CN1322204A - Oxazolidinone antibacterial agents having thiocarbonyl functionality - Google Patents
Oxazolidinone antibacterial agents having thiocarbonyl functionality Download PDFInfo
- Publication number
- CN1322204A CN1322204A CN98814326A CN98814326A CN1322204A CN 1322204 A CN1322204 A CN 1322204A CN 98814326 A CN98814326 A CN 98814326A CN 98814326 A CN98814326 A CN 98814326A CN 1322204 A CN1322204 A CN 1322204A
- Authority
- CN
- China
- Prior art keywords
- methyl
- oxazolidinyl
- oxo
- phenyl
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention provides compounds of formula (1) or pharmaceutical acceptable salts thereof wherein, A,G and R1 are as defined in the claims which are antibacterial agents.
Description
Background of invention
The present invention relates to new and practical De oxazolidone compound and preparation method thereof, the carbonyl functional group who more particularly relates to-NH-C (O)-R is changed thiocarbonyl functionality such as thiocarbamide-NH-C (S)-NH into
2, alkyl thiourea-NH-C (S)-NH-(C
1-C
4Alkyl), thioamides-NH-C (S)-(C
1-C
4Alkyl) or-NH-C (S)-H De oxazolidone compound.
Replace Sauerstoffatom that the antimicrobial acivity of these compounds has been produced unexpected improvement with sulphur atom.These compounds are valuable biocides, it has the effect of anti-some and beastly cause of disease, comprise Gram-positive aerobic bacteria such as multiresistance staphylococcus and suis, Gram-negative organism such as Haemophilus influenzae and micrococcus catarrhalis, and anaerobe such as Bacteroides and fusobacterium, and acidproof organism such as mycobacterium tuberculosis and mycobacterium tuberculosis avium.These compound particularly advantageouies are with being worth, and this is because they have the anti-known AIDS of causing patient infection's acidproof organic effect.
Summary of the invention
One aspect of the present invention is the compound or pharmaceutically acceptable salt thereof of formula I:
Wherein:
G is
R
1Be
a)H，
b)NH
2，
C) NH-C
1-C
4Alkyl,
D) C
1-C
4Alkyl,
E)-OC
1-C
4Alkyl,
F)-SC
1-C
4Alkyl,
G) by 1 to 3 F, 1 to 2 Cl, CN or-COOC
1-C
4The C that alkyl replaces
1-C
4Alkyl,
H) C
3-C
6Cycloalkyl,
I) N (C
1-C
4Alkyl)
2Or
j)N(CH
2)
2-5；
A is
D) have 1 to 35 yuan of heteroaryl moieties that are selected from the atom of S, N and O, wherein this heteroaryl moieties is by carbon atom bonding,
Wherein these 5 yuan of heteroaryl moieties can also have condensed benzene or naphthalene nucleus,
Wherein this heteroaryl moieties is optionally by 1 to 3 R
48Replace,
E) have 6 yuan of heteroaryl moieties of at least one nitrogen-atoms,
Wherein this heteroaryl is by carbon atom bonding,
Wherein these 6 yuan of heteroaryl moieties can also have condensed benzene or naphthalene nucleus,
Wherein this heteroaryl moieties is optionally by 1 to 3 R
55Replace,
F) β-Ka Lin-3-base, or the indolizine base (indolizinyl) that connects by 6 yuan of ring keies, it is optionally by 1 to 3 R
55Replace,
, or
R wherein
2Be
a)H，
b)F，
c)Cl，
d)Br，
E) C
1-C
3Alkyl,
F) NO
2, or
G) R
2And R
3Be together-O-(CH
2)
h-O-;
R
3Be
a)-S(＝O)
iR
4，
b)-S(＝O)
2-N＝S(O)
jR
5R
6，
c)-SC(＝O)R
7，
d)-C(＝O)R
8，
e)-C(＝O)R
9，
f)-C(＝O)NR
10R
11，
g)-C(＝NR
12)R
8，
h)-C(R
8)(R
11)-OR
13，
i)-C(R
9)(R
11)-OR
13，
j)-C(R
8)(R
11)-OC(＝O)R
13，
k)-C(R
9)(R
11)-OC(＝O)R
13，
l)-NR
10R
11，
m)-N(R
10)-C(＝O)R
7，
n)-N(R
10)-S(＝O)
iR
7，
o)-C(OR
14)(OR
15)R
8，
P)-C (R
8) (R
16)-NR
10R
11, or
Q) by one or more remove the α position=O ,-S (=O)
iR
17,-NR
10R
11, C
2-C
5Alkenyl or C
2-C
5The C that alkynyl group replaces
1-C
8Alkyl;
R
4Be
A) optionally by one or more halogens, OH, CN, NR
10R
11Or-CO
2R
13The C that replaces
1-C
4Alkyl,
B) C
2-C
4Alkenyl,
c)-NR
16R
18，
d)-N
3，
e)-NHC(＝O)R
7，
f)-NR
20C(＝O)R
7，
g)-N(R
19)
2，
H)-NR
16R
19, or
i)-NR
19R
20，
When occurring at every turn, R
5And R
6Identical or different, and be
A) C
1-C
2Alkyl, perhaps
B) R
5And R
6Be together-(CH
2)
k-;
R
7Be the C that is optionally replaced by one or more halogens
1-C
4Alkyl;
R
8Be
A) H, or
B) optionally by one or more halogens or C
3-C
8The C of cycloalkyl substituted
1-C
8Alkyl;
R
9The C that is replaced by following group
1-C
4Alkyl:
a)-S(＝O)R
17，
b)-OR
13，
c)-OC(＝O)R
13，
D)-NR
10R
11, or
E) C that is optionally replaced by CHO
1-C
5Alkenyl;
When occurring at every turn, R
10And R
11Identical or different, and be
a)H，
B) C
1-C
4Alkyl, or
C) C
3-C
8Cycloalkyl;
R
12Be
a)-NR
10R
11，
B)-OR
10Or
c)-NHC(＝O)R
10；
R
13Be
A) H, or
B) C
1-C
4Alkyl;
When occurring at every turn, R
14And R
15Identical or different, and be
A) C
1-C
4Alkyl, or
B) R
14And R
15Be together-(CH)
l-;
R
16Be
a)H，
B) C
1-C
4Alkyl, or
C) C
3-C
8Cycloalkyl;
R
17Be
a)C
1-C
4Alkyl, or b) C3-C
8Cycloalkyl; R18A) H, b) C1-C
4Alkyl, c) C2-C
4Alkenyl, d) C3-C
4Cycloalkyl, e)-OR13Or f)-NR21R
22；
R
19A) Cl, b) Br, or c) I; R20It is the acceptable cation of physiology; While occurring at every turn, R21And R22Identical or different, and be a) H, b) C1-C
4Alkyl, or c)-NR21R
22Be together-(CH2)
m-; R wherein23And R24Identical or different while occurring at every turn, and be a) H, b) F, c) Cl, d) C1-C
2Alkyl, e) CN, f) OH, g) C1-C
2Status input signal = '0 'Input Signal = '1'
0: 1 1 1111-1-1-1-1-1 -1
1: -1 -1 -1-1-1-1111111
2: -1 1 1 -1-1-11-1-1111
2: describe -1 -1 111-111-1-1-1
4: -1 -1 1-11-111-11-11
5: 1 Each 1 -1 1-11-1-11-11-1
6: 1 -1 1 1-11-11-1-11-1
7: -1 1 -1 -11-11-111-11
8: -1 -1 -1-1111111-1-1
9: 1 Each 1 1 1 -1-1-1-1-1-111
10: 1 -1 -1 1-1-1-111-111
11: -1 11-1111-1-11-1 -1
12: 1 Each 1 -1 11-1-1-11-1-11
13: -1 -1 1-1-1111-111-1
14: -1 1-1-1-111-1111 -1
15: 1 -1 1 11-1-11-1-1-11
16: 1 Each 1 1 -1 -1-1-1-1-1111
17: -1 -1 -1111111-1-1-1
18: -1 111111-1-1-1-1 -1
19: 1 -1 -1 -1-1-1-111111
20: -1 -1 11-1111-1-11-1
21: 1 Each 1 -1 -11-1-1-111-11
22: 1 -1 1 -11-1-11-11-11
23: -1 1-11-111-11-11 -1
24: -1 -1 -11-1-1111-111
25: 1 Each 1 1-111-1-1-11-1 -1
26: 1-1-1-111-1111 -1 -1
27: -1 1 1 1-1-11-1-1-111
28: 1 Each 1 -1 -1-11-1-1111-1
29: -1 -1 111-111-1-1-11
30: -1 1 -1 11-11-11-1-11
31: 1 -1 1 -1-11-11-111-1
32: -1 -1 -1111111-1-1-1
33: 1 Each 1 1 -1 -1-1-1-1-1111
34: 1 -1 -1 -1-1-1-111111
35: -1 111111-1-1-1-1 -1
36: 1 Each 1 -1 -11-1-1-111-11
37: -1 -1 11-1111-1-11-1
38: -1 1-11-111-11-11 -1
39: 1 -1 1 -11-1-11-11-11
40: 1 Each 1 1-111-1-1-11-1 -1
41: -1 -1 -11-1-1111-111
42: -1 1 1 1-1-11-1-1-111
43: 1-1-1-111-1111 -1 -1
44: -1 -1 111-111-1-1-11
45: 1 Each 1 -1 -1-11-1-1111-1
46: 1 -1 1 -1-11-11-111-1
47: -1 1 -1 11-11-11-1-11
48: -1 -1 -1-1-1-1111111
49: 1 Each 1 1111-1-1-1-1-1 -1
50: 1-1-1111-111-1 -1 -1
51: -1 1 1 -1-1-11-1-1111
52: 1 Each 1 -1 1-11-1-11-11-1
53: -1 -1 1-11-111-11-11
54: -1 1 -1 -11-11-111-11
55: 1 -1 1 1-11-11-1-11-1
56: 1 Each 1 1 1 -1-1-1-1-1-111
57: -1 -1 -1-1111111-1-1
58: -1 11-1111-1-11-1 -1
59: 1 -1 -1 1-1-1-111-111
60: -1 -1 1-1-1111-111-1
61: 1 Each 1 -1 11-1-1-11-1-11
62: 1 -1 1 11-1-11-1-1-11
63: -1 1-1-1-111-1111 -1
64: 1 -1 -1 1-1-1-111-111
65: -1 11-1111-1-11-1 -1
66: -1 -1 -1-1111111-1-1
67: 1 Each 1 1 1 -1-1-1-1-1-111
68: -1 1-1-1-111-1111 -1
69: 1 -1 1 11-1-11-1-1-11
70: 1 Each 1 -1 11-1-1-11-1-11
71: -1 -1 1-1-1111-111-1
72: -1 1 1 -1-1-11-1-1111
73: 1-1-1111-111-1 -1 -1
74: 1 Each 1 1111-1-1-1-1-1 -1
75: -1 -1 -1-1-1-1111111
76: 1 -1 1 1-11-11-1-11-1
77: -1 1 -1 -11-11-111-11
78: -1 -1 1-11-111-11-11
79: 1 Each 1 -1 1-11-1-11-11-1
80: 1-1-1-111-1111 -1 -1
81: -1 1 1 1-1-11-1-1-111
82: -1 -1 -11-1-1111-111
83: 1 Each 1 1-111-1-1-11-1 -1
84: -1 1 -1 11-11-11-1-11
85: 1 -1 1 -1-11-11-111-1
86: 1 Each 1 -1 -1-11-1-1111-1
87: -1 -1 111-111-1-1-11
88: -1 111111-1-1-1-1 -1
89: 1 -1 -1 -1-1-1-111111
90: 1 Each 1 1 -1 -1-1-1-1-1111
91: -1 -1 -1111111-1-1-1
92: 1 -1 1 -11-1-11-11-11
93: -1 1-11-111-11-11 -1
94: -1 -1 11-1111-1-11-1
95: 1 Each 1 -1 -11-1-1-111-11
96: -1 1 1 1-1-11-1-1-111
97: 1-1-1-111-1111 -1 -1
98: 1 Each 1 1-111-1-1-11-1 -1
99: -1 -1 -11-1-1111-111
100: 1 -1 1 -1-11-11-111-1
101: -1 1 -1 11-11-11-1-11
102: -1 -1 111-111-1-1-11
103: 1 Each 1 -1 -1-11-1-1111-1
104: 1 -1 -1 -1-1-1-111111
105: -1 111111-1-1-1-1 -1
106: -1 -1 -1111111-1-1-1
107: 1 Each 1 1 -1 -1-1-1-1-1111
108: -1 1-11-111-11-11 -1
109: 1 -1 1 -11-1-11-11-11
110: 1 Each 1 -1 -11-1-1-111-11
111: -1 -1 11-1111-1-11-1
112: -1 11-1111-1-11-1 -1
113: 1 -1 -1 1-1-1-111-111
114: 1 Each 1 1 1 -1-1-1-1-1-111
115: -1 -1 -1-1111111-1-1
116: 1 -1 1 11-1-11-1-1-11
117: -1 1-1-1-111-1111 -1
118: -1 -1 1-1-1111-111-1
119: 1 Each 1 -1 11-1-1-11-1-11
120: 1-1-1111-111-1 -1 -1
121: -1 1 1 -1-1-11-1-1111
122: -1 -1 -1-1-1-1111111
123: 1 Each 1 1111-1-1-1-1-1 -1
124: -1 1 -1 -11-11-111-11
125: 1 -1 1 1-11-11-1-11-1
126: 1 Each 1 -1 1-11-1-11-11-1
127: -1 -1 1-11-111-11-11
128: 1 -1 1 -11-1-11-11-11
129: -1 1-11-111-11-11 -1
130: -1 -1 11-1111-1-11-1
131: 1 Each 1 -1 -11-1-1-111-11
132: -1 111111-1-1-1-1 -1
133: 1 -1 -1 -1-1-1-111111
134: 1 Each 1 1 -1 -1-1-1-1-1111
135: -1 -1 -1111111-1-1-1
136: -1 1 -1 11-11-11-1-11
137: 1 -1 1 -1-11-11-111-1
138: 1 Each 1 -1 -1-11-1-1111-1
139: -1 -1 111-111-1-1-11
140: 1-1-1-111-1111 -1 -1
141: -1 1 1 1-1-11-1-1-111
142: -1 -1 -11-1-1111-111
143: 1 Each 1 1-111-1-1-11-1 -1
144: 1 -1 1 1-11-11-1-11-1
145: -1 1 -1 -11-11-111-11
146: -1 -1 1-11-111-11-11
147: 1 Each 1 -1 1-11-1-11-11-1
148: -1 1 1 -1-1-11-1-1111
149: 1-1-1111-111-1 -1 -1
150: 1 Each 1 1111-1-1-1-1-1 -1
151: -1 -1 -1-1-1-1111111
152: -1 1-1-1-111-1111 -1
153: 1 -1 1 11-1-11-1-1-11
154: 1 Each 1 -1 11-1-1-11-1-11
155: -1 -1 1-1-1111-111-1
156: 1 -1 -1 1-1-1-111-111
157: -1 11-1111-1-11-1 -1
158: -1 -1 -1-1111111-1-1
159: 1 Each 1 1 1 -1-1-1-1-1-111
160: -1 1 -1 -11-11-111-11
161: 1 -1 1 1-11-11-1-11-1
162: 1 Each 1 -1 1-11-1-11-11-1
163: -1 -1 1-11-111-11-11
164: 1-1-1111-111-1 -1 -1
165: -1 1 1 -1-1-11-1-1111
166: -1 -1 -1-1-1-1111111
167: 1 Each 1 1111-1-1-1-1-1 -1
168: 1 -1 1 11-1-11-1-1-11
169: -1 1-1-1-111-1111 -1
170: -1 -1 1-1-1111-111-1
171: 1 Each 1 -1 11-1-1-11-1-11
172: -1 11-1111-1-11-1 -1
173: 1 -1 -1 1-1-1-111-111
174: 1 Each 1 1 1 -1-1-1-1-1-111
175: -1 -1 -1-1111111-1-1
176: -1 1-11-111-11-11 -1
177: 1 -1 1 -11-1-11-11-11
178: 1 Each 1 -1 -11-1-1-111-11
179: -1 -1 11-1111-1-11-1
180: 1 -1 -1 -1-1-1-111111
181: -1 111111-1-1-1-1 -1
182: -1 -1 -1111111-1-1-1
183: 1 Each 1 1 -1 -1-1-1-1-1111
184: 1 -1 1 -1-11-11-111-1
185: -1 1 -1 11-11-11-1-11
186: -1 -1 111-111-1-1-11
187: 1 Each 1 -1 -1-11-1-1111-1
188: -1 1 1 1-1-11-1-1-111
189: 1-1-1-111-1111 -1 -1
190: 1 Each 1 1-111-1-1-11-1 -1
191: -1 -1 -11-1-1111-111
192: 1 Each 1 -1 -1-11-1-1111-1
193: -1 -1 111-111-1-1-11
194: -1 1 -1 11-11-11-1-11
195: 1 -1 1 -1-11-11-111-1
196: -1 -1 -11-1-1111-111
197: 1 Each 1 1-111-1-1-11-1 -1
198: 1-1-1-111-1111 -1 -1
199: -1 1 1 1-1-11-1-1-111
200: -1 -1 11-1111-1-11-1
201: 1 Each 1 -1 -11-1-1-111-11
202: 1 -1 1 -11-1-11-11-11
203: -1 1-11-111-11-11 -1
204: 1 Each 1 1 -1 -1-1-1-1-1111
205: -1 -1 -1111111-1-1-1
206: -1 111111-1-1-1-1 -1
207: 1 -1 -1 -1-1-1-111111
208: 1 Each 1 -1 11-1-1-11-1-11
209: -1 -1 1-1-1111-111-1
210: -1 1-1-1-111-1111 -1
211: 1 -1 1 11-1-11-1-1-11
212: -1 -1 -1-1111111-1-1
213: 1 Each 1 1 1 -1-1-1-1-1-111
214: 1 -1 -1 1-1-1-111-111
215: -1 11-1111-1-11-1 -1
216: -1 -1 1-11-111-11-11
217: 1 Each 1 -1 1-11-1-11-11-1
218: 1 -1 1 1-11-11-1-11-1
219: -1 1 -1 -11-11-111-11
220: 1 Each 1 1111-1-1-1-1-1 -1
221: -1 -1 -1-1-1-1111111
222: -1 1 1 -1-1-11-1-1111
... 
M) optionally by the diazine of X and Y replacement, n) optionally by the triazine radical of X and Y replacement, o) optionally by the quinoline base of X and Y replacement, p) optionally by the quinoxaline base of X and Y replacement, q) optionally by the phthalazinyl of X and Y replacement
Q and R24Be together
Z wherein1A)-CH2-，
b)-CH(R
104)-CH
2-, c)-C (O)-, or d)-CH2CH
2CH
2-; Z wherein2A)-O2S-，
b)-O-，
c)-N(R
107)-, d)-OS-, or e)-S-; Z wherein3A)-O2S-, b)-O-, c)-OS-, or d)-S-; A wherein1A) H-, or b) CH3 A wherein2A) H-, b) HO-, c) CH3-，
d)CH
3O-，
e)R
102O-CH
2-C(O)-NH-，
f)R
103O-C(O)-NH-，
g)(C
1-C
2) alkyl-O-C (O)-, h) HO-CH2-，
i)CH
3O-NH-，
j)(C
1-C
3) alkyl-O2C-，
k)CH
3O-C(O)-，
l)CH
3-C(O)-CH
2-, m), orOr n)
A
1And A2Be together:R wherein102A) H-, b) CH3-, c) phenyl-CH2-, or d) CH3C (O)-; R wherein103A) (C1-C
3) alkyl-, or b) phenyl-; R wherein104A) H-, or b) HO-; R wherein105A) H-, b) (C1-C
3) alkyl-, c) CH2＝CH-CH
2-, or d) CH3-O-(CH
2)
2-; R wherein106A) CH3-C(O)-，
b)H-C(O)-，
c)Cl
2CH-C(O)-，
d)HOCH
2-C(O)-，
e)CH
3SO
2-，
f)
g)F
2CHC(O)-，
h)
i)H
3C-C(O)-OCH
2-C(O)-，
j)H-C(O)-O-CH
2-C(O)-，
k)
l)HC≡C-CH
2O-CH
2-C (O)-, or m) phenyl-CH2-O-CH
2-C (O)-; R wherein107A) R102O-C(R
110)(R
111)-C(O)-，
b)R
103O-C(O)-，
c)R
108-C(O)-，
d)
e)
f)H
3C-C(O)-(CH
2)
2-C(O)-，
g)R
109-SO
2-，
h)
i)HO-CH
2-C(O)-，
j)R
116-(CH
2)
2-，
k)R
113-C(O)-O-CH
2-C(O)-，
l)(CH
3)
2N-CH
2-C(O)-NH-，
m)NC-CH
2-，
n)F
2-CH-CH
2-, or o) R150R
151NSO
2 R wherein108A) H-, b) (C1-C
4) alkyl, c) aryl-(CH2)
p-，
d)ClH
2C-，
e)Cl
2HC，
f)FH
2C-，
g)F
2HC，
h)(C
3-C
6) cycloalkyl, or i) CNCH2-，
R
109A) alkyl C1-C
4，
b)-CH
2Cl，
c)-CH
2CH＝CH
2, d) aryl, or e)-CH2CN; R wherein110And R111A) H-, b independently) CH3-; Or R wherein112A) H-, b) CH3O-CH
2O-CH
2-, or c) HOCH2-; R wherein113A) CH3-，
b)HOCH
2-，
c)(CH
3)
2N-phenyl, or d) (CH3)
2N-CH
2-; R wherein114A) HO-, b) CH3O-，
c)H
2N-，
d)CH
3O-C(O)-O-，
e)CH
3-C(O)-OCH
2-C (O)-O-, f) phenyl-CH2-O-CH
2-C(O)-O-，
g)HO-(CH
2)
2-O-，
h)CH
3-O-CH
2-O-(CH
2)
2-O-, or i) CH3O-CH
2-O-; R wherein113A) CH3-，
b)HOCH
2-，
c)(CH
3)
2N-phenyl, or d) (CH3)
2N-CH
2-; R wherein115A) H-, or b) Cl; R wherein116A) HO-, b) CH3O-, or c) F; R wherein150And R151Each is H or C naturally1-C
4Alkyl, perhaps R150And R151Form the monocycle heterocycle that contains 3 to 6 carbon atoms together with nitrogen-atoms that they connect separately;
B is the unsaturated 4 atom linking groups that contain a nitrogen-atoms and 3 carbon atoms;
M is
a)H，
B) C
1-C
8Alkyl,
C) C
3-C
8Cycloalkyl,
D)-(CH
2)
mOR
13, or
e)-(CH
2)H-NR
21R
22；
Z is
a)O，
B) S, or
c)NM；
W is
a)CH，
B) N, or
C) when being NM, Z is S or O;
Y is
a)H，
b)F，
c)Cl，
d)Br，
E) C
1-C
3Alkyl, or
f)NO
2；
X is
a)H，
b)-CN，
c)OR
27，
D) halogen,
e)NO
2，
F) tetrazyl,
g)-SH，
h)-S(＝O)
iR
4，
i)-S(＝O)
2-N＝S(O)
jR
5R
6，
j)-SC(＝O)R
7，
k)-C(＝O)R
25，
l)-C(＝O)NR
27R
28，
m)-C(＝NR
29)R
25，
n)-C(R
25)(R
28)-OR
13，
o)-C(R
25)(R
28)-OC(＝O)R
13，
p)-C(R
28)(OR
13)-(CH
2)
h-NR
27R
28，
q)-NR
27R
28，
r)-N(R
27)C(＝O)R
7，
s)-N(R
27)-S(＝O)
iR
7，
t)-C(OR
14)(OR
15)R
28，
U)-C (R
25) (R
16)-NR
27R
26, or
V) by one or more halogens, OH, non alpha position=O ,-S (=O)
iR
17,-NR
27R
28, C
2-C
5Alkenyl, C
2-C
5Alkynyl group or C
3-C
8The C of cycloalkyl substituted
1-C
8Alkyl;
R
4, R
5, R
6, R
7, R
13, R
14, R
15, R
16And R
17Identical with above-mentioned definition;
R
25Be
a)H，
B) C that is replaced by one or more halogen selectivity
1-C
8Alkyl, C
3-C
8Cycloalkyl, by one or more-S (=O)
iR
17,-OR
13Or OC (=O) R
13The C that replaces
1-C
4Alkyl, NR
27R
28, or
C) optionally by CHO or CO
2R
13The C that replaces
2-C
5Alkenyl;
R
26Be
A) R
28, or
b)NR
27R
28；
R when at every turn occurring
27And R
28Identical or different, and be
a)H，
B) C
1-C
8Alkyl,
C) C
3-C
8Cycloalkyl,
d)-(CH
2)
mOR
13，
E)-(CH
2)
h-NR
21R
22, or
F) R
27And R
28Be together-(CH
2)
2O (CH
2)
2-,-(CH
2)
hCH (COR
7) or-(CH
2)
2N (CH
2)
2(R
7)-;
R
29Be
a)-NR
27R
28，
B)-OR
27, or
c)-NHC(＝O)R
28；
R wherein
30Be
a)H，
B) C that is optionally replaced by one or more halogens
1-C
8Alkyl, or
C) optionally by one or more OH or C
1-C
6The C that alkoxyl group replaces
1-C
8Alkyl;
Wherein E is
a)NR
39，
B)-S (=O)
i, or
c)O；
R
38Be
a)H，
B) C
1-C
6Alkyl,
C)-(CH
2)
q-aryl, or
D) halogen;
R
39Be
a)H，
B) optionally by one or more OH, halogen or-C that CN replaces
1-C
6Alkyl,
C)-(CH
2)
q-aryl,
d)-COOR
40，
e)-COR
41，
f)-C(＝O)-(CH
2)
q-C(＝O)R
40，
G)-S (=O)
2-C
1-C
6Alkyl,
H) S (=O)
2-(CH
2)
q-aryl, or
I)-(C=O)
j-heteroaryl;
R
40Be
a)H，
B) optionally by one or more OH, halogen or-C that CN replaces
1-C
6Alkyl,
C)-(CH
2)
q-aryl, or
d)-(CH
2)
q-OR
42；
R
41Be
A) optionally by one or more OH, halogen or-C that CN replaces
1-C
6Alkyl,
B)-(CH
2)
q-aryl, or
c)-(CH
2)
q-OR
42；
R
42Be
a)H，
B) C
1-C
6Alkyl,
C)-(CH
2)
q-aryl, or
D)-C (=O)-C
1-C
6Alkyl;
Aryl is
A) phenyl,
B) pyridyl, or
C) naphthyl; A) to c) optionally by one or more halogens ,-CN, OH, SH, C
1-C
6Alkyl, C
1-C
6Alkoxyl group or C
1-C
6Alkylthio replaces;
R wherein
43Be
a)H，
B) C
1-C
2Alkyl,
C) F, or d) OH; R
44Be a) H, b) CF
3, the c) C that is optionally replaced by one or more halogens
1-C
3Alkyl, d) phenyl that is optionally replaced, e) R by one or more halogens
44And R
45Be together 5,6 or 7 yuan of following formula rings or
F) work as R
46When being electron-withdrawing group, R
44And R
45Be together-(CH
2)
k-; R when at every turn occurring
45And R
46Identical or different, and be a) electron-withdrawing group, b) H, c) trifluoromethyl, d) C that is optionally replaced by a halogen atom
1-C
3Alkyl, e) phenyl, its condition is R at least
45And R
46One of be electron-withdrawing group, or f) R
45And R
46Be 5,6,7 yuan of rings of following formula together
U is a) CH
2, b) O, c) S, or d) and NR
47R
47Be
A) H, or
B) C
1-C
5Alkyl;
R wherein
48Be
A) carboxyl,
B) halogen,
c)-CN，
D) sulfydryl,
E) formyl radical,
F) trifluoromethyl,
G) nitro,
H) C
1-C
6Alkoxyl group,
I) C
1-C
6Carbalkoxy,
J) C
1-C
6Alkylthio,
K) C
1-C
6Acyl group,
l)-NR
49R
50，
M) optionally by OH, C
1-C
5Alkoxyl group, C
1-C
5Acyl group or-NR
49R
50The C that replaces
1-C
6Alkyl,
N) optionally by one or two R
51The C that replaces
2-C
8The alkenyl phenyl,
O) optionally by one or two R
51The phenyl that replaces,
P) have 1 to 3 atom that is selected from S, N and O, optionally by one or two R
51Replace, 5 or 6 yuan of saturated or unsaturated heterocycle parts, perhaps
Q)
R when at every turn occurring
49And R
50Identical or different, and be a) H, b) C
1-C
4Alkyl, c) C
5-C
6Cycloalkyl, or
D) R
49And R
50With nitrogen-atoms is 5 or 6 yuan of saturated heterocyclic parts, and it optionally also contains other heteroatoms that is selected from S, N and O, and, being included on another nitrogen-atoms, itself can be by C
1-C
3Alkyl or C
1-C
3Acyl group optionally replaces;
R
51Be
A) carboxyl,
B) halogen,
C) cyano group,
D) sulfydryl,
E) formyl radical,
F) trifluoromethyl,
G) nitro,
H) C
1-C
6Alkoxyl group,
I) C
1-C
6Carbalkoxy,
J) C
1-C
6Alkylthio,
K) C
1-C
6Acyl group,
L) optionally by OH, C
1-C
5Alkoxyl group, C
1-C
5Acyl group or-NR
49R
50The C that replaces
1-C
6Alkyl,
M) phenyl,
n)-C(＝O)NR
52R
53，
o)-NR
49R
50，
p)-N(R
52)(-SO
2R
54)，
Q)-SO
2-NR
52R
53, or
r)-S(＝O)
iR
54；
R when at every turn occurring
52And R
55Identical or different, and be
a)H，
B) C
1-C
6Alkyl, or
C) phenyl;
R
54Be
A) C
1-C
4Alkyl, or
B) optionally by C
1-C
4The phenyl that alkyl replaces;
R wherein
55Be
A) carboxyl,
B) halogen,
C) cyano group,
D) sulfydryl,
E) formyl radical,
F) trifluoromethyl,
G) nitro,
H) C
1-C
6Alkoxyl group,
I) C
1-C
6Carbalkoxy,
J) C
1-C
6Alkylthio,
K) C
1-C
6Acyl group,
l)-NR
56R
57，
M) optionally by OH, C
1-C
5Alkoxyl group, C
1-C
5Acyl group or-NR
56R
57The C that replaces
1-C
6Alkyl,
N) optionally by one or two R
58The C that replaces
2-C
8The alkenyl phenyl,
O) optionally by one or two R
58The phenyl that replaces,
P) have 1 to 3 atom that is selected from S, N and O, optionally by one or two R
58Replace, 5 or 6 yuan of saturated or unsaturated heterocycle parts, perhaps
Q)
R when at every turn occurring
56And R
57Identical or different, and be a) H, b) formyl radical, c) C
1-C
4Alkyl, d) C
1-C
4Acyl group,
E) phenyl,
F) C
3-C
6Cycloalkyl, or
G) R
56And R
57With nitrogen-atoms is 5,6 yuan of saturated heterocyclics, and it optionally has another heteroatoms that is selected from S, N and O, and, being included on another nitrogen-atoms, itself can be by phenyl, pyrimidyl, C
1-C
3Alkyl or C
1-C
3Acyl group optionally replaces;
R
58Be
A) carboxyl,
B) halogen,
C) cyano group,
D) sulfydryl,
E) formyl radical,
F) trifluoromethyl,
G) nitro,
H) C
1-C
6Alkoxyl group,
I) C
1-C
6Carbalkoxy,
J) C
1-C
6Alkylthio,
K) C
1-C
6Acyl group,
L) phenyl,
M) by OH, azido-, C
1-C
5Alkoxyl group, C
1-C
5Acyl group ,-NR
65R
66,-SR
67,-O-SO
2R
68Or
The C of Qu Daiing optionally
1-C
6Alkyl,
n)-C(＝O)NR
59R
60，
o)-NR
56R
57，
p)-N(R
59)(-SO
2R
54)，
q)-SO
2-NR
59R
60，
r)-S(＝O)
iR
54，
S)-CH=N-R
61, or
t)-CH(OH)-SO
3R
64；
R
54Definition as above;
R when at every turn occurring
59And R
60Identical or different, and be
a)H，
B) C
1-C
6Alkyl,
C) phenyl, or
D) tolyl;
R
61Be
a)OH，
B) benzyloxy,
c)-NH-C(＝O)-NH
2，
D)-NH-C (=S)-NH
2, or
e)-NH-C(＝NH)-NR
62R
63；
R when at every turn occurring
62And R
63Identical or different, and be
A) H, or
B) optionally by the C of phenyl or pyridyl replacement
1-C
4Alkyl;
R
64Be
A) H, or
B) sodium ion;
R when at every turn occurring
65And R
66Identical or different, and be
a)H，
B) formyl radical,
C) C
1-C
4Alkyl,
D) C
1-C
4Acyl group,
E) phenyl,
F) C
3-C
6Cycloalkyl,
G) R
65And R
66Be 5,6 yuan of saturated heterocyclic parts with 1 to 3 atom that is selected from S, N and O together, it is included on the nitrogen-atoms by phenyl, pyrimidyl, C
1-C
3Alkyl or C
1-C
3Acyl group optionally replaces,
H)-P (O) (OR
70) (OR
71), or
i)-SO
2-R
72；
R
67Be
R
68Be C
1-C
3Alkyl;
R
69Be
A) C
1-C
6Carbalkoxy, or
B) carboxyl;
R when at every turn occurring
70And R
71Identical or different, and be
A) H, or
B) C
1-C
3Alkyl;
R
72Be
A) methyl,
B) phenyl, or
C) tolyl;
Wherein K is
A) O, or
b)S；
R when at every turn occurring
73, R
74, R
75, R
76And R
77Identical or different, and be
a)H，
B) carboxyl,
C) halogen,
D) cyano group,
E) sulfydryl,
F) formyl radical,
G) trifluoromethyl,
H) nitro,
I) C
1-C
6Alkoxyl group,
J) C
1-C
6Carbalkoxy,
K) C
1-C
6Alkylthio,
L) C
1-C
6Acyl group,
m)-NR
78R
79，
N) C
1-C
6Alkyl, it is by OH, C
1-C
5Alkoxyl group, C
1-C
5Acyl group ,-NR
78R
79,-N (phenyl) (CH
2-CH
2-OH) ,-O-CH (CH
3) (OCH
2CH
3) or-O-phenyl-[right-NHC (=O) CH
3] optionally replace,
O) optionally by R
51The C that replaces
2-C
8The alkenyl phenyl,
P) optionally by R
51The phenyl that replaces, or
Q) have 1 to 3 be selected from S, N and O atom, optionally by R
515 or 6 yuan of saturated or unsaturated heterocycle parts that replace;
R
51Definition as above;
R when at every turn occurring
78And R
79Identical or different, and be
a)H，
B) C
1-C
4Alkyl,
C) phenyl, or
D) R
78And R
79With nitrogen-atoms is 5,6 yuan of saturated heterocyclics, and it optionally has another heteroatoms that is selected from S, N and O, and, being included on another nitrogen-atoms, itself can be by C
1-C
3Alkyl or C
1-C
3Acyl group optionally replaces;
Wherein T is
a)O，
B) S, or
c)SO
2；
R
75, R
76And R
77Definition as above;
R
80Be
a)H，
B) formyl radical,
C) carboxyl,
D) C
1-C
6Carbalkoxy,
E) C
1-C
8Alkyl,
F) C
2-C
8Alkenyl,
Substituting group (e) and (f) can be wherein optionally by OH, halogen, C
1-C
6Alkoxyl group, C
1-C
6Acyl group, C
1-C
6Alkylthio or C
1-C
6Carbalkoxy or the phenyl replacement that is replaced by the halogen selectivity,
G) have the aromatic nucleus part of 6 to 10 carbon atoms, it is optionally by carboxyl, halogen, cyano group, formyl radical, trifluoromethyl, nitro, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Acyl group, C
1-C
6Alkylthio or C
1-C
6Carbalkoxy replaces;
h)-NR
81R
82，
i)-OR
90，
j)-S(＝O)
i-R
91，
K)-SO
2-N (R
92) (R
93), or
L) group of following formula:
R when at every turn occurring
81And R
82Identical or different, and be
a)H，
B) C
3-C
6Cycloalkyl,
C) phenyl,
D) C
1-C
6Acyl group,
E) C that is replaced by the OH selectivity
1-C
8Alkyl, the C that can be replaced by OH
1-C
6Alkoxyl group, have 1 to 3 heteroatomic 5 or 6 membered aromatic heterocycles part that is selected from S, N and O, by OH, trifluoromethyl, halogen, nitro, C
1-C
4Alkoxyl group ,-NR
83R
84The phenyl that selectivity replaces, or
V is
a)O，
B) CH
2, or
c)NR
87；
R when at every turn occurring
83And R
84Identical or different, and be
A) H, or
B) C
1-C
4Alkyl;
R
85Be
a)OH，
B) C
1-C
4Alkoxyl group, or
c)-NR
88R
89；
R
86Be
A) H, or
B) C
1-C
7Alkyl, its optionally by indyl, OH, sulfydryl, imidazolyl, methylthio group, amino, by OH ,-C (=O)-NH
2,-COOH or-C (=NH)-NH
2The phenyl that selectivity replaces replaces;
R
87Be
a)H，
B) phenyl, or
C) C that is optionally replaced by OH
1-C
6Alkyl;
R when at every turn occurring
88And R
89Identical or different, and be
a)H，
B) C
1-C
5Alkyl,
C) C
3-C
6Cycloalkyl, or
D) phenyl;
R
90Be
A) C
1-C
8Alkyl, it is optionally replaced by following group: C
1-C
6Alkoxyl group or C
1-6Hydroxyl, C
3-C
6Cycloalkyl, 6 yuan of aromatic nucleus, this aromatic nucleus optionally is benzo-fused heterocyclic moiety, wherein has 1 to 3 nitrogen-atoms, itself can be by one or two nitro, trifluoromethyl, halogen, cyano group, OH, C
1-C
5Alkyl, C
1-C
5Alkoxyl group or C
1-C
5Acyl substituted;
b)
C) phenyl, or
D) pyridyl;
R
91Be
A) C
1-C
16Alkyl,
B) C
2-C
16Alkenyl,
Substituting group (a) and (b) can be wherein optionally by C
1-C
6Carbalkoxy or 5,6,7 yuan of fragrant heterocyclic moieties replace, and this virtue heterocycle has 1 to 3 heteroatoms that is selected from S, N and O,
C) have the aromatic nucleus part of 6 to 10 carbon atoms, or
D) have 1 to 3 heteroatomic 5,6,7 yuan of heteroaryl moieties that are selected from S, N and O,
Substituting group (c) and (d) can be wherein optionally by carboxyl, halogen, cyano group, formyl radical, trifluoromethyl, nitro, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Acyl group, C
1-C
6Alkylthio or C
1-C
6Carbalkoxy replaces;
R when at every turn occurring
92And R
93Identical or different, and be
a)H，
B) phenyl,
C) C
1-C
6Alkyl, or
D) benzyl;
R when at every turn occurring
94And R
95Identical or different, and be
a)H，
b)OH，
C) quilt-NR
83NR
84The C that selectivity replaces
1-C
6Alkyl, or
D) R
94And R
95Be together=O;
R
96Be
A) have the aromatic nucleus part of 6 to 10 carbon atoms,
B) 5 or 6 of fused benzene rings yuan of heteroaryl moieties optionally wherein have 1 to 3 heteroatoms that is selected from S, N and O,
Substituting group (a) and (b) itself can be wherein by 1 to 3 nitro, trifluoromethyl, halogen, cyano group, OH, phenyl, C
1-C
5Alkyl, C
1-C
5Alkoxyl group or C
1-C
5Acyl substituted,
C) morpholinyl,
d)OH，
E) C
1-C
6Alkoxyl group,
f)-NR
83R
84，
G)-C (=O)-R
97, or
h)
R
97Be
A) morpholinyl,
B) OH, or
C) C
1-C
6Alkoxyl group;
H is 1,2 or 3;
I is 0,1 or 2;
J is 0 or 1;
K is 3,4 or 5;
L is 2 or 3;
M is 4 or 5;
N is 0,1,2,3,4 or 5;
P is 0,1,2,3,4 or 5; Its condition is that n and p are 1,2,3,4 or 5 together;
Q is 1,2,3 or 4;
R is 2,3 or 4;
T is 0,1,2,3,4,5 or 6;
U is 1 or 2;
W is 0,1,2 or 3.
Detailed Description Of The Invention
New compound of the present invention can Yong Yi Zhi De oxazolidone, isoxazole alkyl and the compound of butyrolactone and intermediate as intermediate, and with synthetic method preparation known in the art.Thioamides of the present invention generally can be by corresponding amide and the preparation of Lawesson ＇ s reagent react.
Disclosed compound is the suitable intermediate of preparation The compounds of this invention in following publication, and therefore the disclosure that wherein can change the suitable compound of thiocarbonyl derivative of the present invention into is incorporated herein by reference.
United States Patent (USP) 5225565; 5182403; 5164510; 5247090; 5231188; 5565571; 5547950; And 5523403.
PCT application and publication PCT/US93/04850, WO94/01110; PCT/US94/08904, WO95/07271; PCT/US95/02972, WO95/25106; PCT/US95/10992, WO96/13502; PCT/US96/05202, WO96/35691; PCT/US96/12766; PCT/US96/13726; PCT/US96/14135; PCT/US96/17120; PCT/US96/19149; PCT/US97/01970; PCT/US95/12751, W096/15130; And PCT/US96/00718, WO96/23788.
Hartke, K., Barrmeyer, S., J.prakt.Chem.1996,338, describe among the 251-6 and on the oxazolidone ring, have CH
2NH
2Multiple intermediate change CH into
2NH-C (S)-CH
3The chemical conversion technology.Similarly, Cava, M.P.; Levinson, M.I., Thionation Reactions of Lawesson ' s Reagents, Tetrahedron 1985,41, and 5061-87 has reported CH
2NHC (=O) CH
3Change CH into
2NHC (S) NHCH
3
For the purposes of the present invention, multiplely contain carbon content in the hydrocarbyl group by showing in this group the prefix designates of minimum and maximum carbonatoms, i.e. prefix C
i-C
jHaving defined the carbonatoms that exists is to integer " j " from integer " i ".Therefore, C
1-C
4Alkyl refers to the alkyl of 1-4 carbon atom, comprises methyl, ethyl, propyl group, butyl and isomeric form thereof.
Term " C
1-C
2Alkyl ", " C
1-C
3Alkyl ", " C
1-C
4Alkyl ", " C
1-C
5Alkyl ", " C
1-C
6Alkyl, " C
1-C
8Alkyl " and " C
1-C
16Alkyl " refer to have the alkyl of 1 to 2,1 to 3,1 to 4,1 to 5,1 to 6,1 to 8 or 1 to 16 carbon atom respectively, for example, methyl; ethyl, propyl group, butyl; amyl group, hexyl, heptyl; octyl group, nonyl, decyl; undecyl; dodecyl, tridecyl, tetradecyl and isomeric form thereof.
Term " C
2-C
4Alkenyl ", " C
2-5Alkenyl ", " C
2-C
8Alkenyl ", " C
2-14Alkenyl " and " C
2-16Alkenyl " refer to contain respectively 2 to 4,2 to 5,2 to 8,2 to 14 or 2 to 16 carbon atoms, have an alkenyl of two keys at least; for example, vinyl, butenyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, heptadiene base, octenyl, octadienyl, sarohornene base, nonene base, nonadiene base, the ninth of the ten Heavenly Stems trialkenyl, undecenyl, 11 carbon dialkylenes, dodecenyl succinic, tridecylene base, tetradecene base and isomeric form thereof.
Term " C
2-C
5Alkynyl group ", " C
2-8Alkynyl group ", and " C
2-10Alkynyl group " refer to contain respectively at least one triple-linked alkynyl groups that has of 2 to 5,2 to 8 or 2 to 10 carbon atoms, for example, ethynyl; proyl, butynyl, pentynyl; pentadiine base, hexin base, hexadiyne base; heptyne base, heptadiyne base, octyne base; hot diynyl, hot three alkynyls, n-heptylacetylene base; the ninth of the ten Heavenly Stems diynyl, the ninth of the ten Heavenly Stems three alkynyl and isomeric form thereof.
Term " C
3-C
4Cycloalkyl ", " C
3-C
6Cycloalkyl ", " C
5-C
6Cycloalkyl ", and " C
3-C
8Cycloalkyl " refer to have respectively the cycloalkyl of 3 to 4,3 to 6,5 to 6 or 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, and isomeric form.
Term " C
1-C
4Alkoxyl group ", " C
1-C
6Alkoxyl group ", and " C
1-C
8Alkoxyl group " refer to have respectively alkyl 1 to 4,1 to 6 or 1 to 8 carbon atom, that connected Sauerstoffatom; for example, methoxyl group, oxyethyl group, propyl group oxygen base, butyl oxygen base, amyl group oxygen base, hexyl oxygen base, heptyl oxygen base or octyl group oxygen base and isomeric form thereof.
Term " C
1-C
6Alkylamino ", and " C
1-8Alkylamino " refer to contain respectively 1 to 6 or 1 to 8 carbon atom connection the alkyl of amino part, for example, methylamino, ethylamino, propyl group amino, butyl amino, amyl group amino, hexyl amino, heptyl amino or octyl group amino and isomeric form thereof.
Term " C
1-C
6Dialkyl amido ", and " C
1-C
8Dialkyl amido " refer to have two alkyl 1 to 6 or 1 to 8 carbon atom respectively, that connected an amino part; for example, dimethylamino, methylethyl amino, diethylamino, dipropyl amino, methyl-propyl amino, ethyl propyl amino, dibutylamino, diamyl amino, dihexyl amino, methyl hexyl amino, diheptyl amino or dioctyl amino and isomeric form thereof.
Term " C
1-C
3Acyl group ", " C
1-C
4Acyl group ", " C
1-C
5Acyl group ", " C
1-C
6Acyl group ", " C
1-C
8Acyl group " and " C
1-C
8Acyl group " refer to have the carbonyl of the alkyl of 1 to 3,1 to 4,1 to 5,1 to 6,1 to 8 or 2 to 8 carbon atom.
Term " C
1-C
4Alkoxy carbonyl ", " C
1-C
6Alkoxy carbonyl ", and " C
1-C
8Alkoxy carbonyl " refers to have the ester group of 1 to 4,1 to 6 or 1 to 8 carbon atom alkyl.
Term " C
1-C
8Alkyl phenyl " refer to alkyl and the isomer thereof that are replaced by at least one phenyl with 1 to 8 carbon atom.
Term " C
2-C
8The alkenyl phenyl " refer to that replaced by at least one phenyl, that have 2 to 8 carbon atoms, as to contain at least one two key alkenyl and isomer thereof.
Term " C
1-C
8Alkylpyridyl " refer to alkyl and the isomer thereof that are replaced by at least one pyridyl with 1 to 8 carbon atom.
Term " C
1-C
8Hydroxyl " refer to connect alkyl and isomer thereof hydroxyl, that have 1 to 8 carbon atom.
Term " C
1-C
8Alkyl sulphonyl " refer to connect SO
2Alkyl and isomer thereof part, that have 1 to 8 carbon atom.
Term " C
1-C
6Alkylthio " refer to connect alkyl and isomer thereof sulphur atom, that have 1 to 6 carbon atom.
Term " heterocyclic radical " refers to contain one or more Sauerstoffatoms, nitrogen-atoms and sulphur atom, 5 to 10 yuan, saturated, unsaturated or aromatic heterocycle, for example, pyridine, thiophene, furans, pyrazoline, pyrimidine, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 3-pyridazinyl, the 4-pyridazinyl, the 3-pyrazinyl, the 2-quinolyl, the 3-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, the 4-isoquinolyl, the 2-quinazolyl, the 4-quinazolyl, the 2-quinoxalinyl, 1-(2, the 3-phthalazinyl), 4-oxo-2-imidazolyl, the 2-imidazolyl, the 4-imidazolyl, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 3-pyrazolyl, the 4-pyrazolyl, the 5-pyrazolyl, the 2-oxazolyl, the 4-oxazolyl, 4-oxo-2-oxazolyl, the 5-oxazolyl, 4,5,-dihydro-oxazole bases, 1,2,3-oxa-thiophene (oxathiole), 1,2, the 3-oxadiazole, 1,2, the 4-oxadiazole, 1,2, the 5-oxadiazole, 1,3, the 4-oxadiazole, the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, the 3-isothiazolyl, the 4-isothiazolyl, the 5-isothiazolyl, the 2-indyl, the 3-indyl, the 3-indazolyl, the 2-benzoxazolyl, the 2-[4-morpholinodithio base, the 2-benzimidazolyl-, the 2-benzofuryl, the 3-benzofuryl, the benzisothiazole base, the benzoisoxazole base, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyrryl, the 3-pyrryl, the different pyrryl of 3-, the different pyrryl of 4-, the different pyrryl of 5-, 1,2,3,-oxa-thiazole-1-oxide compound, 1,2,4 oxadiazoles-3-base, 1,2,4-oxadiazole-5-base, 5-oxo-1,2,4-oxadiazole-3-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, 3-oxo-1,2,4-thiadiazoles-5-base, 1,3,4-thiadiazoles-5-base, 2-oxo-1,3,4 thiadiazoles-5-base, 1,2,4-triazole-3-base, 1,2,4-triazole-5-base, 1,2,3,4-tetrazolium-5-base, the 5-oxazolyl, the 1-pyrryl, the I-pyrazolyl, 1,2, the 3-triazol-1-yl, 1,2, the 4-triazol-1-yl, the 1-tetrazyl, the 1-indyl, the 1-indazolyl, the 2-pseudoindoyl, 7-oxo-2-pseudoindoyl, the l-purine radicals, the 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazoles, 4-oxo-2-thiazolinyl or 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, the thiazole diketone, 1,2,3, the 4-thiatriazole, 1,2,4-thiadiazoles ketone.Each of these parts can suitably be replaced.
Term halogen refers to fluorine, chlorine, bromine or iodine.
If according to ordinary method, compound of the present invention can change its salt into suitably.
Term " pharmaceutical salts " refers to be used for the acid salt of The compounds of this invention administration, and comprises hydrochloride, hydrobromate, hydriodate, vitriol, phosphoric acid salt, acetate, propionic salt, lactic acid salt, mesylate, maleate, malate, succinate, tartrate, citrate, 2-isethionate, fumarate etc.These salt can be the forms of hydrate.
When Q is following structure
Dotted line in the heterocycle refers to that this key can be singly-bound or two key.For dotted line is the situation of two keys, R
39Should be non-existent.
The C of formula I compound Zai isoxazoline ring of the present invention
5The position contains chiral centre, so just has two enantiomers or the racemic mixture of the two.The present invention relates to enantiomorph and contain this two kinds of mixture of isomers.In addition, according to substituting group, at any A or R
1May there be other chiral centre and other isomeric form in the group, and present invention includes all possible steric isomer and geometrical isomer in these groups.
Compound of the present invention is used for the treatment of the infected by microbes of people and other warm-blooded animal, can non-enteron aisle and oral administration.
Pharmaceutical composition of the present invention can be by mixing compound of the present invention with solid or liquid, medicinal carrier, and optionally with standard and routine techniques in medicinal adjuvant and the mixed with excipients used prepare.The composition of solid dosage comprises powder, tablet, dispersible granule, capsule, cachet and suppository.Solid carrier can be at least a material, and it also can be used as thinner, correctives, solubility promoter, lubricant, suspending agent, tackiness agent, tablet disintegrant and becomes capsule.Inert solid carrier comprises magnesiumcarbonate, Magnesium Stearate, talcum, sugar, lactose, pectin, dextrin, starch, gelatin, cellulose family, low melt wax, theobroma oil etc.The liquid form composition comprises solution, suspensoid and emulsion.For example, The compounds of this invention can be dissolved in water and water-propylene glycol and the water-polyoxyethylene glycol system and make solution, wherein optionally contain suitable conventional tinting material, correctives, solubilizing agent and thickening material.
Be that the form of the unit dosage of compound of the present invention uses routine techniques that this pharmaceutical composition is provided preferably to contain effective or an amount of active ingredient.
Active ingredient is the amount of The compounds of this invention in this pharmaceutical composition and unit dosage thereof, can carry out wide variation or adjustment according to effectiveness, the desired concn of concrete application, specific compound.In general, the amount of active ingredient accounts for 0.5 to 90% of said composition weight.
In the therepic use of the infectation of bacteria for the treatment of or resist warm-blooded animal, these compounds or its pharmaceutical composition can oral, non-enteron aisle and/or topicals, its dosage is enough to reach and maintains certain concentration, promptly carries out the amount or the plasma concentration of the active compound of effective antibacterial therapy in animal.In general, the active compound antimicrobial effective amount is about 0.1 to about 100, and preferred about 3.0 to about 50mg/kg body weight/day.Should understand these dosage can change according to patient's needs, the seriousness and the used specific compound of the infectation of bacteria for the treatment of.The initial dose that in addition, it will be appreciated that use exceeds upper limit level so that obtain required plasma concentration fast, and perhaps initial dose can be littler than optimal dose, and increases dosage every day gradually according to particular case in therapeutic process.If desired, every day, dosage can be divided into multiple dose administration, i.e. every day 2-4 time.
When compound of the present invention passes through non-enteron aisle, when promptly passing through injection as intravenous injection or by other parenterai administration approach, but the pharmaceutical composition of parenterai administration generally contains the compound or the soluble salt (acid salt or base addition salt) of pharmacy receiving amount, it is dissolved in the medicinal fluid carrier, as the buffer reagent of water for injection with the isotonic solution that suitable resiliency is provided, for example, pH is for about 3.5-6's.Suitable buffer reagent comprises, for example, trisodium orthophosphate, sodium bicarbonate, Sodium Citrate, N-methylglucosamine, L (+)-Methionin and L (+)-arginine, these are the buffer reagent of a few representative.Compound of the present invention is generally to be enough to provide the about 1mg/mL of the acceptable injection solution concentration range of pharmacy to be dissolved in the carrier to the amount of about 400mg/mL.Use gained composition of liquid medicine administration so that reach above-mentioned antimicrobial effective amount.Compound of the present invention is favourable with solid and liquid dosage form oral administration.
During topical therapeutic, the formula I of significant quantity is mixed in medicinal gel or the white carrier, and it can be applied on patient's the skin in therapeutic area.The preparation of these cremes or gel is well known in the art and can contains short permeate agent.
The MIC experimental technique
Detect the external MIC of test compound by the agar dilution method of standard.At preferred solvent, be generally DMSO: the storage liquid of the every compounds of preparation in the water (1: 3).Sterile purified water with 1.0ml equivalent carries out doubling dilution with each sample.In the medicine of each 1.0ml equal portions, add 9ml fused Mueller Hinton nutrient agar.Hybrid medicine-additional agar is poured in 15 * 100mm culture dish, and allows it solidify before inoculation and drying.
The bottle that every kind of tested microorganism is housed is frozen in the gas phase of liquid nitrogen condensation agent.Tested culture is being suitable for allowing on the organic substratum tested culture grow overnight under 35 ℃.Sign for the collection bacterium colony with sterilization, preparation cell suspending liquid in trypticase soy broth (TSB), turbidity equals 0.5 McFarland standard.1: 20 extent of dilution of each suspension of preparation in TSB.Contain in the culture plate of the agar that medicine replenishes and inoculate the cell suspending liquid that 0.001ml drips, every about 10 with the Steers reproducer
4To 10
5Individual cell.With culture plate 35 ℃ of overnight incubation.
After the cultivation, read and write down minimum inhibition concentration (MIC μ g/ml), suppress the medicine minimum concentration of organism visible growth.Data see Table I and II.
Table 1
* non-compound of the present invention
Table 1 (continuing)
* non-compound of the present invention
Table 1 (continuing)
SAUR:S. the non-compound of the present invention of streptococcus aureus SEPI:S. staphylococcus epidermidis EFAE:E. urine enterococcus SPNE:S. streptococcus pneumoniae SPYO:S. suppuration Sphaerophorus *
Table II
| Embodiment number | ???SAUR ?9213?MIC | ????SEPI ?30593?MIC | ????EFAE ?12712?MIC | ???SPNE ?9912?MIC | ???SPYO ?152?MIC | ????HINF ?30063?MIC | ????MCAT ?30610?MIC | ????EFAE ?9217?MIC |
| ????1 | ?1 | ?0.25 | ?0.5 | ＜0.125 | ＜0.125 | ?8 | ?1 | ?0.5 |
| ????2 | ?8 | ?4 | ?8 | ?2 | ?4 | ?＞16 | ?＞16 | ?4 |
| ????3 | ?4 | ?1 | ?1 | ?0.25 | ?0.5 | ?16 | ?4 | ?2 |
| ????5 | ?1 | ?0.5 | ?0.5 | ＜0.125 | ?0.25 | ?4 | ?2 | ?0.5 |
| ????6 | ?2 | ?2 | ?2 | 0.5 | ?1 | ?16 | ?8 | ?2 |
| ????7 | ?0.5 | ?0.25 | ?0.5 | ＜0.125 | ?0.25 | ?4 | ?1 | ?0.5 |
| ????8 | ?2 | ?1 | ?0.5 | ＜0.125 | ?0.25 | ?4 | ?2 | ?1 |
| ????9 | ?0.5 | ?0.25 | ?0.25 | ＜0.125 | ＜0.125 | ?2 | ?0.5 | ?0.25 |
| ????10 | ?2 | ?1 | ?0.5 | ＜0.125 | ?0.25 | ?2 | ?1 | ?1 |
| ????11 | ?0.25 | ?0.25 | ?0.25 | ＜0.125 | ?0.25 | ?2 | ?1 | ?0.25 |
| ????12 | ?1 | ?0.5 | ?0.25 | ＜0.125 | ＜0.125 | ?1 | ?0.5 | ?0.5 |
| ????13 | ?1 | ?1 | ?2 | ?0.5 | ?1 | ?＞16 | ?8 | ?2 |
| ????14 | ?1 | ?0.5 | ?1 | ?0.25 | ?0.5 | ?8 | ?1 | ?1 |
| ????15 | ?32 | ?16 | ?32 | ?4 | ?8 | ?＞64 | ?64 | ?32 |
| ????16 | ?8 | ?8 | ?16 | ?2 | ?8 | ?＞64 | ?32 | ?16 |
| ????17 | ?2 | ?2 | ?4 | ?1 | ?2 | ?64 | ?16 | ?4 |
| ????18 | ?2 | ?1 | ?2 | ＜0.5 | ?1 | ?32 | ?4 | ?2 |
| ????19 | ?32 | ?16 | ?32 | ?16 | ?16 | ?64 | ?32 | ?32 |
| ????21 | ?4 | ?4 | ?8 | ?2 | ?4 | ?64 | ?16 | ?8 |
| ????22，23 | ?0.5 | ?0.5 | ?1 | ＜0.125 | ?0.25 | ?4 | ?2 | ?1 |
| ????24 | ?1 | ?0.25 | ?0.5 | ＜0.125 | ?0.25 | ?4 | ?2 | ?0.5 |
| ????25 | ?0.5 | ?0.25 | ?0.5 | ＜0.125 | ＜0.125 | ?2 | ?2 | ?0.5 |
| ????26 | ?1 | ?0.5 | ?1 | ?0.25 | ?0.5 | ?16 | ?2 | ?1 |
Table II (continuing)
Key:SAUR 9213: streptococcus aureus
| Embodiment number | ??SAUR ?9213?MIC | ????SEPI ?30593?MIC | ????EFAE ?12712?MIC | ???SPNE 9912?MIC | ??SPYO ?152?MIC | ????HINF ?30063?MIC | ??MCAT ?30610?MIC | ????EFAE ?9217?MIC |
| ????27 | ?0.5 | ?0.5 | ?0.5 | ＜0.125 | ?0.25 | ?4 | ?2 | ?I |
| ????28 | ?0.5 | ?0.25 | ?0.5 | ?0.25 | ?0.25 | ?2 | ?1 | ?0.5 |
| ????29 | ?0.25 | ?0.25 | ?0.25 | ＜0.125 | ＜0.125 | ?2 | ?0.5 | ?0.25 |
| ????30 | ?4 | ?1 | ?0.5 | ＜0.125 | ?0.25 | ?8 | ?2 | ?1 |
| ????31 | ?2 | ?1 | ?1 | ＜0.125 | ?0.25 | ?4 | ?1 | ?1 |
| ????32 | ?16 | ?2 | ?2 | ?0.25 | ?0.25 | ?8 | ?2 | ?4 |
| ????33 | ?4 | ?2 | ?1 | ?0.25 | ?0.25 | ?4 | ?2 | ?4 |
| ????34 | ?2 | ?1 | ?2 | ?0.5 | ?1 | ＞16 | ?4 | ?2 |
| ????35 | ?1 | ?0.5 | ?1 | ?0.25 | ?0.5 | ?16 | ?2 | ?1 |
SEPI 30593: staphylococcus epidermidis
EFAE 12712: urine enterococcus
SPNE 9912: streptococcus pneumoniae
SPYO 152: the suppuration Sphaerophorus
HINF 30063: Haemophilus influenzae
MCAT 30610: morazella catarrhalis
EFAE 9217: enterococcus faecalis
Shown in scheme 1, disclosed intermediate in the intermediate II also Shi oxazolidone patent of The compounds of this invention and the above-mentioned disclosed application (being incorporated herein by reference).End product (embodiment) in intermediate compound IV Shi oxazolidone patent of the present invention and the above-mentioned disclosed application (being incorporated herein by reference).
As scheme 1, shown in the step 1, and, in solvent such as methylene dichloride, under 0 to 25 ℃, allow amine intermediate (II) and 1,1 ＇-thiocarbonyl two-2 (1H)-pyridone react in embodiment 5 illustrated, can prepare lsothiocyanates III easily.Then by III and ammonia or suitable primary amine at solvent as 1,0-50 ℃ of reaction down, shown in step 2, can prepare thiocarbamide (Ia, R ＇=H, C in 4-diox or the tetrahydrofuran (THF)
1-C
4Alkyl).Perhaps, shown in embodiment 6 and be shown in step 3, (R ＇-N=C=S) reaction can prepare thiocarbamide at 0-50 ℃ of following II and suitable lsothiocyanates in solvent such as tetrahydrofuran (THF).II and suitable dithioesters (R S-C (=S)-R ") prepared in reaction thioamides (Ia, R "=H, C
1-C
4Alkyl), see embodiment 4 steps 4.This is reflected in the water-alcohol solvent, under 0-50 ℃, in the presence of the alkali metal hydroxide of equivalent, carry out.Particularly when R was methyl or ethyl, this reaction can be used alkaline metal fluoride cpd catalysis.
II and R S-C (S)-R (R =methyl, ethyl) obtain Ib, and (reaction of step 4) also can in solvent such as THF, diox or methylene dichloride, under 10-50 ℃, be carried out 3 to 48 hours in the presence of tertiary amine base such as triethylamine.
When the substituting group tolerance response condition on the R (for example, see embodiment 1-3), by suitable amide intermediate (IV) and reagent as 2, two (p-methoxyphenyl)-1 of 4-, 3-dithia two phospha butane-2,4-disulphide (Lawesson ＇ s reagent) is 1, in 4-diox, benzene, toluene or the tetrahydrofuran (THF), 60-110 ℃ of reaction down; In tetrahydrofuran (THF), react [Brillon, D., Synthetic Communications down with ten phosphoric sulfides and yellow soda ash at 20-50 ℃, 20,3085 (1990)] or with ten phosphoric sulfides and Sodium Fluoride 1,2-two-methyl ethyl ether is at 20-50 ℃ of reaction [Hartke down, K., Gerber, H.-D., J.Prakt.Chem., 338,763 (1996)] also can prepare (step 5) thioamides (Ib, R " H, C easily
1-C
4Alkyl).
In the mixed solvent of moisture and methyl alcohol, ethanol or Virahol, under 10-50 ℃, II elder generation and dithiocarbonic anhydride and tertiary amine base such as triethylamine reaction 5-24 hour, preparation Compound I c (step 6).Handle the gained intermediate with alkylating reagent (X is R X, alkylsulfonyloxy or the aryl-sulfonyl oxygen of bromine, iodine) down at 0-30 ℃, obtain Compound I c.In step 7, Compound I c and alkali metal alcoholate such as sodium methylate or potassium ethylate react in corresponding alkanol solvent.This is reflected under the reflux temperature of alkanol and carried out easily 1 to 24 hour.
Scheme 1
For essence of the present invention being described more fully and implementing mode of the present invention, provide following EXPERIMENTAL EXAMPLE.
Embodiment 1:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide (I)
With II (PCT/US94/08904,3.37g, the 10.0mmol) stirred mixture in exsiccant diox (100mL), under nitrogen atmosphere, use Lawesson ' s agent treated (4.04g, 10.0mml), at 1 hour internal heating to refluxing and reflux 1.5 hours.Carrying out the TLC monitoring with 10% methyl alcohol-chloroform on silica gel reacts to complete reaction.At room temperature kept 18 hours and vacuum concentration.Mixture with the acetone-methylene dichloride that contains 10-15% acetone on silica gel carries out chromatogram purified product as eluent to resistates, and it is obtained 1:mp 157.5-158.5 ℃ with acetone-hexane crystallization; HRMS theoretical value C
16H
20FN
3O
3S (M
+): 353.1209; Measured value: 353.1212.Ultimate analysis theoretical value C
16H
20FN
3O
3S:C, 54.38; H, 5.38; N, 11.89; S, 9.07.Measured value: C, 54.21; H, 5.58; N, 11.78; S, 8.93.
Embodiment 2:(S)-and N-[[3-[3-fluoro-4-[4-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide (2)
According to embodiment 1, in order to prepare
1,
21(PCT/US97/01970) in backflow De diox, react and obtain with Lawesson ' s reagent
2: mp 222-223 ℃; HRMS theoretical value C
19H
24FN
6O
2S
2(M+H
+): 451.1386; Measured value: 451.1381.
Embodiment 3:(S)-and N-[[3-[3-fluoro-4-[2 ＇, 5 ＇-dioxo spiral shell [piperidines-4,4 ＇-tetrahydroglyoxaline]-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide (3)
Steps A: (S)-N-[[3-[3-fluoro-4-[2 ＇, 5 ＇-dioxo spiral shell [piperidines-4,4 ＇-tetrahydroglyoxaline]-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide (32)
Will
31(WO95/25106,0.349g is 1.00mmol) at 1: 1 EtOH: H
2The suspension of the stirring of O (5mL), under nitrogen atmosphere, with potassium cyanide (0.130g, 2.00mmol) and volatile salt (0.701g 7.30mmol) handles, and heat at 55-60 ℃ also at room temperature kept 17 hours 15 minutes in 5 hours 15 minutes.On silica gel, carry out chromatogram purification then and obtain 0.280g's with the mixture of methanol-hydrogen ammonium oxide-chloroform that contains 5-20% methyl alcohol and 0.5% ammonium hydroxide
32: HRMS theoretical value C
19H
22FN
5O
5: 419.1605 (M
+); Measured value 419.1613; Ultimate analysis theoretical value C
19H
22FN
5O
51H
2O:C, 52.17; H, 5.53; N, 16.01.Measured value: C, 52.44; H, 5.30; N, 16.11.
Step B:(S)-and N-[[3-[3-fluoro-4-[2 ＇, 5 ＇-dioxo spiral shell [piperidines-4,4 '-tetrahydroglyoxaline]-1-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide (3)
32(under nitrogen atmosphere, (0.202g 0.500mmol), refluxed 4 hours and vacuum concentration to use Lawesson ' s agent treated for 0.210g, the 0.500mmol) suspension of the stirring in the Zai diox (5.0mL).This resistates is carried out chromatogram purification with the mixture of the methanol-hydrogen ammonium oxide-chloroform that contains 1-10% methyl alcohol and 0.1-0.5% ammonium hydroxide on silica gel, the products therefrom crystallization is obtained 0.0491g's with methyl alcohol-chloroform-ethyl acetate
3: 218.5 ℃ of mp; HRFAB MS theoretical value C
19H
22FN
5O
4S (M
+): 435.1376; Measured value 435.1370.Ultimate analysis theoretical value C
19H
22FN
5O
4S0.5 H
2O:C, 51.34; H, 5.21; N, 15.76.Measured value: C, 51.69; H, 5.00; N, 15.25.
Embodiment 4:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide (4)
Will
41(148mg, 0.500mmol) and dehydrated alcohol (5mL) solution of 0.97 M KOH (0.515mL) join ethyl dithiocarbamate (57 μ L, 0.50mmol) and Sodium Fluoride (20mg in dehydrated alcohol 0.47mmol) (5mL) solution, and will be under this mixture room temperature keeps 3 hours 40 minutes.Add ethyl dithiocarbamate (5 μ L) after 1 hour 55 minutes again, after 3 hours 5 minutes, add 0.97 M KOH (40mL) and Sodium Fluoride (6mg) again.On silica gel with 10% methyl alcohol-CHCl
3With 30% acetone-CH
2Cl
2Carry out TLC as developping agent and monitor this reaction.Primary product on TLC with
4R
fIdentical.
Embodiment 5:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide (5)
Steps A:
In 30 minutes, under nitrogen atmosphere, will
51(PCT/US94/08904,2.07g, dichloromethane solution 7.00mmol) are added drop-wise to 1,1 ＇-thiocarbonyl two-2 (1H)-pyridone ice-cold, that stir, and (1.95g is in methylene dichloride 8.40mmol) (70mL) solution.This mixture slowly is warming up to room temperature and keep 18h (hour).Dilute with methylene dichloride then, water and salt water washing, dry (sodium sulfate) also concentrates.This resistates is obtained the lsothiocyanates of 1.60g at the enterprising circumstances in which people get things ready for a trip spectrum of silica gel purifying with 10% acetonitrile-methylene dichloride: HRMS theoretical value C
15H
16FN
3O
3S (M
+): 337.0896; Measured value 337.0888.
Step B:
The exsiccant ammonia is fed step I product, and (1.00g in the THF of stirring 2.96mmol) (10mL) solution, and will keep 3 hours 25 minutes and vacuum concentration under this mixture room temperature.With acetone-hexane this residue crystallized is obtained 0.861g's
5: mp 199-199.5 ℃; MSm/z 354 (M
+).Analysis theories value C
15H
19FN
4O
3S:C, 50.84; H, 5.40; N, 15.81.Measured value: C, 50.87; H, 5.39; N, 15.72.
Embodiment 6:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-N ＇-methylthiourea (6)
With stir, ((295mg 1.00mmol) handles Trapex, keeps 18 hours also vacuum concentration under the room temperature with 61 for 93mg, THF solution 1.27mmol).This resistates is obtained 246 mg's with ethyl acetate-hexane recrystallization
6: mp 158-160 ℃; MSm/z 368 (M
+).Ultimate analysis theoretical value C
16H
21FN
4O
3S:C, 52.16; H, 5.74; N, 15.21.Measured value: C, 52.20; H, 5.85; N, 15.17.
Embodiment 7 (S)-suitable-N-[[3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] the second thioamides
Step 1: with (S)-(-)-N-[[3-[3-fluoro-4-(3,6-dihydro-2H-thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide S-oxide compound (4.50g, can prepare according to the method that the open WO 97/09328 of international monopoly describes) and the mixture of platinum oxide (697mg) in methyl alcohol (164mL), in the Parr instrument, shaking 18 hours under the 40psi hydrogen-pressure.Concentrate then by diatomite plate filtration catalizer, and with this filtrate decompression, (the 230-400 order 350g), carries out chromatogram purification with ethanol/methylene (3/97-7/93) gradient elution on silica gel with this resistates.The fraction of the Rf=0.44 of collection and concentrated TLC (methyl alcohol/chloroform, 10/90) obtains (S)-suitable-(-)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, mp 203-204 ℃.
Step 2: in the bottle that the compound (2.50g) and the mixture of hydroxylamine hydrochloride (2.36g) in pyridine (30.6ml) and ethanol (3.4mL) of step 1 preparation had screw cap 100 ℃ times stirrings 22 hours, and at room temperature stirred 16 hours, also add hydroxylamine hydrochloride (944mg) and pyridine (4mL) between the reaction period.With this reaction mixture concentrating under reduced pressure,, adjust pH to 11 and use ethanol/methylene (10/90,5 * 100mL) extraction then with solid sodium carbonate with saturated sodium bicarbonate aqueous solution (100mL) and salt solution (50mL) dilution.With the organic phase concentrating under reduced pressure that merges, and with crude product silica gel (the 230-400 order, 150g) on, with ethanol/methylene gradient (6/94-10/90) wash-out, carry out chromatogram purification.The fraction of the Rf=0.14 of collection and concentrated TLC (methyl alcohol/chloroform, 10/90) obtains (S)-suitable-3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-5-amino methyl-2-oxazolidone, mp 159-161 ℃.
Step 3: with ethyl dithiocarbamate (105mL, 0.919mmol) and Sodium Fluoride (39mg, 0.919mmol) ethanol (9.2mL) solution, under nitrogen atmosphere, use (S)-suitable-3-[3-fluoro-4-(tetrahydrochysene-1-hydroxyl-2H-thiapyran-4-yl) phenyl]-5-amino methyl-2-oxazolidone, step 2 preparation, (300mg, 0.919mmol) and potassium hydroxide aqueous solution (1M, 0.92mL) mixture process in ethanol (46mL).Will be under the gained solution room temperature stir 4 hours, use then methylene dichloride (150mL) dilution and water (50mL), aqueous potassium hydrogen sulfate (1M, 50mL) and salt solution (25mL) wash.This organic phase obtains title compound, mp 176-177 ℃ (decomposition) with this crude product with methylene dichloride/ether grinding and filtration with anhydrous sodium sulfate drying and vacuum concentration.
Embodiment 8 (S)-suitable-[[3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide
Step 1:
With 1,1 '-thiocarbonyl two-2 (1H)-pyridone (235mg, 1.01mmol) anhydrous methylene chloride (10mL) solution, under nitrogen atmosphere, use (S)-suitable-3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl at 0 ℃]-5-amino methyl-2-oxazolidone, preparation is as embodiment 7, step 2, (275mg, anhydrous methylene chloride 0.843mmol) (34mL) solution-treated 30 minutes.The gained mixture was stirred 30 minutes and at room temperature stirred 1 hour at 0 ℃, use methylene dichloride (40mL) dilution then, water (25mL) and salt solution (25ml) washing are with anhydrous sodium sulfate drying and vacuum concentration.With this crude product at silica gel (70-230 order, 20g) enterprising circumstances in which people get things ready for a trip spectrum purifying, with acetonitrile/methylene dichloride (40/60) wash-out, collect and concentrated TLC (acetonitrile/methylene dichloride, 30/70) fraction of Rf=0.07 obtains (S)-suitable-3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-5-isothiocyanato methyl-2-oxazolidone, mp 187-190 ℃ (decomposition).
Step 2: with (S)-suitable-3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-5-isothiocyanato methyl-2-oxazolidone (step 1,290mg, 0.787mmol) anhydrous tetrahydro furan (39mL) solution, under 0 ℃, under nitrogen atmosphere, handled 5 minutes with ammonia flow (feeding).Stirred 1 hour down at 0 ℃ with this reactor sealing and with the gained mixture.Then, remove excess of ammonia gas, and this reaction mixture vacuum concentration is obtained crude product with nitrogen gas stream.Obtain title compound with ethanol/methylene/ether recrystallization, mp 206-208 ℃ (decomposition).
Embodiment 9 (S)-trans-N-[[3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] the second thioamides
Step 1: in the presence of catalyzer and solvent, can be with (S)-(-)-N-[[3-[3-fluoro-4-(3,6-dihydro-2H-thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidine] methyl] ethanamide S-oxide compound (being disclosed in international monopoly WO 97/09328) catalytic hydrogenation is reduced to corresponding cis or trans sulfoxide.Perhaps, the by product sulfide of this reduction reaction can be used oxygenant such as NaIO
4Or m-chloro-benzoic acid peroxide is oxidized to cis and trans sulfoxide in solvent.Perhaps, sulfide side products can be used tertbutyl peroxide and catalyzer such as Ti (OiPr)
4With D-di-isopropyl tartrate selective oxidation in The suitable solvent be trans-isomer(ide).Then, obtain 211-212 ℃ of trans sulfoxide mp (decomposition) by this isomer mixture of chromatographic separation.With this trans sulfoxide, (S)-trans-(-)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, (0.90g) and hydroxylamine hydrochloride (0.85g) in pyridine (11.0mL) and ethanol (1.2ml), having in the bottle of screw cap and stirring 23 hours at 100 ℃, and at room temperature stirred 19 hours, add hydroxylamine hydrochloride (340mg) and pyridine (1mL) between the reaction period again.With this reaction mixture concentrating under reduced pressure, dilute then, and (10/90,6 * 100mL) extracts with ethanol/methylene with saturated sodium bicarbonate aqueous solution (50mL) and salt solution (50mL).With the organic phase concentrating under reduced pressure that merges, and with this crude product (the 230-400 order, 45g) enterprising circumstances in which people get things ready for a trip spectrum purifying is with ethanol/methylene gradient (7.5/92.5-10/90) wash-out at silica gel.The fraction of the RF=0.14 of collection and concentrated TLC (methyl alcohol/chloroform, 10/90) obtains (S)-trans-3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-5-amino methyl-2-oxazolidone, mp 138-140 ℃.
Step 2: with ethyl dithiocarbamate (105mL, 0.919mmol) and Sodium Fluoride (39mg, 0.919mmol) ethanol (9.2mL) solution, under nitrogen atmosphere, use (S)-trans-3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-5-amino methyl-2-oxazolidone, preparation is as step 1, (300mg, 0.919mmol) and potassium hydroxide aqueous solution (1M, 0.92ml) mixture process in ethanol (46mL).Will be under the gained solution room temperature stir 17 hours, use methylene dichloride (150mL) dilution then, water (2 * 50mL) and salt solution (25mL) wash, with anhydrous sodium sulfate drying and vacuum concentration.With this crude product at silica gel (230-400 order, 35g) enterprising circumstances in which people get things ready for a trip spectrum purifying, with ethanol/methylene (3/97) wash-out, and collection and concentrated TLC (methyl alcohol/chloroform, 10/90) fraction of RF=0.56, this resistates with methylene dichloride/ether recrystallization, is obtained title compound, mp 193-194 ℃ (decomposition).
Embodiment 10 (S)-trans-[[3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide
Step 1: with 1,1 '-thiocarbonyl two-2 (1H)-pyridone (192mg, 0.827mmol) anhydrous methylene chloride (8.3mL) solution, ℃ under, under nitrogen atmosphere, with (S)-trans-3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-5-amino methyl-2-oxazolidone, preparation is as embodiment 9, step 1, (225mg, anhydrous methylene chloride 0.689mmol) (28mL) solution-treated 35 minutes.The gained mixture was stirred 30 minutes down at 0 ℃, and at room temperature stirred 40 minutes, use methylene dichloride (20ml) dilution then, water (15mL) and salt solution (15ml) washing are with anhydrous sodium sulfate drying and vacuum concentration.(32-63mm, 40g) enterprising circumstances in which people get things ready for a trip spectrum purifying is with acetonitrile/dichloromethane gradient (30/70-60/40) 15psi N at silica gel with this crude product
2Following wash-out, the fraction of the RF=0.12 of collection and concentrated TLC (acetonitrile/methylene dichloride, 30/70) obtains (S)-trans-3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-isothiocyanato methyl-2-oxazolidone, mp 165-167 ℃.
Step 2: with (S)-trans-3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-5-isothiocyanato methyl-2-oxazolidone (step 1,230mg, 0.624mmol) anhydrous tetrahydro furan (31.2mL) solution, under 0 ℃, under nitrogen atmosphere, handled 5 minutes with ammonia flow (feeding).This reactor is sealed, and the gained reaction mixture was stirred 1 hour down at 0 ℃.Remove excess of ammonia gas with nitrogen gas stream, and this reaction mixture vacuum concentration is obtained crude product.Obtain title compound with ethanol/methylene/ether ether, mp 209-210 ℃ (decomposition).
Embodiment 11 (S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,1-dioxy-2-thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] the second thioamides
Step 1: with (S)-suitable-(-)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] (preparation is as embodiment 7 for ethanamide, step 1) begins, and according to total method steps 2, carry out unessential variation, promptly with (S)-(-)-N-[[3-[3-fluoro-4-(tetrahydrochysene-2H-thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide S, S-dioxide (being disclosed in international monopoly WO 97/09328) replaces (S)-suitable-(-)-N-[[3-[3-fluoro-4 (tetrahydrochysene-1-oxygen-2H-thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, obtain product (S)-(-)-3-[3-fluoro-4-(tetrahydrochysene-1,1-dioxy-2H-thiapyran-4-yl) phenyl]-5-amino methyl-2-oxazolidone, mp194 ℃ (decomposition).
Step 2: with ethyl dithiocarbamate (100mL, 0.876mmol) and Sodium Fluoride (37mg, 0.876mmol) ethanol (8.8mL) solution, under nitrogen atmosphere, use (S)-(-)-3-[3-fluoro-4-(tetrahydrochysene-1,1-dioxy-2H-thiapyran-4-yl) phenyl]-5-amino methyl-2-oxazolidone, prepare as step 1 (300mg, 0.876mmol) and potassium hydroxide aqueous solution (1M, 0.88mL) mixture process in ethanol (43.8mL).Stirred 26 hours under the gained mixture room temperature, add ethyl dithiocarbamate (50mL during the stirring again, 0.438mmol), Sodium Fluoride (19mg, 0.438mmol), potassium hydroxide aqueous solution (1M, 0.44ml) and ethanol (3.0mL), use methylene dichloride (150mL) dilution then, water (50mL), aqueous potassium hydrogen sulfate (1M, 50mL) and salt solution (25mL) washing, with anhydrous sodium sulfate drying and vacuum concentration.With this crude product recrystallization from methylene dichloride/ether, obtain title compound, mp 186-187 ℃ (decomposition).
Embodiment 12 (S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,1-dioxy-2H thiapyran-4-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide
Step 1: with 1,1 '-thiocarbonyl two-2 (1H)-pyridone (304mg, 1.31mmol) the solution of anhydrous methylene chloride (13mL), under 0 ℃, under nitrogen atmosphere, with (S)-(-)-3-[3-fluoro-4-(tetrahydrochysene-1,1-dioxy-2H-thiapyran-4-yl) phenyl]-5-amino methyl-2-oxazolidone, preparation is as embodiment 11, step 1, (375mg, anhydrous methylene chloride 1.09mmol) (88mL) solution-treated 30 minutes.The gained mixture stirred 30 minutes down and stirring at room 30 minutes, uses methylene dichloride (40mL) dilution then at 0 ℃, and water (25mL) and salt solution (25mL) wash, with anhydrous sodium sulfate drying and vacuum concentration.With this crude product at silica gel (230-400 order, 45g) enterprising circumstances in which people get things ready for a trip spectrum purifying, with acetonitrile/methylene dichloride (7.5/92.5) wash-out, and collection and concentrated TLC (acetonitrile/methylene dichloride, 20/80) RF=0.64 fraction obtains (S)-3-[3-fluoro-4-(tetrahydrochysene-1,1-dioxy-2H-thiapyran-4-yl) phenyl]-5-isothiocyanato methyl-2-oxazolidone, mp 158-162 ℃ (decomposition).
Step 2: with (S)-3-[3-fluoro-4-(tetrahydrochysene-1,1-dioxy-2H-thiapyran-4-yl) phenyl]-5-isothiocyanato methyl-2-oxazolidone (step 1,380mg, 0.988mmol) anhydrous tetrahydro furan (49mL) solution, under 0 ℃, under nitrogen atmosphere, handled 5 minutes with ammonia flow (feeding).This reactor is sealed, and the gained mixture was stirred 1 hour down at 0 ℃.Then, under nitrogen gas stream, remove excess of ammonia gas, and, obtain crude product this reaction mixture vacuum concentration.Obtain title compound with ethanol/methylene/ether recrystallization, mp 196-198 ℃ (decomposition).
Embodiment 13:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-thioformamide (7)
Under nitrogen atmosphere, under 50-55 ℃, with stir, diacetyl oxide (0.23mL, 0.0024mol) and 95-97% formic acid (0.10mL, mixture 0.0027mL) heated 2 hours, were cooled to room temperature and used in 2 minutes
39 8(0.45g, 0.0015mol) batch treatment.Kept under this suspension room temperature 4 hours and gained solution is handled with ether (1ml), and kept 18 hours under the room temperature.This mixture is diluted with ether (10ml), and solid collected by filtration with ether washing and dry, obtains 0.38g's
6 9: MS (ES) m/z 324 (M+H
+), 346 (M+Na
+);
1H NMR (300mHz, CDCl
3) d 3.08 (m, 4H), 3.72 (m, 2H), 3.77 (d, d, 1H), 3.89 (m, 4H), 4.04 (t, 1H), 4.80 (m, 1H), 6.33 (s, 1H), 7.05 (m, 2H), 7.45 (d, d, 1H), 8.27 (s, 1H).
With what stir
6(0.38g, 0.00118mol) the mixture in the Zai diox (20ml) is used under nitrogen atmosphere
4(0.51g 0.00126mol) handles, and is warming up to reflux and kept 90 minutes under this temperature in 30 minutes.Then, under nitrogen gas stream, evaporate.This resistates is carried out chromatogram purification with 1.25% methyl alcohol-methylene dichloride wash-out on silica gel, and impure slightly product is carried out chromatogram purification once more with the 25%EtOAc-methylene dichloride on silica gel.Products therefrom is obtained 0.114g's with the crystallization of EtOAc-methyl tertiary butyl ether
7: mp 150-155 ℃ (decomposition); IR (drift) 3322,1752cm
-1MS (ES) m/z 340 (M+H
+), 362 (M+Na
+);
1HNMR[300MHz, (CD
3)
2SO] d 2.94 (m, 4H), 3.72 (m, 4H), 3.77 (d, d, 1H), 3.94 (t, 2H), 4.12 (t, 1H), 4.93 (m, 1H), 7.05 (t, 1H), 7.16 (d, d, 1H), 7.47 (d, d, 1H), 9.33 (d, 1H), 10.59 (s, 1H).Ultimate analysis theoretical value C
15H
18FN
3O
3S:C, 53.08; H, 5.35; N, 12.38.Measured value: C, 53.02; H, 5.44; N, 12.36.
Embodiment 14:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiopropionamide (9)
With ice-cold, stir,
39(0.395g, 0.00134mol) and triethylamine ((0.128mL, methylene dichloride 0.00147mol) (3mL) solution is handled to drip propionyl chloride under nitrogen atmosphere in 2 minutes for 0.186mL, methylene dichloride 0.0027mol) (20ml) solution.This mixture was remained in the ice bath 20 minutes, and at room temperature kept 1 hour.With the methylene dichloride dilution, use saturated sodium bicarbonate, water and salt water washing then, dry (MgSO
4) and concentrate.This resistates (8) is directly used in the next step without being further purified.
(8) are with the stirred mixture of diox (20mL), and under nitrogen atmosphere, used Lawesson ' s reagent in 1 minute (0.58g 0.0014mol) handles and refluxed 2 hours in batches with the product of last step reaction; Concentrate then.This resistates in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, with 2% methyl alcohol-chloroform wash-out, and is obtained 0.259g's with this product with the methyl tertiary butyl ether crystallization
9: mp138-139 ℃; MS (ES) m/z 368 (M+H
+), 390 (M+Na
+); IR (drift) 3284,3266,1748,1744 cm
-1[α]
24 D+ 20 ° (methyl alcohol);
1H NMR[300MHz, (CD
3)
2SO] d 1.12 (t, 3H), 2.56 (q, 2H), 2.94 (m, 4H), 3.72 (m, 4H), 3.78 (d, d, 1H), 3.90 (t, 2H), 4.11 (t, 1H), 4.93 (m, 1H), 7.05 (t, 1H), 7.16 (d, d, 1H), 7.47 (d, d, 1H), 10.30 (wide s, 1H).Ultimate analysis theoretical value C
17H
22FN
3O
3S:C, 55.57; H, 6.03; N, 11.44.Measured value: C, 55.68; H, 6.21; N, 11.37.
Embodiment 15:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-chlorothio ethanamide (11)
With stir,
39(1.54g, 5.2mmol) and triethylamine (750mg, methylene dichloride 7.5mmol) (50mL) solution, under nitrogen atmosphere, (465mL, methylene dichloride 5.8mmol) (30mL) solution is handled, and at room temperature keeps 18 hours to drip chloro-acetyl chloride in 15 minutes.Use saturated NaHCO then
3With rare NaCl washing, dry (sodium sulfate) also concentrates.This resistates is carried out flash chromatography on silica gel,, obtain 1.49g's with 20-30% acetone-methylene dichloride wash-out
10 9, it is directly used in the next step without being further purified.
With stir,
10(0.371g, 1.0mmol) (0.420mg, 1.04mmol) mixture in diox (10mL) refluxed under nitrogen atmosphere 2 hours and concentrating under reduced pressure with Lawesson ＇ s reagent.This resistates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with 3-10% acetone-methylene dichloride wash-out, is obtained 0.143g's
11: MS (CI) m/z 388 (M+H
+);
1H NMR (300MHz, CDCl
3) d 3.07 (m, 4H), 3.77 (d, d, 1H), 3.88 (m, 4H), 4.04 (m, 1H), 4.12 (t, 1H), 4.35 (m, 1H), 4.61 (s, 2H), 4.98 (m, 1H), 6.96 (t, 1H), 7.08 (d, d, 1H), 7.44 (d, d, 1H), 8.69 (s, 1H).Ultimate analysis theoretical value C
16H
19ClFN
3O
3S:C, 49.55; H, 4.94; N, 10.83.Measured value: C, 49.38; H, 5.20; N, 10.27.
Embodiment 16:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-α, α, α-trifluorothio ethanamide (13)
With ice-cold, stir
39(0.590g, 2.0mmol) and triethylamine ((325mL 2.3mmol) handles and remains in the ice bath 10 minutes, at room temperature keeps then with trifluoroacetic anhydride for 640mL, methylene dichloride 4.6mmol) (10mL) solution.By on silica gel, monitoring this reaction as developping agent with 30% acetone-methylene dichloride.Add trifluoroacetic anhydride and triethylamine again, add after 3 days (64mL/125mL), add (100mL/220mL) after 4 days and add (325mL/1.0mL) after 6 days.Adding this reaction in back 1 hour at last finishes; It is mixed with methylene dichloride, water and rare NaCl washing, dry (sodium sulfate) also concentrates.This solid with acetone-heptane recrystallization, is obtained 0.566g 12:mp 161-164 ℃ (decomposition); MS (EI) m/z 391 (M
+).Ultimate analysis theoretical value C
16H
17F
4N
3O
4: C, 49.11; H, 4.38; N, 10.74.Measured value: C, 48.99; H, 4.56; N, 10.73.
With stir,
12(0.391g, 1.0mmol) and Lawesson ' s reagent (0.422g, 1.1mmol) mixture in diox (10mL) refluxed 2 hours under nitrogen atmosphere, slowly was cooled to room temperature and vacuum concentration.This resistates is carried out flash chromatography on silica gel,, and, obtain 0.249g's with acetone-heptane crystallization with 5-15% acetone-methylene dichloride wash-out
13: mp 151-152 ℃; MS (EI) m/z 407 (M
+), 363,209,151,95;
1H NMR (300MHz, CDCl
3) d 3.05 (m, 4H), 3.75 (d, d, 1H), 3.87 (m, 4H), 3.95 (m, 1H), 4.14 (t, 1H), 4.32 (m, 1H), 5.01 (m, 1H), 6.92 (t, 1H), 7.05 (d, d, 1H), 7.38 (d, d, 1H), 9.03 (s, 1H).Ultimate analysis theoretical value C
16H
17F
4N
3O
3S:C, 47.17; H, 4.21; N, 10.31.Measured value: C, 47.09; H, 4.35; N, 10.27.
Embodiment 17:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-α-fluorine thioacetamide (15)
With that stir, ice-cold
39(0.590g, 2.0mmol) and triethylamine (611ML, methylene dichloride 4.4mmol) (10mL) solution, under nitrogen atmosphere, (220mL, methylene dichloride 2.2mmol) (5mL) is handled, and remains in the ice bath 10 minutes and at room temperature keeps 2 hours to drip fluoracyl chloride.With the methylene dichloride dilution, water and rare NaCl wash then, and dry (sodium sulfate) also concentrates.This resistates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with 10-30% acetone-methylene dichloride wash-out, is obtained 0.180g's
14: MS (ES) m/z 356 (M+H
+), 378 (M+Na
+).
Will
14(0.180g, 0.507mmol) De dioxane solution, under nitrogen atmosphere, use Lawesson ' s agent treated (0.206g, 0.51mmol), in 90-100 ℃ of heating 1 hour and vacuum concentration.This resistates is obtained 0.161g's in the enterprising circumstances in which people get things ready for a trip spectrums of silica gel (15% acetone-methylene dichloride)
15: MS (EI) m/z 371 (M
+);
1H NMR (300MHz, CDCl
3) d3.05 (m, 4H), 3.78 (d, d, 1H), 3.87 (m, 4H), 4.03 (m, 1H), 4.11 (t, 1H), 4.38 (m, 1H), 4.98 (m, 1H), 5.07 (s, 1H), 5.23 (s, 1H), 6.93 (t, 1H), 7.08 (dd, 1H), 7.42 (d, d, 1H), 8.42 (s, 1H).Ultimate analysis theoretical value C
16H
19F
2N
3O
3S:C, 51.74; H, 5.16; N, 11.31.Measured value: C, 51.79; H, 5.31; N, 11.02.
Embodiment 18:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-α, α-difluoro thioacetamide (17)
With that stir, ice-cold
39(0.590g, 2.0mmol), difluoroacetic acid (190mL, 2.0mmol) and I-hydroxybenzotriazole (0.297g, 2.2mrnol) mixture in DMF (5mL), under nitrogen atmosphere, (0.843g 4.4mmol) kept 18 hours under processing and the room temperature with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride.With the methylene dichloride dilution, water and rare NaCl washing, dry (sodium sulfate) also concentrates.This solid residue with the crystallization of EtOAc-heptane, is obtained 0.617g's
16: mp 149-150 ℃;
1H NMR (300MHz, CDCl
3) d 3.05 (m, 4H), 3.66 (m, 2H), 3.85 (m, 5H), 4.08 (t, 1H), 4.80 (m, 1H), 5.93 (t, J=53.9Hz, 1H), 6.92 (t, 1H), 7.06 (m, 2H), 7.39 (d, d, 1H); MS (EI) m/z 373 (M
+).Ultimate analysis theoretical value C
16H
18F
3N
3O
4: C, 51.48; H, 4.86; N, 11.26.Measured value: C, 51.59; H, 4.91; N, 11.29.
With stir,
16((0.404g 1.00mmol) handles, and heats 1 hour and vacuum concentration at about 95 ℃ with Lawesson ' s reagent under nitrogen atmosphere for 0.373g, the 1.00mmol) solution of diox (10mL).On silica gel, this resistates is carried out chromatogram,, and, obtain 0.276g's the crystallization from the EtOAc-heptane of this product with 10% acetone-methylene dichloride wash-out
17: mp125-127 ℃; MS (EI) m/z 389 (M
+), 345,305,247,209,195,151,138,123,109,95;
1H NMR (300MHz, CDCl
3) d 3.05 (m, 4H), 3.76 (d, d, 1H), 3.86 (m, 4H), 4.01 (m, 1H), 4.12 (t, 1H), 4.30 (m, 1H), 4.99 (m, 1H), 6.20 (t, J=55.9Hz, 1H), 6.92 (t, 1H), 7.06 (d, d, 1H), 7.38 (d, d, 1H), 8.78 (wide s, 1H).Ultimate analysis theoretical value C
16H
18F
3N
3O
3S:C, 49.35; H, 4.66; N, 10.79.Measured value: C, 49.37; H, 4.71; N, 10.83.
Embodiment 19:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-alpha-cyano thioacetamide (19)
With ice-cold, stir
39(0.646g, 2.19mmol), cyanoacetic acid (0.179g, 2.1mmol) and I-hydroxybenzotriazole (0.351g, 2.6mmol) mixture in DMF (5mL), under nitrogen atmosphere, (0.997g 5.2mmol) kept 24 hours under processing and the room temperature with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride.With the methylene dichloride dilution, water and rare NaCl washing, dry (sodium sulfate) also concentrates.This solid residue with the crystallization of EtOAc-heptane, is obtained 0.546g's
18: mp 172-174 ℃: IR (drift) 3316,2256,1754,1684cm
-1MS (EI) m/z 362 (M
+).Ultimate analysis theoretical value C
17H
19FN
4O
4: C, 56.35; H, 5.28; N, 15.46.Measured value: C, 56.33; H, 5.30; N, 15.36.
With stir, 18 (0.453mg, 1.25mmol) De diox (10mL) solution under nitrogen atmosphere, use Lawesson ' s reagent (0.505g, 1.25mmol) processing, and in about 100 ℃ of heating.When finishing, reaction (carries out TLC), with this mixture cooling and vacuum concentration with 30% acetone-methylene dichloride.This resistates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with 10-20% acetone-methylene dichloride wash-out, and with the crystallization of EtOAc-heptane, is obtained 0.110g's
19: mp 186-187 ℃ (decomposition); MS (ES) m/z 379 (M+H
+), 401 (M+Na
+);
1H NMR (300MHz, CDCl
3) d 3.05 (m, 4H), 3.81 (d, d, 1H), 3.86 (m, 4H), 3.89 (s, 2H), 4.09 (t, 1H), 4.14 (m, 2H), 5.01 (m, 1H), 6.92 (t, 1H), 7.05 (d, d, 1H), 7.34 (d, d, 1H), 9.15 (s, 1H); IR (drift) 3244,2260,1754cm
-1Ultimate analysis theoretical value C
17H
19FN
4O
3S:C, 53.96; H, 5.06; N, 14.81.Measured value: C, 53.88; H, 5.39; N, 14.61.
Embodiment 20:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-α, α-dichloro thioacetamide (21)
With that stir, ice-cold
39(0.885g, 3.00mmol) and triethylamine (975mL, methylene dichloride 7mmol) (15mL) solution, under nitrogen atmosphere, drip dichloro acetic acid acid anhydride (555mL, 3.5mmol) methylene dichloride (5mL) solution handle, and remained in the ice bath 15 minutes, kept 18 hours in room temperature.With methylene dichloride dilution, water, saturated NaHCO
3With rare NaCl washing, dry (sodium sulfate) also concentrates.On silica gel, this resistates is carried out chromatogram, with 10% acetone-methylene dichloride wash-out, and with acetone-heptane with the product crystallization, obtain 0.463g's
20: mp 197-198 ℃ (decomposition); MS (ES) m/z 406 (M+H
+), 428 (M+Na
+);
1HNMR (300MHz, CDCl
3) d 3.05 (m, 4H), 3.75 (m, 3H), 3.86 (m, 4H), 4.07 (t, 1H), 4.83 (m, 1H), 5.94 (s, 1H), 6.92 (t, 1H), 7.06 (m, 2H), 7.41 (d, d, 1H).
With stir,
20(under nitrogen atmosphere, (0.202g 0.5mmol) handles, and heats 1 hour cooling and vacuum concentration at about 90 ℃ to use Lawesson ' s reagent for 0.305g, 0.75mmol) De diox (5ml) solution.This resistates in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, earlier with 30% acetone-heptane, is used 10% acetone-methylene dichloride wash-out again, and with methylene dichloride-heptane with this product crystallization, obtain 0.203g's
21: mp 143-144 ℃; HR
17S (EI) theoretical value C
16H
18Cl
2FN
3O
3S (M) 421.0431.Ultimate analysis theoretical value C
16H
18Cl
2FN
3O
3S, C, 45.51; H, 4.30; N, 9.95.Measured value: C, 45.47; H, 4.24; H, 9.88.
Embodiment 21:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-α-(methoxycarbonyl) thioacetamide (23)
With stir,
39(0.955g, 3.2mmol) and triethylamine (650mL, methylene dichloride 4.5mmol) (50mL) solution, under nitrogen atmosphere, (475mL, methylene dichloride 4.3mmol) (10mL) solution is handled, and at room temperature keeps 3 days to drip methyl malonyl chloride in 15-20 minute.Water and rare NaCl washing then, dry and concentrated.This resistates is carried out flash chromatography on silica gel,,, obtain 22:mp 150-151 ℃ of 0.873g product acetone-hexane crystallization with 15-30% acetone-methylene dichloride wash-out;
1H NMR (300MHz, CDCl
3) d 3.03 (m, 4H), 3.34 (s, 2H), 3.67 (s, 3H), 3.69 (m, 2H), 3.76 (d, d, 1H), 3.85 (m, 4H), 4.00 (t, 1H), 4.78 (m, 1H), 6.90 (t, 1H), 7.06 (d, d, 1H), 7.41 (d, d, 1H), 7.57 (t, 1H); MS (ES) m/z 396 (M+H
+), 418 (M+Na
+); HRMS (FAB) theoretical value C
18H
23FN
3O
6(M+H
+) 396.1571, measured value 396.1579.Ultimate analysis theoretical value C
18H
22FN
3O
6: C, 54.68; H, 5.61; N, 10.63.Measured value: C, 54.69; H, 5.68; N, 10.58.
With stir,
22(under nitrogen atmosphere, (0.202g 0.5mmol) handles, and at room temperature kept 4 hours 10 minutes, keeps 1.5 hours down at 80-90 ℃ to use Lawesson ' s reagent for 0.395g, 1.0mmol) De diox (10ml) solution.React with 10% methyl alcohol-chloroform give developping agent monitoring on silica gel with TLC.At this moment, product new, that polarity is very little begins to form.At room temperature kept 18 hours, and kept 2 hours down at 80 ℃; (40mg 0.099mmol) and at 80 ℃ continues heating 2 hours down to add Laewsson ' s reagent again; Still keep some initiators.This mixture is concentrated and this resistates is composed in the enterprising circumstances in which people get things ready for a trip of silica gel,, obtain 0.348g's with 15% acetone-methylene dichloride wash-out
23:
1H NMR (300MHz, CDCl
3) d 3.05 (m, 4H), 3.71 (s, 3H), 3.81 (d, d, 1H), 3.86 (m, 4H), 3.88 (s, 2H), 4.07 (t, 1H), 4.19 (m, 2H), 4.99 (m, 1H), 6.91 (t, 1H), 7.07 (d, d, 1H), 7.42 (d, d, 1H), 9.52 (s, 1H); IR (drift) 3269,1743cm
-1MS (EI) m/z 411 (M
+).Ultimate analysis theoretical value C
18H
22FN
3O
5S:C, 52.54; H, 5.39; N, 10.21.Measured value: C, 52.58; H, 5.43; N, 10.14.
Embodiment 22:(S)-and N-[[3-[4-[1-[1,2,4] triazolyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide (25)
With stir,
24(0.150g, 0.470mmol) with the mixture of diox (12.5mL), under nitrogen atmosphere, (0.20g 0.50mmol) handles, and refluxes 1.5 hours, keeps 18 hours also vacuum concentration under the room temperature to use Lawesson ' s reagent.This resistates is carried out flash chromatography on silica gel,, obtain product, it is obtained 25:mp 161-163 ℃ of 0.100g (63.4%) with methanol crystallization with 5% methyl alcohol-chloroform wash-out;
1H NMR[300MHz, (CD
3)
2SO] d 2.43 (s, 3H), 3.87 (m, 3H), 4.22 (t, 1H), 4.99 (m, 1H), 7.51 (d, 1H), 7.77 (m, 2H), 8.26 (s, 1H), 8.97 (d, 1H), 10.35 (wide s, 1H); IR (mulling) 3259,3226,3044,1752cm
-1MS (ES) m/z 336 (M+H
+), 358 (M+Na
+).Ultimate analysis theoretical value C
14H
14FN
5O
2S:C, 50.14; H, 4.21; N, 20.88.Measured value: C, 50.18; H, 4.26; N, 20.94.
Embodiment 23:(S)-and N-[[3-[4-[1-[1,2,4] triazolyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide (25)
With stir,
26(0.26g, 0.938mmol), ethyl dithiocarbamate (0.12g, 0.998mmol), Sodium Fluoride (0.040g, 0.953mmol) and the mixture of straight alcohol (10mL), under nitrogen atmosphere, in 5 minutes, handle and at room temperature kept 2 hours with the ethanolic soln of 0.97M KOH (1.03mL).Use methylene dichloride (75mL) dilution then, water, 1M KHSO
4, water and salt water washing and evaporation.This resistates is carried out flash chromatography on silica gel,, and product is obtained 0.118g with methanol crystallization with 5% methyl alcohol-chloroform wash-out, mp 164-165 ℃ of (decomposition) and 0.026g, mp 162-163 ℃ (decomposition) 25.
Embodiment 24:(S)-N-[[3-[l-(hydroxyacetyl)-5-indolinyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide (28)
With that stir, ice-cold
52(8.80g, methylene dichloride 0.0240mol) (25ml) solution used methylene dichloride (10mL) solution-treated of trifluoroacetic acid (25mL) in 20 minutes.This mixture is remained on 2 hours 15 minutes and concentrating under reduced pressure in the ice bath.The solution of this resistates in methylene dichloride is washed with saturated sodium bicarbonate and rare NaCl, and dry (sodium sulfate) also concentrates.With the not purified the next step that is directly used in of this resistates.The sample of this material (
53) have:
1H NMR (300MHz, CDCl
3) d 3.00 (t, 2H), 3.54 (t, 2H), 3.85 (wide s, 1H), 5.17 (s, 2H), 6.59 (d, 1H), 6.66 (wide s, 1H), 6.91 (d, 1H), 7.23 (s, 1H), 7.36 (m, 5H); MS m/z 269 (M+H
+).
With ice-cold, stir
53The mixture of (going up the crude product of step reaction), acetone (200mL), saturated sodium bicarbonate (200mL) and water (30mL), in 20 minutes, (4.70mL, acetone 0.030mmol) (55mL) solution is handled, and slowly is warming up to room temperature and keeps 18 hours to drip the benzyloxy Acetyl Chloride 98Min..Drip the benzyloxy Acetyl Chloride 98Min. (1.0mL) that is present in the 35mL acetone again, and will keep again 3 hours under this mixture room temperature, and dilute with ethyl acetate and water.Filter and collect this solid and the dry crude product that obtains 4.00g.With this ethyl acetate solution drying (sodium sulfate) and concentrate and to obtain 6.35g's altogether
54 14, mp 157-159.5 ℃.This analyzing samples has: mp158-159.5 ℃;
1H NMR (300MHz, CDCl
3) δ 3.16 (t, 2H), 4.01 (t, 2H), 4.21 (s, 2H), 4.69 (s, 2H), 5.19 (s, 2H), 6.67 (s, 1H), 6.97 (d, 1H), 7.36 (m, 10H), 7.50 (wide s, 1H), 8.15 (d, 1H); MS (EI) m/z (relative intensity) 416 (M
+, 9), 310 (8), 202 (10), 133 (8), 92 (8), 91 (99), 79 (7), 77 (9), 61 (12), 51 (6); IR (mulling) 2381,1722,1659,1608,1558cm
-1Ultimate analysis theoretical value C
25H
24N
2O
4: C, 72.10; H, 5.81; N, 6.73.Measured value: C, 72.05; H, 5.86; N, 6.68.
Under nitrogen atmosphere, with stir,
54(1.16g, 2.78mmol) suspension at THF (42ml) is cooled to-78 ℃, drips the n-Butyl Lithium in hexane (1.83mL) in 5 minutes.It was kept 50 minutes at-78 ℃, and (0.500g, 3.47mmol) solution of THF (2mL) is handled, and was warming up to room temperature and kept 18 hours in 3 hours to drip (R)-(-)-glyceryl butyric ester in 5 minutes.Then, with the ethyl acetate dilution, with saturated ammonium chloride, water and salt water washing, dry (MgSO
4) and concentrate.Resistates is carried out chromatogram purification with 3% methyl alcohol-0.2% ammonium hydroxide-chloroform wash-out on silica gel, obtain 55 of 0.60g (56%)
14:
1H NMR[300MHz, (CD
3)
2SO] δ 3.14 (t, 2H), 3.59 (m, 2H), 3.79 (d, d, 1H), 4.03 (m, 3H), 4.29 (s, 2H), 4.58 (s, 2H), 4.65 (m, 1H), 5.20 (t, 1H), 7.31 (m, 6H), 7.55 (s, 1H), 8.03 (d, 1H); MS (ES) m/z 383 (M+H
+), 405 (M+Na
+).
With ice-cold, stir
55(0.60g, 1.57mmol), the mixture of triethylamine (2.2mL) and methylene dichloride (12mL), under nitrogen atmosphere, (0.44g 1.99mmol) handles and remains in the ice bath 30 minutes, at room temperature keeps 60 minutes with the 3-nitrobenzene sulfonyl chloride.Dilute with methylene dichloride then, water and salt water washing, dry (sodium sulfate) also concentrates.This resistates at the enterprising circumstances in which people get things ready for a trip spectrum of silica gel purifying, is used 15%CH
3CN-methylene dichloride wash-out obtains 0.70g's
56:
1H NMR (300MHz, CDCl
3) d 3.19 (t, J=8.3Hz, 2H), 3.88 (d, d, 1H), 4.04 (t, J=8.4Hz, 2H), 4.14 (t, 1H), 4.23 (s, 2H), 4.42 (m, 2H), 4.70 (s, 2H), 4.84 (m, 1H), 6.97 (m, 1H), 7.34 (m, 5H), 7.58 (s, 1H), 7.81 (t, 1H), 8.22 (m, 2H), 8.53 (m, 1H), 8.73 (m, 1H); MS (ES) m/z 568 (M+H
+), 590 (M+Na
+).
With stir,
56(crude product that obtains by 55 of 0.00314mol), acetonitrile (70ml), the mixture of Virahol (70mL) and 29% ammonium hydroxide (70mL) was heated under 40-44 ℃ 7 hours, and at room temperature kept 18 hours.With its vacuum concentration is aqueous residue, uses dichloromethane extraction.With this extract water and salt water washing, dry (sodium sulfate) also concentrates.This resistates is carried out purifying, obtains 1.05g's with 8% methyl alcohol-0.5% ammonium hydroxide-chloroform wash-out on silica gel
57:
1H NMR[300MHz, (CD
3)
2SO] d 2.78 (m, 2H), 3.13 (t, 2H), 3.82 (d, d, 1H), 4.01 (m, 3H), 4.29 (s, 2H), 4.58 (s, 2H), 4.58 (m, 1H), 7.31 (m, 6H), 7.54 (wide s, 1H), 8.03 (d, 1H); MS (ES) m/z 382 (M+H
+), 404 (M+Na
+).
Will
57(0.46g, 1.21mmol), the hydrogenation 5 hours under 49psi of the mixture of methyl alcohol (150mL), 1M HCl (1.2mL) and 5% palladium-carbon catalyst (250mg).Add 1M HCl (0.5mL) and catalyzer (100mg) and continued hydrogenation 18 hours.Filtration catalizer, and filtrate is concentrated, obtain 0.34g's
27:
1H NMR[300MHz, (CD
3)
2SO] δ 3.15 (t, 2H), 3.22 (wide s, 2H), 3.84 (d, d, 1H), 4.00 (t, 2H), 4.15 (s, 2H), 4.15 (m, 1H), 4.92 (m, 1H), 7.24 (q, 1H), 7.50 (d, 1H), 8.03 (d, 1H), 8.37 (wide s, 3H); MS (ES) m/z 2.92 (M+H
+).
Under nitrogen atmosphere, to
27(0.10g, 0.34mmol) add in the suspension in the mixture of ethanol (15mL) and 0.97MKOH (0.7mL), stir, ethyl dithiocarbamate (0.0412g, 0.343mmol) and Sodium Fluoride (0.0137g, 0.326mmol) mixture in ethanol (5mL), and will keep 2 hours 15 minutes under this mixture room temperature.Add 0.97MKOH (0.2mL) again, sodium iodide (6mg) and ethyl dithiocarbamate (20mg) also stir this mixture 2 hours, and (150mL) mixes with methylene dichloride, water, 1M KHSO
4With the salt water washing, dry (sodium sulfate) also concentrates.With the acetone crystallization of this resistates, obtain 0.0404g's
28: mp175-176 ℃ (decomposition); MS (FAB) m/z350 (M+H
+), 349 (M
+), 331,316,205,73; HRMS (FAB) theoretical value C
16H
20N
3O
4S (M+H
+) 350.1174, measured value 350.1183;
1H NMR[300MHz, (CD
3)
2SO] d 2.42 (s, 3H), 3.14 (t, 2H), 3.79 (d, d, 1H), 3.89 (t, 2H), 4.00 (t, 2H), 4.12 (m, 3H), 4.83 (t, 1H), 4.90 (m, 1H), 7.25 (d, 1H), 7.50 (s, 1H), 8.03 (d, 1H), 10.35 (s, 1H); IR (drift) 3255,3223,3068,1747,1639,1614cm
-1
Embodiment 25:(S)-and N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide (30)
Will
58(3.00g, 7.00mmol), the hydrogenation 2 hours 50 minutes under initial pressure 58psi of the mixture of THF (60mL), straight alcohol (100ml) and 10% palladium-carbon catalyst (415mg).Leach catalyzer and, obtain 2.67g's this filtrate vacuum concentration
59, with its not purified the next step that is directly used in:
1H NMR (300MHz, CDCl
3) d 2.16 (wide s), 3.02 (m, 8H), 3.73 (d, d, J=3.9,12.6Hz, 1H), 3.96 (m, 3H), 4.72 (m, 1H), 6.92 (t, J=9.2Hz, 1H), 7.11 (m, 1H), 7.43 (d, d, J=2.6,14.3Hz, 1H); MS (ES) m/z 296 (M+H
+).
2.
With that stir, ice-cold
59(2.67g reaction product of last step), acetone (190mL) and saturated NaHCO
3Mixture (70mL) dripped the benzyloxy Acetyl Chloride 98Min. in 2-3 minute (1.34mL, acetone 8.61mmol) (25mL) solution is handled, and remains in the ice bath 1 hour and dilutes with ethyl acetate.Use the ethyl acetate extraction water layer, and wash the organic solution of this merging with rare NaCl, dry and concentrate.This resistates is carried out chromatogram purification, obtains 2.64g's with 30% acetone-methylene dichloride wash-out on silica gel
60:
1H NMR (300MHz, CDCl
3) d 2.28 (wide s, 1H), 3.00 (m, 4H), 3.66 (m, 2H), 3.77 (m, 3H), 3.96 (m, 3H), 4.22 (s, 2H), 4.61 (s, 2H), 4.74 (m, 1H), 6.88 (t, J=9.2Hz, 1H), 7.12 (m, 1H), 7.35 (s, 5H), 7.46 (d, d, J=2.6,14.2Hz, 1H); IR (mulling) 3406,1748,1647cm
-1HRMS (EI) theoretical value C
23H
26FN
3O
5(M
+) 443.1856, measured value 443.1842.
With that stir, ice-cold
60(2.64g, 6.00mmol) and triethylamine (under nitrogen atmosphere, (1.78g 8.04mmol) handles, and heats to room temperature and keeps 5 hours 20 minutes with the 3-nitrobenzene sulfonyl chloride for 1.14mL, the 8.16mmol) mixture in methylene dichloride (200ml).Add 3-nitrobenzene sulfonyl chloride (180mg) and triethylamine (0.20mL) again and will be under this mixture room temperature keep 18 hours, with methylene dichloride dilution and water and rare NaCl washing, dry (sodium sulfate) also concentrates.This resistates is carried out chromatogram purification, obtains 3.36g's with 40-60% acetone-hexane wash-out on silica gel
77:
1H NMR (300MHz, CDCl
3) d 3.02 (wide s, 4H), 3.66 (wide s, 2H), 3.78 (wide s, 2H), 3.87 (d, d, J=5.9,9.1Hz, 1H), 4.09 (t, J=9.2Hz, 1H), 4.22 (s, 2H), 4.41 (m, 2H), 4.61 (s, 2H), 4.84 (m, 1H), 6.88 (t, J=9.1Hz, 1H), 7.02 (m, 1H), 7.35 (m, 6H), 7.82 (t, J=8.0Hz, 1H), 8.23 (m, 1H), 8.53 (m, 1H), 8.73 (m, 1H); MS (ES) m/z 629 (M+H
+).
With 77 (3.36g, 5.34mmol) solution in acetonitrile (90mL), Virahol (90mL) and dense ammonium hydroxide (90mL) mixture, heated 18 hours at 40-45 ℃, use ammonium hydroxide (30mL) to handle again, heated 8 hours at 40-45 ℃, use again ammonium hydroxide (25mL) handle and 45 ℃ heated 18 hours.Then, mix with water and use dichloromethane extraction.This extract is washed with rare NaCl, and dry (sodium sulfate) also concentrates.This resistates is carried out chromatogram purification, obtains 2.44g's with 5% methyl alcohol-0.5% ammonium hydroxide-chloroform wash-out on silica gel
61:
1H NMR (300MHz, CDCl
3) d 1.50 (wide s), 3.04 (m, 6H), 3.65 (wide s, 2H), 3.81 (m, 3H), 3.99 (t, 1H), 4.21 (s, 2H), 4.61 (s, 2H), 4.66 (m, 1H), 6.88 (t, 1H), 7.12 (m, 1H), 7.33 (m, 5H), 7.47 (d, d, 1H); MS (ES) m/z 443 (M+H
+).
Will
61(1.45g, 3.3mmol) and the solution of 1.0 N HCl (3.65mL) in 95% ethanol (150mL), with 5% palladium-carbon catalyst (500mg) processing and hydrogenation 20 hours 15 minutes under initial pressure 54psi.Add 1.0 N HCl (0.5mL) and catalyzer (100mg) again and under initial pressure 60psi, continue hydrogenation 20 hours 30 minutes.Monitor this reaction to complete with TLC; With dense ammonium hydroxide neutralization, filter and vacuum concentration, obtain 1.18g's
29:
1H NMR[300MHz, (CD
3)
2SO] d 2.94 (wide s, 4H), 3.19 (m, 2H), 3.48 (wide s, 2H), 3.60 (wide s, 2H), 3.84 (m, 1H), 4.14 (m, 3H), 4.66 (wide s, 1H), 4.93 (m, 1H), 7.07 (t, 1H), 7.16 (d, d, 1H), 7.48 (d, d, 1H), 8.04 (wide s); IR (mulling) 3420,3099,3040,3008,1755,1641cm
-1MS (ES) m/z 353 (M+H
+).Ultimate analysis theoretical value C
16H
22ClFN
4O
4: C, 49.42; H, 5.70; Cl, 9.12; N, 14.41.Measured value: C, 48.16; H, 5.82; Cl, 10.00; N, 14.28.
With stir, ethyl dithiocarbamate (180mL, 1.56mmol), Sodium Fluoride (72mg, 1.7mmol), 29 (500mg, 1.29mmol) and the mixture of ethanol (70mL), under nitrogen atmosphere, with 0.97M KOH (1.46mL, 1.42mmol) handle and will keep 3 hours 35 minutes under the gained solution room temperature, with the chloroform dilution, water and rare NaCl washing, dry (sodium sulfate) also concentrates.This resistates is carried out chromatogram purification with 5% methyl alcohol-0.5% ammonium hydroxide-chloroform wash-out on silica gel, and, obtain 0.238mg (44.9%) products therefrom straight alcohol crystallization
30: mp163-165 ℃;
1H NMR (300MHz, CDCl
3) d 2.60 (s, 3H), 3.06 (m, 4H), 3.45 (m, 2H), 3.61 (m, 1H), 3.82 (m, 3H), 4.07 (m, 2H), 4.25 (m, 3H), 4.97 (m, 1H), 6.91 (t, 1H), 7.07 (m, 1H), 7.45 (d, d, 1H), 7.91 (wide s, 1H); MS (FAB) m/z (relative intensity) 411 (M+H
+, 100), 410 (M
+, 66.5), 266 (3.1); IR 3292,1733,1653cm
-1Ultimate analysis theoretical value C
18H
23FN
4O
4S:C, 52.67; H, 5.65; N, 13.65.Measured value: C, 52.76; H, 5.58; N, 13.64.
Embodiment 26:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide (32)
With ice-cold, stir
31(0.38g, 0.0012mol) and triethylamine (under nitrogen atmosphere, (0.16mL 0.0014mol) handles, and keeps 24.5 hours under the room temperature then, and vacuum concentration with ethyl dithiocarbamate for 0.38mL, the 0.0027mol) mixture in THF (12mL).With the saturated NaHCO of the solution of this resistates in methylene dichloride
3, water and salt water washing, dry (MgSO
4) and concentrate.Resistates is obtained 0.355g's with the crystallization of EtOAc-hexane
32: mp155-156 ℃; MS (ES) m/z 370 (M+H
+), 392 (M+Na
+); IR (drift) 3206,3042,1759,1738cm7 ＇;
1H NMR (300MHz, CDCl
3) d 2.60 (s, 3H), 2.95 (s, 4H), 3.43 (m, 4H), 3.82 (d, d, 1H), 4.08 (m, 2H), 4.27 (m, 1H), 4.98 (m, 1H), 7.06 (m, 1H), 7.33 (wide s, 1H), 7.51 (d, 1H), 8.03 (wide s, 1H).Ultimate analysis theoretical value C
16H
20FN
3O
2S
2: C, 52.01; H, 5.46; N, 11.37.Measured value: C, 51.86; H, 5.43; N, 11.20.
Embodiment 27:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide, thiomorpholine S-oxide compound (34)
With ice-cold, the sodium metaperiodate that stirs (1.08g, 5.05mmol) and the mixture of water (12mL), under nitrogen atmosphere, usefulness
62(1.5g, 4.8mmol) and methyl alcohol (17mL) handle, and kept 18 hours down at 6 ℃, kept 3 hours down at 4 ℃.Then, use sodium metaperiodate (0.1g) to handle again, keep 2 hour down, and use chloroform extraction at 4 ℃.With extract drying (MgSO
4) and concentrate and to obtain 1.4g's
63:
1H NMR[300MHz, (CD
3)
2SO] d 2.84 (m, 2H), 3.01 (m, 2H), 3.16 (m, 2H), 3.50 (m, 3H), 3.65 (m, 1H), 3.77 (d, d, 1H), 4.03 (t, 1H), 4.66 (m, 1H), 5.18 (t, 1H), 7.16 (m, 2H), 7.52 (m, 1H); MS (ES) m/z 329 (M+H
+), 351 (M+Na
+).
2.
With ice-cold, stir
63(1.27g, 3.87mmol) and triethylamine (0.732 ML, 5.25mmol) at methylene dichloride (130mL), in mixture, under nitrogen atmosphere, with m-nitrobenzene sulfonyl chloride (1.15g, 5.19mmol) handle and room temperature under kept about 24 hours.With methylene dichloride dilution, water and salt water washing, dry (sodium sulfate) and concentrated obtaining
78, with its not purified the next step that is directly used in.
With stir, on go on foot the mixture of reaction product (78), acetonitrile (70mL) and Virahol (70mL), with dense ammonium hydroxide (70ml, 29.9% NH
3) handle, and kept 2 hours down at 40 ℃, at room temperature kept 18 hours, kept 4 hours at 40-45 ℃; It is concentrated into about 50mL, dilute with water, and use dichloromethane extraction.With this extract water and salt water washing, dry (MgSO
4) and concentrate.This resistates is carried out chromatogram purification, obtains 0.58g's with 5% methyl alcohol-trichloromethane wash-out on silica gel
33: MS (ES) m/z 328 (M+H
+), 350 (M+Na
+);
1H NMR[300MHz, (CD
3)
2SO] d 2.81 (m, 4H), 3.01 (m, 2H), 3.16 (m, 2H), 3.30 (wide s), 3.49 (m, 2H), 3.80 (d, d, 1H), 4.01 (t, 1H), 4.58 (m, 1H), 7.19 (m, 2H), 7.51 (m, 1H).
With stir, 33 (3.7g, 0.011mol) and triethylamine (3.5mL, 0.025mol) suspension in THF (120mL) cools off in ice bath, under nitrogen atmosphere, in 2 minutes, drip ethyl dithiocarbamate (1.47mL, 0.0128mol) solution in THF (2mL) handles, and kept 22 hours under the room temperature.With the gained solution concentration, and, obtain 3.61g's with the acetonitrile crystallization of this resistates
34: mp 176-177 ℃;
1H NMR[300MHz, (CD
3)
2SO] d2.42 (s, 3H), 2.85 (m, 2H), 3.01 (m, 2H), 3.18 (m, 3H), 3.50 (m, 2H), 3.78 (d, d, 1H), 3.89 (wide s, 2H), 4.12 (t, 1H), 4.92 (m, 1H), 7.18 (m, 2H), 7.49 (m, 1H), 10.33 (s, 1H); 1R (drift) 3186,3102,1741cm
-1MS (ES) m/z 386 (M+H
+), 408 (M+Na
+).Ultimate analysis theoretical value C
16H
20FN
3O
3S
20.5 H
2O:C, 48.71; H, 5.37; N, 10.65; S, 16.26; H
2O, 2.38.Measured value: C, 48.75; H, 5.17; N, 10.72; S, 16.07; H
2O, 1.72.
Embodiment 28:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide, thiomorpholine S, S-dioxide (36)
With stir,
62(0.399g, 0.00128mol) mixture in 25% water/acetone (12mL) under nitrogen atmosphere, is used N-methylmorpholine, the N-oxide compound (0.45g, 0.00384mol) and the solution-treated of perosmic anhydride in the trimethyl carbinol of the 2.5wt% of 0.1mL.With keeping 18 hours under its room temperature, with saturated NaHSO
3(50mL) mix, and use dichloromethane extraction.With the saturated NaHSO of this extract
3With the salt water washing, dry (sodium sulfate) also concentrates.This resistates is mixed with 3.5% methyl alcohol-methylene dichloride and filter; This solid is dissolved in 15% methyl alcohol-methylene dichloride and concentrates obtain 0.29g's
64This filtrate in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, is obtained another batch with 3.5% methyl alcohol-methylene dichloride wash-out
64: MS (ES) m/z 345 (M+H
+), 367 (M+Na
+);
1H NMR[300MHz, (CD
3)
2SO] d 3.26 (m, 4H), 3.44 (m, 4H), 3.60 (m, 2H), 3.80 (d, d, 1H), 4.05 (t, 1H), 4.69 (m, 1H), 7.22 (m, 2H), 7.54 (d, 1H).
With stir,
64(0.39g, 0.00113mol) and triethylamine (0.214mL, the 0.00154mol) mixture in methylene dichloride (37mL) cooling is under nitrogen atmosphere, in ice bath, in 5 minutes, with 3-nitrobenzene sulfonyl chloride (0.335g, 0.00151mol) batch treatment.This mixture was remained in the ice bath 20 minutes, and at room temperature kept 18 hours and vacuum concentration.With stir, the solution of this resistates in 2-propyl alcohol (25mL) and acetonitrile (25mL), under nitrogen atmosphere, with 30% ammonium hydroxide (25mL) processing, heat under 50-55 ℃ also at room temperature kept 48 hours in 6 hours.It is concentrated remove organic solvent, dilute with water is also used dichloromethane extraction.With this extract water and salt water washing, dry (MgSO
4) and concentrate.This resistates is carried out flash chromatography on silica gel,, obtain 0.29g's with 6% methyl alcohol-0.4% ammonium hydroxide-chloroform wash-out
35:
1HNMR[300MHz, (CD
3)
2SO] d 1.59 (wide s, 2H), 2.78 (m, 2H), 3.24 (m, 4H), 3.43 (m, 4H), 3.81 (d, d, 1H), 4.01 (t, 1H), 4.57 (m, 1H), 7.18 (m, 2H), 7.52 (m, 1H); MS (ES) m/z 344 (M+H
+), 366 (M+Na
+).
With that stir, ice-cold
35(0.28g is 0.85mmol) at Et
3(0.26mL 1.9mmmol) and the suspension in THF (10mL) mixture, handled and remains in the ice bath 20 minutes with ethyl dithiocarbamate (0.11mL, about 6) N, kept at room temperature then; This reaction is monitored with TLC.After 20 hours, or suspension, and only have partial reaction; Add THF (10mL) and ethyl dithiocarbamate (3) again.After 48 hours, this reaction is incomplete yet; This suspension is handled with methylene dichloride (10mL) and was kept 72 hours.At this moment, almost completely be that solution also almost completely changes products therefrom into.Add several ethyl dithiocarbamates again, and this mixture was at room temperature kept 5 days vacuum concentration.This resistates is mixed with ethyl acetate, use saturated NaHCO
3, water and salt water washing, dry (MgSO
4) and concentrate.This resistates is obtained 0.209g's with methyl alcohol-EtOAc crystallization
36: mp 197-198 ℃;
1H NMR[300MHz, (CD
3)
2SO] d 2.42 (s, 3H), 3.24 (m, 4H), 3.43 (m, 4H), 3.78 (d, d, 1H), 3.88 (m, 2H), 4.12 (t, 1H), 4.92 (m, 1H), 7.18 (m, 2H), 7.50 (m, 1H), 10.37 (wide s, 1H); IR (mulling) 3300,3267,1743cm
-1MS (ES) m/z 424 (M+Na
+).Ultimate analysis theoretical value C
16H
20FN
3O
4S
2: C, 47.87; H, 5.02; N, 10.47.Measured value: C, 47.84; H, 5.23; N, 10.28.
Embodiment 29:(S)-and N-[[3-[3,5-two fluoro-4-[4-(hydroxyacetyl)-1-piperazinyls] phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide (38)
With stir,
65(1.8g, 0.00396mol), the mixture of pyridine (30mL) and straight alcohol (3mL), under nitrogen atmosphere, (1.44g 0.0207mol) handles, and extremely refluxes at 2 hours internal heating with hydroxylamine hydrochloride, refluxed 3.5 hours, and kept under the room temperature 18 hours and refluxed 4 hours.With its vacuum concentration, and this resistates mixed with water, adjust pH to 11 with saturated sodium bicarbonate, and use extracted with diethyl ether.With the salt water washing of this extract, dry (sodium sulfate) also concentrates.This resistates carried out chromatogram purification with 5% methyl alcohol-0.35% ammonium hydroxide-chloroform wash-out on silica gel, obtain the recovery of 0.75g
65With 0.72g's
66:
1H NMR[300MHz, (CD
3)
2SO] d1.40 (s, 9H), 1.72 (wide s, 2H), 2.78 (m, 2H), 2.97 (m, 4H), 3.40 (m, 4H), 3.80 (d, d, 1H), 4.00 (t, 1H), 4.59 (m, 1H), 7.27 (d, 2H); MS (ES) m/z 413 (M+H
+), 435 (M+Na
+).
2.
With 66 (0.75g ice-cold, that stir, 0.0018mol) and triethylamine (0.315mL, 350.00225mol) mixture in THF (12mL), under nitrogen atmosphere, drip benzyl chloride manthanoate (0.29mL, 0.0020mol) handle, remained in the ice bath 15 minutes, and at room temperature kept 2 hours and vacuum concentration.This resistates mixed with methylene dichloride and with saturated sodium bicarbonate, water and salt water washing, dry (sodium sulfate) also concentrates.This resistates mixed and filter with ether obtain 0.939g's
67: mp 116-118 ℃;
1H NMR (300MHz, CDCl
3) d 1.48 (s, 9H), 3.08 (m, 4H), 3.53 (m, 5 4H), 3.60 (m, 2H), 3.73 (m, 1H), 3.96 (t, 1H), 4.76 (m, 1H), 5.10 (s, 2H), 5.21 (m, 1H), 7.07 (d, 2H), 7.31 (s, 5H); MS (ES) m/z 547 (M+H
+), 569 (M+Na
+).
In 5 minutes, under nitrogen atmosphere, stir down, compound
67(0.805g 0.00147mol) joins in the ice-cold trifluoroacetic acid (9mL) in batches.Gained solution was remained in the ice bath 1 hour, under nitrogen gas stream, concentrate then.This resistates and ice and saturated sodium bicarbonate are mixed, and use dichloromethane extraction; With this extract water and salt water washing, dry (sodium sulfate) also concentrates the product that obtains 0.63g.The water layer that merges is extracted with ethyl acetate again; With this extract water and salt water washing, dry (sodium sulfate) and concentrated another batch product that obtains.Merge into 0.68g's
68, it is directly used in the next step without being further purified.
With ice-cold, stir
68(0.68g, 0.00152mol), saturated NaHCO
3(15.2mL) and the compound of acetone (40mL), under nitrogen atmosphere, (0.29mL, acetone 0.0019mol) (5mL) solution is handled, and keeps 6 hours under the room temperature, with ethyl acetate dilution and water and salt water washing to drip the benzyloxy Acetyl Chloride 98Min. in 15 minutes.With this extract drying (MgSO
4) and vacuum concentration obtain 0.72g's
69: MS (ES) m/z 395 (M+H
+), 617 (M+Na
+);
1H NMR (300MHz, CDCl
3) d 3.12 (m, 4H), 3.59 (m, 4H), 3.74 (m, 3H), 3.96 (t, 1H), 4.22 (s, 2H), 4.62 (s, 2H), 4.75 (wide s, 1H), 5.10 (s, 2H), 5.22 (m, 1H), 7.08 (d, 2H), 7.33 (m, 10H).
Will
69(0.72g, 0.0012mol), the hydrogenation 4 hours under initial pressure 45psi of the mixture of methyl alcohol and 5% palladium-carbon catalyst (0.4g).Two kinds of products have been reduced and have formed by TLC (8% methyl alcohol-0.5% ammonium hydroxide-chloroform) monitoring initiator.Add 1M hydrochloric acid (1.34mL) and continue hydrogenation 21 hours with initial pressure 40psi.By two kinds of bigger products of the TLC only remaining polarity of monitoring.Leach catalyzer, and this filtrate concentrating obtained 0.40g's
37: MS (ES) m/z 371 (M+H
+), 393 (M+Na
+);
1H NMR[300MHz, (CD
3)
2SO] d 3.02 (s, 4H), 3.20 (m, 2H), 3.43 (s, 2H), 3.56 (s, 2H), 3.84 (m, 1H), 3.84 (wide s), 4.10 (s, 2H), 4.14 (t, 1H), 4.96 (m, 1H), 7.26 (d, 2H), 8.41 (wide s, 3H).
With stir,
37(0.38g) at Et
3Suspension in N (0.31mL) and THF (10mL) solution under nitrogen atmosphere, is handled with ethyl dithiocarbamate (0.13mL, about 7), and was at room temperature kept 7 days; Monitor this reaction by TLC (8% methyl alcohol, 0.5% ammonium hydroxide-chloroform).Add ethyl dithiocarbamate (2) after 24 hours again; After 30 hours, add methylene dichloride (10mL) and ethyl dithiocarbamate (3); After 48 hours, add triethylamine (0.3mL) again.Mix with ice and saturated sodium bicarbonate with this mixture vacuum concentration and with this resistates, and use dichloromethane extraction.With this extract water and salt water washing, dry (MgSO
4) and concentrate.This resistates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with 2.5% methyl alcohol-methylene dichloride wash-out, and with this product methanol crystallization, is obtained 0.182g's
38: mp 110-111 ℃ (decomposition); MS (ES) m/z 429 (M+H
+), 451 (M+Na
+); HRMS (FAB) theoretical value C
18H
23F
2N
4O
4S (M+H
+) 429.1408, measured value 429.1415; IR (drift) 1760,1652,1639cm
-1[α]
24 D8 ° (methyl alcohol).
Embodiment 30:(S)-and N-[[3-[4-[1-[1,2,4] triazolyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide (44)
Under nitrogen atmosphere, will in 20 minutes
26(0.190g, methylene dichloride 0.685mmol) (20mL) drips of solution adds to 1,1 ＇-thiocarbonyl two-2 (1H)-pyridone ice-cold, that stir, and (0.193g is in methylene dichloride 0.831mmol) (7mL) solution.This mixture was remained in the ice bath 20 minutes and at room temperature kept 2 hours, with methylene dichloride dilution, water and salt water washing, dry (MgSO
4) and concentrate.This resistates is used 10-15%CH on silica gel
3The CN-methylene dichloride carries out chromatogram purification, obtains 0.11g's
79, it is directly used in the next step without being further purified: MS (ES) m/z 320 (M+H
+), 342 (M+Na
+).
With that stir, ice-cold
79(0.10g, THF 0.31mmol) (15mL) solution handled and remain on excessive anhydrous ammonia gas in the ice bath 90 minutes.Under nitrogen gas stream, be evaporated to the about 5mL of volume then, obtain solid, it is filtered collect and wash, obtain 0.105g's with cold THF
44: mp 214-215 ℃;
1H NMR[300MHz, (CD
3)
2SO] d 3.82 (m, 3H), 4.18 (t, 1H), 4.89 (wide s, 1H), 7.20 (wide s, 2H), 7.50 (d, 1H), 7.79 (m, 2H), 7.93 (t, 1H), 8.26 (s, 1H), 8.97 (s, 1H); MS (ES) m/z 337 (M+H
+), 359 (M+Na
+).Ultimate analysis theoretical value C
13H
13FN
6O
2S:C, 46.42; H, 3.90; N, 24.99.Measured value: C, 46.22; H, 3.98; N, 24.55.
Embodiment 31:(S)-and N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl]-methyl] thiocarbamide (45)
With ice-cold, stir 1,1 ＇-thiocarbonyl-2 (1H)-two pyridone (0.123g, 0.530mmol) methylene dichloride (5ml) solution, under nitrogen atmosphere, with 29 (0.17g, 0.4mmol) handle at the suspension of methylene dichloride (20mL), use triethylamine (0.111mL, methylene dichloride 0.8mmol) (10mL) solution-treated 10 minutes then.Hold it in the ice bath 30 minutes, kept 2 hours and ℃ kept 18 hours down in temperature＜0 in room temperature.Then, it is diluted water and salt water washing, dry (MgSO with methylene dichloride
4) and concentrate.With this resistates (
80) the not purified the next step that is directly used in.Will
80A duplicate samples on silica gel, carry out the flash chromatography purifying, with 10-20% acetonitrile-methylene dichloride wash-out:
1H NMR (300MHz, CDCl
3) d 1.60 (wide s), 3.07 (m, 4H), 3.45 (m, 2H), 3.85 (m, 4H), 3.97 (d, d, 1H), 4.16 (t, 1H), 4.21 (s, 2H), 4.82 (m, 1H), 6.95 (t, 1H), 7.13 (d, d, 1H), 7.47 (d, d, 1H); MS m/z 395 (M+H
+); 417 (M+Na
+).
2.
Excessive anhydrous ammonia gas is fed that stir, ice-cold
80In THF (25mL) solution of (go up step reaction crude product), and this mixture remained in the ice bath 90 minutes, under nitrogen gas stream, concentrate.This resistates in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, with 5% methyl alcohol-0.4% ammonium hydroxide-chloroform wash-out, and is obtained 0.0544g's with this product with the acetonitrile crystallization
45: mp 209-210 ℃;
1HNMR[300MHz, (CD
3)
2SO] d 294 (wide s, 4H), 3.47 (wide s, 2H), 3.60 (wide s, 2H), 3.78 (wide s, 3H), 4.07 (t, 1H), 4.10 (d, J=5.5Hz, 2H), 4.63 (t, J=5.5Hz, 1H), 4.81 (wide s, 1H), 7.05 (t, 1H), 7.16 (d, d, 1H), 7.15 (wide s, 2H), 7.49 (d, d, 1H), 7.91 (t, 1H); IR (mulling) 3443,3403,3321,3202,3081,1753,1655,1648cm
-1HRMS (FAB) theoretical value C
17H
23FN
5O
4S (M+H
+) 412.1454, measured value 412.1447.Ultimate analysis theoretical value: C
17H
22FN
5O
4S:C, 49.63; H, 5.39; N, 17.02.Measured value: C, 49.63; H, 5.48; N, 16.99.
Embodiment 32:(S)-N-[[3-[l-(hydroxyacetyl)-5-indolinyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide (46)
With ice-cold, stir 1,1 '-thiocarbonyl two-2 (1H)-pyridone (0.096g, methylene dichloride 0.41mmol) (5mL) solution is with 27 (0.10g, 0.34mmol) methylene dichloride (15ml) suspension handle, use the triethylamine of 0.05mL (0.36mmol) to handle then.Hold it in the ice bath 30 minutes, and keeping 2 hours, with methylene dichloride dilution, water and salt water washing, dry (MgSO in room temperature
4) and concentrate.This resistates is used 20-40%CH on silica gel
3CN-methylene dichloride wash-out carries out chromatogram purification, obtains 81 of 0.04g.
Feed excessive anhydrous ammonia gas ice-cold
81In THF (0.04g) (30mL) solution, and this mixture remained in the ice bath 80 minutes, and under nitrogen gas stream, concentrate.This resistates is obtained 0.0151g's with the acetonitrile crystallization
46: mp 214-215 ℃ (decomposition); MS (FAB) m/z 351 (M+H
+), 350 (M
+), 319,304,147; HRMS (FAB) theoretical value C
15H
19N
4O
4S (M+H
+) 351.1127, measured value 351.1130; IR (drift) 3329,3296,3196,1746,1655,1626cm
-1
Embodiment 33:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide, thiomorpholine S-oxide compound (47)
In 20 minutes, will
33(0.30g, methylene dichloride 0.92mmol) (7mL) suspension join 1,1 '-(0.258g is 1.11mmol) and in ice-cold, the stirred mixture of methylene dichloride (20mL) for thiocarbonyl two-2 (1H)-pyridone.This mixture was remained in the ice bath 20 minutes, and at room temperature kept 2 hours, (50mL) mixes with methylene dichloride, water and salt water washing, dry (MgSO
4) and concentrate.This product is carried out chromatogram purification, obtains 0.27g's with 20-50% acetonitrile-methylene dichloride wash-out on silica gel
82, it is directly used in the next step:
MS(ES)m/z?370(M+H
+)，392(M+Na
+)。
With that stir, ice-cold
82(0.27g, THF 0.73mrnol) (15mL) solution under nitrogen atmosphere, with excessive anhydrous ammonia gas, remained in the ice bath 1 hour, and concentrate; With this residue crystallized, obtain 0.175g's with methyl alcohol
47212213 ℃ of mp;
1H NMR[300MHz, (CD
3)
2SO] d 2.83 (m, 2H), 3.01 (m, 2H), 3.17 (m, 2H), 3.50 (t, 2H), 3.78 (wide s, 3H), 4.08 (t, 1H), 4.80 (wide s, 1H), 7.17 (m, 2H), 7.17 (wide s, 2H), 7.50 (d, 1H), 7.90 (t, 1H); MS (ES) m/z 409 (M+Na
+); IR (mulling) 3335,3284,3211,3175,3097,1750,1630cm
-1Ultimate analysis theoretical value C
15H
19FN
4O
3S
2: C, 46.62; H, 4.95; N, 14.50.Measured value: C, 46.50; H, 4.95; N, 14.40.
Embodiment 34:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl-S-methyl dithiocarbamate (48)
With ice-cold, stir
39(0.59g, 0.0020mol), ethanol (1.5mL), water (2) and triethylamine (0.613mL, mixture 0.00440mol), under nitrogen atmosphere, (0.066mL 0.0011mol) handles with dithiocarbonic anhydride, and remained in the ice bath 2 hours, at room temperature kept 18 hours.(obtain a solution after adding dithiocarbonic anhydride; Soon begin to form white precipitate after this mixture is warming up to room temperature) in 2 minutes, drip methyl iodide (0.137mL, 0.00220mol) this heavy-gravity mixture of ethanol (2mL) solution-treated, and vacuum concentration will be kept 1.5 hours under this mixture room temperature.With the saturated NaHCO of the solution of this resistates in ethyl acetate
3, water and salt water washing, dry (MgSO
4) and concentrate.This resistates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with 1.8% methyl alcohol-methylene dichloride wash-out, is obtained 0.197g's with this product with the ethyl acetate crystallization
48: mp 154-155 ℃; IR (mulling) 3354,3346,1726cm
-1Ultimate analysis theoretical value C
16H
20FN
3O
3S
2: C, 9.85; H, 5.23; N, 10.90.Measured value: C, 49.73; H, 5.25; N, 10.82.
Embodiment 35:(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl-O-methyl thiocarbamate (50)
With what stir
48(0.200g, 0.518mmol), (0.003g's sodium methylate 0.06mmol) and the mixture of methyl alcohol (5mL), under nitrogen atmosphere, refluxed 4 hours, kept 18 hours under the room temperature.Find that initiator has similar flowability with product on TLC.Therefore, monitor this reaction with MS (ES).Initiator still exists.This mixture was refluxed 3 hours, add sodium methylate (0.005g) again, and continue to reflux 2 hours.With keeping 18 hours under its room temperature, refluxed 1 hour, at room temperature keep 1.5 hours, and vacuum concentration.This resistates is mixed with ice, and usefulness 1M sal enixum and saturated sodium bicarbonate to 9-10, are used this mixture of dichloromethane extraction with pH regulator.With this extract water and salt water washing, dry (MgSO
4) and concentrate.With this resistates in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, with 5% acetone-methylene dichloride wash-out, and with the EtOAc-hexane with the product crystallization, obtain 0.107g's
50: mp 128-129 ℃; MS (ES) m/z 370 (M+H
+), 392 (M+Na
+); IR (drift) 3282,3251,1753,1735cm
-1 1H NMR[300MHz, (CD
3)
2SO] d2.94 (m, 4H), 3.47,374 (m, m, 7H), 3.86,3.91 (s, s, 3H), 4.10 (m, 1H), 4.73,4.86 (m, m, 1H), 7.05 (t, 1H), 7.16 (d, d, 1H), 7.47 (d, d, 1H), 9.41,9.50 (s, s, 1H).Ultimate analysis theoretical value C
16H
20FN
3O
4S:C, 52.02; H, 5.46; N, 11.38.Measured value: C, 51.97; H, 5.49; N, 11.35.
In the method for embodiment 35, replace sodium methylate with adequate amount of ethanol sodium, obtain down the compound of the embodiment 36 in the Table A.
In the method for embodiment 1, an amount of (S)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] the sec.-propyl methane amide, (S)-and N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ring propyl formamide or (S)-N-[[3-[3,5-two fluoro-4-morpholinyls] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide replacement (S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide (compound 11), and, obtained the embodiment 37 that provides in the Table A respectively according to total method of embodiment 1, compound in 38 and 39.This sec.-propyl methane amide and cyclopropyl carboxamide are according to the method preparation of embodiment 5 in the United States Patent (USP) 5688792, just with the diacetyl oxide in isobutyric anhydride and the cyclopropane carbonyl chloride replacement step 7.This ethanamide is according to the 4 described preparations of the embodiment in the United States Patent (USP) 5688792.
In the method for embodiment 5 step B, the excessive dimethyl amine that is present among the THF replaces anhydrous ammonia gas, has obtained the compound of the embodiment 40 that provides in time Table A.
Table A
Embodiment number Compound R.R ＇36 (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-R=H, R ＇=OC
2H
5
Oxo-5-oxazolidinyl] methyl]-the O-ethylenebis dithiocarbamate
Carbamate; 120 ℃ of mp, MS (ES) m/z
384(M+H
+)。The ultimate analysis theoretical value
C
17H
22FN
3O
4S：C，53.25；H，5.78；N，
10.96。Measured value: C, 53.23; H, 5.82; N,
10.92。37 (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-R=H, R '=CH (CH
3)
2
Oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-
Acid amides; Mp 152-153 ℃ (decomposition); Ultimate analysis
Theoretical value C
18H
24FN
3O
3S:C, 56.67; H,
6.34; N, 11.02. measured value: C, 56.58; H,
6.41; N, 10.8138 (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-R=H, R ＇=cyclopropyl
Oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic
Acid amides; Mp 155-156 ℃; The ultimate analysis theory
Value C
18H
22FN
3O
3S:C, 56.98; H, 5.84;
N，11.07。Measured value: C, 56.98; H, 5.85;
N, 10.9739 (S)-N-[[3-[3,5-two fluoro-4-(4-morpholinyl)-benzene R=F, R ＇=CH
3
Base]-2-oxo-5-oxazolidinyl] methyl]-sulfo-second
Acid amides 40 (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-R=H, R ＇=N (CH
3)
2
Oxo-5-oxazolidinyl] methyl]-N ＇, N '-dimethyl
Thiocarbamide preparation example Z dithio methyl propionate
With mixture that stir, magnesium chips (12.6g, 0.520 grammeatom) and THF (100mL), under nitrogen atmosphere, usefulness iodine crystallization and about 5% bromic ether (30.0mL, THF 0.40mol) (200mL) solution-treated.When the reaction beginning, add remaining bromic ether solution, drop rate is enough to keep slight backflow.Finish, continue to stir 1 hour; Gained solution is cooled to-20 ℃, and (24.0mL handled 10 minutes 0.40mol) with dithiocarbonic anhydride.This mixture is warming up to 15 ℃, and (28.0mL 0.45mol) handles and kept 1 hour down at 60 ℃ with methyl iodide.Then, it is cooled off in ice bath, handle and use extracted with diethyl ether with ice.With the salt water washing of this extract, dry (MgSO
4) and concentrate.Resistates is distilled the title product that obtains 34.0g, bp48-52 ℃ (12mmHg).
When with the ethylmagnesium bromide in the suitable alkyl magnesium bromide replacement aforesaid method, obtained following methyl dithio compound:
Table B
Rs＝
(b)??????????(CH
3)
2CH-?????(h)????
(c)?????????
??????????(i)?????
(d)??????????CH
3CH
2CH
2-???(j)????
(e)?????????
(k)????
(f)?????????
????(l)????
(g)??????????(CH
3)
3C-CH
2-??(m)????
When according to total method of embodiment 27 steps 4, an amount of following amine and the reaction of following dithio compound have obtained the compound of embodiment 41 to 61 among the table C respectively.
When according to total method of embodiment 25 steps 6, an amount of following amine and the reaction of following dithio compound have obtained the compound of embodiment 62 to 67 among the table C respectively.
Table C embodiment compound amine dithio compound
(deriving from preparation example Z) 41 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-benzene
Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl]-rosickyite generation
Acid amides, thiomorpholine S-oxide compound; Mp 196-
197 ℃; The ultimate analysis theoretical value
C
17H
22FN
3O
3S
2：C，51.11；H，5.55；
N，10.52；S，16.05。Measured value: C, 50.99;
H, 5.60; N, 10.55; S, 15.7542 S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-the 2-methyl
Rosickyite is for acid amides, thiomorpholine S-oxide compound; Mp
195-196 ℃; The ultimate analysis theoretical value
C
18H
24FN
3O
3S
2：C，52.28；H，5.85；
N，10.16；S，15.51。Measured value: C, 52.24;
H, 5.97; N, 10.16; S, 15.2843 (S)-N-[[3-[3-fluoro-4-(the same Z of 4-thiomorpholine (c)
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-
Encircle rosickyite for carboxylic acid amides, thiomorpholine S-oxidation
Thing; Mp 109-110 ℃; The ultimate analysis theoretical value
C
18H
22FN
3O
3S
2：C，52.54；H，5.39；
N，10.21；S，15.58。Measured value: C, 52.48;
H, 5.51; N, 10.28; S, 15.2944 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (d)
Base]-2-oxo-5-oxazolidinyl] methyl]-the Ding sulfo-
Acid amides, thiomorpholine S-oxide compound 45 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (e)
Base]-2-oxo-5-oxazolidinyl] methyl]-the 3-methyl
The fourth thioamides, thiomorpholine S-oxide compound 46 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (f)
Base]-2-oxo-5-oxazolidinyl] methyl]-the 2-methyl
The fourth thioamides, thiomorpholine S-oxide compound 47 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same z of benzene (g)
Base]-2-oxo-5-oxazolidinyl] methyl]-3,3-two
Methyl fourth thioamides, thiomorpholine S-oxidation
Thing 48 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (h)
Base]-2-oxo-5-oxazolidinyl] methyl]-ring fourth sulphur
For carboxylic acid amides, thiomorpholine S-oxide compound 49 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same z of benzene (i)
Base]-2-oxo-5-oxazolidinyl] methyl]-1-ring penta
Thiocarboxamide, thiomorpholine S-oxide compound 50 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same z of benzene (j)
Base]-2-oxo-5-oxazolidinyl] methyl]-hexamethylene sulphur
For carboxylic acid amides, thiomorpholine S-oxide compound 51 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (k)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-ring third
Base second thioamides, thiomorpholine S-oxide compound 52 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (l)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-encircles fourth
Base second thioamides, thiomorpholine S-oxide compound 53 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (m)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-ring penta
Base second thioamides, thiomorpholine S-oxide compound 54 (S)-N-[[3-[3,5-two fluoro-4-(4-thiomorpholines
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-
Thioacetamide, thiomorpholine S-oxide compound 55 (S)-N-[[3-[3,5-two fluoro-4-(the same Z of 4-thiomorpholine (a)
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-
Rosickyite is for acid amides, thiomorpholine S-oxide compound 56 (S)-N-[[3-[3,5-two fluoro-4-(the same Z of 4-thiomorpholine (b)
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-
2-methyl-prop thioamides, thiomorpholine S-oxygen
Change thing 57 (S)-N-[[3-[3,5-two fluoro-4-(the same Z of 4-thiomorpholine (c)
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-
Encircle rosickyite for carboxylic acid amides, thiomorpholine S-oxidation
Thing 58 (S)-N-[[3-[4-(4-thio-morpholinyl)-phenyl]-2-
Oxo-5-oxazolidinyl] methyl]-thioacetyl
Amine, thiomorpholine S-oxide compound 59 (S)-N-[[3-[4-(4-thio-morpholinyl)-phenyl]-the same Z of 2-(a)
Oxo-5-oxazolidinyl] methyl]-rosickyite is for acyl
Amine, thiomorpholine S-oxide compound 60 (S)-N-[[3-[4-(4-thio-morpholinyl)-phenyl]-the same Z of 2-(b)
Oxo-5-oxazolidinyl] methyl]-2-methyl rosickyite
For acid amides, thiomorpholine S-oxide compound 61 (S)-N-[[3-[4-(4-thio-morpholinyl)-phenyl]-the same Z of 2-(c)
Oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic
Acid amides, thiomorpholine S-oxide compound 62 (S)-N-[[3-[3,5-two fluoro-4-(4-glycoloyl
Z (a)
Base)-and the 1-piperazinyl] phenyl]-2-oxo-5-oxazolidine
Base]-methyl] rosickyite is for acid amides 63 (S)-N-[[3-[3, the same Z of 5-two fluoro-(b)
4-(4-hydroxyacetyl)-1-piperazinyl] phenyl]-2-
Oxo-5-oxazolidinyl]-methyl]-2-methyl-rosickyite
For acid amides 64 (S)-N-[[3-[3,5-two fluoro-4-(the same Z of 4-glycoloyl (c)
Base)-and the 1-piperazinyl] phenyl]-2-oxo-5-oxazolidine
Base]-methyl] encircle rosickyite for acid amides 65 (S)-N-[[3-[3-[4-(hydroxyacetyl)-1-piperazine
Z (a)
Base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]
Rosickyite is for acid amides 66 (S)-N-[[3-[3-[4-(hydroxyacetyl)-the same Z of 1-piperazine (b)
Base] phenyl] 2-oxo-5-oxazolidinyl]-methyl]-
2-methyl-rosickyite is for acid amides 67 (S)-N-[[3-[3-[4-(hydroxyacetyl)-the same Z of 1-piperazine (c)
Base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]
The ring rosickyite is for carboxylic acid amides
When according to embodiment 28, the method for step 3 with an amount of following amine and the reaction of following dithio compound, obtains showing the embodiment 68 to 78 among the D respectively.
Table D embodiment compound amine dithio compound 68 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-benzene
Base]-2-oxo-5-oxazolidinyl] methyl]-rosickyite generation
Acid amides, thiomorpholine S, S-dioxide 69 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-the 2-methyl
Rosickyite is for acid amides, thiomorpholine S, S-dioxide 70 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (c)
Base]-2-oxo-5-oxazolidinyl] methyl]-the ring rosickyite
For carboxylic acid amides, thiomorpholine S, S-dioxide 71 (S)-N-[[3-[3,5-two fluoro-4-(4-thiomorpholines
Base)-phenyl]-2-oxo-5-oxazolidinyl]-methyl]
Thioacetamide, thiomorpholine S, S-dioxide 72 (S)-N-[[3-[3,5-two fluoro-4-(the same Z of 4-thiomorpholine (a)
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-
Rosickyite is for acid amides, thiomorpholine S, S-dioxide 73 (S)-N-[[3-[3,5-two fluoro-4-(the same Z of 4-thiomorpholine (b)
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-
2-methyl-prop thioamides, thiomorpholine S, S-
Dioxide 74 (S)-N-[[3-[3,5-two fluoro-4-(the same Z of 4-thiomorpholine (c)
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-
Encircle rosickyite for carboxylic acid amides, thiomorpholine S, S-two
Oxide compound 75 (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-2-
Oxo-5-oxazolidinyl]-methyl] thioacetamide,
Thiomorpholine S, S-dioxide 76 (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-the same Z of 2-(a)
Oxo-5-oxazolidinyl]-methyl] rosickyite is for acyl
Amine, thiomorpholine S, S-dioxide 77 (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-the same Z of 2-(b)
Oxo-5-oxazolidinyl]-methyl]-2-methyl-rosickyite
For acid amides, thiomorpholine S, S-dioxide 78 (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-the same Z of 2-(c)
Oxo-5-oxazolidinyl]-methyl] encircle rosickyite for carboxylic
Acid amides, thiomorpholine S, S-dioxide
When according to embodiment 26 methods,, obtain showing the embodiment 79 to 99 among the E respectively with an amount of following amine and the reaction of following dithio compound.
Table E embodiment compound amine dithio compound
(seeing preparation example Z) 79 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-benzene
Base]-2-oxo-5-oxazolidinyl] methyl]-rosickyite generation
Acid amides 80 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-the 2-methyl
Rosickyite is for acid amides 81 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (c)
Base]-2-oxo-5-oxazolidinyl] methyl]-the ring rosickyite
For carboxylic acid amides 82 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (d)
Base]-2-oxo-5-oxazolidinyl] methyl]-the Ding sulfo-
Acid amides 83 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (e)
Base]-2-oxo-5-oxazolidinyl] methyl]-the 3-methyl
Fourth thioamides 84 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (f)
Base]-2-oxo-5-oxazolidinyl] methyl]-the 2-methyl
Fourth thioamides 85 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (g)
Base]-2-oxo-5-oxazolidinyl] methyl]-3,3-two
Methyl fourth thioamides 86 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (h)
Base]-2-oxo-5-oxazolidinyl] methyl]-ring fourth sulphur
For carboxylic acid amides 87 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (i)
Base]-2-oxo-5-oxazolidinyl] methyl]-ring penta sulphur
For carboxylic acid amides 88 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (j)
Base]-2-oxo-5-oxazolidinyl] methyl]-hexamethylene sulphur
For carboxylic acid amides 89 (S)-N-[[3-[3-5 fluoro-4-(4-thio-morpholinyl)-the same Z (k)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-the 2-ring
Propyl group second thioamides 90 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same z of benzene (l)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-encircles fourth
Base second thioamides 91 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-the same Z of benzene (m)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-ring penta
Base second thioamides 92 (S)-N-[[3-[3,5-two fluoro-4-(4-thiomorpholines
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]
Thioacetamide 93 (S)-N-[[3-[3,5-two fluoro-4-(the same Z of 4-thiomorpholine (a)
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-
Rosickyite is for acid amides 94 (S)-N-[[3-[3,5-two fluoro-4-(the same Z of 4-thiomorpholine (b)
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-
2-methyl-prop thioamides 95 (S)-N-[[3-[3,5-two fluoro-4-(the same Z of 4-thiomorpholine (c)
Base)-phenyl]-2-oxo-5-oxazolidinyl] methyl]-
The ring rosickyite is for carboxylic acid amides 96 (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-2-
Oxo-5-oxazolidinyl]-methyl] thioacetamide 97 (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-the same Z of 2-(a)
Oxo-5-oxazolidinyl]-methyl] rosickyite is for acid amides 98 (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-the same Z of 2-(b)
Oxo-5-oxazolidinyl]-methyl]-2-methyl-rosickyite
For acid amides 99 (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-the same Z of 2-(c)
Oxo-5-oxazolidinyl]-methyl] encircle rosickyite for carboxylic
Acid amides
Be used for the used amine of embodiment 41 to 53 according to embodiment 27, the described preparation of step 3.Be used for the used amine of embodiment 54 to 57 according to the method for embodiment 27 steps 1 to 3, by with suitable (S)-N-[[3-[3,5-two fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl alcohol replaces the compound 62 in embodiment 27 steps 1 to prepare.
The amine that embodiment 58 to 61 uses is according to the method for embodiment 27 steps 1 to 3, with suitable (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] compound 62 in methyl alcohol replacement embodiment 27 steps 1 prepares.Shi Dang De oxazolidinyl carbinol compound makes according to the method for United States Patent (USP) 5688792 embodiment 1 step 1 to 3, just replaces 3 in the step 1 wherein, 4-difluoro nitrobenzene with the 4-fluoronitrobenzene.
Embodiment 62 to 64 used amine are prepared by acid amides 65 according to the compound among the embodiment 29 37, and this acid amides is according to United States Patent (USP) 5700799 embodiment 32 described preparations.The used amine of embodiment 65 to 67 is prepared by acid amides by total method of embodiment 29, and this acid amides is according to United States Patent (USP) 5700799 embodiment 3 described preparations:
The used amine of embodiment 68 to 70 is according to the described preparation of the foregoing description 28 steps 2.
The used amine of embodiment 71 to 74 are according to embodiment 28 preparations, with (S)-N-[[3-[3,5-two fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl alcohol replaces the compound 62 in the step 1, and then carries out the method for step 1 and 2.Suitable De oxazolidinyl carbinol compound is according to the total method preparation to 4 of embodiment 4 steps 1 of United States Patent (USP) 5688792, just replaces morpholine in its step 1 with thiomorpholine.
Amine used among the embodiment 75 to 78 is according to the described preparation of the foregoing description 28 steps 1, with (S)-N-[3-[4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl alcohol replaces the compound 62 in the step 1.Suitable De oxazolidinyl methyl alcohol is according to United States Patent (USP) 5,688, and the total method preparation of step 1 to 3 among 792 embodiment 1 just replaces 3 of step 1 wherein, 4-difluoro nitrobenzene with the 4-fluoronitrobenzene.
Amine used among the embodiment 79 to 91 is according to United States Patent (USP) 5,688, the described preparation of 792 embodiment, 1 step 4.The used amine of embodiment 92 to 95 is according to United States Patent (USP) 5,688, and 792 embodiment, 4 described preparations just replace morpholine in its step 1 with thiomorpholine.The used amine of embodiment 96 to 99 is according to United States Patent (USP) 5,688, and the preparation of the method for 792 embodiment 1 just replaces 3 of its step 1 with 4-fluorine nitro-benzene, the 4-difluoro nitrobenzene.
Embodiment 100 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methyl thiocarbamate, thiomorpholine S-oxide compound
(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-phenyl with 201mg (0.554mmol)]-2-oxo-5-oxazolidinyl] methyl] lsothiocyanates, methyl alcohol (10mL) solution of thiomorpholine S-oxide compound (compounds 82 of embodiment 33 steps 1) refluxed under nitrogen atmosphere 18 hours and cooling.Filter the solid of collecting gained, obtain the title product of 0.138g.M.p.208-209 ℃; Ultimate analysis theoretical value C
16H
20FN
3O
4S
2: C, 47.87; H, 5.02; N, 10.47.Measured value: C, 47.81; H, 5.04:N, 10.49.
When in the method for embodiment 100, replace compound 82 with following isothiocyanic acid ester, obtain the product of the following example 101 to 109.
Table F
Lsothiocyanates
Generation-5-oxazolidinyl] methyl]-O-methyl thiocarbamate,
Thiomorpholine S-oxide compound OS H H 102 (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazole
Alkyl] methyl]-O-methyl thiocarbamate, thiomorpholine
S-oxide compound O
2S H F 103 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-phenyl]-the 2-oxo-
The 5-oxazolidinyl] methyl]-O-methyl thiocarbamate, sulfo-
Morpholine S, S-dioxide O
2S F F 104 (S)-N-[[3-[3,5-two fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxygen
Generation-5-oxazolidinyl] methyl]-O-methyl thiocarbamate,
Thiomorpholine S, S-dioxide O
2S H H 105 (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazole
Alkyl] methyl]-O-methyl thiocarbamate, thiomorpholine
S, the S-dioxide
S H F 106 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-phenyl]-the 2-oxo-
The 5-oxazolidinyl] methyl]-O-methyl thiocarbamate
S F F 107 (S)-N-[[3-[3,5-two fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxygen
Generation-5-oxazolidinyl]-methyl]-O-methyl thiocarbamate
S H H 108 (S)-N-[[3-[4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazole
Alkyl] methyl]-O-methyl thiocarbamate HOCH
2C H H 109 (S)-N-[[3-[3-fluoro-4-(4-(hydroxyacetyl)-1-piperazinyl] benzene (=O) N yl]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-amino
Manthanoate
When in the method for embodiment 100, adequate amount of ethanol and Virahol replace methyl alcohol, obtain following compounds respectively:
Embodiment 110:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-ethyl thiocarbamate, thiomorpholine S-oxide compound.M.p.198-199 ℃; Ultimate analysis theoretical value C
17H
22FN
3O
4S
2: C, 49.14; H, 5.34; N, 10.11.Measured value: C, 49.06; H, 5.27; N, 10.10.
Embodiment 111:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-isopropylthio carbamate, thiomorpholine S-oxide compound.M.p.180-181 ℃; Ultimate analysis theoretical value C
18H
24FN
3O
4S
2: C, 50.33; H, 5.63; N, 9.78.Measured value: C, 50.29; H, 5.69; N, 9.82.
In the method for embodiment 114, with an amount of (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] lsothiocyanates replaces compound 82, and replace methyl alcohol with ethanol or Virahol, obtained following product respectively:
Embodiment 112:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-ethyl thiocarbamate;
Embodiment 113:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-isopropylthio carbamate;
Embodiment 114:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-the N-methylthiourea, thiomorpholine S-oxide compound.
With stir, (embodiment 33, and the THF of step 1) (5ml) solution is under 0 ℃, with the THF of 2M methylamine (0.42mL, 0.845mmol) solution-treated, and keeping 18 hours under the room temperature for 240mg (0.650mmol) compound 82.Filter and collect the title product that this solid obtains 0.221g.
According to the method for embodiment 114, just replace methylamine with an amount of dimethyl amine and azetidine, obtain following compounds:
Embodiment 115:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-N ＇, N ＇-dimethyl thiourea, thiomorpholine S-oxide compound; Ultimate analysis theoretical value C
17H
23FN
4O
3S
2, C, 49.26; H, 5.59; N, 13.52.Measured value C, 49.11; H, 5.57; N, 13.40; Mp 180-182 ℃.
Embodiment 116:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-1-azetidine thiocarboxamide, thiomorpholine S-oxide compound; Ultimate analysis theoretical value C
18H
23FN
4O
3S
2, C, 50.69; H, 5.43; N, 13.14.Measured value: C, 50.79; H, 5.45; N, 12.82; Mp 213-214 ℃.
When in the method for embodiment 114, with an amount of (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] lsothiocyanates replacement compound 82, obtained following compound:
Embodiment 117:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] methyl-N '-methylthiourea.
When in the method for embodiment 117, replace methylamine with an amount of dimethyl amine and azetidine, obtained following product respectively:
Embodiment 118:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-N ＇, N ＇-dimethyl thiourea;
Embodiment 119:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5 oxazolidinyl] methyl]-1-azetidine thiocarboxamide.
When in the method for embodiment 33, replace compounds 33 and, obtain following compounds according to total method of embodiment 33 steps 1 and 2 with an amount of compound 31 that derives among the embodiment 26.
Embodiment 120:(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide.
Embodiment 121:(S)-and N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl-2-oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides
With 29 dithio methyl propionate (247mg that stir, 200mg (0.514mmol), 2.06mmol), triethylamine (0.58mL, 4.11mmol), the mixture of THF (5.4mL) and methylene dichloride (5.4ml), under nitrogen atmosphere, kept 3 days, dilute with water is also used dichloromethane extraction.With this extract drying (MgSO
4) and concentrate.With this resistates at the enterprising circumstances in which people get things ready for a trip of silica gel spectrum purifying, and with methyl alcohol with the product crystallization, obtain title product .m.p.190-191 ℃ of 0.132g; Ultimate analysis theoretical value C
19H
25FN
4O
4S:C, 53.76; H, 5.94; N, 13.20; S, 7.55.Measured value: C, 53.66; H, 5.94; N, 13.20; S, 7.37.
According to the method for embodiment 121, just with the dithio compound Z (b) among the above-mentioned preparation example Z to Z (m) replacement dithio methyl propionate, obtain following compounds.
Table G
Embodiment compound R 122 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyl-ethanoyl)-1-piperazinyl] phenyl]-2-CH (CH
3)
2
Oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides; Ultimate analysis
Theoretical value C
20H
27FN
4O
4S:C, 54.78; H, 6.21; N, 12.78; S,
7.31。Measured value: C, 54.67; H, 6.34; N, 12.41; S, 7.15 123 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyls] phenyl]-the 2-cyclopropyl
Oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides; Mp 179-181
℃; Ultimate analysis theoretical value C
20H
25FN
4O
4S:C, 55.03; H, 5.77;
N，12.84；S，7.34。Measured value: C, 55.15; H, 5.72; N, 12.76;
S, 7.09 124 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyl-ethanoyl)-1-piperazinyls] phenyl]-2-CH
2-CH
2-CH
3
Oxo-5-oxazolidinyl] methyl] fourth thioamides 125 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2-CH
2CH (CH
3)
2
Oxo-5-oxazolidinyl] methyl]-3-methyl fourth thioamides 126 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyls] phenyl]-the 2-sec-butyl
Oxo-5-oxazolidinyl] methyl]-2-methyl fourth thioamides 127 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyl-ethanoyl)-1-piperazinyls] phenyl]-2-CH
2-C (CH
3)
3
Oxo-5-oxazolidinyl] methyl]-3,3-dimethyl-Ding thioamides 128 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyl-ethanoyl)-1-piperazinyl] phenyl]-the 2-cyclobutyl
Oxo-5-oxazolidinyl] methyl] ring fourth thiocarboxamide 129 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyl-ethanoyl)-1-piperazinyls] phenyl]-the 2-cyclopentyl
Oxo-5-oxazolidinyl] methyl] ring penta thiocarboxamide 130 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyl-ethanoyl)-1-piperazinyl] phenyl]-the 2-cyclohexyl
Oxo-5-oxazolidinyl] methyl] hexamethylene thiocarboxamide 131 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyl-ethanoyl)-1-piperazinyl] phenyl]-2-cyclopropyl methyl
Oxo-5-oxazolidinyl] methyl]-2-cyclopropyl-second thioamides 132 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyl-ethanoyl)-1-piperazinyl] phenyl]-the 2-cyclobutylmethyl
Oxo-5-oxazolidinyl] methyl]-2-cyclobutyl-second thioamides
133 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyl-ethanoyl)-1-piperazinyls] phenyl]-the 2-cyclopentyl-methyl
Oxo-5-oxazolidinyl] methyl]-2-cyclopentyl-second thioamides
In the method for embodiment 100, an amount of compound 80 that derives from embodiment 31 replaces compound 82, and replaces methyl alcohol with ethanol or Virahol, has obtained following compound respectively:
Embodiment 134:(S)-and N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2 oxos-5-oxazolidinyl] methyl]-the O-ethyl thiocarbamate;
Embodiment 135:(S)-and N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2 oxos-5-oxazolidinyl] methyl]-O-isopropylthio carbamate;
Embodiment 136:(S)-and N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-N '-methylthiourea
In the method for embodiment 114, replace compound 82 with an amount of compound 80 that derives among the embodiment 31, obtain title compound.
According to the method for embodiment 114, just replace compound 82, and replace methylamine with an amount of dimethyl amine or azetidine with an amount of compound 80 that derives from embodiment 31, obtained the compound of following embodiment 137 and 138:
Embodiment 137:(S)-and N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2 oxos-5-oxazolidinyl] methyl]-N ', N ＇-dimethyl thiourea;
Embodiment 138:(S)-and N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-1-azetidine thiocarboxamide.
Embodiment 139:(S)-and N-[[3-[3,5-two fluoro-4-[4-(hydroxyacetyl)-1-piperazinyls] phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methyl thiocarbamate
Part A: according to the method for embodiment 33 steps 1; just replace compound 33 with an amount of compound in step 29 step 5 37; obtained (S)-N-[[3,5-[3-two fluoro-4-[4-(hydroxyacetyl)-1-piperazinyls] phenyl]-2-oxo-5-oxazolidinyl]-methyl] lsothiocyanates.
Part B: in total method of embodiment 100 with an amount of (S)-N-[[3-[3,5-two fluoro-4-[4 (hydroxyacetyl)-1-piperazinyls] phenyl]-2-oxo-5-oxazolidinyl] methyl] lsothiocyanates replaces compound 82, obtained title compound.
Embodiment 140:(S)-and N-[[3-[4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methyl thiocarbamate
Part A: according to the method for embodiment 33 steps 1; just with an amount of (S)-N-[[3-[4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] amine replacement compound 33, obtained (S)-N-[[3-[4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] lsothiocyanates.
Part B: in total method of embodiment 100, with an amount of (S)-N-[[3-[4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] lsothiocyanates replacement compound 82, obtained title compound.
Embodiment 141:(S)-N-[[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide
Step 1
At 30.4g (70.8mmol) initiator 58 (deriving from embodiment 25 step 1)) and triethylamine (15.4mL ice-cold, that stir, methylene dichloride 110mmol) (2570mL) solution, with-nitrobenzene sulfonyl chloride (18.8g, 84.9mmol) handle and under nitrogen atmosphere, kept 24 hours down in room temperature (24 ℃).Between adding again-nitrobenzene sulfonyl chloride (1.88g) and triethylamine (1.54mL) and will keep 1 day water, saturated sodium bicarbonate water and salt water washing, dry (sodium sulfate) and the concentrated oily product that obtains under this mixture room temperature
85According to Brickner (J.Med.Chem.1996,39, method preparation alcohol 673-679)
58, with compound 5a wherein.
Step 2
With stir 85, keep 3 days also vacuum concentration under the mixture room temperature of acetonitrile (1270mL), Virahol (1270mL) and ammonium hydroxide (1270mL).This resistates is carried out the amine 86 that chromatogram purification obtains 22.4g with 0.5% ammonium hydroxide-1% methyl alcohol-methylene dichloride wash-out on silica gel.
Step 3
With THF (650mL) solution of amine 86 ice-cold, that stir, in 20 minutes, with two-tertiary butyl, two carbonic ethers (12.0g, THF 55.2mmol) (90mL) solution-treated.To keep 18 hours and vacuum concentration under this mixture room temperature.This resistates is dissolved in the methylene dichloride, with rare sodium bicarbonate washing, dry (MgSO
4) and concentrate.Obtain the amine of the Boc protection of 20.0g with methyl alcohol-ethyl acetate.Mother liquor is carried out chromatogram purification with 1-2% methyl alcohol-methylene dichloride wash-out on silica gel, obtain another batch product (4.1g).
Step 4
(5.00g, ethanol 9.46mmol) (150mL) solution is with 10% palladium-carbon catalyst (1.0g) processing and hydrogenation 3 hours under initial pressure 30psi with the amine 87 of protection.Obtain the compound 88 of 3.66g by diatomite plate filtration catalizer and concentrated this filtrate.
Step 5
With stir, (1.10g, (289 μ L 3.07mmol) handle pyridine 2.79mmol) (10mL) solution compound 88, keep 2 hours and vacuum concentration under the room temperature with diacetyl oxide.The dichloromethane solution of this resistates is washed dry (MgSO with weak brine
4) and concentrate the compound 89:MS m/z 436 (M that obtain 1.23g
+).
Step 6
With the solution in the 4N HCl Zai diox (10mL) ice-cold, that stir, (1.10g 2.52mmol) handles with compound 89.This mixture was remained in the ice bath 30 minutes and at room temperature kept 1 hour.Then, it is mixed with methylene dichloride and concentrate.Grind the amine hydrochlorate that this resistates obtains 1.03g with methylene dichloride.
Step 7
With stir, Compound P-90 (250mg), triethylamine (0.75mL, 5.36mmol), ethyl dithiocarbamate (307 μ L, 2.68mmol), keep under the mixture room temperature of methylene dichloride (7.4mL) and THF (7.4mL) 1 day, concentrate and in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with the methyl alcohol-dichloromethane mixture wash-out that contains 1-2% methyl alcohol.This product crystallization is obtained the title product of 0.160g with ethyl acetate-heptane: ultimate analysis theoretical value C
18H
23FN
4O
3S:C, 54.81; H, 5.88; N, 14.20; S, 8.13.Measured value: C, 54.92; H, 5.95; N, 14.08; S, 7.94; Mp158 ℃.
In total method of embodiment 141, an amount of
Replace compound 58, and, obtained following amine compound P-91 and P-92 respectively according to the method for step 1 to 6.
Above-mentioned pure x and y according to Brickner (J.Med.Chem., 1996,39, the preparation of 673-679) method, with an amount of 2,6-two fluoro-4-oil of mirbane (trifluoromethane) sulphonates and 4-fluoronitrobenzene replace 3 in the preparation of 2a wherein, 4-difluoro nitrobenzene respectively.
In the method for embodiment 141, an amount of x or y replace compound 58, and according to the method for step 1 to 4, have obtained the compound of following Boc protection.
In embodiment 141 steps 5, an amount of compound 88, compound x-b or the following agent treated of compound y-b, and, obtained the amine of preparation example P-93 to P-128 according to the method for step 5 and step 6.
By with compound 88 (1.00g, 2.54mmol), (305mg, 3.18mmol) and 1, the solution of 2-glycol dimethyl ether (6mL) refluxes and obtained the amine compound that provides as P-129 in 6 days sulphonamide.Filter and collect this solid precipitation, and on silica gel, carry out chromatogram purification with 5% methyl alcohol-methylene dichloride wash-out.With methyl alcohol-methylene dichloride crystallization, obtain the sulfamyl derivative of 0.551g, the step 6 of using it for embodiment 141 obtains P-129.When compound x-b and y-b replacement compound 88, and, preparation example P-130 and P-131 have been obtained respectively according to this total method.
Total method according to embodiment 141 steps 5 and 6, just replace diacetyl oxide with chloro acetonitrile or 2-fluoro ethyl bromo respectively in the step 5, and the salt of wormwood in the use acetonitrile, and use compound 88, compound x-b or compound y-b, obtained the amine that preparation example P-132 to P-137 provides respectively.
Compound 88 by will providing in embodiment 141 steps 5 (1.10g, 2.75mmol) with N-formyl radical benzotriazole (493mg 3.35mmol) mixes among THF (30mL), and will be under this mixture room temperature maintenance 18 hours.This mixture concentrated and this is present in resistates in the methylene dichloride with 1N sodium hydroxide and dilute sodium chloride washing, dry (MgSO
4), concentrate and on silica gel, carry out chromatographic grade and contain the methyl alcohol of 1-2% methyl alcohol and the mixture wash-out of methylene dichloride, obtain the N-formyl radical derivative of 1.09g, total method that it is used for embodiment 141 steps 6 obtains preparation example P-138.When in aforesaid method, when compound x-b or compound y-b replace compound 88, following preparation example P-139 and P-140 have been obtained.
Reagent Boc compound R R " R ＇ preparation example
Number methoxyl group ethanoyl chlorine 88 CH
3OCH
2C (=O)-H F P-93
x-b????????????????????????F?????F?????P-94
Y-b H H P-95 cyano group ethanoyl chlorine 88 NCCH
2C (=O)-H F P-96
x-b????????????????????????F?????F?????P-97
Y-b H H P-98 alpha-Acetoxyacetyl chloride 88 CH
3C (=O)-O-H F P-99
x-b?????CH
2C(＝O)-????????F?????F?????P-100
Y-b H H P-101 benzyloxy Acetyl Chloride 98Min. 88 PhCH
2OCH
2C (=O)-H F P-102
x-b????????????????????????F?????F?????P-103
Y-b H H P-104 methyl-chloroformate 88 CH
3OC (=O)-H F P-105
x-b????????????????????????F?????F?????P-106
Y-b H H P-107 methylsulfonyl chlorine 88 CH
3SO
2-H F P-108
x-b????????????????????????F?????F?????P-109
Y-b H H P-110 ethylsulfonyl chlorine 88 CH
3CH
2SO
2-H F P-111
x-b????????????????????????F?????F?????P-112
Y-b H H P-113 chloro methylsulfonyl chlorine 88 ClCH
2SO
2-H F P-114
x-b????????????????????????F?????F?????P-115
Y-b H H P-116 cyano group methylsulfonyl chlorine 88 NCCH
2SO
2-H F P-117
x-b????????????????????????F?????F?????P-118
Y-b H H P-119 N-methyl sulfamyl chlorine 88 CH
3NHSO
2-H F P-120
x-b???????????????????????????F??????F?????P-121
Y-b H H P-122N, N-dimethylamino alkylsulfonyl chlorine 88 (CH
3)
2NSO
2-H F P-123
x-b???????????????????????????F??????F?????P-124
y-b???????????????????????????H??????H?????P-125
Chloro ethyl formate 88 CH
3CH
2OC (=O)-H F P-126
x-b???????????????????????????F??????F?????P-127
y-b???????????????????????????H??????H?????P-128
Sulphonamide 88 H
2NSO
2-H F P-129
x-b???????????????????????????F??????F?????P-130
y-b???????????????????????????H??????H?????P-131
Chloro acetonitrile 88 NCCH
2-H F P-132
x-b???????????????????????????F??????F?????P-133
y-b???????????????????????????H??????H?????P-134
2-fluoro monobromoethane 88 FCH
2CH
2-H F P-135
x-b???????????????????????????F??????F?????P-136
Y-b H H P-137 N-formyl radical benzotriazole 88 HC (=O)-H F P-138
x-b???????????????????????????F??????F?????P-139
y-b???????????????????????????H??????H?????P-140
Embodiment 142-161:
According to total method of embodiment 141 steps 7, use an amount of following amine and the following disulfide that derives from preparation example Z, obtained the product of embodiment 142 to 400 among the table H respectively.
Table H embodiment compound amine dithioization
Compound (is seen system
Be equipped with routine Z) 142 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (a)
Generation-5-oxazolidinyl] methyl] rosickyite is for acid amides; Mp161-162 ℃;
Ultimate analysis theoretical value C
19H
25FN
4O
3S:C, 55.87; H, 6.17;
N，13.72；S，7.85。Measured value: C, 55.79; H, 6.26; N,
13.60; S, 7.71143 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (b)
Generation-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 144 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (c)
Generation-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides; Mp 159-
160 ℃; Ultimate analysis theoretical value C
20H
25FN
4O
3S:C, 57.13;
H，5.99；N，13.32；S，7.62。Measured value: C, 57.05; H,
6.01; N, 13.15; S, 7.45.145 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (d)
Generation-5-oxazolidinyl] methyl] fourth thioamides 146 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (e)
Generation-5-oxazolidinyl] methyl]-3-methyl fourth thioamides 147 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (f)
Generation-5-oxazolidinyl] methyl]-2-methyl fourth thioamides 148 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (g)
Generation-5-oxazolidinyl] methyl]-3,3-dimethyl butyrate thioamides 149 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (h)
Generation-5-oxazolidinyl] methyl] ring fourth thiocarboxamide 150 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (i)
Generation-5-oxazolidinyl] methyl] ring penta thiocarboxamide 151 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (j)
Generation-5-oxazolidinyl] methyl] hexamethylene thiocarboxamide 152 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (k)
Generation-5-oxazolidinyl] methyl]-2-cyclopropyl second thioamides 153 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (l)
Generation-5-oxazolidinyl] methyl]-2-cyclobutyl second thioamides 154 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-90 Z (m)
Generation-5-oxazolidinyl] methyl]-2-cyclopentyl second thioamides 155 (S)-N-[[3-[3,5-two fluoro-4-(4-ethanoyl-1-piperazinyl)-phenyl]-P-91 dithio second
2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 156 (S)-N-[[3-[3,5-two fluoro-4-(4-ethanoyl-1-piperazinyl)-phenyl]-P-91 Z (a)
2-oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides 157 (S)-N-[[3-[3,5-two fluoro-4-(4-ethanoyl-1-piperazinyl)-phenyl]-P-91 Z (b)
2-oxo-5-oxazolidinyl] methyl]-2-methyl-rosickyite is for acid amides 158 (S)-N-[[3-[3,5-two fluoro-4-(4-ethanoyl-1-piperazinyl)-phenyl]-P-91 Z (c)
2-oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 159 (S)-N-[[3-[4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxo-5-P-92 sulfo-second
Oxazolidinyl] methyl] thioacetamide acetoacetic ester 160 (S)-N-[[3-[4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxo-5-P-92 Z (a)
Oxazolidinyl] methyl] rosickyite is for acid amides 161 (S)-N-[[3-[4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxo-5-P-92 Z (b)
Oxazolidinyl] methyl]-2-methyl-prop thioamides 162 (S)-N-[[3-[4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxo-5-P-92 Z (c)
Oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 163 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] benzene P-93 sulfo-second
Base]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 164 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] P-93 Z (a)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 165 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] P-93 Z (b)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-acyl
Amine 166 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] benzene P-93 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 167 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] P-93 Z (d)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-Ding thioamides 168 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] P-93 Z (e)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-3-methyl fourth sulfo-acyl
Amine 169 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] P-93 Z (f)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl fourth sulfo-acyl
Amine 170 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] P-93 Z (g)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-3,3-dimethyl butyrate sulphur
For acid amides 171 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] P-93 Z (h)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-ring fourth thiocarboxamide 172 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyls] P-93 Z (i)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-ring penta thiocarboxamide 173 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] benzene P-93 Z (j)
Base]-2-oxo-5-oxazolidinyl] methyl]-hexamethylene thiocarboxamide 174 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] P-93 Z (k)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopropyl second sulfo-
Acid amides 175 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] P-93 Z (l)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclobutyl second sulfo-
Acid amides 176 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazinyl] P-93 Z (m)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopentyl second sulfo-
Acid amides 177 (S)-N-[[3-[3,5-two fluoro-[4-[4-(methoxyl group ethanoyl)-1-piperazine P-94 sulfo-second
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 178 (S)-N-[[3-[3,5-two fluoro-[4-[4-(methoxyl group ethanoyl)-1-piperazine P-94 Z (a)
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 179 (S)-N-[[3-[3,5-two fluoro-[4-[4-(methoxyl group ethanoyl)-1-piperazine P-94 Z (b)
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-
Acid amides 180 (S)-N-[[3-[3,5-two fluoro-[4-[4-(methoxyl group ethanoyl)-1-piperazine P-94 Z (c)
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for the carboxylic acyl
Amine 181 (S)-N-[[3-[4-[4-(methoxyl group ethanoyl)-1-piperazinyl] phenyl]-2-P-95 dithio second
Oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 182 (S)-N-[[3-[4-[4-(methoxyl group ethanoyl)-1-piperazinyl] phenyl]-2-P-95 Z (a)
Oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides 183 (S)-N-[[3-[4-[4-(methoxyl group ethanoyl)-1-piperazinyl] phenyl]-2-P-95 Z (b)
Oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 184 (S)-N-[[3-[4-[4-(methoxyl group ethanoyl)-1-piperazinyl] phenyl]-2-P-95 Z (c)
Oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 185 (S)-N-[[3-[3-fluoro-4-[4-(cyano group ethanoyl)-1-piperazinyl]-benzene P-96 sulfo-second
Base]-2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 186 (S)-N-[[3-[3-fluorine 4-[4-(cyano group ethanoyl)-1-piperazinyl]-benzene P-96 Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides 187 (S)-N-[[3-[3-fluoro-4-[4-(cyano group ethanoyl)-1-piperazinyl]-benzene P-96 Z (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-rosickyite is for acid amides 188 (S)-N-[[3-[3-fluoro-4-[4-(cyano group ethanoyl)-1-piperazinyl]-benzene P-96 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 189 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano group ethanoyl)-1-piperazinyl] P-97 dithio second
Phenyl]-2-oxo-5-oxazolidinyl]-methyl] thioacetamide acetoacetic ester 190 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano group ethanoyl)-1-piperazinyl] P-97 Z (a)
Phenyl]-2-oxo-5-oxazolidinyl]-methyl] rosickyite is for acid amides 191 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano group ethanoyl)-1-piperazinyl] P-97 Z (b)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-acyl
Amine 192 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano group ethanoyl)-1-piperazinyl] P-97 Z (c)
Phenyl]-2-oxo-5-oxazolidinyl]-methyl] encircle rosickyite for carboxylic acid amides 193 (S)-N-[[3-[4-[4-(cyano group ethanoyl)-1-piperazinyl] phenyl]-2-oxygen P-98 dithio second
Generation-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 194 (S)-N-[[3-[4-[4-(cyano group ethanoyl)-1-piperazinyl] phenyl]-2-oxygen P-98 Z (a)
Generation-5-oxazolidinyl] methyl] rosickyite is for acid amides 195 (S)-N-[[3-[4-[4-(cyano group ethanoyl)-1-piperazinyl] phenyl]-2-oxygen P-98 Z (b)
Generation-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 196 (S)-N-[[3-[4-[4-(cyano group ethanoyl)-1-piperazinyl] phenyl]-2-oxygen P-98 Z (c)
Generation-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 197 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 dithio second
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 198 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 Z (a)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 199 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 Z (b)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-acyl
Amine 200 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 Z (c)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 201 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 Z (d)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-Ding thioamides 202 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 Z (e)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-3-methyl fourth sulfo-acyl
Amine 203 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 Z (f)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl fourth sulfo-acyl
Amine 204 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 z (g)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-3,3-dimethyl butyrate sulphur
For acid amides 205 (S)-N-[[3-[3-fluorine 4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 Z (h)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-ring fourth thiocarboxamide 206 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyls] P-99 Z (i)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-ring penta thiocarboxamide 207 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 Z (j)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-hexamethylene thiocarboxamide 208 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 Z (k)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopropyl second sulfo-
Acid amides 209 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 Z (l)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclobutyl second sulfo-
Acid amides 210 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-99 Z (m)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopentyl second sulfo-
Acid amides 211 (S)-N-[[3-[3,5-two-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazine P-100 dithio second
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 212 (S)-N-[[3-[3,5-difluoro 4-[4-(acetoxyl group ethanoyl)-1-piperazine P-100 Z (a)
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 213 (S)-N-[[3-[3,5-two fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazine P-100 Z (b)
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-
Acid amides 214 (S)-N-[[3-[3,5-two fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazine P-100 Z (c)
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for the carboxylic acyl
Amine 215 (S)-N-[[3-[4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] benzene P-101 dithio second
Base]-2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 216 (S)-N-[[3-[4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] benzene P-101 Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides 217 (S)-N-[[3-[4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] benzene P-101 Z (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 218 (S)-N-[[3-[4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] benzene P-101 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 219 (S)-N-[[3-[3-fluoro-4-[4-(benzyloxy ethanoyl)-1-piperazinyl] benzene P-102 dithio second
Base]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 220 (S)-N-[[3-[3-fluoro-4-[4-(benzyloxy ethanoyl)-1-piperazinyl] P-102 Z (a)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 221 (S)-N-[[3-[3-fluoro-4-[4-(benzyloxy ethanoyl)-1-piperazinyl] P-102 Z (b)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-acyl
Amine 222 (S)-N-[[3-[3-fluoro-4-[4-(benzyloxy ethanoyl)-1-piperazinyl] P-102 Z (c)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite encircled for carboxylic acid amides 223 (S)-N-[[3-[3,5-two fluoro-4-[4-(benzyloxy ethanoyl)-1-piperazine P-103 dithio second
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 224 (S)-N-[[3-[3,5-two fluoro-4-[4-(benzyloxy ethanoyl)-1-piperazine P-103 Z (a)
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 225 (S)-N-[[3-[3,5-two fluoro-4-[4-(benzyloxy ethanoyl)-1-piperazine P-103 Z (b)
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-
Acid amides 226 (S)-N-[[3-[3,5-two fluoro-4-[4-(benzyloxy ethanoyl)-1-piperazine P-103 Z (c)
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for the carboxylic acyl
Amine 227 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] benzene P-105 sulfo-second
Base]-2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 228 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] benzene P-105 Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 229 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] benzene P-105 Z (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 230 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyls] benzene P-105 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides-231 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] benzene P-105 Z (d)
Base]-2-oxo-5-oxazolidinyl] methyl]-Ding thioamides 232 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] benzene P-105 Z (e)
Base]-2-oxo-5-oxazolidinyl] methyl]-3-methyl fourth thioamides 233 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyls] benzene P-105 Z (f)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl fourth thioamides 234 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyls] benzene P-105 Z (g)
Base]-2-oxo-5-oxazolidinyl] methyl]-3,3-dimethyl butyrate sulfo-
Acid amides 235 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] benzene P-105 Z (h)
Base]-2-oxo-5-oxazolidinyl] methyl]-ring fourth thiocarboxamide 236 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyls] benzene P-105 Z (i)
Base]-2-oxo-5-oxazolidinyl] methyl]-ring penta thiocarboxamide 237 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] benzene P-105 Z (j)
Base]-2-oxo-5-oxazolidinyl] methyl]-hexamethylene thiocarboxamide 238 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] benzene P-105 Z (k)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopropyl second sulfo-acyl
Amine 239 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] benzene P-105 Z (l)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-cyclobutyl second sulfo-acyl
Amine 240 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] benzene P-105 Z (m)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopentyl second sulfo-acyl
Amine 241 (S)-N-[[3-[3,5-two fluoro-4-[4-(methoxycarbonyl)-1-piperazinyls] P-106 dithio second
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 242 (S)-N-[[3-[3,5-two fluoro-4-[4-(methoxycarbonyl)-1-piperazinyls] P-106 Z (a)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 243 (S)-N-[[3-[3,5-two fluoro-4-[4-(methoxycarbonyl)-1-piperazinyls] P-106 Z (b)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-acyl
Amine 244 (S)-N-[[3-[3,5-two fluoro-4-[4-(methoxycarbonyl)-1-piperazinyls] P-106 Z (c)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 245 (S)-N-[[3-[4-[4-(methoxycarbonyl)-1-piperazinyl] phenyl]-2-oxygen P-107 dithio second
Generation-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 246 (S)-N-[[3-[4-[4-(methoxycarbonyl)-1-piperazinyl] phenyl]-2-oxygen P-107 Z (a)
Generation-5-oxazolidinyl] methyl]-rosickyite is for acid amides 247 (S)-N-[[3-[4-[4-(methoxycarbonyl)-1-piperazinyl] phenyl]-2-oxygen P-107 Z (b)
Generation-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 248 (S)-N-[[3-[4-[4-(methoxycarbonyl)-1-piperazinyls] phenyl]-2-oxygen P-107 Z (c)
Generation-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 249 (S)-N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyl] phenyl]-P-108 dithio second
2-oxo-5-oxazolidinyl] methyl]-thioacetamide; Mp 197-acetoacetic ester
198 ℃; Ultimate analysis theoretical value C
17H
23FN
4O
4S
2: C, 47.43;
H，5.39；N，13.01；S，14.89。Measured value: C, 47.25;
H，5.40；N，12.82；S，14.56。250 (S)-N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyls] phenyl]-P-108 Z (a)
2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides; Mp 207-
208 ℃; Ultimate analysis theoretical value C
18H
25FN
4O
4S
2: C, 48.63;
H，5.67；N，12.60；S，14.42。Measured value: C, 48.51;
H，5.59；N，12.52；S，14.09。251 (S)-N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyls] phenyl]-P-108 Z (b)
2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides; Mp
204-206 ℃; Ultimate analysis theoretical value C
19H
27FN
4O
4S
2:
C，49.76；H，5.93；N，12.22；S，13.98。Measured value: C,
49.63；H，5.92；N，14.14；S，13.91。252 (S)-N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyls] phenyl]-P-108 Z (c)
2-oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides; Element
Analysis theories value C
19H
25FN
40
4S
2: C, 49.98; H, 5.52; N,
12.27；S，14.04。Measured value: C, 49.42; H, 5.50; N,
12.08；S，13.80。253 (S)-N-[[3-[3,5-two fluoro-4-[4-(methylsulfonyl)-1-piperazinyls] benzene P-109 dithio second
Base]-2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 254 (S)-N-[[3-[3,5-two fluoro-4-[4-(methylsulfonyl)-1-piperazinyls] benzene P-109 Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 255 (S)-N-[[3-[3,5-two fluoro-4-[4-(methylsulfonyl)-1-piperazinyls] benzene P-109 Z (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 256 (S)-N-[[3-[3,5-two fluoro-4-[4-(methylsulfonyl)-1-piperazinyls] benzene P-109 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 257 (S)-N-[[3-[4-[4-(methylsulfonyl)-1-piperazinyl] phenyl]-2-oxo P-110 dithio second
-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 258 (S)-N-[[3-[4-[4-(methylsulfonyl)-1-piperazinyl] phenyl]-2-oxo P-110 Z (a)
-5-oxazolidinyl] methyl]-rosickyite is for acid amides 259 (S)-N-[[3-[4-[4-(methylsulfonyl)-1-piperazinyl] phenyl]-2-oxo P-110 Z (b)
-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 260 (S)-N-[[3-[4-[4-(methylsulfonyl)-1-piperazinyls] phenyl]-2-oxo P-110 Z (c)
-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 261 (S)-N-[[3-[3-fluoro-4-[4-(ethylsulfonyl)-1-piperazinyl] phenyl]-P-111 dithio second
2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 262 (S)-N-[[3-[3-fluoro-4-[4-(ethylsulfonyl)-1-piperazinyl] phenyl]-P-111 Z (a)
2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 263 (S)-N-[[3-[3-fluoro-4-[4-(ethylsulfonyl)-1-piperazinyl] phenyl]-P-111 Z (b)
2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 264 (S)-N-[[3-[3-fluoro-4-[4-(ethylsulfonyl)-1-piperazinyls] phenyl]-P-111 Z (c)
2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 265 (S)-N-[[3-[3,5-two fluoro-4-[4-(ethylsulfonyl)-1-piperazinyls] benzene P-112 sulfo-second
Base]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 266 (S)-N-[[3-[3,5-two fluoro-4-[4-(ethylsulfonyl)-1-piperazinyls] benzene P-112 Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 267 (S)-N-[[3-[3,5-two fluoro-4-[4-(ethylsulfonyl)-1-piperazinyls] benzene P-112 Z (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 268 (S)-N-[[3-[3,5-two fluoro-4-[4-(ethylsulfonyl)-1-piperazinyls] benzene P-112 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 269 (S)-N-[[3-[4-[4-(ethylsulfonyl)-1-piperazinyl] phenyl]-2-oxo P-113 dithio second
-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 270 (S)-N-[[3-[4-[4-(ethylsulfonyl)-1-piperazinyl] phenyl]-2-oxo P-113 Z (a)
-5-oxazolidinyl] methyl] rosickyite is for acid amides 271 (S)-N-[[3-[4-[4-(ethylsulfonyl)-1-piperazinyl] phenyl]-2-oxo P-113 Z (b)
-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 272 (S)-N-[[3-[4-[4-(ethylsulfonyl)-1-piperazinyls] phenyl]-2-oxo P-113 Z (c)
-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 273 (S)-N-[[3-[3-fluoro-4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] benzene P-114 dithio second
Base]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 274 (S)-N-[[3-[3-fluoro-4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] benzene P-114 Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 275 (S)-N-[[3-[3-fluoro-4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] benzene P-114 Z (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 276 (S)-N-[[3-[3-fluoro-4-[4-(chloromethane alkylsulfonyl)-1-piperazinyls] benzene P-114 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 277 (S)-N-[[3-[3,5-two fluoro-4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] P-115 dithio second
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 278 (S)-N-[[3-[3,5-two fluoro-4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] P-115 Z (a)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 279 (S)-N-[[3-[3,5-two fluoro-4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] P-115 Z (b)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-acyl
Amine 280 (S)-N-[[3-[3,5-two fluoro-4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] P-115 Z (c)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 281 (S)-N-[[3-[4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxygen P-116 dithio second
Generation-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 282 (S)-N-[[3-[4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxygen P-116 Z (a)
Generation-5-oxazolidinyl] methyl]-rosickyite is for acid amides 283 (S)-N-[[3-[4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxygen P-116 Z (b)
Generation-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 284 (S)-N-[[3-[4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] phenyl]-2-oxygen P-116 Z (c)
Generation-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 285 (S)-N-[[3-[3-fluoro-4-[4-(cyano group methylsulfonyl)-1-piperazinyl] benzene P-117 dithio second
Base]-2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 286 (S)-N-[[3-[3-fluoro-4-[4-(cyano group methylsulfonyl)-1-piperazinyl] P-117 Z (a)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 287 (S)-N-[[3-[3-fluoro-4-[4-(cyano group methylsulfonyl)-1-piperazinyl] P-117 Z (b)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-acyl
Amine 288 (S)-N-[[3-[3-fluoro-4-[4-(cyano group methylsulfonyl)-1-piperazinyl] P-117 Z (c)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite encircled for carboxylic acid amides 289 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano group methylsulfonyl)-1-piperazine P-118 dithio second
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 290 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano group methylsulfonyl)-1-piperazine P-118 Z (a)
Base] phenyl]-2-oxo-5-oxazolidinyl]-methyl] rosickyite is for acid amides 291 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano group methylsulfonyl)-1-piperazine P-118 Z (b)
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-
Acid amides 292 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano group methylsulfonyl)-1-piperazine P-118 Z (c)
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for the carboxylic acyl
Amine 293 (S)-N-[[3-[4-[4-(cyano group methylsulfonyl)-1-piperazinyl] phenyl]-2-P-119 dithio second
Oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 294 (S)-N-[[3-[4-[4-(cyano group methylsulfonyl)-1-piperazinyl] phenyl]-2-P-119 Z (a)
Oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides 295 (S)-N-[[3-[4-[4-(cyano group methylsulfonyl)-1-piperazinyl] phenyl]-2-P-119 Z (b)
Oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 296 (S)-N-[[3-[4-[4-(cyano group methylsulfonyl)-1-piperazinyl] phenyl]-2-P-119 Z (c)
Oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 297 (S)-N-[[3-[3-fluoro-4-[4-(N-methyl sulfamyl)-1-piperazinyl] P-120 dithio second
Phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 298 (S)-N-[[3-[3-fluoro-4-[4-(N-methyl sulfamyl)-1-piperazinyl] P-120 Z (a)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 299 (S)-N-[[3-[3-fluoro-4-[4-(N-methyl sulfamyl)-1-piperazinyl] P-120 Z (b)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-acyl
Amine 300 (S)-N-[[3-[3-fluoro-4-[4-(N-methyl sulfamyl)-1-piperazinyl] P-120 Z (c)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite encircled for carboxylic acid amides 301 (S)-N-[[3-[3,5-two fluoro-4-[4-(N-methyl sulfamyl)-1-piperazine P-121 dithio second
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 302 (S)-N-[[3-[3,5-two fluoro-4-[4-(N-methyl sulfamyl)-1-piperazine P-121 Z (a)
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 303 (S)-N-[[3-[3,5-two fluoro-4-[4-(N-methyl sulfamyl)-1-piperazine P-121 Z (b)
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl rosickyite
For acid amides 304 (S)-N-[[3-[3,5-two fluoro-4-[4-(N-methyl sulfamyl)-1-piperazine P-121 Z (c)
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic
Acid amides 305 (S)-N-[[3-[4-[4-(N-methyl sulfamyl)-1-piperazinyl] benzene P-122 dithio second
Base]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 306 (S)-N-[[3-[4-[4-(N-methyl sulfamyl)-1-piperazinyl] benzene P-122 Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 307 (S)-N-[[3-[4-[4-(N-methyl sulfamyl)-1-piperazinyl] benzene P-122 Z (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 308 (S)-N-[[3-[4-[4-(N-methyl sulfamyl)-1-piperazinyl] benzene P-122 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl]-rosickyite encircled for carboxylic acid amides 309 (S)-N-[[3-[3-fluoro-4-[4-(N, N-dimethylamino alkylsulfonyl)-1-piperazine P-123 dithio second
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 310 (S)-N-[[3-[3-fluoro-4-[4-(N, N-two-methyl sulfamyl)-1-piperazine P-123 Z (a)
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 311 (S)-N-[[3-[3-fluoro-4-[4-(N, N-dimethylamino alkylsulfonyl)-1-piperazine P-123 Z (b)
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl rosickyite
For acid amides 312 (S)-N-[[3-[3-fluoro-4-[4-(N, N-dimethylamino alkylsulfonyl)-1-piperazine P-123 Z (c)
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic
Acid amides 313 (S)-N-[[3-[3,5-two fluoro-4-[4-(N, N-dimethylamino alkylsulfonyl)-1-P-124 dithio second
Piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-the thioacetyl acetoacetic ester
Amine 314 (S)-N-[[3-[3,5-two fluoro-4-[4-(N, N-dimethylamino alkylsulfonyl)-1-P-124 Z (a)
Piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acyl
Amine 315 (S)-N-[[3-[3,5-two fluoro-4-[4-(N, N-dimethylamino alkylsulfonyl)-1-P-124 Z (b)
Piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-the 2-methyl-prop
Thioamides 316 (S)-N-[[3-[3,5-two fluoro-4-[4-(N, N-dimethylamino alkylsulfonyl)-1-P-124 Z (c)
Piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-ring rosickyite generation
Carboxylic acid amides 317 (S)-N-[[3-[4-[4-(N, N-two-methyl sulfamyl)-1-piperazinyl] P-125 dithio second
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 318 (S)-N-[[3-[4-[4-(N, N-dimethylamino alkylsulfonyl)-1-piperazinyl] P-125 Z (a)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 319 (S)-N-[[3-[4-[4-(N, N-dimethylamino alkylsulfonyl)-1-piperazinyl] P-125 Z (b)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-acyl
Amine 320 (S)-N-[[3-[4-[4-(N, N-dimethylamino alkylsulfonyl)-1-piperazinyl] P-125 Z (c)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 321 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] benzene P-126 dithio second
Base]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 322 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] benzene P-126 Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 323 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] benzene P-126 Z (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 324 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyls] benzene P-126 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 325 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] benzene P-126 Z (d)
Base]-2-oxo-5-oxazolidinyl] methyl]-Ding thioamides 326 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] benzene P-126 Z (e)
Base]-2-oxo-5-oxazolidinyl] methyl]-3-methyl fourth thioamides 327 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyls] benzene P-126 Z (f)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl fourth thioamides 328 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyls] benzene P-126 Z (g)
Base]-2-oxo-5-oxazolidinyl] methyl]-3,3-dimethyl butyrate sulfo-
Acid amides 329 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] benzene P-126 Z (h)
Base]-2-oxo-5-oxazolidinyl] methyl]-ring fourth thiocarboxamide 330 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyls] benzene P-126 Z (i)
Base]-2-oxo-5-oxazolidinyl] methyl]-ring penta thiocarboxamide 331 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] benzene P-126 Z (j)
Base]-2-oxo-5-oxazolidinyl] methyl]-hexamethylene thiocarboxamide 332 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] benzene P-126 Z (k)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopropyl second sulfo-acyl
Amine 333 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] benzene P-126 Z (l)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-cyclobutyl second sulfo-acyl
Amine 334 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] benzene P-126 Z (m)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopentyl second sulfo-acyl
Amine 335 (S)-N-[[3-[3,5-two fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyls] P-127 dithio second
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 336 (S)-N-[[3-[3,5-two fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyls] P-127 Z (a)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 337 (S)-N-[[3-[3,5-two fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyls] P-127 Z (b)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop sulfo-acyl
Amine 338 (S)-N-[[3-[3,5-two fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyls] P-127 Z (c)
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 339 (S)-N-[[3-[4-[4-(ethoxy carbonyl)-1-piperazinyl]-phenyl]-2-P-128 dithio second
Oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 340 (S)-N-[[3-[4-[4-(ethoxy carbonyl)-1-piperazinyl]-phenyl]-2-P-128 Z (a)
Oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 341 (S)-N-[[3-[4-[4-(ethoxy carbonyl)-1-piperazinyl]-phenyl]-2-P-128 Z (b)
Oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 342 (S)-N-[[3-[4-[4-(ethoxy carbonyl)-1-piperazinyls]-phenyl]-2-P-128 Z (c)
Oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 343 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl)-phenyl]-2-P-129 dithio second
Oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 344 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl)-phenyl]-2-P-129 Z (a)
Oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 345 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl)-phenyl]-2-P-129 Z (b)
Oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 346 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl)-phenyl]-2-P-129 Z (c)
Oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 347 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) phenyl]-2-P-129 Z (d)
Oxo-5-oxazolidinyl] methyl] fourth thioamides 348 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) phenyl]-2-P-129 Z (e)
Oxo-5-oxazolidinyl] methyl]-3-methyl fourth thioamides 349 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) phenyl]-2-P-129 Z (f)
Oxo-5-oxazolidinyl] methyl]-2-methyl fourth thioamides 350 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) phenyl]-2-P-129 Z (g)
Oxo-5-oxazolidinyl] methyl]-3,3-dimethyl butyrate thioamides 351 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) phenyl]-2-P-129 Z (h)
Oxo-5-oxazolidinyl] methyl] ring fourth thiocarboxamide 352 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) phenyl]-2-P-129 Z (i)
Oxo-5-oxazolidinyl] methyl] ring penta thiocarboxamide 353 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) phenyl]-2-P-129 Z (j)
Oxo-5-oxazolidinyl] methyl] hexamethylene thiocarboxamide 354 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) phenyl]-2-P-129 Z (k)
Oxo-5-oxazolidinyl] methyl]-2-cyclopropyl second thioamides 355 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) phenyl]-2-P-129 Z (l)
Oxo-5-oxazolidinyl] methyl]-2-cyclobutyl second thioamides 356 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) phenyl]-2-P-129 Z (m)
Oxo-5-oxazolidinyl] methyl]-2-cyclopentyl second thioamides 357 (S)-N-[[3-[3,5-two fluoro-4-(4-sulfamyl-1-piperazinyl) benzene P-130 dithio second
Base]-2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 358 (S)-N-[[3-[3,5-two fluoro-4-(4-sulfamyl-1-piperazinyl) benzene P-130 Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides 359 (S)-N-[[3-[3,5-two fluoro-4-(4-sulfamyl-1-piperazinyl) benzene P-130 Z (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 360 (S)-N-[[3-[3,5-two fluoro-4-(4-sulfamyl-1-piperazinyl) benzene P-130 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 361 (S)-N-[[3-[4-(4-sulfamyl-1-piperazinyl) phenyl]-2-oxo-P-131 dithio second
The 5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 362 (S)-N-[[3-[4-(4-sulfamyl-1-piperazinyl) phenyl]-2-oxo-P-131 Z (a)
The 5-oxazolidinyl] methyl] rosickyite is for acid amides 363 (S)-N-[[3-[4-(4-sulfamyl-1-piperazinyl) phenyl]-2-oxo-P-131 Z (b)
The 5-oxazolidinyl] methyl]-2-methyl-prop thioamides 364 (S)-N-[[3-[4-(4-sulfamyl-1-piperazinyl) phenyl]-2-oxo-P-131 Z (c)
The 5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 365 (S)-N-[[3-[3-fluoro-4-[4-(cyano methyl)-1-piperazinyl] phenyl]-P-132 dithio second
2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 366 (S)-N-[[3-[3-fluoro-4-[4-(cyano methyl)-1-piperazinyl] phenyl]-P-132 Z (a)
2-oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides 367 (S)-N-[[3-[3-fluoro-4-[4-(cyano methyl)-1-piperazinyl] phenyl]-P-132 Z (b)
2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 368 (S)-N-[[3-[3-fluoro-4-[4-(cyano methyl)-1-piperazinyls] phenyl]-P-132 Z (c)
2-oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 369 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano methyl)-1-piperazinyls] benzene P-133 dithio second
Base]-2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 370 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano methyl)-1-piperazinyls] benzene P-133 Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides 371 (S)-N-[[3-[3,5-two fluoro-4-[4 cyano methyls)-the 1-piperazinyl] benzene P-133 Z (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 372 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano methyl)-1-piperazinyls] benzene P-133 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 373 373 (S)-N-[[3-[4-[4-(cyano methyl)-1-piperazinyl] phenyl]-2-P-134 dithio second
Oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 374 (S)-N-[[3-[4-[4-(cyano methyl)-1-piperazinyl] phenyl]-2-oxo P-134 Z (a)
-5-oxazolidinyl] methyl] rosickyite is for acid amides 375 (S)-N-[[3-[4-[4-(cyano methyl)-1-piperazinyl] phenyl]-2-oxo P-134 Z (b)
-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 376 (S)-N-[[3-[4-[4-(cyano methyl)-1-piperazinyls] phenyl]-2-oxygen P-134 Z (c)
Generation-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 377 (S)-N-[[3-[3-fluoro-4-[4-(2-fluoro ethyl)-1-piperazinyl] phenyl]-2-P-135 dithio second
Oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 378 (S)-N-[[3-[3-fluoro-4-[4-(2-fluoro ethyl)-1-piperazinyl] phenyl]-2-P-135 Z (a)
Oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides 379 (S)-N-[[3-[3-fluoro-4-[4-(2-fluoro ethyl)-1-piperazinyl] phenyl]-2-P-135 Z (b)
Oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 380 (S)-N-[[3-[3-fluoro-4-[4-(2-fluoro ethyl)-1-piperazinyls] phenyl]-2-P-135 Z (c)
Oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 381 (S)-N-[[3-[3,5-two fluoro-4-[4-(2-fluoro ethyl)-1-piperazinyl] benzene P-136 dithio second
Base]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide acetoacetic ester 382 (S)-N-[[3-[3,5-two fluoro-4-[4-(2-fluoro ethyl)-1-piperazinyl] benzene P-136 Z (a)
Base]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 383 (S)-N-[[3-[3,5-two fluoro-4-[4-(2-fluoro ethyl)-1-piperazinyl] benzene P-136 Z (b)
Base]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 384 (S)-N-[[3-[3,5-two fluoro-4-[4-(2-fluoro ethyl)-1-piperazinyl] benzene P-136 Z (c)
Base]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides 385 (S)-N-[[3-[4-[4-(2-fluoro ethyl)-1-piperazinyl] phenyl]-2-oxo P-137 dithio second
-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 386 (S)-N-[[3-[4-[4-(2-fluoro ethyl)-1-piperazinyl] phenyl]-2-oxo P-137 Z (a)
-5-oxazolidinyl] methyl] rosickyite is for acid amides 387 (S)-N-[[3-[4-[4-(2-fluoro ethyl)-1-piperazinyl] phenyl]-2-oxo P-137 Z (b)
-5-oxazolidinyl] methyl]-2-methyl-prop thioamides 388 (S)-N-[[3-[4-[4-(2-fluoro ethyl)-1-piperazinyl] phenyl]-2-oxo P-137 Z (c)
-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides 389 (S)-N-[[3-[3-fluoro-4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxygen P-138 dithio second
Generation-5-oxazolidinyl] methyl] thioacetamide; Ultimate analysis theoretical acid ethyl ester
Value C
17H
21FN
4O
3S:C, 53.67; H, 5.56; N, 14.73; S,
8.43。Measured value: C, 53.14; H, 5.42; N, 14.25; S,
8.18。390 (S)-N-[[3-[3-fluoro-4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxygen P-138 Z (a)
Generation-5-oxazolidinyl] methyl] rosickyite is for acid amides; Mp166-167 ℃;
Ultimate analysis theoretical value C
18H
23FN
4O
3S:C, 54.81; H,
5.88；N，14.20；S，8.13。Measured value: C, 54.83; H,
6.00；N，14.12；S，7.96。391 (S)-N-[[3-[3-fluoro-4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxygen P-138 Z (b)
Generation-5-oxazolidinyl] methyl]-2-methyl-prop thioamides; Mp 157-
158 ℃: ultimate analysis theoretical value C
19H
25FN
4O
3S:C,
55.87，H，6.17；N，13.72；S，7.85。Measured value: C,
55.67；H，6.19；N，13.50；S，7.70。392 (S)-N-[[3-[3-fluoro-4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxygen P-138 Z (c)
Generation-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides; Mp 178-
179 ℃; Ultimate analysis theoretical value C
19H
23FN
4O
3S:C, 56.14;
H，5.70；N，13.78；S，7.89。Measured value: C, 56.13; H,
5.64；N，13.64；S.7.75。393 (S)-N-[[3-[3,5-two fluoro-4-(4-formyl radical-1-piperazinyl)-phenyl]-P-139 dithio second
2-oxo-5-oxazolidinyl] methyl] thioacetamide acetoacetic ester 394 (S)-N-[[3-[3,5-two fluoro-4-(4-formyl radical-1-piperazinyl)-phenyl]-P-139 Z (a)
2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides 395 (S)-N-[[3-[3,5-two fluoro-4-(4-formyl radical-1-piperazinyl)-phenyl]-P-139 Z (b)
2-oxo-5-oxazolidinyl] methyl]-2-methyl-rosickyite is for acid amides 396 (S)-N-[[3-[3,5-two fluoro-4-(4-formyl radical-1-piperazinyl)-phenyl]-P-139 Z (c)
2-oxo-5-oxazolidinyl] methyl] ring-rosickyite is for carboxylic acid amides
397 (S)-N-[[3-[4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxo-5-P-140 dithio second
Oxazolidinyl] methyl] the thioacetamide acetoacetic ester
398 (S)-N-[[3-[4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxo-5-P-140 Z (a)
Oxazolidinyl] methyl] rosickyite is for acid amides
399 (S)-N-[[3-[4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxo-5-P-140 Z (b)
Oxazolidinyl] methyl]-2-methyl-prop thioamides
400 (S)-N-[[3-[4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxo-5-P-140 Z (c)
Oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides
In total method of embodiment 31 steps 1, replace compound 33 with an amount of following amine, obtained lsothiocyanates corresponding to amine P-90, P-93, P-99, P-105, P-126 and P-129.
In total method of embodiment 114, replace compound 82 and methylamine with an amount of following lsothiocyanates and amine, obtained following product respectively.
Table I embodiment product is corresponding to the different amine of amine sequence number
Thiocyanic ester 401 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-the P-90 methylamine
2-oxo-5-oxazolidinyl]-methyl]-N ＇-methylthiourea 402 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-the P-90 dimethyl amine
2-oxo-5-oxazolidinyl]-methyl]-N ＇, N ＇-dimethyl thiourea 403 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-the P-90 azetidin
2-oxo-5-oxazolidinyl]-methyl]-1-azetidine sulfane
For carboxylic acid amides 404 (S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl)-phenyl]-2-oxygen P-90 anhydrous ammonia
Generation-5-oxazolidinyl] methyl]-thiocarbamide 405 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazine P-93 methylamine
Base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N ＇-methyl
Thiocarbamide 406 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazine P-93 dimethylamine
Base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N ＇, N ＇-two
Methylthiourea 407 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazine P-93 azetidin
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-the 1-azacycloalkyl
Butane thiocarboxamide 408 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazine P-99 methylamine
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N ＇-first
Base thiocarbamide 409 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazine P-99 dimethyl amine
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N ＇, N ＇-
Dimethyl thiourea 410 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazine P-99 azetidin
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-the 1-azane
Heterocycle butane thiocarboxamide 411 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyls] the P-105 methylamine
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N '-methyl sulphur
Urea 412 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] the P-105 dimethyl amine
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N ＇, N '-diformazan
Base thiocarbamide 413 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] the P-105 azetidin
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-the 1-azetidine
Alkane thiocarboxamide 414 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] the P-126 methylamine
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N '-methyl sulphur
Urea 415 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] the P-126 dimethyl amine
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N ＇, N ＇-diformazan
Base thiocarbamide 416 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] the P-126 azetidin
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-the 1-azetidine
Alkane thiocarboxamide 417 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) benzene P-129 methylamine
Base]-2-oxo-5-oxazolidinyl]-methyl]-N '-methylthiourea 418 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) benzene P-129 dimethyl amine
Base]-2-oxo-5-oxazolidinyl]-methyl]-N ＇, N ＇-dimethyl
Thiocarbamide 419 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) benzene P-129 azetidin
Base]-2-oxo-5-oxazolidinyl]-methyl]-1-azetidine alkane
Thiocarboxamide
In the total method at embodiment 100, an amount of following lsothiocyanates and alcohol use in the mode that is similar to compound 82 and methyl alcohol, have obtained following corresponding compounds respectively.
Table J embodiment product is corresponding to the different amine of amine sequence number
Thiocyanic ester 420 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-P-90 methyl alcohol
2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-amino
Manthanoate 421 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-P-90 ethanol
2-oxo-5-oxazolidinyl]-methyl]-O-ethylenebis dithiocarbamate amino
Manthanoate 422 (S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-the P-90 Virahol
2-oxo-5-oxazolidinyl]-methyl]-O-isopropylthio ammonia
Carbamate 423 (S)-N-[[3-[3,5-difluoro 4-(4-ethanoyl-1-piperazinyl) benzene P-91 methyl alcohol
Base]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-
Carbamate 424 (S)-N-[[3-[4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxygen P-92 methyl alcohol
Generation-5-oxazolidinyl]-methyl]-O-methyl thiocarbamate
Ester 425 425 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-P-P-93 methyl alcohol
93 methyl alcohol piperazinyls] phenyl]-2-oxo-5-oxazolidinyl]-first
Base]-O-methyl thiocarbamate 426 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazine P-93 ethanol
Base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-the O-ethyl
Thiocarbamate 427 (S)-N-[[3-[3-fluoro-4-[4-(methoxyl group ethanoyl)-1-piperazine P-93 Virahol
Base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-O-different third
Base thiocarbamate 428 (S)-N-[[3-[3,5-two fluoro-[4-[4-(methoxyl group-ethanoyl)-1-P-94 methylamine
Piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-
Methyl thiocarbamate 429 (S)-N-[[3-[4-[4-(methoxyl group ethanoyl)-1-piperazinyl] benzene P-95 methylamine
Base]-2-oxo-5-oxazolidinyl] methyl]-O-methyl sulfo-ammonia
Carbamate 430 (S)-N-[3-[3-fluoro-4-[4-(cyano group ethanoyl)-1-piperazinyl] P-96 methyl alcohol
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulphur
For carbamate 431 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano group ethanoyl)-1-piperazine P-97 methyl alcohol
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-the O-first
Base thiocarbamate 432 (S)-N-[[3-[4-[4-(cyano group ethanoyl)-1-piperazinyl] benzene P-98 methyl alcohol
Base]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-
Carbamate 433 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazine P-99 methyl alcohol
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-the O-first
Base thiocarbamate 434 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazine P-99 ethanol
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-O-second
Base thiocarbamate 435 (S)-N-[[3-[3-fluoro-4-[4-(acetoxyl group ethanoyl)-1-piperazine P-99 Virahol
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-O-is different
Propyl thiocarbamate 436 (S)-N-[[3-[3,5-two fluoro-4-[4-(acetoxyl group ethanoyl)-P-100 methyl alcohol
The 1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-
O-methyl thiocarbamate 437 (S)-N-[[3-[4-[4-(acetoxyl group ethanoyl)-1-piperazinyl] P-101 methyl alcohol
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulphur
For carbamate 438 (S)-N-[[3-[3-fluoro-4-[4-(benzyloxy ethanoyl)-1-piperazine P-102 methyl alcohol
Base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-the O-methyl
Thiocarbamate 439 (S)-N-[[3-[3,5-two fluoro-4-[4-(benzyloxy-ethanoyl)-1-P-103 methyl alcohol
Piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-
Methyl thiocarbamate 440 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] P-105 methyl alcohol
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulphur
For carbamate 441 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] P-105 ethanol
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-O-ethyl sulphur
For carbamate 442 (S)-N-[[3-[3-fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl] the P-105 Virahol
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-the O-sec.-propyl
Thiocarbamate 443 (S)-N-[[3-[3,5-two fluoro-4-[4-(methoxyl group-carbonyl)-1-piperazine P-106 methyl alcohol
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-first
Base thiocarbamate 444 (S)-N-[[3-[4-[4-(methoxycarbonyl)-1-piperazinyl] benzene P-107 methyl alcohol
Base]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-
Carbamate 445 (S)-N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyl] benzene P-108 methyl alcohol
Base]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-
Carbamate 446 (S)-N-[[3-[3,5-two fluoro-4-[4-(methylsulfonyl)-1-piperazine P-109 methyl alcohol
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-methyl
Thiocarbamate 447 (S)-N-[[3-[4-[4-(methylsulfonyl)-1-piperazinyl] phenyl]-P-110 methyl alcohol
2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-amino
Manthanoate 448 (S)-N-[[3-[3-fluoro-4-[4-(ethylsulfonyl)-1-piperazinyl] benzene P-111 methyl alcohol
Base]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-
Carbamate 449 (S)-N-[[3-[3,5-two fluoro-4-[4-(ethylsulfonyl)-1-piperazine P-112 methyl alcohol
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl] ring rosickyite generation
Carboxylic acid amides 450 (S)-N-[[3-[4-[4-(ethylsulfonyl)-1-piperazinyl] phenyl]-P-113 methyl alcohol
2-oxo-5-oxazolidinyl] methyl]-O-methyl sulfo-amino
Manthanoate 451 (S)-N-[[3-[3-fluoro-4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] P-114 methyl alcohol
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methyl sulfo-
Carbamate 452 (S)-N-[[3-[3,5-two fluoro-4-[4-(chloro-methylsulfonyl)-1-piperazine P-115 methyl alcohol
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-first
Base-thiocarbamate 453 (S)-N-[[3-[4-[4-(chloromethane alkylsulfonyl)-1-piperazinyl] benzene P-116 methyl alcohol
Base]-2-oxo-5-oxazolidinyl] methyl]-O-methyl sulfo-ammonia
Carbamate 454 (S)-N-[[3-[3-fluoro-4-[4-(cyano group methylsulfonyl)-1-piperazine P-117 methyl alcohol
Base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-methyl
Thiocarbamate 455 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano group methylsulfonyl)-1-P-118 methyl alcohol
Piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-
Methyl thiocarbamate 456 (S)-N-[[3-[4-[4-(cyano group methylsulfonyl)-1-piperazinyl] benzene P-119 methyl alcohol
Base]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-
Carbamate 457 (S)-N-[[3-[3-fluoro-4-[4-(N-methyl-sulfamyl)-1-piperazine P-120 methyl alcohol
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-first
Base thiocarbamate 458 (S)-N-[[3-[3,5-two fluoro-4-[4-(N-methyl-sulfamyl)-P-121 methyl alcohol
The 1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-
Methyl thiocarbamate 459 (S)-N-[[3-[4-[4-(N-methyl sulfamyl)-1-piperazinyl] P-122 methyl alcohol
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulphur
For carbamate 460 (S)-N-[[3-[3-fluoro-4-[4-(N, N-dimethyl-sulfamyl)-P-123 methyl alcohol
The 1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-
Methyl thiocarbamate 461 (S)-N-[[3-[3,5-two fluoro-4-[4-(N, N-dimethyl-sulphonamide P-124 methyl alcohol
Base)-and the 1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] first
Base]-O-methyl thiocarbamate 462 (S)-N-[[3-[4-[4-(N, N-dimethylamino alkylsulfonyl)-1-piperazine P-125 methyl alcohol
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-first
Base thiocarbamate 463 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] P-126 methyl alcohol
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulphur
For carbamate 464 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] P-126 ethanol
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-O-ethyl sulphur
For carbamate 465 (S)-N-[[3-[3-fluoro-4-[4-(ethoxy carbonyl)-1-piperazinyl] the P-126 Virahol
Phenyl]-2-oxo-5-oxazolidinyl]-methyl]-the O-sec.-propyl
Thiocarbamate 466 (S)-N-[[3-[3,5-two fluoro-4-[4-(oxyethyl group-carbonyl)-1-piperazine P-127 methyl alcohol
The piperazine base] phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-first
Base thiocarbamate 467 (S)-N-[[3-[4-[4-(ethoxy carbonyl)-1-piperazinyl] benzene P-128 methyl alcohol
Base]-2-oxo-5-oxazolidinyl] methyl]-O-methyl sulfo-ammonia
Carbamate 468 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) benzene P-129 methyl alcohol
Base]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-
Carbamate, 469 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) benzene P-129 ethanol
Base]-2-oxo-5-oxazolidinyl] methyl]-O-ethylenebis dithiocarbamate ammonia
Carbamate 470 (S)-N-[[3-[3-fluoro-4-(4-sulfamyl-1-piperazinyl) benzene P-129 Virahol
Base]-2-oxo-5-oxazolidinyl]-methyl]-O-sec.-propyl sulphur
For carbamate 471 (S)-N-[[3-[3,5-two fluoro-4-(4-sulfamyl-1-piperazinyl) P-130 methyl alcohol
Phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methyl sulfo-
Carbamate 472 (S)-N-[[3-[4-(4-sulfamyl-1-piperazinyl)-phenyl]-2-P-131 methyl alcohol
Oxo-5-oxazolidinyl] methyl]-O-methyl sulfo-amino first
Acid esters 473 (S)-N-[[3-[3-fluoro-4-[4-(cyano methyl)-1-piperazinyl] benzene P-132 methyl alcohol
Base]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-
Carbamate 474 (S)-N-[[3-[3,5-two fluoro-4-[4-(cyano methyl)-1-piperazine P-133 methyl alcohol
Base] phenyl]-2-oxo-5-oxazolidinyl)-methyl]-the O-methyl
Thiocarbamate 475 (S)-N-[[3-[4-[4-(cyano methyl)-1-piperazinyl] phenyl]-P-134 methyl alcohol
2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-amino
Manthanoate
476 (S)-N-[[3-[3-fluoro-4-[4-(2-fluoro ethyl)-1-piperazinyls] benzene P-135 methyl alcohol
Base]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-
Carbamate
477 (S)-N-[[3-[3,5-two fluoro-4-[4-(2-fluoro ethyl)-1-piperazine P-136 methyl alcohol
Base] phenyl]-2-oxo-5-oxazolidinyl]-methyl]-the O-methyl
Thiocarbamate
478 (S)-N-[[3-[4-[4-(2-fluoro ethyl)-1-piperazinyl] phenyl]-2-P-137 methyl alcohol
Oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-amino first
Acid esters
479 (S)-N-[[3-[3-fluoro-4-(4-formyl radical-1-piperazinyl) phenyl]-P-138 methyl alcohol
2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-amino
Manthanoate
480 (S)-N-[[3-[3,5-two fluoro-4-(4-formyl radical-1-piperazinyl) benzene P-139 methyl alcohol
Base]-2-oxo-5-oxazolidinyl]-methyl]-O-methyl sulfo-
Carbamate
481 (S)-N-[[3-[4-(4-formyl radical-1-piperazinyl)-phenyl]-2-oxygen P-140 methyl alcohol
Generation-5-oxazolidinyl] methyl]-O-methyl thiocarbamate
Ester
Embodiment 482. (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene (thiazepin)-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide, thia nitrogen heterocyclic heptantriene S-oxide compound
Step 1. six hydrogen-5-oxo-1,4-thia nitrogen heterocyclic heptantriene is according to Gallego (J.Org.Chem.1993,58, the method preparation of 3905-3911) describing.
Step 2. with lithium aluminium hydride (the 1M THF solution of 5.5ml) be added drop-wise to stirring, six hydrogen-5-oxo-1,0 ℃ of the cooling of 4-thia nitrogen heterocyclic heptantriene (721.5mg), in dry THF (21ml) solution.This reaction mixture was stirred 10 minutes down at 0 ℃, stirred 4 hours under the room temperature then.With this reaction mixture by adding entry (0.2mL), 5N sodium hydroxide solution (0.2ml) and water (0.74mL) carefully successively with stopped reaction.This reaction mixture become thickness and gel.This reaction mixture is filtered with ether (50mL) dilution and by the diatomite plate.(100mL) washs this filter cake with ether.
This filtrate concentrating obtained 1 of 616.6mg, and 4-six hydrogen thia nitrogen heterocyclic heptantrienes are used for the next step immediately with it.
Step 3. to stir, 1, in acetonitrile (14mL) solution of 4-six hydrogen thia nitrogen heterocyclic heptantrienes (596.0mg) and 3,4 difluoro nitrobenzenes (0.51rnL), adding diisopropyl ethyl amine (1.0mL).With this yellow solution reflux 18 hours, cool off then and concentrate.This resistates is washed with methylene dichloride (100ml) dilution and with saturated ammonium chloride solution (35mL).Be separated and with organism drying (MgSO
4), filter and concentrate.By the flash chromatography purifying, use 20% ethyl acetate that is present in the hexane its resistates, obtain the oil of mirbane of 830.2mg as eluent..Mp 115-116 ℃; Ultimate analysis theoretical value C
11H
13FN
2O
2S:C, 51.55; H, 5.11; N, 10.93; S, 12.51.Measured value: C, 51.47; H, 5.12; N, 10.79; S, 12.42.
Step 4. adds 2M CuSO in the suspension of this oil of mirbane (5.5g) in ethanol (260mL) that stir, step 3 preparation
4(11.9ml) aqueous solution.This mixture is cooled to 0 ℃ also adds NaBH in batches
4(4.1g).This reaction mixture becomes very dark and stirred 10 minutes down at 0 ℃, stirs 30 minutes under the room temperature, and reflux is 3 hours then.The refrigerative reaction mixture is washed with ethyl acetate (500ml) dilution and water (200mL).(3 * 200mL) extract with EtOAc with this aqueous mixture.With the organic phase drying (MgSO that merges
4), filter and concentrate and obtain the aniline intermediate.
Step 5. is dissolved in the dark-coloured resistates in the step 4 in 2: 1 acetone (255mL) and is cooled to 0 ℃.In this stirred mixture, add solid carbon potassium hydrogen phthalate (5.4g), add benzyl chloroformate (7.7mL) then.This reaction mixture was stirred 10 minutes at 0 ℃, at room temperature stirred then 24 hours.This reaction mixture with 10% sodium pyrosulfate (200mL) stopped reaction, is poured in the ethyl acetate (300mL) then.Be separated, and (2 * 250mL) extract with ethyl acetate with this water.With the organic phase drying (MgSO that merges
4), filter and concentrate.This resistates is carried out purifying by MPLC,, obtain the carboxylamine benzyl ester of 6.03g, be yellow solid with the 20%EtOAc wash-out that is present in the hexane.Mp 72-74 ℃; Ultimate analysis theoretical value C
19H
21FN
2O
2S:C, 63.31; H, 5.87; N, 7.77; S, 8.89.Measured value: C, 63.31; H, 5.97; N, 7.69; S, 8.79.
Dry THF (33ml) solution of step 6. carbamate (3.0g) that stir, that step 5 obtains is cooled to-78 ℃, by hexane (5.4mL) solution of syringe to the n-Butyl Lithium that wherein drips 1.6M under nitrogen atmosphere.This reaction mixture stirred 35 minutes at-78 ℃, added R-glycidyl butyric ester (1.2mL) then.This reaction mixture was stirred 30 minutes at-78 ℃, at room temperature stir then and spend the night, this intermediate formation precipitation.With this reaction mixture saturated aqueous ammonium chloride (33mL) stopped reaction, and be poured among the EtOAc (100mL).Be separated.Wash this organic phase with saturated sodium bicarbonate aqueous solution (50mL), salt solution (50mL), dry (MgSO
4), filter and concentrate.This resistates by the flash chromatography purifying, as eluent, is obtained the Qiang base methyl oxazolidinone of 2.5g with ethyl acetate.Mp?100-102℃。Ultimate analysis theoretical value C
15H
19FN
2O
3S:C, 55.20; H, 5.87; N, 8.58; S, 9.82.Measured value: C, 55.09; H, 5.91; N, 8.36; S, 9.57.
Step 7. to stir, be cooled in methylene dichloride (35mL) solution of alcohol (1.7g) 0 ℃, step 6 preparation, add triethylamine (1.1mL), add methylsulfonyl chlorine (0.5mL) then.This reaction mixture stirred 10 minutes down at 0 ℃, stirred 1 hour under the room temperature then.This reaction mixture water (35ml) is handled.Be separated and with this water with methylene dichloride (35mL) extraction.With the organic phase drying (MgSO that merges
4), filter and concentrate.By the flash chromatography purifying, use 80% ethyl acetate that is present in the hexane this resistates, obtain the methanesulfonates of 2.1g as eluent.Mp 132-142 ℃. ultimate analysis theoretical value C
16H
21FN
2O
5S
2: C, 47.51; H, 5.23; N, 6.93; S, 15.85.Measured value: C, 47.18; H, 5.28; N, 6.84; S, 15.60.
The methanesulfonates (941.7mg) of that step 8. feed to stir ammonia, step 7 preparation is 1: in the suspension of 1THF/ methyl alcohol (40mL) up to saturated (about 5 minutes).This reaction mixture heated 72 hours at 100 ℃ in the test tube of sealing.The refrigerative reaction mixture concentrated obtains crude product amine, with its immediately suspension in methylene dichloride (35mL) and be cooled to 0 ℃.In the suspension of this stirring, add triethylamine (0.97mL, 6.9mmol), then add di-tert-butyl dicarbonic acid ester (759.5mg, 3.5mmol).This reaction mixture becomes evenly and at room temperature stirred 18 hours.Pour into this reaction mixture in the methylene dichloride (75ml) and water (1 * 50mL) washing.With this organic phase drying (MgSO
4), filter and concentrate.The gained resistates is carried out purifying with the 30-35% ethyl acetate that is present in the methyl alcohol as eluent on Biotage 40S post, obtain the protected amine of 867.4mg.mp?74-75℃。Ultimate analysis theoretical value: C, 56.45; H, 6.63; N, 9.88.Measured value: C, 56.95; H, 6.85; N, 9.55.
Step 9. 1: 1 methanol being cooled in 0 ℃ the suspension of (6mL), adds sodium metaperiodate (113.5mg) to protected amine (205.2mg) that stir, step 8 preparation.To stir 18 hours under the gained suspension room temperature.(2 * 20ml) wash this solid with this reaction mixture filtration and with methylene dichloride.With (1 * 10mL) extraction of this filtrate water.Be separated.With methylene dichloride (1 * 25mL) aqueous phase extracted.With the organic phase drying (MgSO that merges
4), filter and concentrate.The white solid resistates is carried out purifying with 5% methyl alcohol that is present in the methylene dichloride as eluent on Biotage 12 M posts, obtain the sulfoxide of 187.3mg.mp?78-81℃。
Step 10. is methyl alcohol (2mL) solution surface of exsiccant hydrogen chloride gas by sulfoxide (179.3mg) that stir, step 9 preparation, this solution be cooled to 0 ℃ 1 minute.This reaction mixture was stirred 10 minutes down at 0 ℃, at room temperature stirred then 15 minutes, concentrate then.Gained yellow residue suspension in THF (5mL) and methylene dichloride (5mL), and is cooled to 0 ℃.In the suspension of this stirring, add triethylamine (0.46mL), add ethyl dithiocarbamate (0.18mL) then.Reaction mixture that this is dark-coloured stirs and spends the night and concentrate under the room temperature.This dark-coloured resistates is diluted water (2 * 15mL) washings with methylene dichloride (30mL).With this organic phase drying (MgSO
4), filter and concentrate.The resistates that this is dark-coloured carries out purifying with 5% methyl alcohol that is present in the methylene dichloride as eluent on Biotage 12M post, obtain the title compound of 71.5mg, is the tawny solid.mp?85-89℃。
Total method according to embodiment 482 steps 10 provide still with following dithioesters, can obtain showing the compound of embodiment 483 to 495 among the K.
Table K
| ????489 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-3,3-dimethyl butyrate thioamides, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | ??z(g) |
| ????490 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-ring fourth thiocarboxamide, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | ??Z(h) |
| ????491 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-1-encircles penta thiocarboxamide, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | ??Z(i) |
| ????492 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-the hexamethylene thiocarboxamide, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | ??Z(j) |
| ????493 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopropyl second sulfo-an-iide, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | ??Z(k) |
| ????494 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclobutyl second thioamides, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | ??z(l) |
| ????495 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopentyl second thioamides, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | ??Z(m) |
Embodiment 496. (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide, thia nitrogen heterocyclic heptantriene S-oxide compound
According to the method for embodiment 482, by with an amount of 2,6-two fluoro-4-oil of mirbane (trifluoromethane) sulphonates replace 3 in the step 1,4-difluoro nitrobenzene.
With the amine of preparation among the embodiment 496,, obtained the compound of embodiment 497 to 499 among the table L still with the ethyl dithiocarbamate in the following dithioesters replacement final step.
Table L
| ????499 | (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysenes-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | ????Z(c) |
Embodiment 500. (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide, thia nitrogen heterocyclic heptantriene S-oxide compound
According to the method for embodiment 482, by replace 3 in the step 1 with an amount of 4-fluoronitrobenzene, the 4-difluoro nitrobenzene can prepare title compound.
With the amine of preparation among the embodiment 500,, obtained the compound of embodiment 501 to 503 still with the ethyl dithiocarbamate in the following dithioesters replacement final step.
Table M
| ????503 | (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | ????Z(c) |
Embodiment 504. (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide, thia nitrogen heterocyclic heptantriene S, S-dioxide
Step 1. is to the 25%H of thia nitrogen heterocyclic heptantriene (243.7mg) that stir, the preparation of embodiment 482 steps 8
2In O/ acetone (8mL) solution, add 4-methylmorpholine N-oxide compound (201.5mg), add 2-methyl-2-propyl alcohol (2.5wt%, 30 μ L) solution of perosmic anhydride then.To stir 18 hours under this reaction mixture room temperature.This reaction mixture is handled with the full sodium pyrosulfate (8mL) that closes, poured into then in the methylene dichloride (50mL).Be separated.With methylene dichloride (2 * 25mL) aqueous phase extracted.With organic phase salt solution (1 * 25mL) washing, the dry (MgSO that merges
4), filter and concentrate.Use 1% methyl alcohol that is present in the methylene dichloride as the eluent purifying on Biotage 40S post this resistates, obtain the thia nitrogen heterocyclic heptantriene S of 216.1mg (0.47mmol, 83%), the S-dioxide is white solid.mp?144-146℃。
Step 2. is under 0 ℃, with the thia nitrogen heterocyclic heptantriene S of exsiccant hydrogen chloride gas by stirring, step 1 prepares, the surface of methyl alcohol (3mL) solution of S-dioxide (108.2mg).This reaction mixture was stirred 10 minutes down at 0 ℃, at room temperature stirred then 15 minutes.This reaction is concentrated and yellow residue is suspended among methylene dichloride (2mL) and the THF (2ml).The suspension of this stirring is cooled to 0 ℃ and add triethylamine (0.27mL), adds THF (0.5mL) solution of ethyl dithiocarbamate (0.11mL) then, clean with 0.25mL.This yellow-green soln was stirred 10 minutes down at 0 ℃, at room temperature stirred then 18 hours.Pour into this reaction mixture in the methylene dichloride (20mL) and water (2 * 10mL) washings.With this organic phase drying (MgSO
4), filter and concentrate.This resistates is carried out purifying with 2% methyl alcohol that is present in the methylene dichloride as eluent on Biotage 12 M posts, obtain the title compound of 77.3mg, be white solid.mp?88-90℃。
According to total method of embodiment 504 steps 2, but replace ethyl dithiocarbamate, obtained the compound of the embodiment 505 to 507 among the table N with following dithioesters.
Table N
Embodiment 508. (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide, thia nitrogen heterocyclic heptantriene S, S-dioxide
According to the method for embodiment 504 and 482, by with an amount of 2,6-two fluoro-4-oil of mirbane (trifluoromethane) sulphonates replace 3 in embodiment 482 steps 1, and the 4-difluoro nitrobenzene can prepare title compound.
With the amine of embodiment 508 preparations,, obtained the compound of embodiment 509 to 511 among the table O still with the ethyl dithiocarbamate in the following dithioesters replacement final step.
Table O
Embodiment 512. (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide, thia nitrogen heterocyclic heptantriene S, S-dioxide
According to the method for embodiment 504 and 482, replace 3 in embodiment 482 steps 1 with an amount of 4-fluoronitrobenzene, the 4-difluoro nitrobenzene can prepare title compound.
With the amine among the embodiment 512,, obtained the compound of embodiment 513 to 515 among the table P still with the ethyl dithiocarbamate in the following dithioesters replacement final step.
Table P
Embodiment 516. (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide
According to this compound of embodiment 482 steps 8 preparation, but replace di-tert-butyl dicarbonic acid ester with an amount of ethyl dithiocarbamate; Mp 129-131 ℃.
With the amine of embodiment 482 steps 8 preparation, but replace di-tert-butyl dicarbonic acid ester, obtained the compound of the embodiment 517 to 529 among the table Q with an amount of following dithioesters.
Table Q
| ????523 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-3,3-dimethyl butyrate thioamides | The same | ??Z(g) |
| ????524 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-ring fourth thiocarboxamide | The same | ??Z(h) |
| ????525 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-ring penta thiocarboxamide | The same | ??Z(i) |
| ????526 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-the hexamethylene thiocarboxamide | The same | ??Z(j) |
| ????527 | (5S)-N-[[3-[3-5 fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopropyl second thioamides | The same | ??Z(k) |
| ????528 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclobutyl second thioamides | The same | ??Z(l) |
| ????529 | (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-cyclopentyl second thioamides | The same | ??Z(m) |
Embodiment 530. (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide
According to the method for embodiment 482 and embodiment 516, but with an amount of 2,3 of 6-two fluoro-4-nitrophenyl trifluoromethayl sulfonic acid esters replacement embodiment 482 steps 1, the 4-difluoro nitrobenzene can prepare this compound.
With the amine of embodiment 530 preparations, but replace di-tert-butyl dicarbonic acid ester, can prepare the compound of embodiment 531 to 533 among the table R with an amount of following dithioesters.
Table R
Embodiment 534. (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide; Mp 129-131 ℃
According to the method for embodiment 482 and embodiment 516, but replace 3 in embodiment 482 steps 1 with an amount of 4-fluoronitrobenzene, the 4-difluoro nitrobenzene can prepare this compound.
With the amine of embodiment 534 preparations, but replace di-tert-butyl dicarbonic acid ester, can prepare the embodiment 535 to 537 among the table S with an amount of following dithioesters.
Table S
Embodiment 538. (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide, thia nitrogen heterocyclic heptantriene S-oxide compound
According to the method that embodiment 33 describes, still the amine with embodiment 482 preparations replaces amine 33, can prepare this compound.
Listed amine and alcohol reaction among lsothiocyanates by embodiment 538 preparation and the table T can prepare the compound of embodiment 539 to 544.
Table T
Embodiment 545. (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide, thia nitrogen heterocyclic heptantriene S-oxide compound
According to the method that embodiment 33 describes, still the amine with embodiment 496 preparations replaces amine 33, can prepare this compound.
By the lsothiocyanates and amine of showing to list among the U and alcohol reaction of embodiment 545 preparations, can prepare the compound of embodiment 546 to 551.
Table U
| ????549 | (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysenes-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methyl thiocarbamate, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | ?CH 3OH |
| ????550 | (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysenes-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-ethyl thiocarbamate, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | CH 3CH 2OH |
| ????551 | (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysenes-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-isopropylthio carbamate, thia nitrogen heterocyclic heptantriene S-oxide compound | The same | (CH 3) 2CHOH |
Embodiment 552. (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide, thia nitrogen heterocyclic heptantriene S-oxide compound
According to the method that embodiment 33 describes, still the amine with embodiment 500 preparations replaces amine 33, can prepare this compound.
Amine and the alcohol listed in lsothiocyanates by embodiment 552 preparation and the Table V react, and can prepare the compound of embodiment 553 to 558.
Table V
| Embodiment number | Compound | Lsothiocyanates | Amine or alcohol |
Embodiment 559. (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide, thia nitrogen heterocyclic heptantriene S, S-dioxide
According to the method that embodiment 33 describes, still the amine with embodiment 504 preparations replaces amine 33, can prepare this compound.
By the lsothiocyanates and amine of showing to list among the W and alcohol reaction of embodiment 559 preparations, can prepare the compound of embodiment 560 to 565.
Table W
| ????565 | 565 (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysenes-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-isopropylthio carbamate, thia nitrogen heterocyclic heptantriene S, the S-dioxide | The same | (CH 3) 2CHOH |
Embodiment 566. (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide, thia nitrogen heterocyclic heptantriene S, S-dioxide
According to the method that embodiment 33 describes, still the amine with embodiment 508 preparations replaces amine 33, can prepare this compound.
Amine and the alcohol listed in lsothiocyanates by embodiment 566 preparation and the Table X react, and can prepare the compound of embodiment 561 to 572.
Table X
| ????569 | (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysenes-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-1-azetidine thiocarboxamide, thia nitrogen heterocyclic heptantriene S, the S-dioxide | The same | Azetidine |
| ????570 | (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysenes-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methyl thiocarbamate, thia nitrogen heterocyclic heptantriene S, the S-dioxide | The same | ??CH 3OH |
| ????571 | (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysenes-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-ethyl thiocarbamate, thia nitrogen heterocyclic heptantriene S, the S-dioxide | The same | CH 3CH 2OH |
| ????572 | (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysenes-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-isopropylthio carbamate, thia nitrogen heterocyclic heptantriene S, the S-dioxide | The same | (CH 3) 2CHOH |
Embodiment 573. (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide, thia nitrogen heterocyclic heptantriene S, S-dioxide
According to the method that embodiment 33 describes, still the amine with embodiment 512 preparations replaces amine 33, can prepare this compound.
By the lsothiocyanates and amine of showing to list among the Y and alcohol reaction of embodiment 573 preparations, can prepare the compound of embodiment 574 to 579.
Table Y
Embodiment 580. (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide
According to the method that embodiment 33 describes, still the amine with the preparation of embodiment 482 steps 8 replaces amine 33, can prepare this compound.
By the lsothiocyanates and amine of showing to list among the Z and alcohol reaction of embodiment 580 preparations, can prepare the compound of embodiment 581 to 586.
Table Z
Embodiment 587. (5S)-N-[[3-[3,5-difluoro 4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide
According to the method that embodiment 33 describes, still the amine with embodiment 530 preparations replaces amine 33, can prepare this compound.
Amine and the alcohol listed among lsothiocyanates by embodiment 587 preparation and the Table A A react, and can prepare the compound of embodiment 588 to 593.
Table A A
| ????592 | (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-ethyl thiocarbamate | The same | CH 3CH 2OH |
| ????593 | (5S)-N-[[3-[3,5-two fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-isopropylthio carbamate I | The same | (CH 3) 2CHOH |
Embodiment 594. (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thiocarbamide
According to the method that embodiment 33 describes, still the amine with embodiment 534 preparations replaces amine 33, can prepare this compound.
By the lsothiocyanates and amine of showing to list among the BB and alcohol reaction of embodiment 594 preparations, can prepare the compound of embodiment 595 to 600.
Table BB
| ????597 | (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-1-azetidine thiocarboxamide | The same | Azetidine |
| ????598 | (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methyl thiocarbamate | The same | CH 3OH |
| ????599 | (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-ethyl thiocarbamate | The same | CH 3CH 2OH |
| ????600 | (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-isopropylthio carbamate | The same | (CH 3) 2CHOH |
Claims (11)
1. the compound of following formula
Z wherein
2Be-O
2S-,-O-, N (R
107)-,-OS-or-S-;
W is 0,1,2 or 3;
R
23And R
24Identical or different, and can be H or F; And
R
1Be H, NH
2, NH alkyl C
1-C
4N (alkyl C
1-C
4)
2 
Alkyl C
1-C
4O alkyl C
1-C
4S alkyl C
1-C
4By 1-3 F, a 1-2 Cl, CN or-COO alkyl C
1-C
4Or cycloalkyl C
3-C
6The alkyl C that replaces
1-C
4Alkane, wherein each alkyl can be straight or branched when occurring at every turn; And
R
107Be
a)R
102O-C(R
110)(R
111)-C(O)-，
b)R
103O-C(O)-，
c)R
108-C(O)-，
d)R
109-SO
2-，
e)NC-CH
2-，
F) FCHCH
2-, or
g)R
150R
151NSO
2；
R wherein
102Be H, CH
3-, phenyl-CH
2-or CH
3C (O); Each R
110And R
111Be selected from H or CH
3R
103Be alkyl C
1-C
3Or phenyl; R
108Be H, alkyl C
1-C
4, aryl (CH
2)
0-5, CNCH
2-, ClCH
2-, Cl
2HC-, FH
2C-, F
2HC-or cycloalkyl C
3-C
6R
150And R
151Identical or different and be selected from H, alkyl C
1-C
4Or R
150And R
151The nitrogen-atoms that connects with them forms the monocyclic heterocycles that contains 3 to 6 carbon atoms.
2. the compound of claim 1, wherein Z
2Be-O
2S-.
3. the compound of claim 2, its be (5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide, thia nitrogen heterocyclic heptantriene S, S-dioxide.
4. the compound of claim 1, wherein Z
2Be-OS-.
5. the compound of claim 4 wherein is
(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-rosickyite is for acid amides, thiomorpholine S-oxide compound;
(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides, thiomorpholine S-oxide compound;
(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides, thiomorpholine S-oxide compound;
(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-methyl thiocarbamate, thiomorpholine S-oxide compound;
(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-ethyl thiocarbamate, thiomorpholine S-oxide compound;
(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-O-isopropylthio carbamate, thiomorpholine S-oxide compound;
(5S)-N-[[3-[3-fluoro-4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide, thia nitrogen heterocyclic heptantriene S-oxide compound;
(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-N ', N ＇-dimethyl thiourea, thiomorpholine S-oxide compound; Or
(S)-N-[[3-[3-fluoro-4-(4-thio-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-1-azetidine thiocarboxamide, thiomorpholine S-oxide compound.
6. the compound of claim 1, wherein Z
2Be O.
7. the compound of claim 6, it is
(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-the O-ethyl thiocarbamate;
(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides;
(S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-encircle rosickyite for carboxylic acid amides.
8. the compound of claim 1, wherein Z
2Be S.
9. the compound of claim 8, its be (5S)-N-[[3-[4-(tetrahydrochysene-1,4-thia nitrogen heterocyclic heptantriene-4 (5H)-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-thioacetamide.
10. the compound of claim 1, wherein Z
2Be-N (R
107).
11. the compound of claim 10, it is
(S)-and N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl-2-oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides;
(S)-and N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides;
(S)-and N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides;
(S)-N-[[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide;
(S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides;
(S)-N-[[3-[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides;
(S)-and N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides;
(S)-and N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides;
(S)-N-[[3-[3-fluoro-4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide;
(S)-N-[[3-[3-fluoro-4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] rosickyite is for acid amides;
(S)-N-[[3-[3-fluoro-4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-2-methyl-prop thioamides;
(S)-N-[[3-[3-fluoro-4-(4-formyl radical-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] encircle rosickyite for carboxylic acid amides; Or
(S)-N-[[3-fluoro-4-(4-ethanoyl-1-piperazinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1998/025308 WO2000032599A1 (en) | 1998-11-27 | 1998-11-27 | Oxazolidinone antibacterial agents having a thiocarbonyl functionality |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1322204A true CN1322204A (en) | 2001-11-14 |
Family
ID=22268382
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98814326A Pending CN1322204A (en) | 1998-11-27 | 1998-11-27 | Oxazolidinone antibacterial agents having thiocarbonyl functionality |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1133493A1 (en) |
| JP (1) | JP2002531455A (en) |
| KR (1) | KR20010107987A (en) |
| CN (1) | CN1322204A (en) |
| AU (1) | AU764980B2 (en) |
| CA (1) | CA2351062A1 (en) |
| HK (1) | HK1040707A1 (en) |
| WO (1) | WO2000032599A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113603683A (en) * | 2015-07-17 | 2021-11-05 | 结核病药物开发全球联盟公司 | Substituted phenyl oxazolidinones for antimicrobial therapy |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6297242B1 (en) * | 1999-08-12 | 2001-10-02 | Ortho-Mcneil Pharmaceutical, Inc. | N-substituted amidine and guanidine oxazolidinone antibacterials and methods of use thereof |
| AU2001269370B2 (en) * | 2000-07-17 | 2005-10-27 | Ranbaxy Laboratories Limited | Oxazolidinone derivatives as antimicrobials |
| JP4170753B2 (en) * | 2000-10-17 | 2008-10-22 | ファルマシア・アンド・アップジョン・カンパニー・エルエルシー | Method for producing oxazolidinone compound |
| GB0108793D0 (en) * | 2001-04-07 | 2001-05-30 | Astrazeneca Ab | Chemical compounds |
| EP1409464A4 (en) * | 2001-07-16 | 2005-11-02 | Ranbaxy Lab Ltd | Oxazolidinone derivatives as potential antimicrobials |
| US6956040B2 (en) | 2001-07-16 | 2005-10-18 | Ranbaxy Laboratories Limited | Oxazolidinone piperazinyl derivatives as potential antimicrobials |
| WO2004018439A1 (en) * | 2002-08-22 | 2004-03-04 | Orchid Chemicals & Pharmaceuticals Ltd | Novel antibacterial agents |
| EP1620433A1 (en) * | 2003-04-07 | 2006-02-01 | Ranbaxy Laboratories, Ltd. | Oxazolidinone derivatives as antimicrobials |
| US7265140B2 (en) * | 2003-09-23 | 2007-09-04 | Pfizer Inc | Acyloxymethylcarbamate prodrugs of oxazolidinones |
| EP1802613A1 (en) * | 2004-10-11 | 2007-07-04 | Ranbaxy Laboratories Limited | Substituted oxazolidinone derivatives |
| WO2006043121A1 (en) * | 2004-10-20 | 2006-04-27 | Ranbaxy Laboratories Limited | Oxazolidinone derivatives as antimicrobials |
| EP1819702A1 (en) * | 2004-11-29 | 2007-08-22 | Pharmacia & Upjohn Company LLC | Thiazepine oxazolidinones as antibacterial agents |
| AU2006231919A1 (en) | 2005-04-06 | 2006-10-12 | Pharmacia & Upjohn Company Llc | 7-fluoro-1,3-dihydro-indol-2-one oxazolidinones as antibacterial agents |
| EP1899331B1 (en) | 2005-06-29 | 2009-11-25 | Pharmacia & Upjohn Company LLC | Homomorpholine oxazolidinones as antibacterial agents |
| KR20070038236A (en) * | 2005-10-05 | 2007-04-10 | 일동제약주식회사 | A novel oxazolidinone formamide derivative and manufacturing process thereof |
| WO2007070506A2 (en) | 2005-12-14 | 2007-06-21 | Amgen Inc. | Diaza heterocyclic sulfonamide derivatives and their uses |
| CA2647605A1 (en) | 2006-03-31 | 2007-10-11 | Research Foundation Itsuu Laboratory | Novel compound having heterocyclic ring |
| WO2009001192A2 (en) * | 2007-06-22 | 2008-12-31 | Orchid Research Laboratories Limited | Novel compounds and their use |
| WO2009044777A1 (en) | 2007-10-02 | 2009-04-09 | Research Foundation Itsuu Laboratory | Oxazolidinone derivative having 7-membered hetero ring |
| EP2705028B1 (en) * | 2011-05-06 | 2019-08-21 | Egis Gyógyszergyár Zrt. | Process for the preparation of a rivaroxaban and intermediates formed in said process |
| WO2017066964A1 (en) * | 2015-10-22 | 2017-04-27 | Merck Sharp & Dohme Corp. | Oxazolidinone compounds and methods of use thereof as antibacterial agents |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SK283420B6 (en) * | 1992-05-08 | 2003-07-01 | Pharmacia & Upjohn Company | Oxazolidinones containing a substituted diazine moiety and their use as antimicrobials |
| MY115155A (en) * | 1993-09-09 | 2003-04-30 | Upjohn Co | Substituted oxazine and thiazine oxazolidinone antimicrobials. |
| BR9815518A (en) * | 1997-05-30 | 2000-11-21 | Upjohn Co | Antibacterial oxazolidinone agents having thiocarbonyl functionality |
| WO1999012914A1 (en) * | 1997-09-11 | 1999-03-18 | Hokuriku Seiyaku Co., Ltd. | Thiourea derivatives |
-
1998
- 1998-11-27 WO PCT/US1998/025308 patent/WO2000032599A1/en not_active Application Discontinuation
- 1998-11-27 CA CA002351062A patent/CA2351062A1/en not_active Abandoned
- 1998-11-27 AU AU17053/99A patent/AU764980B2/en not_active Ceased
- 1998-11-27 JP JP2000585241A patent/JP2002531455A/en active Pending
- 1998-11-27 KR KR1020017006622A patent/KR20010107987A/en active IP Right Grant
- 1998-11-27 EP EP98961822A patent/EP1133493A1/en not_active Withdrawn
- 1998-11-27 CN CN98814326A patent/CN1322204A/en active Pending
-
2002
- 2002-03-27 HK HK02102339.4A patent/HK1040707A1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113603683A (en) * | 2015-07-17 | 2021-11-05 | 结核病药物开发全球联盟公司 | Substituted phenyl oxazolidinones for antimicrobial therapy |
Also Published As
| Publication number | Publication date |
|---|---|
| AU764980B2 (en) | 2003-09-04 |
| CA2351062A1 (en) | 2000-06-08 |
| HK1040707A1 (en) | 2002-06-21 |
| KR20010107987A (en) | 2001-12-07 |
| JP2002531455A (en) | 2002-09-24 |
| EP1133493A1 (en) | 2001-09-19 |
| AU1705399A (en) | 2000-06-19 |
| WO2000032599A1 (en) | 2000-06-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1138765C (en) | Oxazolidinone antibacterial agents having a thiocarbonyl functionality | |
| CN1322204A (en) | Oxazolidinone antibacterial agents having thiocarbonyl functionality | |
| CN1072222C (en) | Phenyloxazolidinones having a C-C bond to 4-8 membered heterocyclic rings | |
| CN1639135A (en) | N-aryl-2-oxazolidinone-5-carboxamides and their derivatives and their use as antibacterials | |
| CN100338061C (en) | Alkyne-aryl phosphodiesterase-4 inhibitors | |
| CN1434805A (en) | Selective neurokinin antagonists | |
| CN1170827C (en) | Benzofurylpyrone derivatives | |
| CN1444582A (en) | Heterocyclic compound, their preparation and use | |
| CN101068545A (en) | Spiropiperidine compounds useful as beta-secretase inhibitors for the treatment of alzhermer disease | |
| CN1016778B (en) | Spiro-substituted glutaramida diuretic agents | |
| CN1897936A (en) | Cyclic guanidines, compositions containing such compounds and methods of use | |
| CN1657523A (en) | Cyclic compounds | |
| CN1898199A (en) | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer's disease | |
| CN1649863A (en) | Derivatives of 4-(imidazol-5-yl)-2-(4-sulfoanilino)pyrimidine with CDK inhibitory activity | |
| CN1255401C (en) | Aroyl-piperazine derivatives, their preparation and their use as tachykinin antagonists | |
| CN1649859A (en) | Substituted phenylacetamides and their use as glucokinase activators | |
| CN1798738A (en) | Biaryl substituted pyrazoles as sodium channel blockers | |
| CN1934091A (en) | Imidazole compounds for the treatment of neurodegenerative disorders | |
| CN1432015A (en) | Indazoles substituted with 1,1-dioxoisothiazolidine useful as inhibitors of cell proliferation | |
| CN101035765A (en) | Sulfonamide derivatives | |
| CN1630655A (en) | Dual action antibiotics | |
| CN85108556A (en) | The preparation method of novel benzoxazol base and benzothiazolyl amino derivative and application thereof | |
| CN1294126C (en) | N-phenyl-arylsulfonamide compound, drug comprising the compound as active ingredient, intermediate for the compound | |
| CN1642927A (en) | Cyclic amides | |
| CN1197849C (en) | 2,3,4,5-tetrahydro-1H-[1,4] benzodiazepine-3-hydroxamic acid as matrix metalloproteinase inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| AD01 | Patent right deemed abandoned | ||
| C20 | Patent right or utility model deemed to be abandoned or is abandoned | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1040707 Country of ref document: HK |