1. A process for preparing an azetidinone, comprising the step of reacting:
(1) a \u03b2-(substituted-amino)amide, a \u03b2-(substituted-amino)-acid ester, or a \u03b2-(substituted-amino)thiolcarbonic acid ester with
(2) at least one silylating agent and
(3) at least one cyclizing agent which is
(a) selected from the group consisting of alkali metal carboxylates, quaternary ammonium carboxylates, quaternary ammonium hydroxides, quaternary ammonium alkoxides, quaternary ammonium aryloxides and hydrates thereof, or
(b) the reaction product of:
(i) at least one quaternary ammonium halide and at least one alkali metal carboxylate; or
(ii) at least one quaternary ammonium chloride, quaternary ammonium bromide, or quaternary ammonium iodide and at least one alkali metal fluoride,
wherein a quaternary ammonium moiety of the cyclizing agent is unsubstituted or substituted by one to four groups independently selected from the group consisting of alkyl, arylalkyl and arylalkyl-alkyl.
2. The process according to claim 1, wherein the azetidinone is represented by the structural Formula (I):
or pharmaceutically acceptable salts or solvates of the azetidinone of Formula (I), wherein in Formula (I) above:
X\u2032, Y\u2032 and Z can be the same or different and each is independently selected from the group consisting of \u2014CH2\u2014, \u2014CH(alkyl)- and \u2014C(alkyl)2-;
Q1 and Q2 can be the same or different and each is independently selected from the group consisting of H, \u2014(C0-C30 alkylene)-G, \u2014OR6, \u2014OC(O)R6, \u2014OC(O)OR9, and \u2014OC(O)NR6R7M;
Q3, Q4, and Q5 can be the same or different and each is independently 1 to 5 substituents independently selected from the group consisting of acyl, alkyl, alkylaryl, alkylheteroaryl, alkylsulfonyl alkenyl, alkoxy, alkoxycarbonyl, alkynyl, \u2014(C0-C30 alkylene)-G, \u2014(C0-C10 alkylene)-OR6, \u2014(C0-C10 alkylene)-C(O)R6, \u2014(C0-C10 alkylene)-C(O)OR6, \u2014(C0-C10 alkylene)-OC(O)R6, \u2014(C0-C10 alkylene)-OC(O)OR9, \u2014CH\u2550CH\u2014C(O)R6, \u2014CH\u2550CH\u2014C(O)OR6, \u2014C\u2261C\u2014C(O)OR6, \u2014C\u2261C\u2014C(O)R6, \u2014O\u2014(C1-C10 alkylene)-OR6, \u2014O\u2014(C1-C10 alkylene)-C(O)R6, \u2014O\u2014(C1-C10 alkylene)-C(O)OR6, \u2014CN, \u2014C(\u2550N\u2014CN)\u2014NH2, \u2014C(\u2550NH)\u2014NHR10, \u2014O\u2014(C1-C10 alkylene)-C(O)NR6R7, \u2014O\u2014(C0-C10 alkylene)-C(O)NR6NR7C(O)OR6, \u2014O\u2014(C1-C10 alkylene)-C(O)(aryl)-N\u2014N\u2550N\u2212, \u2014OC(O)\u2014(C1-C10 alkylene)-C(O)OR6, \u2014(C0-C10 alkylene)-C(O)NR6R7, \u2014(C0-C10 alkylene)-OC(O)NR6R7, \u2014NO2, \u2014(C0-C10 alkylene)-NR6R7, \u2014O\u2014(C2-C10 alkylene)-NR6R7, \u2014NR6C(O)R7, \u2014NR6C(O)OR9, \u2014NR6C(O)NR7R8, \u2014NR6S(O)0-2R9, \u2014N(S(O)0-2R9)2, \u2014CHNOR6, \u2014C(O)NR6R7, \u2014C(O)NR6NR6R7, \u2014S(O)0-2NR6R7, \u2014S(O)0-2R9, \u2014O\u2014C(O)\u2014(C1-C10 alkylene)-C(O)NR6R7, \u2014OC(O)\u2014(C1-C10 alkylene)-NR6C(O)O-(alkylaryl), \u2014P(O)(OR10)2, \u2014(C1-C10 alkylene)-OSi(alkyl)3, \u2014CF3, \u2014OCF3, halo, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy, alkoxyarylalkoxy, alkoxyiminoalkyl, alkyldioyl, allyl, allyloxy, aryloxycarbonyl, aryl, arylalkyl, aryloxy, arylalkoxy, aroyl, aroyloxy, arylsulfonyl, aroylaroyloxy, aroyl, arylalkoxycarbonyl, benzoylbenzoyloxy, carboxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkyl, heteroarylalkoxy, heteroarylsulfonyl, heteroarylthio, dioxolanyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylcarbonylalkoxy, hydroxy, hydroxyalkyl, and alkylsulfonyl;
wherein optionally one or more carbon atoms of the \u2014(C0-C30 alkylene)- radical of Q1, Q2, Q3, Q4 and Q6 is independently replaced by \u2014O\u2014, \u2014C(O)\u2014, \u2014CH\u2550CH\u2014, \u2014C\u2261C\u2014, \u2014N(alkyl)-, \u2014N(alkylaryl)- or \u2014NH\u2014;
G is selected from the group consisting of a sugar residue, disugar residue, trisugar residue, tetrasugar residue, sugar acid, amino sugar, amino acid residue, oligopeptide residue comprising 2 to 9 amino acids, trialkylammoniumalkyl radical and \u2014S(O)2\u2014OH,
R2 and R3 can be the same or different and each is independently selected from the group consisting of hydrogen, alkyl and aryl;
R6, R7 and R8 can be the same or different and each is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, arylalkyl and a protecting group; and
each R9 is independently alkyl, cycloalkyl, aryl or arylalkyl.
each R13 is independently H or alkyl;
q is 0 or 1;
r is 0 or 1;
m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5.
3. The process according to claim 2, wherein the azetidinone is represented by the structural Formula (IV):
4. The process according to claim 1, wherein the \u03b2-(substituted-amino)amide comprises a carbamoyl portion B\u2014C(O)\u2014, wherein B is a deprotonated chiral auxiliary selected from the group consisting of
wherein X is \u2014O\u2014, \u2014S\u2014 or \u2014N(alkyl)-; Y is \u2550O or \u2550S; and R12 and R13 are each independently selected from the group consisting of alkyl, aryl arylalkyl, and alkoxycarbonyl, or wherein one of R12 or R13 is as defined above and the other is hydrogen.
5. The process according to claim 4, wherein the aryl group of R12 or R13 is independently selected from the group consisting of phenyl, naphthyl, benzyl, substituted phenyl, substituted naphthyl and substituted benzyl, wherein the substituents on the phenyl or naphthyl are 1-3 substituents selected from the group consisting of alkyl, alkoxy, phenyl and benzyl.
6. The process according claim to 4, wherein the \u03b2-(substituted-amino)amide comprises a carbamoyl portion B\u2014C(O)\u2014, where B is (R14)(R15)N\u2014, and R14 and R15 are each independently selected from the group consisting of alkyl, aryl, arylalkyl.
7. The process according to claim 4, wherein the \u03b2-(substituted-amino)amide is represented by Formula (II):
wherein B is as defined in claim 4,
X\u2032, Y\u2032 and Z can be the same or different and each is independently selected from the group consisting of \u2014CH2\u2014, \u2014CH(alkyl)- and \u2014C(alkyl)2-;
Q1 and Q2 can be the same or different and each is independently selected from the group consisting of H, \u2014(C0-C30 alkylene)-G, \u2014OR6, \u2014OC(O)R6, \u2014OC(O)OR9, and \u2014OC(O)NR6R7;
Q3, Q4, and Q5 can be the same or different and each is independently 1 to 5 substituents independently selected from the group consisting of acyl, alkyl, alkylaryl, alkylheteroaryl, alkylsulfonyl alkenyl, alkoxy, alkoxycarbonyl, alkynyl, \u2014(C0-C30 alkylene)-G, \u2014(C0-C10 alkylene)-OR6, \u2014(C0-C10 alkylene)-C(O)R6, \u2014(C0-C10 alkylene)-C(O)OR6, \u2014(C0-C10 alkylene)-OC(O)R6, \u2014(C0-C10 alkylene)-OC(O)OR9, \u2014CH\u2550CH\u2014C(O)R6, \u2014CH\u2550CH\u2014C(O)OR6, \u2014C\u2261C\u2014C(O)OR6, \u2014C\u2261C\u2014C(O)R6, \u2014O\u2014(C1-C10 alkylene)-OR6, \u2014O\u2014(C1-C10 alkylene)-C(O)R6, \u2014O\u2014(C1-C10 alkylene)-C(O)OR6, \u2014CN, \u2014C(\u2550N\u2014CN)\u2014NH2, \u2014C(\u2550NH)\u2014NHR10, \u2014O\u2014(C1-C10 alkylene)-C(O)NR6R7, \u2014O\u2014(C0-C10 alkylene)-C(O)NR6NR7C(O)OR6, \u2014O\u2014(C1-C10 alkylene)-C(O)(aryl)-N\u2014N\u2550N\u2212, \u2014OC(O)\u2014(C1-C10 alkylene)-C(O)OR6, \u2014(C0-C10 alkylene)-C(O)NR6R7, \u2014(C0-C10 alkylene)-OC(O)NR6R7, \u2014NO2, \u2014(C0-C10 alkylene)-NR6R7, \u2014O\u2014(C2-C10 alkylene)-NR6R7, \u2014NR6C(O)R7, \u2014NR6C(O)OR9, \u2014NR6C(O)NR7R8, \u2014NR6S(O)0-2R9, \u2014N(S(O)0-2R9)2, \u2014CHNOR6, \u2014C(O)NR6R7, \u2014C(O)NR6NR6R7, \u2014S(O)0-2NR6R7, \u2014S(O)0-2R9, \u2014O\u2014C(O)\u2014(C1-C10 alkylene)-C(O)NR6R7, \u2014OC(O)\u2014(C1-C10 alkylene)-NR6C(O)O-(alkylaryl), \u2014P(O)(OR10)2, \u2014(C1-C10 alkylene)-OSi(alkyl)3, \u2014CF3, \u2014OCF3, halo, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy, alkoxyarylalkoxy, alkoxyiminoalkyl, alkyldioyl, allyl, allyloxy, aryloxycarbonyl, aryl, arylalkyl, aryloxy, arylalkoxy, aroyl, aroyloxy, arylsulfonyl, aroylaroyloxy, aroyl, aryl alkoxycarbonyl, benzoylbenzoyloxy, carboxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkyl, heteroarylalkoxy, heteroarylsulfonyl, heteroarylthio, dioxolanyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylcarbonylalkoxy, hydroxy, hydroxyalkyl, and alkylsulfonyl;
wherein optionally one or more carbon atoms of the \u2014(C0-C30 alkylene)- radical of Q1, Q2, Q3, Q4 and Q5 is independently replaced by \u2014O\u2014, \u2014C(O)\u2014, \u2014CH\u2550CH\u2014, \u2014C\u2261C\u2014, \u2014N(alkyl)-, \u2014N(alkylaryl)- or \u2014NH\u2014;
G is selected from the group consisting of a sugar residue, disugar residue, trisugar residue, tetrasugar residue, sugar acid, amino sugar, amino acid residue, oligopeptide residue comprising 2 to 9 amino acids, trialkylammoniumalkyl radical and \u2014S(O)2\u2014OH,
R2 and R3 can be the same or different and each is independently selected from the group consisting of hydrogen, alkyl and aryl;
R6, R7 and R8 can be the same or different and each is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, arylalkyl and a protecting group; and
each R9 is independently alkyl, cycloalkyl, aryl or arylalkyl.
each R10 is independently H or alkyl;
q is 0 or 1;
r is 0 or 1;
m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5.
8. The process according to claim 7, wherein the \u03b2-(substituted-amino)amide is represented by Formula (III):
9. The process according claim 1, wherein the \u03b2-(substituted-amino)acid ester comprises a carboxylic acid ester portion R14\u2014O\u2014C(O)\u2014, wherein R14 is alkyl or aryl.
10. The process according claim 1, wherein the \u03b2-(substituted-amino)thiolcarbonic acid ester comprises a thiolcarbonic acid ester portion R14\u2014S\u2014C(O)\u2014, wherein R14 is alkyl or aryl.
11. The process according claim 1, wherein the silylating agent is a silylenol ether.
12. The process according claim 11, wherein the silylating agent is selected from the group consisting of bistrimethylsilylacetamide, N-methyl-O-trimethyl silylacetamide or isopropenyloxy trimethylsilane.
13. The process according to claim 1, wherein the alkali metal carboxylate is a carboxylate salt of an alkali metal selected from the group consisting of lithium, sodium, potassium and cesium.
14. The process according to claim 1, wherein the alkali metal carboxylate or quaternary ammonium carboxylate comprises a carboxylate moiety selected from the group consisting of formate, acetate, propionate, butyrate, valerate, caproate, caprylate, laurate, myristate, palmitate, stearate, oleate, linoleate, linolenate, cyclohexanecarboxylate, phenylacetate, benzoate and toluate.
15. The process according to claim 14, wherein the carboxylate moiety of the alkali metal carboxylate is acetate.
16. The process according to claim 14, wherein the alkali metal carboxylate is potassium acetate.
17. The process according to claim 14, wherein the carboxylate moiety of the quaternary ammonium carboxylate is acetate.
18. The process according to claim 1, wherein the quaternary ammonium moiety of the cyclizing agent is tetra n-butylammonium.
19. The process according to claim 14, wherein the quaternary ammonium carboxylate is tetra n-butylammonium acetate.
20. The process according to claim 1, wherein the quaternary ammonium hydroxide is tetra n-butylammonium hydroxide.
21. The process according to claim 1, wherein the quaternary ammonium halide comprises a halide moiety selected from the group consisting of fluoride, chloride, bromide and iodide.
22. The process according to claim 1, wherein the cyclizing agent is the reaction product of tetra n-butylammonium bromide and potassium acetate.
23. The process according to claim 1, wherein the cyclizing agent is the reaction product of tetra n-butylammonium bromide and cesium fluoride.
24. The process according to claim 1, wherein the reaction product (3)(b) is formed in situ in the presence of reactants (1) and (2).
25. The process according to claim 1, further comprising the step of forming the reaction product (3)(b) prior to reaction with reactants (1) and (2).
26. The process according to claim 1, wherein the silylating agent is bistrimethylsilylacetamide and the cyclizing agent is tetra n-butylammonium acetate.
27. The process according to claim 1, further comprising adding a second cyclizing agent which is a fluoride ion catalyst.
28. The process according to claim 1, comprising pre-reacting reactant (1) with reactant (2).
29. The process according to claim 1, for preparing an azetidinone represented by the structural Formula (IV):
comprising reacting:
(1) a \u03b2-(substituted-amino)amide of the formula (III)
with (2) at least one silylating agent and
(3) at least one cyclizing agent which is
(a) selected from the group consisting of alkali metal carboxylates, quaternary ammonium carboxylates, quaternary ammonium hydroxides, quaternary ammonium alkoxides, quaternary ammonium aryloxides and hydrates thereof; or
(b) the reaction product of:
(i) at least one quaternary ammonium halide and at least one alkali metal carboxylate; or
(ii) at least one quaternary ammonium chloride, quaternary ammonium bromide, or quaternary ammonium iodide and at least one alkali metal fluoride,
wherein a quaternary ammonium moiety of the cyclizing agent is unsubstituted or substituted by one to four groups independently selected from the group consisting of alkyl, arylalkyl and arylalkyl-alkyl.
30. A process for preparing a compound represented by the Formula (IV):
comprising the step of:
cyclizing the \u03b2-(substituted-amino)amide of formula XII
wherein X is \u2014O\u2014, \u2014S\u2014 or \u2014N(C1-C6 alkyl); Y is \u2550O or \u2550S; and R1 is alkyl, aryl or alkoxycarbonyl, and wherein Prot is a silyl protecting group with at least one silylating agent and at least one cyclizing agent which is:
(a) selected from the group consisting of alkali metal carboxylates, quaternary ammonium carboxylates, quaternary ammonium hydroxides, quaternary ammonium alkoxides, quaternary ammonium aryloxides and hydrates thereof; or
(b) the reaction product of:
(i) at least one quaternary ammonium halide and at least one alkali metal carboxylate; or
(ii) at least one quaternary ammonium chloride, quaternary ammonium bromide, or quaternary ammonium iodide and at least one alkali metal fluoride,
wherein a quaternary ammonium moiety of the cyclizing agent is unsubstituted or substituted by one to four groups independently selected from the group consisting of alkyl, arylalkyl and arylalkyl-alkyl,
to obtain the compound of Formula XI:
and removing the silyl protecting groups to form the compound of Formula (IV).
31. The process according to claim 30, further comprising the steps of:
reacting a chiral alcohol of Formula VIII, an imine of Formula IX and a silyl protecting agent, then condensing the silyl-protected compounds to obtain a \u03b2-(substituted-amino)amide of Formula XII, wherein X is \u2014O\u2014, \u2014S\u2014 or \u2014N(C1-C6 alkyl); Y is \u2550O or \u2550S; and R1 is alkyl, aryl or alkoxycarbonyl, and wherein Prot is a silyl protecting group:
prior to cyclizing the \u03b2-(substituted-amino)amide of Formula XII.
32. The process according to claim 30, further comprising the steps of:
(a) reacting p-fluorobenzoylbutyric acid of Formula V with pivaloyl chloride and acylating the product with a chiral auxiliary of Formula VI to obtain a ketone of Formula VII:
wherein X is \u2014O\u2014, \u2014S\u2014 or \u2014N(C1-C6 alkyl); Y is \u2550O or \u2550S; and R1 is alkyl, aryl or alkoxycarbonyl;
(b) reducing the ketone of Formula VII in the presence of a chiral catalyst to an alcohol of Formula VIII:
(c) reacting the chiral alcohol of Formula VIII, an imine of formula IX and a silyl protecting agent, then condensing the silyl-protected compounds to obtain a \u03b2-(substituted-amino)amide of Formula XII, wherein Prot is a silyl protecting group:
prior to cyclizing the \u03b2-(substituted-amino)amide of Formula XII.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A light-stimulus illumination apparatus comprising:
a light source configured to emit light-stimulus laser light;
a scanning unit including a first acousto-optic device configured to scan the light-stimulus laser light emitted from the light source in a first direction intersecting an optical axis, and a second acousto-optic device configured to scan the light-stimulus laser light emitted from the light source in a second direction intersecting the optical axis and orthogonal to the first direction; and
a control unit configured to control the scanning unit so that the light-stimulus laser light irradiates a plurality of spatially separated regions including a first region and a second region in a time-division manner,
wherein the control unit is configured to control the scanning unit to scan the light-stimulus laser light in the second region right after finishing scanning the light-stimulus laser light in the first region by switching a frequency of each command signal input to the first and second acousto-optic devices discontinuously from a frequency corresponding to a scanning end point of the first region to a frequency corresponding to a scanning starting point of the second region so that the light-stimulus laser light does not irradiate an area between the first region and the second region.
2. A light-stimulus illumination apparatus according to claim 1, wherein the control unit adjusts the amplitudes of the command signals input to the first and second acousto-optic devices according to a scanning position of the light-stimulus laser light scanned by the scanning unit.
3. A light-stimulus illumination apparatus according to claim 1, further comprising:
a focal-position adjusting unit configured to change a focal position of the light-stimulus laser light in a direction of the optical axis, wherein the control unit controls the focal-position adjusting unit in synchronization with the scanning unit.
4. A light-stimulus illumination apparatus according to claim 1, wherein the light-stimulus laser light is ultrashort pulsed laser light.
5. A light-stimulus illumination apparatus according to claim 4, further comprising a light detector configured to detect fluorescence due to multiphoton excitation produced by irradiation with the light-stimulus laser light, without the fluorescence returning to the scanning unit.
6. A microscope apparatus comprising the light-stimulus illumination apparatus according to claim 1.
7. A laser-scanning microscope apparatus comprising:
a light-stimulus illumination apparatus according to claim 1; and
a laser-scanning microscope comprising:
an observation light source configured to emit observation laser light;
an observation scanning unit configured to two-dimensionally scan the observation laser light on a specimen;
an objective lens configured to converge the observation laser light on the specimen and to collect observation light emitted from the specimen by irradiation with the observation laser light;
a detection unit configured to detect the observation light collected by the objective lens; and
an image-generating unit configured to generate an observation image of the specimen based on a detection signal from the detection unit,
wherein the light-stimulus laser light irradiates the specimen via the objective lens of the laser-scanning microscope.
8. A laser-scanning microscope apparatus according to claim 7, further comprising:
a combining unit, between the observation scanning unit and the objective lens, configured to combine the light-stimulus laser light from the light-stimulus illumination apparatus,
wherein the light-stimulus laser light scanned by the scanning unit of the light-stimulus illumination apparatus is guided to the combining unit.