Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 283173-50-2 | MDL No. : | |
Formula : | C19H18FN3O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HMABYWSNWIZPAG-UHFFFAOYSA-N |
M.W : | 323.36 | Pubchem ID : | 9931954 |
Synonyms : |
AG014699;PF-01367338;AG-014447
|
Num. heavy atoms : | 24 |
Num. arom. heavy atoms : | 15 |
Fraction Csp3 : | 0.21 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 96.03 |
TPSA : | 56.92 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.5 cm/s |
Log Po/w (iLOGP) : | 2.48 |
Log Po/w (XLOGP3) : | 2.49 |
Log Po/w (WLOGP) : | 2.87 |
Log Po/w (MLOGP) : | 2.6 |
Log Po/w (SILICOS-IT) : | 4.65 |
Consensus Log Po/w : | 3.02 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.68 |
Solubility : | 0.0679 mg/ml ; 0.00021 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.33 |
Solubility : | 0.151 mg/ml ; 0.000467 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -7.67 |
Solubility : | 0.0000069 mg/ml ; 0.0000000213 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.81 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
88% | Stage #1: at 20℃; for 46 h; Stage #2: With sodium hydroxide In water at 0 - 35℃; |
Example 13 Synthesis of 8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (15) Lactam 14 (14.42 g, 0.038 mol) was dissolved in hydrobromic acid in acetic acid (30percent-32percent, 140 ml). The reaction solution was stirred for 46 hours at room temperature in a 500 ml flask that was connected to an ethanolamine scrubber system. HPLC analysis indicated the completion of the reaction. Ice (30 g) was added to the reaction solution followed by addition of aqueous NaOH (327 ml, 10 M, 3.27 mol) while the temperature was maintained between 25° C. and 35° C. When addition of NaOH was complete, the pH was 10. The resulting solid was collected by filtration, washed with water (2*50 ml). The filter cake was then suspended in water (125 ml) and stirred for 2 hours. The solid was collected by filtration, washed with water (2*25 ml) and dried to afford 10.76 g of product (88percent yield). 1H NMR (300 MHz, DMSO-d6) δ 2.577(s, 3H), 3.053(m, 2H), 3.406(m, 2H), 4.159(s, 2H), 7.36(dd, 1H, J=2.4 Hz and J=9.3 Hz), 7.44(dd, 1H, J=2.4 Hz and J=11.1 Hz), 7.63(d, 2H, J=8.1 Hz), 7.70(d, 2H, J=8.1 Hz), 8.265(t, 1H, J=5.7 Hz), 11.77(s, 1H). Exact mass calculated for C19H19FN3O: 324.1512. Found: 324.1497. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.82 g | With bis(acetato)bis(triphenylphosphine)palladium(0); sodium carbonate In methanol; water at 60℃; for 4 h; Inert atmosphere | 2-Bromo-8-fluoro-4,5-dihydro-lH-azepino[5,4,3-cd]indol-6(3H)-one (10 g; 35.3 mmol), prepared according to process described in Example 3, sodium carbonate (3.74 g; 35.3 mmol), bis(triphenylphosphine)palladium(II) diacetate (0.529 g; 0.71 mmol) and (4-((methylamino)methyl)phenyl)boronic acid solution (75 ml; 45.9 mmol), prepared according to process described in Example 2, are charged into a three-necked round bottom flask, followed by inertisation with nitrogen. A previously degassed mixture of methanol (130 mL) and water (40 mL) is added and the reaction mixture is stirred at 60°C for 4 hours. The reaction mixture is cooled to ambient temperature followed by addition of activated carbon. The mixture is stirred at ambient temperature for one hour, heated to 50 °C, stirred for another hour and then filtered through a layer of celite. The solution of 8-fluoro-2-(4- ((methylamino)methyl)phenyl)-4,5-dihydro-lH-azepino[5,4,3-cd]indol-6(3H)-one is concentrated to about 110 mL, heated to 40°C followed by dropwise addition of water (40 mL). Reaction mixture is cooled to ambient temperature and stirred for 17 hours at ambient temperature and additional one hour at 0-5°C. Solid is filtered off, washed with water and dried in vacuum oven at 50°C for 5 hours. Crude material (9.5 g) is suspended in methanol (95mL) at reflux temperature and stirred for 20 minutes. Suspension is than cooled down and stirred for 17 hours at ambient temperature and 1.5 hour at 0-5°C. Crystals are filtered off, washed with methanol and dried in vacuum oven at 50°C for 4 hours to obtain 6.82 g of Rucaparib base. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In methanol; | 8-Fluoro-2- (4-methylaminomethyl-phenyl)-1,3,4, 5-tetrahydro-azepino [5,4, 3-cd] indol-6-one (259 mg, 0.801 mmol) was partially dissolved in methanol (5 mL) and was then treated with methane sulfonic acid (1.0 M methanolic solution, 0.801 mL). The amine was completely dissolved by gently heating the solution and by using an additional amount of methanol (10 mL). The solution was filter through cotton to separate any particulates. The solution was partially concentrated down in vacuo. 1 mL of deionized water was added and the methanol was completely evaporated in vacuo. The product was lyophilized to give 326 mg (97percent) as a bright yellow solid: Anal. (C20H22FN3O42H20) C, H, N. |
In tetrahydrofuran; acetone; at 50℃; | A vial was charged with <strong>[283173-50-2]rucaparib</strong> free base (60 mg, e.g. prepared according to the procedure disclosed in example 1111 of WO 00/42040 Al), acetone (1.2 mL) and methane sulfonic acid (1.1 mol equivalents, 1M in THF). The reaction mixture was warmed to 50 °C and subsequently cooled to 5 °C at a cooling rate of -0.5 °Klmin. The reaction mixture was left for 10 days at 5°C before the solid material was isolated and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.7% | With hydrogen bromide; acetic acid; at 20℃; for 12h; | 4-(8-Fluoro-6-oxo-3,4,5,6-tetrahydro-1H-aza-[5,4,3-cd]indol-2-yl)benzyl (methyl) Methyl carbonate (Va)(43 g) was dissolved in hydrogen bromide in acetic acid (86 mL, 30% w/w) and stirred at room temperature for 12 hours. After the reaction was completed by HPLC, ice water (215 mL) was added, 2N aqueous sodium hydroxide solution was added dropwise, and the pH was adjusted to 10, and the precipitated solid was filtered, and dried under reduced pressure to give a white solid (32.7 g, yield: 89.7%). |
88% | Example 13 Synthesis of 8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (15) Lactam 14 (14.42 g, 0.038 mol) was dissolved in hydrobromic acid in acetic acid (30%-32%, 140 ml). The reaction solution was stirred for 46 hours at room temperature in a 500 ml flask that was connected to an ethanolamine scrubber system. HPLC analysis indicated the completion of the reaction. Ice (30 g) was added to the reaction solution followed by addition of aqueous NaOH (327 ml, 10 M, 3.27 mol) while the temperature was maintained between 25 C. and 35 C. When addition of NaOH was complete, the pH was 10. The resulting solid was collected by filtration, washed with water (2*50 ml). The filter cake was then suspended in water (125 ml) and stirred for 2 hours. The solid was collected by filtration, washed with water (2*25 ml) and dried to afford 10.76 g of product (88% yield). 1H NMR (300 MHz, DMSO-d6) delta 2.577(s, 3H), 3.053(m, 2H), 3.406(m, 2H), 4.159(s, 2H), 7.36(dd, 1H, J=2.4 Hz and J=9.3 Hz), 7.44(dd, 1H, J=2.4 Hz and J=11.1 Hz), 7.63(d, 2H, J=8.1 Hz), 7.70(d, 2H, J=8.1 Hz), 8.265(t, 1H, J=5.7 Hz), 11.77(s, 1H). Exact mass calculated for C19H19FN3O: 324.1512. Found: 324.1497. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methylamine; | Example IIII 8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 for 2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with methylamine (1.62 mmol) as described for Compound PPP to yield 8-fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 32 mg (31%) as a yellow solid: m.p. 1543-155 C.; 1H NMR (300 MHz, d6-DMSO) 2.28 (s, 3H), 3.04 (m, 2H), 3.40 (m, 2H), 3.69 (s, 2H), 7.32 (dd, J=9.0, 2.4 Hz, 1H), 7.44 (m, 3H), 7.57 (d, J=8.1 Hz, 2H), 8.25 (br t, 1H), 11.67 (br s, 1H). HRMS (MALDI MH+) Calcd for C19H18N3OF: 324,1512. Found: 325.1524. Anal. (C19H18N3OF.0.3 H2O) C, H, N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Polymorphic Form IV of Compound I was prepared by the following procedure. A 500 mL round bottom flask was charged with the compound 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 , 3,4,5- tetrahydro-6H-azepino[5,4,3-cd]indol-6-one represented by formula 1 (1.65 g, 5.10 mmol, 1.0 equiv.) and EPO <DP n="30"/>methanol (200 ml_). The mixture was agitated until clear solution was obtained (~10 minutes). A 0.5 M phosphoric acid solution in methanol (11.0 ml_, 5.87 mmol, 1.15 equiv., prepared by dissolving 0.7 g of 85percent phosphoric acid in 11.0 mL of methanol) was added. The resulting mixture was stirred for at 30 minutes at ambient temperature. The solids obtained were filtered and dried at 45°C to afford polymorphic Form IV of the phosphate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H- azepino[5,4,3-cd]indol-6-one (1.43 g).Figure 10 is an X-ray powder diffractogram of polymorphic Form IV of Compound I. Figure 11 is an infrared absorption spectrum of polymorphic Form IV. Polymorphic Form IV of Compound I was further characterized by differential scanning calorimetry (Figure 12). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In isopropyl alcohol;Product distribution / selectivity; | Example 3: Preparation of a Maleate Salt of Compound 1., Maleate Polymorph Form B, Using Isopropyl Alcohol.A solution of Compound 1 (18 g; 55.7 mmol) in isopropyl alcohol (1500 mL) was prepared by heating in a jacketed reaction vessel with overhead stirring. A solution of maleic acid (7.1 1 g, 1.1 eq) in isopropyl alcohol (100 mL) was prepared and was added dropwise (over 1 hour) following the addition of seed crystals of the title compound (45 mg). Once the addition was complete, the suspension was cooled to 0 °C (at natural rate) and granulated for 2 days. Following filtration the product was dried under vacuum at 50 °C to furnish 23.7 g of a crystalline product (97 percent theoretical yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; isopropyl alcohol; at 70℃; for 0.166667h;Product distribution / selectivity; | Example 18: Preparation of a 1 R:9S-Camsylate Salt.A slurry of Compound (1 .5 g) was prepared in isopropyl alcohohwater (25 ml 40:60 % v/v). R-camphor sulfonic acid (0.13 g) and S-camphor sulfonic acid (1.17 g) were added, as a solution, in water (1 .5 ml_). The slurry was heated to 70 C over a 10 minute period. The resultant solution was cooled to 10 C over a 10 minute period.Solid crystallized after holding this solution at a temperature of 10 C for one hour. This resulted in the formation of a slurry. This slurry was granulated for a total of 48 hours.The crystals were filtered and washed with water and then dried overnight at 50 C providing a pale yellow powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; isopropyl alcohol; at 70℃; for 0.166667h; | Example 17: Preparation of a1 R:1 S-Camsylate Salt.A slurry of Compound 1 (1 .5 g) was prepared in isopropyl alcohohwater (25 ml40:60 percent v/v). R-camphor sulfonic acid (0.65 g) and S-camphor sulfonic acid (0.65g) were added, as a solution, in water (1 .5 ml_). The slurry was heated to 70 °C over a 10 minute period. The resultant solution was cooled to 0 °C over a 10 minute period. Solid crystallized after holding this solution at a temperature of 0 °C for one hour. This resulted in the formation of a slurry. This slurry was granulated for a total of 36 hours. The crystals were filtered and washed with water and then dried overnight at 50 °C providing a pale yellow powder (1.9 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water; for 0.833333h;Reflux;Product distribution / selectivity; | Example 4: Preparation of an S-camsylate Salt of Compound 1., S-camsylate Polymorph Form A, Using Tetrahydrofuran.Compound (20 g) was slurried at reflux in tetrahydrofuran (42 ml.) and water (40 ml.) in a jacketed reaction vessel with overhead stirring, and remained as a free base slurry. S-camphor sulfonic acid solution (17.25 g in 20 ml. of water) was added slowly over approximately 10 minutes, to form a clear yellow solution, which was held at reflux for 30 minutes. Water (135 ml.) was then added, over approximately 20 minutes, maintaining reflux. The resulting yellowish slurry was cooled to 10 C and granulated at this temperature to improve crystallinity and yield for a suitable amount of time. Suitable granulation times can be chosen by one of skill in the art. Typical granulation times can range, for example, from about 1 hour to about 48 hours. Filtered solids were washed with chilled water (20 ml.) and dried under vacuum at 50 C to give the final product. | |
for 2.5h; | 56 mg of <strong>[283173-50-2]Rucaparib</strong> Form II and 44 mg of 1 S-(+)-camphor-10- sulphonic acid are placed in an agate jar with 4 agate balls and milled on a rotation ball mill for 2.5 hours. The prepared sample was analyzed by XRD. The XRD pattern is given in Figure 47. | |
In 1,4-dioxane; water; at 30℃; for 12h; | Example 5 Preparation of <strong>[283173-50-2]Rucaparib</strong> Camsylate Form Alpha <strong>[283173-50-2]Rucaparib</strong> base (0.2 g) and S-camphorsulfonic acid (0.14 g) were dissolved in a 1,4-dioxane-water (1:1; 6 mL) mixture at 30 C. The clear solution was stirred at 30 C. for 12 h. The resulting product was filtered and dried at 50 C. under vacuum for 2 h. The resulting product was identified as crystalline (S)-<strong>[283173-50-2]rucaparib</strong> camsylate salt Form alpha. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; isopropyl alcohol; at 70℃; for 0.166667h; | Example 21 : Preparation of an R-Camsylate Salt of Compound , R-Camsylate Polymorph Form A.A slurry of Compound (1 .5 g) was prepared in isopropyl alcohohwater (25 ml 40:60 % v/v). R-camphor sulfonic acid (1.3 g) was added, as a solution, in water (1 .5 ml_). The slurry was heated to 70 C over a 10 minute period. The resultant solution was cooled to 10 C over a 10 minute period. Solid crystallized after holding this solution at a temperature of 10 C. This resulted in the formation of a slurry. This slurry was granulated for a total of 4 hours. The crystals were filtered and washed with water and then dried overnight at 50 C providing a pale yellow powder. | |
0.25 g | In ethanol; at 75 - 85℃; for 3h; | 0.2 g of <strong>[283173-50-2]Rucaparib</strong> Form M2 was dissolved in 4 mL of ethanol at 80±5C. To the clear solution was added (S)-Camphor sulfonic acid solution [dissolved (S)-camphor sulfonic acid (0.l4g) in ethanol (lmL)] slowly at 80±5C for 5-10 min and maintained under stirring for 3h. The reaction mass was cooled to 25±5C and further stirred for 12 h. The reaction mass was filtered and dried under vacuum at 50C for 3h. The product obtained was identified as <strong>[283173-50-2]Rucaparib</strong> S- Camsylate Form Ml. (0130) Yield: 0.25 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.17 g | With hydrogen bromide; In methanol; water; at 20℃; for 48h; | To the water/methanol (1/1.5) solution of <strong>[283173-50-2]Rucaparib</strong> base (27.5 mL; 7.7 mmol), prepared according to the process described in Example 4, solution of hydrobromic acid in water/methanol mixture (27 mL of following solution: 4.37 mL of hydrobromic acid dissolved in 35 mL of water and 10 mL of methanol) is added dropwise while stirring at ambient temperature. Yellow suspension is stirred for 48 hours at ambient temperature, then at 0°C for 1 hour. Crystals are filtered off, washed with cold water and filtered off under vacuum. Wet crystals are dried in vacuum oven at 50°C for 2 hours to obtain 2.17 g of <strong>[283173-50-2]Rucaparib</strong> Hydrobromide salt. XRPD is given in Figure 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.32 g | In methanol; water; at 20℃; for 48h; | To the water/methanol (1/1.5) solution of <strong>[283173-50-2]Rucaparib</strong> base (27.5 mL; 7.7 mmol), prepared according to the process described in Example 4, solution of acetic acid in water/methanol mixture (29 mL of following solution: 2.21 mL of acetic acid dissolved in 35 mL of water and 10 mL of methanol) is added dropwise while stirring at ambient temperature. Thick brown suspension is stirred for 48 hours at ambient temperature, then at 0°C for 1 hour. Crystals are filtered off under vacuum. Wet crystals are dried in vacuum oven at 50°C for 5 hours to obtain 3.32 g of <strong>[283173-50-2]Rucaparib</strong> Acetate salt. XRPD is given in Figure 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.395 g | In tetrahydrofuran; water; at 40 - 50℃; | lg of <strong>[283173-50-2]Rucaparib</strong> base (3.09 mmol), prepared according to the process described in Example 5, was dissolved in 15 mL of THF/H20 mixture (2: 1) while heating at 40-50°C. To the clear solution of <strong>[283173-50-2]Rucaparib</strong> base, 1.42 g (2 eq) of citric acid dissolved in 5 mL of water, was added while stirring at 40-50°C. Clear reaction mixture was then cooled down and crystallization occurred while stirring in ice bath. Obtained suspension was stirred for 1 hour at 0-5°C. Crystals were filtered off under vacuum and analyzed by XRPD as Form I of <strong>[283173-50-2]Rucaparib</strong> Citrate. Obtained Form I of <strong>[283173-50-2]Rucaparib</strong> Citrate was dried in vacuum oven at 50°C for 4 hours to obtain 1.395 g of material that was analyzed by XRPD as Form II of <strong>[283173-50-2]Rucaparib</strong> Citrate. XRPD of <strong>[283173-50-2]Rucaparib</strong> Citrate Form I is given in Figure 12. XRPD of <strong>[283173-50-2]Rucaparib</strong> Citrate Form II is given in Figure 13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.07 g | In tetrahydrofuran; water; at 40 - 50℃; | lg of <strong>[283173-50-2]Rucaparib</strong> base (3.09 mmol), prepared according to the process described in Example 5, was dissolved in 15 mL of THF/H2O mixture (2: 1) while heating at 40-50°C. To the clear solution of <strong>[283173-50-2]Rucaparib</strong> base, 0.93 g (2 eq) of D-(-)- tartaric acid dissolved in 5 mL of water, was added while stirring at 40-50°C. Clear reaction mixture was then cooled down and crystallization occurred while stirring in ice bath. Obtained suspension was stirred for 1 hour at 0-5°C. Crystals were filtered off under vacuum and analyzed by XRPD as Form I of <strong>[283173-50-2]Rucaparib</strong> D-(-)-Tartrate. Wet crystals were dried in vacuum oven at 50°C for 4 hours to obtain 1.07 g of material, that was analyzed by XRPD as Form II of <strong>[283173-50-2]Rucaparib</strong> D-(-)-Tartrate. XRPD of <strong>[283173-50-2]Rucaparib</strong> D-(-)-Tartrate Form I is given in Figure 14. XRPD of <strong>[283173-50-2]Rucaparib</strong> D-(-)-Tartrate Form II is given in Figure 15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.81 g | In methanol; water; at 20℃; for 48h; | To the water/methanol (1/1.5) solution of <strong>[283173-50-2]Rucaparib</strong> base (27.5 mL; 7.7 mmol), prepared according to the process described in Example 4, solution of 1,2-ethanedisulfonic acid in water/methanol mixture (45 mL of following solution: 3.67 g of ethanedisulphonic acid dissolved in 35 mL of water and 10 mL of methanol) was added dropwise while stirring at ambient temperature. Thick suspension was stirred for 48 hours at ambient temperature, then at 0°C for 1 hour. Crystals were filtered off, washed with cold water and dried in vacuum oven at 50°C for 2 hours to obtain 1.81 g of <strong>[283173-50-2]Rucaparib</strong> Hemi- Edisylate salt, that was analyzed by XRPD as Form I. XRPD of <strong>[283173-50-2]Rucaparib</strong> Hemi-Edisylate Form I is given in Figure 16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.18 g | In methanol; water; at 20 - 35℃; | To the water/methanol (1/1.5) solution of <strong>[283173-50-2]Rucaparib</strong> base (27.5 mL; 7.7 mmol), prepared according to the process described in Example 4, solution of p-toluenesulphonic acid in water/methanol mixture (45 mL of following solution: 6.65 g of p- toluenesulfonic acid dissolved in 35 mL of water and 10 mL of methanol) was added dropwise while stirring at ambient temperature. Oily product was heated to 35°C, and crystallization occurred while cooling to ambient temperature. Obtained crystals were stirred at ambient temperature overnight. Crystals were filtered off, washed with water and dried in vacuum oven at 50°C for 2 hours to obtain 3.18 g of <strong>[283173-50-2]Rucaparib</strong> Tosylate salt that was analyzed by XRPD as Form I. XRPD of <strong>[283173-50-2]Rucaparib</strong> Tosylate Form I is given in Figure 17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.057 g | In tetrahydrofuran; water; at 40 - 50℃; | lg of <strong>[283173-50-2]Rucaparib</strong> base (3.09 mmol), prepared according to the process described in Example 5, was dissolved in 15 mL of THF/H20 mixture (2: 1) while heating at 40-50°C. To the clear solution of <strong>[283173-50-2]rucaparib</strong> base, 574muIota. (2 eq) of methanesulfonic acid, was added while stirring at 40-50°C. Clear reaction mixture was then cooled down and crystallization occurred while stirring at ambient temperature for 20 hours. Crystals were filtered off under vacuum and analyzed by XRPD as Form I of R<strong>[283173-50-2]rucaparib</strong> Mesylate. Wet crystals were dried in vacuum oven at 50°C for 4 hours to obtain 1.057g of <strong>[283173-50-2]Rucaparib</strong> Mesylate salt, that was analyzed by XRPD as Form II. XRPD of <strong>[283173-50-2]Rucaparib</strong> Mesylate Form I is given in Figure 18. XRPD of <strong>[283173-50-2]Rucaparib</strong> Mesylate Form II is given in Figure 19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.82 g | In tetrahydrofuran; water; at 40 - 50℃; | 4g of <strong>[283173-50-2]rucaparib</strong> base (12.36 mmol), prepared according to the process described in Example 5, was dissolved in 60 mL of THF/H20 mixture (2: 1) while heating at 40-50°C. To the clear filtered solution of <strong>[283173-50-2]rucaparib</strong> base, 3,72 g (2 eq) of L-(+)-tartaric acid dissolved in 15 mL of water, was added while stirring at 40-50°C. Clear reaction mixture was then cooled down and crystallization occurred while stirring at 20-25°C. Obtained suspension was additionally stirred for 1 hour at 0-5°C. Crystals were filtered off under vacuum, washed with 2*20 mL H20 and analyzed by XRPD as Form I of <strong>[283173-50-2]rucaparib</strong> L-(+)-tartarate. Wet crystals were dried in vacuum oven at 50°C for 4 hours to obtain 3.82 g of material that was analyzed by XRPD as Form II of <strong>[283173-50-2]rucaparib</strong> L-(+)-tartrate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.79 g | In ethanol; at 20 - 80℃; | 1 g (0.309 mmol) of <strong>[283173-50-2]Rucaparib</strong> free base was suspended at room temperature in 40 mL of 96percent EtOH. Reaction mixture was then heated to 75-80°C and clear yellow solution was obtained. 0.74 mL (0.927 mmol) of Ethanesulfonic acid was added dropwise. The reaction mixture was then slowly cooled down to 0-5°C. Solvent was partly removed under reduced pressure and crystallization occurred. Suspension was stirred at 0-5°C for 1.5 hour at 20- 25°C. Crystals were filtered off and dried in vacuum oven at 50°C/10 mbar for 3 hours to obtain 0.79 g of <strong>[283173-50-2]Rucaparib</strong> Esylate Form I. XRPD pattern is given in Figure 29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; acetone; at 30℃; for 1.5h; | 5.0 g of Rucaparib Phosphate Form III was suspended in 150 ml acetone:water mixture (1 :2). Suspension is heated up to 30°C and 1.05 eq of 20percent sodium hydroxide solution was gradually added. Suspension was stirred for 1.5 hour and then filtrated off. The obtained product was analyzed by XRD, indicating that Form I was obtained. Product was further dried at 40- 60°C under vacuum until constant mass. The dried product was analyzed by XRD, indicating that Form II was obtained. The XRD pattern is presented in Figure 35. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.82 g | With bis(acetato)bis(triphenylphosphine)palladium(0); sodium carbonate; In methanol; water; at 60℃; for 4h;Inert atmosphere; | 2-Bromo-8-fluoro-4,5-dihydro-lH-azepino[5,4,3-cd]indol-6(3H)-one (10 g; 35.3 mmol), prepared according to process described in Example 3, sodium carbonate (3.74 g; 35.3 mmol), bis(triphenylphosphine)palladium(II) diacetate (0.529 g; 0.71 mmol) and (4-((methylamino)methyl)phenyl)boronic acid solution (75 ml; 45.9 mmol), prepared according to process described in Example 2, are charged into a three-necked round bottom flask, followed by inertisation with nitrogen. A previously degassed mixture of methanol (130 mL) and water (40 mL) is added and the reaction mixture is stirred at 60°C for 4 hours. The reaction mixture is cooled to ambient temperature followed by addition of activated carbon. The mixture is stirred at ambient temperature for one hour, heated to 50 °C, stirred for another hour and then filtered through a layer of celite. The solution of 8-fluoro-2-(4- ((methylamino)methyl)phenyl)-4,5-dihydro-lH-azepino[5,4,3-cd]indol-6(3H)-one is concentrated to about 110 mL, heated to 40°C followed by dropwise addition of water (40 mL). Reaction mixture is cooled to ambient temperature and stirred for 17 hours at ambient temperature and additional one hour at 0-5°C. Solid is filtered off, washed with water and dried in vacuum oven at 50°C for 5 hours. Crude material (9.5 g) is suspended in methanol (95mL) at reflux temperature and stirred for 20 minutes. Suspension is than cooled down and stirred for 17 hours at ambient temperature and 1.5 hour at 0-5°C. Crystals are filtered off, washed with methanol and dried in vacuum oven at 50°C for 4 hours to obtain 6.82 g of Rucaparib base. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With GLUTATHIONE; In aq. buffer; at 37℃; | General procedure: To (2S)-2-amino-5-[[(lR)-2-(carboxymethylamino)-2-oxo-l-(sulfanylmethyl)ethyl] amino]-5-oxo-pentanoic acid (4.90 mg, 0.0159 mmol) was added 2 mL of 1M Tris HC1 buffer (pH 7.0) to create an 8 mM solution. An aliquot of 1 mL of this solution was added to Example 3 (0.400 mg, 9.8lxl05mmol) to create a 100 mM solution. This mixture was heated at 37 C with time points taken at 15 minute intervals to measure for conjugate integrity. A steady loss of conjugate is observed with commensurate appearance of 2-[4- (hydroxymethyl)phenyl]-l~{H}-benzimidazole-4-carboxamide. The cleavage was complete by the 60 min time point as observed/confirmed by MSD. HPLC conditions: ES Industries Sonoma 4.6x50 mm; 5-100% CH3CN/H2O (0.1% TFA); 5.5 min run Conjugate RT: 3.71 Product RT: 2.24. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
734 mg | With hydrogenchloride; 5%-palladium/activated carbon; hydrogen; In methanol; water; at 20℃; for 18h; | A suspension of 9 - b ro mo - 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-l,3,4,5- tetrahydro-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one (1.61 g, 89% AUC at 254 nm) in MeOH (80 mL) was heated to reflux for ~5 min. until a solution was obtained. Solution was allowed to cool to room temperature over 30 min. before 5% Pd/Carbon (Degussa type E101 NO/W, 800 mg) and concentrated HC1 (1.00 mL, 12 mmol) was added. Hydrogen gas (~ 3 - 5 L) was bubbled through the reaction before it was allowed to vigorously stir at room temperature under an atmosphere of hydrogen for 18 h. Nitrogen (~ 3 - 5 L) was bubbled through the reaction before it was filtered through celite under an inverse funnel of nitrogen. The celite was rinsed with 200 mL of MeOH and NEh (7 mL) was added to the mother liquor obtained before it was concentrated in vacuo. The residue (3.6 g) was dissolved in MeOH and split into 3 equal batches that were independently concentrated in vacuo and chromatographed on a Cl 8 reverse phase column (50 g Isco gold column, 5% MeOH in water for 1 min., then 5% to 100% MeOH in water over 12.5 min.) to give 734 mg of rucaparib as an off white solid.1H NMR (400MHz, DMSO-d6) d = 11.78 (s, 1H), 8.27 (t, =5.8 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.65 - 7.60 (m, 2H), 7.44 (dd, J=2A, 11.0 Hz, 1H), 7.35 (dd, J=2A, 9.1 Hz, 1H), 4.10 (s, 2H), 3.43 - 3.37 (m, 2H), 3.09 - 3.02 (m, 2H), 2.54 (s, 3H).19L NMR (376MHz, DMSO-d6) d = -120.95 (dd, J=92, 10.9 Hz, 1L LC/MS RT = 0.14 min., 324.2 [M+H]+, 322.2 [M-H] , (0158) HPLC RT = 3.586 min., 96.6218 % at 254 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane; water; at 30℃; for 5h; | <strong>[283173-50-2]Rucaparib</strong> base (0.1 g) and DL-10-camphorsulfonic acid (0.072 g) were dissolved in a 1,2-dimethoxy ethane and water mixture (1:1; 3 mL) at 30 C. The clear reaction mass was filtered to remove the undissolved particulates and stirred at 30 C. for 5 h. The resulting product was filtered, washed with isopropyl ether (1 mL) and dried at 40 C. under vacuum for 3 h. The resulting product was identified as crystalline <strong>[283173-50-2]rucaparib</strong> camsylate salt Form beta. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In methanol; water; at 0 - 5℃; for 12h; | Rucaparib hydrochloride was added in solution containing 40% sodium hydroxide solution (100 ml) in water (500 mL), methanol and 300 mL process water at 0-5 C. The reaction mass was stirred for 12 hours at 0-5 C. After completion of salt formation, the solid was filtered, washed with water (200 ml). The material was dried at 50-55 C. to afford rucaparib camsylate free base (Formula III). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.4% | With palladium on activated charcoal; hydrogen; In ethanol; ethyl acetate; at 20℃; for 2h; | 4-(8-Fluoro-6-oxo-3,4,5,6-tetrahydro-1H-aza-[5,4,3-cd]indol-2-yl)benzyl (methyl) BenzyloxycarbonylThe ester (Vb) (39g) was dissolved in a mixed solvent of ethyl acetate (117 mL) and ethanol (78 mL), replaced with nitrogen three times, and palladium on carbon was added.(3.9 g, 5% w/w), hydrogen was introduced, and after replacing three times, the reaction was carried out at room temperature for 2 hours at room temperature. After the reaction is completed, it is removed by filtration.Palladium carbon, concentrated at least,Crystallization from tetrahydrofuran and n-heptane afforded a white solid, 24.1 gg, yield: 87.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.8% | With palladium on activated charcoal; hydrogen; In tetrahydrofuran; ethanol; at 20℃; for 2h; | 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-aza-[5,4,3-cd]indol-2-yl)benzyl (methyl)benzylamine(Vc) (42g) was dissolved in a mixed solvent of tetrahydrofuran (126 mL) and ethanol (84 mL), replaced with nitrogen three times, and added with palladium on carbon(4.2g, 5% w/w), after passing hydrogen, after replacing 3 times,The reaction was carried out at room temperature for 2 hours at room temperature. After the reaction is completed, it is removed by filtration.Palladium carbon, the filtrate was concentrated at least in an amount, and recrystallized from toluene and n-heptane to give a white solid, 27.6 g, yield: 86.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.2 g | With sodium hydroxide; In methanol; water; at 15 - 30℃; for 1h; | 0.43 g of sodium hydroxide dissolved in a mixture of 42 mL of water and 16.5 mL of methanol at 25+5C and then cooled to l5+5C, to this was added 3 g of Rucaparib S-Camsylate salt for 10 min. Further, 42 mL of water was added to the reaction suspension and stirred for lh at 20+5C. The reaction mass was filtered and dried under vacuum at 50 C for 2 h. The product obtained was identified as Rucaparib form ML Yield: 2.2 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.1 g | With ammonium hydroxide; at 50 - 55℃; for 6h; | Add 300 g of acetonitrile to a 500 ml stainless steel autoclave,32.5 g (0.05 mol) 2- [1- (4-N-methyl-N-benzylaminomethyl) benzoyl-3-p-toluenesulfonate] n-propyl-3-nitro Methyl-5-fluorobenzoate (Compound V1, prepared from Example 1), 1.0 g of 10% palladium-carbon catalyst, after nitrogen substitution for three times, hydrogen gas was passed in, maintaining the hydrogen pressure at 0.1-0.2 MPa, and reaction at 20-25 C 5 hours. Replaced with nitrogen three times, filtered to remove palladium on carbon, transferred the filtrate to a four-necked flask, added 15 g of 17% ammonia water, reacted at 50-55 C for 6 hours, cooled to 10-15 C, filtered, washed with 20 g of acetonitrile, and dried to obtain 15.1 g of rucaparib(I), yield 93.2%, liquid phase purity 99.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.3 g | With ammonia; In acetonitrile; at 55 - 60℃; for 5h; | Add 300 g of acetonitrile to a 500 ml stainless steel autoclave, 33.2 g (0.05 mole)2- [1- (4-N-methyl-N-benzylaminomethyl) benzoyl-3-benzenesulfonate] n-propyl-3-nitro-5-fluorobenzoate ( Compound V1, prepared from Example 2),1.0 g of a 10% palladium-carbon catalyst was replaced with nitrogen three times, and then hydrogen gas was passed in, keeping the hydrogen pressure at 0.1-0.2 MPa, and reacting at 20-25 C for 5 hours.Replaced with nitrogen three times, filtered to remove palladium carbon, transferred the filtrate to a four-necked flask, added 20 g of 10% ammonia acetonitrile solution, reacted at 55-60 C for 5 hours, cooled to 10-15 C, filtered, washed with 20 g of acetonitrile, and dried 15.3 g of rucaparib(I) was obtained with a yield of 94.6% and a liquid phase purity of 99.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With pentamethylcyclopentadienyl(benzene)cobalt(III) hexafluorophosphate; potassium carbonate; silver carbonate In 2-methyltetrahydrofuran at 100℃; for 16h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With trifluoroacetic acid at 100℃; for 24h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: Rucaparib; methyl 4-formylbutanoate With sodium tris(acetoxy)borohydride In dichloromethane at 23℃; for 1h; Inert atmosphere; Stage #2: With water; lithium hydroxide In tetrahydrofuran at 23℃; for 2h; | 4.1 Step 1. Synthesis of C5-carboxylylrucaparib (7) To a solution of rucaparib (10.0 mg, 31.0 pmol, 1 equiv) and sodium triacetoxyborohydride (328 mg, 1.55 mmol, 50 equiv) in methylene chloride (3 mL) was added methyl 5-oxo- pentanoate (20.2 mg, 155 pmol, 5 equiv) under argon. After stirring at 23 °C for 1 h, the mixture was washed with saturated sodium bicarbonate solution followed by brine, dried with anhydrous sodium sulfate, concentrated, and re-dissolved in tetrahydrofuran (0.5 mL). Aqueous lithium hydroxide solution (2M) was then added the reaction was stirred at 23 °C for 2 h before acidified, concentrated, and purified by reversal phase HPLC to give 7 as a white solid (7.0 mg, 54% yield). NMR (400 MHz, CDiOD) d 7.70 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.52 (dd, J = 10.8, 2.2 Hz, 1H), 7.31 (dd, J= 9.0, 2.2 Hz, 1H), 4.49 (d, J = 11.6 Hz, 1H), 4.29 (d , J = 11.6 Hz, 1H), 3.52 (d, .7 = 4.2 Hz, 2H), 3.28-3.10 (m, 4H), 2.40 (t, J = 7.1 Hz, 2H), 1.94-1.76 (m, 2H), 1.74-1.58 (m, 2H); 13C NMR (101 MHz, CD3OD) d 176.7, 172.4, 160.8 (d, J= 236.7 Hz), 138.7(d, J= 12.2 Hz), 136.1 (d, .7= 3.4 Hz), 135.1, 132.7, 130.0, 129.7, 126.2 (d, J = 8.9 Hz), 124.8, 114.0, 111.6 (d, J = 26.3 Hz), 102.4 (d, J = 26.3 Hz), 60.5, 56.8, 43.7, 40.0, 33.9, 30.0, 24.7, 22.8; 19F NMR (376 MHz, CD3OD) d -121.42; MS (ESI)+ calculated for C24H27FN3O3 (M+H)+ 424.2, found 424.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium tris(acetoxy)borohydride In dichloromethane at 0 - 23℃; for 2h; | 4.3 Step 3. Synthesis of rucaparib-PEG5-pomalidomide (9a) To a solution of rucaparib (5.0 mg, 15.4 pmol, 1.0 equiv) and l ie (10.0 mg, 18.6 pmol, 1.2 equiv) in methylene chloride (1 mL) was added sodium triacetoxyborohydride (163.9 mg, 773.1 pmol, 50.0 equiv) at 0 °C. After stirring at 23 °C for 2 h, the mixture was washed with saturated sodium bicarbonate solution followed by brine, dried with anhydrous sodium sulfate, concentrated, and purified by HPLC to 9a as a yellow solid (11.7 mg, 90% yield). NMR (400 MHz, CD3OD, selected signals) d 7.72 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.52 (dd, J = 10.8, 2.2 Hz, 1H), 7.49-7.43 (m, 1H), 7.31 (dd, J = 8.9, 2.2 Hz, 1H), 6.99 (d, J= 3.6 Hz, 1H), 6.97 (d, .7= 5.2 Hz, 1H), 5.02 (dd, J= 12.7, 5.5 Hz, 1H), 4.54 (d , J= 13.0 Hz, 1H), 4.35 (d, J = 12.9 Hz, 1H), 3.86 (t, J = 4.9 Hz, 2H); 19F NMR (376 MHz, CD3OD) d -121.5; MS (ESI)+ calculated for C44H52FN6O10 (M+H)+ 843.4, found 843.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium tris(acetoxy)borohydride In dichloromethane at 23℃; for 1h; Inert atmosphere; | 4.1 Step 1. Synthesis of C6-alkynylrucaparib (2) To a solution of rucaparib (10.0 mg, 31.0 pmol, 1 equiv) and sodium triacetoxyborohydride (328 mg, 1.55 mmol, 50 equiv) in methylene chloride (3 mL) was added 5-hexynal (14.9 mg, 155 pmol, 5 equiv) under argon. After stirring at 23 °C for 1 h, the mixture was washed with saturated sodium bicarbonate solution followed by brine, dried with anhydrous sodium sulfate, concentrated, and purified by silica gel flash column chromatography to give 2 (11.4 mg, 74% yield) as a white solid. NMR (400 MHz, CDCb) d 8.49 (br, 1H), 7.74 (dd, J = 10.7, 2.1 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.23 (dd, J = 10.7, 2.1 Hz, 1H), 6.59 (t, J= 5.8 Hz, 1H), 3.62-3.55 (m, 2H), 3.54 (s, 2H), 3.17-3.15 (m, 2H), 2.42 (t, J= 7.0 Hz, 2H), 2.22 (s, 3H), 2.22-2.19 (m, 2H), 1.95 (t, J= 2.5 Hz, 1H), 1.69-1.62 (m, 2H), 1.61-1.54 (m, 2H); 13C NMR (101 MHz, CDCb) d 170.4, 159.6 (d, J = 238.6 Hz), 139.6, 136.6 (d, J = 11.9 Hz), 135.5 (d, J = 3.5 Hz), 130.5, 129.7, 127.8, 125.2 (d, J = 8.9 Hz), 123.9, 112.4, 111.9 (d, J= 25.9 Hz), 101.4 (d, J= 26.4 Hz), 84.6, 68.6, 62.1, 56.9, 43.2, 42.3, 29.0, 26.5, 26.4, 18.4; 19F NMR (376 MHz, CDCb) d -119.9; MS (ESI)+ calculated for C25H27FN3O (M+H)+ 404.2, found 404.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 23℃; for 0.5h; | 4 To a solution of rucaparib (20.0 mg, 62.0 pmol, 1 equiv) in methylene chloride (0.6 mL) was added di-/er/-butyl dicarbonate (16.2 mg, 74.2 pmol, 1.2 equiv) and Hiinig’s base (12.0 mg 92.8 pmol, 1.5 equiv). After stirring at 23 °C for 30 min, the mixture was washed with saturated sodium bicarbonate solution followed by brine, dried with anhydrous sodium sulfate, concentrated, and purified by silica gel flash column chromatography to give 13 (23.3 mg, 89% yield). NMR (400 MHz, CD3OD) d 7.57 (d, J = 8.0 Hz, 2H), 7.50 (dd, J = 10.8, 2.3 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.28 (dd, J= 9.0, 2.3 Hz, 1H), 4.48 (s, 2H), 3.51 (d, J = 4.6 Hz, 2H), 3.17-3.05 (m, 2H), 2.85 (s, 3H), 1.48 (d , J= 10.4 Hz, 9H); 13C NMR (101 MHz, CD3OD) d 171.1, 171.1, 159.1 (d, J = 235.9 Hz), 137.1 (d, J = 12.0 Hz), 135.8 (d, J = 3.4 Hz), 131.0, 127.9, 127.4 (d, = 18.0 Hz), 124.3 (d, .7 = 8.9 Hz), 123.6, 111.5, 109.8 (d, = 26.2 Hz), 100.9(d, J = 26.3 Hz), 79.9, 51.9, 42.4, 33.2, 28.5, 27.3; MS (ESI)+ calculated for C24H27FN3O3 (M+H)+ 424.2, found 424.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With diphenylether; trifluoroacetic acid at 100℃; for 24h; | 1-v I-V: Compound Ig (599.3 mg, 1 mmol), trifluoroacetic acid (2 mL) and phenyl ether (0.2 mL) were added to the reaction tube, and the system was heated to 100° C. to react for 24 hours. After the reaction, the solvent was removed under reduced pressure, diluted with 2M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and a white solid was obtained by column chromatography. Compound I Rucaparib (0.28 g, 0.88 mmol, 88%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: Rucaparib; (3aR,6aS)-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate With zinc(II) chloride In tetrahydrofuran at 55℃; for 1h; Stage #2: With sodium cyanoborohydride In tetrahydrofuran | 39.1 tert-butyl(3aR,6aS)-5-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate The raw material 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2] Benzazepine-6-one (34A) (240mg, 0.743mmol) was dissolved in a mixed solvent of 8mL methanol and 2mL tetrahydrofuran, and (3aR, 6aS)-5-oxahydrocyclopenta[c]pyrrole-2( 1H)-tert-butyl carboxylate (270 mg, 1.2 mmol), anhydrous zinc chloride (545 mg, 4 mmol), stirred at 55°C for 1 h, sodium cyanoborohydride (188 mg, 3 mmol) was added, and the reaction was continued overnight. After the reaction, it was cooled to room temperature, and 50 mL of dichloromethane and 20 mL of water were added for extraction. The organic phase was dried with anhydrous sodium sulfate and concentrated. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10:1-5:1) to obtain the title compound (39A) (200mg, yield 49%) as a yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; for 2h; | 34 2-(2,6-dioxopiperidin-3-yl)-5-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd ]indol-2-yl)benzyl)(methyl)amino)isoindoline-1,3-dione 8-Fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2]benzazepine-6-one (34A) (120mg, 0.372mmol),2-(2,6-dioxo-3-piperidinyl)-5-fluorodihydroisoindole-1,3-dione (114mg, 0.412mmol) was dissolved in 2mL DMSO,Add N,N-diisopropylethylamine (222mg, 1.72mmol), and react at 90°C for 2 hours after the addition is complete.After the reaction, cool to room temperature, add 10 mL of water, filter, dissolve the filter cake with 20 mL of dichloromethane, wash with 5 mL of saturated sodium chloride, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude silica gel column purification, eluent : DCM-2% MeOH/DCM-5% MeOH/DCM, the crude product was obtained and then sent to liquid phase preparation to obtain compound 34 as a yellow solid (100 mg, 46%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.9% | Stage #1: tert-butyl 3-oxoazetidine-1-carboxylate; Rucaparib With zinc(II) chloride In tetrahydrofuran at 55℃; for 1h; Stage #2: With sodium cyanoborohydride In tetrahydrofuran | 35.1 tert-butyl 3-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl )amino)azetidine-1-carboxylate The raw material 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2] Benzazepine-6-one (34A) (240mg, 0.743mmol) was dissolved in a mixed solvent of 8mL methanol and 2mL tetrahydrofuran, and 1-Boc-3-azetidinone (205mg, 1.2mmol) was added, anhydrous Zinc chloride (545 mg, 4 mmol) was stirred at 55° C. for 1 h, sodium cyanoborohydride (188 mg, 3 mmol) was added, and the reaction was continued overnight. After the reaction, it was cooled to room temperature, and 50 mL of dichloromethane and 20 mL of water were added for extraction. The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain the crude title compound (35A) as a yellow solid (220 mg, yield 61.9%), which was directly used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: Rucaparib; N-tert-butyloxycarbonylpiperidin-4-one With zinc(II) chloride In tetrahydrofuran at 55℃; for 1h; Stage #2: With sodium cyanoborohydride In tetrahydrofuran | 37.1 tert-butyl4-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino) piperidine-1-carboxylate The 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2]benzazepine-6-one (34A)(320mg, 1mmol) dissolved in 10mL N,N-dimethylacetamide,Add N-Boc-piperidone (239mg, 1.2mmol),Anhydrous zinc chloride (545 mg, 4 mmol) was stirred at 55° C. for 1 h, sodium cyanoborohydride (188 mg, 3 mmol) was added, and the reaction was continued overnight.After the reaction, it was cooled to room temperature, and 50 mL of dichloromethane and 20 mL of water were added for extraction. The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a yellow solid. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10:1-5:1) to obtain the title compound as a yellow solid (37A ) (240 mg, yield 48%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: Rucaparib; tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate With zinc(II) chloride In tetrahydrofuran at 55℃; for 1h; Stage #2: With sodium cyanoborohydride In tetrahydrofuran | 38.1 tert-butyl 2-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl )amino)-7-azaspiro[3.5]nonane-7-carboxylate The raw material 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2] Benzazepine-6-one (34A) (240mg,0.743mmol) dissolved in a mixed solvent of 8mL methanol and 2mL tetrahydrofuran,Add tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (286mg, 1.2mmol),Anhydrous zinc chloride (545mg, 4mmol), stirring at 55°C for 1h,Sodium cyanoborohydride (188mg, 3mmol) was added, and the reaction was continued overnight. After the reaction, it was cooled to room temperature, and 50 mL of dichloromethane and 20 mL of water were added for extraction. The organic phase was dried with anhydrous sodium sulfate and concentrated. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10:1-5:1) to obtain the title compound as a yellow solid (38A) (150 mg, yield 38%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With tris-(dibenzylideneacetone)dipalladium(0); copper(II) nitrate trihydrate; caesium carbonate In N,N-dimethyl acetamide at 160℃; for 24h; Inert atmosphere; regiospecific reaction; | 8-Fluoro-2-{4-[(methylamino)methyl]phenyl}-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6-one (Rucaparib) (Scheme 2) [CAS Reg.No. 283173-50-2] 8-Fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6-one (51.1 mg, 0.25 mmol), Cs2CO3 (162.9 mg, 0.50 mmol), Pd2dba3 (2.88 mg, 0.0032 mmol), and Cu(NO3)2·3H2O (9.08 mg, 0.075 mmol) was weighed in a glass vial under ambient atmosphere. DMA was added to obtain a total volume of 5 mL. 4-Bromo-N-methylbenzylamine (100.0 μL, 0.50mmol) was volumetrically injected into the reaction mixture. The reaction proceeded at 160 °C under magnetic stirring. After 24 h, the resulting product mixture was quenched with sat. aq NaHCO3 (50 mL), followed by extraction with EtOAc (3 × 50 mL). The crude product mixture was dried (anhyd Na2SO4) and filtered. The solvent was evaporated, and the product was purified via column chromatography (DCM-MeOH 95:5, Rf = 0.4). The silica gel column was eluted with 1 vol% of TEA prior to the separation; yield: 57.3 mg (71%); whitish solid; mp 171-173 °C; Rf = 0.4 (DCM-MeOH 95:5). IR (KBr): 3460, 3176, 3033, 2423, 1651, 1606, 1516, 1466, 1412, 1350,1209, 1105, 787, 609 cm-1. 1H NMR (400 MHz, DMSO-d6): = 2.31 (s, 3 H, CH3), 2.99 (m, 2 H,CH2), 3.46 (m, 2 H, CH2), 3.73 (s, 2 H, CH2), 7.44-7.56 (m, 5 H), 7.61 (s,1 H), 8.33 (t, J = 5.8 Hz, 1 H, CONH). 13C NMR (400 MHz, DMSO-d6): = 28.2, 36.1, 42.1, 54.9, 100.7, 100.9,110.9, 111.1, 117.0, 123.5, 124.0, 127.5, 129.9, 130.6, 136.3, 137.3,158.2, 160.4, 168.3. 19F NMR (400 MHz, DMSO-d6): = -119.9. MS (ES+): m/z (%) = 293.1 (100), 324.2 (23). HRMS: m/z [M + H]+ calcd for C19H19FN3O: 324.1512; found:324.1504. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
239 mg | With trifluoroacetic acid In dichloromethane at 20℃; Inert atmosphere; | |
236 mg | With trifluoroacetic acid In dichloromethane at 20℃; | 4-1 After dissolving the mixture of compound 8 in dichloromethane (10 mL),After adding trifluoroacetic acid (TFA; 1.6 mL, 20 mmol) to the mixed solution at 20° C., the progress of the reaction was observed by TLC while stirring.After complete consumption of compound 8, the reaction mixture was concentrated,dichloromethane,A mixed solution of methanol and triethylamine (90:10:1) was separated and purified by silica-based column chromatography as an eluent to obtain rucaparib 1 (236 mg, 0.73 mmol, 73% yield in the second step) as a white solid. |
236 mg | With trifluoroacetic acid In dichloromethane at 20℃; Inert atmosphere; | 4-1 After dissolving the mixture of compound 8 in dichloromethane (10 mL),After adding trifluoroacetic acid (TFA; 1.6 mL, 20 mmol) to the mixed solution at 20° C., the progress of the reaction was observed by TLC while stirring.After complete consumption of compound 8, the reaction mixture was concentrated,dichloromethane,A mixed solution of methanol and triethylamine (90:10:1) was separated and purified by silica-based column chromatography as an eluent to obtain rucaparib 1 (236 mg, 0.73 mmol, 73% yield in the second step) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium tris(acetoxy)borohydride In methanol at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98 % | With methoxybenzene; trifluoroacetic acid at 100℃; | |
98 % | With methoxybenzene; trifluoroacetic acid at 100℃; | 4.4-2 Preparation of rucaparib (Compound 1) After dissolving compound 12 (270 mg, 0.5 mmol) in a mixed solution of trifluoroacetic acid and anisole (10:1, 5.0 mL), the progress of the reaction was observed by TLC while stirring at 100°C.After complete consumption of compound 12, the reaction mixture was concentrated, separated and purified by silica-based column chromatography using a mixed solution (90:10:1) of dichloromethane, methanol and triethylamine as an eluent to obtain a white solid. Lucaparib (Compound 1) (160 mg, 0.49 mmol, 98%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In methanol at 60℃; | ||
260 mg | With triethylamine In methanol at 20 - 60℃; | 4-2 After dissolving the mixture of compound 7 in methanol (10 mL),After adding triethylamine (0.14 mL, 1.0 mmol) at 20 °C, the progress of the reaction was observed by TLC while stirring at 60 °C.After complete consumption of compound 7, the reaction mixture was concentrated,dichloromethane,It was separated and purified by silica-based column chromatography using a mixture of methanol and triethylamine (90:10:1) as an eluent to obtain rucaparib 1 (260 mg, 0.80 mmol, 80% yield in 3 steps) as a white solid. |
260 mg | With triethylamine In methanol at 60℃; Inert atmosphere; | 4-2 After dissolving the mixture of compound 7 in methanol (10 mL),After adding triethylamine (0.14 mL, 1.0 mmol) at 20 °C, the progress of the reaction was observed by TLC while stirring at 60 °C.After complete consumption of compound 7, the reaction mixture was concentrated,dichloromethane,It was separated and purified by silica-based column chromatography using a mixture of methanol and triethylamine (90:10:1) as an eluent to obtain rucaparib 1 (260 mg, 0.80 mmol, 80% yield in 3 steps) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 20℃; | 2.4. Preparation of Ruc-Thp MH cocrystal Bulk powders of Ruc-Thp MH were prepared by liquid-assistedgrinding method using an XM-2017S oscillatory ball mill (ShanghaiJingxin Industrial Development Co., ltd., Shanghai, China) with stainlesssteel grinding jars (50 mL). Approximately 0.5 mL of ethanol was addedto a mixture of Ruc MH and Thp with a molar ratio of 1:1 (Ruc MH, 2mmol, 682.7 mg, and Thp, 2 mmol, 360.3 mg), and the materials wereground at a frequency of 40 Hz during two periods of 10 min with aninterruption time of 1 min. The resulting materials were determinedusing powder X-ray diffraction (PXRD) and then air-dried for standby.The drug was stable when ground for 20 min to prepare Ruc-Thp MHcocrystal, which was verified by high-performance liquid chromatography(HPLC). Ruc MH (10 mg) and Thp (10.6 mg) were added to 1 mLof ethanol and slurried overnight at room temperature. The excessivesolids were then removed by centrifugation. After a week, yellow bulkcrystals of Ruc-Thp MH were harvested by slow evaporation of ethanolat ambient conditions. |
A424427[ 459868-92-9 ]
8-Fluoro-2-(4-((methylamino)methyl)phenyl)-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6(3H)-one phosphate
Reason: Free-salt
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :