[ CAS No. 179087-93-5 ] {[proInfo.proName]}

Name: 179087-93-5|2-(4-((2,4-Dioxothiazolidin-5-yl)methyl)phenoxy)acetic acid|97%
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SKU: A110661
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Quality Control of [ 179087-93-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 179087-93-5 ]

Product Details of [ 179087-93-5 ]

CAS No. :	179087-93-5	MDL No. :	MFCD11113230
Formula :	C₁₂H₁₁NO₅S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SXAASESEPRXRTR-UHFFFAOYSA-N
M.W :	281.28	Pubchem ID :	11323485
Synonyms :

Calculated chemistry of [ 179087-93-5 ]

Physicochemical Properties

Num. heavy atoms :	19
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	71.88
TPSA :	118.0 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.92 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.05
Log Po/w (XLOGP3) :	1.55
Log Po/w (WLOGP) :	0.66
Log Po/w (MLOGP) :	0.41
Log Po/w (SILICOS-IT) :	1.41
Consensus Log Po/w :	1.02

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.46
Solubility :	0.966 mg/ml ; 0.00343 mol/l
Class :	Soluble
Log S (Ali) :	-3.64
Solubility :	0.0648 mg/ml ; 0.00023 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.86
Solubility :	0.39 mg/ml ; 0.00139 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.9

Safety of [ 179087-93-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 179087-93-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 179087-93-5 ]
Downstream synthetic route of [ 179087-93-5 ]

[ 179087-93-5 ] Synthesis Path-Upstream 1~5

1
[ 172648-06-5 ]
[ 179087-93-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium carbonate In methanol; water	Preparation 38 [4-[[2,4-Dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid: To a stirred solution of ethyl [4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetate (110 g, 0.36 mol) in methanol (0.65 L) was added as solutino of Na₂CO₃ (200 g, 1.88 mol) in water (0.65 L) and stirred for 5 h at 25 to 30° C. After completion of the reaction, methanol was removed under reduced pressure; water was added to the residue and was acidified with hydrochlori acid. The precipitated while solid was filtered and dired to yield the title compound (80 g, 80percent). mp: 181-183° C. ¹H NMR (DMSO-d₆): δ 12.40 (bs, 1H, D₂O exchangeable), 8.60 (bs, 1H, D₂O exchangeable), 7.16 (d, J=8.40 Hz, 2H), 6.50 (d, J=8.40 Hz, 2H), 4.87 (dd, J=9.14, 4.20 Hz, 1H), 4.65 (s, 2H), 3.32 (dd, J=14.12, 4.20 Hz, 1H), 3.05 (dd, J=14.12, 9.14 Hz, 1H).

Reference： [1] Patent: US6310069, 2001, B1,

2
[ 123021-85-2 ]
[ 179087-93-5 ]

Reference： [1] Archiv der Pharmazie, 2015, vol. 348, # 6, p. 421 - 432

3
[ 6192-52-5 ]
[ 179087-93-5 ]

Reference： [1] Patent: US2003/8907, 2003, A1,

4
[ 22042-71-3 ]
[ 179087-93-5 ]

Reference： [1] Archiv der Pharmazie, 2015, vol. 348, # 6, p. 421 - 432

5
[ 123-08-0 ]
[ 179087-93-5 ]

Reference： [1] Archiv der Pharmazie, 2015, vol. 348, # 6, p. 421 - 432

[ 179087-93-5 ] Synthesis Path-Downstream 1~87

1
[ 179087-93-5 ]
4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; thionyl chloride; In dichloromethane; at 20℃; for 3.5h;Heating / reflux;	Examples (Example 1) 4-[(2,4-Dioxothiazolidin-5-yl)methyl]phenoxyacetyl chloride Thionyl chloride (170 mg, 1.34 mmol) and then pyridine (1 drop) were added to a suspension of <strong>[179087-93-5]4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetic acid</strong> (220 mg, 0.78 mmol) in dichloromethane (10 ml) at room temperature, and the mixture was refluxed for 3.5 hours. The resulting solution was concentrated under reduced pressure to obtain about 250 mg of the gummy target compound. Nuclear magnetic resonance spectrum (400 MHz, DMSO-d6) delta (ppm): 3.05 (1H, dd, J = 9.0 Hz, J = 14.1 Hz, CH2CH), 3.31 (1H, dd, J = 4.1 Hz, J = 14.1 Hz, CH2CH), 4.64 (2H, s, CH2O), 4.87 (1H, dd, J = 4.1 Hz, J = 9.0 Hz, CH2CH), 6.85 (2H, d, J = 8.6 Hz, aromatic), 7.16 (2H, J = 8.6 Hz, aromatic), 12.02 (1H, s, NH).

Reference： [1]Patent: EP1894929,2008,A1 .Location in patent: Page/Page column 17

2
[ 179087-93-5 ]
C₁₂H₁₀ClNO₄S*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;N,N-dimethyl-formamide; In acetonitrile; at 8 - 15℃; for 3.5h;	Acetonitrile (140.9 kg) was added to <strong>[179087-93-5]4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetic acid</strong> (18.0 kg, 64.0 mol) produced according to the process described in Japanese Patent Application (Kokai) No. 2001-72671, and after cooling to an internal temperature of 8C, thionyl chloride (8.3 kg, 69.8 mol) was added. Dimethylformamide (14.4 L) was further added followed by stirring for 3.5 hours at a temperature of 8 to 15C. An acetonitrile (84.6 kg) solution of tert-butyl N-(2-amino-5-methoxyphenyl)-N-methylcarbamate (15.7 kg, 62.2 mol) and triethylamine (8.4 kg, 83.0 mol) held at a temperature of 0 to 10C was added dropwise thereto over 1 hour while cooling so as to maintain at a temperature of 0 to 5C followed by further stirring for 2 hours at the same temperature. Next, water (144 L) was added over 22 minutes followed by stirring for 30 minutes while holding at an internal temperature of 0 to 6C and allowing to stand undisturbed for 12 hours. After filtering out the resulting crystals, the crystals were washed with a 2:1 aqueous solution (54 L) to obtain wet crystals of tert-butyl N- {2-{4-(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-methylcarbamate.

Reference： [1]Patent: EP1902713,2008,A1 .Location in patent: Page/Page column 9

3
[ 55783-47-6 ]
[ 179087-93-5 ]
[ 314271-26-6 ]

Reference： [1]Patent: EP1191019,2002,A1 .Location in patent: Page 55

4
[ 299175-79-4 ]
[ 179087-93-5 ]
C₂₅H₂₉N₃O₆S₂ [ No CAS ]

Reference： [1]Patent: EP1167357,2002,A1 .Location in patent: Page 126

5
[ 314271-24-4 ]
[ 179087-93-5 ]
[ 314271-25-5 ]

Yield	Reaction Conditions	Operation in experiment
89 - 93%		(Example 2) tert-Butyl N-{2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-methylcarbamate Thionyl chloride (27.66 g, 232.5 mmol) and dimethylformamide (12 ml) were poured into a suspension of <strong>[179087-93-5]4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetic acid</strong> (60.0 g, 213.3 mmol) in dichloromethane (390 ml), and the mixture was heated to reflux (39C). After completion of dissolution, the solution was stirred for 30 minutes and cooled to 0 to 5C. A solution of tert-butyl N-(2-amino-5-methoxyphenyl)-N-methylcarbamate (53.84 g, 213.4 mmol) and triethylamine (25.92 g, 256.2 mmol) in dichloromethane (624 ml) was added dropwise while maintaining the internal temperature at 5C or less. The reaction solution was stirred at 5C for one hour. Then, dichloromethane (300 ml) was poured in, followed by addition of a solution prepared from sodium bicarbonate (24 g) and water (480 ml). The mixture was stirred at 20C for 20 minutes, allowed to stand, and then separated, and the aqueous layer was discarded. Water (480 ml) was added to the organic layer, the mixture was stirred at 20C for 20 minutes, allowed to stand, and then separated, and the aqueous layer was discarded. A solution of 38% hydrochloric acid (19.8 ml) and water (480 ml) was poured into the organic layer. The mixture was stirred at 20C for 20 minutes, and then the aqueous layer was discarded. Activated carbon (1.8 g) and dichloromethane (18 ml) were further added to the organic layer, and the mixture was stirred for 30 minutes. Thereafter, activated carbon was filtered off. The residue was washed with dichloromethane (90 ml) and the filtrate and the washing liquid were combined and concentrated under reduced pressure at an internal temperature of 25C to a fluid volume of 300 ml. After stirring at normal pressure for 10 minutes, methanol (300 ml) was added and the mixture was concentrated under reduced pressure at an internal temperature of 25C to a fluid volume of 300 ml. Methanol (300 ml) was further added and the mixture was concentrated under reduced pressure at an internal temperature of 30C to a fluid volume of 300 ml. Methanol (198 ml) was added thereto and the mixture was cooled to 0 to 5C and further stirred for one hour. The resulting crystals were separated by filtration, washed with cold methanol (240 ml), and then dried under reduced pressure at 50C to obtain tert-butyl N-{2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-methylcarbamate (97.09 g, 188.3 mmol) (yield: 89%).(Example 5) {5-4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzyl}thiazolidine-2,4-dione hydrochloride (5-1) Thionyl chloride (28.15 kg, 236.6 mol) and dimethylformamide (6.1 L) were poured into a suspension of <strong>[179087-93-5]4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetic acid</strong> (61.0 kg, 216.9 mol) in dichloromethane (398 L), and the mixture was refluxed for six hours. After cooling the resulting solution to 0 to 5C, a solution of tert-butyl N-(2-amino-5-methoxyphenyl)-N-methylcarbamate (54.72 kg, 216.9 mol) and triethylamine (26.35 kg, 260.4 mol) in dichloromethane (562 L) was added dropwise over one hour while maintaining the internal temperature at 5C or less, and the mixture was stirred at 0 to 5C for 15 minutes. Water (488 L) was poured in with stirring and sodium bicarbonate (24.4 kg) was added (the internal temperature was raised to about 20C). Then, dichloromethane (305 L) was poured in and the mixture was stirred for 20 minutes while cooling to 0 to 3C. Water (488 L) was poured in, the mixture was stirred at 10 to 20C for five minutes and allowed to stand for 30 minutes, and the aqueous layer was discarded. Water (488 L) and then 38% hydrochloric acid (23.8 kg) were poured in, the mixture was stirred for five minutes and then allowed to stand for 10 minutes, and the aqueous layer was discarded. Water (488 L) was poured in, the mixture was stirred for five minutes and then allowed to stand for 12 hours, and the aqueous layer was discarded. A suspension of activated carbon (1.83 kg) in dichloromethane (18 L) was added thereto. After stirring for 30 minutes, activated carbon was separated by filtration. Activated carbon was washed with dichloromethane (92 L) and the filtrate and the washing liquid were combined and concentrated under reduced pressure at an internal temperature of 20 to 30C to about 300 L. Methanol (305 L) was poured in and the mixture was concentrated under reduced pressure at an internal temperature of 20 to 30C to about 300 L. Methanol (305 L) was further poured in and the mixture was concentrated under reduced pressure at an internal temperature of 20 to 30C to about 300 L. Methanol (201 L) was poured in and the mixture was stirred at 5C for one hour. Then, the resulting crystals were separated by filtration, washed with methanol (244 L), and then dried under reduced pressure at 50C to obtain tert-butyl N-{2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-methylcarbamate (103.9 kg, ...
85 - 89%		(Example 3) tert-Butyl N-{2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-methylcarbamate Acetonitrile (400 ml) was added to <strong>[179087-93-5]4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetic acid</strong> (40.0 g, 142.2 mmol). After cooling to an internal temperature of 7C, thionyl chloride (18.4 g, 155.0 mmol) was added. Dimethylformamide (32 ml) was further added and the mixture was stirred at the same temperature to 11.4C for three hours. A solution of tert-butyl N-(2-amino-5-methoxyphenyl)-N-methylcarbamate (38.4 g, 137.9 mmol) and triethylamine (18.7 g, 184.9 mmol) in acetonitrile (240 ml) maintained at 0 to 10C was added dropwise thereto over 65 minutes while cooling to maintain the reaction temperature at 0 to 5C, and then the mixture was further stirred at the same temperature for two hours. Next, water (320 ml) was added over 15 minutes and the mixture was stirred at an internal temperature of 0 to 5C for 2.5 hours. Thereafter, the precipitated crystals were separated by filtration. The resulting crystals were washed with a 2:1 solution of acetonitrile and water (160 ml) and dried under reduced pressure at 50C for 19 hours to obtain crystals of tert-butyl N-{2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-methylcarbamate (63.6 g, 123.4 mmol) (yield: 89%).(Example 4) tert-Butyl N-{2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-methylcarbamate (4-1) (The same lots of <strong>[179087-93-5]4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetic acid</strong> and tert-butyl N-(2-amino-5-methoxyphenyl)-N-methylcarbamate as used in Example 3 were used in this example, respectively). Acetonitrile (400 ml) was added to <strong>[179087-93-5]4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetic acid</strong> (40.0 g, 142.2 mmol). After cooling to an internal temperature of 8C, thionyl chloride (18.4 g, 155.0 mmol) was added. Dimethylformamide (32 ml) was further added and the mixture was stirred at the same temperature to 12C for three hours. A solution of tert-butyl N-(2-amino-5-methoxyphenyl)-N-methylcarbamate (38.4 g, 137.9 mmol) and triethylamine (18.7 g, 184.9 mmol) in acetonitrile (240 ml) maintained at 0 to 10C was added dropwise thereto over 65 minutes while cooling to maintain the reaction temperature at 0 to 3C, and then the mixture was further stirred at the same temperature for 3.5 hours. Next, water (320 ml) was added over 27 minutes and the mixture was stirred at 0 to 5C for 2.5 hours. Thereafter, the precipitated crystals were separated by filtration. The resulting crystals were washed with a 2:1 solution of acetonitrile and water (160 ml) and then dried under reduced pressure at 50C for 15 hours to obtain crystals of tert-butyl N-{2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-methylcarbamate (67.6 g, 131.0 mmol) (yield: 92%).(4-2) A suspension of the crystals of tert-butyl N-{2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-methylcarbamate obtained in (4-1) (56.1 g, 108.6 mmol) in methanol (1680 ml) was heated with stirring (the crystals were completely dissolved when the internal temperature reached 65.5C). The reaction solution was cooled to 0 to 5C over two hours and further stirred at the same temperature for 95 minutes, and then the precipitated crystals were separated by filtration. The resulting crystals were washed with methanol (224 ml) and then dried under reduced pressure at 50C for 15 hours to obtain purified crystals of tert-butyl N-{2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-methylcarbamate (51.6 g, 100.0 mmol) (yield: 92%, total yield: 85%).(Example 6) {5-4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzyl}thiazolidine-2,4-dione hydrochloride (6-1) Acetonitrile (140.9 kg) was added to <strong>[179087-93-5]4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetic acid</strong> (18.0 kg, 64.0 mol). After cooling to an internal temperature of 8C, thionyl chloride (8.3 kg, 69.8 mol) was added. Dimethylformamide (14.4 L) was further added and the mixture was stirred at the same temperature to 15C for 3.5 hours. A solution of tert-butyl N-(2-amino-5-methoxyphenyl)-N-methylcarbamate (15.7 kg, 62.2 mol) and triethylamine (8.4 kg, 83.0 mol) in acetonitrile (84.6 kg) maintained at 0 to 10C was added dropwise thereto over one hour while cooling to maintain the reaction temperature at 0 to 5C, and then the mixture was further stirred at the same temperature for two hours. Next, water (144 L) was added over 22 minutes, and the mixture was stirred for 30 minutes while maintaining the internal temperature at 0 to 6C and then allowed to stand for 12 hours. The resulting crystals were separated by filtration and then washed with a 2:1 solution of water (54 L) to obtain wet crystals of tert-butyl N-{2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-methylcarbamate.(6-2) A suspension of the wet crystals of tert-butyl N-{2-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetylamino}-5-methoxyphenyl}-N-m...

Reference： [1]Patent: EP1894929,2008,A1 .Location in patent: Page/Page column 17; 18
[2]Patent: EP1191019,2002,A1 .Location in patent: Page 55
[3]Patent: EP1894929,2008,A1 .Location in patent: Page/Page column 17; 18; 19

6
[ 223133-34-4 ]
[ 179087-93-5 ]
t-butyl N-[5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate [ No CAS ]

Reference： [1]Patent: EP1167366,2002,A1 .Location in patent: Page 117

7
[ 299176-01-5 ]
[ 179087-93-5 ]
t-butyl N-{5-hydroxy-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethylcarbonylamino]phenyl}-N-methylcarbamate [ No CAS ]

Reference： [1]Patent: EP1167357,2002,A1 .Location in patent: Page 137

8
t-butyl N-[2-amino-5-(4-t-butoxycarbonylaminophenoxy)phenyl]-N-methylcarbamate [ No CAS ]
[ 179087-93-5 ]
t-butyl N-[5-(4-t-butoxycarbonylaminophenoxy)-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate [ No CAS ]

Reference： [1]Patent: EP1167366,2002,A1 .Location in patent: Page 118

9
t-butyl N-[2-amino-5-[4-(t-butoxycarbonyl-n-hexylamino)phenoxy]phenyl]-N-methylcarbamate [ No CAS ]
[ 179087-93-5 ]
C₄₁H₅₂N₄O₉S [ No CAS ]

Reference： [1]Patent: EP1167366,2002,A1 .Location in patent: Page 119

10
[ 301548-22-1 ]
[ 179087-93-5 ]
t-butyl N-[5-(3-t-butoxycarbonylaminophenoxy)-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate [ No CAS ]

Reference： [1]Patent: EP1167366,2002,A1 .Location in patent: Page 119

11
[ 301548-25-4 ]
[ 179087-93-5 ]
t-Butyl N-[5-[4-(2-t-butoxycarbonylaminoethyl)phenoxy]-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate [ No CAS ]

Reference： [1]Patent: EP1167366,2002,A1 .Location in patent: Page 120

12
[ 301548-29-8 ]
[ 179087-93-5 ]
[ 301548-30-1 ]

Reference： [1]Patent: EP1167366,2002,A1 .Location in patent: Page 121

13
t-butyl [7-[4-amino-3-(t-butoxycarbonylmethylamino)phenoxy]naphthalen-1-yl]carbamate [ No CAS ]
[ 179087-93-5 ]
t-butyl (7-[3-(t-butoxycarbonylmethylamino)-4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenoxy]naphthalen-1-yl)carbamate [ No CAS ]

Reference： [1]Patent: EP1167366,2002,A1 .Location in patent: Page 122

14
t-butyl N-[2-amino-5-(3-amino-4-t-butyl)benzyloxyphenyl]-N-methylcarbamate [ No CAS ]
[ 179087-93-5 ]
t-butyl N-[5-(3-amino-4-t-butyl)benzyloxy-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate [ No CAS ]

Reference： [1]Patent: EP1167366,2002,A1 .Location in patent: Page 123 - 124

15
t-butyl N-[2-amino-5-(3-amino-4-t-butylphenyl)ethoxyphenyl]-N-methylcarbarnate [ No CAS ]
[ 179087-93-5 ]
t-butyl N-[5-[2-(3-amino-4-t-butylphenyl)ethoxy]-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate [ No CAS ]

Reference： [1]Patent: EP1167366,2002,A1 .Location in patent: Page 124

16
4-(2,4-dioxo-3-tritylthiazolidin-5-ylmethyl)phenoxyacetic acid t-butyl ester [ No CAS ]
[ 6192-52-5 ]
[ 179087-93-5 ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; toluene;	Reference Example 6 4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxyacetic Acid To a solution of 4-(2,4-dioxo-3-tritylthiazolidin-5-ylmethyl)phenoxyacetic acid t-butyl ester (6.2 g) in toluene (25 ml) was added p-toluenesulfonic acid mono-hydrate (204 mg) and the mixture was heated under reflux for 3 hours. At elevated temperature ethyl acetate (10 ml) was added and the mixture was stirred at 25 C. for 1.5 hours. The precipitated crystals were filtered to give the desired compound (2.5 g). IR spectrum (KBr, nu cm-1): 3435, 3011, 1753, 1693, 1513, 1244, 1203. 1H-NMR spectrum (DMSO-d6, 400 MHz, delta ppm): 3.04(1H, dd, J=14.2, 9.0 Hz), 3.30(1H, dd, J=14.2, 4.3 Hz), 4.63(2H, s), 4.86(1H, dd, J=9.0, 4.3 Hz), 6.84(2H, d, J=8.7 Hz), 7.15(2H, d, J=8.7 Hz), 11.20(1H, s), 12.94(1H, br.s).

Reference： [1]Patent: US2003/8907,2003,A1

17
[ 314271-24-4 ]
[ 144-55-8 ]
[ 179087-93-5 ]
N-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-methoxyphenyl]-N-methylcarbamic acid t-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine; In methanol; dichloromethane; ethyl acetate;	Example 3 N-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-methoxyphenyl]-N-methylcarbamic Acid t-butyl Ester (Exemplification Compound Number 9-8) To a suspension at 0 C. of N-(2-amino-5-methoxyphenyl)-N-methylcarbamic acid t-butyl ester (4.2 g) and <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (5.2 g) in methylene chloride (30 ml) was added triethylamine (5.1 ml) and 50% propylphosphonic acid cyclic anhydride in ethyl acetate (12.7 g) and the mixture was stirred at the same temperature for 2 hours. At the end of this time to the reaction mixture was added 5% aqueous sodium hydrogencarbonate solution and the mixture was extracted with methylene chloride. The extract was washed with water and diluted hydrochloric acid and concentrated in vacuo. To the residue was added methanol (40 ml) and the precipitated crystals were filtered to give the title compound (7.3 g, yield 85%). IR spectrum (KBr, nu cm-1): 3323, 1751, 1697, 1534, 1510, 1232, 1153. 1H-NMR spectrum (DMSO-d6, 400 MHz, delta ppm): 1.28(9H, br.s), 3.02(3H, s), 3.07(1H, dd, J=14.0, 9.1 Hz), 3.31(1H, dd, J=14.0, 4.3 Hz), 3.74(3H, s), 4.65(2H, s), 4.87(1H, dd, J=9.1, 4.3 Hz), 6.80-6.95(2H, m), 6.92(2H, d, J=8.5 Hz), 7.19(2H, d, J=8.5 Hz), 7.69(1H, br.s), 8.95(1H, br.s), 12.00(1H, br.s).

Reference： [1]Patent: US2003/8907,2003,A1

18
4-methoxy-N₂-methyl-1,2-phenylenediamine di-hydrochloride [ No CAS ]
[ 144-55-8 ]
[ 179087-93-5 ]
[ 314271-26-6 ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine; In ethanol; dichloromethane; ethyl acetate;	Example 6 2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxy]-N-(4-methoxy-2-methylaminophenyl)acetamide To a suspension at 0 C. of 4-methoxy-N2-methyl-1,2-phenylenediamine di-hydrochloride (5.5 g) and <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (7.6 g) in methylene chloride (55 ml) were added triethylamine (14.3 ml) and 50% propylsulfonic acid cyclic anhydride in ethyl acetate (18.7 g) and the mixture was stirred at 0 C. for 2.5 hours. At the end of this time, to the reaction mixture was added 5% aqueous sodium hydrogencarbonate solution and it was extracted with methylene chloride. The extract was washed with saturated aqueous sodium chloride solution and concentrated in vacuo to give the crude product (10.6 g). A suspension of the crude product (6.0 g) in methylene chloride (12.3 ml) was heated under reflux. To the solution was added ethanol (18.5 ml) and the mixture was cooled to 25 C. After 1 hour the solution was stirred at 0 C. for 30 minutes and the precipitated crystals were filtered to give the title compound (3.4 g, yield 63%) IR spectrum (KBr, nu cm-1): 3383, 1753, 1696, 1528, 1512, 1216, 830. -1H-NMR spectrum (DMSO-d6, 400 MHz, delta ppm): 2.67(3H, d, J=4.8 Hz), 3.07(1H, dd, J=14.0, 9.1 Hz), 3.31(1H, dd, J=14.0, 4.1 Hz), 3.70(3H, s), 4.62(2H, s), 4.87(1H, dd, J=9.1, 4.1 Hz), 5.08(1H, d, J=4.8 Hz), 6.09(1H, d, J=8.4 Hz), 6.13(1H, dd, J=8.4, 2.7 Hz), 6.90(1H, d, J=8.4 Hz), 6.95(1H, d, J=8.7 Hz), 9.06(1H, s), 11.99(1H, br.s).

Reference： [1]Patent: US2003/8907,2003,A1

19
[ 299175-79-4 ]
[ 299176-06-0 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
Methyl 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; triethylamine;palladium; In tetrahydrofuran; 1,4-dioxane; hydrogenchloride; methanol; water; ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 41 Methyl 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionate (Methyl Ester of Exemplification Compound Number 5-67) Crude 2-(N-t-butoxycarbonyl-N-methylamino)-4-methylthioaniline (54.8 g, Rf=0.16: thin layer chromatography on a silica gel plate using hexane:ethyl acetate=3:1 as the eluant) was obtained by a similar procedure to that described in Reference example 5 using 2-(N-t-butoxycarbonyl-N-methylamino)-4-methylthionitrobenzene (55.9 g), palladium on carbon (7.25 g, 10%) and a mixture of methanol:1,4-dioxane=1:1 (600 ml). A mixture of 2-(N-t-butoxycarbonyl-N-methylamino)-4-methylthioaniline (54.8 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (64.0 g), diethyl cyanophosphonate (36.8 g), triethylamine (22.8 g) and anhydrous tetrahydrofuran (300 ml) was stirred for 67 hours at room temperature. The reaction mixture was concentrated and water was added to the residue. The mixture was neutralized with 3N hydrochloric acid and sodium bicarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in 4N hydrogen chloride/dioxane (150 ml) and the solution was stirred at room temperature for 15 hours and then at 80 C. for 5 hours. The reaction mixture was concentrated, neutralized with sodium bicarbonate and extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent of the extract was evaporated and the residue was reprecipitated using N,N-dimethylformamide and ethyl acetate to give a precipitate. The precipitate was suspended in 4N hydrogen chloride/ethyl acetate and insoluble material was obtained by filtration which was washed with ethyl acetate and dried in the air to give the desired intermediate. A solution of the intermediate (35.2 g) in water (200 ml) and a methanolic solution of sodium methoxide (300 ml, 28%) was stirred at 80 C. for 90 minutes. The reaction mixture was concentrated and acidified with 6N hydrochloric acid to give a precipitate. The precipitate was collected by filtration, successively washed with water and ethyl acetate and then dried under reduced pressure to afford the desired product. A mixture of the product (22.4 g), 4N hydrogen chloride/dioxane (150 ml) and methanol (150 ml) was stirred at room temperature for 65 hours. The reaction mixture was concentrated, neutralized with aqueous sodium bicarbonate solution (5%) and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using hexane:ethyl acetate=1:3 as the eluant to afford the title compound (7.49 g, mp 97-100 C.).

Reference： [1]Patent: US2003/69294,2003,A1

20
[ 301548-22-1 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-[5-(3-t-butoxycarbonylaminophenoxy)-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triethylamine; In tetrahydrofuran; 1,4-dioxane;	Reference Example 16 5-[4-[6-(3-Aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride t-Butyl N-[5-(3-t-butoxycarbonylaminophenoxy)-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate (16.39 g) was obtained by a similar procedure to that described in Reference Example 4 using t-butyl N-[2-amino-5-(3-t-butoxycarbonylaminophenoxy)phenyl]-N-methylcarbamate (9.83 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (8.44 g), diethyl cyanophosphonate (4.95 g), triethylamine (3.07 g) and anhydrous tetrahydrofuran (200 ml). To a solution of this product in 1,4-dioxane (40 ml) was added 4N hydrogen chloride in 1,4-dioxane (70 ml) and the mixture was stirred at room temperature for 2 hours and allowed to stand overnight.

Reference： [1]Patent: US2003/78426,2003,A1

21
[ 301548-25-4 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-Butyl N-[5-[4-(2-t-butoxycarbonylaminoethyl)phenoxy]-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	Reference Example 19 t-Butyl N-[5-[4-(2-t-butoxycarbonylaminoethyl)phenoxy]-2-[4(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate The desired compound (16.2 g, Rf=0.11: thin layer chromatography on a silica gel plate using n-hexane:ethyl acetate=2:1 as the eluant) was obtained by a similar procedure to that described in Reference Example 4 using t-butyl N-[2-amino-5-[4-(2-t-butoxycarbonylaminoethyl)phenoxy]phenyl]-N-methylcarbamate (12 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (6.52 g), diethyl cyanophosphonate (6.52 g), triethylamine (4.04 g) and anhydrous tetrahydrofuran (150 ml).

Reference： [1]Patent: US2003/78426,2003,A1

22
[ 301548-29-8 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
[ 301548-30-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	Reference Example 24 t-Butyl N-[5-[2-(4-t-butoxycarbonylaminophenyl)ethoxy]-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate The desired compound (18.3 g, Rf=0.25: thin layer chromatography on a silica gel plate using n-hexane:ethyl acetate=3:2 as the eluant) was obtained by a similar procedure to that described in Reference Example 4 using t-butyl N-[2-amino-5-[2-(4-t-butoxycarbonylaminophenyl)ethoxy]phenyl]-N-methylcarbamate (11.5 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (9.8 g), diethyl cyanophosphonate (5.7 g), triethylamine (3.54 g) and anhydrous tetrahydrofuran (150 ml).

Reference： [1]Patent: US2003/78426,2003,A1

23
[ 223134-15-4 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-[5-(4-t-butoxycarbonylaminophenoxy)-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	Reference Example 9 t-Butyl N-[5-(4-t-butoxycarbonylaminophenoxy)-2-[4-(2,4dioxothiazolidin 5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate The desired compound (395 mg, Rf=0.51: thin layer chromatography on a silica gel plate using n-hexane:ethyl acetate=2:3 as the eluant) was obtained by a similar procedure to that described in Reference Example 4 using t-butyl N-[2-amino-5-(4-t-butoxycarbonylaminophenoxy)phenyl]-N-methylcarbamate (500 mg), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (366 mg), diethyl cyanophosphonate (212 mg), triethylamine (132 mg) and anhydrous tetrahydrofuran (10 ml).

Reference： [1]Patent: US2003/78426,2003,A1

24
[ 438577-86-7 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl (7-[3-(t-butoxycarbonylmethylamino)-4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenoxy]naphthalen-1-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	Reference Example 29 t-Butyl (7-[3-(t-butoxycarbonylmethylamino)-4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenoxy]naphthalen-1-yl)carbamate The desired compound (20.7 g, Rf=0.31: thin layer chromatography on a silica gel plate using n-hexane:ethyl acetate=1:1 as the eluant) was obtained by a similar procedure to that described in Reference Example 4 using t-butyl [7-[4-amino-3-(t-butoxycarbonylmethylamino)phenoxy]naphthalen-1-yl]carbamate (14.2 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (9.16 g), diethyl cyanophosphonate (5.31 g), triethylamine (3.30 g) and anhydrous tetrahydrofuran (280 ml).

Reference： [1]Patent: US2003/78426,2003,A1

25
[ 301548-41-4 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
[ 301548-43-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	Reference Example 37 t-Butyl N-[5-(3-amino-4-t-butyl)benzyloxy-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate The desired compound (1.66 g, Rf=0.53: thin layer chromatography on a silica gel plate using n-hexane:ethyl acetate=1:2 as the eluant) was obtained by a similar procedure to that described in Reference Example 4 using t-butyl N-[2-amino-5-(3-amino-4-t-butyl)benzyloxyphenyl]-N-methylcarbamate (1.86 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (1.44 g), diethyl cyanophosphonate (0.84 g), triethylamine (0.52 g) and anhydrous tetrahydrofuran (40 ml).

Reference： [1]Patent: US2003/78426,2003,A1

26
[ 299176-01-5 ]
diethyl cyanophosphaonate [ No CAS ]
[ 179087-93-5 ]
[ 332944-40-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	Example 28 5-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione hydrochloride A mixture of t-butyl N-(2-amino-5-hydroxyphenyl)-N-methylcarbamate (0.43 g), 5-(4-carboxymethoxybenzyl)thiazolidine-2,4-dione (0.51 g), diethyl cyanophosphaonate (0.29 g) triethylamine (0.18 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 8 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane: ethyl acetate=2:3 as the eluant to afford t-butyl N-{5-hydroxy-2-[4-(2,4-dioxothiazolidin-5-ylmethyl) phenoxymethylcarbonylamino]phenyl}-N-methylcarbamate (0.75 g).

Reference： [1]Patent: US2003/69294,2003,A1

Yield	Reaction Conditions	Operation in experiment
		Reference Example 6 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid To a solution of 4-(2,4-dioxo-3-tritylthiazolidin-5-ylmethyl)phenoxyacetic acid t-butyl ester (6.2 g) (obtained in Reference Example 5) in toluene (25 ml) was added p-toluenesulfonic acid monohydrate (204 mg). The resulting mixture was heated under reflux for 3 hours. Ethyl acetate (10 ml) was added while heating and then the mixture stirred at 25 C. for 1.5 hours. The resulting crystals were collected by filtration to afford the desired compound (2.5 g). IR spectrum (KBr, nucm-1): 3435, 3011, 1753, 1693,1513,1244, 1203. 1H NMR spectrum (DMSO-d6, 400 MHz, delta ppm): 3.04 (1H, dd, J=14.2, 9.0 Hz), 3.30 (1H, dd, J=14.2, 4.3 Hz), 4.63 (2H, s), 4.86 (1H, dd, J=9.0, 4.3 Hz), 6.84 (2H, d, J=8.7 Hz), 7.15 (2H, d, J=8.7 Hz), 11.20 (1H, s), 12.94 (1H, br.s).
		EXAMPLE-25 Preparation of 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2,4-dione A suspension of the 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in any of Examples 16-22 (135 g, 0.44 M) and water (540 ml, 4 times w/v) was taken in a round bottom flask fitted with a mechanical stirrer. Aq. sodium hydroxide solution (37 g of NaOH in 135 ml of water) was added slowly over a period of 5-10 minutes at 20-25 C. Stirring was continued at ambient temperature for a further period of 2-3 h, while monitoring the reaction by TLC. After the completion of reaction, the pH of the reaction mixture was adjusted to 2 using conc. HCl (temp. raises to ~40-45 C.) and allowed to attain room temperature. The mass was cooled to ~10-15 C. and the solid thus obtained was filtered and dried at 60-70 C. under 1-2 mm Hg of vacuum to afford 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2,4-dione (121 g, Y=99% P=99.2%).
		EXAMPLE-26 Alternative Preparation of 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2,4-dione 5-[4-[(Carboethoxy)methoxy]benzylidine]thiazolidine-2,4-dione, obtained by following a procedure described in any of Examples 8-11 (100 g, 0.33 M), magnesium (95 g, 3.96 M) and methanol (2 L) were taken into a 5 L round bottom flask fitted with a mechanical stirrer and stirred for 10 minutes at room temperature during which period the magnesium starts reacting, as evinced by effervescence. The temperature of the reaction mass was maintained at 20-25 C. for 12 hours, while monitoring the reaction by HPLC. After the complete reduction and trans-esterification, water (2 L) was added to the reaction mass and stirred at ambient temperature for a further 12 hours period, while monitoring the reaction by TLC. After complete hydrolysis, the reaction mixture was acidified to pH 2 and extracted with ethyl acetate (3*200 ml). The combined organic extract was concentrated under vacuum. Pure 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2,4-dione was precipitated as a white solid by adding pet, ether (125 ml) followed by stirring at room temperature for 1 hour (60 g, Y=66%, P=97%).

EXAMPLE-28 Alternative Preparation of 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2,4-dione 5-[4-[(Carbomethoxy)methoxy]benzylidine]thiazolidine-2,4-dione obtained by following a procedure described in any of Examples 12-15 (100 g, 0.34 M). magnesium (95 g, 3.96 M) and methanol (2 L) were taken into a 5 L round bottom flask fitted with a mechanical stirrer and stirred for 10 minutes at room temperature during which period the magnesium starts reacting, as evinced by effervescence. The temperature of the reaction mass was maintained at 20-25 C. for 12 hours, while monitoring the reaction by HPLC. After the complete reduction and trans-esterification, water (2 L) was added to the reaction mass and stirred at ambient temperature for a further 12 hours period while monitoring the reaction by TLC. After complete hydrolysis, the reaction mixture was acidified to pH 2 and extracted with ethyl acetate (3*200 ml). The combined organic extract was concentrated under vacuum. Pure 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2,4-dione was precipitated as a white solid by adding pet. ether (125 ml) followed by stirring at room temperature for 1 hour (62 g, Y=65%, P=97%).

28
[ 223133-61-7 ]
N-[2-amino-5-(4-hydroxy-3-methylphenoxy)phenyl]-N-methylcarbamate [ No CAS ]
[ 2942-58-7 ]
[ 141-78-6 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-hydroxy-2-methylphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; hexane;	(31-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-hydroxy-2-methylphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using a mixture of t-butyl N-[2-amino-5-(4-hydroxy-2-methylphenoxy)phenyl]-N-methyl-carbamate and N-[2-amino-5-(4-hydroxy-3-methylphenoxy)phenyl]-N-methylcarbamate (1.88 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (1.69 g), diethyl cyanophosphonate (0.98 g), triethylamine (0.61 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give a mixture of the desired products (1.57 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/2: Rf=0.53

Reference： [1]Patent: US6432993,2002,B1

29
N-(2-amino-5-benzyloxyphenyl)-N-methylcarbamic acid t-butyl ester [ No CAS ]
[ 2942-58-7 ]
[ 179087-93-5 ]
N-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-benzyloxyphenyl]-N-methylcarbamic acid t-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	2-1 N-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-benzyloxyphenyl]-N-methylcarbamic acid t-butyl ester To a mixture of N-(2-amino-5-benzyloxyphenyl)-N-methylcarbamic acid t-butyl ester (2.29 g) (obtained in Reference Example 1), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (1.96 g) (obtained in Reference Example 6), triethylamine (0.97 ml) and anhydrous tetrahydrofuran (100 ml) was added diethyl cyanophosphonate (1.06 ml) and the resulting mixture was stirred at room temperature for 29 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the crude desired product (4.27 g).

Reference： [1]Patent: US2002/137776,2002,A1

30
[ 299175-79-4 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
N-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-methylthiophenyl]-N-methylcarbamic acid t-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	4-1 N-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-methylthiophenyl]-N-methylcarbamic acid t-butyl ester To a mixture of N-(2-amino-5-methylthiophenyl)-N-methylcarbamic acid t-butyl ester (2.0 g) (obtained in Reference Example 4), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (2.31 g) (obtained in Reference Example 6), triethylamine (1.14 ml) and anhydrous tetrahydrofuran (40 ml) was added diethyl cyanophosphonate (1.34 g) and the resulting mixture was stirred at room temperature for 4 hours and allowed to stand overnight. To the reaction mixture were further added <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.84 g), triethylamine (0.3 g) and diethyl cyanophosphate (0.49 g) and the resulting solution was stirred at room temperature for 1.5 hours. At the end of this time the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was chromatographed on a silica gel column using n-hexane/ethyl acetate (2/1) as the eluant to give the desired product (3.54 g).

Reference： [1]Patent: US2002/137776,2002,A1

31
[ 223133-70-8 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[4-(1-adamantyl)phenoxy]phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(16-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[4-(1-adamantyl)phenoxy]phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[4-(1-adamantyl)phenoxy]phenyl}-N-methylcarbamate (1.34 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.83 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.29

Reference： [1]Patent: US6432993,2002,B1

32
[ 223133-29-7 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3,5-di-t-butyl-4-hydroxyphenylthio)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;palladium; In tetrahydrofuran; methanol; water;	(7-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3,5-di-t-butyl-4-hydroxyphenylthio)phenyl}-N-methylcarbamate A mixture of 359 mg of t-butyl N-[2-nitro-5-(3,5-di-t-butyl-4-hydroxyphenylthio)phenyl]-N-methylcarbamate, 360 mg of 10% palladium on carbon and 50 ml of methanol was vigorously stirred at room temperature for 9 hours under a hydrogen atmosphere. From the reaction mixture, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of anhydrous tetrahydrofuran. 248 mg of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong>, 144 mg of diethyl cyanophosphonate and 89 mg of triethylamine were added to the resulting solution. The resulting mixture was allowed to stand at room temperature for 15 hours. The reaction was then concentrated by evaporation. Water was added to the concentrate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (eluding solvent: n-hexane/ethyl acetate=3/2), whereby 275 mg of the desired compound were obtained. Silica gel thin-layer chromatography (developing solvent: n-hexane/ethyl acetate=1/1): Rf value=0.44.

Reference： [1]Patent: US6432993,2002,B1

33
[ 223133-17-3 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-methoxymethoxy-2,3,5-trimethylphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; water;	(2-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-methoxymethoxy-2,3,5-trimethylphenoxy)phenyl}-N-methylcarbamate 7.34 g of diethyl cyanophosphonate were added to a mixture of 18.7 g of t-butyl N-[2-amino-5-(4-methoxymethoxy-2,3,5-trimethylphenoxy)phenyl]-N-methylcarbamate, 12.6 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong>, 4.55 g of triethylamine and 300 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated by evaporation. Water was then added to the concentrate. After extraction with ethyl acetate, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography through a silica gel column (eluding solvent: n-hexane/ethyl acetate=1/1), whereby 23.1 g of the desired compound were obtained. Silica gel thin-layer chromatography (developing solvent: n-hexane/ethyl acetate=2/3): Rf value=0.41.

Reference： [1]Patent: US6432993,2002,B1

34
[ 223133-34-4 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-Butyl N-{2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(8-1) t-Butyl N-{2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)phenyl}-N-methylcarbamate Using 1.56 g of t-butyl N-[2-amino-5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)phenyl]-N-methylcarbamate, 1.05 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong>, 0.61 g of diethyl cyanophosphonate, 0.38 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to that described in Example (2-1), whereby 1.89 g of the desired compound were obtained. Silica gel thin-layer chromatography (developing solvent: n-hexane/ethyl acetate=3/2): Rf value=0.19.

Reference： [1]Patent: US6432993,2002,B1

35
[ 321595-76-0 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
N-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-chlorophenyl]-N-methylcarbamic acid t-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	3-1 N-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-chlorophenyl]-N-methylcarbamic acid t-butyl ester To a mixture of N-(2-amino-5-chlorophenyl)-N-methylcarbamic acid t-butyl ester (2.50 g) (obtained in Reference Example 2), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (3.01 g) (obtained in Reference Example 6), triethylamine (1.49 ml) and anhydrous tetrahydrofuran (50 ml) was added diethyl cyanophosphonate (1.75 g) and the resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was chromatographed on a silica gel column using n-hexane/ethyl acetate (2/1) as the eluant to give the desired product (3.26 g). Rf=0.41 (thin-layer chromatography on a silica gel plate using n-hexane/ethyl acetate (2/3) as the eluant).

Reference： [1]Patent: US2002/137776,2002,A1

36
[ 223133-32-2 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-hydroxyphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(3-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-hydroxyphenoxy)phenyl}-N-methylcarbamate Using 0.79 g of t-butyl N-[2-amino-5-(4-hydroxyphenoxy)phenyl]-N-methylcarbamate, 0.84 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong>, 0.49 g of diethyl cyanophosphonate, 0.30 g of triethylamine and 60 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to that described in Example (2-1), whereby 1.49 g of the desired compound were obtained. Silica gel thin-layer chromatography (developing solvent: n-hexane/ethyl acetate=1/2): Rf value=0.35.

Reference： [1]Patent: US6432993,2002,B1

37
[ 223133-33-3 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-methoxymethoxy-3,5-dimethylphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(4-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-methoxymethoxy-3,5-dimethylphenoxy)phenyl}-N-methylcarbamate Using 0.96 g of t-butyl N-[2-amino-5-(4-methoxymethoxy-3,5-dimethylphenoxy)phenyl]-N-methylcarbamate, 0.84 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong>, 0.49 g of diethyl cyanophosphonate, 0.30 g of triethylamine and 60 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to that described in Example (2-1), whereby 1.44 g of the desired compound were obtained. Silica gel thin-layer chromatography (developing solvent: n-hexane/ethyl acetate=1/1): Rf value=0.27.

Reference： [1]Patent: US6432993,2002,B1

38
[ 223133-27-5 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
[ 223131-84-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;palladium; In tetrahydrofuran; 1,4-dioxane; hydrogenchloride; methanol; water;	(5a) 5-{4-[6-(2-Chloro-4-hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione A mixture of 9.19 g of t-butyl N-[5-(2-chloro-4-methoxymethoxy-3,5-dimethylphenoxy)-2-nitrophenyl]-N-methylcarbamate, 2.5 g of 10% palladium on carbon and 400 ml of methanol was stirred vigorously at room temperature for 90 minutes under a hydrogen atmosphere. The catalyst was then filtered off and the solvent of the filtrate was distilled off under reduced pressure. The residue was dissolved in 250 ml of anhydrous tetrahydrofuran. To the resulting solution, 15.8 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong>, 9.18 g of diethyl cyanophosphonate and 5.69 g of triethylamine were added. The resulting mixture was stirred at room temperature for 64 hours. The reaction mixture was concentrated by evaporation. Water was added to the concentrate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by chromatography through a silica gel column (eluding solvent: n-hexane/ethyl acetate=1/1) and then dissolved in 200 ml of a 2N hydrochloric acid/dioxane solution. The resulting solution was allowed to stand at room temperature for 19 hours. The reaction mixture was concentrated by evaporation. The concentrate was neutralized with an aqueous sodium bicarbonate solution, followed by extraction with a mixed solvent of ethyl acetate and tetrahydrofuran. The extract solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography through a silica gel column (eluding solvent: n-hexane/ethyl acetate=1/2) and reversed-phase preparative high-performance liquid chromatography (developing solvent: acetonitrile/water=7/3), whereby 2.56 g of the title compound were obtained. Melting point: 240-243 C. Silica gel thin-layer chromatography (developing solvent: n-hexane/ethyl acetate=1/2): Rf value=0.21.

Reference： [1]Patent: US6432993,2002,B1

39
[ 223133-28-6 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(pyridin-2-yloxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;palladium; In tetrahydrofuran; methanol; water;	(6-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(pyridin-2-yloxy)phenyl}-N-methylcarbamate A mixture of 0.34 g of t-butyl N-[2-nitro-5-(pyridin-2-yloxy)phenyl]-N-methylcarbamate, 50 mg of 10% palladium on carbon and 10 ml of methanol was stirred vigorously at room temperature for 90 minutes under a hydrogen atmosphere. From the reaction mixture, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of anhydrous tetrahydrofuran. To the resulting solution, 0.34 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong>, 0.20 g of diethyl cyanophosphonate and 0.12 g of triethylamine were added and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated by evaporation. Water was added to the concentrate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography through a silica gel column (eluding solvent: n-hexane/ethyl acetate=1/2), whereby 0.37 g of the desired compound were obtained. Silica gel thin-layer chromatography (developing solvent: n-hexane/ethyl acetate=1/2): Rf value=0.36.

Reference： [1]Patent: US6432993,2002,B1

40
[ 223133-37-7 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[2-(morpholin-4-yl)phenoxy]phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(10-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[2-(morpholin-4-yl)phenoxy]phenyl}-N-methylcarbamate Using 1.18 g of t-butyl N-{2-amino-5-[2-(morpholin-4-yl)phenoxy]-phenyl}-N-methylcarbamate, 0.92 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong>, 0.53 g of diethyl cyanophosphonate, 0.33 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to Example (2-1), whereby 1.47 g of the desired compound were obtained. Silica gel thin-layer chromatography (developing solvent: n-hexane/ethyl acetate=1/1): Rf value=0.30.

Reference： [1]Patent: US6432993,2002,B1

41
[ 223133-38-8 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[3-(morpholin-4-yl)phenoxy]phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(11-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[3-(morpholin-4-yl)phenoxy]phenyl}-N-methylcarbamate Using 1.18 g of t-butyl N-{2-amino-5-[3-(morpholin-4-yl)phenoxy]phenyl}-N-methylcarbamate, 0.92 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong>, 0.53 g of diethyl cyanophosphonate, 0.33 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to Example (2-1), whereby 1.48 g of the desired compound were obtained. Silica gel thin-layer chromatography (developing solvent: n-hexane/ethyl acetate=1/1): Rf value=0.26.

Reference： [1]Patent: US6432993,2002,B1

42
[ 223133-39-9 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[2-(piperidin-1-yl)phenoxy]phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(12-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[2-(piperidin-1-yl)phenoxy]phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[2-(piperidin-1-yl)phenoxy]phenyl}-N-methyl-carbamate (1.19 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.80 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.39

Reference： [1]Patent: US6432993,2002,B1

43
[ 223133-68-4 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(pyridin-2-ylthio)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(13-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(pyridin-2-ylthio)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(pyridine-2-ylthio)phenyl]-N-methylcarbamate (0.78 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (1.06 g), diethyl cyanophosphonate (0.61 g), triethylamine (0.38 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (0.68 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/2: Rf=0.51

Reference： [1]Patent: US6432993,2002,B1

44
[ 223133-42-4 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[2-(pyrrolidin-1-yl)phenoxy]phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(14-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[2-(pyrrolidin-1-yl)phenoxy]phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[2-(pyrrolidin-1-yl)phenoxy]phenyl}-N-methyl-carbamate (0.77 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.90 g), diethyl cyanophosphonate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.26 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.40

Reference： [1]Patent: US6432993,2002,B1

45
[ 223133-69-5 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(2-hydroxyphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(15-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(2-hydroxyphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.99 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.18 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=2/3: Rf=0.47

Reference： [1]Patent: US6432993,2002,B1

46
[ 223133-71-9 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
[ 223132-85-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(17-1) t-Butyl N-{5-(3-dimethylaminophenoxy)-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-dimethylaminophenoxy)phenyl]-N-methylcarbamate (1.00 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (1.57 g), diethyl cyanophosphonate (0.91 g), triethylamine (0.57 g) and anhydrous tetrahydrofuran (40 ml) and the reaction mixture was purified to give the desired product (1.69 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.26

Reference： [1]Patent: US6432993,2002,B1

47
[ 223133-72-0 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[4-(imidazole-1-yl)phenoxy]phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(19-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[4-(imidazole-1-yl)phenoxy]phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[4-(imidazole-1-yl)phenoxy]phenyl}-N-methylcarbamate (1.14 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.75 g). Thin layer chromatography on a silica gel plate using ethyl acetate/methanol=10/1: Rf=0.51

Reference： [1]Patent: US6432993,2002,B1

48
[ 223133-73-1 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(2-phenylphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(20-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(2-phenylphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.33 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=3/2: Rf=0.25

Reference： [1]Patent: US6432993,2002,B1

49
[ 223133-75-3 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-phenoxyphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(22-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-phenoxyphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-phenoxyphenoxy)phenyl]-N-methylcarbamate (1.66 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.99 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/2: Rf=0.62

Reference： [1]Patent: US6432993,2002,B1

50
[ 223133-76-4 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
[ 223131-21-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(23-2a) 5-{4-[6-(4-Hydroxyphenylthio)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}-thiazolidine-2,4-dione In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-hydroxyphenylthio)phenyl]-N-methylcarbamate (2.36 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (2.87 g), diethyl cyanophosphonate (1.67 g), triethylamine (1.03 g) and anhydrous tetrahydrofuran (60 ml) and the reaction mixture was purified.

Reference： [1]Patent: US6432993,2002,B1

51
[ 223133-77-5 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3-phenylphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(24-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3-phenylphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.57 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.32

Reference： [1]Patent: US6432993,2002,B1

52
[ 223133-78-6 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3-t-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(25-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3-t-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-t-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate (1.11 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.89 g), diethyl cyanophosphonate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.75 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate 1/1: Rf=0.26

Reference： [1]Patent: US6432993,2002,B1

53
[ 223133-80-0 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(2-t-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(26-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(2-t-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-t-butyl-4-hydroxyphenoxy)phenyl]-N-methyl-carbamate (0.95 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.76 g), diethyl cyanophosphonate (0.44 g), triethylamine (0.27 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.24 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.19

Reference： [1]Patent: US6432993,2002,B1

54
[ 223133-81-1 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-phenylphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(27-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-phenylphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.39 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.32

Reference： [1]Patent: US6432993,2002,B1

55
[ 223133-82-2 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-hydroxy-2,5-dimethylphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(28-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-hydroxy-2,5-dimethylphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-hydroxy-2,5-dimethylphenoxy)phenyl]-N-methylcarbamate (0.54 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.51 g), diethyl cyanophosphonate (0.29 g), triethylamine (0.18 g) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified to give the desired product (0.71 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/2: Rf=0.68

Reference： [1]Patent: US6432993,2002,B1

56
[ 223133-84-4 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3,5-di-t-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(29-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3,5-di-t-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3,5-di-t-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.55 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.42 g), diethyl cyanophosphonate (0.24 g), triethylamine (0.15 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (0.72 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate 1/2: Rf=0.68

Reference： [1]Patent: US6432993,2002,B1

57
[ 223133-93-5 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-methylthiophenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(34-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-methylthiophenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-methylthiophenoxy)phenyl]-N-methylcarbamate (1.93 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (3.01 g), diethyl cyanophosphonate (1.75 g), triethylamine (1.08 g) and anhydrous tetrahydrofuran (80 ml) and the reaction mixture was purified to give the desired product (2.96 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=7/3: Rf=0.11

Reference： [1]Patent: US6432993,2002,B1

58
[ 223133-94-6 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-methoxyphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(35-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-methoxyphenoxy)phenyl}-N -methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-methoxyphenoxy)phenyl]-N-methylcarbamate (2.0 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (2.0 g), diethyl cyanophosphonate (1.3 g), triethylamine (0.81 g) and anhydrous tetrahydrofuran (50 ml) and the reaction mixture was purified to give the desired product (3.3 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.61

Reference： [1]Patent: US6432993,2002,B1

59
[ 223133-95-7 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-trifluoromethylphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(36-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-trifluoromethylphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-trifluoromethylphenoxy)phenyl]-N-methylcarbamate (0.68 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.73 g), diethyl cyanophosphonate (0.49 g), triethylamine (0.30 g) and anhydrous tetrahydrofuran (50 ml) and the reaction mixture was purified to give the desired product (0.97 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=2/1: Rf=0.23

Reference： [1]Patent: US6432993,2002,B1

60
[ 223133-97-9 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-benzylphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(37-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-benzylphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-benzylphenoxy)phenyl]-N-methylcarbamate (0.61 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.51 g), diethyl cyanophosphonate (0.29 g), triethylamine (0.18 g) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified to give the desired product (0.91 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.26

Reference： [1]Patent: US6432993,2002,B1

61
[ 223133-98-0 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3-hydroxyphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(38-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3-hydroxyphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.95 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.89 g), diethyl cyanophosphonate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.18 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.28

Reference： [1]Patent: US6432993,2002,B1

62
[ 313345-67-4 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetylamino]-5-[4-(tetrazol-5-yl)phenoxy]phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(39-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetylamino]-5-[4-(tetrazol-5-yl)phenoxy]phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[4-(tetrazol-5-yl)phenoxy]phenyl}-N-methylcarbamate (0.69 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.37 g), diethyl cyanophosphonate (0.21 g), triethylamine (0.13 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (0.76 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.49

Reference： [1]Patent: US6432993,2002,B1

63
[ 223134-10-9 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(2,5-di-t-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(42-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(2,5-di-t-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2,5-di-t-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.71 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.68 g), diethyl cyanophosphonate (0.39 g), triethylamine (0.24 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.13 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/1: Rf=0.41

Reference： [1]Patent: US6432993,2002,B1

64
[ 223134-15-4 ]
[ 2942-58-7 ]
[ 179087-93-5 ]
[ 223133-09-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(46-1) t-Butyl N-{5-(4-aminophenoxy)-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-t-butoxycarbonylaminophenoxy)phenyl]-N-methylcarbamate (500 mg), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (366 mg), diethyl cyanophosphonate (212 mg), triethylamine (132 mg) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified to give the desired compound (395 mg). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=2/3: Rf=0.51

Reference： [1]Patent: US6432993,2002,B1

65
[ 223133-47-9 ]
[ 179087-93-5 ]
t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(pyridin-3-yloxy)phenyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	(18-1) t-Butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(pyridin-3-yloxy)phenyl}-N-methylcarbamate In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(pyridin-3-yloxy)phenyl]-N-methylcarbamate (0.63 g), <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> (0.62 g), diethyl cyanophsphonate (0.36 g), triethylamine (0.22 g) and anhydrous tetrahydrofuran (15 ml) and the reaction mixture was purified to give the desired product (0.88 g). Thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=1/2: Rf=0.38

Reference： [1]Patent: US6432993,2002,B1

Yield	Reaction Conditions	Operation in experiment
		Aq. sodium hydroxide solution (37 g of NaOH in 135 ml of water) was added slowly over a period of 5-10 minutes at 20-25 C. Stirring was continued at ambient temperature for a period of 2-3 h, while monitoring the reaction by TLC. After the completion of the reaction, the pH of the reaction mixture was adjusted to 2 using conc. HCl (temp. raises to 40-45 C.) and allowed to attain room temperature. The mass was cooled to 10-15 C. and the solid thus obtained was filtered and dried at 60-70 C. under 1-2 mm Hg of vacuum to afford 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2,4-dione (121 g, Y=99%, P=99.2%).

Yield	Reaction Conditions	Operation in experiment
68%		Method B The title compound (278 mg, 68%) was obtained from 4-[[2,4-2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid (281 mg, 1.0 mmol) (obtained from preparation 38) and 2-amino-N-methyl benzamide (164 mg, 1.0 mmol) by a similar procedure to that described in example 22 in method B. mp=218 C. 1H NMR (CDCl3): delta 9.20 (bs, 1H, D2O exchangeable) 8.30 (d, J=7.84 Hz, 1H), 7.84-7.64 (m, 2H), 7.60-7.48 (m, 1H), 7.19 (d, J=8.46 Hz, 2H), 7.02 (d, J=8.46 Hz, 2H), 5.25 (s, 2H), 4.51 (dd, J=9.30, 3.95 Hz, 1H), 3.94 (q, J=6.92 Hz, 2H), 3.42 (dd, J=14.12, 3.95 Hz, 1H), 3.11 (dd, J=14.2, 9.30 Hz, 1H), 1.35 (t, J=6.92 Hz, 3H).

68
[ 172648-06-5 ]
[ 179087-93-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium carbonate; In methanol; water;	Preparation 38 [4-[[2,4-Dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid: To a stirred solution of ethyl [4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetate (110 g, 0.36 mol) in methanol (0.65 L) was added as solutino of Na2CO3 (200 g, 1.88 mol) in water (0.65 L) and stirred for 5 h at 25 to 30 C. After completion of the reaction, methanol was removed under reduced pressure; water was added to the residue and was acidified with hydrochlori acid. The precipitated while solid was filtered and dired to yield the title compound (80 g, 80%). mp: 181-183 C. 1H NMR (DMSO-d6): delta 12.40 (bs, 1H, D2O exchangeable), 8.60 (bs, 1H, D2O exchangeable), 7.16 (d, J=8.40 Hz, 2H), 6.50 (d, J=8.40 Hz, 2H), 4.87 (dd, J=9.14, 4.20 Hz, 1H), 4.65 (s, 2H), 3.32 (dd, J=14.12, 4.20 Hz, 1H), 3.05 (dd, J=14.12, 9.14 Hz, 1H).

Reference： [1]Patent: US6310069,2001,B1

69
[4-[[1,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid [ No CAS ]
[ 179087-93-5 ]

Yield	Reaction Conditions	Operation in experiment
		Method B To a stirred solution of [4-[[1,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid (1.9 g, 6.75 mmol) (obtained form preparation 38) in dichloromethane (15 ml) was added triethyl amine (1.876 ml, 1.36 g, 13.48 mmol) followed by pivaloyl chloride (0.913 ml, 899 mg, 5.46 mmol) at 0 C. and stirring was continued for 1 h at 0 C.

Reference： [1]Patent: US6310069,2001,B1

70
[ 515164-48-4 ]
[ 179087-93-5 ]
[ 945457-77-2 ]

Yield	Reaction Conditions	Operation in experiment
	With diethyl cyanophosphonate; triethylamine; In tetrahydrofuran; at 20℃; for 4.5h;	Production Example 1 5-(4-(6-(3-Isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione·dihydrochloride A mixture of 0.74 g of N-(2-amino-5-(3-isopropylamino-phenoxy)-phenyl)-N-methylcarbamic acid t-butyl ester obtained in Reference Example 2, 0.70 g of 4-(2,4-diothiazolidin-5-ylmethyl)-phenoxyacetic acid (Japanese Patent Application (Kokai) No.), 0.41 g of diethyl cyanophosphonate, 0.25 g of triethylamine, and 30 ml of anhydrous tetrahydrofuran was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated, followed by addition of water and extraction with ethyl acetate. After the extraction solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (eluding solvent: ethyl acetate/n-hexane =2/3) to give N-(5-(3-isopropylamino-phenoxy)-2-(4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxyacetylamino)-phenyl)-N-methylcarbamic acid t-butyl ester as an intermediate. After this intermediate was dissolved in 50 ml of 4N hydrochloric acid/1,4-dioxane, the mixture was left to stand at room temperature for 16 hours, and the product which deposited was filtered and washed with ethyl acetate to give the title compound (0.76 g, 64% yield). 1H-NMR (DMSO-d6) delta: 1.21 (6H, d, J=6.4Hz), 3.11 (1H, dd, J=14 and 9.0Hz), 3.34 (1H, dd, J=14 and 4.4Hz), 3.57-3.65 (1H, m), 3.95 (3H, s), 4.91 (1H, dd, J=9.0 and 4.4Hz), 5.63 (2H, s), 6.70-7.20 (3H, m), 7.14 (2H, d, J=8.7Hz), 7.25 (2H, d, J=8.7Hz), 7.25 (1H, d, J=3.3Hz), 7.35-7.45 (1H, m), 7.68 (1H, d, J=1.9Hz), 7.83 (1H, d, J=8.9Hz), 12.05 (1H, s; disappeared due to addition of deuterium oxide).

Reference： [1]Patent: EP1982718,2008,A1 .Location in patent: Page/Page column 15

71
None [ No CAS ]
[ 179087-93-5 ]

Reference： [1]Patent: EP1191019,2002,A1 .Location in patent: Page 52

72
[ 3282-30-2 ]
[ 179087-93-5 ]
[ 7137-32-8 ]
acid anhydride of {4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tributyl-amine; In tetrahydrofuran; at -10 - -5℃;Industry scale;Product distribution / selectivity;	Example 5 5-(4-[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dione dihydrochloric acid monohydrate (Steps 2 and 3) Tributylamine (7.27 kg) was added to a suspension of <strong>[179087-93-5]{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetic acid</strong> (11.04 kg) in tetrahydrofuran (130 L) to prepare a solution. This solution was cooled to -5 C. Pivaloyl chloride (4.73 kg) was added dropwise thereto, and then, the mixture was stirred at -10 C. for 30 minutes to obtain a mixed acid anhydride of <strong>[179087-93-5]{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetic acid</strong> and pivalic acid.

Reference： [1]Patent: US2012/238759,2012,A1 .Location in patent: Page/Page column 11-12

73
[ 1309375-69-6 ]
[ 179087-93-5 ]
N-[(4-amino-3,5-dimethylphenoxy)-2-(methylamino)phenyl]-2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 0 - 10℃; for 0.666667h;	Example 2 N-[(4-Amino-3,5-dimethylphenoxy)-2-(methylamino)phenyl]-2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetamide (Compound No: (II)-1, Step 2) {4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetic acid (3.76 g) was added to a solution of the 4-(4-amino-3,5-dimethylphenoxy)-N2-methylbenzenediamine (3.18 g) obtained in Example 1 in dichloromethane (31 mL), and the mixture was cooled to 0 C. Then, triethylamine (3.73 mL) and subsequently a 50% solution of propylphosphonic acid cyclic anhydride in ethyl acetate (8.69 mL) were added dropwise thereto, and the mixture was stirred at 0 C. to 10 C. for 40 minutes. A 5% aqueous sodium bicarbonate solution (31 mL) was added thereto, and the mixture was well stirred and then separated into organic and aqueous layers. The organic layer was washed with water (15 mL) and then concentrated to obtain the compound of interest (5.72 g, yield: 97% (based on phenoxyacetic acid)).

Reference： [1]Patent: US2012/238759,2012,A1 .Location in patent: Page/Page column 9-10

74
4-(4-amino-3,5-dimethylphenoxy)-N₂-methylbenzenediamine dihydrochloric acid [ No CAS ]
[ 179087-93-5 ]
N-[(4-amino-3,5-dimethylphenoxy)-2-(methylamino)phenyl]-2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 5 5-(4-[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dione dihydrochloric acid monohydrate (Steps 2 and 3)Tributylamine (7.27 kg) was added to a suspension of <strong>[179087-93-5]{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetic acid</strong> (11.04 kg) in tetrahydrofuran (130 L) to prepare a solution. This solution was cooled to -5 C. Pivaloyl chloride (4.73 kg) was added dropwise thereto, and then, the mixture was stirred at -10 C. for 30 minutes to obtain a mixed acid anhydride of <strong>[179087-93-5]{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetic acid</strong> and pivalic acid. This mixed acid anhydride was added dropwise over 77 minutes to a solution of the 4-(4-amino-3,5-dimethylphenoxy)-N2-methylbenzenediamine dihydrochloric acid (12.96 kg) obtained in Example 4 and tributylamine (24.00 kg) in tetrahydrofuran (130 L) cooled to -10 C., and the mixture was further stirred for 1 hour to obtain a mixed solution of N-[(4-amino-3,5-dimethylphenoxy)-2-(methylamino)phenyl]-2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetamide in tetrahydrofuran. The obtained mixed solution was heated to 0 C. Water (130 L) and 38% hydrochloric acid (11.01 kg) were added thereto, and then, the mixture was stirred at 60 C. for 30 minutes. The obtained reaction solution was cooled to 5 C. and stirred for 12 hours. Then, a 25% aqueous sodium hydroxide solution (19.44 kg) and a solution of sodium chloride (24.92 kg) in water (130 L) were added dropwise thereto at 20 C., and the mixture was stirred for 15 minutes and then left standing for 1.5 hours. The aqueous layer (lower layer) was discarded. A suspension of active carbon (3.89 kg) in tetrahydrofuran (65 L) was added to the obtained solution of 5-(4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-yl]methoxy}benzyl-2,4-dioxo-1,3-thiazolidine (upper layer), and the mixture was stirred at 20 C. for 40 minutes. The active carbon was collected by filtration, and the reaction container and the active carbon were washed with tetrahydrofuran (91 L). The filtrate and the washes were combined and stirred at -10 C. for 12 hours. This solution was concentrated under reduced pressure at approximately 20 C. until its volume became approximately 260 L. To this concentrate, a 38% solution of hydrochloric acid (18.79 kg) in tetrahydrofuran (65 L) was added dropwise at 30 C. over 1.5 hours, and the mixture was cooled to 5 C. After further stirring for 1 hour, the obtained crystals were collected by filtration and washed with water (4 L), tetrahydrofuran (35 L), and then water (65 L) to obtain wet crystals of the compound of interest. (23.80 kg). A portion of the crystals was sampled and dried under reduced pressure at 40 C., and the NMR spectrum thereof agreed with that obtained in Example 3.

Reference： [1]Patent: US2012/238759,2012,A1 .Location in patent: Page/Page column 11-12

75
[ 1309375-71-0 ]
[ 179087-93-5 ]
[ 1309375-68-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 9) t-Butyl (4-{4-[({4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetyl)amino]-3-(methylamino)phenoxy}-2,6-dimethylphenyl)carbamate (Compound No: (II)-10, Step 2) Pivaloyl chloride (320 mg) and subsequently tributylamine (493 mg) were added dropwise to a solution of <strong>[179087-93-5]{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}acetic acid</strong> (747 mg) in ethyl acetate (6 mL) at 0 C., and the mixture was stirred for 30 minutes. The obtained solution of the mixed acid anhydride was added dropwise to a solution of the t-butyl {4-[4-amino-3-(methylamino)phenoxy]-2,6-dimethylphenyl}carbamate (970 mg) obtained in Example 8 and triethylamine (717 mg) in ethyl acetate (8 mL) at 0 C., and the mixture was stirred at the same temperature as above for 1 hour. Ethyl acetate (10 mL) and water (20 mL) were poured to the reaction mixture, and the organic layer was separated, then washed with 10% hydrochloric acid (20 mL) twice, a 5% aqueous sodium bicarbonate solution (20 mL) twice, and water (20 mL) once, and dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was filtered off, and then, the organic layer was concentrated to obtain the compound of interest. HPLC (column: L-column ODS 4.6*250 mm, mobile phase: acetonitrile-0.02 M aqueous ammonium acetate solution=1:1, flow rate: 1.0 mL/min, column temperature: 40 C., detection wavelength: 220 nm) retention time (min): 12.01.

Reference： [1]Patent: US2012/238759,2012,A1 .Location in patent: Page/Page column 11-12

76
6-(4-amino-3-methylaminophenoxymethyl)-4-methyl-2-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-benzimidazole hydrochloride [ No CAS ]
[ 179087-93-5 ]
[ 1350439-65-4 ]

Yield	Reaction Conditions	Operation in experiment
		A weight of 2.8 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> and 1.6 g of 1,1'-carbonylbis-1H-imidazole was combined with 30 mL of dry tetrahydrofuran, made liquid by sonication, and stirred at room temperature for 1.5 hours. This solution was combined with 3.88 g of a coarse product material of 6-(4-amino-3-methylaminophenoxymethyl)-4-methyl-2-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-benzimidazole hydrochloride (the compound of Reference Example 3) and stirred at room temperature for thirty minutes, then combined with 1.5 g of triethylamine and stirred at room temperature overnight. The reaction mixture was poured into water and a precipitated solid was collected by filtration and dried to give 3.5 g of a coarse product material of the intended compound as a light brown powder.

Reference： [1]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0499

77
[ 1350439-67-6 ]
[ 179087-93-5 ]
[ 1350439-68-7 ]

Yield	Reaction Conditions	Operation in experiment
0.81g	With diethyl cyanophosphonate; triethylamine; In tetrahydrofuran; at 20℃; for 48h;	A solution of 0.75 g of 4'-[6-(4-amino-3-(N-t-butoxycarbonyl-N-methylamino)phenoxymethyl)-4-methyl-2-propyl-1H-benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid t-butyl ester (the compound of Reference Example 8) and 0.305 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> diethyl in 5 mL of dry tetrahydrofuran was combined with 0.177 g of diethyl cyanophosphonate, then combined with 0.13 g of triethylamine and stirred at room temperature for two days. The reaction mixture was refined by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 1/1 to 1/2) to give 0.81 g of the intended compound as a light yellow solid. Rf value (relative difference) (silica gel thin layer chromatography, n-hexane/ethyl acetate = 1/1): 0.20.

Reference： [1]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0504

78
[ 1350439-80-3 ]
[ 179087-93-5 ]
[ 1350439-82-5 ]

Yield	Reaction Conditions	Operation in experiment
0.62g	With diethyl cyanophosphonate; triethylamine; In tetrahydrofuran; at 20℃; for 48h;	A solution of 0.94 g of 6-{6-[N-[2-(4-amino-3-(N-t-butoxycarbonyl-N-methylamino)phenoxy)ethyl]-N-methylamino]-1-methyl-1H-benzimidazol-2-yl}-4-methyl-2-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-benzimidazole (the compound of Reference Example 16) and 0.32 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> in 7 mL of dry tetrahydrofuran was combined with 0.273 g of diethyl cyanophosphonate, then combined with 0.185 g of triethylamine, sonicated for ten minutes, and stirred at room temperature for two days. The reaction mixture was refined by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 1/1 to 10/1) to give 0.62 g of the intended compound as a yellow solid. Rf value (relative difference) (silica gel thin layer chromatography, ethyl acetate): 0.37.

Reference： [1]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0512

79
[ 1350439-99-4 ]
[ 179087-93-5 ]
4'-[2-propyl-6-{N-2-(3-(N-t-butoxycarbonyl-N-methylamino)-4-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethylcarbonylamino]phenoxy)ethyl-N-methylamino}-1H-benzimidazol-1-ylmethoxy]biphenyl-2-carboxylic acid t-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.88g	With diethyl cyanophosphonate; triethylamine; In tetrahydrofuran; at 20℃; for 120h;	A solution of 1.64 g of 4'-[6-[N-2-{N-2-(4-amino-3-(N-t-butoxycarbonyl-N-methylamino)phenoxy)ethyl-N-methylamino }-2-propyl-1H-benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid t-butyl ester (the compound of Reference Example 25) and 0.65 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> in 10 mL of dry tetrahydrofuran was combined with 0.38 g of diethyl cyanophosphonate, then combined with 0.25 g of triethylamine and stirred at room temperature for five days. The reaction mixture was combined with ethyl acetate, then refined by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 1/3) to give 1.88 g of the intended compound as a white solid. Rf value (relative difference) (silica gel thin layer chromatography, n-hexane/ethyl acetate = 1/3): 0.54.

Reference： [1]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0522

80
[ 1350440-01-5 ]
[ 179087-93-5 ]
[ 1350440-05-9 ]

Yield	Reaction Conditions	Operation in experiment
0.68g	With diethyl cyanophosphonate; triethylamine; In tetrahydrofuran; at 20℃; for 48h;	A solution of 0.72 g of 4'-[5-{N-2-(4-amino-3-(N-t-butoxycarbonyl-N-methylamino)phenoxy)ethyl-N-methylamino}-2-propyl-1H-benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid t-butyl ester (the compound of Reference Example 26) and 0.282 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> in 4 mL of dry tetrahydrofuran was combined with 0.164 g of diethyl cyanophosphonate, then combined with 0.12 g of triethylamine and stirred at room temperature for two days. The reaction mixture was treated and refined in the same manner as Reference Example 27 to give 0.68 g of the intended compound as a white solid. Rf value (relative difference) (silica gel thin layer chromatography, n-hexane/ethyl acetate = 1/3): 0.50.

Reference： [1]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0523

81
[ 1350440-13-9 ]
[ 179087-93-5 ]
[ 1350440-15-1 ]

Yield	Reaction Conditions	Operation in experiment
0.96g	With diethyl cyanophosphonate; triethylamine; In tetrahydrofuran; at 20℃; for 120h;	A solution of 1.39 g of 4'-[6-{4-(4-amino-3-(N-t-butoxycarbonyl-N-methylamino)phenoxy)phenylthiomethyl}-4-methyl-2-propyl-1H-benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid t-butyl ester (the compound of Reference Example 32) and 0.52 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> in 6 mL of dry tetrahydrofuran was combined with 0.31 g of diethyl cyanophosphonate, then combined with 0.2 g of triethylamine and stirred at room temperature for five days. The residue resulting from distilling off the solvent was refined by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 5/7) to give 0.96 g of the intended compound as a light yellow powder. Rf value (relative difference) (silica gel thin layer chromatography, n-hexane/ethyl acetate = 1/1): 0.24.

Reference： [1]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0528

82
[ 1350440-20-8 ]
[ 179087-93-5 ]
[ 1350440-22-0 ]

Yield	Reaction Conditions	Operation in experiment
2.69g	With diethyl cyanophosphonate; triethylamine; In tetrahydrofuran; at 20℃; for 120h;	A solution of 2.4 g of 4-(4-amino-3-(N-t-butoxycarbonyl-N-methylamino)phenoxymethyl)-2-propyl-1-[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylic acid ethyl ester (the compound of Reference Example 35) and 0.75 g of <strong>[179087-93-5]4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid</strong> in 5 mL of dry tetrahydrofuran was combined with 0.44 g of diethyl cyanophosphonate, then combined with 0.3 g of triethylamine and stirred at room temperature for five days. The reaction mixture was combined with ethyl acetate and silica gel, the solvent was distilled off, and the residue was refined by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 3/2) to give 2.69 g of the intended compound as a light yellow solid. Rf value (relative difference) (silica gel thin layer chromatography, n-hexane/ethyl acetate = 1/1): 0.17.

Reference： [1]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0531

83
[ 1350440-33-3 ]
[ 179087-93-5 ]
[ 1350440-35-5 ]

Yield	Reaction Conditions	Operation in experiment
1.56g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	A mixture of 1.38 g of 4-[4-{4-amino-3-(N-t-butoxycarbonyl-N-methylamino)phenoxy}phenylthiomethyl]-2-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylic acid ethyl ester (the compound of Reference Example 39(b)), 0.501 g of 4-(2,4-dixothiazolidin-5-ylmethyl)phenoxyacetic acid, and 3 mL of dry dimethylformamide was combined with 0.341 g of WSC (1-methyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and stirred at room temperature overnight. The reaction mixture was combined with ethyl acetate and physiological saline, and the ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated physiological saline, then dried over anhydrous sodium sulfate. After the solvent had been distilled off, 1.96 g of the resulting residue was refined by silica gel column chromatography (elution solvent: ethyl acetate/methanol = 40/1) to give 1.56 g of the intended compound as a light yellow powder.

Reference： [1]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0541

84
[ 179087-93-5 ]
[ 1350439-09-6 ]

Reference： [1]Patent: EP2581373,2013,A1

85
[ 179087-93-5 ]
[ 1350439-10-9 ]

Reference： [1]Patent: EP2581373,2013,A1

86
[ 1350441-98-3 ]
[ 179087-93-5 ]
[ 1350440-48-0 ]

Yield	Reaction Conditions	Operation in experiment
0.27g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 72h;	A mixture of 0.46 g of 5-[4-amino-3-(N-t-butoxycarbonyl-N-methylamino)phenylthiomethyl]-2-butyl-4-chloro-1-[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazole (the compound of Reference Example 52), 0.21 g of 4-(2,4-dixothiazolidin-5-ylmethyl)phenoxyacetic acid, and 2 mL of dry dimethylformamide was combined with 0.143 g of WCS (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and stirred at room temperature for three days. The reaction mixture was combined with ethyl acetate, and the ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated physiological saline, then dried over anhydrous sodium sulfate. After the solvent had been distilled off, 0.70 g of the resulting residue was refined by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 2/20/1) to give 0.27 g of the intended compound as a light yellow solid. Rf value (relative difference) (silica gel thin layer chromatography, elution solvent: ethyl acetate/methanol = 20/1): 0.50. Mass spectrum: 922 (M+1)+. 1H-NMR: spectra (500MHz, DMSO-d6), deltappm:0.8 0(t, 3H), 1.2 5 (m, 2H), 1. 15-1.5 ( broad s, 9H), 1.45 (m, 2H), 2.45 (t, 2H), 3.00 (s, 3 H), 3.08 (q, 1H), 3.33 (d, 1H), 4.04 (s, 2H ), 4.71 (s, H), 4. 8 8 (q, 1H), 5.28 (s, 2H), 6. 92-7. 67 (m, 15H), 7. 92 (s, 1H), 9.09 (s , 1H).

Reference： [1]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0558; 0559

87
[ 1350440-51-5 ]
[ 179087-93-5 ]
[ 1350440-52-6 ]

Yield	Reaction Conditions	Operation in experiment
0.99g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 240h;	A mixture of 2.32 g of N-[4-{4-amino-3-(N-t-butoxycarbonyl-N-methylamino)phenylthio}-2-(N-t-butoxycarbonyl-N-methylamino)phenyl]-4-methyl-2-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-benzoimidazol-6-yl carboxamide (the compound of Reference Example 56), 0.57 g of 4-(2,4-dixothiazolidin-5-ylmethyl)phenoxyacetic acid, and 10 mL of dry dimethylformamide was combined with 0.42 g of WSC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and stirred at room temperature for ten days. The reaction mixture was combined with ethyl acetate and physiological saline, and the ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated physiological saline, then dried over anhydrous sodium sulfate. After the solvent had been distilled off, 3.08 g of the resulting residue was refined by silica gel column chromatography (elution solvent: ethyl acetate) to give 0.99 g of the intended compound as a light yellow powder. Rf value (relative difference) (silica gel thin layer chromatography, ethyl acetate): 0.43. Mass spectrum: 1172 (M+1)+.

Reference： [1]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0566; 0567

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H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 179087-93-5 ] {[proInfo.proName]}

Quality Control of [ 179087-93-5 ]

Related Doc. of [ 179087-93-5 ]

Product Details of [ 179087-93-5 ]

Calculated chemistry of [ 179087-93-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 179087-93-5 ]

Application In Synthesis of [ 179087-93-5 ]

[ 179087-93-5 ] Synthesis Path-Upstream 1~5

[ 179087-93-5 ] Synthesis Path-Downstream 1~87

Related Functional Groups of [ 179087-93-5 ]

Aryls

Ethers

Amides

Carboxylic Acids

Thioesters

Related Parent Nucleus of [ 179087-93-5 ]

Aliphatic Heterocycles

Thiazolidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 179087-93-5 ]

Related Parent Nucleus of
[ 179087-93-5 ]