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[ CAS No. 122320-73-4 ] {[proInfo.proName]}

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Chemical Structure| 122320-73-4
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Product Details of [ 122320-73-4 ]

CAS No. :122320-73-4 MDL No. :MFCD00871760
Formula : C18H19N3O3S Boiling Point : -
Linear Structure Formula :- InChI Key :YASAKCUCGLMORW-UHFFFAOYSA-N
M.W : 357.43 Pubchem ID :77999
Synonyms :
BRL 49653
Chemical Name :5-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione

Calculated chemistry of [ 122320-73-4 ]

Physicochemical Properties

Num. heavy atoms : 25
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.28
Num. rotatable bonds : 7
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 101.63
TPSA : 96.83 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.27 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.41
Log Po/w (XLOGP3) : 3.11
Log Po/w (WLOGP) : 2.11
Log Po/w (MLOGP) : 1.64
Log Po/w (SILICOS-IT) : 2.54
Consensus Log Po/w : 2.36

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.91
Solubility : 0.0441 mg/ml ; 0.000123 mol/l
Class : Soluble
Log S (Ali) : -4.81
Solubility : 0.00551 mg/ml ; 0.0000154 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -5.71
Solubility : 0.000689 mg/ml ; 0.00000193 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.35

Safety of [ 122320-73-4 ]

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

Application In Synthesis of [ 122320-73-4 ]

* 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 [ 122320-73-4 ]
  • Downstream synthetic route of [ 122320-73-4 ]

[ 122320-73-4 ] Synthesis Path-Upstream   1~19

  • 1
  • [ 160596-25-8 ]
  • [ 122320-73-4 ]
YieldReaction ConditionsOperation in experiment
93% With sodium hydroxide; sodium tetrahydroborate; butane-2,3-dione dioxime In water; N,N-dimethyl-formamide at 55℃; for 4.41667 h; [1] Preparation of the catalyst: 1.2 g of cobalt(II) chloride hexahydrate was dissolved in120 ml of DMF, followed by addition of 8.O g of dimethylglyoxime; a clear blue-green solution was obtained after a while of stirring.[2] Preparation of a solution of the reducing agent: 27.2 g of sodium borohydride was dissolved, under stirring, in 300 ml of a 0.1 M solution of sodium hydroxide at room temperature.[3] The actual reduction: 16.8 g of sodium hydroxide was dissolved in 1200 ml of distilled water and the resulting solution was subsequently poured to 12O g of reduced rosiglitazone EPO <DP n="12"/>benzylidene. The mixture was stirred until a solution was formed, and thus obtained solution was stirred and heated to a temperature of 55+/-5 °C. After the temperature conditions were reached, the catalyst (1/5 of the volume according to [1], over about 1 minute) was added dropwise to the solution, followed by addition of the reducing agent (1/5 of the volume according to [2], over about 2 minutes), and the mixture was stirred at 55+/-5 0C for about 50 minutes. The addition of the catalyst (1/5 of the volume according to [I]) and of the reducing agent (1/5 of the volume according to [2]), including the stirring and heating of the reaction mixture at 55+/-5 °C, were repeated in the same way four times more (including about 50-minute pauses between the individual additions). [4] Isolation of the crude product: To the reaction mixture (according to [3]), being intensely stirred, still 55+/-5 0C warm, 300 ml of ethyl acetate was added, followed by gradual addition of 260 ml of hydrochloric acid (1:1) in such a way that the temperature of the reaction mixture is maintained at 55+/-5 °C without any external heating. Very slow addition of 600 ml of a 10percent solution of sodium hydrogen carbonate followed. The precipitated lumpy suspension was, while it cooled slowly, stirred for about 20 minutes until it reached the target temperature of 30 - 40 0C. Filtration was carried out after that, and the filter cake was washed with water (6 x 200 ml) and ethanol (3 x 200 ml). The product obtained was dried in a vacuum drier until a constant weight. Crude free rosiglitazone base I with a melting point of 153 - 155 0C was obtained. The yield was 93 percent (HPLC 99,0 percent, the content of residual cobalt 11 μg/g).; EXAMPLE 9 (representative example for the crystallization of free rosiglitazone base) 110 g of crude free rosiglitazone base I was, at about 70 - 80 0C, dissolved in 200 ml of acetic acid (over about 15 minutes), and ethanol was added to the solution obtained in the following regimen: 250 ml of ethanol added over 5 minutes, followed by filtration, the temperature of the filtrate being 65 0C; as the filtrate cooled slowly, it was stirred for about 15 minutes, and the temperature dropped to 57 °C, yielding a turbid solution; stirring continued for about 20 minutes, the temperature dropped from 57 to about 50 °C, a thick suspension of the product formed; 250 ml of ethanol added over 1 minute, stirring for about 10 minutes, the temperature dropped to 45 0C; EPO <DP n="13"/> 250 ml of ethanol added over 1 minute, stirring for about 10 minutes, the temperature dropped to 38 0C; 250 ml of ethanol added over 1 minute, stirred for about 10 minutes, the temperature dropped to 30 °C. 1000 ml of ethanol was added altogether in four doses over about 70 minutes, and the temperature of the suspension reached 30 °C. Finally, filtration was carried out, and the filter cake was washed with 2 x 150 ml of ethanol, yielding a white lumpy product. After the product was dried in a vacuum drier until a constant weight, 90 - 95 g of a white crystalline product with a melting point of 155 - 156 °C was obtained (HPLC 99.90 percent, the content of residual cobalt lμg/g).; EXAMPLE 10110 g of crude free rosiglitazone base I was, at 70 to 80 °C, dissolved in 200 ml of acetic acid, and ethanol was added to the solution obtained, under stirring, in the following regimen: 250 ml of ethanol added over 5 minutes, stirring for 10 minutes at 75 - 70 °C; 250 ml of ethanol added over 5 minutes, stirring for 20 minutes at 65 - 60 °C; 250 ml of ethanol added over 1 minute, stirring for 10 minutes at 55 - 50 °C; 250 ml of ethanol added over 1 minute, stirring for 10 minutes at 45 - 40 0C.1000 ml of ethanol was added altogether in the doses over about 1 hour, and the temperature of the suspension reached 40 °C. Finally, filtration was carried out, and the filter cake was washed with 2 x 150 ml of ethanol. After the product was dried in a vacuum drier until a constant weight, 92.2 g of a white crystalline product was obtained. The yield of crystallization was 83.8 percent (HPLC > 99.95 percent, the content of residual cobalt 1.5 μg/g).; EXAMPLE 1112O g of crude free base of rosiglitazone I was, at about 80 0C, dissolved in 200 ml of acetic acid, and ethanol was added to the solution obtained, under stirring, in the following regimen: 250 ml of ethanol added over 5 minutes (75 - 78 0C), stirred for 20 minutes at 75-65 0C; stirring for another 15 minutes, during which time the temperature dropped from 65 to 55 0C; stirring for another about 15 minutes until the temperature dropped to 50 0C, after which time 250 ml of ethanol was added in one portion (leading to a temperature of 48 0C); EPO <DP n="14"/> stirring for another 10 minutes, 250 ml of ethanol was, at a temperature of about 46 °C, added (leading to a temperature of 45 °C); stirring for another 10 minutes, 250 ml of ethanol was, at a temperature of about 44 °C, added, and the stirring continued for about 10 minutes until reaching a temperature of 40 °C. 1000 ml of ethanol was added altogether in four equal doses over about 75 minutes, and the temperature of the suspension reached 40 0C. Finally, filtration was carried out, and the filter cake was washed with ethanol (2 x 150 ml). After the product was dried in a vacuum drier until reaching a constant weight, 102.3 g of a white crystalline product was obtained. The yield of crystallization was 85.25 percent (HPLC 99.87 percent, the content of residual cobalt 2.7 μg/g).; EXAMPLE 12120 g of crude free rosiglitazone base I was, at about 75 °C, dissolved in 220 ml of acetic acid (over 15 minutes), and ethanol was added to the solution obtained (about 70 °C) in the following regimen: ^250 ml of ethanol added over 5 minutes, filtration carried out, the temperature of the filtrate was 50 0C;the temperature of the filtered solution was raised to 55 0C over 10 minutes and to 60 °C after another 10 minutes, and the solution was stirred at this temperature for 15 minutes (the solution growing turbid gradually); the mixture was, at 60 °C, stirred for another 45 minutes, after which time 250 ml of ethanol was added and the stirring continued at 55 - 50 0C for 30 minutes; external heating was stopped, and as the mixture was stirred, freely cooling down, for 90 minutes until reaching a temperature of 35 °C.500 ml of ethanol was added altogether in two doses over about 3 hours and 25 minutes, and the temperature of the suspension reached 35 °C. Finally, filtration was carried out, and the filter cake was washed with ethanol (2 x 150 ml). After the product was dried in a vacuum drier until a constant weight, 97.7 g of a white crystalline product was obtained. The yield of crystallization was 81.4 percent (HPLC > 99,95 percent, the content of residual cobalt 0.95 μg/g).; EXAMPLE 13HO g of crude free rosiglitazone base I was, at about 70 - 80 0C, dissolved in 200 ml of acetic acid (over 15 minutes), and ethanol was added to the solution obtained in the following regimen: EPO <DP n="15"/>250 ml of ethanol added over 5 minutes, filtration carried out, the temperature of the filtrate was 65 °C;the filtrate was stirred, gradually cooling down, for about 15 minutes, leading to a drop in the temperature to 57 °C and yielding a turbid solution; stirring for another about 20 minutes, the temperature dropped from 57 to about 50 0C, a thick suspension of the product formed; 250 ml of ethanol added over 1 minute, stirring for about 10 minutes, the temperature dropped to 45 0C;250 ml of ethanol added over 1 minute, stirring for about 10 minutes, the temperature dropped to 38 0C; 250 ml of ethanol added over 1 minute, stirring for about 10 minutes, the temperature dropped to 30 °C.1000 ml of ethanol was added altogether in four doses over about 70 minutes, and the temperature of the suspension reached 30 0C. Finally, filtration was carried out, and the filter cake was washed with ethanol (2 x 150 ml). After the product was dried in a vacuum drier until a constant weight, 95.2 g of a white crystalline product was obtained. The yield of crystallization was 86.5 percent (HPLC 99.90 percent, the content of residual cobalt 4.1 μg/g).; EXAMPLE 14 25 g of crude free rosiglitazone base I was, at 70 - 80 0C, dissolved in 50 ml of acetic acid, and ethanol (250 ml) was added to the solution obtained, the mixture was boiled for a while, and then stirred, under slow cooling, for 45 minutes. Ethanol (50 ml) was added to the suspension of the product before filtration. The precipitated crystals were sucked off, washed with ethanol (2 x 50 ml), and dried in a vacuum drier. 21.2 g of crystalline free rosiglitazone base I was obtained. The yield of crystallization was 85 percent.; EXAMPLE 1525 g of crude free rosiglitazone base I was, at 70 - 80 °C, dissolved in 50 ml of acetic acid, and methanol (200 ml) was added to the solution obtained. The mixture was stirred, under slow cooling, for about 120 minutes. Methanol (150 ml) was added to the suspension of the product before filtration. The precipitated crystals were sucked off, washed with methanol (2 x 50 ml), and dried in a vacuum drier. 18 g of crystalline free rosiglitazone base I was obtained. The yield of crystallization was 72 percent.; EXAMPLE 1625 g of crude free rosiglitazone base I was, at 70 - 80 °C, dissolved in 50 ml of acetic acid, and isopropyl alcohol (300 ml) was added to the solution obtained. The mixture was stirred, under slow cooling, for about 60 minutes. Isopropyl alcohol (250 ml) was added to the suspension of the product before filtration. The precipitated crystals were sucked off, washed with isopropyl alcohol (2 x 50 ml), and dried in a vacuum drier. 22.3 g of crystalline free rosiglitazone base I was obtained. The yield of crystallization was 89 percent.; EXAMPLE 1725 g of crude free rosiglitazone base I was, at 70 - 80 °C, dissolved in 50 ml of acetic acid, and N-butyl alcohol (300 ml) was added to the solution obtained. The mixture was stirred, under slow cooling, for about 60 minutes. N-butyl alcohol (250 ml) was added to the suspension of the product before filtration. The precipitated crystals were sucked off, washed with n-butyl alcohol (2 x 50 ml), and dried in a vacuum drier. 21.8 g of crystalline free rosiglitazone base I was obtained. The yield of crystallization was 87 percent.; EXAMPLE 1825 g of crude free rosiglitazone base I was, at 70 - 80 0C, dissolved in 50 ml of acetic acid, and isoamyl alcohol (200 ml) was added to the solution obtained. The mixture was stirred, under slow cooling, for about 60 minutes. Isoamyl alcohol (300 ml) was added to the suspension of the product before filtration. The precipitated crystals were sucked off, washed with isoamyl alcohol (2 x 50 ml), and dried in a vacuum drier. 22.6 g of crystalline free rosiglitazone base I was obtained. The yield of crystallization was 90 percent.; EXAMPLE 19 (comparative example)140 g of crude rosiglitazone base I was, at the boil, dissolved in 3.5 1 of ethanol. The solution obtained was stirred for 4 hours and then allowed to stand overnight. After the product was filtered, the filter cake washed with 200 ml of ethanol and dried in a vacuum drier, 125 g of a white crystalline powder with HPLC purity of 99.6 percent was obtained. The content of residual cobalt was 9 μg/g. The yield of crystallization was 89 percent.; EXAMPLE 20A mixture of 100 ml of acetic acid and 500 ml of ethanol was poured to 50 g of crude free rosiglitazone base I. The suspension obtained was stirred and heated to the boil until a solution was formed. The heating was stopped after that, and the mixture was stirred, under slow cooling, for 4 hours, leading to the formation of a thick suspension of the product. Filtration was carried out, and the filter cake was washed with ethanol (2 x 50 ml). 43.4 g of a finely crystalline product was obtained after drying in a vacuum drier. The yield of crystallization was 87 percent.
90% With sodium hydroxide; lithium borohydride In water; N,N-dimethyl-formamide at 0 - 55℃; for 5 h; The reduction was carried out in the same way as in example 1 with the only difference that sodium borohydride was replaced by the same molar amount of lithium borohydride (L1BH4). The crude product was obtained with a yield of 90 percent. The yield of crystallization was 85 percent.
89% With sodium hydroxide; sodium tetrahydroborate In water; N,N-dimethyl-formamide at 0 - 55℃; for 5 h; The reduction was carried out in the same way as in example 1 with the only difference that cobalt(II) chloride was replaced by the same amount of cobalt(II) acetate tetrahydrate. The crude product was obtained with a yield of 89 percent. The yield of crystallization was 80 percent.
87% With sodium hydroxide; sodium tetrahydroborate In water; N,N-dimethyl-formamide at 0 - 55℃; for 5 h; The reduction was carried out in the same way as in example 1 with the only difference that cobalt(II) chloride was replaced by the same amount of cobalt(II) nitrate hexahydrate. The crude product was obtained with a yield of 87 percent. The yield of crystallization was 84 percent.
87% With sodium hydroxide; tetraethylammonium borohydride In water; N,N-dimethyl-formamide at 0 - 55℃; for 5 h; The reduction was carried out in the same way as in example 1 with the only difference that ;,sodium borohydride ,;was: replaced , by. :the same molar amount of tetraethylammoniumborohydride (TEAB), The crude product was obtained with a yield of 87 percent. The yield of crystallization was 82 percent.
86% With sodium hydroxide; sodium tetrahydroborate In water; N,N-dimethyl-formamide at 0 - 55℃; for 5 h; The reduction was carried out in the same way as in example 1 with the only difference that dimethylglyoxime was replaced by the same molar amount of 1,10-phenanthroline. The crude product was obtained with a yield of 86 percent. The yield of crystallization was 85 percent.
85% With sodium hydroxide; sodium tetrahydroborate In water; N,N-dimethyl-formamide at 0 - 55℃; for 5 h; The reduction was carried out in the same way as in example 1 with the only difference that cobalt(H) chloride was replaced by the same amount of cobalt(III) chloride. The crude product was obtained with a yield of 85 percent. The yield of crystallization was 82 percent.
80% With iodine; magnesium In methanol for 3 h; Reflux To the solution of (Z)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]-methylene]-2,4-thiazoldinedione (7) (0.02 mole) in methanol (80 mL), Mg (0.31 mmol) and crystal of iodine (0.5 g) was added. The reaction mass was refluxed and stirred. The progress of the reaction was monitored by thin layer chromatography. After 3 h of reflux the reaction mass was allowed to cool at rt. The reaction mass was then added in ice and it was neutralized by HCl. Aqueous layer was extracted using DCM (130 .x. 2 mL). The combined organic layers were dried over magnesium sulphate. The dried organic layer was concentrated under vacuum. The obtained white product was crystallized using ethanol. 5-[[4-[2-(Methyl-2-pyridinylamino) ethoxy] phenyl]-methyl]-2,4-thiazoldinedione, rosiglitazone (BRL 49652) (8): Yield, 80percent; white solid; mp 152-153 °C; 1H NMR (300 MHz, DMSO-d6): δ ppm 3.10 (s, 3H, NCH3), 3.30 (dd, 2H, J = 7. 8 Hz, J = 10.2 Hz, C6H5CH2CH),3.91 (t, 2H, J = 5.4 Hz, CH2CH2), 4.12 (t, 2H, J = 5.4 Hz, CH2CH2), 4.83 (m, 1H, C6H5CH2CH), 6.19 (d, 2H, J = 8.14 Hz, ArH), 6.65 (m, 1H, ArH), 6.86 (d, 1H, J = 8.1 Hz, ArH), 7.13 (d, 2H, J = 8.1 Hz, ArH), 7.62 (m, 1H, ArH), 8.04 (d, 1H, J = 4.80 Hz, ArH), 11.99 (br s, 1H, NH, exchangeable with D2O); 13C NMR (100 MHz, DMSO-d6): 36.19, 37.30, 39.91, 53.0, 65.14, 114.27 (2C), 128.48 (2C), 130.40, 147.10, 157.34, 166.81, 171.68, 175.70; DART-MS (ESI+, m/z): 358 (M+).
76% With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In xylene for 12 h; Heating / reflux Preparation of Rosiglitazone (I) by an analogous process to that described in Example 1, wherein xylene is used as solvent instead of toluene, yielding 76percent of Rosiglitazone (I).
76% With sodium hydroxide; lithium borohydride In water; N,N-dimethyl-formamide at 35 - 45℃; for 3 h; 10 g of substance II was dissolved in a solution of 1 g of sodium hydroxide and 150 ml of water. 2.2 g of cobalt(II) chloride deposited on silica gel, 0.4 g of dimethylglyoxime (DMG) and 14 ml of dimethylformamide (DMF) were added into the solution. The mixture was stirred and heated to 35 °C, and an aqueous solution of lithium borohydride (1.8 g) was gradually added into it. The temperature of the reaction mixture was kept in the interval of 35 to 45 °C for 3 hours. The catalyst was then filtered off, pH of the filtrate was adjusted to 6 using diluted hydrochloric acid (1:1), and ethyl acetate (80 ml) was added. Ethyl acetate was slowly evaporated, which led to the precipitation of a lumpy product. The product was filtered, dried, and crystallized from ethanol. White crystalline powder with a melting point of 154-155 °C and chemical purity of 99.7 percent (HPLC) was obtained. The yield of rosiglitazone was 76 percent. The content of cobalt in the product, determined using inductively coupled plasma mass spectrometry, is 220 ppm.
70% With sodium hydroxide; sodium tetrahydroborate In water; N,N-dimethyl-formamide at 0 - 55℃; for 5.8 - 8 h; [1] Preparation of the catalyst: 0.2 g of cobalt(H) chloride hexahydrate and 1.33 g ofdimethylglyoxime were dissolved in 20 ml of DMF yielding a clear blue-green solution(volume ca. 25 ml).[2] Preparation of the solution of the reducing agent: 4.5 g of sodium borohydride wasdissolved in 50 ml of a 0.1 M solution of sodium hydroxide under cooling in ice bath (thesolution was, before its use, stored in a refrigerator, volume ca. 50 ml).[3] Carrying out the reduction itself: 2.75 g of sodium hydroxide and, subsequently, 20 g ofstarting substance II were dissolved in 200 ml of water. The obtained solution was stirred andheated to a temperature of 55+/-5 °C. The catalyst was added dropwise (1/5 of the volumeaccording to [1], during of ca. 2 minutes) into the solution, then the reducing agent was added(1/5 of the volume according to [2], during of ca. 5 minutes) and the mixture was subsequentlystirred at 55+/-5 °C for 50 minutes. The adding of the catalyst (1/5 of the volume according to[1]) and the reducing agent (1/5 of the volume according to [2]), including the stirring andheating of the reaction mixture, was repeated four more times in the same way. The totalreaction time was approximately 5 hours.[4] Isolation of the crude product: 50 ml of ethyl acetate, 40 ml of hydrochloric acid (1:1), and,very slowly, 100 ml of a 10percent solution of sodium hydrogen carbonate were added into thereaction mixture (according to [3]). The precipitated lumpy suspension was filtered, washedwith water (2x100 ml) and ethanol (2x50 ml) and dried in a vacuum drier at 70 °C. Theproduct with a melting point of 154-155 °C, and yield of 91 percent was obtained. The content ofcobalt in the product, determined using inductively coupled plasma mass spectrometry, is 8ppm.[5] Crystallization: The crude substance according to [4] was dissolved in boiling ethanol (450ml), the hot solution was filtered through a sorbent layer (AI2O3 or SiCh), and the filteredsolution was, under stirring, allowed to cool freely. The precipitated crystals were sucked off,washed with ethanol (45 ml) and dried in a vacuum drier at 70 °C. The product with a meltingpoint of 154.4-155.5 °C was obtained. The yield of crystallization was 86 percent. The content ofcobalt in the product, determined using inductively coupled plasma mass spectrometry, is 5ppm.; EXAMPLE 910 g of substance II was dissolved in a solution of 1 g of sodium hydroxide and 150 ml of water. A solution of 0.089 g of cobalt(H) chloride hexahydrate and 0.51 g of DGM dissolved in 10 ml DMF was added into the solution heated to 40 °C. The mixture was stirred and warmed to 35 - 45 °C and an aqueous solution of sodium borohydride (2.38 g) was gradually added into it during eight hours. The pH of the reaction mixture was then adjusted to 6 using diluted hydrochloric acid (1:1), and the product was extracted with ethyl acetate. After evaporation of the solvent from the organic phase the residue was crystallized from ethanol. White crystalline powder with a melting point of 155-156 °C and chemical purity of 99.8 percent (HPLC) was obtained. The yield of rosiglitazone was 70 percent.
67% With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In toluene for 12 h; Heating / reflux A mixture of 50.0 g (141 mmols) of 5-{4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy]benzylidene-2,4-thiazolidinedione (II), 71.3 g (281 mmols) of 3,5- dicarbethoxy-2,6-dimethyl-1,4-dihydropyridine (Hantzsch ethyl ester), 30.0 g of silica gel and 300 mL of toluene are stirred under nitrogen atmosphere at reflux temperature for 12 hours with azeotropic distillation of water. After cooling to room temperature, the resulting solid, containing the product and silica gel, is filtered. Silica gel is removed by digestion of the solid with tetrahydrofuran and filtration. The solvent is removed by distillation and the resulting crude residue is purified by crystallization from n-butyl acetate, yielding 33.7 g (67percent) of Rosiglitazone (I).
61% With 2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-dihydropyridine In toluene for 12 h; Heating / reflux Preparation of Rosiglitazone (I) by an analogous process to that described in Example 1, wherein 3,5-dicarbomethoxy-2,6-dimethyl-1,4-dihydropyridine (Hantzsch methyl ester) is used as reducing agent instead of 3,5- dicarbethoxy-2,6-dimethyl-1,4-dihydropyridine, yielding 61 percent of Rosiglitazone (I).
61.35% With sodium dithionite; potassium carbonate In water; N,N-dimethyl-formamide at 8 - 74℃; for 8.5 h; EXAMPLE 4
Preparation of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione (rosiglitazone)
1.0 kg (2.81 mol) of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene] thiazolidine-2,4-dione, 6.0 I of N,N-dimethylformamide are added to a solution of 1.62 kg (11.72 mol) of potassium carbonate in 6.0 I of water and the contents are heated at 69-74°C during stirring. A solution of 3.8 kg (21.83 mol) of sodium dithionite, 1.2 kg (8.68 mol) of potassium carbonate in 17.0 I of water is added slowly to the reaction mass over the period of 2.5 hours. The reaction mixture is maintained during stirring at 69-74°C for about 3 hours and is allowed to cool to 500C during stirring over the period of 2 hours. The reaction mixture is allowed to cool to 8-100C and stirred for 1 hour. The separated solid is then filtered off, washed with 20 I of water and the wet product is dried at 68-72°C under reduced pressure for 15 hours to obtain 617.0 g (61.35percent theoretical) of the title product.
50% With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In acetic acid butyl ester for 12 h; Heating / reflux Preparation of Rosiglitazone (I) by an analogous process to that described in Example 1, wherein n-butyl acetate is used as solvent instead of toluene, yielding 50percent of Rosiglitazone (I).
50% With sodium tetrahydroborate; cobalt(II) chloride hexahydrate; butane-2,3-dione dioxime; sodium hydroxide In water at 20℃; for 24 h; (Z)-5-[[4-[2-(Methyl-2-pyridinylamino)ethoxy]phenyl]-methylene]-1,3-thiazolidine-2,4-dione (8, 3.60 g, 10.1 mmol) was mixed in water (450 mL) with stirring, to which was added aqueous sodium hydroxide (0.5 mol/L) to pH = 11 until the material 8 dissolved completely. The solution was added with cobalt chloride hexahydrate (0.20 g, 0.84 mmol), DMG (0.20 g, 1.72 mmol), and sodium boron hydride (4.50 g, 120 mmol). The mixture was kept at room temperature for 24 h until the reaction was complete. The insoluble residue was removed by filtration. The filtrate was adjusted with hydrochloride to pH = 3, then a small amount of solids appeared. The filtrate from the second filtration was adjusted to pH 6–7 with aqueous sodium hydroxide, then a large amount of solids appeared from the solution and was collected by filtration. The filter cake was washed with a small amount of water and dried under vacuum to give the final product 1 (0.80 g), m.p. 154–155 °C. The filtrate was extracted with dichloromethane (50.0 mL 9 3), washed with saturated brine (50.0 mL 9 2), and dried over anhydrous sodium sulfate. The solid was obtained via filtration and concentration as the second portion of 1 (2.50 g, total amount: 3.30 g, crudeyield: 91 percent). Pale-white crystals were obtained via recrystallization from ethanol as pure 1 (1.80 g, 50 percent)
43% With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In butan-1-ol for 12 h; Heating / reflux Preparation of Rosiglitazone (I) by an analogous process to that described in Example 1, wherein n-butanol is used as solvent instead of toluene, yielding 43percent of Rosiglitazone (I).
39% With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In n-heptane for 12 h; Heating / reflux Preparation of Rosiglitazone (I) by an analogous process to that described in Example 1, wherein heptane is used as solvent instead of toluene, yielding 39percent of Rosiglitazone (I).
35% With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In 4-methyl-2-pentanone for 12 h; Heating / reflux Preparation of Rosiglitazone (I) by an analogous process to that described in Example 1, wherein 4-methyl-2-pentanone is used as solvent instead of toluene, yielding 35percent of Rosiglitazone (I).

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[2] Tetrahedron, 2010, vol. 66, # 18, p. 3314 - 3317
[3] Patent: WO2006/125402, 2006, A1, . Location in patent: Page/Page column 10-16
[4] Patent: WO2006/26934, 2006, A1, . Location in patent: Page/Page column title page; 3; 7; 9
[5] Patent: WO2006/26934, 2006, A1, . Location in patent: Page/Page column title page; 3; 7; 9
[6] Patent: WO2006/26934, 2006, A1, . Location in patent: Page/Page column title page; 3; 7; 9
[7] Patent: WO2006/26934, 2006, A1, . Location in patent: Page/Page column title page; 3; 7-9
[8] Tetrahedron, 2000, vol. 56, # 26, p. 4531 - 4537
[9] Patent: WO2006/26934, 2006, A1, . Location in patent: Page/Page column title page; 3; 7; 9
[10] Patent: WO2006/26934, 2006, A1, . Location in patent: Page/Page column title page; 3; 7; 9
[11] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 22, p. 3319 - 3324
[12] Organic and biomolecular chemistry, 2003, vol. 1, # 24, p. 4392 - 4395
[13] Tetrahedron, 2000, vol. 56, # 26, p. 4531 - 4537
[14] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
[15] Journal of Organic Chemistry, 1999, vol. 64, # 5, p. 1723 - 1726
[16] Patent: WO2005/108394, 2005, A1, . Location in patent: Page/Page column 9
[17] Patent: WO2006/26934, 2006, A1, . Location in patent: Page/Page column title page; 3; 8-9
[18] Patent: EP1219620, 2002, A1, . Location in patent: Page 5
[19] Patent: WO2006/26934, 2006, A1, . Location in patent: Page/Page column title page; 3; 6; 8-9
[20] Patent: WO2005/108394, 2005, A1, . Location in patent: Page/Page column 9
[21] Journal of Medicinal Chemistry, 1994, vol. 37, # 23, p. 3977 - 3985
[22] Patent: WO2005/108394, 2005, A1, . Location in patent: Page/Page column 10
[23] Patent: WO2007/17095, 2007, A1, . Location in patent: Page/Page column 14
[24] Patent: WO2005/108394, 2005, A1, . Location in patent: Page/Page column 10
[25] Research on Chemical Intermediates, 2016, vol. 42, # 3, p. 2023 - 2033
[26] Patent: WO2005/108394, 2005, A1, . Location in patent: Page/Page column 10
[27] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 22, p. 3319 - 3324
[28] Patent: WO2005/108394, 2005, A1, . Location in patent: Page/Page column 10
[29] Patent: WO2005/108394, 2005, A1, . Location in patent: Page/Page column 9-10
[30] Patent: EP1219620, 2002, A1, . Location in patent: Page 5
[31] Patent: EP1219620, 2002, A1, . Location in patent: Page 5
  • 2
  • [ 122320-74-5 ]
  • [ 122320-73-4 ]
YieldReaction ConditionsOperation in experiment
77% With pyridine; lithium borohydride In tetrahydrofuran; water (b)
Using Lithium Borohydride
A solution of lithium borohydride (67.5 g, 3.1 mole) in tetrahydrofuran (1.54 L) was added via cannular to a stirred suspension of (IIB) (500 g, 1.4 mol) in tetrahydrofuran (950 ml) and pyridine (1.13 L) at room temperature under nitrogen over 1.5 hours.
The mixture was heated to reflux, stirred for 3 hours and cooled to room temperature.
The stirred reaction mixture was quenched into hydrochloric acid (670 ml) and water (4.4 L) at 8° C. over 0.67 hours using tetrahydrofuran (250 ml) to wash out residual material.
The quench mixture was stirred at 26° C. for 0.25 hours, heated to reflux and stirred for 0.75 hours.
The hot mixture was allowed to stand for 0.17 hours, filtered through celite, the residue was pulled to dryness and washed with water (500 m1).
The aqueous washings were added to the filtrate and stirred at room temperature for 14 hours.
The precipitated product was collected by filtration under vacuo, pulled to dryness, washed with water (2.8 L) and pulled dry.
The damp solid was washed with industrial methylated spirit (2*500 ml), and dried at 45° C. for 72 hours to give (IA) (386.5 g, 77percent).
73% With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; silica gel In toluene for 24 h; Heating; Reflux Example 2
Preparation of Rosiglitazone Base
130.3 g (366.6 mmol) of 5-{4-[2-(methylpyridin-2-ylamino)ethoxy]benzylidene}-thiazolidine-2,4-dione, 181.0 g (714.7 mmol) of diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and 76.2 g of silica gel (0.063-0.200 mm particle size) were added over 885 mL of toluene.
The resulting suspension was heated to reflux temperature for 24 hours, with azeotropical removal of water (from silica gel).
The suspension was cooled down to 15° C. and was filtered using a Buechner funnel.
The filter cake was washed with 300 mL of toluene.
The solid was then suspended in 1.25 L of tetrahydrofuran.
The mixture was heated to reflux temperature and cooled down to 30° C.
Silica gel was removed by filtration (filter cake was washed with 125 mL of tetrahydrofuran).
The filtered solution was concentrated by distillation of 875 mL of tetrahydrofuran under atmospheric pressure.
The resulting solution was cooled down to 30° C. and non-reacted diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate was removed by filtration.
1 L of isopropanol was added to the filtered solution, and tetrahydrofuran was removed by distillation of 1 L of the solvent mixture, under atmospheric pressure.
The resulting suspension was cooled down to 10° C. and filtered using a Buechner funnel.
The filter cake was washed with 200 mL of isopropanol. 94.8 g (73percent yield, 93.23percent purity by HPLC) of Rosiglitazone base were obtained, m.p. 153.5-154.9° C.
The following characterization data was generated for the rosiglitazone base:
60% With sodium dithionite; water; potassium carbonate In DMF (N,N-dimethyl-formamide) at 10 - 80℃; for 7 h; Preparation of pure 5- 4- (2- pyridinyl)-N-methyl) ethoxy] phenyl] methyl-2, 4- thiazolidinedione (rosiglitazone base) To a solution of 14 g potassium carbonate in25 ml water, Sg of5- [4- [N- (2- pyridinyl)-N- methyl) ethoxy] phenyl] methenyl-2,4-thiazolidinedione are added followed by25 ml dimethyl formamide in a round bottom flask. The resulting solution is then heated to about80 C under agitation. At about80oC a solution of 9 g of sodium dithionite in 90 ml water is added drop wise within about 60 minutes. The reaction mixture is stirred at about80 C for approximately two hours and then cooled to about50 C. It is subsequently stirred at about 50 C for about two hours before cooling to about10 C and the reaction mixture is then stirred for about two hours. The precipitate is filtered, washed with 100 ml water, and the title compound is collected after drying in a vacuum oven for about 8 hours at approximately65 C. Yield (crystalline rosiglitazone free base): 3.0 g (60 percent w/w related to5- [4- [N- (2- pyridinyl)- N-methyl)ethoxy] phenyl] methenyl-2, 4-thiazolidinedione) HPLC-Assay:99 percent.; The following Table A indicates HPLC analyses for rosiglitazone (ROS-90) and the precursor5- [4- [N- (2-pyridinyl)-N-methyl) ethoxy] phenyl] methenyl-2, 4-thiazolidinedione abbreviated"ROS-60". The amounts of unreacted precursor are very low for ethanol/water, methanol/water and DMF/water solvent media. The reaction conditions used are as used above, or analogous to the above reaction parameters. The HPLC results are area-percent.
60% With formic acid; ammonium formate In acetic acid at 100℃; for 25 h; 20 g of the substance of formula II was dissolved in 100 ml of acetic acid, a solution of 15 g of ammonium formate in 100 ml of formic acid was poured therein and 5 g of 5percent palladium on carbon added. The mixture was closed in an autoclave and heated to 100 0C for 25 hours; the catalyst was then filtered off and the solvent evaporated. The residue was neutralized with a solution of sodium hydroxide, extraction with ethyl acetate was carried out, the solvent was evaporated, and crystallization of the crude product from ethanol was carried out. The product obtained had a melting point of 152-154 °C, and the yield was 60 percent.
51% for 18 - 22 h; Heating / reflux 3.55 g of the substance of formula II was dissolved in 45 ml of formic acid, 2 g of 5percent palladium on carbon were added, and, under stirring, 20 ml of triethylamine were slowly added dropwise.
The reaction mixture was refluxed for 20 hours, the catalyst was then filtered off and the solvent evaporated.
The residue was neutralized with a solution of sodium hydroxide, extraction with ethyl acetate was carried out, the solvent was evaporated, and crystallization of the crude product from ethanol was carried out.
The product obtained had a melting point of 152-154 degree;C, and the yield was 55 percent.
EXAMPLE 2
10 g of the substance of formula II was dissolved in 100 ml of formic acid, 10 g of5percent palladium on carbon was added, and, under stirring, 10 ml of triethylamine were slowly added dropwise.
The reaction mixture was refluxed for 18 hours, the catalyst was then filtered off and the solvent evaporated.
The residue was neutralized with a solution of sodium hydroxide, extraction with ethyl acetate was carried out, the solvent was evaporated, and crystallization of the crude product from ethanol was carried out. The product obtained had a melting point of 153-155 °C, and the yield was 75 percent
EXAMPLE 4
5 g of the substance of formula II was dissolved in 50 ml of formic acid, 5 g of 5percent palladium on carbon was added, and, under stirring, 3.5 ml of triethylamine were slowly added dropwise.
The reaction mixture was refluxed for 22 hours, the catalyst was then filtered off and the EPO <DP n="7"/>solvent evaporated.
Ethanol (100 ml) was added, the obtained solution was stirred for 7 hours, and filtration of the product was carried out.
The product obtained had a melting point of 152- 153 degree;C, and the yield was 51 percent.

Reference: [1] Patent: US2002/42519, 2002, A1,
[2] Patent: US2009/234128, 2009, A1, . Location in patent: Page/Page column 5
[3] Patent: WO2005/49610, 2005, A1, . Location in patent: Page/Page column 15-16
[4] Patent: WO2006/32218, 2006, A1, . Location in patent: Page/Page column 5
[5] Patent: WO2006/32218, 2006, A1, . Location in patent: Page/Page column 5-6
[6] Patent: WO2005/49610, 2005, A1, . Location in patent: Page/Page column 15-16
[7] Patent: WO2005/49610, 2005, A1, . Location in patent: Page/Page column 15-16
[8] Patent: WO2005/49610, 2005, A1, . Location in patent: Page/Page column 15-16
[9] Patent: WO2005/49610, 2005, A1, . Location in patent: Page/Page column 15-16
[10] Patent: WO2005/49610, 2005, A1, . Location in patent: Page/Page column 15-16
[11] Patent: US2002/42519, 2002, A1,
[12] Patent: EP1903042, 2008, A2, . Location in patent: Page/Page column 5
[13] Patent: EP1903042, 2008, A2, . Location in patent: Page/Page column 5-6
[14] Patent: WO2005/49532, 2005, A2, . Location in patent: Page/Page column 12-13
  • 3
  • [ 105355-27-9 ]
  • [ 122320-73-4 ]
YieldReaction ConditionsOperation in experiment
95% at 50 - 80℃; Preparation of Amorphous Form of [(+/-)5-[[2-(5-ethyl-2-pyridinyl)ethoxyl]phenyl]methyl]-thiazolidine-2,4-dione (Free Pioglitazone) Crystalline material of free pioglitazone (400 mg, prepared according to Example 1 of U.S. Pat. No. 4,687,777) was dissolved in ethanol (80 ml) under stirring at 50° C., and the solution is heated to boiling (about 70 to 80° C.) until the material goes into solution. The solvent was completely distilled off under reduced pressure at 65° C. to 75° C. and the solid residue was isolated and dried in vacuum at 45° C. Thus 0.38 g of amorphous form of free pioglitazone is obtained (yield 95percent). X-ray powder diffraction examination (FIG. 2 as shown in the accompanied drawings) confirmed the amorphous nature of the product.
90% at 50 - 70℃; Preparation of Amorphous Form of (+/-)5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy]benzyl]thiazolidine-2,4-dione (Free Rosiglitazone) Crystalline material of free rosiglitazone (500 mg, prepared according to Example 30 of U.S. Pat. No. 5,002,953) was dissolved in acetonitrile (100 ml) under stirring at 50° C., and the solution is heated to boiling (about 60 to 70° C.) until the material goes into solution. The solvent was completely distilled off under reduced pressure at 55° C. to 65° C. and the solid residue was isolated and dried in vacuum at 45° C. Thus 0.45 g of amorphous from of free rosiglitazone is obtained (yield 90percent). X-ray powder diffraction examination (FIG. 1 as shown in the accompanied drawings) confirmed the amorphous nature of the product.
Reference: [1] Patent: US2006/89387, 2006, A1, . Location in patent: Page/Page column 12
[2] Patent: US2006/89387, 2006, A1, . Location in patent: Page/Page column 12
  • 4
  • [ 2295-31-0 ]
  • [ 122321-03-3 ]
  • [ 122320-73-4 ]
YieldReaction ConditionsOperation in experiment
58%
Stage #1: With pyrrolidine; acetic acid In toluene at 110℃; for 2 h;
Stage #2: With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In toluene for 13 h; Heating / reflux
A mixture of 20.0 g (78 mmol) of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzaldehyde (IV), 9.6 g (82 mmol) of thiazolidine-2,4-dione (V), 0.3 mL (3.9 mmol) of pyrrolidine, 0.2 mL (3.9 mmol) of glacial acetic acid and 120 mL of toluene is stirred under nitrogen atmosphere at reflux temperature with azeotropic distillation of water for two hours. After cooling to room temperature, 39.5 g (156 mmol) of 3,5-dicarbethoxy-2,6-dimethyl-1,4- dihydropyridine (Hantzsch ethyl ester), 13.9 g of silica gel and 46 mL of toluene are added. The resulting suspension is heated to reflux temperature with azeotropic distillation of water for 13 hours. The reaction is cooled to room temperature, and the resulting solid is filtered. Silica gel is removed after digestion with tetrahydrofuran and filtration of the solid. The solvent is removed by distillation delivering a crude material that is purified by crystallization from n-butyl acetate, yielding 16.3 g (58percent) of Rosiglitazone (I).
Reference: [1] Patent: WO2005/108394, 2005, A1, . Location in patent: Page/Page column 10 - 11
  • 5
  • [ 122320-74-5 ]
  • [ 122320-73-4 ]
Reference: [1] Patent: US2002/42519, 2002, A1,
  • 6
  • [ 2295-31-0 ]
  • [ 122320-73-4 ]
Reference: [1] Patent: WO2005/105794, 2005, A1, . Location in patent: Page/Page column 16
[2] Patent: WO2005/105794, 2005, A1, . Location in patent: Page/Page column 16
  • 7
  • [ 109-09-1 ]
  • [ 122320-73-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
[3] Research on Chemical Intermediates, 2016, vol. 42, # 3, p. 2023 - 2033
[4] Research on Chemical Intermediates, 2016, vol. 42, # 3, p. 2023 - 2033
  • 8
  • [ 122321-04-4 ]
  • [ 122320-73-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
[2] Research on Chemical Intermediates, 2016, vol. 42, # 3, p. 2023 - 2033
[3] Research on Chemical Intermediates, 2016, vol. 42, # 3, p. 2023 - 2033
  • 9
  • [ 372-48-5 ]
  • [ 122320-73-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
  • 10
  • [ 623-05-2 ]
  • [ 122320-73-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
  • 11
  • [ 459-57-4 ]
  • [ 122320-73-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
  • 12
  • [ 103258-64-6 ]
  • [ 122320-73-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
  • 13
  • [ 122321-03-3 ]
  • [ 122320-73-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
  • 14
  • [ 196810-03-4 ]
  • [ 122320-73-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
  • 15
  • [ 142558-11-0 ]
  • [ 122320-73-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
  • 16
  • [ 666846-74-8 ]
  • [ 122320-73-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
  • 17
  • [ 122321-04-4 ]
  • [ 122320-73-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
  • 18
  • [ 2295-31-0 ]
  • [ 372-48-5 ]
  • [ 123-08-0 ]
  • [ 147687-15-8 ]
  • [ 122320-73-4 ]
Reference: [1] Journal of Organic Chemistry, 1999, vol. 64, # 5, p. 1723 - 1726
  • 19
  • [ 110-16-7 ]
  • [ 122320-73-4 ]
  • [ 155141-29-0 ]
YieldReaction ConditionsOperation in experiment
96% for 1 h; Heating; Reflux Example 3
Preparation of Rosiglitazone Maleate
93.3 g (261.0 mmol) of Rosiglitazone base as prepared in example 2 and 36.4 g (313.2 mmol) of maleic acid were suspended in 510 mL of isopropanol.
The suspension was heated to reflux temperature for 1 hour.
The initial suspension turned into a clear colorless solution.
The resulting solution was cooled down to 10° C. and filtered using a Buechner funnel.
The filter cake was washed with 200 mL of isopropanol. 105.0 g of crude Rosiglitazone maleate were obtained (85percent yield, 99.57percent purity by HPLC).
41.1 g (86.9 mmol) of the crude solid and 1.7 g (14.5 mmol) of maleic acid were suspended in 200 mL of ethanol (0.17 equivalents of maleic acid per 2.3 liters of ethanol which is approximately a maleic acid:ethanol ratio of about 13.5). The suspension was heated to reflux temperature for 20 minutes. The resulting solution was cooled down to 65° C. Seeding particles of the desired polymorph of Rosiglitazone maleate were added to the solution. The resulting suspension was cooled down to 0° C. and filtered using a Buechner funnel. The filter cake was washed with 50 mL of ethanol. 39.5 g of Rosiglitazone maleate were obtained (96percent yield, 99.89percent purity by HPLC), m.p. 120.6-121.7° C.
90%
Stage #1: at 45 - 50℃;
Stage #2: at 5 - 30℃; for 2 h;
5- [4- [2- (N-METHYL-N- (2-PYRIDYL) amino) ethoxy] benzyl] thiazolidine-2,4-dione (rosiglitazone free base, 50GMS, 0. 140MOL) was charged in 100ML methanol and a solution of maleic acid (18. 7gms, 0.16 mol) in methanol (SOML) was added under stirring and was further heated to 45-50°C to obtain a clear solution. This solution was filtered (hot) through celite and ethyl acetate (500ML) was added slowly to this clear filtrate under stirring at 25-30°C, and further stirred for 1 hour at 30°C, then chilled to 5-10°C and stirred at the same temperature for LHOUR. The solid obtained was filtered under argon atmosphere and washed with 50ML ethyl acetate. This solid was dried under vacuum at 50-55°C to get rosiglitazone maleate Form A (60GMS) in 90percent yield.
79% for 0.5 h; Heating / reflux A 500 ml balloon flask is charged with 20 g (56.0 mmoles) of rosiglitazone base and 6.50 g (56.0 mmoles) of maleic acid. To these solids are added 160 ml of water and 80 ml of absolute ethanol. The mixture obtained is brought to reflux for 30' to obtain a clear solution. The solution is filtered on a panel of celite and allowed to cool to ambient temperature. The resultant solid is filtered on a Buchner filter, washed twice with 20 ml of water each time. A product is discharged which when desiccated under vacuum at 45-50°C for 12 hours weighs 21.0 g (yield 79percent) and consists of rosiglitazone maleate Form II. The water content of the desiccated product is 0.3percent.
76% Heating / reflux A mixture of 30 ml of acetic acid and 350 ml of ethanol was poured to a mixture of 50 g of crude free rosiglitazone base I and 16.5 g of maleic acid. The suspension obtained was stirred and heated to the boil until a solution was formed. Then the heating was stopped, and the mixture was stirred, under slow cooling, for 4 hours, followed by stirring overnight at 10 °C. The mixture was filtered, and the filter cake was washed with ethanol (2 x 25 ml). After drying in a vacuum drier, 50.2 g of a finely crystalline product with a melting point of 121 - 125 0C was obtained. The yield of crystallization was 76 percent.
75% for 0.5 h; Heating / reflux A 500 ml balloon flask is charged with 15 g (42.0 mmoles) of rosiglitazone base and 9.70 g (84.0 mmoles) of maleic acid. To these solids are added 150 ml of ethanol, and the mixture obtained is brought to reflux for 30'. The mixture is then slowly cooled to ambient temperature and the resultant solid is filtered on a Buchner filter, washing twice with 20 ml of ethanol each time. A product is discharged which when desiccated under vacuum at 45-50°C for 12 hours weighs 14.9 g (yield 75percent) and consists of rosiglitazone maleate Form III.
75% for 0.5 h; Heating / reflux A 500 ml balloon flask is charged with 20 g (56.0 mmoles) of rosiglitazone base and 6.50 g (56.0 mmoles) of maleic acid. To these solids are added 350 ml of water, and the mixture obtained is brought to reflux for 30'. The mixture is then slowly cooled to ambient temperature and the resultant solid is filtered on a Buchner filter, washing twice with 20 ml of water each time. A product is discharged which when desiccated under vacuum at 45-50°C for 12 hours weighs 19.9 g (yield 75percent) and consists of rosiglitazone maleate Form II. The water content of the desiccated product is 0.3percent. A 500 ml balloon flask equipped with reflux condenser and dropping funnel is charged with 20 g (56.0 mmoles) of rosiglitazone base and 330 ml of deionised water. In a becker are charged 6.50 g (56.0 mmoles) of maleic acid and 23 ml of deionised water, whereby a solution is formed. The solution obtained is then charged in the dropping funnel. The suspension of rosiglitazone base in water is heated to reflux and from the dropping funnel the solution of maleic acid is added in approximately 5'. The mixture is then slowly cooled to ambient temperature and the resultant solid is filtered on a Buchner filter, washing twice with 20 ml of water each time. A product is discharged which when desiccated under vacuum at 45-50°C for 12 hours weighs 20.5 g (yield 77percent) and consists of rosiglitazone maleate Form II. The water content of the desiccated product is 0.4percent.
73% for 0.5 h; Heating / reflux A 250 ml balloon flask equipped with mechanical stirring, coolant and thermometer, is charged with 10 g (28.0 mmoles) of rosiglitazone base, 3.25 g (28.0 mmoles) of maleic acid and 75 ml of isopropanol. The mixture is brought to reflux and maintained for 30' under such conditions. The mixture is then slowly cooled to ambient temperature and the product is filtered on a Buchner filter, washing twice with 10 ml of isopropanol. The filtered product is then desiccated for 12 hours at 45-50°C. 9.7 g of rosiglitazone maleate Form I (yield 73percent) are obtained. The content of residual isopropanol in the product is 0.16percent by weight.
73% Heating / reflux A mixture of 4.0 g 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -2,4-thiazolidine- dione and 1.31 g maleic acid are stirred in 37 ml absolute ethanol and heated at boiling temperature until a clear solution is obtained. 0.4 g charcoal is added and after 5 min the hot solution is filtered and allowed to cool to room temperature under stirring. After standing in a refrigerator at4 C for 17 hours, the precipitated product is filtered and dried at50 C under vacuum for 20 hours to give 3.9 g (73percent) of the product.
73% for 0.5 - 1 h; Heating / reflux 10 g (28.0 mmol) of rosiglitazone base, 3.25 g (28.0 mmol) of maleic acid and 120 ml ofa 2 : 1 mixture of water and ethanol are introduced into a 250-ml flask provided withmechanical agitation, a cooler and a thermometer. The mixture is heated under refluxand maintained under those conditions for 30 minutes. The mixture is then slowly cooledto ambient temperature and the product is filtered on a Buchner funnel, washing twicewith 10 ml of water. The filtered product is then dried for 12 hours at 45-50°C. 9.7 g ofform V rosiglitazone maleate are obtained (yield 73percent).EXAMPLE 2Synthesis of form V rosiglitazone maleate20 g (56.0 mmol) of rosiglitazone base and 6.50 g (56.0 mmol) of maleic acid areintroduced into a 500-ml flask. 160 ml of water and 80 ml of ethanol are added to thosesolids and the mixture obtained is heated under reflux for 60 minutes. The mixture isthen slowly cooled to ambient temperature and 80 ml of water are added thereto. Theresultant solid is filtered on a Buchner funnel, washing twice with 20 ml of water eachtime. A product is discharged which, after being dried under vacuum at 45-50°C for 12hours, weighs 19.9 g (yield 75percent) and is constituted by form V rosiglitazone maleate.The water content of the dried product is 1.3percent.EXAMPLESSynthesis of form V rosiglitazone maleate15 g (42.0 mmol) of rosiglitazone base and 4.85 g (42.0 mmol) of maleic acid areintroduced into a 500-ml flask. 60 ml of ethanol and 120 ml of water are added to thosesolids and the mixture obtained is heated under reflux for 60 minutes. The mixture isthen cooled to 80°C and is seeded with a small amount of form V rosiglitazone maleate.The mixture is then cooled slowly to ambient temperature and the resultant solid isfiltered on a Buchner funnel, washing twice with 20 ml of a 2 : 1 water-ethanol mixture.A product is discharged which, after being dried under vacuum at 45-50°C for 12 hours,weighs 19.9 g (yield 75percent) and is constituted by form V rosiglitazone maleate.
72% for 0.5 h; Heating / reflux Example 1 is repeated, using isopropyl acetate as solvent in place of the isopropanol. After desiccation, 9.5 g of rosiglitazone maleate Form I (yield 72percent) are obtained.
72%
Stage #1: With pyrographite In acetone at 27℃; for 0.5 h; Heating / reflux
Stage #2: at 30 - 40℃; for 18 h;
5- [4- [2- (N-METHYL-N- (2-PYRIDYL) amino) ethoxy] benzyl] THIAZOLIDINE-2, 4-dione (rosiglitazone free base, LOOGMS, 0. 280MOL) was suspended in 500ML of dry acetone and a solution of maleic acid (38.99gms, 0. 336MOL) in 200ML of dry acetone was added at 27°C to obtain a clear solution. Activated charcoal (5GMS) was added and refluxed for 30 minutes. The solution was filtered (hot) through celite. To the clear filtrate seeds of Form A were added at 40°C and stirred for 18 hours at 30°C. The precipitated solid was filtered under argon atmosphere and washed with 100ml of dry acetone. The resulting solid was dried under vacuum at 30°C for 5 hours, and at 50°C for 6 hours, to obtain rosiglitazone maleate Form A (95GMS) in 72percent yield.
71%
Stage #1: at 27 - 82℃; for 0.5 h; Heating / reflux
Stage #2: at 25 - 30℃; for 5 h;
5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] THIAZOLIDINE-2, 4-dione (rosiglitazone free base, 50GMS, 0. 140MOL) was stirred with 250ML of dry acetonitrile and a suspension of maleic acid (19. 50GMS, 0. 168MOL) in 100ML of dry acetonitrile was added at 27°C to obtain a clear solution, followed by reflux for 30 minutes at 80-82°C. The reaction mass was gradually allowed to cool to 30°C and stirred for 5 hours at 25-30°C. The precipitated solid was filtered under argon atmosphere and washed with 50ML of dry acetonitrile. The filtered solid obtained was dried under vacuum at 30°C for 5 hours, and at 50°C for 6 hours, to obtain rosiglitazone maleate Form A (45GMS) in 71percent yield.

Reference: [1] Patent: US2009/234128, 2009, A1, . Location in patent: Page/Page column 5-6
[2] Patent: WO2005/21541, 2005, A2, . Location in patent: Page/Page column 15
[3] Patent: EP1468997, 2004, A2, . Location in patent: Page 7
[4] Patent: WO2006/125402, 2006, A1, . Location in patent: Page/Page column 20
[5] Patent: EP1468997, 2004, A2, . Location in patent: Page 7
[6] Patent: EP1468997, 2004, A2, . Location in patent: Page 6-7
[7] Patent: EP1468997, 2004, A2, . Location in patent: Page 6
[8] Patent: WO2004/62667, 2004, A1, . Location in patent: Page/Page column 17
[9] Patent: WO2005/49610, 2005, A1, . Location in patent: Page/Page column 15
[10] Patent: WO2006/10653, 2006, A1, . Location in patent: Page/Page column 4-5
[11] Patent: EP1468997, 2004, A2, . Location in patent: Page 7
[12] Patent: WO2005/21541, 2005, A2, . Location in patent: Page/Page column 15
[13] Patent: WO2005/21541, 2005, A2, . Location in patent: Page/Page column 15-16
[14] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 11
[15] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 12-13
[16] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 13
[17] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 10
[18] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 13
[19] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 14-15
[20] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 11
[21] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 10
[22] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 13
[23] Patent: WO2005/21541, 2005, A2, . Location in patent: Page/Page column 14
[24] Patent: WO2005/21541, 2005, A2, . Location in patent: Page/Page column 16
[25] Patent: WO2005/95390, 2005, A2, . Location in patent: Page/Page column 16
[26] Patent: WO2005/95390, 2005, A2, . Location in patent: Page/Page column 15
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