Structure of 376592-93-7
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CAS No. : | 376592-93-7 |
Formula : | C13H11NO3 |
M.W : | 229.23 |
SMILES Code : | O=C(C1=CC(C2=CC=CC(N)=C2O)=CC=C1)O |
MDL No. : | MFCD10001467 |
InChI Key : | ZXLYSSHNDUXXIN-UHFFFAOYSA-N |
Pubchem ID : | 11492332 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 3.0 |
Molar Refractivity | 65.26 |
TPSA ? Topological Polar Surface Area: Calculated from |
83.55 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.18 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.04 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.35 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.95 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.68 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.84 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.94 |
Solubility | 0.265 mg/ml ; 0.00116 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.42 |
Solubility | 0.0866 mg/ml ; 0.000378 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.36 |
Solubility | 0.0996 mg/ml ; 0.000435 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.25 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.92 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With palladium 10% on activated carbon; hydrogen; In ethanol; water; at 50℃; under 3750.38 - 7500.75 Torr; | The above product was added to a hydrogenation vessel, and 2 g of 10% palladium carbon (about 63% aqueous), and 150 ml of ethanol were added.The reaction was carried out by introducing hydrogen gas at 0.5-1.0 MPa/50 C.After the reaction was completed, it was filtered, concentrated, dissolved in 100 ml of water, and adjusted to pH 5.5 with 1 M hydrochloric acid.The solid is precipitated, suction filtered and dried to give a pale yellow solid(9 g, yield: 95%, HPLC purity: 99%). |
72.8% | With palladium on activated charcoal; hydrazine hydrate; In water; at 25 - 85℃; for 2h; | 2) 300g of Intermediate I, 6g of Pd / C, and 1.5L of water were added into a 5L three-necked flask, and 1.5L of hydrazine hydrate (98%) was added to the system dropwise. During this period, exothermic gas was released and the temperature was controlled at 25 C. After the dropwise addition was completed, the temperature was raised to 85 C. After two hours of reaction, the temperature was reduced to room temperature with suction filtration. The filtrate was cooled to 5 C, the pH was adjusted to 7-8 with concentrated hydrochloric acid, and the filtration cake was washed with 500 ml of water and blow dried at 55 C. 193.14 g of light brown solid intermediate II was obtained with a yield of 72.8% and a purity of 97.3%. |
50.5% | With hydrogen;5% Pd(II)/C(eggshell); In methanol; at 20℃; for 8h; | A solution of 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid (800 g, 3.2 mol) in methanol (5 L) was hydrogenated over 5% Pd/C (160 g) at room temperature for 8 hours. The reaction mixture was filtered, concentrated and slurried in THF (2.5 L) to give 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (690 g, 50.5%) as a brown solid. PXRD analysis provided the diffractogram as shown in FIG. 32. |
With hydrogen; potassium acetate;palladium over charcoal; | Scheme I [0137] The process of Scheme I is a mult-step synthetic sequence that commences with the palladium catalyzed cross-coupling of a phenylboronic acid such as structure 2 and an aryl bromide such as structure 1 to form the biaryl structure 3 Deprotection of the methyl ether is followed by nitration and hydrogenation to give the biphenyl ammo acid such as structure 4 The ammo group is then diazotized under standard conditons and is treated with the approp?ate coupling partner to give the final product of structure 6; Example 187: 3 '- ITV-^-Aza- 1 -(3 ,4-dimethylph.enyl)-2-oxo- 1.2-dihvdroindol-3 - ylidenelhvdrazino|-2'-nydroxybiphenyl-3-carbox:ylic acid ("Compound 287) [0371] This compound was prepared as described in Scheme I. 1H NMR (500 MHz, DMSO-4) 13.10 (s, IH), 13.04 (s, IH), 9.36 (s, IH), 8.16 (dd, J= 5.1, 1.6 Hz, IH), 8.12 (t, J= 1.6 Hz, IH), 8.04 (dd, J= 7.4, 1.6 Hz, IH), 7.94 (ddd, J= 7.7, 1.6, 1.2 Hz, IH), 7.80 (ddd, J= 7.7, 1.6, 1.2 Hz, IH), 7.74 (dd, J= 7.8, 1.6 Hz, IH), 7.60 (t, J = 7.7 Hz, IH), 7.34 (d, J= 1.8 Hz, IH), 7.30 (d, J = 8.1 Hz, IH), 7.28 (dd, J = 8.1, 1.8 Hz, I H), 7.21 (dd, J = 7.4, 5.1 Hz, IH), 7.13 (t, J = 7.8 Hz, IH), 7.03 (dd, J= 7.8, 1.6 Hz, IH), 2.30 (s, 3H), 2.29 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.15% | Methanolic HCl acid (22 ml, 1.25 M), 50 ml methanol and 2.5 g BPCA (2',3'-dihydroxybiphenyl-3-carboxylic acid) were stirred and cooled down to 0-5 C. at which point 0.770 g NaNO2 (dissolved in 3 ml water) was added dropwise. The resulting solution was stirred at 0-5 C. for 30 min., and then 2 ml of conc. HCl acid were added dropwise. The resulting solution was stirred at 0-5 C. for 30 min. followed by addition of 40 mg sulfamic acid (dissolved in 3 ml water). The resulting reaction mixture was stirred for 45 min at 5-25 C. followed by addition 2.2 g of 1-(3,4-dimethylphenyl)-3-methyl-1,2-dihydropyrazol-5-one. The resulting solution was stirred for 10-15 min at room temperature and 4 ml of ethanolamine was added. The resulting suspension was stirred for 45 min, followed by filtration. 4.56 g of purple powder was obtained. Yield 74.15% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.4% | 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid (?BPCA?) Form I (90 g, 392.6 mmol), was added slowly with stirring at room temperature to a solvent mixture of tech. methanol (1.8 L) and 4 M hydrochloric acid (0.245 L, 981.5 mmol) in 3 L reactor. The resulting red solution was stirred for thirty minutes. The solution was then cooled to 0-5 C. and a cold solution of sodium nitrite (27 g, 391.3 mmol) in 90 mL of water was added over twenty minutes such that the reaction mixture temperature did not rise above 10 C. The reaction mixture was stirred for one hour at 5-10 C. Sulfamic acid (4 g, 41.2 mmol) in 90 mL of water was added at 5 C. and the resulting mixture was stirred for additionally one hour at the same temperature. The reaction mixture was warmed to room temperature and triethylamine (ca 104 mL) was added to adjust pH 7-8. 1-(3,4-dimethylphenyl)-3-methyl-1H-pyrazol-5-ol (?pyrazole?) form I (72 g, 357.8 mmol), was added in one portion to the reaction mixture and the resulting mixture was stirred for additionally two hours at room temperature. Hydrochloric acid (4M, ca 140 mL) was slowly added with stirring over twenty minutes to adjust pH to 1.8. A solid precipitated and was collected by filtration, washed with of mixture MeOH:water (1:1, 100 mL) and dried at 40 C./0 bar in vacuum oven for about 18 hours giving 151 g of crude orange to brown crystals of Eltrombopag crude (XRPD: form III with small percentage (less than 10%) of form I. (HPLC: 98.5%, Yield=95.4%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Scheme I [0137] The process of Scheme I is a mult-step synthetic sequence that commences with the palladium catalyzed cross-coupling of a phenylboronic acid such as structure 2 and an aryl bromide such as structure 1 to form the biaryl structure 3 Deprotection of the methyl ether is followed by nitration and hydrogenation to give the biphenyl ammo acid such as structure 4 The ammo group is then diazotized under standard conditons and is treated with the approp?ate coupling partner to give the final product of structure 6; Example 187: 3 '- ITV-^-Aza- 1 -(3 ,4-dimethylph.enyl)-2-oxo- 1.2-dihvdroindol-3 - ylidenelhvdrazino|-2'-nydroxybiphenyl-3-carbox:ylic acid ("Compound 287) [0371] This compound was prepared as described in Scheme I. 1H NMR (500 MHz, DMSO-4) 13.10 (s, IH), 13.04 (s, IH), 9.36 (s, IH), 8.16 (dd, J= 5.1, 1.6 Hz, IH), 8.12 (t, J= 1.6 Hz, IH), 8.04 (dd, J= 7.4, 1.6 Hz, IH), 7.94 (ddd, J= 7.7, 1.6, 1.2 Hz, IH), 7.80 (ddd, J= 7.7, 1.6, 1.2 Hz, IH), 7.74 (dd, J= 7.8, 1.6 Hz, IH), 7.60 (t, J = 7.7 Hz, IH), 7.34 (d, J= 1.8 Hz, IH), 7.30 (d, J = 8.1 Hz, IH), 7.28 (dd, J = 8.1, 1.8 Hz, I H), 7.21 (dd, J = 7.4, 5.1 Hz, IH), 7.13 (t, J = 7.8 Hz, IH), 7.03 (dd, J= 7.8, 1.6 Hz, IH), 2.30 (s, 3H), 2.29 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Scheme II [0138] The process of Scheme II is a multi-step synthetic sequence that commences with the copper catalyzed cross-coupling of an oxindole such as structure 7 and an aryl or alkyl bromide to provide an N-substituted oxindole of structure 8. This is then followed by coupling the N-substituted oxindole with the diazonium salt of the biphenyl amino acid such as structure 4 to give the final product of structure 9.; Example 1: 3'-{N'-[l-(3,4-Dimethyl-phenyl)-2-oxo-l,2-dihvdro-indol-3-ylidene1-hydrazino|- 2'-hydroxy-biphenyl-3-carboxylic acid (Compound 101 ) [0185] This compound was prepared as described in Scheme II. 1H NMR (500 MHz, DMSO-O delta 13.07 (s, I H), 13.03 (s, IH), 9.26 (s, IH), 8.12 (t, J=1.6 Hz, IH), 7.94 (ddd, /=7.7, 1.6, 1.3 Hz, IH), 7.79 (ddd, J=7.7, 1.6, 1.3 Hz, IH), 7.73 (dd, /==7.9, 1.6 Hz, IH), 7.72 (m, IH), 7.60 (t, /=7.7 Hz, IH), 7.35 (d, /=8.1 Hz, IH), 7.30 (d, /=2.1 Hz, IH), 7.28 (td, /=7.7, 1.3 Hz, IH), 7.23 (dd, /=8.1, 2.1 Hz, IH), 7.18 (td, /=7.7, 0.9 Hz, IH), 7.11 (t, /=7.9 Hz, IH), 7.00 (dd, /=7.9, 1.6 Hz, IH), 6.85 (m, IH), 2.31 (s, 3H), 2.30 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Scheme IV [0140] The process of Scheme IV is a multi-step synthetic sequence that commences with the conversion of an amine of structure 13 into an N-aryl rhodanine of structure 14 with bis(carboxymethyl) trithiocarbonate. The rhodanine is then coupled to the diazonium salt of the biphenyl amino acid such as structure 4 to give the final product of structure 15. Example 19: 3 '- |N'-[3 -(3 ,4-Dimethyl-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ylicLene1 -hydrazinol - 2'-hydroxy-biphenyl-3-carboxylic acid (Compound 119) [02031 This compound was prepared as described in Scheme IV. 1H INMR (500 MHz, DMSO-dbeta) delta 12.83 (s, IH), 10.76 (s, IH), 9.35 (s, IH), 8.15 (t, 7=1.5 Hz, IH), 7.91 (m, IH), 7.79 (dt, 7=7.7, 1.5 Hz, IH), 7.56 (t, 7=7.7 Hz, IH), 7.34 (m, IH), 7.29 (d, 7=7.9 Hz, i H), 7.14-6.96 (m, 4H), 2.28 (s, 3H), 2.26 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Scheme III [0139] The process of Scheme III is a multi-step synthetic sequence that commences with the reductive animation of an aniline such as structure 10 with a benzaldehyde and conversion into the chloroacetanilide of structure 11 with chloroacetyl chloride. Palladium catalyzed ring closure gives the N-benzyl oxindole such as structure 12, which is then coupled to the diazonium salt of the biphenyl amino acid of structure 4 to give the final product of structure 9. ; Example 11: 3 '-[N'-( 1 -Benzyl-5 -chloro-2-oxo - 1 ,2-dihvdro-indol-3 -ylidene)-hvdrazino] -T- hydroxy-biphenyl-3-carboxylic acid (Compound 111) [0195] This compound was prepared as described in Scheme III. 1H NMR (500 MHz, DMSCW5) delta 13.10 (s, IH), 13.03 (s, IH), 9.36 (s, IH), 8.13 (t, j =1.7 Hz, IH), 7.95 (ddd, J =7.7, 1.7, 1.3 Hz, IH), 7.80 (ddd, J=7.7, 1.7, 1.3 Hz, IH), 7.76 (dd, J=7.7, 1.6 Hz, IH), 7.68 (d, /=2.1 Hz, EPO <DP n="66"/>IH), 7.60 (t, J=I .1 Hz, IH), 7.37-7.32 (m, 4H), 7.30 (dd, 7=8.5, 2.1 Hz, IH), 7.27 (m, IH), 7.11 (t, J=7.7 Hz, IH), 7.09 (d, J=8.5 Hz, IH), 7.03 (dd, 7=7.7, 1.6 Hz, IH), 5.05 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.7% | With palladium 10% on activated carbon; hydrogen; triethylamine; In methanol; at 20℃; under 7500.75 Torr; for 21h;Autoclave; | [0058] 5'-Chloro-2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid (Compound 2b) (5.0 g) was dissolved in a mixture of MeOH (300 mL) and Et3N (4.75 mL). Pd/C (0.5 g) was added to the solution and the mixture was hydrogenated for 21 h at room temperature and 10 bars pressure. The catalyst was then removed by filtration, the filtrate was concentrated to dryness, and the residue was dissolved in water (40 mL). The pH was adjusted to 5.5 by dropwise addition of 0.5 M HC1 and the resulting suspension was stirred at RT for 30 min. The suspension was filtered, and the collected solid was washed with water (2 x 10 mL) and dried at 50 C/50 mbar to provide BPCA (3.4 g; 86.7%; HPLC purity 97.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With palladium 10% on activated carbon; hydrogen; In methanol; at 20 - 25℃; | A mixture of 2'-(benzyloxy)-3'-nitro-1,1'-biphenyl-3-carboxylic acid (270 mg, 0.777 mmol) and Pd/C (paste 10%, 170 mg) in MeOH (10 mL) was stirred under hydrogen atmosphere overnight at room temperature. The reaction mixture was filtered through a pad of Celite and the pad was washed with MeOH. The filtrate was concentrated to give 3'-amino-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid as a brown solid (235 mg, 89%). |
89% | With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; | A mixture of 2'-(benzyloxy)-3'-nitro-1 ,1 '-biphenyl-3-carboxylic acid (270 mg, 0.777 mmol) and Pd/C (paste 10%, 170 mg) in MeOH (10 mL) was stirred under hydrogen atmosphere overnight at room temperature. The reaction mixture was filtered through a pad of Celite and the pad was washed with MeOH. The filtrate was concentrated to give 3'-amino-2'-hydroxy-1 ,1 '- biphenyl-3-carboxylic acid as a brown solid (235 mg, 89%). |
80% | With 5%-palladium/activated carbon; hydrogen; In methanol; at 50℃; under 3000.3 Torr; for 8h; | The solution obtained by dissolving in methanol (400 ml) the 2'-benzyloxy-3'-nitrobiphenyl-3-carboxylic acid (97 g, 0.278 mol) obtained as in Example 2 is placed in a 1 L hydrogenator. 5% Pd/C (23.68 g, 13.9 mmol Pd, moisture about 50%) is added to the solution.The suspension is purged under nitrogen atmosphere, placed at a hydrogen pressure of about 4 bars and maintained under stirring at about 50C for 8 hours. The suspension is then cooled to about 25C and filtered through a Celite bed. The panel is washed with hot methanol, and the organic phases are combined and concentrated at low pressure. The solid residue thus obtained is suspended in hexane (400 ml), and the resulting suspension is heated at 55C for 2 hours. The suspension is then cooled to about 25C and filtered, and the solid is stove-dried at 50C. 50 g of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid of formula (II) is obtained, with a yield of 80% and HPLC chemical purity exceeding 98%. 1H-NMR (DMSO-d6, 300 MHz), delta: 8.12 (s, 1H), 7.81 (d, 1H) 7.63 (d, 1H), 7.45 (t, 1H), 6.75-6.60 (m, 2H), 6.45 (d, 1H). |
With palladium 10% on activated carbon; hydrogen; In ethyl acetate; for 10h; | 3 '- nitro - 2' hydroxy-biphenyl-3-formic acid (V) dissolved in ethyl acetate (350 ml) and catalyst 10% (1.05g) Palladium-carbon was added, the hydrogen gas undergoes a reduction reaction for 10 hours, cooled, filtered, and concentrated to dryness to give 6.6 g of a dark yellow solid which was recrystallized from methanol to give a yellow solid, namely 3'-amino-2'-hydroxybiphenyl-3-formic acid(VI). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To a mixture of <strong>[376592-93-7]3'-amino-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid</strong> (100 mg, 0.44 mmol) in water (0.44 mL) cooled at 0/5 C was added HCl 15% (0.29 mL). A solution of NaNO2 (30 mg, 0.44 mmol) in water (0.30 mL) was added and then the mixture stirred for I h. A solution of ethyl acetoacetate (0.06 mL, 0.44 mmol) in EtOH/water 1:1 (0.88 mL) was added and then triethylamine (0.80 mL) was added and the mixture stirred at 0/5 C for 2 h. The reaction mixture was warmed to room temperature and stirred for 1.5 h. Water was added and then HCl 15% was added dropwise until pH 2. The mixture was filtered to give 3'-{(2E)-2-[1-(ethoxycarbonyl)-2-oxopropylidene]hy-drazino}-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid as an orange solid (137 mg, 85%). | |
85% | To a mixture of 3'-amino-2'-hydroxy-1 ,1 '-biphenyl-3-carboxylic acid (100 mg, 0.44 mmol) in water (0.44 mL) cooled at 0/5 C was added HCI 15% (0.29 mL). A solution of NaNO2 (30 mg, 0.44 mmol) in water (0.30 mL) was added and then the mixture stirred for I h. A solution of ethyl acetoacetate (0.06 mL, 0.44 mmol) in EtOH/water 1 :1 (0.88 mL) was added and then triethylamine (0.80 mL) was added and the mixture stirred at 0/5 C for 2 h. The reaction mixture was warmed to room temperature and stirred for 1 .5 h. Water was added and then HCI 15% was added dropwise until pH 2. The mixture was filtered to give 3'-{(2E)-2-[1 -(ethoxycarbonyl)-2-oxopropylidene]hy-drazino}-2'- hydroxy-1 ,1 '-biphenyl-3-carboxylic acid as an orange solid (137 mg, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With water; sodium hydroxide; for 5h;Reflux; | Compound III10g (39.2mmol), 2.5N aqueous sodium hydroxide (630mmol, 253mL), warmed to reflux, the reaction 5h, TLC the reaction was complete, cooled to room temperature, 2N HCl adjusting the pH = 5 ~ 6, 200mL ethyl acetate was added and extracted, The organic phase was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (compound IV) 9g, 93% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With palladium 10% on activated carbon; ammonium formate; triethylamine; In methanol; water; at 50 - 60℃; | Methanol (2.5 L) was added sequentially to the reaction flask,Compound IV-1 (250.0 g, 0.65 mol),Triethylamine (65.9 g, 0.65 mol) and 10% palladium on carbon (25 g) were added and stirred well,Heated to 50-60 C reaction,After addition of ammonium formate (410.7 g, 6.51 mol) and water (250 g)Continue to respond 3-4h. The reaction was stopped and concentrated hydrochloric acid was added dropwise at room temperature to pH = 1-2.The filter cake was rinsed with methanol (1.5 L) and the filter cake was used.Filter with ammonia to adjust the pH = 5-7, filter, filter cake with methanol,Water followed by washing, drying were white solid: 132.9g, yield 89%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | To a cooled at 0 to 10C mixture of 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid (100 g) in methanol (2000 ml) was added aq. hydrochloric acid solution (150ml cone, hydrochloric acid in 150 ml water). Aq. sodium nitrite solution (31.87 g sodium nitrite in 100 ml water) was added to the reaction mixture at 0C to 10C within 15min and stirred further for lh. Triethylamine (200 ml) was added to the reaction mixture at 0C to 10C till pH 6 to 8 was obtained. 2-(3,4-dimethyl-phenyl)-5-methyl-l,2-dihydro-pyrazol-3-one (88.24 g) was added to the reaction mixture and stirred for 2h at 25C to 35C. After completion of the reaction on TLC, triethylamine (176.57g) was added to the reaction mixture and heated at 50C to 60C for 2h. The reaction mixture is distilled out under vacuum to get residue. Methanol (1000 ml) was added to the residue and heated at 50C to 60C for 30min. The reaction mixture was cooled to 25C to 35C for 2h. The suspension was filtered and obtained solid was washed with methanol (2 X 50 ml) to give wet cake. Water (1000 ml) was added to this wet cake and heated at 50C to 60C for lh. The reaction mixture is filtered, obtained solid was washed with water (2 X 50 ml) and suck dried to give wet cake. Water (1000 ml) was added to this wet cake and heated at 50C to 60C for lh. The reaction mixture was filtered, obtained solid was washed with water (2 X 50 ml) and suck dried. The solid was dried at 60C to 70C for 12- 15h to give eltrombopag triethylamine salt (180.0 g). Yield: 76.0%.Purity by HPLC: 99.6%. Eta NMR (DMSO) delta: 1.08-1.11 (9H, t), 2.19-2.33 (6H, m), 2.38 (3H,s), 2.87-2.92 (6H, q), 7.06- 7.13 (3H, t), 7.55-7.65 (2H, d), 7.74-7.89 (4H, d), 8.16-8.23(1H, d).Triethylamine content by titration: 18.5%.The XRPD of above obtained Eltrombopag triethylamine salt is given in fig 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium nitrate; sodium hydrogencarbonate; | Take 11.5g82.4%) of 3'-amino-2'-hydroxybiphenyl-3-formic acid(VI) obtained in step ( 2), (6.8 g, 82.4%) 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (VII) was added, condensation and cyclization reactions took place, and then Ethanolamine was added under the action of hydrogen to produce the synthesis reaction of Eltrombopag (IX); The 3'-amino-2' hydroxybiphenyl-3-formic acid and 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazole- 3-one(VII) in step (3), reacted in a mixed solution of sodium nitrate and sodium bicarbonate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With palladium 10% on activated carbon; hydrogen; In methanol; water; at 20℃; under 750.075 - 2250.23 Torr; | The above product was added to a hydrogenation vessel, and 2 g of 10% palladium carbon (about 63% aqueous) and 150 ml of methanol were added.The mixture was stirred at room temperature with hydrogen gas at 0.1-0.3 MPa.After the reaction was completed, it was filtered, concentrated, dissolved in 100 ml of water, and adjusted to pH 5.5 with 1 M hydrochloric acid.The solid is precipitated, suction filtered and dried to give a reddish brown solid(9 g, yield: 95%, HPLC purity: 99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrogenchloride; In water; at 50℃; | The above product was added to 100 ml of water, and 20 ml of 6 M hydrochloric acid was added thereto and stirred at 50 C, and the reaction was completed, followed by filtration.The solid was washed with 30 ml of ethanol to give a pale yellow solid(5.8 g, yield: 94%, HPLC purity: 99%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; In water; at 50℃; | The above product was added to 100 ml of water, and 20 ml of 6 M hydrochloric acid was added thereto and stirred at 50 C, and the reaction was completed, followed by filtration.The solid was washed with 30 ml of ethanol to give a pale yellow solid(9.5 g, yield: 90%, HPLC purity: 99%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 5%-palladium/activated carbon; hydrogen; triethylamine; In methanol; at 30 - 40℃; under 1140.08 - 1216.08 Torr; for 4h;Autoclave; | To a 10 L autoclave, 283 g (0.8 mol) of 2-benzyloxy-3-m-carboxyphenyl-4-chloroaniline (X), 3 L of methanol, 91 g of triethylamine, 14 g of 5% palladium carbon, and three times of nitrogen were replaced with hydrogen. Replace three times, pressurize to 1.5-1.6 atmospheres, control temperature 30-40 C, react 4h, cool down to 20 C filtration, concentrate the filtrate, add 300 ml of methyl tertiary ether, beat for 1 h, filter, filter cake to dry to obtain 165.1 g (0.72 mol), a compound of formula I 2-hydroxy-3-(m-carboxyphenyl)aniline, yield 90%.The HPLC purity was 98.1%. |
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