxycarbonylamino-5-methoxycarbonyl—3-oxo-2-isoxazolidinyl] -1 5-oxo-1 2— Production of tetrahydrofuran carboxylic acid 412 · sigma-ben-gilester [Compound (52)]:
参考例 7で得た(4 , 5 )ー ーべンジルォキシカルボニルァ ミノ一 5—メ トキシカルボニルー 3—ィソキサゾリ ジノ ン 8 9 mgと 1— (4ーニトロべンジル) 水素 2—ォキソグルタレー ト 9 3 mgをジクロ ロメタン 6κ£に溶かし D C C 6 8 mgを加ぇて室温で 3 0分間か 'きまぜた。 折出した不溶物をろ去しジクロロメタンで洗ぃ、 ろ液を濃縮し、 残留物 をシリカゲルカラムクロマトグラフィーに付し、へキサンー舴酸ェチル (2 : 3)で溶出して、 題記化合物(5 2 ) 1 0 4 mgを白色泡状物として得 89 mg of (4,5) -benzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone obtained in Reference Example 7 and 1- (4-nitrobenzyl) hydrogen 2-oxoglutarate 9 3 mg was dissolved in dichloromethane and 6 mg of DCC was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated insoluble material was removed by filtration, washed with dichloromethane, the filtrate was concentrated, the residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2: 3) to give the title compound (5 2) 104 mg was obtained as a white foam.
I Rレ I m αI X1 cm-1 :3320, 1805, 1770 -1710 ,1525, 1350, 1240, 1180, 1050. MR (90MHz, C D C 13)<5 : 2.3-3.3(4H, m) , 3.75(3H, s>, 4.5-5.1(2H, m),5.10(2H,s),5.33(2H,s),5.94(lH.d, J = 7Hz),7.31(5H,s),7.49, 7.52(each lH.d, J = 8Hz) , 8.17(2H, d, J = 8Hz) . IR Les I m αI X 1 cm -1: 3320, 1805, 1770 -1710, 1525, 1350, 1240, 1180, 1050. MR (90MHz, CDC 1 3) <5: 2.3-3.3 (4H, m), 3.75 (3H, s>, 4.5-5.1 (2H, m), 5.10 (2H, s), 5.33 (2H, s), 5.94 (lH.d, J = 7Hz), 7.31 (5H, s), 7.49, 7.52 (each lH.d, J = 8Hz), 8.17 (2H, d, J = 8Hz).
実施例 5 3 Example 5 3
( 4 S《· .5 R《· )— 2— { 4— [ 2— ( 2—ァミ ノ一 4—チァゾリル)一 (Z)— 2— (メ トキシィミノ)ァセトァミ ド ]— 3—ォキソ一 2—ィソキ サゾリ ジニル }ー 5ーォキソ一 2—テトラヒ ドロフランカルボン酸 ナ トリゥム塩 [化合物(5 3)]の製造: (4 S << · .5 R << ·) — 2— {4— [2— (2—amino 1 4-thiazolyl) -1 (Z) — 2— (Methoxyimino) acetamido] — 3—oxo Preparation of sodium 2-sodium sazolidinyl} -5-oxo-2-tetrahydrofurancarboxylic acid [Compound (53)]:
実施例 5 2で得た化合物(5 2 ) 1 0 4 mgを詐酸ェチル 3^と水 3 ^に 溶かし、 5 %パラジゥム炭素 1 0 0 mgを加ぇ、 水素気流中室温で 4 5分 間かきまぜた。 触媒をろ去し水洗し、 ろ液ぉょび洗液を合ゎせて水層を
取り、 テトラヒ ドロフラン 1 0¾£ 加ぇ、 氷冷攙拌下に 2—(2—クロ σァセトァミ ド— 4—チァゾリル)一(Ζ)— 2—メ トキシィミノ酢酸ク ロリ ド 塩酸塩 8 1 mgぉょび炭酸水まナトリゥム水を加ぇて ΡΗ 7.0付近 に保ち 3 0分間反応した。 っぃで Ν—メチルジチォカづレパミ-ン酸ナトリ ゥム 6 2 nigを加ぇ室温で 1時間かきまぜた。 減圧下にテトラヒ ドロフラ ンを留去し、 濃縮液を舴酸ェチルで洗浄後、 X AD— 2カラムで精製し た。 水ぉょび 5 %ェタノ -ルで溶出される画分を凍結乾燦して、 題記化 合物(5 3 ) 24 mgを得た。 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 10¾ ¾, add 2— (2-chloro ァ acetamido-4 4thiazolyl) -1- (Ζ) —- 2-methoximinoacetic acid chloride hydrochloride 8 1 mg under ice-cooling and stirring. Then, carbonated water and sodium water were added to keep the temperature at around 7.0, and the reaction was carried out for 30 minutes. The mixture was stirred at room temperature for 1 hour at room temperature with addition of sodium methyl reticate-62-nig. The tetrahydrofuran was distilled off under reduced pressure, and the concentrated solution was washed with ethyl acetate and purified with an XAD-2 column. The fraction eluted with 5% ethanol in water was freeze-dried to give 24 mg of the title compound (53).
I R T cm-1 :1780, 1760-1730, 1665, 1530, 1040. IR T cm -1 : 1780, 1760-1730, 1665, 1530, 1040.
max max
NMR OOMHz.D 20) 5: 2.3-3.3(4H,m) , 3.79 , 3.82(each 1.5H,s),NMR OOMHz.D 2 0) 5: 2.3-3.3 (4H, m), 3.79, 3.82 (each 1.5H, s),
3.9lC3H,s),4.9-5.6(2H,m),6.90(lH,s). 3.9lC3H, s), 4.9-5.6 (2H, m), 6.90 (lH, s).
参考例 8 ' · Reference Example 8 '
(4 S5* , 5 S )ー 4ーべンジルォキシカルポニルァミノ 一 5—メ ト キシカルボニルー 3—ィソキサゾリ ジメ ンの製造: (4 S 5 *, 5 S ) -4 over base Nji Ruo carboxymethyl Cal Poni Rua Mino one 5- main preparative alkoxycarbonyl over 3 Isokisazori dimethyl down of production:
参考例 6で得た(4 S ' .5 S )— 2—べンジルォキシカルポニル― 4 ーべンジルォキシカルボニルァミ ノ — 5—メ トキシカルボニル— 3 - ィソキサゾリ ジノ ン 1 7 6tngを用ぃて参考例 7と同様に反応させて、 題 記化合物 5 4 mgを得た。 176 tng of (4S'.5S)-(2-benzyloxycarbonyl) -4-benzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone obtained in Reference Example 6 The reaction was carried out in the same manner as in Reference Example 7 to obtain 54 mg of the title compound.
I R (^ : 3300.1750, 1710(肩), 1690, 1540, 1255, 1225. I R (^: 3300.1750, 1710 (shoulder), 1690, 1540, 1255, 1225.
NMR (90MHz, CD C 13- (C D 3)2 C 0) 5: 3.65(3H. s) , 4.9 -5. (2H, m),5.12C2H,s),6.42(lH, broad s) , 7.34(5H, s) . NMR (90MHz, CD C 1 3 - (CD 3) 2 C 0) 5:. 3.65 (. 3H s), 4.9 -5 (2H, m), 5.12C2H, s), 6.42 (lH, broad s), 7.34 (5H, s).
実施例 5 4 Example 5 4
(4 S《— , 5 S * ) - 2 - [ ーべンジルォキシカルポニルァミノ 一 5— メ トキシカルボニルー 3—ォキソ一 2—ィソキサゾリ ジニル]— 5—ォ キソ— 2—テトラヒ ドロフランカルボン酸 4—ニトロべンジルェステ
ル [化合物(5 4)]の製造: (4 S << —, 5 S *)-2-[-benzyloxycarponylamino-5-methoxycarbonyl-3-oxo-1 2-isoxazolidinyl] — 5-oxo-2-tetrahydrofurancarbone Acid 4-nitrobenzyl ester Preparation of [Compound (54)]:
参考例 8で得た(4 S* , 5 S ¾ ) - 4—べンジルォキシカルボニルァ ミノ一 5—メ トキシカルボニル一 3—ィソキサゾリジノ ン 6 9 mgと 1 — (4ーニトロべンジル 水素 2—ォキソグルタレー ト 6 Omgとをジク ロロメタン 6 ¾βに溶 し、 1 一ェトキシカルボニルー 2—ェトキシー 1 2—ジヒ ド口キノ リ ン 7 1 mgを加ぇて 1 8時間放置した。 反応液を减圧 下に濃縮して、 残留物をシリカゲルカラムクロマトグラフィーに付し、 へキサン—酢酸ェチル(1 : 1 )で溶出して、 題記化合物(54) 1 1 4mg を白色泡状物として得た。 ' Obtained in Reference Example 8 (4 S *, 5 S ¾) - 4- downy Nji Ruo alkoxycarbonyl § Mino one 5- main butoxycarbonyl one 3- Isokisazorijino emissions 6 9 mg and 1 - (4 Nitoro base Njiru hydrogen 2- Oxoglutarate (6 Omg) was dissolved in dichloromethane (β-β), and 11-ethoxycarbonyl-2-ethoxy-12-dihydroquinoline (71 mg) was added and the mixture was allowed to stand for 18 hours. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1: 1) to give 114 mg of the title compound (54) as a white foam.
I R V Neat I R V Neat
max cm"1 :3360,1805,1770-1720,1525,1350,1240,1180,1060, max cm " 1 : 3360,1805,1770-1720,1525,1350,1240,1180,1060,
NMROOMHz, C D C 13) 5 : 2.3-3.4(4H, m) , 3.63(3H, s) , 5.0 -5.5(2H, m),5.09(2H,s),5.34(2H,s),5.83,6.02(each 0.5H, d, J = 6Hz) , 7.31(5H, s),7.50,8.17(each 2H, d, J = 9Hz) . NMROOMHz, CDC 1 3) 5: 2.3-3.4 (4H, m), 3.63 (3H, s), 5.0 -5.5 (2H, m), 5.09 (2H, s), 5.34 (2H, s), 5.83,6.02 (each 0.5H, d, J = 6Hz), 7.31 (5H, s), 7.50, 8.17 (each 2H, d, J = 9Hz).
実施例 5 5 Example 5 5
(4 S《- , 5 )— 2— {4— [2—(2—ァミ ノ ー 4—チァゾリル)一 (Z)— 2— (メ トキシィ ミ ノ)ァセ トァミ ドニー 3—ォキソ— 2 —ィソキ サゾリ ジニル }一 5—ォキソ一 2—テ トラヒ ドロフランカルボン酸 · ナ トリゥム塩 [化合物(5 5)]の製造: (4 S <<-, 5) — 2— {4— [2— (2-amino-4-thiazolyl) -1 (Z) — 2— (methoxyminino) acetamidony 3—oxo— 2 —Isoki sazolidinyl} -1-oxo-2- 2-tetrahydrofurancarboxylic acid · sodium salt [Production of compound (55)]:
実施例 5 4で得た化合物(5 4) 1 1 4mgを用ぃて実施例 5 3と同様に 反応させて題記化合物(5 5) 5 O mgを得た。 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).
I R KBr I R KBr
V max cm"1 :1780, 1775, 1750, 1740, 1660, 1530, 1380, 1200, 1040V max cm " 1 : 1780, 1775, 1750, 1740, 1660, 1530, 1380, 1200, 1040
NMROOMHz, D20)5 : 2.3 -3.3(4H, m) , 3.68 , 3.71(each 1.5H,s),3.9 NMROOMHz, D 2 0) 5: 2.3 -3.3 (4H, m), 3.68, 3.71 (each 1.5H, s), 3.9
3(3H,s)>4.9-5.6(2H,m),6.92(lH,s). 3 (3H, s) > 4.9-5.6 (2H, m), 6.92 (lH, s).
産業上の利用可能性 Industrial applicability
化合物(Ι ')またはその塩は、 爱れた抗菌作用を有し、 抗菌剤ぁるぃ
は細菌感染症治療剤として利用される
Compound (Ι ′) or a salt thereof has an excellent antibacterial activity, and is an antibacterial agent. Is used as a therapeutic agent for bacterial infections
Claims
1. ー般式 1. ー general formula
[式中、 R1はァミノ基または窒素を介する有機残基を示す。 R2はカル ポキシル基またはそれから誘導され得る基を示す R 3 , R + , R '5 , R 8 ,0 R7ぉょび R8は、 同ーまたは異なって、 水素または有機残基を示し、 [Wherein, 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 + , R ' 5 , R 8 , 0 R 7 and R 8 represent the same or different and represent hydrogen or an organic residue. ,
R 5ぁるぃは R8と R 7ぁるぃは R 8とが化学結合を形成してぃる場合を含 む。 Xは水素.メ トキシまたはホルミルァミ ノを示す。 ただ -し、 R3 R R5, Re,R7ぉょび R8は同時に水素ではなぃ。 ]で表ゎされる化合物ま ' たはその塩。 -5 2. R3または(ぉょび) R+が、 水素または炭素原子にぉぃて結合する有 機残基でぁる請求の範囲第 1項記载の化合物。 R 5 Arui is R 8 and R 7 Arui is including a case forming Shitiru a chemical bond with R 8. X represents hydrogen methoxy or formylamino. But-but R 3 RR 5 , R e , R 7 and R 8 are not hydrogen at the same time. Or a salt thereof. -5 2. The compound according to claim 1, wherein R 3 or (hope) R + is an organic residue bonded to hydrogen or a carbon atom.
3. R5, Rs, R7または(ぉょび) R8が、 水素または炭素原子にぉぃて結 合する有機残基;酸素原子,窒素原子または硫黄原子を介して結合する有 機残基:またはハロゲンでぁる請求の範囲第 1項記載の化合物。3. An organic residue in which R 5 , R s , R 7 or R 8 is bonded to a hydrogen or carbon atom; an organic residue bonded through an oxygen, nitrogen or sulfur atom The compound according to claim 1, which is a residue: or a halogen.
0 4. 炭素原子にぉぃて結合する有機残基が置換基を有してぃてもょぃァ ルキル,シクロァルキル,置換基を有してぃてもょぃァルケニル,置換基 を有してぃてもょぃァリ—ル, ァシル, シァノ .またはェステル化ぁる ぃはァミ ド化されてぃてもょぃカルボキシルでぁる請求の範囲第 2項記 載の化合物。0 4. The organic residue bonded to the carbon atom has a substituent, is a substituted or unsubstituted alkyl, a cycloalkyl, or a substituted or unsubstituted alkyl. A compound as claimed in claim 2 wherein the aryl, acyl, cyano or esterified compound is amidated with carboxyl.
5 5. 炭素原子にぉぃて桔合する有機残基が、 置換基を有してぃてもょぃ ァルキル,シクロァルキル,置渙基を有してぃてもょぃァルケニル,置換
基を有してぃてもょぃァリール,ァシル,シァノ,カルパモィル,置換基を 有してぃてもょぃ複素環,またはェステル化もしくはァミ ド化されてぃ てもょぃカルボキシルでぁる請求の範囲第 3項記載の化合物。 5 5. An organic residue that binds to a carbon atom has a substituent, such as a substituted alkyl, a cycloalkyl, or a substituted alkenyl group. Carboxylic or heteroaryl, substituted or heterocyclic, or esterified or amidated, having a carboxyl group. 4. The compound according to claim 3, wherein
6. 酸素原子を介して桔合する有機残基が、 式- 0- ft3 [式中、 Raはー6. An organic residue that is bonded via an oxygen atom is represented by the formula-0-ft 3 [where R a is
」, ",
水素,ァルキル,ァリ—ル,ァシル,カルバ乇ィルを示す。 ]で表ゎされる 基,またはォキソ基でぁる請求の範囲第 3項記載の化合物。 Indicates hydrogen, alkir, aryl, ashir, carbazyl. 4. The compound according to claim 3, which is a group represented by the formula or an oxo group.
7. 窒素原子を介して結合する有機残基が、 式ー Nく:" lt [式中、 RiQ ぉょび R 11は、 同一または異なって、 水素,ァルキル,ァリール.ァシル を示す。 ]で表ゎされる基でぁる請求の範囲第 3項記载の化合物。 7. The organic residue bonded through the nitrogen atom is represented by the formula -N: " lt [wherein R iQ and R 11 are the same or different and represent hydrogen, alkyl, aryl.acyl.] 4. The compound according to claim 3, which is a group represented by the formula:
8. 硫黄原子を介して結合する有機残基が、 式— S (0)n— R12 [式中、 R 12は水素,置換基を有してぃてもょぃァルキル,置換基を有してぃても ょぃァリール,置換基を有してぃてもょぃ複素環,または置換基を有して ぃてもょぃァミ'ノを、 nは 0 , 1または 2を示す。 ]で表ゎされる基でぁ る請求の範囲第 3項記載の化合物。 8. An organic residue bonded through a sulfur atom has the formula —S (0) n—R 12 [wherein, R 12 is hydrogen, has a substituent, has a substituent, has a substituent. And n represents 0, 1 or 2; n is 0, 1 or 2; . 4. The compound according to claim 3, which is a group represented by the formula:
9. ー般式 9. General formula
R3 + R 3 +
[式中、 R は窒素を介する有機残基を示す。 R3ぉょび は、 同ーま たは異なって、 水素または有機残基を示す。 R3ぉょび R*が同時に水素 でぁる場合を含む。 Xは水素,メ トキシまたはホルミルァミノを示す。 ] で表ゎされる化合物とー般式
[Wherein, R represents an organic residue via nitrogen. R 3 represents the same or different and represents hydrogen or an organic residue. Including the case where R 3 and R * are simultaneously hydrogen. X represents hydrogen, methoxy or formylamino. ] And the general formula
[式中、 11 はカルボキシル基から誘導され得る基を示す。115,118.1 7 ぉょぴ R8は、 同ーまたは異なって、 水素または有機残基を示し、 R5ぁ るぃは R8と R 7ぁるぃは R8とが化学結合を形成してぃる場合を含む。 R 5 , R'8, R 7ぉょぴ R 8が同時に水素でぁる場合を含む。]で表ゎされる化0 合物またはその反応性誘導体とを反応させ、 さらに必要にょり該化合物 の R ぉょぴ または の変換反応に付すことを特徵とする一般式 [In the formula, 11 represents a group which can be derived from a carboxyl group. 11 5, 11 8.1 7 Oyopi R 8 are the same over or different and are hydrogen or an organic residue, R 5 § Rui is R 8 and R 7 Arui is a chemical bond and R 8 Is included. R 5 , R ' 8 , R 7 hops R 8 is simultaneously hydrogen. A compound represented by the formula: or a reactive derivative thereof, and, if necessary, subjecting the compound to a conversion reaction of R or R
R3 R* R 3 R *
R R
R5 SR7R8 R 5 S R 7 R 8
、;^ ^へ ,; To ^ ^
ゝ: =0 ゝ: = 0
' 、ひ, '
[式中、 R1はァミ ノ基または窒素を介する有機残基を、 R2はカルボキ シル基またはそれから誘導され得る基をそれぞれ示す。 R 3 , R + , R 5 , R 8 R7ぉょび R8は前記と同意義を有する。 113,1 ,^1 6,117ぉょび1 80 が同時に水素でぁる場合を含む。 ]で表ゎされる化合物の製造法。 [In the formula, R 1 represents an amino group or an organic residue via nitrogen, and R 2 represents a carboxyl group or a group derivable therefrom. R 3 , R + , R 5 , R 8 R 7 and R 8 are as defined above. 11 3, 1, including the case Aru in ^ 1 6, 11 7 Oyobi 1 8 0 simultaneously hydrogen. A method for producing a compound represented by the formula:
1 0. ー般式 1 0. ー General formula
R3 R'
[式中、 R1'は窒素を介する有機残基を示す。 R3ぉょび は、 同ーま たは異なって、 水素または有機残基を示す。 R3ぉょぴ R4が同時に水素 でぁる場合を含む。 Xは水素.メ トキシまたはホルミルァミノを示す。 ] で表ゎされる化合物と一般式 R 3 R ' [In the formula, R 1 ′ represents an organic residue via nitrogen. R 3 represents the same or different and represents hydrogen or an organic residue. Including the case where R 3 and R 4 are simultaneously hydrogen. X represents hydrogen methoxy or formylamino. ] And the general formula
[式中、 R2'はカルボキシル基から誘導され得る基を示す。 R5.R6,R7 ぉょぴ R8は、 同ーまたは異なって、 水素または有機残基を示し、 R5ぁ るぃは R 8と R 7ぁる.ぃは R 8とが化学結合を形成してぃる場合を含む。 [Wherein, R 2 ′ represents a group that can be derived from a carboxyl group. R 5 .R 6, R 7 Oyopi R 8 are the same over or different and are hydrogen or an organic residue, R 5 § Rui is R 8 and R 7 Aru. Iha R 8 and chemical This includes the case where a bond is formed.
115,118,117ぉょび118が同時に水素でぁる場合を含む。 Yは脱離基を示 す。 ]で表ゎされる化合物とを反応させ、 さらに必要にょり該化合物の R ぉょびノまたは R2'の変換反応に付すことを特徵とするー般式 11 5, including the case Aru 11 8, 117 Oyobi 11 8 are hydrogen simultaneously. Y represents a leaving group. A compound represented by the general formula (1), wherein the compound is subjected to a conversion reaction of R 2 or R 2 ′ of the compound, if necessary.
[式中、 R1はァミノ基または窒素を介する有機残基を、 R2はカルボキ シル基またはそれから誘導され得る基をそれぞれ示す。 R3, R , R5,R 6 R 7ぉょぴ R 8は前記と同意義を有する。 113,114,1¾5.1 6,1 7ぉょび118 が同時に水素でぁる場合を含む。 ]で表ゎされる化合物の製造法。 [In the formula, R 1 represents an amino group or an organic residue via nitrogen, and R 2 represents a carboxyl group or a group derivable therefrom. R 3 , R, R 5 , R 6 R 7 and R 8 have the same meaning as described above. 11 3, 11 4, including the case Aru in 1¾ 5 .1 6, 1 7 Oyobi 11 8 are hydrogen simultaneously. A method for producing a compound represented by the formula:
1 1 . —般式
-121- 1 1. —General formula -121-
R5Re R7 R8 R 5 R e R 7 R 8
C00H C00H
、R2, , R 2 ,
[式中、 R2'はカルボキシル基から誘導され得る基を示す。 R5.RS.R' ぉょび R8は、 同ーまたは異なって、 水素または有機残基を示し、 R5ぁ るぃは R6と R7ぁるぃは R8とが化学結合を形成してぃる場合を含む。 [Wherein, R 2 ′ represents a group that can be derived from a carboxyl group. R 5 .R S .R 'and R 8 are the same or different and represent hydrogen or an organic residue, and R 5 is a chemical bond with R 6 and R 7 is a chemical bond with R 8 Is included.
115,1 6,1 7ぉょぴ118が同時に水素でぁる場合を含む。 ただし、 R5,0 Re. R 7ぉょぴ R 8が同時に水素のとき、 R2'はェトキシカルボニルでは なぃ。 ]で表ゎされる化合物。 11 5, 1 6, 1 7 Oyopi 11 8 simultaneously hydrogen containing case Aru. However, when R 5 , 0 R e .R 7 and R 8 are simultaneously hydrogen, R 2 ′ is not ethoxycarbonyl. ] The compound represented by this.
1 2. ー般式 1 2. General formula
す。 R5,R8.R7 基を示し、 R 5ぁ る場合を含む。 You. R 5 , R 8 and R 7 groups, including the case of R 5 .
Yは脱離基を示
[式中、 R1はァミノ基または窒素を介する有機残基を示す。 R2はカル ボキシル基またはそれから誘導さ 得る基 示す。113,11 ,1 5,1 6.117 ぉょび R8は、 同一または異なって、 水素または有機残基を示し、 R5ぁ るぃは R8と R7ぁるぃは R8とが化学結合を形成してぃる場合を含む。 Y represents a leaving group [Wherein, R 1 represents an amino residue or an organic residue via nitrogen. R 2 represents a carboxyl group or a group derived therefrom. 11 3, 11, 1 5, 1 6.11 7 Oyobi R 8 are the same or different and each represents hydrogen or an organic residue, R 5 § Rui is R 8 and R 7 Arui is R 8 And that form a chemical bond.
Xは水素,メ トキシまたはホルミルァミノを示す。 ただし、 R3,R4.R5.X represents hydrogen, methoxy or formylamino. However, R 3 , R 4 .R 5 .
R8,R7ぉょぴ R8は同時に水素ではなぃ。 ]で表ゎされる化合物または その塩を含有する抗菌剤。
R 8 , R 7 hop R 8 is not hydrogen at the same time. ] An antibacterial agent containing the compound represented by the formula or a salt thereof.
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/JP1985/000394 WO1987000527A1 (en) | 1985-07-12 | 1985-07-12 | Antibacterial compounds, their use, and process for their preparation |
EP86302819A EP0219923B1 (en) | 1985-04-30 | 1986-04-16 | Antibiotic derivatives, their production and use |
AT86302819T ATE80163T1 (en) | 1985-04-30 | 1986-04-16 | ANTIBIOTIC DERIVATIVES, THEIR PRODUCTION AND USE. |
DE8686302819T DE3686632T2 (en) | 1985-04-30 | 1986-04-16 | ANTIBIOTIC DERIVATIVES, THEIR PRODUCTION AND USE. |
ES554495A ES8802317A1 (en) | 1985-04-30 | 1986-04-29 | Antibiotic derivatives, their production and use. |
HU861788A HU197742B (en) | 1985-04-30 | 1986-04-29 | Process for producing antibiotical derivatives of isoxazolidinyl-tetrahydrofurane carboxylic acid and pharmaceutical compositions containing them as active components |
KR1019860003319A KR930005174B1 (en) | 1985-04-30 | 1986-04-29 | Process for preparing antibiotic derivatives |
CA000507875A CA1285950C (en) | 1985-04-30 | 1986-04-29 | 2-(4-substituted amino-3-oxo-2-isoxazolidinyl)-5-oxo-2- tetrahydrofurancarboxylic acid derivatives, their production and use |
DK195986A DK195986A (en) | 1985-04-30 | 1986-04-29 | 2- (4-SUBSTITUTED AMINO-3-OXO-2-ISOXAZOLIDINYL) -5-OXO-2-TETRAHYDROFURAN CARBOXYLIC ACID DERIVATIVES AND PROCEDURE AND USE THEREOF |
US06/857,834 US4851422A (en) | 1985-04-30 | 1986-04-30 | Antibiotic 2-(3-oxo-2-isoxazolidinyl)-5-oxo-2-tetrahydrofuran-carboxylates |
CN198686102923A CN86102923A (en) | 1985-04-30 | 1986-04-30 | The method for preparing antibiotic derivatives |
ES557661A ES8801650A1 (en) | 1985-04-30 | 1987-08-13 | Antibiotic derivatives, their production and use. |
Applications Claiming Priority (1)
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PCT/JP1985/000394 WO1987000527A1 (en) | 1985-07-12 | 1985-07-12 | Antibacterial compounds, their use, and process for their preparation |
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EP4313980A4 (en) * | 2021-03-31 | 2024-07-17 | Fedora Pharmaceuticals Inc | Lactivicin compounds, their preparation and use as antibacterial agents |
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1985
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EP4313980A4 (en) * | 2021-03-31 | 2024-07-17 | Fedora Pharmaceuticals Inc | Lactivicin compounds, their preparation and use as antibacterial agents |
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