Structure of 2644-70-4
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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| CAS No. : | 2644-70-4 |
| Formula : | ClH5N2 |
| M.W : | 68.51 |
| SMILES Code : | NN.[H]Cl |
| English Name : | Hydrazine hydrochloride |
| MDL No. : | MFCD00044368 |
| InChI Key : | BIVUUOPIAYRCAP-UHFFFAOYSA-N |
| Pubchem ID : | 115031 |
| Num. heavy atoms | 3 |
| Num. arom. heavy atoms | 0 |
| Fraction Csp3 | None |
| Num. rotatable bonds | 0 |
| Num. H-bond acceptors | None |
| Num. H-bond donors | None |
| Molar Refractivity | 14.49 |
| TPSA ? Topological Polar Surface Area: Calculated from |
52.04 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
None |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
None |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
None |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
None |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
None |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
None |
| Log S (ESOL):? ESOL: Topological method implemented from |
None |
| Solubility | None mg/ml ; None mol/l |
| Class? Solubility class: Log S scale |
None |
| Log S (Ali)? Ali: Topological method implemented from |
None |
| Solubility | None mg/ml ; None mol/l |
| Class? Solubility class: Log S scale |
None |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
None |
| Solubility | None mg/ml ; None mol/l |
| Class? Solubility class: Log S scale |
None |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
None |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
None |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
None |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
None |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
None |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
None |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
None |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
None |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
None cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
None |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
None |
| Egan? Egan (Pharmacia) filter: implemented from |
None |
| Muegge? Muegge (Bayer) filter: implemented from |
None |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
None |
| PAINS? Pan Assay Interference Structures: implemented from |
None alert |
| Brenk? Structural Alert: implemented from |
None alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
None |
* 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 |
|---|---|---|
| 70% | In methanol for 1h; Heating / reflux; | 1-1 5-(4-Benzyloxyphenyl)-1H-pyrazole-3-carboxylic acid methyl ester A mixture of sodium 3-(4-benzyloxyphenyl)-1-methoxycarbonyl-3-oxopropen-1-olate (starting compound 1A) (0.500 g, 1.496 mmol), hydrazine monohydrochloride (0.330 g, 4.82 mmol) and methanol (15 mL) was heated at reflux for 1 hour. After cooled to room temperature, the mixture was diluted with water (15 mL). The resulting precipitate was collected by filtration, washed with 50 % methanol/water, and dried under reduced pressure to give 5-(4-benzyloxyphenyl)-1H-pyrazole-3-carboxylic acid methyl ester (0.324 g, 70 %) as a colorless solid. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| In ethanol; ethyl acetate | 68 2-Chloro-4-(1H-pyrazol-3-yl)-benzoic Acid, Methyl Ester EXAMPLE 68 2-Chloro-4-(1H-pyrazol-3-yl)-benzoic Acid, Methyl Ester To a suspension of 2-chloro-4-(3-dimethylamino-2-propen-1-on-1-yl)-benzoic acid, methyl ester (13.67g) in ethanol (53 ml) was added hydrazine monohydrochloride (7.0 g). The mixture was heated in an oil bath at 75-80° C. for one hour. The solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to yield the tide compound as a crude solid (12 g). A purified sample had a melting point of 130-131° C. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| In ethanol; ethyl acetate | 19 2-Chloro-4-(1H-pyrazol-3-yl)-benzoic acid, methyl ester EXAMPLE 19 2-Chloro-4-(1H-pyrazol-3-yl)-benzoic acid, methyl ester To a suspension of 2-chloro-4-(3-dimethylamino-2-propen-1-on-1-yl)-benzoic acid, methyl ester (13.67 g) in ethanol (53 ml) was added hydrazine monohydrochloride (7.0 g). The mixture was heated in an oil bath at 75-80° C. for one hour. The solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to yield the title compound as a crude solid (12 g). A purified sample had a melting point of 130-131° C. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With hydrazine hydrate In ethylene glycol | 1 2-HYDRAZINOBENZOTHIAZOLE EXAMPLE 1: 2-HYDRAZINOBENZOTHIAZOLE To a slurry of 30 g. (0.2 mole) 2-aminobenzothiazole in 150 ml. ethylene glycol was added 23.7 g. (0.4 mole) 85% hydrazine hydrate and 13.7 g. (0.2 mole) hydrazine monohydrochloride. The mixture was stirred under a nitrogen atmosphere and heated at a temperature of 140°C. for 2 hours. The product crystallized on cooling. After addition of 50 ml. water and stirring, the material was filtered, washed with 100 ml. water in three portions, and dried in vacuo at 60°C. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 89% | With hydrazine hydrate In water; ethylene glycol | 16 4-METHYL-2-HYDRAZINOBENZOTHIAZOLE EXAMPLE 16: 4-METHYL-2-HYDRAZINOBENZOTHIAZOLE 4-Methyl-2-aminobenzothiazole (8.21 g.; 0.05 mole), hydrazine monohydrochloride (1.14 g.; 0.017 mole), 85% hydrazine hydrate (1.96 g.; 0.033 mole), and 41 ml. of ethylene glycol were mixed, and the mixture heated under N2 atmosphere to 140°C. These reaction conditions were continued for 15 hours; the reaction mixture was then permitted to cool slowly to romm temperature and, for convenience only, stored overnight under N2 atmosphere. Water (45 ml.) was added to the reaction mixture in the morning to force crystallization. The reaction mixture was then filtered to separate the desired 4-methyl-2-hydrazinobenzothiazole compound. It was dried in vacuo overnight at 60°C. The yield was 8.00 g., 89% yield, m.p. 143°-51°C. Non-aqueous titration showed the product to be 85.8% pure. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| In ethanol | VII 1-(2,6-dimethylphenyl)-1-methyl-2-aminoguanidine.HCl EXAMPLE VII 1-(2,6-dimethylphenyl)-1-methyl-2-aminoguanidine.HCl To 8.2 g of 1-(2,6-dimethylphenyl)-1-methylcyanamide dissolved in 30 ml of ethanol, 3.4 g of hydrazine.hydrochloride are added. The mixture is refluxed for 20 hours followed by evaporation. The residue is recrystallized from ethanol/ether. Yield: 7.8 g; melting point: 187°-188°C. By using 1.1-dimethyl-hydrazine instead of hydrazine.hydrochloride 1-(2,6-dimethylphenyl)-1-methyl-2-dimethylaminoguanidine is obtained as an oily substance. Rf in methanol:acetic acid (98:2) = 0.63 (SiO2). | |
| In ethanol | VII 1-(2,6-dimethylphenyl)-1-methyl-2-aminoguanidine.HCl EXAMPLE VII 1-(2,6-dimethylphenyl)-1-methyl-2-aminoguanidine.HCl To 8.2 g of 1-(2,6-dimethylphenyl)-1-methylcyanamide dissolved in 30 ml of ethanol, 3,4 g of hydrazine.hydrochloride are added. The mixture is refluxed for 20 hours followed by evaporation. The residue is recrystallized from ethanol/ether. Yield: 7.8 g; melting point: 187°-188° C. By using 1.1-dimethyl-hydrazine instead of hydrazine. hydrochloride 1-(2,6-dimethylphenyl)-1-methyl-2-dimethylaminoguanidine is obtained as an oily substance. Rf in methanol:acetic acid (98:2) = 0.63 (SiO2). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With hydrogenchloride In water pptn. of N2H4*HCl by addn. of HCl to an acidic soln.;; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 24.78% | Stage #1: acetonitrile With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h; Stage #2: methyl 3-(4-methoxypyridin-2-yl) propionate In tetrahydrofuran at -78 - 20℃; for 0.666667h; Stage #3: hydrazine hydrochloride; acetonitrile more than 3 stages; | 9 Acetonitrile (1.078 mL, 20.64 mmol, 1.3eq) was added dropwise to lithium diisopropylamide (10.32 mL, 20.64 mmol, 1.3eq) in THF (10OmL) at -780C over a period of 5 mins under nitrogen. The resulting solution was stirred at -78 0C for 10 mins. Methyl 3-(4-methoxypyridin-2-yl)propanoate (3.1g, 15.88 mmol, leq) was added in one portion and the reaction was stirred for 30 mins before being allowed to warm to ambient temperature. After stirring for 10 mins, a further 1.3 equivalents of acetonitrile anion was added to the reaction flask at -78 0C. The reaction was allowed to warm back up to ambient temperature and stirred for 1 h. The reaction mixture was diluted with ethanol (100 mL) and hydrazine hydrochloride (2.83 g, 41.29 mmol, 2.6eq) was added. The reaction was heated at reflux for 3 h until formation of pyrazole was complete. The resulting mixture was evaporated to dryness and the residue was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM with ammonia. Pure fractions were evaporated to dryness to afford 5-(2-(4-methoxypyridin-2-yl)ethyl)-lH-pyrazol-3-amine (859mg, 24.78 %) as a yellow gum.IH NMR (400.132 MHz, DMSO) δ 2.79 - 2.87 (2H, m), 2.87 - 2.96 (2H, m), 3.83 (3H, s), 6.73 (IH, s), 6.77 - 6.81 (IH, m), 6.83 (IH, d), 7.33 (IH, s), 8.30 (IH, d). MS: m/z 219 (MH+) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 38% | Stage #1: acetonitrile; 3-(3-cyano-phenyl)-propionic acid methyl ester With sodium hydride In 1,4-dioxane at 20℃; for 0.166667h; Heating / reflux; Stage #2: hydrazine hydrochloride In 1,4-dioxane; ethanol Heating / reflux; | 10 Sodium hydride (60%, 3.Og, 75.6mmol) was added to a stirred solution of methyl 3-(3- cyanophenyl)propanoate (11.9g, 63.0mmol) in dry 1,4 dioxane (35OmL) and dry acetonitrile (3.95mL, 75.6mmol) under nitrogen to give a cloudy grey mixture. This was stirred at room temperature for 10 mins and then refluxed under nitrogen overnight to give a dark orange solution. The reaction mixture was cooled and ethanol (25mL) was added followed by hydrazine monohydrochloride (8.635g, 126mmol). The reaction mixture was refluxed overnight. The reaction mixture was cooled, filtered, and evaporated to dryness to afford crude 3-[2-(5-amino-2H-pyrazol-3-yl)ethyl]benzonitrile (16g). Purified by flash silica chromatography, eluted isocratically with 8% MeOH in DCM. Pure fractions evaporated to dryness to afford 3-[2-(5-amino-2H-pyrazol-3-yl)ethyl]benzonitrile as an orange gum, (5.1g, 38%). IH NMR (399.9 MHz, DMSOd6) δ 2.73 - 2.76 (2H, m), 2.88 - 2.92 (2H, m), 4.07 - 4.08 (IH, m), 4.50 (2H, s), 5.17 (IH, s), 7.47 - 7.51 (IH, m), 7.55 - 7.58 (IH, m), 7.64 - 7.66 (2H, m) MS: m/z 213.41 (MH+) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 86% | In ethanol; water; ethyl acetate | 14.B Preparation of Substituted Quinolines 88 Step B: Preparation of 3-trifluoromethyl-1H-pyrazole 86a. To a stirred solution of hydrazine monochloride (6.62 g, 1.6 eq.) in EtOH (300 mL) was added dropwise compound 84 (10.16 g, 1 eq.) in EtOH (200 mL). The reaction mixture was refluxed for 6 hrs and evaporated to dryness. Water and EtOAc were added to the residue. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 86a as a brown solid in 86% yield. 1H NMR (CDCl3, 376 MHz) δ 6.66 (d, J=2.30 Hz, 1H), 7.72 (d, J=2.30 Hz, 1H); 19F NMR (CDCl3, MHz) δ 61.41 (s, 3F). |
| 86% | In ethanol; water; ethyl acetate | 19.A.B Method A Step B: Preparation of 3-trifluoromethyl-1H-pyrazole 233a. To a stirred solution of hydrazine monochloride (6.62 g, 1.6 eq.) in EtOH (300 mL) was added dropwise compound 231 (10.16 g, 1 eq.) in EtOH (200 mL). The reaction mixture was refluxed for 6 hrs and evaporated to dryness. Water and EtOAc were added to the residue. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 233a as a brown solid in 86% yield. 1H NMR (CDCl3, 376 MHz) δ (ppm) 6.66 (d, J=2.30 Hz, 1H), 7.72 (d, J=2.30 Hz, 1H); 19F NMR (CDCl3, MHz) δ (ppm) 61.41 (s, 3F). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 94% | With sulfuric acid In water | 14.D Preparation of Substituted Quinolines 88 Step D: Preparation of 3-isopropyl-1H-pyrazole 86b. Compound 85 (6.6 g, 1 eq.) was added dropwise to a stirred solution of hydrazine monochloride (3.2 g, 1 eq.), sulfuric acid (1.13 mL) and H2O (6 mL). The reaction mixture was stirred at 68° C. for 2 hrs. The mixture was then neutralized with 1N NaOH and extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 86b as a beige solid in 94% yield. 1H NMR (DMSO-d6, 400 MHz) δ 1.17 (s, 3H), 1.19 (s, 3H), 2.87-2.93 (m, 1H), 5.99 (s, 1H), 7.40 (s, 1H). 1.39-1.43 (t, J=7.04 Hz, 3H), 4.08-4.13 (q, J=7.04 Hz, 2H), 5.86 (d, J=12.40 Hz, 1H), 7.90 (d, J=12.40 Hz, 1H). |
| 94% | With sulfuric acid In water | 19.A.D Method A Step D: Preparation of 3-isopropyl-1H-pyrazole 233b. Compound 232 (6.6 g, 1 eq.) was added dropwise to a stirred solution of hydrazine monochloride (3.2 g, 1 eq.), sulfuric acid (1.13 mL), and H2O (6 mL). The reaction mixture was stirred at 68° C. for 2 hrs. The mixture was then neutralized with 1N NaOH and extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 233b as a beige solid in 94% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.17 (s, 3H), 1.19 (s, 3H), 2.87-2.93 (m, 1H), 5.99 (s, 1H), 7.40 (s, 1H). 1.39-1.43 (t, J=7.04 Hz, 3H), 4.08-4.13 (q, J=7.04 Hz, 2H), 5.86 (d, J=12.40 Hz, 1H), 7.90 (d, J=12.40 Hz, 1H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | Stage #1: hydrazine hydrochloride With triethylamine In dichloromethane for 0.5h; Stage #2: 2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzoic acid pentafluorophenyl ester In dichloromethane for 5h; | 69.6; 141.1 Example 69; 2-{5-[2-(4-Ethyl-2-fluoro-phenylamino)-3,4-difluoro-phenyl]-[1,3,4]oxadiazol-2-ylamino}-ethanol; Step 6 To a stirring solution of hydrazine hydrochloride (0.68g, 9.87 mmol) in dichloromethane (50 ML) was added triethylamine (2.63 mL, 18.84 mmol) and allowed to stir for 30 minutes. 2- (4-ethyl-2-fluoro-phenylamino)-3, 4-difluoro- benzoic acid pentafluorophenyl ester (4.14g, 8.79 mmol) was added and the mixture was allowed to stir an additional 5 hours. The reaction mixture was partitioned between dichloromethane and water. Organics were washed twice with water, twice with brine, twice with saturated NAHCO3 and a final wash with brine. Organics were collected, dried over NA2SO4, filtered and concentrated in vacuo. Afforded 2- (4-ETHYL-2-FLUORO-PHENYLAMINO)-3, 4-DIFLUORO-BENZOIC acid hydrazide 6 (3.07g, >100% yield due to solvents remaining) as a yellow solid. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 92% | Stage #1: diethyl oxalacetate sodium salt In benzene for 0.333333h; Stage #2: With acetic acid for 0.5h; Stage #3: hydrazine hydrochloride at 100℃; for 24.5h; Heating / reflux; | 1 Example 1; 5-HYDROXY-LH-PYRAZOLE-3-CARBOXYLIC acid ethyl ester Diethyloxalacetate, sodium salt (14. 53 g, 69. 15 mmol) was dissolved in 100 mL of benzene and stirred for 20 min. To the solution was added 100 ML of acetic acid and the reaction mixture was stirred for a further 30 min. Hydrazine monohydrochloride (9. 47 g, 138 mmol) was added and the reaction mixture was stirred for an additional 30 min. The reaction was brought to reflux at 100 C for 24 h. The reaction was then removed from heat and cooled to room temperature and extracted with ethyl acetate and washed with 10% hydrochloric acid, saturated sodium bicarbonate solution, water and then brine. The solvent was removed IN VACUO TO yield an oily solid which was then triturated with a 2 : 1 mixture of diethyl ether : hexanes to yield 3 (10. 00 g, 92%) as an off-white solid : LRMS (electrospray) ; m/z [M+H1+ = 157. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | Stage #1: 3,3'-diamino-2,2',4,4',6,6'-hexanitrodiphenylamine With sodium hydroxide In water at 80℃; for 0.5h; Stage #2: hydrazine hydrochloride In water at 20℃; for 1h; |