What is claimed is:
1. A process for preparing a compound of formula (3)
99
wherein
R1 is selected from the group consisting of hydrogen, an amino protecting group, and OR2;
R2 is hydrogen or a hydroxy protecting group;
L1 is O or N(R3), wherein R3 is hydrogen or an amino protecting group;
and
X is O or S,
the process comprising:
(a) reacting a compound of formula (2)
100
wherein
R4 is a carboxyl protecting group,
with a reducing agent to provide a first reaction mixture;
and
(b) adjusting the pH of the first reaction mixture to about 2 to about 6;
and
(c) isolating the compound of formula (3).
2. The process of claim 1 further comprising reacting a compound of formula (1)
101
a base, and a reagent selected from the group consisting of phosgene, thiophosgene, triphosgene, carbonyldiimidazole, thiocarbonyldiimidazole, and a dialkyl carbonate.
3. The process of claim 1, wherein the compound of formula (3) is (4R)-4-(hydroxymethyl)-1,3-oxazolidin-2-one.
4. A process for preparing a compound of formula (5-a)
102
or
a compound of formula (5-b)
103
wherein
Q1 is selected from the group consisting of halide, methanesulfonate, and trifluoromethanesulfonate;
Y is nitrogen or C(H);
R6 is selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, aminosulfonyl, aminosulfonylalkyl, aryl, arylalkyl, cyano, cyanoalkyl, halo, haloalkyl, (heterocycle)oxy, (heterocycle)oxyalkyl, hydroxy, hydroxyalkyl, phenylalkoxy, phenylalkoxyalkyl phenoxy, phenoxyalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl, perfluorothioalkoxy, perfluorothioalkoxyalkyl, sulfinyl, sulfinylalkylsulfonyl, sulfonylalkyl, thioalkoxy, and thioalkoxyalkyl;
and
L2 is O or S,
the process comprising:
(a) activating the hydroxyl of the compound of formula (3)
104
(b) reacting the product of step (a), a compound of formula (4)
105
and base to provide the compound of formula (5-a)
106
(c) optionally oxidizing the product of step (b);
and
(d) optionally reacting the product of step (b) or step (c) and a compound of formula (6)
107
wherein
Q2 is selected from the group consisting of trialkylstannanes, boronic acid, boronic esters, magnesium halides, zinc halides, and silyl(alkyl)cyclobutanes,
and a coupling catalyst.
5. The process of claim 4, wherein the compound of formula (5-a) is (4R)-4-((4-bromophenoxy)methyl)-1,3-oxazolidin-2-one and the compound of formula (5-b) is (4R)-4-(((4-(trifluoromethoxy)(1,1-biphenyl)-4-yl)oxy)methyl)-1,3-oxazolidin-2-one.
6. A process for preparing a compound of formula (5-c)
108
the process comprising:
(a) reacting a compound of formula (7)
109
wherein
R4 is alkyl,
a compound of formula (4)
110
and base to provide a compound of formula (8)
111
(b) optionally reacting the product from step (a) and an oxidant;
(c) reacting the product of step (a) or step (b), hydrogen, and a hydrogenation catalyst to provide a compound of formula (9)
112
(d) reacting the product from step (c) and base to provide a compound of formula (10)
113
(e) reacting the product from step (d) and a compound of formula H2NOR2, or a salt thereof,
wherein
R2 is a hydroxyl protecting group,
under dehydrating conditions to provide a compound of formula (11)
114
(f) reacting the product of step (e) under Mitsunobu conditions to provide a compound of formula (12)
115
(g) reacting the product from step (f) and base to provide a compound of formula (13)
116
and
(h) reacting the product from step (g) and azide under dehydrating conditions.
7. The process of claim 6, wherein the compound of formula (5-c) is (5R)-1-(benzyloxy)-5-((4-bromophenoxy)methyl)-2-imidazolidinone.
8. A process for preparing a compound of formula (15)
117
wherein
R5 is Q1 or
118
the process comprising:
(a) reacting a compound of formula (5)
119
and base.
9. The process of claim 8, wherein the compound of formula (15) is selected from the group consisting of
(2S)-2-amino-3-((4-(trifluoromethoxy)(1,1-biphenyl)-4-yl)oxy)-1-propanol,
(2S)-2-amino-3-(4-bromophenoxy)-1-propanol,
and
(2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)-1-propanamine.
10. A process for preparing of a compound of formula (20),
120
or a salt thereof,
wherein
R7 and R8, together with the atoms to which they are attached, form a heterocycle selected from the group consisting of 5,5-dimethyl-1,3-oxazolidine-2,4-dionyl; 1-methyl-2,4-imidazolidinedionyl; 1,5,5-trimethyl-2,4-imidazolidinedionyl; 2,4-imidazolidinedionyl; 5,5-dimethyl-2,4-imidazolidinedionyl; 1,2-dimethyl-1,2,4-triazolidine-3,5-dionyl; 4,4-dimethyl-2,6-piperidinedione; 8-azaspiro(4.5)decane-7,9-dionyl; 3a,6-dihydro-1H-benzo(de)isoquinoline-1,3(2H)-dionyl; 2,4(1H,3H)-quinazolinedionyl; 1-methyl-2,4(1H,3H)-pyrimidinedionyl;
and 1,1-dioxo-1,2-benzisothiazol-3(2H)-onyl,
the process comprising:
(a) reacting a compound of formula (15-a)
121
and a compound of formula R9CHO,
wherein
R9 is optionally substituted aryl,
to provide a compound of formula (16)
122
(b) reacting the product of step (a) and a compound of formula (17) under Mitsunobu conditions
123
to provide a compound of formula (18)
124
(c) reacting the product of step (b) and an oxaziridine forming agent to provide a compound of formula (19)
125
(d) reacting the product of step (c) and a compound of formula H2NOR2, or a salt thereof, and base;
and
(e) optionally deprotecting the product of step (d).
11. The process of claim 10, wherein the compound of formula (20) is selected from the group consisting of
3-((2S)-2-(hydroxyamino)-3-((4-(trifluoromethoxy)(1,1-biphenyl)-4-yl)oxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione
and
3-((2S)-3-(4-bromophenoxy)-2-(hydroxyamino)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
12. A process for preparing of a compound of formula (20-b)
126
or a salt thereof
the process comprising:
(a) reacting the compound of formula (20-a)
127
the coupling catalyst, and the compound of formula (6)
128
13. The process of claim 12, wherein the compound of formula (20-b) is 3-((2S)-2-(hydroxyamino)-3-((4-(trifluoromethoxy)(1,1-biphenyl)-4-yl)oxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
14. A process for preparing of a compound of formula (20-c)
129
or a salt thereof,
the process comprising:
(a) reacting a compound of formula (15-b)
130
and a compound of formula (21)
131
to provide a compound of formula (22)
132
and
(b) reacting the product from step (a) and acid.
15. The process of claim 14, wherein the compound of formula (20-c) is 3-((2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
16. A process for preparing a compound of formula (23)
133
the process comprising:
(a) N-formylating the compound of formula (20);
and
(b) optionally deprotecting the product of step (a).
17. The process of claim 16, wherein the compound of formula (23) is selected from the group consisting of
(1S)-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-1-(((4-(trifluoromethoxy)(1,1-biphenyl)-4-yl)oxy)methyl)ethyl(hydroxy)formamide
and
benzyloxy((1R)-2-(4-bromophenoxy)-1-((4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)methyl)-ethyl)formamide.
18. A process for preparing a compound of formula (23-b)
134
the process comprising:
(a) reacting a compound of formula (23-a)
135
the coupling catalyst, and the compound of formula (6)
136
and
(b) optionally deprotecting the product of step (a).
19. The process of claim 18, wherein the compound of formula (23-b) is 4-(((2R)-2-((benzyloxy)(formyl)amino)-3-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-propyl)oxy)-4-(trifluoromethoxy)-1,1-biphenyl.
20. A process for preparing a compound of formula (23-b)
137
the process comprising:
(a) reacting a compound of formula (1)
138
a base, and a reagent selected from the group consisting of phosgene, thiophosgene, triphosgene, carbonyldiimidazole, thiocarbonyldiimidazole, and a dialkyl carbonate to provide a compound of formula (2);
139
(b) reacting the product of step (a) with a reducing agent to provide a compound of formula (3);
140
(c) activating the hydroxyl of the product of step (b);
(d) reacting the product of step (c) with base and a compound of formula (4)
141
to provide a compound of formula (5-a),
142
(e) optionally oxidizing the product of step (d);
(f) reacting the product of step (d) or step (e), a coupling catalyst, and a compound of formula (6)
143
to provide a compound of formula (5-b),
144
(g) reacting the product of step (f) with base to provide a compound of formula (15),
145
(h) reacting the product of step (g) with a compound of formula R9CHO, to provide a compound of formula (16),
146
(i) reacting the product of step (h) with a compound of formula (17)
147
to provide a compound of formula (18)
148
(j) reacting the product of step (i) and an oxaziridine forming agent to provide a compound of formula (19)
149
(k) reacting the product of step (j) with H2NOR2, or a salt thereof, and base to provide a compound of formula (20-b);
150
(l) N-formylating the product from step (k) to provide a compound of formula (23-b);
151
and
(m) optionally deprotecting the product of step (l).
21. A process for the preparation of a compound of formula (23-b)
152
the process comprising:
(a) reacting a compound of formula (1)
153
a base, and a reagent selected from the group consisting of phosgene, thiophosgene, triphosgene, carbonyldiimidazole, thiocarbonyldiimidazole, and a dialkyl carbonate, to provide a compound of formula (2);
154
(b) reacting the product of step (a) with a reducing agent to provide a compound of formula (3);
155
(c) activating the hydroxyl of the product of step (b);
(d) reacting the product of step (c) with base and a compound of formula (4)
156
to provide a compound of formula (5-a),
157
(e) optionally oxidizing the product of step (d);
(f) reacting the product of step (e) with base to provide a compound of formula (15),
158
wherein
R5 is Q1;
(g) reacting the product of step (f) with a compound of formula R9CHO to provide a compound of formula (16),
159
wherein
R5 is Q1;
(h) reacting the product of step (g) with a compound of formula (17)
160
to provide a compound of formula (18)
161
wherein R5 is Q1;
(i) reacting the product of step (h) with an oxaziridine forming agent to provide a compound of formula (19)
162
wherein
R5 is Q1;
(j) reacting the product of step (i) with H2NOR2, or a salt thereof, and base to provide a compound of formula (20);
163
wherein
R5 is Q1;
(k) reacting the product of step (j) with a coupling catalyst and a compound of formula (6)
164
to provide a compound of formula (20),
165
wherein
R5 is
166
(l) N-formylating the product from step (k) to provide a compound of formula (23)
167
wherein
R5 is
168
and
(m) optionally deprotecting the product of step (l).
22. A process for the preparation of a compound of formula (23)
169
wherein
R2 is hydrogen;
and
170
R5 is
the process comprising:
(a) reacting a compound of formula (7)
171
a compound of formula (4)
172
and base to provide a compound of formula (8)
173
(b) optionally oxidizing the product from step (a);
(c) hydrogenating the product of step (a) or step (b) to provide a compound of formula (9)
174
(d) reacting the product from step (c) with base to provide a compound of formula (10)
175
(e) reacting the product from step (d) with H2NOR2 or a salt thereof, wherein R2 is a a hydroxyl protecting group, under dehydrating conditions to provide a compound of formula (11)
176
wherein
R2 is a hydroxyl protecting group;
(f) reacting the product of step (e) under Mitsunobu conditions to provide a compound of formula (12)
177
wherein
R2 is a hydroxyl protecting group;
(g) reacting the product from step (f) with base to provide a compound of formula (13)
178
(h) activating the product from step (g) with azide to provide a compound of formula (5-c);
179
wherein
R2 is a hydroxyl protecting group;
(i) reacting the product from step (h) with base to provide a compound of formula (15)
180
wherein
R1 is OR2;
R2 is a hydroxyl protecting group;
R5 is Q1;
and
L1 is NH;
(j) reacting the product from step (i) with a compound of formula (21)
181
to provide a compound of formula (22)
182
wherein
R2 is a hydroxyl protecting group;
(k) reacting the product from step (j) with acid to provide a compound of formula (20-c)
183
wherein
R2 is a hydroxyl protecting group;
(l) N-formylating the product from step (k) to provide a compound of formula (23)
184
wherein
R2 is a hydroxyl protecting group;
(m) reacting the product from step (l) with a coupling catalyst and a compound of formula (6)
185
to provide a compound of formula (23)
186
wherein
R2 is a hydroxyl protecting group R5 is
187
and
(n) deprotecting the product of step (m).
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. An image denoising method, comprising the steps of:
sequentially selecting a pixel in an image as a current pixel, wherein pixels around the current pixel are defined as neighborhood pixels;
dynamically determining a current search block enclosing the current pixel and a strength parameter, and determining a comparison block for each of the pixels in the current search block, wherein the comparison block encloses the each pixel;
pre-denoising the comparison blocks for the pixels in the current search block;
comparing the pre-denoised comparison blocks for the neighborhood pixels with the pre-denoised comparison block for the current pixel to obtain a similarity between each of the neighborhood pixels and the current pixel in the current search block;
determining a weighting for each of the neighborhood pixels related to the current pixel according to the strength parameter, the similarity and a distance between the each neighborhood pixel and the current pixel in the current search block; and
weighted averaging each of the neighborhood pixels and the current pixel in the current search block according to the weighting to obtain a reconstruction value of the current pixel,
wherein the step of dynamically determining comprises:
determining a maximal search block enclosing the current pixel and a comparison block for each of the pixels in the maximal search block, wherein the comparison block encloses the each pixel;
calculating the ratios of the edge pixels for the sub-search blocks in the maximal search block; and
selecting the sub-search block that has the smallest ratio of the edge pixels as the current search block and determining the strength parameter according to the ratio of the edge pixels of the current search block.
2. The image denoising method as claimed in claim 1, wherein the step of calculating the ratios of the edge pixels for the sub-search blocks in the maximal search block comprises:
pre-denoising the comparison blocks for the pixels in the maximal search block;
calculating a sum of the absolute values of the differences between the pixels in the comparison blocks not to be pre-denoised for the pixels in the maximal search block and the corresponding pixels in the pre-denoised comparison blocks;
determining the pixel to be an edge pixel when the sum of the absolute values of the differences is greater than a predetermined threshold value; and
calculating the ratios of the edge pixels for the sub-search blocks in the maximal search block according to the determined result.
3. The image denoising method as claimed in claim 2, wherein the pre-denoising is performed by a mean filter or a neighborhood filter.
4. The image denoising method as claimed in claim 2, wherein the sub-search blocks have sizes of (n\u22122m)\xd7(n\u22122m), n is the side length of the maximal search block and n is zero or an integer.
5. The image denoising method as claimed in claim 4, wherein the smallest sub-search block has a size of 3\xd73 and the largest sub-search block is equal to the maximal search block.
6. The image denoising method as claimed in claim 1, wherein the largest sub-search block has a size of 7\xd77.
7. The image denoising method as claimed in claim 1, wherein when the ratio of edge pixels is higher, the strength parameter is smaller, and when the ratio of edge pixels is lower, the strength parameter is larger.
8. The image denoising method as claimed in claim 1, wherein the current search block and comparison block have a shape of square, rectangle, rhombus, circle or ellipse.
9. The image denoising method as claimed in claim 1, further comprising:
determining whether reconstruction values for all the pixels in the image have been obtained.
10. The image denoising method as claimed in claim 1, wherein the similarity is a sum of the squared differences between the pixels in the pre-denoised comparison block for the neighborhood pixel and the corresponding pixels in the pre-denoised comparison block for the current pixel.