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. : | 147-94-4 | MDL No. : | MFCD00066487 |
Formula : | C9H13N3O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UHDGCWIWMRVCDJ-CCXZUQQUSA-N |
M.W : | 243.22 | Pubchem ID : | 6253 |
Synonyms : |
Cytosine β-D-arabinofuranoside;Cytosine Arabinoside;U-19920A;NSC 287459;NSC 63878;1-β-D-Arabinofuranosylcytosine;Ara-C
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335-H351-H361 | 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 |
---|---|---|
96% | With hydrogenchloride In methanol at 2 - 25℃; for 4 h; | An oven- dried 250 mL round bottom flask equipped with a magnetic stir bar was charged with 3.35 g of cytarabine-HCl and 6.0 mL of DMPU. Into this flask the reaction mixture from example 12 was filtered directly and the DABCO-HCl salt was washed quickly with acetonitrile (1.x.15 mL). Volatiles were removed on a rotary-evaporator under aspirator vacuum (bath temp <35° C.). The residual oil was briefly kept under high vacuum and stirred at room temperature for 48 h. The reaction mixture was treated with 100 mL of MeOH and stirred for 2 hours at room temperature. The pH of the reaction mixture was adjusted to 7.0 using 25 wt percent NaOMe solution in methanol (approximately 13 mL were required). At this stage the reaction mixture was turbid. HPLC was run to insure integrity of the reaction profile. The reaction mixture was evaporated to dryness and the residue was stirred with 50 mL of dichloromethane for 30 minutes at room temperature. The precipitate was collected by filtration, washed with methylene chloride (1.x.20 mL) and transferred back to the flask, stirred again with 50 mL of dichloromethane for 15 minutes and filtered. The solid was stirred with 200 mL of ethanol for 1-2 hours, filtered and washed with ethanol (2.x.10 mL). The filtrate was evaporated to dryness to give 4.90 g of a white solid. This solid was dissolved in 10 mL of H2O and stirred at room temperature overnight to give a solid which was collected by filtration, washed with water (2.x.3 mL) and dried in a vacuum oven to give compound 9, 1.38 g, (26percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In ethanol; water; | EXAMPLE 2 <strong>[10212-25-6]2,2'-O-<strong>[10212-25-6]cyclocytidine hydrochloride</strong></strong> (6.5 g) was dissolved in 35 mL water at 80 C. The solution was cooled to room temperature and t-butylarnine (2.8 g) was added and the mixture stirred for 2 hours. Thereafter, the solvent was evaporated under vacuum and ethanol (16 g) was added. The mixture was stirred at room temperature for 12 hours. Filtration of the resulting precipitation yielded 5 g of pure cytarabine after drying, which corresponds to a yield of 83%. The product was characterized by comparison of its melting point, and NMR and IR spectra with those previously reported for cytarabine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With ammonia at 25℃; | |
With ammonia for 16h; Ambient temperature; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide Ambient temperature; | |
85% | In N,N-dimethyl-formamide at 20℃; | 11 Ara-C (500 mg, 2.05 mmol) in DMF (10 mL) was reacted with N-(dimethoxy methyl)piperidine (2.7 g, 16.8 mmol) for several hours at room temperature. The contents were evaporated and the residue chromoatographed over silica gel using 1-6% MeOH in CH2Cl2. The desired fractions were collected and evaporated. The foam obtained was recrystallized from a mixture of ethanol, CH2Cl2, and ethyl acetate to give N4-[Piperidinomethylene]arabinocytidine (594 mg, 85%). This procedure is taken from Kerr et al., J. Pharm. Sci. 83(4): 582-586 (1994). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In N,N-dimethyl-formamide for 8h; Ambient temperature; | |
90% | In N,N-dimethyl-formamide | 7 Ara-C (500 mg, 2.05 mmol) in DMF (2 mL) was reacted with diethylformamide dimethyl acetal (2.16 g, 14.7 mmol). After evaporation, the recrystallization of the residue from a variety of solvents proved difficult. The residue was finally crystallized from a solution of 4% MeOH in CH2Cl2, to give N4-[(Diethylamino)methylene]arabinocytidine as fine colorless, whitish crystals (601 mg, 90%). This procedure is taken from Kerr et al., J. Pharm. Sci. 83(4): 582-586 (1994). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In N,N-dimethyl-formamide for 8h; Ambient temperature; | |
93% | In N,N-dimethyl-formamide | 10 Ara-C (500 mg, 2.05 mmol) in DMF (10 mL) was reacted with diisopropylformamide dimethyl acetal (2.3 g, 13.2 mmol). After evaporation, the residue was crystallized from ethanol-ether to give pale lemon-colored crystals of N4-[(Diisopropylamino)methylene]arabinocytidine (723 mg, 93%). This procedure is taken from Kerr et al., J. Pharm. Sci. 83(4): 582-586 (1994). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide for 8h; Ambient temperature; | |
85% | In N,N-dimethyl-formamide | 8 Ara-C (85 mg, 0.35 mmol) in DMF (2 mL) was reacted with dipropylformamide dimethyl acetal (0.9 g, 5.14 mmol). Evaporation and crystallization from ethanol-ethyl acetate gave N4-[(Dipropylamino)methylene]arabinocytidine (104 mg, 85%). This procedure is taken from Kerr et al., J. Pharm. Sci. 83(4): 582-586 (1994). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In pyridine for 1h; Ambient temperature; | |
90% | With pyridine at 20℃; for 4h; | |
70% | With pyridine at 25℃; for 2h; | 470 Preparative Example 470:1 ,3-dichloro-i ,1 ,3,3-tetraisopropyl-disiloxane (1.70 mL, 5.50 mmol) was added to a solution of the starting material (1.22 g, 5.00 mmol) in anhydrous pyridine (20 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h, evaporated and the residue was partitioned between H2O (100 mL) and CH2Cl2 (50 mL). The aqueous part was extracted with CH2Cl2 (2x50 mL) and the combined extracts were dried over MgSO4, filtered, the solvent was evaporated and then PhCH3 (2x100 mL) was added to the residue and it was evaporated . The residue was purified by chromatography on silica gel with 15:1 CHgCl2ZMeOH as eluent. 1.70 g (70 %) of the product was obtained as white solid. MH+ = 486. |
In pyridine for 3h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyridine In N,N-dimethyl-formamide at -5℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With phospholipase D from Streptomyces sp. AA 586 In chloroform; water at 45℃; for 6h; sodium acetate buffer, CaCl2, pH=5.8; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With CaCl2 buffer; sodium acetate; acetic acid In chloroform at 30℃; for 4h; phospholipase D from Streptomyces sp., pH 6.5; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In hydrogenchloride; chloroform at 45℃; for 6h; pH 4.5; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In hydrogenchloride; chloroform at 45℃; for 6h; pH 4.5; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In N,N-dimethyl-formamide for 8h; Ambient temperature; | |
89% | In N,N-dimethyl-formamide | 13 Ara-C (100 mg, 0.41 mmol) in DMF (5 mL) was reacted with N-(dimethoxymethyl)pyrrolidine (0.9 g, 6.2 mmol). Evaporation and subsequent crystallization from ethyl acetate-ether gave N4-[Pyrrolidinomethylene]arabinocytidine (119 mg, 89%). This procedure is taken from Kerr et al., J. Pharm. Sci. 83(4): 582-586 (1994). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 3-picoline-N-oxide; silver nitrate In tetrahydrofuran for 2h; Ambient temperature; | |
92% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 14h; | |
With 1H-imidazole In N,N-dimethyl-formamide; toluene at -5 - 5℃; | 1.1 Synthesis of compound 2 Commercial cytarabine (400g, 1.65mol, 1.0equiv) and imidazole (4.1mol) were added to anhydrous DMF (3.6L, 9vol), the reaction system was reduced to -5 to 5 ° C, and then 50% wt tert A toluene solution of butyldimethylchlorosilane (3.54 mol) was reacted at 5 to 15 ° C for 15 to 20 hours. 15% sodium chloride solution (8vol) was added to quench the reaction, and then ethyl acetate (12vol) was added for extraction. The organic phase was collected for the next reaction. Proton spectrum (400MHz, DMSO-d6) is shown in Figure 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In N,N-dimethyl-formamide for 8h; Ambient temperature; | |
100% | In N,N-dimethyl-formamide | 6 Ara-C (300 mg, 1.23 mmol) in DMF (5 mL) was reacted with dimethylformamide dimethyl acetal (1.7 g, 14.2 mmol). On evaporation and crystallization from a minimum amount of ethanol, white crystals of N4-[(Dimethylamino)methylene]arabinocytidine were obtained (371 mg, 100%). This procedure is taken from Kerr et al., J. Pharm. Sci. 83(4): 582-586 (1994). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With acetic acid In chloroform |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In N,N-dimethyl-formamide for 8h; Ambient temperature; | |
93% | In N,N-dimethyl-formamide | 12 Ara-C (100 mg, 0.41 mmol) in DMF (5 mL) was reacted with N-(dimethoxymethyl)morpholine (1.35 g, 9.3 mmol). Evaporation and subsequent crystallization from ethyl acetate-ether gave N4-[Morpholinomethylene]arabinocytidine (130 mg, 93%). This procedure is taken from Kerr et al., J. Pharm. Sci. 83(4): 582-586 (1994). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 99% | With cytidine deaminase enzyme; In aq. phosphate buffer; at 37℃; for 0.0833333h;pH 7;Enzymatic reaction; | Comparative Example 6: Deamination of cytarabine (cytosine arabinoside) to uridine arabinoside A 100 mM solution of cytarabine (495 muIota_) in 100 mM phosphate buffer at pH 7 was mixed with 50 muIota_ of cytidine deaminase enzyme solution containing >300 AU in phosphate buffer. The reaction was performed at 37C during 5 minutes and stopped with HCI. Then, the crude reaction was filtered through a 10 KDa membrane, and a portion was diluted and analyzed by HPLC-UV-DAD. The expected uridine arabinoside was identified by comparison to a standard sample, and formed in quantitative yield (>99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium hydroxide; hydrogen at 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine; silver nitrate; triethylamine In tetrahydrofuran at 20℃; for 26h; | |
90% | With 1H-imidazole; dmap In N,N-dimethyl-formamide at 63℃; Cooling with ice; Inert atmosphere; | 1.1 Step 1) Synthesis of compound PA4101-2 dissolving a compound PA4101-1 (Cytarbine, 9.5 g, 39 mmol) and imidazole (18 g, 264 mmol) in DMF (100 mL), adding 4-dimethylaminopyridine ((DMAP, 3.8 g, 31 mmol), adding tert-butyldimethylsilyl chloride (TBSCI, 30 g, 198 mmol) slowly in an ice bath, under nitrogen protection, carrying out reaction at 63 °C while stirring overnight, after completing the reaction, adding a reaction solution slowly to water (400 mL), followed by extraction with ethyl acetate (3 × 300 mL), washing by saturated brine, drying over anhydrous sodium sulfate, followed by filtration, spin-drying, and separation and purification by silica gel chromatographic column to obtain PA4101-2 (20.6 g), with yield of 90%. |
85% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; |
84% | With 1H-imidazole; dmap In N,N-dimethyl-formamide at 22℃; for 48h; | |
72% | With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20 - 60℃; | |
69% | With 1H-imidazole In N,N-dimethyl-formamide | |
With pyridine; 1H-imidazole at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With TEA In pyridine at 80℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With TEA In pyridine at 80℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With hydrogen In methanol for 30h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With sodium hydrogencarbonate In 2,4-dichlorophenoxyacetic acid dimethylamine for 168h; | 7 Cytarabine (243 mg, 1.0 mmol), 2-Chlorocarbonyloxymethyl-l-methyl-5- nitroimidazole (439 mg, 2.0 mmol), sodium bicarbonate (336 mg, 4.0 mmol) and DMA (10 mL) were stirred for 7 days. The suspension was filtered and the filtrate concentrated in vacuo. The resultant oil was triturated with DCM; the suspension was filtered, and the solid was washed with DCM then dried at the pump. The solid was dissolved in methanol and then adsorbed on to flash silica. Column chromatography, eluting with 33% then 50% methanol / DCM, furnished an off-white wax (53 mg, 12%); TLC Rf=0.3, 10% methanol / ethyl acetate. NMR (500Mhz, DMSO-d6, δ)7.98 (IH, s, HarH), 7.35 (IH, bs, HarH), 5.99 (IH, s, NCHO), 5.86 (IH, bs, HarH), 5.65 (IH, bs, OH), 5.47 (IH, bs, OH), 5.26 (2H, m, HarCH2O), 5.05 (IH, s, OH), 4.08 (IH, bs, CHOH), 3.95 (3H, s, NCH3), 3.90 (IH, bs, OCHCH2OH), 3.73 (IH, bs, CHOH), 3.62 (2H, m, CH2OH) ppm.The 2-chlorocarbonyloxymethyl-l-methyl-5-nitroimidazole used in the above synthesis was prepared as follows: 2-Hydroxymethyl-l-methyl-5-nitroimidazole (314 mg, 2.0 mmol) in THF (10 mL) was added to phosgene (4 mL, 8.0 mmol) and THF EPO (15 mL) at O0C. The reaction was stirred for 16 h then the solvent was removed in vacuo. The crude chloroformate was used without further purification.2-Hydroxymethyl-l-methyl-5-nitroiniidazole was prepared as follows: Methanolic ammonia (3.6 mL, 25 mmol) was added to a suspension of ronidazole (5 g, 25 mmol) and methanol (25 mL). Potassium carbonate (1.75 g, 12.5 mmol) was added and the reaction mixture heated to 5O0C for 18 h. The solution was cooled to ambient temperature then partitioned (ethyl acetate and brine), the aqueous phase was extracted (ethyl acetate); the organic phases were combined, washed (water then brine) then dried in vacuo. The desired product was obtained as an orange solid (2.3 g, 59%) and was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: arabinosyl cytosine; [4-(3-chloro-phenyl)-[1,3,2]dioxaphosphinan-2-yl]-diisopropyl-amine With 5-methylsulfanyl-1H-tetrazole In N,N-dimethyl-formamide at 20℃; Stage #2: With tert.-butylhydroperoxide In n-heptane; N,N-dimethyl-formamide at -40 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With pyridine at 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With pyridine at 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine at 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine at 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With lipase acrylic resin from Candida antarctica In acetone at 50℃; for 96h; | |
With lipase acrylic resin from Candida antarctica In acetone at 50℃; Enzymatic reaction; regioselective reaction; | 2.2 Synthesis of the comonomers General procedure: 5-O-vinylsebacoyl-cytarabine (VSC) and 3-O-vinyladipoyl-fluorodeoxyuridine (VAF) were prepared by controllable regio-selective enzymatic transesterifications. The reactions were initiated by adding CAL-B to anhydrous acetone containing cytarabine and divinyl sebacate, or adding PSL-C to THF containing fluorodeoxyuridine and divinyl adipate. The solutions were then incubated at 50 °C and stirred at 250 rpm. The process of the reactions was monitored by TLC. The reactions were terminated by filtering the enzyme and the product was purified by silica gel chromatography. 6-O-vinylsebacoyl-glucose (VSG) was synthesized in the same way while using subtilisin as the catalyst and pyridine as the solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With lipase acrylic resin from Candida antarctica In acetone at 50℃; for 96h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyridine; 1H-imidazole at 20℃; for 3h; | |
85.4% | With pyridine Cooling with ice; Inert atmosphere; | 42.1 To an ice-cold solution of arabinocytidine (20.0 g, 82.2 mmol) in anhydrous pyridine (200 mL) was added TBSCl (14.9 g, 98.7 mmol) in small portions under N2. The reaction mixture was stirred at RT overnight. The solvent was removed under vacuum and the residue was diluted with EA (300 mL), washed with water and brine. The organic layer was separated, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give 5'-O-(?-butydimethylsilyl)arabinocytidine (25.1 g, 85.4%) as a white solid which was used without further purification. |
With pyridine; 1H-imidazole In 1,4-dioxane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-triisopropylphenylsulfonyl chloride In pyridine at 40℃; for 24h; | 5.a A solution of 1-O-octadecyl-2-O-benzyl-sn-glycero-3-phosphatidic acid (1) and ara-C in pyridine was treated with TIPS at a temperature of 40°C, over a period of 24h. The reaction was stopped by addition of water and the solvent evaporated under reduced pressure. The crude product purified by chromatography to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 72 percent / imidazole; DMAP / dimethylformamide / 20 - 60 °C 2: 64 percent / acetic acid / H2O / 10 h / 50 - 60 °C | ||
Multi-step reaction with 2 steps 1: 85 percent / imidazole / dimethylformamide / 20 °C 2: 65 percent / aq. trifluoroacetic acid / tetrahydrofuran / 18 h / -10 °C | ||
Multi-step reaction with 2 steps 1: imidazole; pyridine / 20 °C 2: TFA*H2O / tetrahydrofuran / 0 °C |
Multi-step reaction with 2 steps 1: 1H-imidazole; dmap / N,N-dimethyl-formamide / 63 °C / Cooling with ice; Inert atmosphere 2: hydrogenchloride / ethanol / 4.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap In DMF (N,N-dimethyl-formamide); dichloromethane at 20℃; for 12h; | 22 EXAMPLE 22; Compound 22 A solution of 6 (2.0 g, 0.378 mmol), AraC (0.191 g, 0.756 mmol), and DMAP (0.093 g, 0.756 mmol) in anhydrous DMF/DCM (20 mL/20 ML) is stirred at room temperature for 12 hrs. The solvents are partially removed under reduced pressure and the final product is precipitated with ethyl ether (80 mL). The solid is filtered and recrystallized from DMF/METHANOL (35 mL/25 mL) to give 22, shown below. The structure of 22 is confirmed by 13C NMR |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrogenchloride; In methanol; at 2 - 25℃; for 4h; | An oven- dried 250 mL round bottom flask equipped with a magnetic stir bar was charged with 3.35 g of cytarabine-HCl and 6.0 mL of DMPU. Into this flask the reaction mixture from example 12 was filtered directly and the DABCO-HCl salt was washed quickly with acetonitrile (1×15 mL). Volatiles were removed on a rotary-evaporator under aspirator vacuum (bath temp <35 C.). The residual oil was briefly kept under high vacuum and stirred at room temperature for 48 h. The reaction mixture was treated with 100 mL of MeOH and stirred for 2 hours at room temperature. The pH of the reaction mixture was adjusted to 7.0 using 25 wt % NaOMe solution in methanol (approximately 13 mL were required). At this stage the reaction mixture was turbid. HPLC was run to insure integrity of the reaction profile. The reaction mixture was evaporated to dryness and the residue was stirred with 50 mL of dichloromethane for 30 minutes at room temperature. The precipitate was collected by filtration, washed with methylene chloride (1×20 mL) and transferred back to the flask, stirred again with 50 mL of dichloromethane for 15 minutes and filtered. The solid was stirred with 200 mL of ethanol for 1-2 hours, filtered and washed with ethanol (2×10 mL). The filtrate was evaporated to dryness to give 4.90 g of a white solid. This solid was dissolved in 10 mL of H2O and stirred at room temperature overnight to give a solid which was collected by filtration, washed with water (2×3 mL) and dried in a vacuum oven to give compound 9, 1.38 g, (26%). |
With hydrogenchloride; In diethyl ether; | A suspension of cytarabin hydrochloric salt (prepared from cytarabin and 1M HC1 in diethyl ether) (839 mg, 3.0 mmol) in DMA (10 ml) was added to the acid chloride of monomethyl azelaic acid (761 mg, 3.45 mmol) in DMA (2 ml) and the mixture stirred at room temperature overnight. NEt3 was added to the reaction mixture (303 mg, 3.0 mmol) and the mixture evaporated in vacuo. The residue was transferred to a flash column with silica gel and separated with (CH2C12/MEOH 10 : 1) as eluent system to leave the product as a white solid. Yield: 278 mg, (21.6 %). 1H-NMR (DMSO-D6, 300 MHz): 5 7.47 (d, 1 H), 7.10 (br d, 2 H), 6.09 (d, 1 H), 5.67 (d, 1 H), 5.60-5. 56 (m, 2 H), 4.33-3. 88 (m, 2 H), 3.98-3. 96 (m, 1 H), 3.94-3. 88 (m, 2 H), 3.57 (s, 3 H), 3.33 (br s, 1 H), 2.34-2. 25 (m, 4 H), 1.54-1. 47 (m, 4 H), 1.22 (br s, 6 H). 3C-NMR (DMSO-D6, 75 MHz) : 8 173.3, 172.8, 165.5, 155.0, 142.8, 92.5, 86.1, 81.7, 76.7, 74.2, 63.6, 51.1, 45.2, 33.5, 33.1, 28.2, 28.1, 24.3, 8.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In pyridine at 20 - 40℃; | 17.7 A Mixture of 7a (0. 50 g, 1.3 mmol), ara-C (1.26 g, 5.2 mmol), HOBT (0.70 g, 5.2 mmol) and EDC-HCl (1.99 g, 10.4 mmol) in anhydrous pyridine (30 ml) was stirred at room temperature for 2h followed by stirring at 40 °C overnight. The solvent was removed in vacuo and the residue was dissolved in CH2CL2 (50 ml) followed by extraction with water (3 x 30 ml) and 0.1 M HCl (2 x 30 ml). The organic phase was dried over anhydrous MGS04 and evaporated in vacuo. The residue was purified by flash chromatography (5-10 % MEOH in CH2C12) to give white crystalline material. Yield: 0.29 g (36 %). H NMR (CDC13) 5 9.70 (d, broad, 1H), 8.08 (s, 1H), 7.28 (q, 1H), 6.79 (s, 1H), 6.59 (s, 1H), 6.10 (s, LH), 5.83 (S, 1H), 5.55-5. 39 (m, 2H), 4.71 (S, 1H), 4.47 (s, 1H), 4.25 (s, 1H), 4.07 (d, 3H), 3.81 (s, broad, 2H), 3. 01- 2.77 (m, 2H), 2.49 (s, 3H), 2.18 (s, 3H), 1.56-1. 43 (m, 6+9H). |
36% | With ethylene dichloride hydrochloride; benzotriazol-1-ol In pyridine at 20 - 40℃; | 17.7 A Mixture of 7a (0.50 g, 1.3 mmol) , ara-C (1.26 g, 5.2 mmol), HOBT (0.70 g, 5.2 mmol) and EDC-HCl (1.99 g, 10.4 mmol) in anhydrous pyridine (30 ml) was stirred at room temperature for 2h followed by stirring at 40 0C overnight. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (50 ml) followed by extraction with water (3 x 30 ml) and 0.1 M HCl (2 x 30 ml) . The organic phase was dried over anhydrous MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (5-10 % MeOH in CH2Cl2) to give white crystalline material. Yield: 0.29 g (36 %) .1H NMR (CDCl3) δ 9.70 (d, broad, IH), 8.08 (s, IH), 7.28 (q, IH), 6.79 (s, IH), 6.59 (s, IH), 6.10 (s,lH), 5.83 (s, IH), 5.55-5.39 (m, 2H), 4.71 (s, IH), 4.47 (s, IH), 4.25 (s, IH), 4.07 (d, 3H), 3.81 (s, broad, 2H), 3.01- 2.77 (m, 2H), 2.49 (s, 3H), 2.18 (s, 3H), 1.56-1.43 (m, 6+9H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In pyridine at 20 - 40℃; | 17.8 A mixture of 7b (0.67 g, 1.4 mmol), ara-C (1.36 g, 5.6 MMOL), HOBT (0.76 g, 5.6 mmol) and EDC-HC1 (2.15 g, 11.2 mmol) in anhydrous pyridine (35 ml) was stirred at room temperature for 2h followed by stirring at 40 °C overnight. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (50 ml) followed by extraction with water (3 x 30 ml) and 0.1 M HC1 (2 x 30 ml). The organic phase was dried over anhydrous MGS04 and evaporated in vacuo. The residue was purified by flash chromatography (5-10 % MEOH in CH2Cl2) to give white crystalline material. Yield: 0.35 g. H NMR (CDC13) 5 9.35-9. 01 (m, 1H), 8.59 (m, 1H), 8.15 (m, 1H), 7.69 (m, 1H), 7.28 (m, 6H), 6.75 (d, 1H), 6.23 (t, 1H), 6.16 (t, LH), 5.90-5. 74 (m, 1H), 5.25 (s, 1H), 4.84 (m, 1H), 4.59 (s, 1H), 4.33 (s, 1H), 4.15 (s, 1H), 3.92-3. 67 (m, 2H), 3.35-3. 25 (m, 1H), 3.20-3. 12 (m, 1H), 2.88 (s, 2H), 2.54-2. 41 (m, 3H), 2.23 (d, 3H), 1.58-1. 44 (m, 6H), 1.38 (s, 9H); 3C NMR 5 173.59, 172.30, 162.45, 156.40, 156.03, 150.23, 149.99, 147.04, 138.60, 137.13, 136. 65, 136. 42,133. 71, 133. 31, 129.92, 129.70, 129.01, 127.52, 124.28, 123.02, 96.95, 89.22, 86.50, 80.63, 74.77, 62. 36, 55.53, 50.71, 40. 02, 38. 33, 32. 57, 31. 93, 28. 71, 25. 82, 20.56. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With benzotriazol-1-ol; diisopropyl-carbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; | A solution of <strong>[23361-28-6]Boc-Val-Pro-OH</strong> (94.5 mg, 0,30 mmmol) in DIMETHYLFORMAMIDE (1.5 mL), was successively treated, at room temperature, with 1-HYDROXIBENZOTRIAZOL (40.5 mg, 0.30 MMOL), N, N-DIISOPROPYLCARBODIIMIDE (46.7 ßL, 0.30 MMOL) and Ara-C (60.9 mg, 0.25 MMOL). The stirring was continued until complete disappearance of the starting material (overnight stirring). Then, the solvent was evaporated, the residue was dissolved in ethyl acetate and washed with citric acid (10%), NAHCO3 (10%) and brine. The organic layer was dried (NA2SO4) and evaporated to give a residue that was purified by CCTLC on the chromatotron with DICHLOROMETHANE : METANOL (20 : 1) to yield Ara-C-dipeptide (A) (21 % yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With benzotriazol-1-ol; diisopropyl-carbodiimide In DMF (N,N-dimethyl-formamide) at 20℃; | 13 A solution of Z-Val-Pro-Val-Pro-OH (134.4 mg, 0,24 MMOL) in DIMETHYLFORMAMIDE (1.5 mL), was successively treated at room temperature with 1-HYDROXIBENZOTRIAZOL (33.3 mg, 0.24 mmol), N, N'- diisopropylcarbodiimide (38. 4, UL, 0.24 MMOL) and Ara-C (50 mg, 0.20 MMOL). The stirring was continued until complete disappearance of the starting material (overnight). Then, the solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with citric acid (10%), NaHCOs (10%) and brine. The organic layer was dried (NA2SO4) and evaporated to dryness leaving a residue that was purified by CCTLC on the chromatotron with dichloromethane : metanol (20: 1) to give D (22 % yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide | 9 Ara-C (85 mg, 0.35 mmol) in DMF (2 mL) is reacted with dibutylformamide dimethyl acetal (0.9 g, 5.14 mmol). Evaporation and crystallization from ethanol-ethyl acetate gave N4-[(Dibutylamino)methylene]arabinocytidine (104 mg, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide at 20℃; | 14 Ara-C (500 mg, 2.05 mmol) in DMF (10 mL) is reacted with N-(dimethoxy methyl)dimethyl piperidine (2.7 g, 16.8 mmol) for several hours at room temperature. The contents are evaporated and the residue chromatographed over silica gel using 1-6% MeOH in CH2Cl2. The desired fractions are collected and evaporated. The foam obtained is recrystallized from a mixture of ethanol, CH2Cl2, and ethyl acetate to give N4-[Dimethylpiperidinomethylene]arabinocytidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With pyridine In 1,4-dioxane; methanol; chloroform | N-allyloxycarbonyl Arabinosylcytosine (7) N-allyloxycarbonyl Arabinosylcytosine (7) Diallyl pyrocarbonate (86.8 mg, 0.452 mmol) was diluted in 1,4-dioxane (5 mL) and added to a solution of arabinosylcytosine (100 mg, 1.61 mmol) dissolved in ddH2O (1 mL) at room temperature. After the reaction mixture was refluxed for two hours in an oil bath, the solvent was removed under reduced pressure and co-evaporated the white residue with anhydrous pyridine (3*5mL). Purified by silica gel chromatography (15% MeOH in CHCl3) to give 7 (91 mg, 76% based on recovered starting material) as a white foam. 1H NMR (DMSO6): d 10.75 (br, 1H); 8.04 (d, 1H, J=7.51 Hz); 7.00 (d, 1h, J=7.51 Hz); 6.04 (d, 1H, J=3.85 Hz); 5.95 (m, 1H); 5.46 (m, 1H); 5.39 & 5.25 (dd, 1H, J=1.47 & 35.34 Hz); 5.32 & 5.21 (dd, 1H, J=1.1 & 23.32 Hz), 5.11 (m, 1H); 4.62 (d, 2H, J=5.31 Hz); 4.04 (m, 1H); 3.91 (m, 1H); 3.81 (m, 1H); 3.60 (m, 2 H). HPLC (Gradient 0% to 70% CH3CN/H2O [0.1% TFA] over 30 min): 12.18 min; 99%. ESI MS (low resolution): (M+H)=328 m/z; MW=327 for C13H17N3O7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With sodium hydrogencarbonate In 2,4-dichlorophenoxyacetic acid dimethylamine for 168h; | 11 Cytarabine (735 mg, 3.0 mmol), l-chlorocarbonyloxy-l-(4-nitrophenyl)ethane (2.29 g, 10.0 mmol), sodium bicarbonate (882 mg, 10.5 mmol) and DMA (20 mL) were stirred for 7 days. The suspension was filtered and the filtrate concentrated in vacuo. The solid was dissolved in methanol and then adsorbed on to flash silica. Column chromatography, eluting with ethyl acetate then 10% methanol / ethyl acetate, produced a yellow oil. The oil was triturated with acetonitrile; the suspension was filtered, and the solid was washed with ice-cold acetonitrile then dried at the pump. The title compound was obtained as a cream powder (292 mg, 22%); mpt=144- 146°C; TLC Rf=O-I, ethyl acetate. 1H NMR (270 MHz, DMSO) δ 10.86 (IH, s, NH), 8.27 (2H, d, J=8.1, ArH), 8.04 (IH, d, J=8.1, NCH=CH), 7.68 (2H, d, J=8.1, ArH), 6.95 (IH, d, J=8.1, NCH=CH), 6.04 (IH, d, J=5.4, NCHO), 5.95 (IH, q, J=5.4, OCHCH3), 5.49 (2H, m, 2 x OH), 5.05 (IH, t, J=5.4, OH), 4.05 (IH, bs, CHOH), 3.91 (IH, bs, OCHCH2OH), 3.83 (IH, bs, CHOH), 3.59 (2H, t, J=5.4, CH2OH), 1.54 (3H, d, J=5.4, OCHCH3) ppm. l-Chlorocarbonyloxy-l-(4-nitrophenyl)ethane was synthesized as follows:2-(4-Nitroρhenyl)ethanol (1.67 g, 10.0 mmol) in THF (10 mL) was added to phosgene (5.5 mL, 11.0 mmol) and THF (30 mL) at 0°C. The reaction was stirred for 16 h then the solvent was removed in vacuo. The crude chloroformate was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With sodium hydrogencarbonate In 2,4-dichlorophenoxyacetic acid dimethylamine for 72h; | 12 Cytarabine (812 mg, 3.31 mmol), 2-Chlorocarbonyloxymethyl-5-nitrofuran (2.05 g, 10.00 mmol), sodium bicarbonate (980 mg, 11.66 mmol) and DMA (10 mL) were stirred for 72 h. The suspension was filtered and the filtrate concentrated in vacuo to give a solid, which was dissolved in methanol and then adsorbed on to flash silica. Column chromatography, eluting with ethyl acetate then 10% methanol / ethyl acetate, produced an impure oil. Further flash chromatography, eluting with DCM then 5%, 10%, and 15% methanol / DCM, afforded an amber oil. The oil was triturated with ether; the suspension was filtered, and the solid was washed with ether then dried at the pump. The title compound was obtained as a beige powder (95 mg, 7%); mpt=105-107°C; TLC RjHD.18, 10% methanol / ethyl acetate. 1H NMR (270 MHz, DMSO) δ 10.91 (IH, s, NH), 8.07 (2H, s, HarH), 7.70 (IH, s, HarH), 6.98 (IH, s, NCH=CH), 6.04 (IH, s, NCHO), 5.49 (2H, s, 2 x OH), 5.26 (2H, s, HarCH2O), 5.05 (IH, s, OH), 4.10 (IH5 bs, CHOH), 3.91 (IH, bs, OCHCH2OH), 3.82 (IH, bs, CHOH), 3.59 (2H, m, CH2OH) ppm.2-Chlorocarbonyloxymethyl-5-nitrofuran was prepared as follows: 2-Hydroxymethyl- 5-nitrofuran (1.43 g, 10.0 mmol) in THF (10 mL) was added to phosgene (5.5 mL, 11.0 mmol) and THF (30 mL) at O0C. The reaction was stirred for 16 h then the solvent was removed in vacuo. The crude chloroformate was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In 2,4-dichlorophenoxyacetic acid dimethylamine at 20℃; for 24h; | 13 3-Hydroxvmethyl-5-methoxy-l,2-dimethylindole-4,7-dione (150 mg, 0.64 mmol) was dissolved in pyridine (0.5 mL) and the solution cooled to 00C. A solution of 4- nitrophenylchloroforniate (200 mg, 1 mmol) in pyridine (0.5 mL) was then added drop-wise and the solution warmed to 20°C over 1 h. The solution was partitioned (ethyl acetate / brine) and extracted further with ethyl acetate, dried and evaporated to dryness. The crude 4-nitrophenylcarbonate was dissolved in DMA (2 mL) together with cytarabine (500 mg, 2.05 mmol) and sodium bicarbonate (500 mg, 5.95 mmol). The solution was stirred at 2O0C for 24 h and then evaporated to dryness at 30°C, dissolved in methanol, filtered and absorbed onto silica gel (2.5 g). The material was then purified by flash chromatography, eluting with ethyl acetate followed by 10 % methanol / ethyl acetate to afford the title compound as an orange solid (20 mg, 10 %); mpt=>250°C (dec). TLC Rf=0.2, (10 % methanol / ethyl acetate). LC-RT 2.16 min (TFA20-50%); MS m/z 235/220/151. 1H NMR (500 MHz, DMSO) δ 10.55 (IH, s, NH)5 8.05 (IH, s, NCH=CH), 7.00 (IH, s, NCH=CH)3 6.05 (IH, s, NCHO), 5.79 (IH, s, HarH), 5.54 (2H, s, 2 x OH), 5.25 (s, 2H, HarCH2OCONH), 5.10 (IH, s, OH), 4.05 (IH, bs, CHOH), 3.90 (s, 3H, HarOCH3), 3.91 (IH, bs, OCHCH2OH), 3.85 (s, 3H5 HarNCHs), 3.84 (IH, bs, CHOH), 3.61 (2H, m, CH2OH), 2.28 (3H5 s, HarCH3) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine In methanol; ethanol; ISOPROPYLAMIDE; water; Petroleum ether | 1 EXAMPLE 1 EXAMPLE 1 To a solution of 4.0 g of arabinofuranosylcytosine dissolved in 50 ml of dimethylacetamide, there are added 5.0 g of triethylamine and 3.37 g of butyloxycarbonyl chloride. The reaction is carried out by stirring the mixture at room temperature for 3 hours. After completion of the reaction, the solvent is evaoprated under reduced pressure. The residue is diluted with 20 ml of ethanol, followed by addition of 150 ml of petroleum ether. After the mixture is stirred at 0° to 5° C. for one hour, the resultant precipitates are collected by filtration. The precipitates are dissolved in 15 ml of methanol and then 100 ml of water is added to the resultant solution. The mixture is left to stand in a refrigerator and the precipitated crystals are filtered to give 2.8 g of N4 -butyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:50%). Elemental analysis for C14 H21 H3 O7: Calcd. (%): C 48.98; H 6.17; N 12.24; Found (%): C 49.17; H 6.32; N 12.30. NMR (in DMSO-d6) δ value: --CH3 0.94, --(CH2)2 -- 1.0-2.0, H2 '-H5 ' 3.4-4.4, --OCH2 4.14, H1 ' 6.08, H5 7.04, H6 8.08 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With sodium bicarbonate In ice-water; ISOPROPYLAMIDE; toluene | 10 EXAMPLE 10 EXAMPLE 10 In 130 ml of dimethylacetamide, 7.3 g of arabinofuranosylcytosine is dissolved and to the resultant solution is added 40 ml of a toluene solution containing 7.56 g of sodium hydrogen carbonate and 7.0 g of undecyloxycarbonyl chloride. The mixture is then stirred at room temperature for 3 hours. After the reaction is over, the solvent is removed under reduced pressure and ice-water is added to the residue, whereby the cyrstals are precipitated. The crystals are filtered and washed with water, followed by sufficient drying. Recrystallization of the product is performed twice, using 80 ml of chloroform-n-hexane, to give 4.0 g of N4-undecyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:30%). Elemental analysis for C21 H35 N3 O7: Calcd. (%): C 57.03; H 8.14; N 9.50; Found (%): C 56.88; H 8.31; N 9.37. NMR(DMSO-d6) δ value: --CH3 0.86, --(CH2)9 -- 1.1-1.8, H2 '-H5 ' 3.5-4.3, --OCH2 -- 4.16, H1 ' 6.14, H5 7.08, H6 8.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With pyridine; In ISOPROPYLAMIDE; water; | EXAMPLE 4 To a solution of 4.0 g of arabinofuranosylcytosine dissolved in 50 ml of dimethylacetamide, there are added 3.0 g of pyridine and 4.06 g of n-hexylchloroformate. The reaction is carried out by stirring the mixture at room temperature for 3 hours. After the reaction is over, dimethylacetamide is evaporated under reduced pressure. The residue is diluted with 100 ml of cold water and the mixture is stirred under ice-cooling for one hour. The precipitated solids are filtrated and dried. The resultant white powders are washed with ethyl ether to obtain 2.9 g of N4 -hexyloxycarbonyl-1-beta-D-arabinofuranosylcytosine (Yield:47%). Elemental analysis for C16 H25 N3 O7: Calcd. (%): C 51.75; H 6.79; N 11.31; Found (%): C 51.53; H 6.88; N 11.26. NMR(DMSO-d6) delta value: --CH3 0.88, --(CH2)3 -- 1.1-1.9, H2 '-H5 ' 3.3-4.3, --OCH2 -- 4.12, H1 ' 6.10, H5 7.04, H6 8.08 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With sodium bicarbonate In ISOPROPYLAMIDE; water | 6 EXAMPLE 6 EXAMPLE 6 To a solution of 4.0 g of arabinofuranosylcytosine dissolved in 50 ml of dimethylacetamide, there are added 4.15 g of sodium hydrogen carbonate and 4.41 g of heptylchloroformate. The resultant mixture is allowed to react under stirring at room temperature for 3 hours. After the reaction, dimethylacetamide is removed under reduced pressure and 150 ml of cold water is added to the residue. After the mixture is stirred for 2 hours, the solids are collected by filtration and dried. Recrystallization of the white powders obtained is performed twice, using 200 ml and 150 ml of a mixture of chloroform-acetonitrile (1:1), to give 2.5 g of N4 -heptyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:40%). Elemental analysis for C17 H27 N3 O7: Calcd. (%): C 52.98; H 7.06; N 10.90; Found (%): C 53.13; H 6.87; N 10.85. NMR(DMSO-d6) δ value: --CH3 0.88, --(CH2)5 -- 1.1-1.9, H2 '-H5 ' 3.4-4.3, --OCH2 -- 4.16, H1 ' 6.12, H5 7.08, H6 8.12 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium bicarbonate In ISOPROPYLAMIDE; water | 8 EXAMPLE 8 EXAMPLE 8 In 120 ml of dimethylacetamide, 6.0 g of arabinofuranosylcytosine is dissolved and to the resultant solution are added 4.15 g of sodium hydrogen carbonate and 7.66 g of nonyloxycarbonyl chloride. The mixture is then allowed to react under stirring at 20 to 25° C. for 2 hours. After the reaction, the solvent is removed under reduced pressure and the residue is dissolved in a small amount of ethanol. Water is then added to the resultant solution and the precipitated solids are collected by filtration, followed by drying. The white powders obtained are washed thoroughly with ethyl ether to obtain 3.8 g of N4 -nonyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:37%). Elemental analysis for C19 H31 N3 O7: Calcd. (%): C 55.19; H 7.56; N 10.16; Found (%): C 55.04; H 7.66; N 10.14. NMR(DMSO-d6) δ value: --CH3 0.84, --(CH2)7 -- 1.0-1.8 H2 '-H5 ' 3.5-4.3, --OCH2 -- 4.10, H1 ' 6.06, H5 6.98, H6 8.02 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ethylene dichloride hydrochloride; benzotriazol-1-ol In pyridine at 20 - 40℃; | 17.8 A mixture of 7b (0.67 g, 1.4 mmol), ara-C (1.36 g, 5.6 mmol), HOBT (0.76 g, 5.6 mmol) and EDC-HCl (2.15 g, 11.2 mmol) in anhydrous pyridine (35 ml) was stirred at room temperature for 2h followed by stirring at 40 0C overnight. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (50 ml) followed by extraction with water (3 x 30 ml) and 0.1 M HCl (2 x 30 ml) . The organic phase was dried over anhydrous MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (5-10 % MeOH in CH2Cl2) to give white crystalline material. Yield: 0.35 g.1H NMR (CDCl3) δ 9.35-9.01 (m, IH), 8.59 (m, IH), 8.15 (m, IH), 7.69 (m, IH), 7.28 (m, 6H), 6.75 (d, IH), 6.23 (t, IH), 6.16 (t,lH), 5.90-5.74 (m, IH), 5.25 (s, IH), 4.84 (m, IH), 4.59 (s, IH), 4.33 (s, IH), 4.15 (s, IH), 3.92-3.67 (m, 2H), 3.35-3.25 (m, IH), 3.20-3.12 (m, IH), 2.88 (s, 2H), 2.54-2.41 (m, 3H), 2.23 (d, 3H), 1.58-1.44 (m, 6H) , 1.38 (s, 9H) ;13C NMR δ 173.59, 172.30, 162.45, 156.40, 156.03, 150.23, 149.99, 147.04, 138.60, 137.13, 136.65, 136.42, 133.71, 133.31, 129.92, 129.70, 129.01, 127.52, 124.28, 123.02, 96.95, 89.22, 86.50, 80.63, 74.77, 62.36, 55.53, 50.71, 40.02, 38.33, 32.57, 31.93, 28.71, 25.82, 20.56. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyridine at 0 - 20℃; for 72h; | 35 M-PEOZ-O-CH2-CO2-NHS (M-PEOZ-SCM 5000) (180 mg, 0.034 mmol) was dissolved in 11 mL of pyridine and added to a solution of cytosine arabinose (Ara-C) (5.7 mg, 0.023 mmol), previously dissolved in 5 mL of anhydrous pyridine at 0 C. The resulting solution stirred for 72 hours at room temperature. Reverse phase HPLC (C- 18 column) showed that reaction was complete. After evaporation of the solvent, the product was dissolved in methylene chloride (5 mL) and added drop by drop into 150 mL ether. The precipitate was collected by centrifugation at 4 °C and dried under vacuum. Yield 150 mg, 80%. NMR showed the usual peaks of the M-PEOZ backbone (above) plus the pyrimidine protons of Ara- C at 7.31, 7.67, 8.16, and 8.62 ppm. Exposure of the conjugate to pH 8 buffer showed that Ara-C is slowly released (15% after 24 hours), so the conjugate can be regarded as a prodrug. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: arabinosyl cytosine With trimethyl phosphite; trichlorophosphate at -10 - 0℃; for 4h; Stage #2: benzyl alcohol at 4℃; for 48h; | 19 POC13 (0.5 ml) was added to a mixture of ara-C (0.73 g, 3 mmol) and trimethyl phosphate (15 ml) AT-10 °C. The reaction mixture was stirred at 0 °C for 4h before benzylalcohol (15 mmol) was added. After 48h at 4 °C the reaction mixture was poured into H20 (250 ml) containing NAHCO3 (1 g). The reaction was evaporated in vacuo and dissolved in MeOH (5 ml). Insoluble material was filtred and the filtrate was added diethyl ether to precipitate the product as white crystalline material. H NMR (CDC13) 5 9.40-9. 09 (d, 1H), 7.90 (d, 7. 1 Hz, 1H), 7.30-7. 15 (m, 5H), 6.05 (d, 3.0 Hz, 1H), 4.35-3. 64 (m, 7H), 3.66 (d, 11.0 HZ, 1H), 3.43 (S, 2H), 3.40 (S, 2H), 2.84 (t, 2H); I-3C NMR 5 162.03, 150.79, 144.96, 138.86, 129.26, 128. 56, 126.45, 93.18, 87.05, 84.35, 76.19, 74.87, 65.67, 64.74, 54.40, 52.28, 36.97. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl acetamide at 30℃; for 22h; | 12 Example 12:The hydroxamic acid derivatives with P represented bysynthesized according to the synthetic scheme below:1 to 3: To a solution of Cytarabine (36 mmol) in 150 mL dimethylacetamide (DMA) was added a solution of compound 2 (42 mmol) in 50 mL DMA, and the mixture was stirred at 30 degree C for 22h. The solvent was evaporated at high vacuum and the residue was treated with hot ethyl acetate and filtered. The crude product was treated with 2 M NaHCO3 solution, filtered off and purified by silica gel column t afford compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: arabinosyl cytosine With trimethyl phosphite; trichlorophosphate at 0℃; for 4h; Stage #2: benzyl alcohol at 4℃; for 48h; Stage #3: With sodium hydrogencarbonate In water | 19 POCl3 (0.5 ml) was added to a mixture of ara-C (0.73 g, 3 mmol) and trimethyl phosphate (15 ml) at -10 "C. The reaction mixture was stirred at 0 "C for 4h before benzylalcohol (15 mmol) was added. After 48h at 4 "C the reaction mixture was poured into H2O (250 ml) containing NaHCO3 (1 g) . The reaction was evaporated in vacuo and dissolved in MeOH (5 ml) . Insoluble material was filtred and the filtrate was added diethyl ether to precipitate the product as white crystalline material.1H NMR (CDCl3) δ 9.40-9.09 (d, IH), 7.90 (d, 7.1 Hz, IH), 7.30-7.15 (m, 5H), 6.05 (d, 3.0 Hz, IH), 4.35-3.64 (m, 7H), 3.66 (d, 11.0 Hz, IH), 3.43 (s, 2H), 3.40 (s, 2H), 2.84 (t, 2H);13C NMR δ 162.03, 150.79, 144.96, 138.86, 129.26, 128.56, 126.45, 93.18, 87.05, 84.35, 76.19, 74.87, 65.67, 64.74, 54.40, 52.28, 36.97. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | Stage #1: arabinosyl cytosine With pyridine; chloro-trimethyl-silane In dichloromethane at 0℃; for 2h; Stage #2: phosgene; (5-nitrothiophen-2-yl)methanol In dichloromethane; toluene for 18h; | 2 Chlorotrimethylsilane (76μL, 0.60mmol) was added to Ara-C (48mg, 0.20mtnol), pyridine (97μL, 1.20mmol) and DCM (0.3mL) at O0C. After 2h, 5-nitrothien-2- ylmethanol (48mg, 0.30mmol) in DCM (0.2mL) was added, followed by dropwise addition of phosgene solution (0.2mL, 0.24mmol, 2M in toluene). The reaction was stirred for a further ISh. The crude mixture was partitioned (ethyl acetate and brine), the aqueous phase was extracted (ethyl acetate); the organic phases were combined, washed (water then brine) then adsorbed on to flash silica in vacuo. Flash chromatography, eluting with DCM then 2%, 5%, and 10% methanol / ethyl acetate, afforded the title compound as a white wax (7mg, 8%); TLC Rf=0.3, 10% methanol / ethyl acetate. 1H NMR (500Mhz, DMSO-d6, δ) 10.98 (IH, s, NH), 8.10 (2H, s,HarH), 7.35 (IH, s, HarH), 7.07 (IH, s, NCH=CH), 6.08 (IH, s, NCHO), 5.51 (2H, s, 2 x OH), 5.43 (2H, s, HarCH2O), 5.05 (IH, s, OH), 4.10 (IH, bs, CHOH), 3.95 (IH, bs, OCHCH2OH), 3.85 (IH, bs, CHOH), 3.61 (2H, m, CH2OH) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: (4E,8E,12E,16E)-4,8,13,17,21-pentamethyl-4,8,12,16,20-docosapentaenoic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.333333h; Inert atmosphere; Stage #2: arabinosyl cytosine In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; for 72h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: cholic acid With triethylamine; isobutyl chloroformate In N,N-dimethyl-formamide at -15℃; for 0.25h; Inert atmosphere; Stage #2: arabinosyl cytosine With triethylamine In N,N-dimethyl-formamide at -15 - 20℃; for 0.5h; Inert atmosphere; | 2.2.1 (R)-N-(1-((3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-furan-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-(R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) pentanamide (2) To a stirred solution of cholic acid (0.49g, 1.2mmol) in anhydrous N, N-dimethylformamide (DMF, 10mL), triethylamine (0.20mL, 1.5mmol) was added under nitrogen atmosphere. The mixture was cooled to -15°C and a solution of isobutyl chloroformate (0.20mL, 1.5mmol) was added dropwise. The mixture was stirred at -15°C for 15min and a solution of cytarabine (0.24g, 1.0mmol) and triethylamine (0.20mL, 1.5mmol) in 10mL anhydrous DMF was added dropwise to the reaction mixture at the same temperature. The reaction mixture was continually stirred for 30min at room temperature. After the reaction had been completed, the solvent was removed by RE-52A rotary evaporation (Shanghai Yarong Biochemical Instrument Plant, China). The residue was then purified by chromatography on silica gel eluting with dichloromethane/methanol (10:1) to obtain pure compound 2 as an amorphous white solid (0.50g, 78%). 1H NMR(300MHz, d6-DMSO, δ ppm): 10.8 (s, 1H), 8.04 (d, 1H, J=7.5Hz), 7.20 (d, 1H, J=7.5Hz), 6.05 (d, 1H, J=3.9Hz), 5.47(d, 2H, J=3.0), 5.05 (t, 2H), 4.31 (d, 1H, J=3.9Hz), 4.09 (d, 1H, J=3.3), 3.98 (d, 1H, J=3.3), 3.78 (s, 1H), 3.61 (s, 1H), 3.18 (t, 1H), 2.51-1.21 (m, 24H), 1.15 (d, 2H, J=7.2Hz) 0.93 (d, 3H, J=6.2Hz), 0.80 (s, 3H), 0.59 (s, 3H). 13C NMR (75MHz, d6-DMSO, δ ppm): 174.4, 162.3, 154.6, 146.7, 94.5, 87.0, 85.8, 76.2, 74.7, 71.1, 70.5, 66.4, 61.0, 46.3, 45.8, 41.6, 41.4, 35.4, 35.3, 34.9, 34.5, 33.8, 31.0, 30.5, 28.6, 27.3, 26.3, 22.9, 22.7, 17.1, 12.4. MS (ESI) (m/z): calcd for C33H51N3O9: m/z 634.2 [M+H]+, 656.2 [M+Na]+. |
75% | Stage #1: cholic acid With chloroformic acid ethyl ester; triethylamine In N,N-dimethyl-formamide at -15℃; for 0.333333h; Stage #2: arabinosyl cytosine In N,N-dimethyl-formamide at -15 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In water at 30℃; for 24h; Green chemistry; Enzymatic reaction; Overall yield = 57.37 %; regioselective reaction; | General procedure of whole-cell acylation of ara-C: 2 ml organic solvents containing 20 mM ara-C, 600 mM VP, 4% water and 50 mg/ml freeze-dried Aspergillus oryzae 3.5232 (Collection No.3.5232) were incubated by shaking (140 rpm) at a fixed temperature for 24 h. Aliquots were withdrawn at specified time intervals from the reaction mixture, and then diluted 100 times with water-methanol prior to HPLC analysis. To structurally characterize the product of the whole-cell catalyzed acylation of ara-C with VP, the reaction was scaled up. Upon completion of the reaction, the reaction mixture was centrifuged to remove the cell masses, isolated, and purified by half-preparation HPLC with a semi-preparation column. The acquisition was concentrated to about 1 mL by vacuum rotary evaporation. After crystallization under 4 °C, two products were obtained and then determined by 13C NMR (Bruker AVANCE Digital 400 MHz Nuclear Magnetic Resonance Spectrometer, Bruker Co., Germany) at 100 MHz. The ESI-MS spectra of the product were recorded on a Thermo LCQ DECA XP Plus ESI Mass Spectrometer with a spray voltage of 4.5 kV (Thermo Finnigan, USA). All the experiment was repeated twice. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2% | With pyridine at 20℃; for 20h; Inert atmosphere; regioselective reaction; | 1 4.1. 5′-Tr-cytarabine Triphenylmethyl chloride (153.3 g, 0.55 mol) was added in portions to an ice-cooled suspension of cytarabine (1, 121.6 g, 0.50 mol) in anhydrous pyridine (800 mL). It was stirred at room temperature for 20 h until the completion of the reaction detected by TLC, then concentrated under reduced pressure to remove pyridine. The residual was diluted with ethanol (250 mL), poured into ice-water (2.0 L) with stirring. The formed solid was filtrated and washed with water to give the crude, which was recrystallized from ethyl acetate to afford the product (231.1 g, 95.2%) as white solid. Mp 210-213 °C; 1H NMR (300 MHz, DMSO-d6): δ 3.11-3.15 (m, 2H), 3.81-3.88 (m, 3H), 5.33 (d, J=4.8 Hz, 1H), 5.42 (d, J=4.4 Hz, 1H), 5.55 (d, J=7.4 Hz, 1H), 6.05 (d, J=4.4 Hz, 1H), 7.00 (brs, 2H), 7.26-7.33 (m, 15H), 7.42 (d, J=7.4 Hz, 1H); ESI-MS(m/z)=486.2[M+H]+, 508.3[M+Na]+, 524.2[M+K]+. |
95.2% | With pyridine In water at 30℃; for 22h; Inert atmosphere; | 1.1 Example 1: S-2-Amino-3-methylbutanoic acid 2 - {(2R, 3S, 4S, 5R) -5- [4-amino-2-oxo-1 (1H)Yl] -3,4-dihydroxytetrahydrofuryl} methyl ester hydrochloride (cytosine 5'-position L-valinate, I1a) Step 1: argon protection, cold water cooling,willTrichloromethyl chloride 256.5 g (0.92 mol)Slowly addTo arabinoside (VII1) 194.6 g (0.80 mol)And anhydrous pyridine 1500mL of the mixture,Note that the reaction system is sufficiently stirred by mechanical agitation,The feed rate is controlled so that the added material is gradually dispersed or dissolved in the system.Plus finished, continue to stir 2h,And then slowly heated to 30 ° C and continue to respond for 20h,TLC detection reaction is completed.Concentration under reduced pressure to recover the reaction system of pyridine,And 300 mL of absolute ethanol was added to the residue to sufficiently disperse the contents.The mixture was slowly poured into ice water (5.0 L), and the mixture was rapidly stirred to precipitate a white solid.Filter, washed, dried, pale yellow crude 480.5g.The crude product was recrystallized from ethyl acetate (1000 mL), suction filtered,The filtrate cools and gradually precipitates a white solid. Placed overnight, suction filter,dry,A white solid (VI1) of 462.2 g, yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A suspension of 1 mM cytosine and 1 mM 1-(B-D-arabinofuranosyl)uracil in aqueous 50 mM MES buffer was thermostated at 50 C. during 30 min. Then, NDT enzyme (SEQ ID NO: 2) was added (0.085 mg/ml) dropwise and the reaction was stirred at 50 C. during at least 1 day under the same conditions. Then, the suspension was hot filtered, and the solid was washed and dried. The aqueous filtrate was partially concentrated, cooled down and filtered. The recovered solid was allowed to partially precipitate and concentrate. Once filtered and washed, the solid was crystallized using a suitable solvent, such as a polar protic or polar aprotic solvent, in combination with water or a suitable apolar solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: chenodeoxycholic acid With triethylamine; isobutyl chloroformate In N,N-dimethyl-formamide at -15℃; for 0.25h; Inert atmosphere; Stage #2: arabinosyl cytosine With triethylamine In N,N-dimethyl-formamide at -15 - 20℃; for 0.5h; Inert atmosphere; | 2.2.1 (R)-N-(1-((3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-furan-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-(R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) pentanamide (2) General procedure: To a stirred solution of cholic acid (0.49g, 1.2mmol) in anhydrous N, N-dimethylformamide (DMF, 10mL), triethylamine (0.20mL, 1.5mmol) was added under nitrogen atmosphere. The mixture was cooled to -15°C and a solution of isobutyl chloroformate (0.20mL, 1.5mmol) was added dropwise. The mixture was stirred at -15°C for 15min and a solution of cytarabine (0.24g, 1.0mmol) and triethylamine (0.20mL, 1.5mmol) in 10mL anhydrous DMF was added dropwise to the reaction mixture at the same temperature. The reaction mixture was continually stirred for 30min at room temperature. After the reaction had been completed, the solvent was removed by RE-52A rotary evaporation (Shanghai Yarong Biochemical Instrument Plant, China). The residue was then purified by chromatography on silica gel eluting with dichloromethane/methanol (10:1) to obtain pure compound 2 as an amorphous white solid (0.50g, 78%). |
Stage #1: chenodeoxycholic acid With triethylamine; isobutyl chloroformate In N,N-dimethyl-formamide at -15℃; for 0.0833333h; Stage #2: arabinosyl cytosine With triethylamine In N,N-dimethyl-formamide at -15 - 20℃; for 2.5h; | 1 Preparation of arabinosylcocoodeoxycholic acid conjugate 3.93 g of chenodeoxycholic acid and 1.2 mL of triethylamine were dissolved in 50 mL of dimethylformamide, cooled to -15 ° C, Slowly add isobutyl chloroformate 1. 2mL, 5 minutes after the reaction, adding 2. 43g of cytarabine with triethylamine 1. 2mL dissolved in 20mL Dimethylformamide was added and the reaction was stirred at -15 ° C for 30 minutes and then at room temperature for 2 hours. The reaction solution was filtered to remove To which triethylamine chloride is added and the filtrate is concentrated under reduced pressure to give a crude product. The product was added to 20 mL of dichloromethane Solution, filter to remove the insoluble material, the filtrate mixed with silica gel, silica gel column chromatography, methanol and dichloromethane gradient elution, collecting column layer The precipitate was concentrated to give a white powder of the cytarabine chenodeoxycholic acid conjugate solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: To a stirred solution of cholic acid (0.49g, 1.2mmol) in anhydrous N, N-dimethylformamide (DMF, 10mL), triethylamine (0.20mL, 1.5mmol) was added under nitrogen atmosphere. The mixture was cooled to -15C and a solution of isobutyl chloroformate (0.20mL, 1.5mmol) was added dropwise. The mixture was stirred at -15C for 15min and a solution of cytarabine (0.24g, 1.0mmol) and triethylamine (0.20mL, 1.5mmol) in 10mL anhydrous DMF was added dropwise to the reaction mixture at the same temperature. The reaction mixture was continually stirred for 30min at room temperature. After the reaction had been completed, the solvent was removed by RE-52A rotary evaporation (Shanghai Yarong Biochemical Instrument Plant, China). The residue was then purified by chromatography on silica gel eluting with dichloromethane/methanol (10:1) to obtain pure compound 2 as an amorphous white solid (0.50g, 78%). | |
3.93 g of hyodeoxycholic acid and 1.2 mL of triethylamine were dissolved in 50 mL of dimethylformamide and cooled to -15 C. Slowly add isobutyl chloroformate 1. 2mL, 5 minutes after the reaction, adding 2. 43g of cytarabine with triethylamine 1. 2mL dissolved in 20mL Dimethylformamide was added and the reaction was stirred at -15 C for 30 minutes and then at room temperature for 2 hours. The reaction solution was filtered to remove To which triethylamine chloride is added and the filtrate is concentrated under reduced pressure to give a crude product. The product was added to 20 mL of dichloromethane Solution, filter to remove the insoluble material, the filtrate mixed with silica gel, silica gel column chromatography, methanol and dichloromethane gradient elution, collecting column layer The precipitate was concentrated to give a white powdery cytarabine hyodeoxycholate conjugate solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | General procedure: To a stirred solution of cholic acid (0.49g, 1.2mmol) in anhydrous N, N-dimethylformamide (DMF, 10mL), triethylamine (0.20mL, 1.5mmol) was added under nitrogen atmosphere. The mixture was cooled to -15C and a solution of isobutyl chloroformate (0.20mL, 1.5mmol) was added dropwise. The mixture was stirred at -15C for 15min and a solution of cytarabine (0.24g, 1.0mmol) and triethylamine (0.20mL, 1.5mmol) in 10mL anhydrous DMF was added dropwise to the reaction mixture at the same temperature. The reaction mixture was continually stirred for 30min at room temperature. After the reaction had been completed, the solvent was removed by RE-52A rotary evaporation (Shanghai Yarong Biochemical Instrument Plant, China). The residue was then purified by chromatography on silica gel eluting with dichloromethane/methanol (10:1) to obtain pure compound 2 as an amorphous white solid (0.50g, 78%). | |
3. 93 g of <strong>[128-13-2]ursodeoxycholic acid</strong> and 1.2 mL of triethylamine were dissolved in 50 mL of dimethylformamide and cooled to -15 C. Slowly add isobutyl chloroformate 1. 2mL, 5 minutes after the reaction, adding 2. 43g of cytarabine with triethylamine 1. 2mL dissolved in 20mL Dimethylformamide was added and the reaction was stirred at -15 C for 30 minutes and then at room temperature for 2 hours. The reaction solution was filtered to remove To which triethylamine chloride is added and the filtrate is concentrated under reduced pressure to give a crude product. The product was added to 20 mL of dichloromethane Solution, filter to remove the insoluble material, the filtrate mixed with silica gel, silica gel column chromatography, methanol and dichloromethane gradient elution, collecting column layer The precipitate was concentrated to give a white powder of the cytarabine <strong>[128-13-2]ursodeoxycholic acid</strong> conjugate solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In ethanol at 65℃; for 4h; | 1 preparation of N 4-( N,N-dimethylaminomethylene)cytarabine The 82mLN, N- dimethylformamide dimethyl acetal (DMF-DMA) and added to a 60g cytarabine 240mL ethanol mixture, the reaction was warmed to 65 °C, four hours after the end of the reaction. The reaction was cooled to room temperature, filtered and the solid was washed with methyl tert-butyl ether (MTBE), 45°C dried in vacuo to give the N4- (the N, of N- dimethylaminomethylene) - cytarabine (N4 -DMA- cytarabine) 69.5 g, as a white solid, yield 96%, purity 99.6% (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.9% | Gambogic Acid (500 mg, 0.71 mmol) Cytarabine(156 mg, 0.64 mmol)At room temperature in N, N-dimethylformamide (5.0 mL), And then DIEA (100 mg, 0.78 mmol) was added to the mixture,And HOBT (105 mg, 0.78 mmol),After stirring for 5 minutes, TBTU (249 mg, 0.78 mmol) was added,The temperature was raised to 40 C,Stir for 3 hours.Ethyl acetate (50 ml) was added to the reaction to quench,And then washed with saturated brine (3 x 10 ml)Dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off. Column chromatography [V (methanol): V (dichloromethane) = 1.5: 100]To obtain orange yellow amorphous powder 357mg,The yield was 58.9% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.3% | Stage #1: 1-hexadecylcarboxylic acid With chloroformic acid ethyl ester; triethylamine In N,N-dimethyl-formamide for 0.333333h; Inert atmosphere; Cooling with ice; Stage #2: arabinosyl cytosine In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere; | 1 Example 1 Synthesis of PA-Ara Prodrug Molecules Analytical balance accurately weighs a certain amount of palmitic acid, dissolves in anhydrous N,N-dimethylformamide (DMF) and places it in doubleIn the flask, triethylamine and ethyl chloroformate were added under stirring, nitrogen protection and reaction under ice bath conditions for 20 minutes. Weigh a certain amountCytarabineSoluble in 5 mL of warm anhydrous DMF,The above reaction solution was slowly dropped under stirring with a molar amount of palmitic acid:triethylamine:ethyl chloroformate:cytarabine=10:11:11:12, and the reaction was returned to room temperature and continued under a nitrogen atmosphere. After 72 hours of reaction, the progress of the reaction was monitored using a thin layer plate. After completion of the reaction, dry DMF was evaporated under reduced pressure and vacuum dried overnight to give a crude product. The crude product was dissolved in ethyl acetate, a little column chromatography silica gel, silica gel column chromatography, twoThe gradient elution of methyl chloride and methanol (100:1-30:1) gave pure PA-Ara as a white solid with a yield of 64.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With α-L-rhamnosidase In aq. phosphate buffer at 60℃; for 24h; Enzymatic reaction; | 1.2.1; 1.2.2; 1.2.3 2. α-L-rhamnosidase catalyzes the synthesis of cytarabine rhamnoside(1) The concentration of rhamnose is 1.1M and the concentration of cytarabine is 0.5M using sodium phosphate buffer.The amino acid sequence is a reaction system in which the amount of α-L-rhamnosidase shown in SEQ ID NO. 1 is 10 μg/mL;The buffer in the step (1) is a sodium phosphate buffer with a concentration of 100 mM and pH 8.(2) The reaction system prepared in step (1) is reacted in a water bath at 60°C for 24 hours.The reaction was stopped by boiling at 100°C for 5 minutes, centrifuged at 12,000 rpm for 30 minutes, and the supernatant was taken;(3) The supernatant obtained in step (2) is passed through the Agilent 1200 HPLC system.The column was Waters Spherisorb 5.0μm NH2 4.6mm×250mm, flow rate 1.0mL/min, mobile phase acetonitrile: water volume ratio 70:30,UV detection wavelength is 305nm, combined with the same retention time product,The freeze-dried powder is cytarabine rhamnoside. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.3% | Stage #1: 1-decanoic acid With chloroformic acid ethyl ester; triethylamine In N,N-dimethyl-formamide for 0.333333h; Inert atmosphere; Cooling with ice; Stage #2: arabinosyl cytosine In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere; | 1 Example 1 DA-Ara Prodrug Molecular Synthesis Analytical Balance Precision Weigh a certain amount of capric acid,Dissolved in anhydrous N,N-dimethylformamide (DMF) and placedIn a double-necked flask, triethylamine and ethyl chloroformate were added under stirring, and nitrogen was protected.The reaction was carried out for 20 min under ice bath conditions. Weigh a certain amount of cytarabine dissolved in 5mL of warm anhydrous DMF.Slowly drip the above reaction solution under stirring.The molar amount is citric acid: triethylamine: ethyl chloroformate: cytarabine=12:11:11:10,The reaction was returned to room temperature and the reaction was continued under nitrogen for 72 h.The progress of the reaction was monitored using a thin layer of plates. After the reaction was completed, anhydrous DMF was removed by vacuum distillation under reduced pressure.Dry overnight in vacuo to give the crude material.The crude product was dissolved in ethyl acetate, and the mixture was purified by silica gel column chromatography.Gradient elution with dichloromethane and methanol (150:1-70:1),The pure DA-Ara product was obtained as a white solid with a yield of 64.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 35.0℃; for 24.0h; | Add cytarabine (12.2 mg) and <strong>[154-42-7]thioguanin</strong>e (8.4 mg) to the vial.Add 5 ml of N,N'-dimethylformamide and stir at 35 C for 24 hours.Upon cooling to room temperature, an amphiphilic base conjugate is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.2% | Stage #1: n-tetradecanoic acid With chloroformic acid ethyl ester; triethylamine In N,N-dimethyl-formamide for 0.333333h; Cooling with ice; Inert atmosphere; Stage #2: arabinosyl cytosine In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere; | 1 Example 1 MA-Ara Prodrug Molecular Synthesis Analyze the balance precision to weigh a certain amount of myristic acid,Soluble in anhydrous N,N-dimethylformamide (DMF)And placed in a double-necked flask, and added with triethylamine and ethyl chloroformate under stirring, nitrogen protection,The reaction was carried out for 20 min under ice bath conditions. Weigh a certain amount of cytarabine dissolved in 5mL of warm anhydrous DMF.The above reaction solution was slowly added dropwise under stirring, wherein the molar amount was myristic acid: triethylamine:Ethyl chloroformate: cytarabine = 12:11:11:10, the reaction returned to the roomThe reaction was continued under nitrogen protection for 72 h, and the progress of the reaction was monitored using a thin plate. After the reaction is over,The anhydrous DMF was evaporated under reduced pressure and dried in vacuo to give a crude material. The crude product was dissolved in ethyl acetate.A few column chromatography chromatography on silica gel, silica gel column chromatography, gradient elution with dichloromethane and methanol (150: 1-70:1),The pure MA-Ara product was obtained as a white solid with a yield of 67.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: Adipic acid With thionyl chloride; triethylamine In 1,4-dioxane at 110℃; for 4h; Inert atmosphere; Stage #2: arabinosyl cytosine With triethylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 6 Example 6 Preparation of cytarabine-succinic acid monoester prodrug (prodrug 6) 0.44 g (3 mmol) of adipic acid was dissolved in 15 ml of anhydrous dioxane, and 0.25 g (2.5 mmol) of triethylamine was added. Then, 0.28 g (2.4 mmol) of thionyl chloride was added dropwise, and the mixture was vacuumed under nitrogen, refluxed at 110 ° C for 4 h, and concentrated under reduced pressure. To a pale yellow oil, reconstituted with 10 ml of DMF. Add cytarabine 0.73g (3mmol), and add three at room temperature Ethylamine 0.19 g (1.8 mmol) was added to a vacuum of nitrogen and the reaction was stood overnight. Concentrate the reaction solution under reduced pressure A reddish brown oil was obtained. Column chromatography gave a white solid in 35% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.25 g | Stage #1: bis(trichloromethyl) carbonate; C29H58NO9PS2 With dmap In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: arabinosyl cytosine In dichloromethane for 3h; | 7 Synthesis of palmitic acid-sn-2-arabinosyl carbamate ethyldithiopropionate glycerophosphocholine (see Figure 6 for the route) 0.35 g palmitic acid-sn-2-hydroxyethyl dithiopropionic acid glycerol phosphate choline,0.10 g of triphosgene (BTC) was uniformly mixed in 100 mL of anhydrous dichloromethane. Under a nitrogen atmosphere, 0.15 g of a DMAP solution in dichloromethane was slowly added dropwise, and the reaction was stirred at room temperature for 2 h. To the above system, 0.15 g of Cytarabine was added and reacted for 3 hours. After that, the crude product was washed with aq. The product was purified by column chromatography to give 0.25 g of the product palmic acid-sn-2- cyanosyl carbamate ethyl dithiopropionate glycerol phosphate choline as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; triethylamine In N,N-dimethyl-formamide at 20℃; for 8h; | 4-N-acetyl-3',4',6'-O-triacetyl-cytarabine The cytarabine (300 mg) was dissolved in an acetic anhydride/DMF/TEA (1:1:1) mixture, and after the DMAP (5 mol%) is added. The reaction mixture was stirred at room temperature for 8 h (see reaction scheme). 4-N-acetyl-3’4’,6’-O-triacetyl-cytarabine. The product was isolated as yellow solid in quantitative yield. 1H NMR (300 MHz; CDCl3), d ppm (multiplicity; integration; J (Hz); position) 1.89 (s; 3H; H-2’’ acetyl linked to O-3’ arabinofuranosyl ring), 2.09-1.98 (m; 6H; H-2’’ acetyl linked to O-4’ and O-6’ arabinofuranosyl ring), 2.21 (s; 3H; H-2’’ acetyl linked to 4-N arabinofuranosyl ring), 4.16 (t; 1H; J = 10.5; H-5’ arabinofuranosyl ring), 4.33 (t; 2H; J = 12.3; H-6’ arabinofuranosyl ring), 5.04 (d; 1H; J = 12.2; H-4’ arabinofuranosyl ring), 5.49 (d; 1H; J = 2.5; H-3’ arabinofuranosyl ring), 6.29 (d; 1H; J = 3.4; H-2’ arabinofuranosyl ring), 7.43 (d; 1H; J = 7.6 Hz; H-5 cytosine ring), 7.88 (d; 1H; J = 7.6 Hz; H-6 cytosine ring). ESI-HRMS (positive mode) m/z: Calculated for C17H21N3O9: 411.3634; found, 434.1173 [M+Na]+. NMR carbon characterization and 2D correlation spectroscopy were reported previously. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: butyric acid With triethylamine; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 6h; Stage #2: arabinosyl cytosine With dmap In N,N-dimethyl-formamide at 20℃; for 8h; | Percylation reaction with butyric acid The DIC (1.5 equivalents with respect to theoretical amount of aliphatic acid) was dissolved in a butyric acid/ DMF/TEA (1:1:1) mixture; this was stirred at room temperature for 6 h for a pre-activation of the coupling agent, after the cytarabine (300 mg) and DMAP (5 mol%) were added. The reaction mixture was stirred at room temperature for 8 h (see reaction scheme in Fig. 1). 4-N-butyryl-3’,4’,6’-tributyryl-cytarabine. The product was isolated as yellow solid (60% yield). 1H NMR (600 MHz, DMSO-d6) d ppm (multiplicity; integration; J (Hz); position):1.3-1.0 (m; 20H; H-3’’ y H-4’’ butanoyl or butyryl chain), 1.8-1.6 (m; 8H; H-2’’ (a protons) butanoyl chain), 3,96 (m; 1H; H-6’ arabinofuranosyl ring), 4,05 (m; 1H; H-6’ arabinofuranosyl ring), 5.62 (m; 1H; H-5’ arabinofuranosyl ring), 5.67 (d; 1H; H-3’ arabinofuranosyl ring), 5,72 (d; 1H; H-4’ arabinofuranosyl ring), 6,05 (d; 1H; J = 4.5 Hz; H-2’ arabinofuranosyl ring), 7,61 (d; 1H; J = 8.1 Hz; H-5 cytosine ring), 7,78 (d; 1H; J = 8,2; H-6 cytosine ring). ESI-HRMS (positive mode) m/z: Calculated for C25H37N3O9: 523.5759; found, 546.4113 [M + Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: n-tetradecanoic acid With triethylamine; dicyclohexyl-carbodiimide In chloroform; N,N-dimethyl-formamide at 20℃; for 6h; Stage #2: arabinosyl cytosine With dmap In chloroform; N,N-dimethyl-formamide at 20℃; for 168h; | Per-acylation of amine and two hydroxyls groups General procedure: The esterification reaction for amine group (H2N-4) cytosine ring and hydroxyl groups (OH-4’ and OH-6’) of arabinofuranosyl ring of cytarabine with fatty was performed by Steglich esterification. DCC (1.5 equivalents with respect to fatty acid) was aggregated to fatty acid (4.5 equivalents with respect to nucleoside) solution in Chloroform/ DMF/TEA (1:2:1) mixture; this mix was stirred at room temperature for 6 h for a pre-activation, after DMAP (5 mol%) and cytarabine (300 mg) was added [13]. The reaction mixture was stirred at room temperature for 7 days (see reaction scheme). 4-N-myristoyl-4’,6’-O-dimyristoyl-cytarabine. The product was isolated as white solid (30% yield). 1H NMR (600 MHz; CDCl3), d ppm (multiplicity; integration; J (Hz); position): 0.92 (t; 9H; J = 6.6; H-14’’ myristoyl chain), 1.32 (m; 48H; H-4’’ to H-1300 myristoyl chain), 1.70 (m; 6H; H-3’’ (b protons) myristoyl chain), 2.40 (m; 6H; H-2’’ (a protons) myristoyl chain), 4.14 (m; 2H; H-6’ arabinofuranosyl ring), 4.44 (m; 1H; H-5’ arabinofuranosyl ring), 4.76 (d; 1H; J = 2.8; H-3’ arabinofuranosyl ring), 5.15 (m; 1H; H-4’ arabinofuranosyl ring), 6.08 (d; 1H; J = 3.2; H-2’ arabinofuranosyl ring), 7.45 (d; 1H; J = 7.8; H-5 cytosine ring), 7.90 (d; 1H; J = 7.8; 6 cytosine ring). ESI-HRMS (positive mode) m/z: Calculated for C51H91N3O8: 874.2835; found, 897.7647 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Stage #1: stearic acid With triethylamine; dicyclohexyl-carbodiimide In chloroform; N,N-dimethyl-formamide at 20℃; for 6h; Stage #2: arabinosyl cytosine With dmap In chloroform; N,N-dimethyl-formamide at 20℃; for 168h; | Per-acylation of amine and two hydroxyls groups General procedure: The esterification reaction for amine group (H2N-4) cytosine ring and hydroxyl groups (OH-4’ and OH-6’) of arabinofuranosyl ring of cytarabine with fatty was performed by Steglich esterification. DCC (1.5 equivalents with respect to fatty acid) was aggregated to fatty acid (4.5 equivalents with respect to nucleoside) solution in Chloroform/ DMF/TEA (1:2:1) mixture; this mix was stirred at room temperature for 6 h for a pre-activation, after DMAP (5 mol%) and cytarabine (300 mg) was added [13]. The reaction mixture was stirred at room temperature for 7 days (see reaction scheme). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.016 g | With sodium hydroxide In tetrahydrofuran; water at 20℃; for 3h; | 5.5-1 Synthesis Example 5-1 Synthesis of (((4-((S)-5-allyl-4-(allyloxycarbonylamino)-5-oxopentanamido)benzyl)oxy)carbonyl)cytarabine Allyl (S)-2-(allyloxycarbonylamino)-5-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-5-oxopentanoate (0.030 g) was dissolved in tetrahydrofuran (1.85 mL), cytarabine (0.014 g) was added to the solution, and then a 1 N aqueous solution of sodium hydroxide (0.15 mL) was added thereto. The mixture was stirred for 3 hours at room temperature, subsequently ethyl acetate was added thereto, and an organic layer was obtained. The organic layer thus obtained was dried over anhydrous sodium sulfate, subsequently the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=20/1 to 5/1). Thus, (((4-((S)-5-allyl-4-(allyloxycarbonylamino)-5-oxopentanamido)benzyl)oxy)carbonyl)cytarabine (0.016 g) was obtained. NMR [400 MHz, DMSO-d6, TMS] ppm: 1.79-1.93 (1H, m), 2.02-2.34 (1H, m), 3.49-3.63 (2H, m), 4.05-4.16 (1H, m), 4.47 (2H, d), 4.60 (2H, d), 4.92-5.09 (3H, m), 5.16-5.34 (4H, m), 5.68 (1H, d), 5.83 (1H, d), 5.84-5.97 (2H, m), 6.17 (1H, d), 7.24 (2H, d), 7.56 (2H, d), 7.63 (1H, d), 7.76 (1H, d), 10.00 (1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Stage #1: 4-(((25R)-spirost-5-ene-3β-yl)oxy)-4-oxobutanoic acid With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 30h; Cooling with ice; Stage #2: arabinosyl cytosine In N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere; | |
Stage #1: 4-(((25R)-spirost-5-ene-3β-yl)oxy)-4-oxobutanoic acid With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 30h; Cooling with ice; Stage #2: arabinosyl cytosine In N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere; | 1.2; 2.2 Step 2. Synthesis of Diosgenin-Cytarabine (DG-Ara-C) Polymer Dissolve 100 mg of the diosgenin-succinate (DG-SA) obtained in the above steps in 5 mL of anhydrous dichloromethane, shake well, take 29.8 mg of N-hydroxysuccinimide (NHS) and add the above DG -SA solution system, shake well, take 70mg of N,N'-dicyclohexylcarbodiimide (DCC), add the above-obtained DG-SA and DCC dichloromethane solution system, mix well, ice bath for 6 hours , The reaction system was allowed to stand at room temperature for 24 hours to activate DG-SA.(2) The above reaction system is filtered to remove precipitation, the filtrate contains activated DG-SA, and the filtrate is concentrated and used for subsequent reactions.(3) Accurately weigh 130 mg of cytarabine and dissolve in 2 mL of N,N-dimethylformamide (DMF), shake well, add to the activated DG-SA solution system after preheating, and under the protection of nitrogen React at room temperature for 48 hours.(4) The resulting reaction system was removed solvent under vacuum conditions, and purified by flash chromatography, eluted with a 5% methanol-trichloromethane solution system to obtain diosgenin-cytarabine (DG- Ara-C) Polymer. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide at 0 - 60℃; | 9 Example 9, 2’,3’,5’-tri-O-tetradecanoyl cytarabine Cytarabine (VI,244mg, 1.0mmol) was dissolved in N,N-dimethylformamide solution (15ml), Boc2O (437mg, 2.0mmol) was added to the solution at 0, and after stirring for 10 minutes, Heat to 60°C and stir for 6-8 hours. Post-treatment: the reaction solution was washed with water and extracted with ethyl acetate (10ml). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain compound VII/. Compound VII/ was dissolved in dichloromethane solution (10ml), and then triethylamine (417μl, 3mmol) and myristyl chloride (VIII/, 890mg, 3.6mmol) were added to the reaction solution, after stirring for 3-6 hours at room temperature, The reaction is complete. Post-treatment: Concentrate the reaction solution, and use the residue (X/) directly in the next reaction. | |
In N,N-dimethyl-formamide at 0 - 60℃; | 1.9 Example 9, 2', 3', 5'-tri-O-tetradecanoyl cytarabine Cytarabine (VI, 244mg, 1.0mmol) was dissolved in N,N-dimethylformamide solution (15ml), and Boc2O (437mg, 2.0mmol) was added to the solution at0and stirred for 10 minutes Then, it was heated to 60°C and stirred for 6-8 hours.Post-treatment: the reaction solution was washed with water and extracted with ethyl acetate (10ml).The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was separated and purified by column chromatography to obtain compound VII/.Compound VII/ wasdissolved in dichloromethane solution (10ml), and triethylamine (417μl, 3mmol) and myristyl chloride (VIII/, 890mg,3.6mmol) were addedto the reaction solution in turn. After stirring at room temperature for 3-6 hours, The reaction is complete.Post-treatment: Concentrate the reaction solution, and use the residue (X/) directly in the next reaction.The above product / wasdissolved in dichloromethane solution (10ml), and trifluoroacetic acid (2ml) was added to remove the protective group to obtain a white solid compound II/as the title compound with an HPLC purity of >97.6%. |
Tags: 147-94-4 synthesis path| 147-94-4 SDS| 147-94-4 COA| 147-94-4 purity| 147-94-4 application| 147-94-4 NMR| 147-94-4 COA| 147-94-4 structure
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 :