CN1044473C - Tropone-substituted phenyloxazolidinone antibacterial agents - Google Patents
Tropone-substituted phenyloxazolidinone antibacterial agents Download PDFInfo
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- CN1044473C CN1044473C CN93120887A CN93120887A CN1044473C CN 1044473 C CN1044473 C CN 1044473C CN 93120887 A CN93120887 A CN 93120887A CN 93120887 A CN93120887 A CN 93120887A CN 1044473 C CN1044473 C CN 1044473C
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- oxo
- methyl
- phenyl
- oxazolidinyl
- ethanamide
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Abstract
The invention discloses a novel phenyl star-shaped azole alkane alkone antibiotics; the obvious structural characteristic is that the antibiotics has an addition portion of tropone to replace. The invention also discloses the intermediate body and method for manufacturing these antibiotics. The compounds are the useful antibiotics for eliminating or controlling the sensitive organism.
Description
The present invention relates to the phenyl oxazolidone compound that new tropone replaces, this compounds can be used as antiseptic-germicide.
The oxazolidone compounds is a class tool Orally active, synthetic antiseptic-germicide, and has many reference to disclose Ge Zhong oxazolidone derivative in the art.For example, there are many reference to relate on phenyl ring, to have one, two or trisubstituted 3-phenyl-2-oxazolidone compounds.The open mono-substituted reference of phenyl ring comprises United States Patent (USP) 4,948, No. 801,4,461, and No. 773,4,340, No. 606,4,476, No. 136,4,250, No. 318,4,128, No. 654 and Re29, No. 607.Relating to 3-[(-replaces) phenyl]-other reference of 2-oxazolidone compounds sees European publication No. 0312000: Gregory etc., J.Med.Chem.35:1673 (1989); J.Med.Chem.33:2569 such as Gregory (1990); Park etc., J.Med.Cbem.35:1156 (1992) and Wang etc., Tetrahedron 45:1323 (1989).This compounds also comprises antiseptic-germicide DuP721.
3-[(two replaces, three replace or condensed ring replaces) phenyl]-2-oxazolidone compounds is reported in United States Patent (USP) 4,977, and No. 173,4,921, No. 869 and 4,801, No. 600; EP bulletin No. 0316594, No. 0184170 and No. 0127902; And the U. S. application sequence number 07/880,492 of PCT patent application PCT/US89/03548, PCT/US90/06220, PCT/US92/08267 and submission on May 8th, 1992.
We have found that as the effectively 3-[(one, two and three replacements of antiseptic-germicide) phenyl]-2-oxazolidone compounds.The compounds of this invention is characterised in that 3-phenyl-2-oxazolidone compounds has the tropone ring of tropone or replacement in the contraposition of phenyl ring, and the position is optional in addition between phenyl ring is replaced by various groups.
Following reference discloses has mono-substituted 3-phenyl-2-oxazolidone compounds on phenyl ring.
United States Patent (USP) 4,948 discloses 3-[(aryl and the heteroaryl with anti-microbial activity No. 801) phenyl]-2-oxazolidone compounds.
United States Patent (USP) 4,476 discloses 3-[(P-arylalkyl, aromatic yl alkenyl and aromatic yl polysulfide yl with anti-microbial activity for No. 136 and has replaced) phenyl]-5-(aminomethyl)-2-oxazolidone compounds.
United States Patent (USP) 4,461 discloses 3-phenyl-5-(the methylol)-2-oxazolidone compounds of the replacement with anti-microbial activity No. 773.
United States Patent (USP) 4,340 discloses the 3-[(P-alkyl sulphonyl of the replacement that has anti-microbial activity in Mammals No. 606) phenyl]-5-(methylol)-or (acyl-oxygen methyl)-2-oxazolidone compounds.
United States Patent (USP) 4,250 discloses 3-phenyl-5-(the methylol)-2-oxazolidone compounds of the replacement with antidepressant effectiveness No. 318.
United States Patent (USP) 4,128 discloses 3-phenyl-5-(the halogenated methyl)-2-oxazolidone compounds of the replacement of the fungi that can be used for controlling plant and bacterial disease for No. 654.
The U.S. issue again patent disclose for 29, No. 607 have antidepressant, 3-phenyl-5-(the methylol)-2-oxazolidone compounds of the replacement of stable and calm effectiveness.
Belgian patent discloses for 892, No. 270 corresponding to the 3-[(arylalkyl aromatic yl alkenyl of No. 4,476,136, above-mentioned United States Patent (USP) or aromatic yl polysulfide yl and has replaced) phenyl]-5-(aminomethyl)-2-oxazolidone compounds.
The Europe publication discloses the 3-phenyl-2-oxazolidone compounds that replaces corresponding to the aryl of No. 4,948,801, above-mentioned United States Patent (USP) and heteroaryl for No. 0352781.
European publication discloses the 3-phenyl-2-oxazolidone compounds of phenmethyl and pyridylmethyl replacement for No. 0312000 as being reported in Derwent98-116142/16.
3-[(one-replacement is disclosed) phenyl]-other nearest reference of 2-oxazolidone compounds has C.-H.Park etc., J.Med.Chem.35:1156 (1992), W.A.Gregory etc., J.Med.Chem 33:2569 (1990) and J.Med.Chem.32:1673 (1989); C.J.Wang etc., Tetrahedron 45:1323 (1989); And A.M.slee etc., Antimicrobial Agents and Chemotherapy 31:1791 (1981) and D.C.Eustice etc., Antimicrobial Agents and Chemotherapy 32:1218 (1988).
Following reference discloses 3-[(two-replacement) phenyl]-, 3-[(three-replacement) phenyl]-or the 3-[(condensed ring replace) phenyl]-2-oxazolidone compounds:
United States Patent (USP) 4,977 discloses the 3-phenyl-2-oxazolidone compounds (formula X III) that contraposition has lactan and the position has fluorine between phenyl ring at phenyl ring for No. 173.
United States Patent (USP) 4,921 No. 869 and 4,801, discloses 6 ＇-indolinyl-or alkane ketone oxazolidinone compounds (wherein the nitrogen of the nitrogen Chu Yu oxazolidone of indolinyl between position) for No. 600.
United States Patent (USP) discloses the amino methyl Yang Dai oxazolidinyl benzene derivative of the replacement with anti-microbial activity for 4705, No. 799, comprises sulfide, sulfoxide, sulfone and sulphonamide.
C.-H.Park etc., J.Med.Chem.35:1156 are other one piece of nearest reference, disclose 3-[(two-replacement) phenyl]-and 3-[(three-replacement) phenyl]-2-oxazolidone compounds.
The Europe publication discloses for No. 0316594 and 3-(styryl)-2-oxazolidone compounds corresponding to the replacement of No. 4,977,173, above-mentioned United States Patent (USP).
No. 4,705,799, No. 0184170, the publication in Europe and No. 0127902 and United States Patent (USP) discussed above are corresponding.
PCT/US89/03548 and PCT/US90/06220 disclose that the 3-[(condensed ring that can be used as antiseptic-germicide replaces) phenyl]-2-oxazolidine compounds.
PCT/US92/08267 discloses the aryl of the replacement that can be used as antiseptic-germicide-and heteroaryl-phenyl oxazolidone compounds.
The U.S. Patent Application Serial Number of submitting on May 8th, 1,992 07/880,492 discloses the phenyl oxazolidone compound that contains the substituted diazine moieties part.
The reference of quoting as proof does not above have one piece to disclose the phenyl oxazolidone compound that tropone of the present invention replaces.
Have the compound of formula I and pharmacologically acceptable salt thereof with and hydrate.
R wherein
1Be:
(a) hydrogen
(b) (the C that is randomly replaced by one or more F, Cl, hydroxyl, alkoxyl group, acyloxy
1-C
8) alkyl,
(c) (C
3-C
6) cycloalkyl,
(d) amino,
(e) (C
1-C
8) alkylamino,
(f) (C
1-C
8) dialkyl amido,
(g) (C
1-C
8) alkoxyl group,
R wherein
2And R
3Be identical or different, and be selected from following groups, precondition is to work as R
2And R
3When not all being hydrogen, R
2And R
3Identical:
(a) hydrogen
(b) fluorine
(c) chlorine
(d) (C
1-C
8) alkyl
(e) trifluoromethyl
(f) hydroxyl
(g) (C
1-C
8) alkoxyl group
(h) nitro
(i) amino
R wherein
4Be selected from following groups:
Wherein R and R
5Be identical or different, and be selected from by the optional (C that replaces of following groups
1-C
8) alkyl: chlorine, fluorine, hydroxyl, (C
1-C
8) alkoxyl group, amino, (C
1-C
8) alkylamino, (C
1-C
8) dialkyl amido;
R wherein
5Be selected from following groups: hydrogen, OR
6, SR
6, NH
7,
And NR
7R
12
R wherein
6Be:
(a) hydrogen
(b) by the optional (C that replaces of one or more halogens
1-C
8) alkyl
(c) by amino, C
1-C
8Alkylamino, C
1-C
8Optional (the C that replaces of dialkyl amido
1-C
8) alkyl
(d) by one or more hydroxyls and by amino, alkylamino, the optional (C that replaces of dialkyl amido
1-C
8) alkyl
(e) by one or more C
1-C
8Optional (the C that replaces of alkoxyl group
1-C
8) alkyl
(f) by amino, (C
1-C
8) alkylamino, (C
1-C
8) optional (C that replaces of dialkyl amido
2-C
8) alkenyl (C
1-C
8) alkyl
(g) by amino, (C
1-C
4) alkylamino, (C
1-C
8) optional (C that replaces of dialkyl amido
2-C
8) alkynyl (C
1-C
8) alkyl
(h) by hydroxyl, amino, (C
1-C
8) alkylamino, (C
1-C
4) optional (C that replaces of dialkyl amido
2-C
8) acyl group
(i) the amino, (C of quilt on phenyl
1-C
8) alkylamino, (C
1-C
8) the optional phenyl (C that replaces of dialkyl amido
1-C
8) alkyl
(j) the amino, (C of quilt on pyridyl
1-C
8) alkylamino, (C
1-C
8) the optional pyridyl (C that replaces of dialkyl amido
1-C
8) alkyl
(k) by one or two (C
1-C
6) the optional amino that replaces of alkyl
R wherein
7Be:
(a) hydrogen
(b) by one or more chlorine, fluorine, hydroxyl, amino, (C
1-C
8) alkylamino, (C
1-C
8) dialkyl amido, phenyl, pyridyl, (C
1-C
8) alkoxyl group, (C
1-C
8) the partly optional (C that replaces of carbalkoxy
1-C
8) alkyl
(c) by amino, (C
1-C
8) alkylamino or (C
1-C
8) optional (C that replaces of dialkyl amido
3-C
6) cycloalkyl
(d) amino
(e) (C
1-C
8) alkylamino
(f) (C
1-C
8) dialkyl amido
(g) hydroxyl
(h) (C
1-C
8) alkoxyl group
(i) by amino, (C
1-C
4) alkylamino, (C
1-C
4) optional (C that replaces of dialkyl amido
2-C
8) alkenyl (C
1-C
10) alkyl
(j) by amino, (C
1-C
4) alkylamino, (C
1-C
4) optional (C that replaces of dialkyl amido
2-C
8) alkynyl (C
1-C
10) alkyl
R wherein
8Be:
(a) hydrogen
(b) (C
1-C
8) alkyl
(c) (C
3-C
8) cycloalkyl
(d) (C
1-C
8) acyl group
(e) (C
1-C
8) carbalkoxy
(f) (C
1-C
8) alkyl sulphonyl
R wherein
9And R
10Can be identical or different, and be:
(a) hydrogen
(b) (C
1-C
8) alkyl
R wherein
11Be:
(a) hydrogen
(b) hydroxyl
(c) (C
1-C
8) alkoxyl group
(d) amino
(e) alkylamino
(f) (C
1-C
8) dialkyl amido
(g) by amino, (C
1-C
4) alkyl nitrogen base and (C
1-C
4) optional (C that replaces of dialkyl amido
1-C
8) alkyl;
R wherein
12Be (C
1-C
8) alkyl.
Phenyl oxazolidone chemical compounds I a, I b, I c and I d that tropone replaces contain at least one chiral centre, when having a chiral centre, described compound can two kinds the racemic mixture of possible optically active isomer [(R)-and (S)-enantiomorph] one or both of exist, this point is conspicuous for those of ordinary skills.Independent (R)-reach (S)-enantiomorph and composition thereof is all in the scope of the phenyl oxazolidone compound that tropone of the present invention replaces.If there is additional chiral centre, the resulting diastereomer that exists with racemize and enantiomorph enriched form is also in the claimed antiseptic-germicide I a of the present invention, I b, I c and I d scope.
The preferred absolute configuration of De oxazolidone compounds of the present invention is represented with formula I a-I d.According to the Cabn-Ingold-Prelog nomenclature this absolute configuration is called (S).This just (S)-enantiomorph is the optical isomer of anti-microbial activity.Racemic mixture can use with the same method of pure (S)-enantiomorph and for same purpose, difference be must with the racemic mixture of twice with produce with (S)-the same antibacterial effect of enantiomorph.
The preferred embodiments of the invention are by formula I a and the represented De oxazolidone of I b compounds.
Preferred compound is R wherein
2Be hydrogen and R
3Chemical compounds I a and I b for hydrogen or fluorine.Most preferred is R wherein
2And R
3Be fluorine and R
1Chemical compounds I a and I b for methyl.
The amount of carbon atom of various hydrocarbonaceous parts is represented with the minimum of carbon atom and the head of maximum number in this part of mark; Head (Ci-Cj) shows the part that contains altogether from integer " i " to the individual carbon atom of integer " j ".Therefore (C
1-C
8) alkyl is meant the alkyl that contains 1 to 8 carbon atom altogether, or methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group and isomeric form thereof.
Term (C
1-C
8) alkylamino is meant the amino part that comprises a moieties with 1 to 8 carbon atom.Term (C
1-C
8) dialkyl amido is meant the amino part that comprises two moieties with 1 to 8 carbon atom, for example, the two is respectively propyl group amino and dipropyl amino.
The meaning that term " is optionally substituted " is that described part can be replaced by 1 to 4 described substituting group.For example, optional by chlorine, fluorine, hydroxyl, (C
1-C
8) alkoxyl group, amino, (C
1-C
8) alkylamino, (C
1-C
8) (the C that replaces of dialkyl amido
1-C
8) alkyl comprises: 1-chloropropyl, 1-fluoropropyl, 3-chloropropyl, 3-fluoropropyl, 1-hydroxybutyl, 2-hydroxybutyl, 1-methoxycarbonyl propyl, the hot oxygen propyl group of 1-, 1-aminopropyl, the amino octyl group of 1-, 1-butyl aminopropyl, 1-dibutylamino propyl group etc.
The preparation of formula I a compound
The exemplary process of preparation The compounds of this invention is summarized in reaction process 1-7.Reaction process 1-4 has narrated the preparation method of the oxazolidine ketone of the tropone replacement of being rich in enantiomorph.Reaction process 5-7 shows the synthetic route of racemic intermediate and analogue.These only are representational methods, and the synthetic schemes that is provided is improved other example that can prepare the phenyl oxazolidone that tropone replaces slightly, and this point is conspicuous to those skilled in the art.
Reaction process 1
Shown in reaction process 1, under suitable temperature (70-100 ℃ usually), in appropriate solvent (N for example, dinethylformamide (DMF) or 1, the 4-diox) in, (for example two (triphenylphosphine) palladiums of tetrakis triphenylphosphine palladium or chlorination (prepare intermediate 6 (preparation method is shown in reaction process 3 and 4) and new tropone 7 down from known bromo tropone 8 in suitable palladium catalyst, see Banwell etc., Org.Prep.Proc. (1989) 393; Banwell etc., Tetrahedron Lett. (1985), 26,4543. shown in the bottom of reaction process 1) react with preparation coupled product 9.Compound 9 is phenyl oxazolidone-individual examples that the tropone of structure I a replaces, if necessary, can further process, by reacting with the nucleophilic reagent (for example a kind of amine) that suits 9 in (envrionment temperature is to reflux temperature) and the suitable solvent system under suitable temperature (for example toluene or tetrahydrofuran (THF)/water), obtain other example of I a, in the presence of the alkali (for example sodium hydride) of catalytic amount, by compound 9 and common excessive required alcohol are reacted, also the methoxy group of compound 9 can be replaced by other alkoxyl group, to obtain target adducts (seeing the experimental section of an embodiment).Required R
1Base can be present on the tropone 7 before palladium catalytic coupling step, and this is conspicuous for those of ordinary skills.Simultaneously for those skilled in the art, on employed bromo tropone (above reference, Takaya etc., J.Am.Chem.Soc. (1978), 100,1778 etc.) and on the substituting group of various intermediates change, the phenyl oxazolidone that the tropone that other enantiomorph that can preparation formula I a-d is rich in replaces will be conspicuous, this purpose of the present invention just.
Reaction process 2
Reaction process 2 illustrates the synthetic method of another alternative product, and wherein the bromine or iodine of intermediate 6 (the such preparations shown in reaction process 3 and 4) obtains metal substitutive derivative 10 (M=Me through halogen-metal exchange reaction
3Sn or ZnX), this metal substitutive derivative 10 in the presence of suitable palladium catalyst (for example tetrakis triphenylphosphine palladium or chlorination two (triphenylphosphine) palladiums) at appropriate solvent (N for example, dinethylformamide (DMF) or 1, the 4-diox) in proper temperature (usually 70-100 ℃) down and bromo tropone 8 carry out linked reaction, obtain coupled product 9.If necessary, compound 9 can further be processed then as stated above.
Reaction process 3
Table 3 has been summarized the method for the intermediate that is rich in enantiomorph of preparation structure 6, and this is the phenyl oxazolidinones I a (seeing reaction process 1 and 2) needed (seeing above) that preparation optical activity tropone replaces, and the latter is a purpose of the present invention.In this method, the crucial the first step relates to the reaction of randomly substituted phenyl isocyanate (11) and commercially available (-)-(R)-Glycidyl butyrate, use and at first (see Tetrahedron Lett. (1971) by the condition of uses such as Herweh, 809), obtain phenyl oxazolidinones intermediate 12.At United States Patent (USP) 4,705, the method for using Glycidyl butyrate Zhi oxazolidinones intermediate in this reaction is disclosed in No. 799.The publication that this respect is also arranged in the document is formerly arranged, Gregory etc. for example, J.Med.Chem. (1989), 32,1673.Then by with a kind of alkoxide, preferably in methyl alcohol, remove butyryl radicals with sodium methylate reaction, obtain alcohol 13 (R=H).Then compound 13 is changed into corresponding methanesulfonates (R=SO
2CH
3) or aromatic yl sulphonate (R=SO
2Ar) derivative, preferred methanesulfonates or tosylate (by the effect of methylsulfonyl chloride/pyridine or methylsulfonyl chloride/triethylamine/methylene dichloride or Tosyl chloride/pyridine).Then under 50 ° to the 90 ℃ temperature randomly in the presence of catalyzer (for example hexaoxacyclooctadecane-6-6), in aprotonic solvent (for example DMF or 1-Methyl-2-Pyrrolidone), with resulting sulphonate and trinitride (for example sodiumazide or potassium azide) reaction, obtain trinitride 14.Then trinitride 14 is used palladium/charcoal or platinum catalyst hydro-reduction in appropriate solvents such as ethyl acetate or methyl alcohol.In addition, can in appropriate solvent (as tetrahydrofuran (THF) (THF)), in the presence of water, handle, with described trinitride reduction with trivalent phosphorous compound (as triphenylphosphine).The amino methyl compound that obtains by reduction trinitride 14 then passes through the known reaction acidylate of those of ordinary skills is obtained the intermediate of structure 15.For example, can in-30 ℃ to 50 ℃ temperature ranges, in basic solvents such as pyridine, described amine and acyl chlorides or anhydride reaction be prepared acylated intermediate 15, wherein R
1=optional substituted alkyl.By the known standard acidylate of those of ordinary skills technology, other acyl group can easily be added on the amino methyl intermediate among the present invention, and this is apparent and obvious for those of ordinary skills.Intermediate 15 under 0 ° to 70 ℃ temperature in acetate/trifluoroacetic acid usefulness-iodine chloride or with the iodate of iodine and trifluoroacetic acid silver, obtain the phenyl-iodide oxazolidinone intermediate 6 (X=I) of enantiomorph enrichment.In addition, 15 can use the N-bromosuccinimide bromination, obtain bromated with compounds of group 6 (X=Br).
Reaction process 4
Reaction process 4 has been described a kind of variant of synthetic schemes described in the reaction process 3, and wherein the iodine of structure 6 or bromine part (X) has been present in the first step of this sequence in the employed aromatic isocyanate 16.Utilize the reaction described in the reaction process 3 (seeing above), at first, change into derivative 18 and 19 then aromatic isocyanate 16 Zhuanization Cheng oxazolidones 17.Then with trinitride 19 by in appropriate solvents such as THF, in the presence of water, and react such as trivalent phosphorous compounds such as triphenylphosphines and be reduced.With the amino methyl intermediate acidylate that obtains, obtain the compound 6 that enantiomorph is rich in then.
Reaction process 4a
Reaction process 4a has described the structure 13 (seeing reaction process 3) that the preparation enantiomorph is rich in and the another kind of method of 18 (seeing reaction process 4) intermediate.In this sequence; with a kind of aniline (making easily) of suitable carbobenzoxy-(Cbz) protection by known other method variant of Schotten-Baumann conditioned disjunction those of ordinary skills of standard under proper temperature (for example-78 ℃ to-68 ℃); in appropriate solvents such as tetrahydrofuran (THF), carry out deprotonation with n-Butyl Lithium.Add commercially available (-)-(R)-Glycidyl butyrate and then be warmed to envrionment temperature, directly obtain the phenyl oxazolidinones intermediate 13 (A=H) and 18 (A=Br, I) that methylol replaces then.Use listed method among the reaction process 1-4, compound 13 and 18 can easily transform the phenyl oxazolidone compound that tropone that accepted way of doing sth I a is rich in to the enantiomorph of I d replaces.
Reaction process 5
Reaction process 5 has been described the route of preparation racemize tropone replacement De oxazolidone antiseptic-germicide.In a representative example, the carbobenzoxy-(Cbz) derivative 20 (X=Br) that is made by 4-bromo aniline by the Schotten-Baumann condition of standard is under-78 ℃ to-40 ℃, in tetrahydrofuran (THF), handle with the normal n-Butyl Lithium of two-phase, with tributyltin chloride reaction is stopped then, obtain tin derivative 21 (R=n-Bu).Compound 21 is under proper temperature (70-100 ℃ usually), at N, dinethylformamide (DMF) or 1, in the appropriate solvents such as 4-diox, in the presence of suitable palladium catalyst such as tetrakis triphenylphosphine palladium or two (triphenylphosphine) palladiums of chlorination, with 8 reactions of bromo tropone, make coupled product 22.22 allylation is by finishing with suitable alkali deprotonations such as sodium hydrides in appropriate solvents such as THF, follow in envrionment temperature to reflux temperature, randomly in the presence of catalysis propiodal such as tetrabutylammonium iodide, reaction mixture is made 23 with the allyl bromide 98 processing.Intermediate 23 is carried out Cardillo-Ohno carbamate cyclization, this is included in (usually at ambient temperature) under the proper temperature, with iodinate 23, obtains iodo methyl oxazolidinone 24 in appropriate solvents such as chloroform, see Cardillo etc., Tetrahedron (1987), 43,2505, Ohno etc., Tetrahedron Lett. (1987), 28,3123.Compound 24 then can change into 25 by the reaction sequence that three reactions are arranged, and this is an example of the analogue of structure I a.These comprise that nitrine replaces, reduction obtains corresponding amino methyloxazolidinonesas, and acidylate, and institute all finishes by method mentioned above in steps.Can prepare the phenyl oxazolidone compound of the tropone replacement of other racemic formula I a-d to the substituent reasonable change of various residues, this is conspicuous for those of ordinary skills.The latter is a purpose of the present invention.
Reaction process 6
I 2 (racemic)
Reaction process 6 has been listed the another kind of method of Wai Xiao Xuan oxazolidone compounds of synthesis type I a, and this can regard the mixing of reaction process 1,2 and 5 as.Schotten-Baumann condition with standard is at first carried out allylation by carry out deprotonation with suitable alkali such as sodium hydrides in appropriate solvents such as THF by the carbobenzoxy-(Cbz) derivative 26 that corresponding aniline makes, then envrionment temperature to the reflux temperature randomly in the presence of catalysis propiodal such as tetrabutylammonium iodide, use the allyl bromide 98 reaction mixture, obtain 27.Intermediate 27 is through Cardillo-Ohno carbamate cyclization, and this is included under the proper temperature and (is generally under the envrionment temperature), with iodinate 27, obtains iodo methyl oxazolidinone 28 in appropriate solvents such as chloroform.Iodide 28 are then under 50 ℃ to 90 ℃ temperature, randomly in the presence of catalyzer (for example hexaoxacyclooctadecane-6-6), in aprotonic solvent (for example DMF or 1-Methyl-2-Pyrrolidone),, obtain trinitride 29 with trinitride source (for example sodiumazide or potassium azide) reaction.Trinitride 29 is then at appropriate solvent (for example in ethyl acetate or the methyl alcohol), with palladium/charcoal or platinum catalyst hydro-reduction.In addition, described trinitride can in the presence of water, reduce with trivalent phosphorous compound (for example, triphenylphosphine) processing by in appropriate solvent (for example tetrahydrofuran (THF) (THF)).The amino methyl compound that will be obtained by trinitride 29 obtains the intermediate of structure 30 with the known reaction acidylate of those of ordinary skills then.The bromination of 30 phenyl ring or iodization adopt the condition of above-mentioned preparation optical activity intermediate 6, obtain racemic compound 31 thus.Can utilize with the same technology that structure 6 intermediates of enantiomorph enrichment is converted into I a (seeing reaction process 1 and 2) structure 31 intermediates are processed into the phenyl oxazolidone that racemic formula I a tropone replaces.For those skilled in the art, the substituent reasonable change of various remnants can prepare phenyl oxazolidone that the tropone of other racemic formula I a-d replaces and shows and see that the latter is a purpose of the present invention.
Reaction process 7
I 2 (racemic)
Reaction process 7 has been described a kind of variant of the scheme shown in the reaction process 6, and wherein the bromine or iodine atom of structure 31 has been present in the initial substance 32 of carbobenzoxy-(Cbz) replacement.With 32 as stated above allylation obtain adducts 33.Under common Cardillo-Ohno condition, carry out 33 iodo carbamate cyclisation then, make iodo methyl oxazolidinone intermediate 34.Trinitride is replaced the azido methyl oxazolidinone 35 provide by in appropriate solvents such as THF, in the presence of water, react with trivalent phosphorous compound such as triphenylphosphine and to reduce.Then resulting amino methyl intermediate is carried out acidylate, obtain racemic compound 31, this compound can easily be converted into racemic I a.For those of ordinary skills, this programme is improved slightly, can prepare other example of Suo Shu oxazolidone compounds I a-d.
The initial substance that uses in the method for reaction process 1 to 7 all is that known method is easy to make in the commercially available or available prior art.
When basic group (for example amino) when existing, the present invention includes the pharmaceutically useful acid salt of formula I compound.Particularly preferably be by mineral acid (HCl, HBr, H
3PO
4, H
2SO
4Deng), those salt of making of organic sulfonic acid (methylsulfonic acid, P-toluenesulphonic acids etc.), organic carboxyl acid (acetate, succsinic acid, tartrate, citric acid, lactic acid, toxilic acid, oxalic acid etc.), amino acid, saccharic acid (for example glyconic acid and galacturonic acid etc.).When having acidic-group (for example carboxylic acid) or working as R
1When being hydroxyl, also comprise the pharmaceutically useful base addition salt of formula I compound.This class salt comprises following positively charged ion but is not limited thereto, alkalimetal ion (for example potassium, sodium, lithium); Alkaline-earth metal ions (for example magnesium or calcium); Ammonium ion (for example ammonium, TBuA or pyridine).
But The compounds of this invention oral administration, part or parenteral administration.Say that generally the antibiotic effective dose of this active constituent is 0.1 to 100, more preferably from about 3 to about 50 mg/kg body weight/day, and this depends on patient's body weight, age and symptom.The preferred gradation administration of this dosage, administration every day 2 to 4 times.Preferred route of administration and the particular case that depends on the state of an illness for the concrete formulation of parenteral or oral route, comprise the character (relating to concrete microorganism, its toxicity) of infection, the degree that infects, and patient's age, body weight, sex and general physical condition.The common pharmaceutical dosage form (tablet, capsule, syrup, suspension etc.) that is suitable for the common pharmaceutical dosage form (solution, the suspension in oil) of parenteral administration and is suitable for oral administration is known for those of ordinary skills, and those formulations of the phenyl oxazolidone compound that replaces of the tropone of the formula of use I are not seen any unusual.
The antibacterial activity in vitro of the anti-streptococcus aureus of all cpds of the present invention is measured by methods known in the art, is listed in the table 1.These compounds are useful antiseptic-germicides, are used for the treatment of in the Mammals (humans and animals, for example ox, horse, sheep, dog, cat etc.) infection that causes because of Gram-positive and anaerobic organisms.The patient that the phenyl oxazolidone compound that the tropone of formula I replaces is infected by one or more mycobacteriums for treatment also is useful.Making us interested especially is, The compounds of this invention I a-I d is useful for treatment by the patient of Mycobacterium tuberculosis and bird mycobacterium infection.
The phenyl oxazolidone compound that the tropone of formula I replaces can use separately, and perhaps antibiotic with other or non-antiseptic-germicide is used in combination, and this is known to those skilled in the art.Preparation example 1 three-normal-butyl [4-(benzyloxycarbonyl amino) phenyl] tin
N-carbobenzoxy-(Cbz)-4-bromo aniline (3.08 grams, 11.2 mmoles) is dissolved among 50 milliliters of anhydrous THF, solution is cooled to-78 ℃ with dry ice/acetone batch.Then in 5 minutes, add n-butyllithium solution (the hexane solution of 1.6M, Aldrich, 23.52 mmoles).Solution becomes deep yellow.With this solution stirring 10 minutes, and handle with chlorination three-normal-butyl tin (3.83 grams, 11.76 mmoles).The yellow soup compound solution that becomes colorless.After stirring 30 minutes, be warmed to-20 ℃, use saturated NH
4The Cl aqueous solution (50 milliliters) stops reaction.With reaction mixture in 250 milliliters of ether and 100 ml water impouring separating funnels.Shake this mixture, isolate organic phase, use anhydrous Na
2SO
4Drying is filtered and is concentrated, and obtains a kind of oily matter, uses silica gel chromatography (with 20: 1 hexane/ether wash-out purifying.Isolate the title compound of 2.99 gram colorless oil.MS (EI): m/z (relative abundance), 460 (25), 404 (5), 227.91 (100).
1H NMR CDCl
3): δ 7.48-7.31 (m, 9H), 5.19 (s, 2H), 1.55-1.47 (m, 6H), and 1.38-1.26 (m, 6H), 1.03 (t.6H, J=8.33Hz), 0.877 (t.9H, J=7.26Hz). preparation example 2 N-(carbobenzoxy-(Cbz))-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) aniline
Three-normal-butyl [4-(benzyloxycarbonyl amino) phenyl] tin (726 milligrams, 1.4 mmoles) is dissolved in 10 milliliters of 1.4-dioxs, and adds 5-bromo-2-methoxy basic ring heptan-2,4,6-triolefin-1-ketone (215 milligrams, 1.0 mmoles).With the soup compound vacuumize degassing that obtains and use N
2Flushing (three times).Add two (triphenylphosphine) palladiums (II) of catalyzer chlorination, at N
2Down mixture heating up is extremely refluxed.By TLC monitoring reaction process.After 2 hours, show to react and carry out fully.Reaction solution is cooled to envrionment temperature, under reduced pressure concentrates.With resistates at 75 milliliters of CH
2Cl
2Middle pulping stirred 15 minutes with saturated and the KF aqueous solution (75 milliliters).Isolate organic phase, water (50 milliliters) and salt solution (50 milliliters) washing.Use anhydrous Na
2SO
4Dry organic phase is filtered and is concentrated, and obtains yellow solid, uses radial chromatography (with 1: 1CHCl
3/ ethyl acetate and 1% methanol-eluted fractions) this solid of purifying.Obtain 361 milligrams of solid-state title compounds of yellow.
MP:193-195℃
HRMS (EI): [M]+. calculated value C
12H
19N
2O
4: 361/1314: measured value: 361.1311.
1H NMR (CDCl
3): δ 7.54-7.23 (m, 6H), 6.84 (d, 2H), 5.23 (s, 1H), 3.98 (s, 3H). preparation example 3 N-(2-propenyl)-N-(carbobenzoxy-(Cbz))-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) aniline
With N-(carbobenzoxy-(Cbz))-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) aniline (195 milligrams, 0.54 mmole) pulping in 5 milliliters of anhydrous THF, suspension in the oil of adding 50%NaH.Observing gas emits.At N
2At ambient temperature mixture is stirred 20 fens kinds down, add allyl bromide 98 with iodate four-normal-butyl ammonium-Dao.At N
2Stir this mixture down at ambient temperature.3.5 after hour, TLC shows that 6 have been consumed.Consume superfluous NaH by the phosphate buffer (25 milliliters) that adds pH7.Mixture and 25 ml waters are together poured in the separating funnel, used CH
2Cl
2(2 * 25 milliliters) aqueous phase extracted.Use anhydrous Na
2SO
4The dry organic phase that merges.Concentrating the oily matter that obtains after the organic phase uses radial chromatography (with 1% methyl alcohol/CHCl
3(300 milliliters) and 2% methyl alcohol/CHCl
3(100 milliliters) wash-out) purifying.Obtain 198 milligrams of oily title compounds, solidify through placing.HRMS (EI): [M]+, calculated value C
25H
13NO
4: 401.1627; Measured value: 401.1630
1H NMR (CDCl
3): δ 7.52 (dd, 1H, J=12.6Hz), 7.46-7.42 (m, 2H), 7.34-7.33 (m, 8H), 7.26 (dd1H, J=10.6Hz), 6.845 (d, 1H, J=10.6Hz), 5.93 (m, 1H), and %20-5.18 (bs, 3H), 5.15-5.14 (m, 1H), 4.32 (d, 2H, J+5.6Hz), (3.99 s, 3H) preparation example 4 (±) 5-(iodo-methyl)-3-[4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-the 2-oxazolidone
N-(2-propenyl)-N-(carbobenzoxy-(Cbz))-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) aniline (180 milligrams, 0.449 mmole) is dissolved in 8 milliliters of chloroforms, and adds I
2(285 milligrams, 1.12 mmoles).Mixture becomes purple grape, and at N
2Stir at ambient temperature down.After 20 hours reaction times, TLC shows that 7 have been consumed, and forms new low R
1Product.With reaction mixture and 50 milliliters of CHCl
3Together pour in the separating funnel, wash this solution with 20% sodium thiosulfate solution (25 milliliters).Isolate organic phase, use anhydrous Na
2SO
4Drying is filtered and is concentrated, and obtains orange solid-state title compound, uses radial chromatography (with 200 milliliters of 1% methyl alcohol/CHCl
3And 200 milliliters of 2% methyl alcohol/CHCl
3Wash-out) purifying.Separate and obtain 139 milligrams of light yellow solid-state title compounds.MP:194-196 ℃ of ultimate analysis calculated value C
18H
16NO
4I:C, 49.45; H, 3.69; N, 3.20. measured value: C, 49.03; H, 3.62; N, 3.00,
HRMS: calculated value C
18H
16INO
4: 437.0126.Measured value: 437.0110.
1H NMR(CDCl
3):δ7.65(d,2H,j=8.8Hz),7.55(dd,1H,J=11.5,12.6Hz),7.52(d,2H,J=
8.8Hz),7.34(dd,1H,J=10.4Hz),7.28(d,1H,J=11.5Hz),6.88(d,1H,j=10.6Hz),4.79(m,
1H,4.24(t,1H,J=8.9Hz),4.00(s,3H),3.855(dd,1H,J=9.2Hz),3.505(dd,1H,J=14.5
Hz),3.395(dd,1H,J=10.4Hz)。Preparation example 5 (±)-5-(azido methyl)-3-[4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-the 2-oxazolidone
With (±)-5-(iodo-methyl)-3-[4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-(125 milligrams of 2-oxazolidones, 0.286 mmole) be dissolved in 6 milliliters of dry DMF, and together add sodiumazide (93 milligrams, 1.43 mmoles) with hexaoxacyclooctadecane-6-6 (10 milligrams).With mixture at N
2Under be heated to 60 ℃, with TLC monitoring reaction process.TLC shows that 8 have been consumed after 2 hours.Reaction solution is cooled to envrionment temperature, removes DMF under the decompression.Remaining resistates is at CHCl
3Pulping in (75 milliliters) washes (2 * 30 milliliters) with water except that desalting.Isolate organic phase, with salt solution (30 milliliters) washing.Use the anhydrous sodium sulfate drying organic phase, filter and concentrate, obtain 105 milligrams of solid-state title compounds of yellow.The purity of this material do not need to be enough to any just being further purified directly to be used.
MP:170-171 ℃ of ultimate analysis calculated value C
18H
16N
4O
4: C, 61.36; H, 4.58; N, 15.90. measured value: C, 61.08; H, 4.52; N, 15.75
HRMS: calculated value C
18H
16N
4O
4: 352.1171 measured values: 352.1169
1H NMR(CDCl
3):δ7.645(d,2H,J=8.8Hz),7.545(dd,1H,J=16,12.5Hz),7.515(d,2H,J=
8.8Hz),7.34(d,1H,J=12.5Hz),7 285(dd,1H,J=10.6Hz),6.88(d,1H,J=10.6Hz),4.84-
4.85(m,1H),4.16(t,1H,J=8.9Hz),4.00(s,3H),3.91(dd,1H,J=8.9Hz),3.755(dd,1H,
J=13.2Hz), 3.625 (dd, 1H, J=13.2Hz). preparation example 6 trimethylammoniums (4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) tin
Hexa methyl ditin (305 milligrams, 0.930 mmole) is dissolved in 5 milliliter 1, in the 4-diox,, uses N the solution vacuumize degassing
2Flushing (three times).Two (triphenylphosphine) palladiums (II) (1.63 milligrams, 2.5 moles of %) of bromo tropone 8 (200 milligrams, 0.930 mmole) and catalyzer chlorination are together added.Mixture is outgased for the last time, and at N
2Under be heated to backflow.Use the TLC monitoring reaction.Reaction mixture darkens when warm.1.5 after hour, TLC shows that 3 have been consumed.Reaction mixture is cooled to envrionment temperature and concentrating under reduced pressure.Obtain the dark oil thing, use silica gel column chromatography (with 1: 1 ethyl acetate/CHCl
3And 1% methanol-eluted fractions) purifying.Obtain oily title compound (239 milligrams), in refrigerator, solidify through placing.
MP:60-61℃
HRMS: calculated value C
11H
16O
2Sn:300.0170. measured value: 300.0159.
1H NMR(CDC
3l):δ7.36(d,1H,J=11.8Hz),7.23(d,1H,j+9.6Hz),7.15(d,1H,J=11.8Hz)
6.725(d,1H,J=9.6Hz),3.94(s,3H),0.32(s,9H,
119SnJ=129.3Hz,
119SnJ=55.2Hz,
119Sn
J=52.9Hz). preparation example 7 butyric acid (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl] methyl ester
With lithiumbromide (0.181 gram, 2.08 mmoles), the mixture azeotropic drying of three-normal-butyl phosphine oxide (0.454 gram, 2.08 mmoles) and anhydrous o-Xylol (10 milliliters) 1 hour.After being cooled to below the reflux temperature, in 10 minutes, in this hot solution, add (R)-Glycidyl butyrate (5.000 grams, 34.68 mmole) and the solution (in adition process observe some backflows) of 3-fluorophenyl isocyanic ester (4.755 grams or 3.96 milliliters, 34.68 mmoles) in anhydrous o-Xylol (10 milliliters).After adding is finished, solution is heated to backflow, and kept 2 hours, then cool to room temperature.Solvent removed in vacuo, resistates separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, the usefulness hexane/ethyl acetate (6: 1,4: 1,2: 1 then) wash-out, colourless pulpous state title compound 8.758 grams (90%) that obtain having following feature.[α]
25 D-46.7 ° of (c1.0, CHCl
3) .IR (mineral oil mulling) 1758,1615,1591,1498,1229,1197,1169cm
-1.
1H-NMR, CDCl
3, 300MHz) δ 7.44 (＂ dt ＂, J=11.2,2.3Hz, 1H), 7.34 (＂ dt ＂, J=8.3,6.5Hz, 1H, 7.23 (ddd, J=8.3,2.1,0.9Hz, 1H), 6.86 (dddd, J=8.2,8.2,2.5,0.9Hz, 1H), 4.88 (m, 1H, 4.39 (dd, J=12.3,3.8Hz, 1H), 4.32 (dd, J=12.3,4.7Hz, 1H), 4.13 (＂ t ＂, J=9.0Hz, 1H), 3.82 (dd, J=9.0,6.1Hz, 1H), 2.33 (t, J=7.3Hz, 2H), 1.63 (m, 2H), 0.92 (t, J=7.4Hz, 3H) MS m/z (relative abundance) 281 (33.1, M
+), 193 (9.9), 180 (3.3), 150 (28.7), 148 (68.6), 137 (59.3), 123 (41.7), 95 (38.3), 43 (100) HRMS m/z281.1068 (calculated value C
14H
16FNO
4: 281.1063) ultimate analysis calculated value C
14H
16FNO
4: C, 59.78; H, 5.73; N, 4.98 measured values: C, 59.98; H, 5.72; N, 4.88. preparation example 8 (R)-3-(3-fluorophenyl)-5-(methylol)-2-Yang Dai oxazolidine
At ambient temperature, methanol solution (0.57 microlitre with 25% (weight) sodium methylate, 0.99 mmole) handle the solution of butyric acid (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl] methyl ester (2.789 grams, 9.91 mmoles) in methyl alcohol (10 milliliters).(5% methyl alcohol/CHCl of TLC after 45 minutes
3) show that initial substance has been consumed.By adding 1NHCl (0.99 milliliter, 0.99 mmole) careful stopped reaction mixture, vacuum concentration then.On silica gel, crude product is carried out chromatography purification,, uses eluent ethyl acetate again, obtain the white solid state title compound that 1.903 grams (91%) have following feature earlier with 1: 1 hexane/ethyl acetate:
mp106.5-107.5℃
[a]
25 D-66.8°(c1.1,CH,CN).
IR (mineral oil mulling) 3520,1724,1612,1590,1496,1428,1420,1232,1199cm
-1
1H-NMR(CDCl
3,300MHz)δ7,44(＂dt＂,J=11.3,2.3Hz,1H),7.32(＂dt＂,J=8.3,6.5Hz,
1H),7.23(ddd,J=8.3,21,1.0Hz,1H),6.84(dddd,J=8.2,8.2,2.5,1.0Hz,1H),4.77(m,
1H),4.07-3.96(m,3H),3.76(dd,J=12.7,3.9Hz,1H)-2.44(br s,1H).
MS m/z (relative abundance) 211 (100, M
+), 180 (6.8), 136 (34.3), 124 (84.7), 95 (71.6).
HRMS m/z211.0641 (calculated value C
10H
10FNO
3: 211.0645) ultimate analysis calculated value C
10H
10FNO
3: C, 56.87; H, 4.77; N, 6.63 measured values: C, 56.85; H, 494; N, 6.56
Led to the oxazolidine keto-alcohol with (R)-(+)-α-methoxyl group-α-(trifluoromethyl) phenylacetic acid (DCC, DMAP, CH
2Cl
2, room temperature) and check gained Mosher ester
1The H-NMR spectrum is surveyed the enantiomeric excess enantiomeric excess per-cent of deciding the oxazolidine keto-alcohol and is estimated 〉=95%.Preparation agent 9 (R)-3-(3-fluorophenyl)-5-(methylol)-2-Yang Dai oxazolidine
With dry ice/acetone batch anhydrous tetrahydro furan (10 milliliters) solution of N-(carbobenzoxy-(Cbz))-3-fluoroaniline (1.000 gram, 4.08 mmoles) is cooled to-78 ℃ approximately, then adds n-Butyl Lithium (1.87 milliliters, 1.6M hexane solution, 2.91 mmoles).Add (R)-Glycidyl butyrate (0.420 restrains or 0.413 milliliter 2.91 mmoles) with syringe then, and the ice bath loss is spent the night, make reaction mixture reach envrionment temperature.Careful add saturated aqueous ammonium chloride stopped reaction mixture, and whole mixtures are transferred in the separating funnel, use washed with dichloromethane, and with this mixture of dichloromethane extraction.With the organic extract liquid dried over sodium sulfate that merges, filter and vacuum concentration, obtain a kind of oily matter, use the silica gel chromatography purifying, with 10% acetonitrile that contains 1% methyl alcohol/chloroform wash-out, obtain 0.555 gram (in Glycidyl butyrate, 90%) white solid state title compound, all aspects of the sample of the gained of describing in this thing and the front experimental technique through examining and determine are all identical.Preparation example 10 4-toluene sulfonic acides (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl] methyl ester
The solution of (R)-3-(3-fluorophenyl)-5-(methylol)-2-Yang oxazolidine (1.800 grams, 8.52 mmoles) in anhydrous pyridine (10 milliliters) is cooled to about 5 ℃, uses p-toluenesulfonyl chloride (1.706 grams, 8.95 mmoles) to handle then.Solution placed under this temperature spend the night.TLC (5% methyl alcohol/chloroform or 1: 1 hexane/ethyl acetate) demonstration initial substance is consumed and is over.Reaction mixture is discharged in the frozen water (30 milliliters), by the agglomerating glass funnel of middle isoporosity, the resulting precipitation of vacuum filtration.With the solid of collecting cold water thorough washing, vacuum-drying, recrystallization from ethyl acetate/hexane obtains the white solid state title compound that 2.743 grams (88%) have following feature.
mp114-115℃
[a]
25 D-62.6°(c1.0,CH
3CN).
1R (mineral oil mulling) 1751,1617,1591,1499,1415,1362,1227,1202,1191,1172,1093,967
cm
-1
1H-NMR(CDCl
3,300MHz)δ7.78(＂d＂=8.4Hz,2H),7.38(＂dt＂,J=11.2,2.3Hz,1H).
7.36(＂d＂,J=7.8Hz,2H),7.33(＂dt＂,J=8.3,6.6Hz,1H),7,16(ddd,J=8.3,2.2,1.0Hz,1H).
6.86(dddd,J=8.2,8.2,2.5,1.0Hz,1H),484(m,1H),4.29(dd,J=11.1,4.1Hz,1H),4.24
(dd,J=11.1,4.6Hz,1H),4.10(＂t＂,J=9.1Hz,1H),3.88(dd,J=9.2,6.0Hz,1H),2.46(s,
3H).
MS m/z (relative abundance) 365 (70.6, M
+), 149 (100), 122 (32.8), 91 (52.8)
HRMS m/z365.0738 (calculated value C
17H
16FNO
5S:365.0733). ultimate analysis calculated value C
17H
16FNO
5S:C, 55.88; H, 4.41; N, 3.83. measured value: C, 55.96; H, 4.38; N, 3.80 preparation examples 11 (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl] triazo-methane thing
At ambient temperature, handle anhydrous THF (60 milliliters) solution of 4-toluene sulfonic acide (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl] methyl ester (2.340 grams, 6.40 mmoles) with solid-state sodiumazide (3.331 grams, 51.23 mmoles).The soup compound that obtains is warmed to 65 ℃, and kept 4.5 hours, be cooled to envrionment temperature then, and place and spend the night.Use ethyl acetate and water diluted reaction mixture then, it is transferred in the separating funnel, use ethyl acetate extraction, the acetic acid ethyl acetate extract that the water thorough washing merges, dry then (Na
2SO
4), filtering, vacuum concentration obtains the white solid state title compound of substantially pure.Its characteristic is as follows:
mp81-82℃
[a]
25 D-136.5°(c0.9,CHCl
3).
IR (mineral oil mulling 1) 2115,1736,1614,1591,1586,1497,1422,1233,1199,1081,1049cm
-1
1H-NMR(CDCl
3,300MHz)δ7.45(＂dt＂,J=11.2,2.3Hz,1H),7.34(＂dt＂,J=8.3,6.4Hz,
1H),7.23(ddd,J=8.1,2.1,1.0Hz,1H),6.86(dddd,J=8.2,8.2,2.5,1.0Hz,1H),4.81(m,
1H3,4.09(＂t＂,J=8.9Hz,1H),3.86(dd,J=90,6.2Hz,1H),3.72(dd,J=1.3.2,4.5Hz,1H).
3.60(dd,J=13.2,4.4Hz,1H).
MS m/z (relative abundance) 236 (59.0, M
+), 1.79 (94.9), 1.36 (59.5), 122 (62.4), 109 (71.8), 95
(100),75(40.7)
HRM Sm/z236.0708 (calculated value C
10H
9FN
4O
2: 236.0709) ultimate analysis calculated value C
10H
9FN
4O
2: C, 50.85; H, 3.84; N, 23.72. measured value: C, 50.74; H, 3.76; N, 23.71, preparation example 12 (S)-N-[[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl] methyl] ethanamide
Under nitrogen atmosphere, handle ethyl acetate (100 milliliters) solution of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl] triazo-methane thing (8.200 grams, 34.71 mmoles) with 10% palladium/charcoal (0.820 gram).Replace this atmosphere with repeatedly pumping and fill method with hydrogen (balloon) then.Stir under nitrogen atmosphere after 17 hours, TLC (5% methyl alcohol/chloroform) demonstration trinitride is consumed and is over, and this atmosphere nitrogen replacement adds pyridine (6 milliliters) and diacetyl oxide (4.1 milliliters, 43.40 mmoles) then in reaction mixture.At ambient temperature reaction mixture was stirred 1 hour, use diatomite filtration then, wash backing plate with ethyl acetate.Vacuum concentrated filtrate immerses resistates in the methylene dichloride.Add ether, obtain precipitation.After placement is spent the night in refrigerator, collect solid, use cold hexane wash by vacuum filtration, and vacuum-drying, make 4.270 gram white solid state title compounds, from mother liquor, obtain other 3.700 gram products, overall yield is 91%.In another test, with silica gel chromatography purifying crude product, with 5% methyl alcohol/chloroform wash-out.Its characteristic is as follows:
mp140.0-140.5℃
[α]
25 D-66 ° of (c1.0, CHCl
3). preparation example 13 (S)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl] methyl] ethanamide
With (S)-N-[[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl] methyl] ethanamide (0.280 gram, 1.11 mmole) be dissolved in the mixture of ethyl acetate (20 milliliters) and trifluoroacetic acid (5 milliliters), and use monochlor(in)ate sulphur (2.343 grams, 14.43 mmoles) to handle at ambient temperature.Under nitrogen atmosphere and room temperature, stir this reddish dark brown mixture.Gradually form a kind of orange precipitation.After about 24 hours, use the ether diluted reaction mixture, and with in the fritted glass filter of isoporosity collect solid by vacuum filtration, wash with ether.Crude product being dissolved in the chloroform of heat (to add small amount of methanol to help dissolving) transfers to it in separating funnel, and with saturated sodium bicarbonate aqueous solution, 20% sodium thiosulfate solution and salt water washing.Use the dried over sodium sulfate organic phase, filter and vacuum concentration, obtain 0.295 gram (70%) white solid state title compound.Its characteristic is as follows:
mp185.5-186.5℃
[a]
25 D-37.6 ° (c1.0, DMF). preparation example 14 (±)-5-acetylamino methyl-3-(4 ＇-tin trimethyl phenyl) oxazolidine-2-ketone
(solution of 4 ＇-iodophenyl) oxazolidine-2-ketone (1.840 restrain 5.11 mmoles) in 23 milliliters of dioxs is alternately found time and inflated with nitrogen, repeats this process three times with hexa methyl ditin (1.772 gram, 5.41 mmoles) and (±)-5-acetylamino methyl-3-.Add two (triphenylphosphine) palladiums (II) of chlorination (0.155 gram, 0.22 mmole) then, this system found time and inflated with nitrogen again, triplicate, and with this system 96 ℃ of heated overnight.Evaporating solvent and with in press silica column (40 * 63 μ, 2.5cm * 25cm, with 1% methyl alcohol/chloroform packed column, use the methylene dichloride application of sample, gradient solvent wash-out with methyl alcohol/chloroform) the thick material of purifying, obtain the desired material of 1.148 gram (56.5%) white solid state, mp130-132 ℃, and contain the slight impure material of 0.537 gram (26.5%).
1H NMR(CDCl
3,300MHz)δ:7.48(s,4H),6.71(bt,J=6.0Hz,1H),4.77(ddd,J=13.2Hz,
J＇=8.7Hz,J＂=4.5Hz,1H),4.05(t,J=9.0Hz,1H),3.80(dd,J=9.0Hz,J＇=6.6Hz,1H),
3.63(dd,J=6.0Hz,J＇=4.5Hz,2H),2.01(s,3H),0.28(t,J=27.0Hz,9H).
IR (mineral oil mulling .cm
-1): 3356 (m), 1746 (s), 1665 (s)
MS:m/e (relative abundance): 398 (8.8, M
-), 383 (100), 382 (36.9), 381 (75.3), 380
(29.0), 379 (42.7), 43 (23.1), 29 (27.5); Accurate mass calculated value C
15H
22N
2O
3Sn:398.0650.
Measured value: 398.662. (ultimate analysis calculated value C
15H
22N
2O
3Sn:C, 45.37; H, 5.58; N, 7.06 measured values: C, 45.28; H, 5.51;
N,6.87
TLC:5%; Methyl alcohol/chloroform: R
f=0.34. preparation example 15 (R)-[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl alcohol
With N-carbobenzoxy-(Cbz)-3, anhydrous THF (250 milliliters) solution of 5-difluoroaniline (10.9 grams, 30.01 mmoles) is cooled to-78 ℃, with dripping n-Butyl Lithium (19.7 milliliters, 31.51 mmoles) it is handled in 15 minutes then.Reaction solution was stirred one hour at-78 ℃, then in 10 fens clock times to wherein dripping (R)-(-)-Glycidyl butyrate (4.67 milliliters, 33.01 mmoles).Reaction solution-78 ℃ of restir two hours, is placed spend the night (17 hours) then and made it slowly be warming up to room temperature.Dilute reaction solution with ethyl acetate (300 milliliters) this moment, uses NH then
4Cl (300 milliliters) and salt solution (300 milliliters) washing.Use anhydrous Na
2SO
4Dry organic layer filters and concentrating under reduced pressure, obtains golden oily matter, and (250 gram SG are with the 10%CH of 0-3% methyl alcohol with silica gel chromatography with this oily matter
3CN/CHCl
3The gradient solvent wash-out) purifying obtains 6.82 gram (99%) wax shape white solid state title compounds, and fusing point is 84-85 ℃, HRMS (M
+) C
10H
9NO
3F
2Calculated value: 229.0550, measured value: 229.0552.Preparation example 16 tosic acid (R)-[[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl] ester
(R)-[3-(3, the 5-difluorophenyl)-2-oxo-S-oxazolidinyl] methyl alcohol (4.68 grams, 20.42 mmoles) is dissolved in the pyridine (35 milliliters), is cooled to 0 ℃ (ice bath) then.Then handle this cold soln with Tosyl chloride (4.67 grams, 24.50 mmoles).Reaction solution is stirred spend the night (17 hours) in refrigerating chamber.In second day morning,, be settled out product by with frozen water (100 milliliters) stopped reaction.Suction filtration separates this material, then under high vacuum, and dried overnight (20 hours).Obtaining reaction yield is 7.46 gram (95%) white powder title compounds, mp110.5-111.5 ℃.
HRMS (M
+) calculated value C
17H
15NO
5F
2S383.0639. measured value 383.0639 preparation examples 17 (R)-[[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl] trinitride
Tosic acid (R)-[[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl] ester (7.34 grams, 19.15 mmoles) is dissolved in the dry DMF (50 milliliters), and uses solid state N aN
3(3.73 grams, 57.44 mmoles) are handled.Reaction solution is heated to 60 ℃, and kept 2.5 hours, be cooled to ambient temperature overnight (17 hours) then.This moment is by TLC (6%CH
3CN/CHCl
3, the ultraviolet shortwave) find to react completely.The vacuum concentration reaction solution obtains pale solid.Crude product is dissolved in the ethyl acetate (1 liter) water (400 milliliters) washing then.Strip to containing water section with more ethyl acetate (5 * 100 milliliters).Water (400 milliliters) washs the organic extract liquid that merges again, and with salt solution (400 milliliters) washing once.Use anhydrous Na then
2SO
4Dry organic moiety is filtered and concentrating under reduced pressure, obtains canescence crystalline solid title compound 4.45 grams (91%), mp96.5-98 ℃.
HRMS (M
+) calculated value C
10H
8N
4O
2F
2254.0615, measured value 254.0609 preparation example 18 (S)-N-[[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] and methyl] ethanamide
With (R)-[[3-(3, the 5-difluorophenyl)-and 2-oxo-5-oxazolidinyl] methyl] trinitride (6.8 grams, 26.75 mmole) be dissolved among the anhydrous THF (50 milliliters), then added triphenylphosphine (10.52 grams, 40.13 mmoles) in the clock time it is handled in batches at 30 minutes.After 2 hours, TLC (10%MeOH/CHCl
3, the ultraviolet shortwave) find to react completely.Then add entry (11.57 milliliters, 642 mmoles), reaction solution is heated to 50 ℃ and kept 4 hours.Once cooling, TLC (10% methyl alcohol/CHCl
3, the ultraviolet shortwave) and find reaction not exclusively, so add 2.9 ml waters again.Reheat (50 ℃) is after 4 hours, records to react completely.Use CH
2Cl
2(300 milliliters) dilute reaction solution is extracted into product among the 2NHCl (3 * 150 milliliters), carefully adds 50% (weight) NaOH with the acid layer PH14 that carefully neutralizes.Use CH then
2Cl
2The water that (3 * 150 milliliters) extraction has been alkalized.With the organic phase anhydrous Na that merges
2SO
4Drying is filtered and concentrating under reduced pressure, obtains white crystalline solid 4.53 grams (74%).Thick amine (4.53 gram) is dissolved in CH
2Cl
2In (100 milliliters) and the pyridine (10 milliliters).This solution is cooled to 0 ℃ (ice bath), adds diacetyl oxide (5.05 milliliters, 53.5 mmoles) with the another one addition funnel then.With reaction solution at N
2At room temperature stir down spend the night (20 hours).Second day morning, TLC (5% methyl alcohol/CHCl
3, the ultraviolet shortwave) find to react completely.With ethyl acetate (200 milliliters) diluted reaction mixture, and with 2NHCl (200 milliliters), saturated NaHCO
3(200 milliliters) and salt solution (200 milliliters) washing.With the organic layer anhydrous Na
2SO
4Dry, filtration, concentrating under reduced pressure obtains 4.61 gram (overall yield is 64%) white solid state title compounds then, and fusing point is 145-148 ℃.
HRMS (M
+) calculated value C
10H
12N
2O
3F:270.0816. measured value 270.0815. preparation example 19 (S)-N-[[3-(4-iodo-3,5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl] ethanamide
With (S)-N-[[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl] ethanamide (1.25 gram, 4.64 mmoles) is dissolved in Glacial acetic acid (12 milliliters) and the trifluoroacetic acid (3 milliliters), uses solid-state I then
2(4.52 grams, 27.84 mmoles) are handled.Resulting deep purple solution is at room temperature stirred spend the night (20 hours).Almost from solution, begin to separate out orange solids at once.In second day morning,, filter by frit then with ether (100 milliliters) dilute reaction solution.With more ether (3 * 50 milliliters) rinsing orange solids, then be dissolved in 10% warm methyl alcohol/CHCl
3In.Use 20%Na
2S
2O
3(100 milliliters), saturated NaHCO
3(100 milliliters) and salt solution (100 milliliters) washing methyl alcohol/CHCl
3Solution.Use anhydrous Na
2SO
4Dry organic moiety is filtered and concentrating under reduced pressure, obtains the solid-state title compound of 1.31 gram (71%) canescence, mp192-193 ℃.
HRMS (M
+) calculated value C
12H
11N
2O
3F
2I395.9784, measured value 395.9779. preparation example 20 N-carbobenzoxy-(Cbz)s-3,5-difluoroaniline
With 3,5-difluoro nitrobenzene amine (10 grams, 77.45 mmoles) slowly joins NaHCO
3In the slurries of the anhydrous THF (200 milliliters) of (13.01 grams, 154.9 mmoles).This solution is cooled to 0 ℃ (ice bath), drips chloroformic acid benzyl ester (22.11 milliliters, 154.9 mmoles) then it is handled.Add once finishing, remove ice bath, at N
2Under the atmosphere reaction solution was stirred 4 hours.After this TLC (15% ethyl acetate/hexane, ultraviolet shortwave) assaying reaction is complete.Use saturated NaHCO
3Solution (300 milliliters) stopped reaction, collection is gone into CH
2Cl
2In (3 * 200 milliliters).Then with the organic extract water (400 milliliters) and salt solution (400 milliliters) washing that merge.Then use anhydrous Na
2SO
4Dry organic layer, filtration be concentrating under reduced pressure also, obtains being covered with the crystalline material of amber oily thing.This material with 5% and 10% ethyl acetate/hexane wash-out, obtains 20.6 gram (100%) white solid state title compounds with silica gel (312 gram SG) chromatography purification.mp86-87℃。
MS (M
+) calculated value C
14H
11F
2NO
2263, measured value 263 preparation examples 21 N-allyl group-N-carbobenzoxy-(Cbz)-3,5-difluoroaniline
With N-carbobenzoxy-(Cbz)-3, (10 grams are dissolved among the minimum THF 5-difluoroaniline, 37.99 mmole) be added drop-wise to (0 ℃, ice bath) NaH (60% fluid, 2.28 grams of precooling, 56.99 in the soup compound of anhydrous THF mmole) (150 milliliters), add once finishing, with reaction solution in 0 ℃ of N
2Stirred 30 minutes under the atmosphere.Add catalyzer (n-Bu) this moment
4NI (1.0 grams, 10% (weight)) and allyl bromide 98 (4,93 milliliters, 56.99 mmoles).Reaction solution slowly is warmed to room temperature, at N
2Stir under the atmosphere spend the night (17 hours).In second day morning, TLC (15% ethyl acetate/hexane, ultraviolet shortwave) finds to react completely.Water (150 milliliters) stopped reaction, collection is gone in the ethyl acetate (3 * 150 milliliters) then.Then wash the organic extract that merges, and use anhydrous Na with salt solution (400 milliliters)
2SO
4Dry.After the drying, solution is filtered and concentrating under reduced pressure, obtain yellow oil.Described oily matter with silica gel (250 gram) chromatography purification, with 5% and 10% ethyl acetate/hexane wash-out, is obtained 10.58 gram (92%) title compounds, be water white transparency oily thing.
MS (M
+) calculated value C
17H
15F
2NO
2303, measured value 303. preparation examples 22 (±)-[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl iodide
With N-allyl group-N-carbobenzoxy-(Cbz)-3,5-difluoroaniline (11.5 grams, 38.9 mmoles) is dissolved in CHCl
3In (100 milliliters), use solid I2 (19.37 grams, 76.19 mmoles) to handle then.At N
2Under the atmosphere gained solution at room temperature stirred spend the night (20 hours).In second day morning, TLC (15% ethyl acetate/hexane, ultraviolet shortwave) finds to react completely.With reaction mixture CHCl
3(200 milliliters) dilution, and use 20%Na
2S
2O
3(250 milliliters) and salt solution (250 milliliters) washing.Then with the organic layer anhydrous Na
2SO
4Drying is filtered and is concentrated, and obtains golden oily matter.This oily matter with silica gel (300 gram) chromatography purification, with 15% and 50% ethyl acetate/hexane wash-out, is obtained cream-colored solid-state title compound 12.67 grams (98%).
HRMS (M
+) calculated value C
10H
8F
2INO
2338.9570.Measured value 338.9572. preparation example 23 (±)-[[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl] trinitride
(±)-[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl iodide (12.64 grams, 37.3 mmoles) is dissolved among the DMF (100 milliliters), uses solid NaN then
3(7.28 grams, 111.9 mmoles) are handled.With gained solution at N
2Be heated to 60 ℃ under the atmosphere, kept 2.5 hours, fall back room temperature then, stir spend the night (16 hours).Second day morning, TLC (6%CH
3CN/CHCl
3, the ultraviolet shortwave) find to react completely.Water (1000 milliliters) stopped reaction mixture, and collection is gone in ethyl acetate (3 * 150 milliliters).With organic extract water (400 milliliters) and usefulness salt solution (400 milliliters) (once) washing again that merges.Use anhydrous Na then
2SO
4Dry organic layer filters, and concentrating under reduced pressure obtains 9.41 gram (99%) faint yellow solid-state title compounds, mp72-73 ℃.
HRMS (M
+) calculated value C
10H
8F
2N
4O
2254.0615, measured value 254.0617. preparation example 24 (±)-N-[[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] and methyl] ethanamide
(±)-[[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl] trinitride (2.36 gram, 9.30 mmoles) is dissolved in 5% methanol/ethyl acetate (200 milliliters) obtains glassy yellow solution.With this solution N
2Outgas three times, use 10%Pd-C (460 milligrams, 20% (weight)) to handle then.Again with this solution degassing three times, by balloon H
2Atmosphere displacement N
2Atmosphere.Reaction solution was at room temperature stirred 20 hours.After this, complete by TLC (30% ethyl acetate/hexane ultraviolet shortwave) assaying reaction.Reaction mixture by diatomite filtration, is used excessive CH
2Cl
2Washing diatomite filter cake.Vacuum concentrated filtrate obtains water white transparency oily thing.Again this oily matter is dissolved in CH
2Cl
2In (20 milliliters) and the pyridine (10 milliliters), use diacetyl oxide (1.76 milliliters, 18.60 mmoles) to handle then.With reaction solution at N
2At room temperature stir under the atmosphere spend the night (17 hours).Morning with reaction solution with ethyl acetate (100 milliliters) dilution and with 2NHCl (2 * 100 milliliters), saturated NaHCO
3(100 milliliters) and salt solution (100 milliliters) washing.The organic layer anhydrous Na
2SO
4Drying, filtration and concentrating under reduced pressure obtain white solid.This solid is with silica gel (175 gram) chromatography purification, with the 10%CH that 0.5-2% methyl alcohol is arranged
3CN/CHCl
3The gradient solvent wash-out obtains 1.07 gram (42%) white solid state title compounds, mp131.5-132.5 ℃.
HRMS (M
+) calculated value C
12H
12F
2N
2O
3270.0816, measured value 270.0810. preparation example 25 (±)-N-[[3-(4-iodo-3,5-difluorophenyl)-2-oxo-5-oxazolidinyl] and methyl] ethanamide
With (±)-N-[[3-(3, the 5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl] ethanamide (500 milligrams, 1.85 mmoles) is dissolved in the acetate (5 milliliters), uses ICl (1.8 grams, 11.1 mmoles) to handle then.Resulting red tan solution is at room temperature stirred spend the night (17 hours).In the morning, with ether (50 milliliters) dilute reaction solution, filter with frit then.Use the remaining orange solids of more ether (3 * 30 milliliters) washing again, be dissolved in 10% warm methyl alcohol/CHCl then
3In (100 milliliters).Use 20%Na
2S
2O
3(100 milliliters), saturated NaHCO
3(100 milliliters) and salt solution (100 milliliters) wash this solution.Use anhydrous Na
2SO
4After the drying, filter organic layer, concentrating under reduced pressure obtains 387 milligrams of white solid state title compounds then.After 2 hours, separate out more product in the filtrate.Decantation solution washs remaining solid with ether.Also these solids are dissolved in 10% warm methyl alcohol/CHCl then
3In (50 milliliters), use 20%Na again
2S
2O
3(50 milliliters), saturated NaHCO
3(50 milliliters) and salt solution (50 milliliters of washings) are also with the organic layer anhydrous Na
2SO
4Drying, filtration and concentrating under reduced pressure obtain other 142 milligrams of solid-state title compounds of canescence, isolate the desired compound of 529 milligrams of (72%) white solid state altogether, mp191-192 ℃.
HRMS (M
+) calculated value C
12H
21F
2IN
2O
3395.9784, measured value 395.9774. preparation example 26 (±)-N-[[3-[4-(trimethylammonium stannyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
With (±)-N-[[3-(4-iodo-3,5-difluorophenyl)-2-oxo-5-oxazolidinyl] methyl] ethanamide (100 milligrams, 0.25 mmole) is dissolved in 1, in the 4-diox (15 milliliters), uses hexa methyl ditin (165 milligrams, 0.50 mmole) to handle then.With reaction mixture N
2Outgas after three times, add two (triphenylphosphine) palladiums (II) (9 milligrams, 0.0125 mmole) of chlorination.Again with the solution degassing (3 times) and reflux (110 ℃) 5 hours.After this, TCL (10% methyl alcohol/CHCl
3, the ultraviolet shortwave) and assaying reaction is complete.Solvent removed in vacuo with silica gel (75 gram) chromatography purification, is used 0.5-5% methyl alcohol/CHCl with remaining oily matter
3The gradient solvent wash-out obtains 105 milligrams of light yellow solid-state title compounds of (97%) spumescence.
HRMS (M
+) calculated value C
15H
20N
2O
3F
2Sn434.0461, measured value 434.0457 embodiment 1 (±)-N-[[3-[4[(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
By means of sonic treatment and warm, with (±)-5-(azido methyl)-3-[4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl-2-oxazolidone (100 milligrams, 0.286 mmole) is dissolved in the mixture of 10 milliliters of ethyl acetate and 4 ml methanol.At N
2Air-flow adds catalyzer (10%Pd/C, 50 milligrams) down.Flask is found time, and use N
2Gas flushing (3 times) imports hydrogen with balloon then.With mixture at normal pressure H
2Stir under the atmosphere, by TLC monitoring reaction process.After 3 hours, TLC demonstration 9 is consumed and is over.Reaction mixture is filtered concentrating under reduced pressure filtrate by the diatomite plunger.Oily matter is dissolved in 10 milliliters of CH
2Cl
2In and add 1 milliliter of pyridine, add 500 microlitre diacetyl oxides simultaneously.Concentrated reaction mixture after 10 minutes obtains light yellow solid, (uses CHCl with radial chromatography
3/ carbinol mixture, 1%-5%, each 100 milliliters of wash-outs) this solid of purifying.Obtain 78 milligrams of light yellow solid-state title compounds.
MP:231-232℃
HRMS calculated value C
20H
20N
2O
5: 368.1372, measured value: 368.1364.
1H NMR:(CDCl
3):δ7.61(d,2H,J=8.8Hz),7.53-7.51(m,1H).7.515(d,2H,J=8.8Hz),7.34
(d,1H,j=11.7Hz),7.31-7.28(m,1H),6.97(bt,1H),6.89(d,1H,J=11.7Hz),4.82(m,1H),
4.12 (1,1H, J=9.1Hz), 4.00 (s, 3H), 3.85 (dd, 1H, J+9.2Hz), and 3.67-3.65 (M, 2H), 2.03 (s, 3H). embodiment 2 (±)-N-[[3-[4[(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Trimethylammonium (4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) tin (50 milligrams, 0.167 mmole) is dissolved in 5 milliliter 1, in the 4-diox, and adds aryl iodide (50 milligram of 0.139 mmole).Mixture is found time to outgas, and use N
2Flushing (3 times).Then add catalyzer molybdenyl dichloride (triphenylphosphine) palladium (10 milligrams), mixture is outgased for the last time.At N
2Under the atmosphere mixture heating up is extremely refluxed.By TLC monitoring and reaction process, mixture becomes homogeneous once heating.TLC demonstration initial substance is consumed and is over after 5 hours.Reaction mixture is cooled to envrionment temperature, then it is filtered with the diatomite plunger, from mixture, to remove palladium black.Concentrated mother liquor obtains solid residue, by this residue of radial chromatography purifying, uses CHCl
3/ carbinol mixture (1% to 5%) is wash-out in batches, 100 milliliters of the every batch of usefulness.By TLC, will collect and concentrate corresponding to the fraction of sample 10 through identifying, obtain yellow foam.This foam is dissolved in the CH of minimum volume
2Cl
2In, and go out solid by adding ether sedimentation.With this solid filtering,, obtain 37 milligrams of title compounds with ether washing and vacuum-drying.By TLC,
1The comparison of HNMR and mp., this material are in every respect all with identical through the sample of evaluation.Embodiment 3 (±)-N-[[3-[3-fluoro-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Aryl iodide 19 (50 milligrams, 0.132 mmole) is dissolved in 4 milliliter 1, in the 4-diox, and adds tropyl stannane 11 (43.5 milligrams, 0.146 mmole).Mixture is found time to outgas and use N
2Flushing (3 times) adds catalyst P d (Ph
3P)
2Cl
2(9.3 milligrams).Mixture is outgased for the last time, be heated to backflow thereupon.By TLC monitoring reaction process.TLC demonstration 19 is consumed basically and is over after 8 hours, concentrates and obtains brown solid, and it is dissolved in 10% methyl alcohol/CHCl
3In and filter by little silica gel plunger.The concentrated solid that obtains is through the radial chromatography purifying, with CHCl
3/ carbinol mixture (contain 1% to 6% methyl alcohol, volume is 75 milliliters) wash-out.Isolate 40 milligrams of solid-state title compounds 20 of canescence.
MP:200-201 ℃ of ultimate analysis calculated value C
20H
19FN
2O
5: C63.17; H, 4.96:N, 7.25 measured values: C, 60.62; H, 4.99; N, 6.98HRMS: calculated value C
20H
19FN
2O
5: 388.1278: measured value 386.1271
1H NMR (CDCl
3): δ 7.55 (d, 1H), 7.42-7.31 (m, 4H), 7.205 (d, 1H, J=10.5Hz), 6.82 (d, 1H, J=10.5Hz), 6.10 (bt.1H), 4.82 (m, 1H), 4.09 (t, 1H, J=9.00Hz), 4.00 (s, 3H), 3.85 (m, 1H), 3.70 (m, 2H), 2.04 (s, 3H)
Be the representative method of the amine substitution reaction of the example that replaces of the methoxyl group of formula I a-c below.Embodiment 4 (±)-N-[[2-oxo-3-[4-[5-oxo-4-[(phenyl methyl) amino]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide
With (±)-N-[[3-[4[(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide (25 milligrams, 0.07 mmole) pulping in the mixture of 1.5 milliliters of benzylamines and 5 milliliters of dry toluenes.At N
2Under the atmosphere this mixture heating up is extremely leniently refluxed.After 16 hours, TLC shows that compound 10 has been consumed in the mixture.This mixture is cooled to envrionment temperature, and dilutes with 15 milliliters of ether.Filtering-depositing, and wash with ether.Dry this light yellow solid under vacuum.Obtain 32 milligrams of title compounds.
MP:239-240 ℃ of ultimate analysis calculated value C
26H
25N
3O
3: C, 70.41; H, 5.68; N, 9.47. measured value: C, 70.06; H, 5.67; N, 9.41, HRMS: calculated value C
26H
25N
3O
4: 443.1845: measured value 443.1859.
1H NMR (CDCl
3): δ 7.66-7.54 (m, 3H), 7.465 (d, 1H), 7.48-7.32 (m, 7H), 7.27 (d, 1H, J=11.5Hz), 6.70 (d, 1H, J=11.5Hz), 4.80 (m, 1H), 4.63 (s, 2H), 4.12 (T, 1H, J=9.1Hz), 3.85-3.80 (m, 1H), 3.65-3.59 (m, 2H), 2.02 (s, 3H)
Use is similar to method used among the embodiment 4, and different is to replace benzylamine with the amine that is fit to, and has obtained following compounds:
(±)-N-[[2-oxo-3-[4-[5-oxo-4-[(diethyl) amino]-1,3,6-cycloheptatriene-2-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:164-165 ℃ calculated value C
23H
27N
3O
4: 409.2001: measured value 409.1994
1H NMR (CDCl
3): δ 7.57-7.46 (m, 3H), 7.37-7.24 (m, 3H), 6.97 (d, 1H, J=12.2Hz), 6.655 (d, 1H, J=11.2Hz), 4.82 (m, 1H), 4.12 (t, 1H, J=9.0Hz), 3.88-3.83 (m, 1H)
(±)-N-[[2-oxo-3-[4-[5-oxo-4-[(2-hydroxyethyl) amino]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:212-213 ℃ HRMS calculated value: C
21H
23N
3O
5:+H
1: 398.1716: measured value: 398.1735
1H NMR (CDCl
3): δ 7.56-7.43 (m.6H), 7.20 (d, 1H, J=11.5Hz), 4.78-4.87 (m, 1H), 4.10 (t, 1H, J=9.0Hz), 3.94 (bt, 2H), 3.86-3.84 (m, 1H), 3.66 (bt, 2H), 3.53 (bt, 2H), 2.03 (s, 3H)
(±)-N-[[2-oxo-3-[4-[5-oxo-(4-morpholinyl)-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:231-232 ℃ HRMS: calculated value: C
23H
25N
3O
5: 423.1794: measured value 423.1785
1H NMR (CDCl
3): δ 7.585 (d, 2H, J=8.8Hz), 7.485 (d, 2H, J=8.8Hz), 7.38 (dd, 1H, J=12.5Hz), 7.225 (dd, 1H, J=10.7Hz), 7.12 (d, 1H, J=12.5Hz), 6.775 (d, 1H, J=10.7Hz), 6.11 (bt, 1H), 4.81 (m, 1H), 4.10 (t, 1H, J=9.1Hz), 3.90 (bt, 4H, J=4.6Hz), 3.835 (dd, 1H, J=9.1Hz) .3.70-3.67 (m, 2H), 3.39 (bt, 4H, J=4.6Hz), 2.04 (s, 3H)
(±)-N-[[2-oxo-3-[4-[5-oxo-4[(one cyclopropyl) amino]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:233-234 ℃ MS (EI): m/z (relative abundance) 393[M+] (68), 337 (31,222 (30), 181 (34), 42 (100)
1H NMR (CDCl
3): δ 7.88-7.48 (m, 6H), 7.195 (d, 1H, J=12.1Hz), 7.125 (d, 1H, J=10.8Hz), 4.81 (m, 1H), 4.10 (1,1H, J=9.0Hz), 3.875 (dd, 1H, J=90Hz), 3.64 (bt, 2H, J-5.5Hz), 2.65-2.62 (m, 1H), 2.01 (s, 3H), 1.01-0.95 (m, 2H), 0.73-0.68 (m, 2H).
(±)-N-[[2-oxo-3-[4-[5-oxo-4-[(4-formaldehyde) piperazinyl]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:255-257 ° (decomposition) MS (EI): m/z (relative abundance) 450[M+] (5), 406 (86), 56 (100)
1H NMR (CDCl
3): δ 7.61-7.57 (m, 2H), 7.51-7.42 (m, 3H), 7.28-7.23 (m, 1H), 7.18 (d, 1H, J=12.5Hz), 6.82 (d, 1H, J=10.7Hz), 6.73 (bt, 1H), 4.80 (m, 1H), 4.11 (t, 1H, J=90Hz), 3.84-3.78 (m, 2H), 3.70-3.60 (m, 4H), 3.40 (bt, 3H), 3.32 (bt, 1H), 3.09 (bt, 1H), 2.03 (s, 3H)
(±)-N-[[2-oxo-3-[4-[5-oxo-4-[(2-propenyl) amino]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:213-215 ℃ HRMS: calculated value C
22H
23N
3O
4: 393.1688: measured value 393.1673
1H NMR (CDCl
3) δ 7.62-7.43 (m, 6H), 7.255 (d, 1H, J=12.1Hz), 6.645 (d, 1H, J=110Hz), 600-6.63 (m, 1H), 5.29-5.26 (m, 1H), 4.81 (m, 1H), 4.11 (t, 1H, J=9.0Hz), 4.06 (m, 2H), and 3.87-3.81 (m, 1H), 3.68-3.66 (m, 2H), 2.03 (s, 3H)
(±)-N-[[2-oxo-3-[4-[5-oxo-4-[tetramethyleneimine-1-yl]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:230-231HRMS:C
23H
25N
3O
4: 407.1845: measured value 407.1859
1H NMR (CDCl
3): δ 7.555 (d, 2H, J=8.9Hz), 7.455 (d, 2H, J=8.9Hz), 7.345 (dd, 1H, J=10.1Hz), 7.26 (dd, 1H, J=11.3Hz), 6.98 (d, 1H, J=12.1Hz), 6.78 (bt, 1H), 6.445 (d, 1H, J=11.2H7), 4.79 (m, 1H), 4.10 (1,1H, J=9.0Hz), 3.825 (dd, 1HJ=9.0Hz), 3.69 (bs, 6H), 2.03 (s, 3H), 1.98 (bs, 4H).
(±)-N-[[2-oxo-3-[4-[5-oxo-4-(4-methylpiperazine-1-yl)-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:204-206 ℃ HRMS: calculated value: C
21H
22N
4O
4: 436.2110: measured value 436.2117
1H NMR (CDCl
3): δ 7.575 (d, 2H, J=8.8Hz), 7.475 (d, 2H, J=8.8Hz), 7.375 (dd, 1H, J=12.5Hz), 7,255 (dd, 1H, J=10.7Hz), 7.10 (d, 1H, J=12.5Hz), 6.80 (d, 1H J-10.7Hz), 6.17 (bt, 1H), 4.81 (m, 1H), 4.10 (t, 1H, J=9.0Hz), 3.835 (dd, 1H, J=9.0Hz), 2.72-3.61 (m, 2H), 3.43 (bt, 4H, J=4.90Hz), 2,62 (bt, 4H, J=4.80Hz), 2.36 (s, 3H), 2.04 (s, 3H)
(±)-N-[[2-oxo-3-[4-[5-oxo-4-[(cyclopentyl) amino]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:208-210 ℃ HRMS: calculated value C
24H
27N
3O
4: 421.2001: measured value 421.1987
1H NMR (CDCl
3): δ 7.61-7.44 (m, 6H), 7.20 (d, 1H, J=12.0Hz), 6.71 (d, 1H, J=11.2Hz), 4.81 (m, 1H), 4.10 (1,1H, J=9.0Hz), 4.00 (m, 1H), 3.865 (dd, 1H, J=10.0Hz), 3.68-3.66 (m2H), and 2.20-2.10 (m, 2H), 2.04 (s, 3H), and 1.81-1.68 (m, 6H)
(±)-N-[[2-oxo-3-[4-[5-oxo-4-piperazine-1-yl]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:＞300 ℃ of HRMS: calculated value: C
23H
26N
3O
4: 422.1954: measured value 422.1964
1H NMR (CDCl
3): δ 7.585 (d, 2H, J=8.8Hz), 7.485 (d, 2H, J=8.8Hz), 7.395 (dd, 1H, J=12.5Hz), 7.255 (dd, 1H, J=10.8Hz), 7.12 (d, 1H, J=12.5Hz), 6.815 (d, 1H, J=10.8Hz), 6.70 (bt, 1H), 4.81 (m, 1H), 4.11 (t, 1H, J-9.0Hz), 3.854 (dd, 1H, J-8.8Hz), 3.68 (m, 2H), 3.38 (bt, 4H, J=4.8Hz), 3.08 (bt, 4H, J=4.8Hz), 2.03 (s, 3H).
(±)-N-[[2-oxo-3-[4-[5-oxo-44-[(normal-butyl) amino]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:197-198 ℃ HRMS
1H NMR (CDCl
3): δ 7.58-7.45 (m, 6H), 7.22 (d, 1H, J=12.0Hz), 6.66 (d, 1H, J=11.0Hz), 4.80 (m, 1H), 4.11 (t, 1H, J=9.0Hz), 3.835 (dd, 1H, J=9.1Hz), 3.68 (m, 2H), 3.36 (t, 2H, J=7.2Hz), 2.03 (s, 3H), 1.78-1.74 (m, 2H), 1.53-1.45 (m, 2H), 1.00 (t, 3H, J=7.2Hz).
(±)-N-[[2-oxo-3-[4-[5-oxo-4-(suitable-3,5-lupetazin-1-yl)-1,3,6-cycloheptatriene-1-yl]-2-oxo-5-oxazolidinyl] methyl] MP:142-144 ℃ of MS of acetyl ammonia (EI): m/z (relative abundance) 450[M+] (45), 380 (54), 366 (43), 367 (53), 84 (100)
1H NMR (CDCl
3) δ 7.585 (d, 2H, J=8.8Hz), 7.475 (d, 2H, J=8.8Hz), 7.355 (dd, 1H, J=12.5Hz), 7.215 (dd, 1H, J=10.8Hz), 7.10 (d, 1H, J=12.5Hz), 6.79 (d, 1H, J=10.8Hz), 6.12 (bt, 1H), 4.80 (m, 1H), 4.11 (t, 1H, J=9.0Hz), 3.89-3.81 (m, 3H) 3.49-3.47 (m, 2H), 3.16 (m, 2H), 2.45 (bt, 2H, J=112.4Hz), 2.04 (s, 3H), 1.18 (d, 6H, J=6.30Hz)
(±)-N-[[2-oxo-3-[4-[5-oxo-4-[piperidines-1-yl]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide
MP:211-212℃
HRMS: calculated value C
21H
23N
3O
4: 421.2001; Measured value: 421.2007
1H NMR(CDCl
3):δ7.565(d,2H,J=8.8Hz),7.465(d,2H,J=8.8Hz),7.33(dd,1H,J=12.4
Hz),7.195(dd,1H,J-10.8Hz),7.07(d,1H,J=12.4Hz),6.80(d,1H,J=10.8Hz)6.25(bt,
1H),4.81(m,1H),4.10(t,1H,J=9.0Hz),3.835(dd,1H,J=9.0Hz),3.72-3.61(m,2H),3.41-
3.39(m,4H),2.04(s,3H),1.74-1.72(m,6H).
(±)-N-[[2-oxo-3[4-[5-oxo-4-(3-methylpiperazine-1-yl]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide
MP:189-191℃
HRMS calculated value: C
24H
28N
5O
4: 436.2110: measured value: 436.2110
1H NMR(CDCl
3):δ7.575(d,2H,J=8.8Hz),7,485(d,2H,J=8.8Hz),7.395(d,1H,J=12.5
Hz),7.255(dd,1H J=10.7Hz),7.255(dd,1H,J=10.7Hz),7.12(d,1H,J=12.4Hz),6.82(d,
1H,J=10.7Hz),4.81(m,1H),4.11(t,1H,J-9.0Hz),3.86-3.83(m,3H),3.67-3.63(m,2H),
2.87(m,1H),2.50(bt,1H,J=104Hz),2.03(s,3H),1.14(d,3H,J=6.3Hz),
(±)-N-[[2-oxo-3-[4-[5-oxo-4-[3-hydroxyl pyrrolidine-1-yl]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl] ethanamide MP:223-224 ℃ HRMS: calculated value: C
23H
25N
3O
5+ H
1: 424.1872 measured values 424.1900
1H NMR (CDCl
3): δ 7.495 (d, 2H, J=8.8Hz), 7.395 (d, 2H, J=8.8Hz), 7.32 (d, 1H, J-12.2Hz), 7.23 (d, 1H, J=11.2Hz) 6.95 (d, 1H, J=12.2Hz),, 6.465 (d, 1H, J=11.2Hz), 4.81 (m, 1H), 4.56 (m, 1H), 4.09 (t, 1H, J-9.0Hz), and 3.99-3.95 (bd, 1H), 3.85-3.77 (m, 3H), and 3.67-3.66 (m, 2H), 2.93-2.88 (m, 1H), 2.07 (bs, 2H), 2.03 (s, 3H). embodiment 5 (±) N-[[3-[4-(4-oxyethyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
With (±)-N-[[3-[4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide (0.100 gram, 0.27 mmole) sodium hydride of the usefulness of the soup compound in dehydrated alcohol (10 milliliters) catalytic amount is (5 milligrams, 60% dispersion in mineral oil) handle under nitrogen atmosphere mixture heating up to refluxing, this mixture becomes homogeneous phase solution during this period.Reflux and after 15 minutes described solution is cooled to envrionment temperature, notice solid precipitation.Use the ether diluted reaction mixture, and pass through solid collected by filtration.After the vacuum-drying, obtain the light yellow solid-state title compound that 0.088 gram (85%) has following feature.
mp228-229℃
1H-NMR (CDCl
3, 300MHz) δ 7.60 (d, J=8.7Hz, 2H), 7.52-7.47 (m, 1H), 7.48 (d, J=8.5Hz, 2H), 7.33-7.26 (m, 1H), 7.24 (d, J=10.5Hz, 1H), 6.87 (d, J=10.6Hz, 1H), 6.80 (bt, 1H), 4.82 (m, 1H), 4.19 (q, J=6.9H7,2H), 4.11 (＂ t ＂, J=8.9Hz, 1H), 3.86 (dd, J=9.0,6.8Hz, 1H), 3.75-3.60 (m, 2H), 2.03 (s, 3H), 1.56 (t, J=6.9Hz, 3H), MS m/z (relative abundance) 382 (36.5, M+), 338 (55.0), 310 (26.3), 254 (26.8), 226 (100.0) HRMS m/z382.1536 (calculated value C
21H
22N
2O
5: 382.1529) embodiment 6 (S)-N-[[3-[3-chloro-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
With above-mentioned (S)-N-[[3-(3-fluoro-4-sulfophenyl)-2-oxo-5-oxazolidinyl] methyl] ethanamide (4.200 grams, 11.11 mmole) and trimethylammonium (4-methoxyl group-5-oxo 1,3,6-cycloheptatriene-1-yl) soup compound of tin (4.150 grams, 13.88 mmoles) in 1.4-diox (50 milliliters) outgases by finding time repeatedly and filling ammonia.Add two (triphenylphosphine) palladiums (II) of chlorination (0.545 gram, 0.78 mmole), again with the reaction solution degassing, then at N
2Under the atmosphere mixture is refluxed.After 3 hours, TLC shows still residual-a little iodide.Add tin reagent (0.400 gram, 1.34 mmoles) and palladium catalyst (0.100 gram, 0.14 mmole) in addition, mixture was refluxed 4 hours.Reaction mixture is cooled to envrionment temperature and concentrating under reduced pressure.Resistates is dissolved in 20% methyl alcohol/chloroform filtration over celite and vacuum concentration.With methylene dichloride/ether development crude product solid,,, obtain 4.200 gram (98%) title compounds with ether washing and vacuum-drying with solid filtering.This thing has following feature:
mp227-228℃
[α]
25 D+39.5°(c0.9,DMF)
With other-kind of method; on state the oxazolidone iodide and can use among the TR7246-92-050 for the disclosed condition of corresponding racemize material, be converted into (S)-N-[[3-[3-fluoro-4-(trimethylammonium stannyl) phenyl]-2 oxos-5-oxazolidinyl] methyl] ethanamide.With the intermediate (0.180 gram, 0.43 mmole) and 5-bromo-2-methoxy basic ring heptan-2 of this tin replacement, 4,6-triolefin-1-ketone (0.103 gram, 0.48 mmole) is dissolved in the dry DMF (3 milliliters), and gained solution is outgased by finding time repeatedly and filling nitrogen.Add two (triphenylphosphine) palladiums (II) of chlorination (0.015 gram, 0.02 mmole), will react the degassing again, with mixture heating up to 80 ℃ and kept 2 hours.Therefore TLC shows still residual-a little initial substances add palladium catalyst (0.015 gram) again, with further heating 5 hours of mixture.The vacuum concentration reaction mixture with resistates silica gel chromatography purifying, with methyl alcohol chloroform gradient solvent wash-out, obtains 0.096 gram (57%) title compound, and its each side is all identical with the material that makes with top method.
Embodiment 7 (two)-N-[[3-[4-(4-methoxyl group-3-oxo-1,4,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide].
With (two)-5-acetylamino methyl-3-(4 ＇-tin trimethyl phenyl) azoles alkane-2-ketone (1.172 grams, 2.95 mmole) and 6-bromo-2-methoxy basic ring heptan-2,4, dioxane (50 milliliters) solution of 6-triolefin-1-ketone (0.677 gram, 3.13 mmoles) is alternately found time and is filled nitrogen three times.Add two (triphenylphosphine) palladiums (II) of chlorination (0.200 gram, 0.28 mmole) then.Again system is found time and fill nitrogen three times and 90 ℃ of following heated overnight.Reaction not exclusively; Therefore add 0.103 gram (0.15 mmole) palladium catalyst, this system is alternately found time and fill nitrogen four times.Reflux after 2 hours, reaction mixture is passed through to filter through methylene dichloride and the careful washed diatomite plunger of methyl alcohol.Evaporating solvent obtains thick material, in middle pressure silica column (40 * 63 μ, 26 centimetres of 2.5 cm x, with 1% methyl alcohol/chloroform packed column, use the chloroform application of sample, with methyl alcohol/chloroform gradient solvent wash-out) go up purifying, obtain the desired material of 0.889 gram (productive rate 82%) white solid state.This material obtains 0.577 gram (51.2%) white solid, mp213-214 ℃ by analysis again through acetone recrystallization.
1H NMR (CDCl
3, 300MHz) δ: 7.63 (d, J=9.0Hz, 2H), 7.60 (d, J=9.0Hz, 2H), 7.45 (s, 1H), 7.10 (m, 2H), 6.73 (d, J=8.7Hz, 1H), 6.02 (bt, J=6.0Hz, 1H), 4.81 (m, 8lines, 1H), 4.12 (t, J=9.0Hz, 1H), 3.98 (s, 3H), 3.78 (dd, J=9.0Hz, J ＂=6.9Hz, 1H), 3.74 (ddd, J=14.7Hz, J ＇=6.0Hz, J ＂=3.3Hz, 1H), 3.64 (dt, J=14.7Hz, J ＇=6.0Hz, 1H), 2.04 (s, 3H)
13C NMR (75.47MHz, CDCl
3): 23.11,41.93,47.46,56.34,72.00,111.63,118.25,128.62,129.52,1.32.17,135.72,137.97,1.38.75,148.91,154.38,165.16,170.63,179.38, IR (mineral oil mulling 1, cm
-1): 3307 (m), 1739 (s), 1649 (m), 1592 (s), 1575 (s), 1561 (s).
MS:m/e (relative abundance): 368 (9.8, M
+), 340 (32.3), 296 (24.1), 240 (26.5), 237 (20.5), 212 (100), 199 (34.3), 85 (37.6), 56 (28.2), 43 (29.5), 29 (34.1); Accurate mass calculated value C
20H
20N
2O
5: 368.1372 measured value 368.1385. ultimate analysis calculated value: C
20H
20N
2O
5: C, 65.21; H, 5.47; N, 7.60 measured values: C, 64.79; H, 5.28; N, 7.60.TLC:5% methyl alcohol/chloroform: R
1=0.21. embodiment 8 (±)-N-[[3-[4-(6-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, I c
With (±)-5-acetylamino methyl-3-(4 ＇-tin trimethyl phenyl) oxazolidine-2-ketone (0.352 gram, 0.89 mmole) and 4-bromo-2-methoxy basic ring heptan-2,4, acetonitrile (25 milliliters) solution of 6-triolefin-1-ketone (0.200 gram, 0.93 mmole) is alternately found time and is filled nitrogen three times.Add two (triphenylphosphine) palladiums (II) of chlorination (0.076 gram, 0.11 mmole) then, again system is found time and fill nitrogen three times.Again mixture is refluxed and spend the night, filter then through the careful washed diatomite plunger of methylene dichloride.Evaporating solvent obtains thick material, presses silica column (40 * 63 μ in the warp, 2.5 27 centimetres of cm x with 1% methyl alcohol/chloroform post of filling a vacancy, are used the chloroform application of sample, and with methyl alcohol/chloroform gradient solvent wash-out) purifying, obtain the yellow solid-state desired material of 0.277 gram (85%).This material obtains 0.123 gram (38%) yellow solid, mp107-110 ℃ through acetone and water recrystallization.
1H NMR (CDCl
3, 300MHz) δ: 7.63 (d, J=9.0Hz, 2H), 7.56 (d, J=9.0Hz, 2H), 7.31 (m, 1H), 7.20 (dd, J=12.0Hz, J ＇=0.9Hz, 1H), 7.02 (dd, J=7.5Hz, J ＇=0.9Hz, 1H), 6.94 (s, 1H), 6.07 (t, J=6.0Hz, 1H), 4.83 (m, 9lines, 1H), 4.13 (t, J=9.0Hz, 1H) 3.99 (s, 3H), 3.87 (dd, J=9.0Hz, J ＇=6.9Hz, 1H), 3.74 (ddd, J=14.7Hz, J ＇=6.3Hz, J ＂=3.6Hz, 1H), 3.66 (dt, J=14.7Hz, J ＇=6.0Hz, 1H), 204 (s, 3H)
13C NMR (75.47MHz, CDCl
3): 23.12,41.96,47.55,56.37,72.09,114.39,118.55,126.87,128.39,135,41,136,52,138.13,139,06,145,78,154,22,164.53,171.09,179,84IR (mineral oil mulling cm
-1): 3469 (wide), 3288 (wide), 1745 (s), 1662 (m),
MS:m/e (relative abundance): 368 (72.4, M
+), 296 (33.3), 237 (35.9), 236 (34.3), 212 (100), 199 (56.8), 85 (53.8), 56 (49.8), 44 (30.3), 43 (50.1); Accurate mass calculated value C
20H
20N
2O
15: 368.1372. measured value: 368.1384. ultimate analysis calculated value C
20H
20N
2O
5: C, 65.21; H, 5.47; N, 7.60 measured values: C, 62.05; H, 5.74; N, 7.09TLC:5% methyl alcohol/chloroform: R
f=0.17. embodiment 9 (±)-N-[[3-[4-[4-(2-propenyl) amino-3-oxo-1,4,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxo 5-oxazolidinyl] methyl] ethanamide (I b)
At N
2The solution that under the atmosphere methoxyl group tropone is replaced De oxazolidone (0.077 gram, 0.21 mmole) and allylamine (3.5 milliliters, 46.6 mmoles) refluxes and spends the night.With the reaction mixture vacuum concentration, obtain thick material then, this thing is gone up purifying at 1000 μ preparation property TLC plates (with 3% ethanol/methylene wash-out three times) and is obtained the yellow solid-state desired compound of quantitative yield.This material is further purified on another preparation property TLC plate (250 μ, with 75% acetone/ethylene dichloride wash-out three times), obtains 0.033 gram (40%) yellow solid-state title compound, mp169-171 ℃, also have 0.026 to restrain (32%) impurity slightly.
1H NMR (CDCl
3, 300MHz) δ: 7.59 (bs, 4H), 7.47 (bt, J=6.0Hz, 1H), 7.40 (d, J=1.8Hz, 1H), 7.25 (t, J=10.5,1H), 6.88 (dd, J=10.5Hz, J ＇=1.8Hz, 1H), 6.51 (d, J=10.5Hz, 1H), 6.13 (bt, J=6.0Hz, 1H), 5.94 (m, 10lines, 1H), 5.29 (m, 2H), 4.81 (m, 9lines.1H), 4.12 (t, J=9.0Hz, 1H), 4.03 (t, J=5.7Hz, 2H), 3.84 (dd, J=9.3Hz, J ＇=6.9Hz, 1H), 3.73 (ddd, J=14.7Hz, J ＇=6.0Hz, J ＂=3.3Hz, 1H), 3.64 (dt, J=14.7Hz, J ＇=6.0Hz, 1H), 2.04 (s, 3H)
13C NMR (75.47MHz, CDCl
3): 0.01,23.13,41.88,45.15,47.53,71.95,108.21,117.57,118.23.123.59,128.78,132.05,135.46,137.81,139.38,149.38,154.06,155.16,170.63,175.16IR (mineral oil mulling, cm
-1): 3348 (m), 3293 (m), 1745 (s), 1662 (s), 1589 (s).
MS:m/e (relative abundance): 393 (100, M
+), 394 (24.7), 265 (18.7), 152 (11.0), 56 (33.0), 44 (14.6), 43 (22.9), 29 (31.3); Accurate mass calculated value C
22H
23N
3O
4: 393.1688 measured values: 393,1685 ultimate analysis calculated value C
22H
23N
3O
4: C, 67.16; H, 5.89; N, 10.68 measured value C, 64.74; H, 5.7; N, 9.83TLC:2.5% methyl alcohol/chloroform 1 * 2:R
f=0.36 embodiment 10 (±)-N-[[3-[4-[4-(4-morpholinyl)-3-oxo-1,4,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide (I b)
Solution backflow in 3.5 milliliters of toluene is spent the night with methoxyl group tropone replacement De oxazolidone (0.078 gram, 0.21 mmole) and morpholine (0.3 milliliter, 3.43 mmoles).Evaporating solvent, thick material obtain the yellow solid-state desired material of quantitative yield through preparation property TLC plate (1000 μ are with 3% ethanol/methylene wash-out secondary) purifying.This material is further purified through another preparation property TLC plate (250 μ, with 75% acetone/methylene dichloride wash-out three times), obtains 0.050 and restrains (56%) yellow solid-state title compound.Mp143-144 ℃, also has 0.016 gram (18%) impurity slightly simultaneously.
1H NMR(CDCl
3,300MHz)δ:7.60(d,J=9.0Hz,2H),7.58(d,J=9.0Hz,2H),7.21(d,J=
1.8Hz,1H),7.08(t,J=10.8Hz,1H),6.93(dd,J=10,8Hz,J＇=1,8Hz,1H),6.66(d,J=9.9
Hz,1H),6.30(bt,J=6.3Hz,1H),4,80(m,10lines,1H),4.11(t,J=9.0Hz,1H),3.90(t,J=
4.8Hz,4H),3.84(dd,J=9.3Hz,J＇=6.9Hz,1H),3.70(ddd,J=14.7Hz,J＇=6.0Hz,J＂=
3.3Hz,1H),3.64(dt,J=14.7Hz,J＇=6.0Hz,1H),3.37(t,J=4.8Hz,4H),2.03(s,3H)
13C NMR(75.47MHz,CDCl
3):0.01,23.13,41.98,47.50,49.09,66.71,72.01,117.43,118.26,
127.85,128.59,132.92,134.45,138.24147.58,154.32,159.57,171.11,181.55
IR (mineral oil mulling cm
-1): 3307 (m), 1731 (s), 1658 (m), 1563 (s),
MS:m/e (relative abundance): 423 (1030, M
+), 424 (27.0), 380 (179), 379 (23.9), 364
(23.8), 280 (28.5), 152 (18.8), 86 (34.7), 56 (23.8), 29 (23.3); The accurate mass calculated value
C
23H
25N
3O
5: 423.1794 measured values: 423.1814
Ultimate analysis calculated value: C
23HN
3O
5: C, 65.23; H, 5.95; N, 992. measured values: C, 63.83; H, 5.90; N
9.66.
TLC:5% methyl alcohol/chloroform: R
f=0.29. embodiment 11 (S)-N-[[3-[4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl)-3, the 5-difluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
1, in the 4-diox (25 milliliters), with (450 milligrams of three (dibenzalacetones), two palladiums (0)-chloroform adducts, 0.492 mmole) and (460 milligrams of three furyl phosphines, 1.969 mmole) stir 5 minutes jointly, add (S)-N-[[3-(4-iodo-3,5-difluorophenyl)-2-oxo-5-oxazolidinyl then] methyl] ethanamide (1.3 grams, 3.28 mmoles).With solution N
2Outgas after three times, add trimethylammonium (4-methoxyl group-5-oxo-1,3,6-cycloheptatriene 1-yl) tin (1.47 grams, 4.92 mmoles).Again with the solution degassing (3 times), then at N
2Under the atmosphere solution is heated to backflow (110 ℃), and kept 12 hours.-through cooling, TLC (10% methyl alcohol/CHCl
3, the ultraviolet shortwave) and assaying reaction is complete.The concentrating under reduced pressure reaction solution, and then be dissolved in CH
2Cl
2In (100 milliliters).Solution was stirred 45 minutes with the KF aqueous solution (100 milliliters), separate then.With salt solution (100 milliliters) washing organic moiety, use anhydrous Na then
2SO
4Dry.After the drying, it is filtered and concentrating under reduced pressure, obtain brown solid.(175 gram silica gel are used 10%CH with silica gel chromatography with crude product
3CN/CHCl
3Fill, with the 10%CH of 1-5% methyl alcohol
3CN/CHCl
3The gradient solvent wash-out) purifying obtains light yellow solid.This solid is dissolved in CH
2Cl
2/ methyl alcohol carries out recrystallization, and with the ether development, obtains 907 milligrams of solid-state title compounds of (68%) canescence, mp129 ℃ (decomposition), HRMS (M
+) calculated value C
20H
18N
2O
5F
2404.1184. actual measurement measured value 404.1183 embodiment 12 (±)-N-[[3-[4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene 1-yl)-3, the 5-difluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
With (±)-N-[[3-4-(trimethylammonium stannyl)-3, the 5-difluorophenyl]-2-oxo-5-oxazolidinyl] methyl] (80 milligrams of ethanamides, 0.185 mmole) be dissolved in 1, in the 4-diox (5 milliliters), use 5-bromo-2-methoxyl group tropone (49.5 milligrams, 0.230 mmole) to handle then.Use N
2After the solution degassing 3 times, add two (triphenylphosphine) palladiums (II) (28 milligrams, 0.40 mmole) of chlorination.With the solution degassing 3 times, then reaction solution is heated to backflow (110 ℃), and kept 5 hours again.Reaction this moment not exclusively; Add catalyzer (28 milligrams, 0.040 mmole) again, and after the degassing 3 times, again solution is heated to and refluxes and kept 5 hours.At this moment, reaction is still incomplete; Use more fresh catalyzer (28 milligrams) that said process is repeated for the third time again.Last solvent removed in vacuo is dissolved in CH with remaining oily matter
2Cl
2In (50 milliliters).With KF (75 milliliters) and salt solution (50 milliliters) washing CH
2Cl
2Solution.Use anhydrous Na
2SO
4After the drying, organic layer is filtered and concentrating under reduced pressure, obtain the spumescence solid.With this solid preparation property TLC (5% methyl alcohol/CHCl
3Wash-out) purifying uses radial chromatography (to use 0-5% methyl alcohol at 10%CH then
3CN/CHCl
3In the gradient solvent wash-out) purifying, obtain 7 milligrams of (9%) solid-state title compounds,
HRMS (M
+) calculated value C
20H
18F
2N
2O
5404.1184. measured value 404.1183.
With (±)-N-[[3-(4-iodo-3, the 5-difluorophenyl)-and 2-oxo-5-oxazolidinyl] methyl] ethanamide (250 milligrams, 0.631 mmole) is dissolved in 1, in the 4-diox (15 milliliters), use stannyl tropone (226 milligrams, 0.757 mmole) to handle then.With this solution N
2Outgas after three times, add two (triphenylphosphine) palladiums (II) (70 milligrams, 0.10 mmole) of chlorination.Again with the solution degassing 3 times, be heated to backflow (110 ℃) then and kept 7 hours.At this moment, reaction not exclusively; Add live catalyst (70 milligrams, 0.10 mmole), outgas again after 3 times, again solution is heated to and refluxes and kept 7 hours.This moment, solvent removed in vacuo was dissolved in CH with remaining oily matter
2Cl
2In (50 milliliters).With the KF aqueous solution (40 milliliters) and salt solution (40 milliliters) washing CH
2Cl
2Solution.Use anhydrous Na
2SO
4After the drying, organic layer filtered and be evaporated to obtain the spumescence brown solid.This solid with silica gel (100 gram) chromatography purification, is used in 10%CH
3CN/CHCl
3In 0-10% methyl alcohol gradient solvent wash-out, obtain not pure products.This product is used preparation property TLC (5% methyl alcohol/(CHCl again
3Wash-out) purifying obtains 72 milligrams of solid-state title compounds of (28%) canescence, and mp218 ℃ (decomposition), this thing each side is all identical with above-mentioned preparation material.
Compound title code name
1. (±)-N-[[3-[4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-the 2-oxazolidinyl] methyl]-ethanamide
2. (±)-N-[[3-[4-(4-diethylamino-5-oxo-1,3,6 cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
3. (±)-N-[[2-oxo-3-[4-[5-oxo-4-[(phenyl methyl) amino]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl]-ethanamide
4. amino (±)-N-[[3-[4-[4-[(2-hydroxyethyl)]-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
5. (±)-N-[[3-[4-[4-(4-morpholino)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
6. (±)-N-[[3-[4-(4-cyclopropyl amino-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
7. (±)-N-[[3-[4-[4-(4-formyl radical-1-piperazinyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
8. (±)-N-[[3-[4-[4-(2-propenyl amino)-5-oxo-1,3.6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
9. (±)-N-[[3-[4-[4-(1-pyrrolidyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
10. (±)-N-[[3-[4-[4-(4-methyl isophthalic acid-piperazinyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(11. ±)-N-[[3-[4-(4-cyclopentyl amino-5-oxo-1,3,6-cycloheptatriene-1 base) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(12. ±)-N-[[3-[4-[4-(1-piperazinyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(13. ±)-N-[[3-[4-(4-butyl amino-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(14. ±)-N-[[3-[4-[4-(suitable-3,5-dimethyl-1-piperazinyl) 5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(15. ±)-N-[[3-[4-[4-(piperidino)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(16. ±)-N-[[3-[3-fluoro-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(17. ±)-N-[[3-[4-[4-(3-methyl isophthalic acid-piperazinyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(18. ±)-N-[[3-[4-[4-(3-hydroxyl-1-pyrrolidyl)-5-oxo-1,3,6 cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
19. (S)-N-[[3-fluoro-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(20. ±)-N-[[3-[4-[4-methoxyl group-3-oxo-1,4,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(21. ±)-N-[[3-[4-(6-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(22. ±)-N-[[3-[4-(4-oxyethyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(23. ±)-N-[[3-[4-[4-(3-amino-1-pyrrolidyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(24. ±)-N-[[3-[4-[4-(1-methyl ethoxy)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
25. (S)-and N-[[3-[[4-[4-(4-horse quinoline generation)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(26. ±)-N-[[3-[4-[4-(2-propenyl amino)-3-oxo-1,4,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(27. ±)-N-[[3-[4-[4-(4-morpholinyl)-3-oxo-1,4,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide, and
28. (S)-N-[[3-[4-methoxyl group-5-oxo-1,3, the methyl phenyl-2-oxo-5-oxazolidinyl of 6-cycloheptatriene-yl))]-ethanamide
(29. ±)-N-[[3-[4-[4-(2-propynyl amino)-3-oxo-1,4,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl-ethanamide
Methyl (30. ±)-N-[[3-[4-[-[[(methoxycarbonyl)] the nitrogen base]-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(31. ±)-N-[[3-[4-(4-methylamino-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(32. ±)-N-[[3-[4-[4-(2,5-two chloro-1H-ratios are coughed up-the 1-yl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(33. ±)-N-[[3-[4-[4-(2-propenyl oxygen base)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
34. (S)-N-[[3-[3-fluoro-4-[(2-proyl amino)-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl-ethanamide
(35. ±)-N-[[3-[4-[4-(2-methoxy ethoxy)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
36. (S) N-[[3-[3-fluoro-4-[(4-morpholino)-and 5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
Table 1
| External minimum inhibition concentration (mcg/ml) | ||
| The compound sequence number | Streptococcus aureus UC 9213 | Acid Streptococcus pyrogenes UC 152 |
| Compound 1 | 2 | 0.25 |
| Compound 2 | 4 | 1 |
| Compound 3 | ＞64 | 4 |
| Compound 4 | 4 | 0.5 |
| Compound 5 | 2 | 0.5 |
| Compound 6 | 2 | 0.5 |
| Compound 7 | 4 | 0.5 |
| Compound 8 | 2 | 0.5 |
| Compound 9 | 4 | 1 |
| Compound 10 | 2 | 0.12 |
| Compound 11 | 4 | 1 |
| Compound 12 | 8 | 0.25 |
| Compound 13 | 2 | 0.5 |
| Compound 14 | 8 | 0.5 |
| Compound 15 | 2 | 1 |
| Compound 16 | 1 | 0.25 |
| Compound 17 | 8 | 0.25 |
| Compound 18 | 4 | 1 |
| Compound 19 | 1 | 0.25 |
| Compound 20 | 4 | 0.5 |
| Compound 21 | 64 | 8 |
| Compound 22 | 4 | 0.5 |
| Compound 23 | 16 | 0.25 |
| Compound 24 | 4 | 1 |
| Compound 25 | 2 | 0.5 |
| Compound 26 | 2 | 1 |
| Compound 27 | 4 | 1 |
| Compound 28 | 1 | |
| Compound 29 | 2 | 0.5 |
| Compound 30 | 4 | 1 |
| Compound 31 | 2 | 0.25 |
| Compound 32 | 32 | 4 |
| Compound 33 | 4 | 1 |
| Compound 34 | 1 | 0.25 |
| Compound 35 | 4 | 1 |
| Compound 36 | 2 | 0.5 |
Claims (10)
1, have the compound of formula I and pharmacologically acceptable salt thereof with and hydrate,
R wherein
1Be:
(a) hydrogen
(b) (the C that is randomly replaced by one or more F, Cl, hydroxyl, alkoxyl group, acyloxy
1-C
8) alkyl;
(c) (C
3-C
6) cycloalkyl,
(d) amino,
(e) (C
1-C
8) alkylamino,
(f) (C
1-C
8) dialkyl amido,
(g) (C
1-C
8) alkoxyl group,
R wherein
2And R
3Be identical or different, and be selected from following groups, precondition is to work as R
2And R
3When not all being hydrogen, R
2And R
3Identical:
(a) hydrogen
(b) fluorine
(c) chlorine
(d) (C
1-C
8) alkyl
(e) trifluoromethyl
(f) hydroxyl
(g) (C
1-C
8) alkoxyl group
(h) nitro
(i) amino
R wherein
4Be selected from following groups:
Wherein R and R
aCarry identical or differently, and be selected from by the optional (C that replaces of following groups
1-C
8) alkyl: chlorine, fluorine, hydroxyl, (C
1-C
8) alkoxyl group, amino, (C
1-C
8) alkylamino, (C
1-C
8) dialkyl amido;
R wherein
5Be selected from following groups: hydrogen, OR
6, SR
6, NHR
7,
And NR
7R
12
R wherein
6Be:
(a) hydrogen
(b) by the optional (C that replaces of one or more halogens
1-C
8) alkyl
(c) by amino, C
1-C
8Alkylamino, C
1-C
8Optional (the C that replaces of dialkyl amido
1-C
8) alkyl
(d) by one or more hydroxyls and by amino, alkylamino, the optional (C that replaces of dialkyl amido
1-C
8) alkyl
(e) by one or more C
1-C
aOptional (the C that replaces of alkoxyl group
1-C
8) alkyl
(f) by amino, (C
1-C
8) alkylamino, (C
1-C
8) optional (C that replaces of dialkyl amido
2-C
8) alkenyl (C
1-C
8) alkyl
(g) by amino, (C
1-C
4) alkylamino, (C
1-C
8) optional (C that replaces of dialkyl amido
2-C
8) alkynyl (C
1-C
8) alkyl
(h) by hydroxyl, amino, (C
1-C
8) alkylamino, (C
1-C
4) optional (C that replaces of dialkyl amido
2-C
8) acyl group
(i) the amino, (C of quilt on phenyl
1-C
8) alkylamino, (C
1-C
8) the optional phenyl (C that replaces of dialkyl amido
1-C
8) alkyl
(j) the amino, (C of quilt on pyridyl
1-C
8) alkylamino, (C
1-C
8) the optional pyridyl (C that replaces of dialkyl amido
1-C
8) alkyl
(k) by one or two (C
1-C
6) the optional amino that replaces of alkyl
R wherein
7Be:
(a) hydrogen
(b) by one or more chlorine, fluorine, hydroxyl, amino, (C
1-C
8) alkylamino, (C
1-C
8) dialkyl amido, phenyl, pyridyl, (C
1-C
8) alkoxyl group, (C
1-C
8) the partly optional (C that replaces of carbalkoxy
1-C
8) alkyl
(c) by amino, (C
1-C
8) alkylamino or (C
1-C
8) optional (C that replaces of dialkyl amido
3-C
6) cycloalkyl
(d) amino
(e) (C
1-C
8) alkylamino
(f) (C
1-C
8) dialkyl amido
(g) hydroxyl
(h) (C
1-C
8) alkoxyl group
(i) by amino, (C
1-C
4) alkylamino, (C
1-C
4) optional (C that replaces of dialkyl amido
2-C
8) alkenyl (C
1-C
10) alkyl
(j) by amino, (C
1-C
4) alkylamino, (C
1-C
4) optional (C that replaces of dialkyl amido
2-C
8) alkynyl (C
1-C
10) alkyl
R wherein
8Be:
(a) hydrogen
(b) (C
1-C
8) alkyl
(c) (C
3-C
8) cycloalkyl
(d) (C
1-C
8) acyl group
(e) (C
1-C
8) carbalkoxy
(f) (C
1-C
8) alkyl sulphonyl
R wherein
9And R
10Can be identical or different, and be:
(a) hydrogen
(b) (C
1-C
8) alkyl
R wherein
11Be:
(a) hydrogen
(b) hydroxyl
(c) (C
1-C
8) alkoxyl group
(d) amino
(e) alkylamino
(f) (C
1-C
8) dialkyl amido
(g) by amino, (C
1-C
4) alkylamino and (C
1-C
4) optional (C that replaces of dialkyl amido
1-C
8) alkyl;
R wherein
12Be (C
1-C
8) alkyl.
2, the compound that has the claim 1 of formula I a,
R wherein
1, R
2, R
3And R
5Identical with the definition in the claim 1.
3, the compound of claim 2, it is selected from following compounds:
(±)-N-[[3-[4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-the 2-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-(4-diethylamino-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[2-oxo-3-[4-[5-oxo-4-[(phenyl methyl) amino]-1,3,6-cycloheptatriene-1-yl] phenyl]-the 5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-[4-[(2-hydroxyethyl) amino]-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-[4-(4-morpholino)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-(4-cyclopropyl amino-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-[4-(4-formyl radical-1-piperazinyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-[4-(2-propenyl amino)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-[4-(1-pyrrolidyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-[4-(4-methyl isophthalic acid-piperazinyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-(4-cyclopentyl amino-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-[4-(1-piperazinyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-(4-butyl amino-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-[4-(suitable-3,5-dimethyl-1-piperazinyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-[4-(piperidino)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[3-fluoro-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-[4-(3-methyl isophthalic acid-piperazinyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-[4-(3-hydroxyl-1-pyrrolidyl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(S)-N-[[3-fluoro-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide
(±)-N-[[3-[4-(4-oxyethyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(±)-N-[[3-[4-(3-amino-1-pyrrolidyl)-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(±)-[N-[[3-[4-[4-(1-methyl ethoxy)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(S)-and N-[[3-[4-[4-(4-morpholino)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(S)-and N-[[3-[4-methoxyl group-5-oxo-1,3, the phenyl-2-oxo-5-oxazolidinyl of 6 one cycloheptatriene-yl)] methyl]-ethanamide,
(±)-N-[[3-[4-[-[[(methoxycarbonyl) methyl] amino]-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(±)-N-[[3-[4-(4-methylamino-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(±)-N-[[3-[4-[4-(2,5-dihydro-1H-pyrroles-1-yl)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(±)-N-[[3-[4-[4-(2-propenyloxy group)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(S)-N-[[3-[3-fluoro-4-[(2-proyl amino)-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(±)-N-[[3-[4-[4-(2-methoxy ethoxy)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(S)-N-[[3-[3-fluoro-4-[(4-morpholino)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(±)-N-[[3-[3,5-two fluoro-4-[4-methoxyl group-5-oxos-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl) methyl]-ethanamide,
(S)-N-[[3-[4-(4-methylamino-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl-ethanamide, (S)-N-[[3-fluoro-4-(4-methylamino-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl-ethanamide
(S)-N-[[3-(4-(4-cyclopropyl) amino-5-oxo-1,3,6-cycloheptatriene-1-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide.
4, the compound of claim 2, wherein R
2And R
3Be selected from hydrogen and fluorine.
5, the compound of claim 4, this compound is selected from following compounds:
(±)-N-[[3-[3-fluoro-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(S)-N-[[3-[3-fluoro-4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(S)-N-[[3-[3-fluoro-4-[(2-proyl amino)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(S)-N-[[3-[3-fluoro-4-[(4-morpholino)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(±)-N-[[3-[3,5-two fluoro-4-[4-methoxyl group-5-oxos-13,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl) methyl]-ethanamide,
(S)-and N-[[3-fluoro-4-(4-methylamino)-5-oxo-1,3,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl-ethanamide, and
(S)-and N-[[3-[4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl)-3, the 5-difluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, and
(±)-N-[[3-[4-(4-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl)-3, the 5-difluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
6, the compound that has the claim 1 of formula I b,
R wherein
1, R
2, R
3And R
5Identical with the definition in the claim 1.
7, the compound of claim 6, this compound is selected from following compounds:
(±)-N-[[3-[4-(4-methoxyl group-3-oxo-1,4,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide,
(±)-N-[[3-[4-[-(2-propenyl amino)-3-oxo-1,4,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxo-5-oxazolidinyl] methyl]-ethanamide,
(±)-N-[[3-[4-[4-(4-morpholinyl)-3-oxo-1,4,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide, and
(±)-N-[[3-[4-[4-(2-propynyl amino)-3-oxo-1,4,6-cycloheptatriene-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide.
8, the compound that has the claim 1 of formula I c,
R wherein
1, R
2, R
3And R
5Identical with the definition in the claim 1.
9, the compound of claim 8, this compound is
(±)-N-[[3-[4-(6-methoxyl group-5-oxo-1,3,6-cycloheptatriene-1-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-ethanamide.
10, the compound that has the claim 1 of formula I d,
Wherein R, R
1, R
2, R
3And R
5Identical with the definition in the claim 1.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US98858992A | 1992-12-08 | 1992-12-08 | |
| US988,589 | 1992-12-08 | ||
| US6635693A | 1993-05-21 | 1993-05-21 | |
| US066,356 | 1993-05-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1092413A CN1092413A (en) | 1994-09-21 |
| CN1044473C true CN1044473C (en) | 1999-08-04 |
Family
ID=26746668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93120887A Expired - Fee Related CN1044473C (en) | 1992-12-08 | 1993-12-08 | Tropone-substituted phenyloxazolidinone antibacterial agents |
Country Status (6)
| Country | Link |
|---|---|
| CN (1) | CN1044473C (en) |
| IL (1) | IL107663A (en) |
| MX (1) | MX9307705A (en) |
| MY (1) | MY117563A (en) |
| PH (1) | PH31085A (en) |
| TW (1) | TW299332B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104327007B (en) * | 2014-10-20 | 2016-07-27 | 安徽师范大学 | 3,4,5-tri-substituted (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides compound and preparation method thereof |
| CN107118173B (en) * | 2017-07-12 | 2019-10-29 | 阿里生物新材料（常州）有限公司 | A kind of cycloheptatriene and oxazine compound and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3149608A1 (en) * | 1981-12-15 | 1983-08-04 | Dr. Madaus & Co, 5000 Köln | Substituted tropolones, process for the preparation thereof and pharmaceutical compositions containing these |
| EP0127902A2 (en) * | 1983-06-07 | 1984-12-12 | E.I. Du Pont De Nemours And Company | Aminomethyl oxooxazolidinyl benzene derivatives useful as antibacterial agents |
| EP0316594A1 (en) * | 1987-10-21 | 1989-05-24 | The Du Pont Merck Pharmaceutical Company | Aminomethyl oxooxazolidinyl ethenylbenzene derivatives useful as antibacterial agents |
-
1993
- 1993-10-19 TW TW82108669A patent/TW299332B/zh active
- 1993-11-03 PH PH47191A patent/PH31085A/en unknown
- 1993-11-18 IL IL10766393A patent/IL107663A/en not_active IP Right Cessation
- 1993-11-29 MY MYPI9302517 patent/MY117563A/en unknown
- 1993-12-07 MX MX9307705A patent/MX9307705A/en not_active IP Right Cessation
- 1993-12-08 CN CN93120887A patent/CN1044473C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3149608A1 (en) * | 1981-12-15 | 1983-08-04 | Dr. Madaus & Co, 5000 Köln | Substituted tropolones, process for the preparation thereof and pharmaceutical compositions containing these |
| EP0127902A2 (en) * | 1983-06-07 | 1984-12-12 | E.I. Du Pont De Nemours And Company | Aminomethyl oxooxazolidinyl benzene derivatives useful as antibacterial agents |
| EP0316594A1 (en) * | 1987-10-21 | 1989-05-24 | The Du Pont Merck Pharmaceutical Company | Aminomethyl oxooxazolidinyl ethenylbenzene derivatives useful as antibacterial agents |
Also Published As
| Publication number | Publication date |
|---|---|
| IL107663A0 (en) | 1994-02-27 |
| PH31085A (en) | 1998-02-05 |
| TW299332B (en) | 1997-03-01 |
| CN1092413A (en) | 1994-09-21 |
| MY117563A (en) | 2004-07-31 |
| MX9307705A (en) | 1994-06-30 |
| IL107663A (en) | 1996-10-16 |
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