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CAS No. : | 95058-81-4 | MDL No. : | |
Formula : | C9H11F2N3O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SDUQYLNIPVEERB-QPPQHZFASA-N |
M.W : | 263.20 | Pubchem ID : | 60750 |
Synonyms : |
LY 188011;DDFC;NSC 613327
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.56 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 7.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 54.83 |
TPSA : | 110.6 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.94 cm/s |
Log Po/w (iLOGP) : | 0.61 |
Log Po/w (XLOGP3) : | -1.46 |
Log Po/w (WLOGP) : | -0.76 |
Log Po/w (MLOGP) : | -1.61 |
Log Po/w (SILICOS-IT) : | -0.94 |
Consensus Log Po/w : | -0.83 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.67 |
Solubility : | 56.7 mg/ml ; 0.215 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.36 |
Solubility : | 115.0 mg/ml ; 0.438 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.34 |
Solubility : | 121.0 mg/ml ; 0.459 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.71 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-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 |
---|---|---|
Ethylenediphosphonic acid (173 mg, 0.91 mmol) was treated with oxalyl chloride (2 mL, as solvent) and anhydrous DMF (0.1 ml, cat.). After heating at reflux for 10 minutes under argon, a solution was obtained and after a further 3 h the reaction mixture was cooled to room temperature and evacuated in vacuo. The residue was co-evaporated with anhydrous acetonitrile (3×10 ml). The residue was dissolved in anhydrous trimethyl phosphate (2 mL), cooled to -15 C. and 2'deoxy-2',2'-difluorocytidine (93 mg, 0.46 mmol) was added under argon. After stirring for 2 h the reaction mixture was quenched with ice-cold TEAB solution (1.0 M, 5 mL) and stirred for 30 minutes. Purification by HPLC gave 7.8 mg of the titled compound 81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ethanol; dichloromethane; at 20℃; | To prepare the free-base of gemcitabine, add gemcitabine hydrochloride (5. 0G) and potassium carbonate (4.0 g, 1.5 molar equivalents) to a 1.0 L round bottom flask. Then add dichloromethane (350 mL) and ethanol (300 mL). Stir vigorously the contents of the flask at room temperature overnight. Filter the milky white solution with a fritted funnel to a clean bottle. Remove a majority of the solvent by evaporation with the aid of forced dry air. Place the solids under high vacuum for 8 hours at 30 C. Free-base verification was done BYH-NMR. Yeild = 86wt% | |
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 0.0833333h; | In a separate flask (hereinafter Flask II), gemcitabine-HCl (259.2 mg, 0.667 mmol, 1.0 eq., Formula. Wt. = 299.70 g/mol) was suspended in DMF (5 mL) and treated with triethylamine (0.1 mL, 0.667 mol, 1.0 eq). This mixture was stirred for five minutes at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.4% | With hydrogenchloride; In water; isopropyl alcohol; at 20 - 70℃; | 2'-deoxy-2 ', 2'-difluoro-cytidine-3', 5'-benzoate (75.0g, 0.16mol, alpha-isomer content of 0.08%),Sodium tert-butoxide (33.6 g, 0.34 mol),Methanol (800ml) in 2L three-necked flask and mix well,Reaction at room temperature 2h,TLC detection reaction was completed,1M hydrochloric acid to adjust the pH to 7,Concentrate to dryness under reduced pressure,Water (1 L),Extraction with ethyl acetate impurity,After the ethyl acetate layer was backwash with a small amount of water,Merged water layer,Activated carbon bleaching,filter,Filtrate spin dry,Isopropyl alcohol (1 L) and concentrated hydrochloric acid (40 ml) were added to the residue,Heated to 70 C,After 30min incubation at room temperature overnight.filter,The filter cake was washed successively with cold isopropanol and n-hexane,dry,Gemcitabine hydrochloride 44.8g,Purity 99.5%alpha isomer content of 0.02%Yield 93.4%. |
91.5 - 91.9% | With hydrogenchloride; In water; acetone; at 20℃; for 2h;Product distribution / selectivity; | Example 6-1 3.5 g of 2'-Deoxy-2',2'-difluorocytidine hemihydrate (moisture content: 3.8%) obtained in Example 3-1 was dissolved in 35 ml of acetone and 1.2 ml of concentrated hydrochloric acid was added dropwise thereto. The resulting mixture was stirred at room temperature for 2 hours. The solid formed was filtered, washed with acetone and dried with warm wind to obtain 3.52 g (yield: 91.9%) of the title compound in the form of a pure white crystal. 1H-NMR (300 MHz, DMSO, d6): 9.95 (s, 1H), 8.81 (s, 1H), 8.05 (d, 1H), 6.15 (d, 1H), 5.96 (m, 1H), 4.14-4.03 (m, 1H), 3.79 (d, 1H), 3.70-3.51 (m, 2H) m.p: 287-292 C.; Example 6-2 3.5 g of 2'-Deoxy-2',2'-difluorocytidine dihydrate (moisture content: 11.5%) obtained in Example 3-2 was dissolved in 35 ml of acetone and 1.2 ml of concentrated hydrochloric acid was added dropwise thereto. The resulting mixture was stirred at room temperature for 2 hours. The solid formed was filtered, washed with acetone and dried with warm wind to obtain 3.23 g (yield: 91.5%) of the title compound in the form of a pure white crystal. H-NMR data and melting point were the same as in Example 6-1. |
90% | With hydrogenchloride; In isopropyl alcohol; at 0 - 5℃; for 2h;pH 2; | Example 11 Preparation for <strong>[95058-81-4]gemcitabine</strong> hydrochlorideCompound 2 was dissolved in isopropyl alcohol and cooled to 0 ~ 50C, and cone, hydrochloric acid was added to adjust pH to 2, maintained the temperature to let the crystal grow for 2 hours, filtered. The crystal was washed with 100 ml isopropyl alcohol to furnish 51.2g of <strong>[95058-81-4]gemcitabine</strong> hydrochloride (purity: 99.8%), yields: 90.0%. |
90% | With hydrogenchloride; In ethanol; water; for 0.5h;Reflux; | Example 7Preparation of 2'-deoxy-2',2'-difluorocytidine Hydrochloride; To 2'-deoxy-2',2'-difluorocytidine (5.4 g, 0.02 mole) was added ethanol (54 mL) and a strong hydrochloric acid (1.82 mL). The mixture was stirred under reflux for 30 minutes. The reacting solution was cooled, followed by filtration of crystals, so formed. The filtrated crystals was washed with ethanol and dried by a heat wind for 12 hours to give, in greater than 99.9% purity, 2'-deoxy-2',2'-difluorocytidine hydrochloride(5.5 g, 90%).1H-NMR (DMSO-d6)delta:3.603.64 (dd, J=3.6 Hz, 1H), 3.753.78 (dd, 1H), 3.88 (m, 1H), 4.16 (m, 1H), 6.04 (m, 1H), 6.24(d, 1H), 8.14 (d, 1H), 8.89 (s, 1H), 10.04 (s, 1H) |
90% | With hydrogenchloride; In water; isopropyl alcohol; at 0 - 5℃; for 2h;pH 2; | Example 11Preparation for <strong>[95058-81-4]gemcitabine</strong> hydrochlorideCompound 2 was dissolved in isopropyl alcohol and cooled to 05 C., and conc. hydrochloric acid was added to adjust pH to 2, maintained the temperature to let the crystal grow for 2 hours, filtered. The crystal was washed with 100 ml isopropyl alcohol to furnish 51.2 g of <strong>[95058-81-4]gemcitabine</strong> hydrochloride (purity: 99.8%), yields: 90.0%. |
90% | With hydrogenchloride; In ethanol; water; for 0.5h;Heating / reflux; | To 2'-deoxy-2',2'-difluorocytidine (5.4g, 0.02 mole) was added ethanol (54 mL) and a strong hydrochloric acid (1.82 mL). The mixture was stirred under reflux for 30 minutes. The reacting solution was cooled, followed by filtration of crystals, so formed. The filtrated crystals was washed with ethanol and dried by a heat wind for 12 hours to give, in greater than 99.9% purity, 2'-deoxy-2',2'-difluorocytidine hy- <n="15"/>drochloride(5.5 g, 90 %). [154] [155] IH-NMR (DMSO-d )delta: 3.60 ~ 3.64 (dd, J = 3.6Hz, IH), 3.75 ~ 3.78 (dd, IH), 3.88(m, IH), 4.16 (m, IH), 6.04 (m, IH), 6.24 (d, IH), 8.14 (d, IH), 8.89 (s, IH), 10.04 (s,IH) |
18.9% | With hydrogenchloride; In methanol; water; at 0 - 5℃; for 1h;Product distribution / selectivity; | ExampIe-8 Preparation of Gemdtbine Hydrochloride (lib)The residue obtained from Example-7 (Gemcitabine free base, lie) was dissolved in methanol (20 ml) and decolourised with activated carbon (0.35 gm). The carbon was filtered off and to the filtrate was added Cone, hydrochloric acid (1.0 ml) and the mixture cooled to 0 C and agitated at a temperature of 0 C to 5 C for 1 hr and the precipitated solid filtered and dried to give 0.43 gm (18.9%) of the title compound as a white crystalline solid. HPLC analysis showed the product to be comprising of 95% of the beta-anomer. ExampIe-9 Purification of Gemcitabine Hydrochloride (lib) The Gemcitabine hydrochloride (0.43 gm; obtained from Example-8 was dissolved in D.M water (3.5 ml) at 55 - 60 C. The solution was decolourised with activated carbon (50 mg) and the carbon filtered off. The filtrate was mixed with acetic acid (34 ml) and the mixture was stirred at room temperature for 2hrs. The precipitated solid was filtered and dried at 60-70 C under vacuum for 5-6 hr to give 0.35gm (81%) of Gemcitabine hydrochloride (lib) having an anomeric purity of 99.94 % of the beta- anomer. |
12.7% | With hydrogenchloride; In methanol; water; at 0 - 5℃; for 1h;Product distribution / selectivity; | Example-5 Preparation of Gemcitabine Hydrochloride QIb)The residue obtained from Example-4 (Gemcitabine free base, lie) was dissolved in methanol (28 ml) and decolourised with activated carbon (0.7 gm). The carbon was filtered off and to the filtrate was added Cone, hydrochloric acid (1.12 ml) and the mixture cooled to 0 C and agitated at a temperature of 0 C to 5 C for 1 hr and the precipitated solid filtered and dried to give 0.56 gm (12.7%) of the title compound as a white crystalline solid. HPLC analysis showed the product to be comprising of 95% of the beta-anomer. ExampIe-6 Purification of Gemcitabine Hydrochloride (lib)The Gemcitabine hydrochloride (0.56 gm; obtained from Example-5 was dissolved in D.M water (4.5 ml) at 55 - 60 C. The solution was decolourised with activated carbon (56 mg) and the carbon filtered off. The filtrate was mixed with acetic acid (45 ml) and the mixture was stirred at room temperature for 2h. The precipitated solid was filtered and dried at 60-70 C under vacuum for 5-6 hr to give 0.45gm (80%) of Gemcitabine hydrochloride (Hb) having an anomeric purity of 99.94 % of the beta- anomer. |
With hydrogenchloride; In ethanol; water; at 0℃; | 8.4 g of Compound 11 i.e. beta-1-(2'-deoxy-2'2'-difluoro-D-ribofuranosyl)-4-aminopyrimidine-2-one was mixed with 20 ml deionized water. At 0 C., 4N HCl was slowly dropped into the mixture until complete dissolution of Compound 11. Then 50-100 times of volume of anhydrous ethanol was added and the temperature of the solution was lowered to -5 C. While maintaining at this temperature, the solution was stirred, filtered and washed with cool anhydrous ethanol and then dried in vacuum. Finally 6.2 g of Compound 12 was obtained. The data of the optical rotation and various spectrometry of the obtained Compound 12 were identical with those reported by Chou, T. S. in Synthesis, 1992, 565. i.e. [alpha]D (c=1.0, D2O) +47.56; [alpha]365 +255.7, elemental analysis: C9H11ClF2N3O4: calcd. for: C, 36.07; H, 4.04; Cl, 11.83; F, 12.68; N, 14.02. found: C, 36.13; H, 4.10; Cl, 11.90; F, 12.63; N, 13.89. IR (KBr): upsilon=3490, 3345, 1660, 1623, 1036 cm-1, 13C NMR (D2O) delta=61.01 (C-5'), 70.12 (C-3'), 82.16 (C-4'), 85.50 (C-1'), 97.40 (C-5), 124.03 (C-2'), 145.16 (C-6), 150.56 (C-2), 164.23 (C-4). | |
With hydrogenchloride; In methanol; water; ethyl acetate; at 5 - 20℃;Product distribution / selectivity; | The oil obtained according to Example 8 (15 g) was added with 45 ml of MeOH and 3.7 g of 37% HCl at room temperature, after a few minutes a precipitate formed. After addition of 45 ml of AcOEt, the mixture was stirred for 2h at room temperature, then overnight at 5C. The solid was filtered and washed with 1 ml of cold MeOH and 2x2 ml of AcOEt to give 2.79 g of form beta (HPLC purity: 97%; area corresponding to the content in form alpha: 2.7%). | |
In isopropyl alcohol; at 0 - 5℃;pH 2; | Step-VII: The residue (3.5 gm, obtained in step-VI) is dissolved in isopropyl alcohol (50 ml), the pH is adjusted to 2 with 20% hydrochloric acid at 0 - 50C and then distilled the solvent to get residue. To the residue acetone (60 ml) is added and stirred for 5 minutes. The separated solid is filtered, washed three times with acetone (50 ml) and then dissolved in water (1 ml). To this solution added acetone (15 ml). The separated solid is filtered and dried to give 2.5 gm of <strong>[95058-81-4]gemcitabine</strong> hydrochloride (HPLC Purity: 99.6%). | |
(1) Gemcitabine HCl 89% GEM HCl, 10% Isomalt, 1% Lubritab (water insoluble), or |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.6% | With ammonia; In methanol; at 20℃;Product distribution / selectivity; | 32.2 g of cytosine and 184 mg of ammonium sulfate were added to 184 mi of hexamethyldisilazane. The mixture was refluxed for 1 hour and 250 mi of heptane was added thereto and heated to 135 to 140 0C to distil 5 off unreacted hexamethyldisilazane. 150 mi of heptane and 10.0 g of 1 -alpha-bromo-2 '-deoxy-2 ',2 '-difluoro-D-ribofalpharanosyl-5-benzoyl-3-(4-phenyl) benzoate obtained in Preparation 1 were added to the resulting solution and then 38.7 mi of diphenylether was added thereto. The resulting mixture was allowed to react for 10 hours while adding dropwise 1.5 i of heptane o thereto and at the same time carrying out distillation with maintaining the reaction temperature at 135 to 140 C . This procedure allowed the continuous removal of trimethylsilyl bromide from the reaction mixture during the course of the reaction. After completing the reaction, 240 mi of heptane was added to the resulting solution and 11.6 ml of water was slowly 5 added thereto. The solid formed was stirred, filtered, washed with heptane and dried at room temperature, to obtain a mixture of alpha- and beta-nucleoside isomers including unreacted cytosine in the form of a white solid. The nucleoside mixture was examined by HPLC analysis to find that the alpha-nucleoside : beta-nucleoside ratio was 1:6.1 (See Fig. 1). The solid was 0 suspended in 300 mi of methylene chloride and 60 mi of methanol solution, and refluxed for 2 hours. The resulting mixture was filtered, the filtered solid was washed with a mixture of methylene chloride (150 mi) and methanol (30 mi) and distilled under a reduced pressure, to obtain an alpha/beta mixture of 1 -(2 '-deoxy-2 ',2 '-difluoro-5-benzoyl-3-(4-phenyl)benzoyl-D- 5 ribo:fi^mosyl-4-amMopyrimidin-2-one. The residue solid was added with200 mi of methanol and 83 mi of 7N-ammonia/methanol solution, and stirred at room temperature overnight. After completing the reaction, the solvent was removed under a reduced pressure, and 80 mi of ethyl acetate and 90 mi of water were added to the residue. The aqueous layer was o separated and the ethyl acetate layer was extracted with 40 mi of water.The aqueous layers were combined and washed with 40 mi of ether (x2). EPO <DP n="22"/>The water was distilled off under a reduced pressure until water was left in the amount of 5 times based on the theoretical weight of the desired product, and the residue was heated to 50 to 55 "C and cooled to room temperature with stirring for 2 hours to induce the precipitation of a solid. The precipitated solid was filtered, washed with water and acetone and dried with warm wind overnight, to obtain 3.69 g (yield: 72.6%) of the title compound in the form of a pure white crystal.Moisture content: 3.5% H-NMR data and melting point were the same as in Example 3-1. HPLC purity (area %): beta-anomer - 99.9%, alpha-anomer - less than 0.01% cytosine - less than 0.02% |
72.6% | With ammonia; In methanol; at 20℃;Product distribution / selectivity; | 32.2 g of cytosine and 184 mg of ammonium sulfate were added to 184 mi of hexamethyldisilazane. The mixture was refluxed for 1 hour and 250 mi of heptane was added thereto and heated to 135 to 140 C to distil off unreacted hexamethyldisilazane. 150 ml of heptane and 10.0 g of l-alpha-bromo-2'-deoxy-2',2'-difluoro-D-ribofuranosyl-5-benzoyl-3-(4-phenyl) benzoate obtained in Preparation 1 were added to the resulting solution and then 38.7 ml of diphenylether was added thereto. The resulting mixture was allowed to react for 10 hours while adding dropwise 1.5 I of heptane thereto and at the same time carrying out distillation with maintaining the reaction temperature at 135 to 140 C . This procedure allowed continuous removal of trimethylsilyl bromide from the reaction mixture during the course of the reaction. After completing the reaction, 240 mi of heptane was added to the resulting solution and 11.6 ml of water was slowly added thereto. The solid formed was stirred, filtered, washed with heptane and dried at room temperature, to obtain a mixture of alpha- and beta-nucleoside isomers including unreacted cytosine in the form of a white solid. The nucleoside mixture was examined by HPLC analysis to find that the alpha-nucleoside : beta-nucleoside ratio was 1:6.1 (See Fig. 1). The solid was suspended in 300 mi of methylene chloride and 60 mi of methanol solution, and refluxed for 2 hours. The resulting mixture was filtered, the filtered solid was washed with a mixture of methylene chloride (150 mi) and methanol (30 mi) and distilled under a reduced pressure, to obtain an alpha/beta mixture of l-(2'-deoxy-2',2'-difluoro-5-benzoyl-3-(4-phenyl)benzoyl-D- ribofuranosyl-4-aminopyrimidin-2-one. The residue solid was added with 200 mi of methanol and 83 mi of 7N-ammonia/methanol solution, and stirred at room temperature overnight. After completing the reaction, the solvent was removed under a reduced pressure, and 80 mi of ethyl acetate and 90 mi of water were added to the residue. The aqueous layer was separated and the ethyl acetate layer was extracted with 40 mi of water. EPO <DP n="23"/>The aqueous layers were combined and washed with 40 ml of ether (x2). The water was distilled off under a reduced pressure until water was left in the amount of 5 times based on the theoretical weight of the desired product, and the residue was heated to 50 to 55 C and cooled to room temperature with stirring for 2 hours to induce the precipitation of a solid. The precipitated solid was filtered, washed with water and acetone and dried with warm wind overnight, to obtain 3.69 g (yield: 72.6%) of the title compound in the form of a pure white crystal.Moisture content: 3.5%H-NMR data and melting point were the same as in Example 3-1. HPLC purity (area %): beta-anomer - 99.9%, alpha-anomer - less than 0.01% cytosine - less than 0.02% |
With ammonia; In methanol; at 20℃;Product distribution / selectivity; | 2'-Deoxy-2',2'-difluorocytidine (Compound of formula (I)-2: Gemicitabine) 32.2 g of cytosine and 184 mg of ammonium sulfate were added to 184 ml of hexamethyldisilazane. The mixture was refluxed for 1 hour and 250 ml of heptane was added thereto and heated to 135 to 140 C. to distil off unreacted hexamethyldisilazane. 150 ml of heptane and 10.0 g of 1-alpha-bromo-2'-deoxy-2',2'-difluoro-D-ribofuranosyl-5-benzoyl-3-(4-phenyl)benzoate obtained in Preparation 1 were added to the resulting solution and then 38.7 ml of diphenylether was added thereto. The resulting mixture was allowed to react for 10 hours while adding dropwise 1.5 l of heptane thereto and at the same time carrying out distillation with maintaining the reaction temperature at 135 to 140 C. This procedure allowed continuous removal of trimethylsilyl bromide from the reaction mixture during the course of the reaction. After completing the reaction, 240 ml of heptane was added to the resulting solution and 11.6 ml of water was slowly added thereto. The solid formed was stirred, filtered, washed with heptane and dried at room temperature, to obtain a mixture of alpha- and beta-nucleoside isomers including unreacted cytosine in the form of a white solid. The nucleoside mixture was examined by HPLC analysis to find that the alpha-nucleoside:beta-nucleoside ratio was 1:6.1 (See FIG. 1). The solid was suspended in 300 ml of methylene chloride and 60 ml of methanol solution, and refluxed for 2 hours. The resulting mixture was filtered, the filtered solid was washed with a mixture of methylene chloride (150 ml) and methanol (30 ml) and distilled under a reduced pressure, to obtain an alpha/beta mixture of 1-(2'-deoxy-2',2'-difluoro-5-benzoyl-3-(4-phenyl)benzoyl-D-ribofuranosyl-4-aminopyrimidin-2-one. The residue solid was added with 200 ml of methanol and 83 ml of 7N-ammonia/methanol solution, and stirred at room temperature overnight. After completing the reaction, the solvent was removed under a reduced pressure, and 80 ml of ethyl acetate and 90 ml of water were added to the residue. The aqueous layer was separated and the ethyl acetate layer was extracted with 40 ml of water. The aqueous layers were combined and washed with 40 ml of ether (×2). The water was distilled off under a reduced pressure until water was left in the amount of 5 times based on the theoretical weight of the desired product, and the residue was heated to 50 to 55 C. and cooled to room temperature with stirring for 2 hours to induce the precipitation of a solid. The precipitated solid was filtered, washed with water and acetone and dried with warm wind overnight, to obtain 3.69 g (yield: 72.6%) of the title compound in the form of a pure white crystal. Moisture content: 3.5% H-NMR data and melting point were the same as in Example 3-1. HPLC purity (area %): beta-anomer-99.9%, alpha-anomer-less than 0.01% cytosine-less than 0.02% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With ammonia; water; at 20℃; for 3h; | Example 6 Preparation of 2'-deoxy-2',2'-difluorocytidine; To 2',2'-difluoro-3',5'-bis-(3-fluorobenzoyloxy)-2'-deoxycytidine (10.4 g, 0.02 mole) were added methanol (104 mL) and 30% ammonia water (20.8 mL). The mixture was stirred at room temperature for 3 hours. With completion of the reaction, the reacting mixture was evaporated under reduced pressure. The concentrate was diluted with water (104 mL) and washed with ethyl acetate (100 mL) two times. The aqueous layer was evaporated under reduced pressure to give 2'-deoxy-2',2'-difluorocytidine (5.4 g, 100%).1H-NMR (DMSO-d6)delta:3.603.64 (dd, J=3.6 Hz, 1H), 3.753.78 (dd, 1H), 3.88 (m, 1H), 4.16 (m, 1H), 6.04 (m, H), 6.24 (d, 1H), 8.14 (d, 1H), 8.89 (s, 1H), 10.04 (s, 1H) |
100% | With methanol; ammonia; water; at 20℃; for 3h; | To 2',2'-difluoro-3',5'-bis-(3-fluorobenzoyloxy)-2'-deoxycytidine (10.4g, 0.02 mole) were added methanol (104 mL) and 30% ammonia water (20.8 mL). The mixture was stirred at room temperature for 3 hours. With completion of the reaction, the reacting mixture was evaporated under reduced pressure. The concentrate was diluted with water (104 mL) and washed with ethyl acetate (100 mL) two times. The aqueous layer was evaporated under reduced pressure to give 2'-deoxy-2',2'-difluorocytidine (5.4g, 100 %).[149][150] IH-NMR (DMSO-d )delta: 3.60 ~ 3.64 (dd, J = 3.6Hz, IH), 3.75 ~ 3.78 (dd, IH), 3.88(m, IH), 4.16 (m, IH), 6.04 (m, H), 6.24 (d, IH), 8.14 (d, IH), 8.89 (s, IH), 10.04 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; | To a mixture of 4-amino-i -((2R,4R,5R)-3 ,3-difluoro-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (527 mg, 2 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (434 mg, 2 mmol) in DMF (5 mL) was added Et3N (0.92 mL, 6.6 mmol) followed by PyBOP (1.24 g, 2.4 mmol). The reaction mixture was stilTed at room temperature overnight then concentrated. The crude residue was treated with aq. NaHCO3 then extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over Na2SO4 The mixture was filtered, concentrated and the residue purified twice by ISCO using DCM/MeOH (0-10%) as eluent to afford 260 mg (28%) of product. C,9H28F2N407: 462.19; found: 463.3 (M + Hj. |
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; N,N-dimethyl-formamide; at 55℃; for 17h;Inert atmosphere; | General procedure: To a solution of <strong>[95058-81-4]gemcitabine</strong> (1.0 equiv), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (1.3 equiv), 4-methylmorpholine (1 equiv), and 1-hydroxybenzotriazole (1 equiv)in DMF/DMSO (5 mL, 3:1) was added dropwise N-Boc protected amino acid (1.1 equiv) at roomtemperature in a N2 atmosphere. The reaction mixture was then stirred in an oil bath at 55 C for 17 h, cooled to room temperature and quenched by adding brine (5 mL). The mixture was then extractedusing ethyl acetate (3 x 10 mL) and the combined organic layer was washed with 20% LiCl solution,saturated NaHCO3 aqueous solution, and brine, dried over MgSO4, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography (DCM/methanol = 15:1)to afford the desired product 2. To a solution of the mixture of aforementioned intermediate inanhydrous DCM (1 mL) was added 4N HCl in dioxane (1 mL). The mixture was then stirred for 12 hat room temperature, solvent was removed, and the residue was purified by silica gel flash columnchromatography (DCM/methanol = 3:1) to afford the desired product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: gemcitabine With trichlorophosphate at 20℃; for 0.15h; Flow reactor; Green chemistry; Stage #2: With water at 20℃; Flow reactor; Green chemistry; chemoselective reaction; | |
53% | With trimethyl phosphite; trichlorophosphate at -5℃; for 2h; | |
With recombinant deoxyribonucleoside kinase AtdNK from Arabidopsis thaliana (ecotype Columbia); ATP In aq. buffer Enzymatic reaction; |
Multi-step reaction with 5 steps 1: pyridine / 4 h / 0 - 20 °C 2: pyridine / 2 h / 0 - 20 °C 3: toluene-4-sulfonic acid / dichloromethane / 2 h / 20 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 4 h / 20 °C 5: ammonium hydroxide | ||
Multi-step reaction with 7 steps 1: pyridine / 4 h / 0 - 20 °C 2: pyridine / 2 h / 0 - 20 °C 3: toluene-4-sulfonic acid / dichloromethane / 2 h / 20 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane 5: 1H-tetrazole; water / acetonitrile 6: pyridine; iodine; triethylamine; water 7: ammonium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ethylenediphosphonic acid (173 mg, 0.91 mmol) was treated with oxalyl chloride (2 mL, as solvent) and anhydrous DMF (0.1 ml, cat.). After heating at reflux for 10 minutes under argon, a solution was obtained and after a further 3 h the reaction mixture was cooled to room temperature and evacuated in vacuo. The residue was co-evaporated with anhydrous acetonitrile (3×10 ml). The residue was dissolved in anhydrous trimethyl phosphate (2 mL), cooled to -15 C. and 2'deoxy-2',2'-difluorocytidine (93 mg, 0.46 mmol) was added under argon. After stirring for 2 h the reaction mixture was quenched with ice-cold TEAB solution (1.0 M, 5 mL) and stirred for 30 minutes. Purification by HPLC gave 7.8 mg of the titled compound 81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With water; hydrogen;Rh/Al2O3; under 2068.65 Torr; for 96h; | 2'2'-DiFluoro-DiHydro-lJridine (DFDHU, 25). Gemcitabine 24 (3.0 g, 11.4 mmol) is dissolved in H2O (50 mL). Rhodium on alumina (900 mg) is added to the solution and the mixture is hydrogenated overnight at 40 psi. The next day, the mixture is filtered, the water is removed in vacuo and the resulting sticky solid is dissolved in H2O again. Rhodium on alumina is added to the solution (900 mg) and the material is hydrogenated overnight at 40 psi.The rhodium is filtered off and the resulting filtrate is concentrated to afford a crude mixture of difluorodihydrouridine (5, DFDHU) and -10% of difluorotetrahydrouridine Ia and Ib(DFTHU). The crude mixture is purified on reverse phase HPLC (reverse phase C18 (at) 5%CH3CN/H2O) to afford 1.84 g (61%, 14.5 minutes) of DFDHU 25 and 175 mg (17%, Ia, 9.5 minutes and Ib, 13.9 minutes) of the epimers of DFTHU. The absolute configuration of C-4 for compound Ia is determined by single crystal X-ray diffraction, and is consistent with literature precedents on the crystal structure of cytidine deaminase in complex with a single <n="32"/>epimer of tetrahydrouridine. 1HNMR of 5: 6.00 (dd, IH), 4.20 (q, IH), 3.92-3.72 (m, 3H), 3.64 (m, IH), 3.43 (m, IH), 2.68 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | 0.209 g (0.522 mmol) of SQCOOH obtained in a) dissolved in 1 ml of anhydrous tetrahydrofuran (THF) was placed in a three-necked flask provided with a flow meter and then 0.053 g (0.522 mmol) of triethylamine (TEA) dissolved in 0.5 ml of anhydrous THF were added, with stirring with a magnetic stirrer and with a stream of argon. The flask was then cooled to -15 C. 0.057 g (0.522 mmol) of ethylchloroformate dissolved in 2.15 ml of anhydrous THF was added dropwise to the reaction mixture. After 20 minutes at -15 C., 0.137 g (0.522 mmol) of <strong>[95058-81-4]gemcitabine</strong> dissolved in 2.72 ml of dimethylformamide (DMF) was added and the temperature was increased to +5 C. and finally to ambient temperature. The reaction was monitored by thin layer chromatography (dichloromethane/acetone, 50:50) and magnetic stirring was continued for several days until the amide had formed. The crude product was purified by silica gel flash chromatography eluting with dichloromethane/acetone 95:5 mixture. Yield: 55% (0.185 g, 0.287 mmol).1H NMR (pyridine-d5 99.5% 300 MHz) delta: 12.05 (1H, s, NHCO), 8.77 (1H, d, CH-6), 7.74 (1H, d, CH-5), 6.99 (1H, t, CH-1'), 5.30-5.02 (1H, m, CH-3' and 5H, m, CH vinyl), 4.47-4.31 (3H, m, CH-4' and CH2-5'), 2.81 (2H, t, NHCOCH2), 2.53 (2H, t, NHCOCH2CH2), 2.18-2.00 (16H, m, CH2 allyl), 1.68-1.55 (18H, m, CH3 allyl). CIMS (isobutane) m/z 646 (100).EIMS m/z 645 (10), 577 (8), 523 (7), 509 (18), 494 (10), 454 (15), 429 (24), 372 (100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6,8-5/s-benzylthio-octanoic acid (259.2 mg, 0.667 mmol, 1.0 eq., Mol. Wt. = 388.60 g/mol) was dissolved in dimethyl formamide (DMF, 5 mL) and treated with O-il- Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 253.6 mg, 0.667 mmol, 1.0 eq., Mol. Wt. = 380.23 g/mol) and triethylamine (0.14 mL, 1 mmol, 1.5 eq.). This reaction mixture was stirred at room temperature for five minutes.[0091] Part II: In a separate flask (hereinafter Flask II), gemcitabine-HCl (259.2 mg, 0.667 mmol, 1.0 eq., Formula. Wt. = 299.70 g/mol) was suspended in DMF (5 mL) and treated with triethylamine (0.1 mL, 0.667 mol, 1.0 eq). This mixture was stirred for five minutes at room temperature.[0092] Part III: The contents of the flask containing the activated 6,8-bz's-benzylthio- octanoic acid (from Part I) were cannulated into Flask II (from Part II). The pH of the reaction mixture was ensured to be >7 by testing with wet pH paper. The reaction was allowed to proceed overnight at room temperature. Then, the solvent (DMF) was evaporated under reduced pressure at 44 C to yield the crude product as an oil. The crude product was purified by preparative thin layer chromatography on silica gel: 2 x 1 mm thick plates, eluent: 8% methanol in dichloromethane. The two bands with the highest polarity (lowest Rf) other than the baseline were isolated and the products were recovered by separately eluting the scrapings with 10% methanol in ethyl acetate. These two products, which were verified by mass spectrometry (634 (M + 1), 650 (M + Na)), NMR (DMSO-d<5, at 400 mHz), NMR-COSY and D20-exchange experiments, corresponded to the ester and amide formed by the reaction of 6,8- bz's-benzylthio-octanoic acid with gemcitabine. The structure of each formed conjugate is provided below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 4 - 25℃; for 2h; | 2',2'-difluorodeoxycytidine (0.79 g, 3.0 mmol) was co-evaporated with anhydrous pyridine (15 mL × 3) and re-suspended in 3 mL of the solvent. A solution of trimethylchlorosilane (1.95 g, 18.0 mmol) in 10 mL anhydrous pyridine was then added to the nucleoside at 4 C. The reaction mixture was vigorously stirred for 2 h at 25 C, and then butyryl chloride (0.48 g, 4.5 mmol) was added dropwise. The reaction was continued for additional 2 h, and then the precipitate was filtered. The combined filtrates were evaporated to dryness and treated with a dioxane-water mixture (5:3 v/v) for 6 h at 25 C. The reaction progress was monitored by TLC on silicagel in methanol-dichloromethane (1:9 v/v). The concentrated in vacuo product was purified by flash chromatography on silica gel column using a concentration gradient of methanol (0 to 10% v/v) in dichloromethane as an eluent. Fractions with N-acylated Gemcitabine were collected and concentrated in vacuo with a yield of 74%. | |
With pyridine; In N,N-dimethyl-formamide; for 1h;Cooling with ice; | Gemcitabine base (2.00 g, 7.60 mmol) was dissolved in a round bottom flask with DMF (10 mL). Anhydrous pyridine (3.06mL, 38 mmol) was added to the solution and stirred using a magnetic stirrer over an ice bath. Chlorotrimethylsilane (4.82 ml_, 38 mmol) was added to the solution dropwise and the reaction was stirred for one hour. The product showed a positive ion m/Z of 408. Oleyl chloroformate (2.56. g, 7.6 mmol, 1 :1 molar ratio with <strong>[95058-81-4]gemcitabine</strong>) was dissolved in DMF (2 ml_) and was added to the solution dropwise. The reaction was left to stir at room temperature for two hours. The reaction was quenched and the protecting silyl ether was removed at the conclusion of the reaction by the addition of deionized water (3 ml_) followed by stirring for three hours. The reaction mixture was evaporated under reduced pressure and the resulting residue was taken up in diethyl ether and a small amount of water before being separated in an extraction funnel. The organic phase was collected and dried over Na2S04 followed by evaporation under reduced pressure, resulting in the crude product. The crude product was purified using a Reveleris C18 40 g in a preparative HPLC. The pure fractions were collected and evaporated to dryness to give 2.30 g of a white wax (yield: 54.3 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With pyridine; at 20℃; for 48h; | To the solution of <strong>[95058-81-4]gemcitabine</strong> (2 g, 7.60 mmol) in dry pyridine (20 mL), 1,3- dichloro-l,l,3,3-tetraisopropyldisloxane (TPDSC12) (2.91 mL, 9.12 mmol) was added slowly with stirring. The mixture was stirred at room temperature for 48 h. Pyridine was then removed under reduced pressure and the residue was subjected to a silica gel column chromatography, with a gradient of methanol (1-2.5%) in CH2CI2 to give the title compound as a white foam (3.20 g, 84%). 1H NMR (600 MHz, DMSO-d6) delta 7.48 (d, J = 7.8 Hz, 1H), 7.42 (br s, 2H, NH2) 6.11 (m, 1H), 5.78 (d, J= 7.8 Hz, 1H), 4.26-4.48 (br s, 1H), 4.17 (dd, J = 3.6 and 13.2 Hz, 1H), 3.952-4.42 (m, 2H), 0.98-1.10 (m, 28H) |
82.3% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | 36.1 mmol of compound A-1 was dissolved in 300 mL of DMF under nitrogen protection.39.7 mmol of 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSCl2) was added with stirring and79.5 mmol of imidazole was reacted at room temperature for 16 hours. Remove the solvent by vacuum and add 1L of distilled water.The solid was filtered and recrystallized from tert-butyldimethylsilyl ether (TBDME-OR).15g of white solid compound A-2 was obtained with a yield of 82.3% |
72% | With pyridine; at 20℃; for 48h; | j00231j To the solution of <strong>[95058-81-4]gemcitabine</strong> (Compound 1 in Figure 1) (136.6 mg, 0.52 mmol) in dry pyridine (40 mL), 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSiC12) (0.17 mL) was added slowly with stirring. The mixture was stirred at room temperature for 48 h. Pyridine was then removed under reduced pressure and the residue was subjected to a silica gel column chromatography, with a gradient of methanol (1-2.5%) in CH2C12 to give Compound 2 as a white foam (189.7 mg, 72%). |
72% | With pyridine; at 20℃; for 48h; | [00153j To a solution of gemeitahine (136.6 rug, 0.52 mmol) in dry pyridine (40 rnh), 1,3- dichloro- 1,1 ,3,3-tetraisopropyidisiloxane (TIPDSiC12) (0.1 7 mL) was added slowly with stirring. The mixture was stirred at room temperature for 48 h. Pyridine was then removed under reduced pressure arid the residue was subjected to a silica gel column chromatography?, with a gradient of methanol (1-2.5%) in CH2CI2 to give 3? ,5 ?-O-( 1,1 ,3,3-tetraisopropyldisiioxane- I ,3- dily) gerneitahine as a white foam (189.7 mg, 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyridine; at 20℃; for 4h; | Taking <strong>[95058-81-4]gemcitabine</strong> as an example, the synthesis of phosphoramidite monomers was carried out according to the following synthetic route.First, 4,4-bismethoxytrityl chloride (DMT-Cl) (3.38 g, 10 mmol) and <strong>[95058-81-4]gemcitabine</strong> (2.63 g, 10 mmol) were weighed, 50 mL of anhydrous pyridine was added, stirred well, and stirred at room temperature for 4 h. . Then 5 mL of methanol was added and the reaction was stirred for a further 30 min. Vacuum distillation to removeSeparation product by column chromatographyA white powder (Compound 2) was obtained in a yield of 80%. |
64% | With pyridine; at 0 - 20℃; for 4h; | 4,4-Dimethoxytrityl chloride (745mg; 2.2 mmol) was added to a solution of <strong>[95058-81-4]gemcitabine</strong> (680mg, 2 mmol) in dry pyridine (20 mL). The reaction mixture was stirred at 0C for 3 hours andthen allowed to stand 1h at room temperature. Pyridine was then removed under reducedpressure and the residue was dissolved in CHCl3 (10 mL) and washed with H2O (3x 10 mL),dried over anhydrous MgSO4 and concentrated in vacuo. The product was isolated by silicagel column chromatography using methanol in chloroform (08%) as an eluent. 5?-ODimethoxytrityl-2?,2?-difluoro-2?-deoxycytidine was obtained in 64% yield. FAB- MS m/z:(M-1) 564; 1H NMR (CDCl3): 7.74-7.70 (d, 2H), 7.43-7.28 (m, 9H), 6.85-6.80 (d, 4H), 6.47-6.39 (t, 1H), 5.52-5.48 (d, 1H), 4.46-4.12 (m, 1H), 4.07-4.03 (d, 1H), 3.77 (s, 6H), 3.58-3.39(m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | With triethylamine; In pyridine; at 20℃; for 6h;Inert atmosphere; Cooling with ice; | A suspension of <strong>[95058-81-4]gemcitabine</strong> (2, 39.5 g, 0.15 mol), Et3N (41.8 mL, 0.30 mol) in anhydrous pyridine (500 mL) was placed in an ice bath. Triphenylmethyl chloride (47.4 g, 0.17 mol) was added in potions within 1 h. The resulting mixture gradually became homogenous and was further stirred at room temperature for 5 h until the completion of the reaction detected by TLC. The reaction solution was concentrated under reduced pressure to remove pyridine. Then the residual was diluted with ethanol (100 mL) and poured into ice-water (1.0 L) with stirring. The formed solid was collected by filtration and washed with water to give the crude, which was recrystallized from ethyl acetate to afford the pure 5'-Tr-<strong>[95058-81-4]gemcitabine</strong> (69.2 g, 91.2%) as white solid. mp 267-269 C; 1H NMR (600 MHz, DMSO-d6): delta 3.27-3.29(m, 2H), 3.98(d, J=8.4 Hz, 1H), 4.26-4.31(m, 1H), 5.63(d, J=7.5 Hz,1H), 6.17(s, 1H), 6.33(s, 1H), 7.18-7.24(m, 2H), 7.35-7.40(m, 15H), 7.62(d, J=7.5 Hz, 1H); ESI-MS(m/z): 506.2[M+H]+, 528.2[M+Na]+,544.2[M+K]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.54 g | In N,N-dimethyl-formamide; at 20℃; for 5h; | A solution of gemcitabine (5.0g, 19mmol) and <strong>[14316-61-1]phenoxyacetic anhydride</strong> (6.0g, 20.9mmol) in anhydrous Nu,Nu-dimethylformamide (200ml) was stirred at room temperature. After 5 hours, the mixture was concentrated in vacuo and triturated with ethyl acetate. The solids were isolated by filtration and dried in a vacuum oven for 30 minutes furnishing N-phenoxyacetyl-gemcitabine (6.54g) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 1 1.15 (1 H, s), 8.29 (1 H, d), 7.31 (2H, t), 7.20 (1 H, d), 7.06-6.88 (3H, m), 6.32 (1 H, d), 6.19 (1 H, t), 5.36-5.25 (1 H, m), 4.85 (2H, s), 4.28-4.12 (1 H, m), 3.97-3.87 (1 H, m), 3.81 (1 H, d), 3.74-3.60 (1 H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; | S1. The anticancer prodrug molecule <strong>[95058-81-4]gemcitabine</strong> Gem (1 g, 3.8 mmol)Dissolved in 25 mL of anhydrous DMF (dimethylformamide), imidazole (0.78 g, 11.5 mmol) and TBDMSCl (tert-butyldimethylchlorosilane) (1.5 g, 9.6 mmol) were added sequentially; the mixture was stirred at room temperature overnight. After completion, the solvent was removed under reduced pressure and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography to give TBSGem. |
93% | With 1H-imidazole; triethylamine; In N,N-dimethyl-formamide; at 20℃; | The compound a 8.8 g (33.5 mmol) was dissolved in 200 ml of DMF, to which was added imidazole 6.8 g (100.5 mmol) and 5.1 ml of triethylamine (36.9 mmol), and 12.7 g (83.8 mmol) of TBSCl was added thereto in portions under ice, Plus finished, naturally rose to room temperature reaction overnight. TLC monitoring of the basic reaction is complete. The reaction was quenched by adding saturated aqueous ammonium chloride solution to the system, extracted with ethyl acetate (EA) three times. The organic phases were combined, washed with saturated brine five times, dried over anhydrous sodium sulfate, dried and the column was passed through EA to give white Solid 15.4 g. Yield 93% . |
88% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; | Gemcitabine (Compound 3, 1.0 g, 3.80 mmol) was dissolved in 10 mL of dry DMF, TBDMS-Cl (1.15 g, 7.64 mmol) and 1.03 g of imidazole were added, stirred at room temperature, and the reaction was completed by thin layer chromatography. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced vacuo. Crude chromatographyPurification (mobile phase methanol: dichloromethane = 1:25-1:15) gave 1.64 g, yield 88%. |
87.3% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18h; | Gemcitabine 2 (2.63 g, lO.OO mmol) was dissolved in 200 mL of dry DMF and TBDMS-Cl (6.00 g, 40 Ommol) and imidazole (2.72 g, 40 O mmol) were added and stirred at room temperature After 18 h, the solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (mobile phase methanol: ethyl acetate = 1: 20) to give 4.28 g of a white solid in 87.3% |
69% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 36h; | The compound was prepared following a procedure in Biomacromolecules, 2013, 2837-2847, incorporated by reference in its entirety herein. To a solution of4-amino-i -((2R,4R,5R)-3 ,3-difluoro-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl) pyrimidin-2(1H)-one (i g, 3.8 mmol) in DMF (23 mL) was added Imidazole (0.78 g, ii.5 mmol) and TBDMSC1 (i.5 g, 9.6 mmol). The reaction mixture was stuffed at room temperature for i .5 d. The solvent was removed and the residue partitioned between ethyl acetate and aq. NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by ISCO using DCM/MeOH (0-i0%) as eluent to afford i.3 g (69%) of the title compound. ESMS calculated for C21H39F2N3O4Si2: 49i.24; found: 492.4 (M + Hj. |
With 1H-imidazole; In dichloromethane; at 20℃; | (a) Gemcitabine (2.00 g, 7.599 mmol) dissolved in 50 mL of dichloromethane,Add tert-butyldimethylsilyl chloride (TBSCl) (4.01 g, 26.597 mmol)And imidazole (1.81 g, 26.597 mmol)),The reaction was stirred at room temperature.After completion of the reaction, the reaction liquid was washed successively with a saturated ammonium chloride solution, a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution.The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated.The crude product was purified by column chromatography to give compound 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 50h; | Di-tert-butyl dicarbonate (DBDC) (0.414 g, 1.8996 mmol) was added to the solution of (1) (0.5 g, 1.899 mmol) and Na2CO3 (1.0 g, 9.498 mmol) in dioxane-water (5:1, v/v.) and the reaction was continued at room temperature for 50 h. TLC (CH2Cl2-acetone-EtOH, 5:4:1, v/v) showed almost complete consumption of (1). The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined extract was washed with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was washed with diethyl ether to give a whitesolid (2) (0.65 g, 94%). 1H NMR of (2) 400 MHz, DMSO-d6, 25C: delta = 7.63 (d, J = 7.5 Hz, 1H), 7.41 (d, J 9.9 Hz, 2H), 6.21 (t, J = 9.4 Hz,1H), 5.80 (d, J = 7.5 Hz, 1H), 5.25 (t, J = 5.7 Hz, 1H), 5.16 (m, 1H), 4.13(m, 1H), 3.74 (m, 1H), 3.63 (m, 1H), 1.45 (s, 9H) ppm. 13C NMR of (2) 400 MHz, DMSO-d6, 25C: delta = 165.74 (C), 154.51 (C), 151.32 (C),141.37 (CH), 121.60 (CF2), 94.84 (CH), 83.73 (C), 83.35 (CH), 78.36(CH), 72.35 (CH), 59.26 (CH2), 27.16 (CH3) ppm. Mass: (ESI) MS m/z Calcd. for C14H19F2N3O6: 363.12, found: 362.1 [M-H]-. |
89% | With sodium carbonate; In water; at 20℃; for 30h; | (BOC)2O (352 mg, 1.6 mmol) in 32 mL dioxane was added to a well stirred solution of 1 (480 mg, 1.6 mmol) and sodium carbonate (848 mg, 8 mmol) in 8 mL water. The reaction mixture was stirred at room temperature about 30 h and the progress was monitored by TLC (dichloromethane/methanol mixture (15:1). After completion, 16 mL water was added, the reaction mixture was extracted twice with acetic ether (2 × 150 mL), the combined organic layers was washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and removed by rotary evaporation. The residue was applied into silica gel column which was flushed with a large amount of CH2Cl2/EtOH mixture (50:1) to give 2 (428mg, 89%). 1H NMR (CDCl3, 400 M Hz), delta 7.71 (s, H-6)6.27 (t, H-5)5.96 (s, H-1')5.24 (m, H-3')4.14 (d, H-4')4.05 (d, Ha-5')3.82 (m, Hb-5')1.51s, 9H, DIBOC-CH3. ESI-MS m/z: 324.1 [M + Na]+, 300.1 [M - H]-. |
88% | With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 72h; | Example 48: 3'-0-(ferf-Butoxycarbonyl emcitabine To a stirring mixture of <strong>[95058-81-4]gemcitabine</strong> (1 .05 g, 4.0 mmol) and Na2C03 (3.12 g, 20.0 mmol) in a mixture of dioxane (40 mL) and water (1 mL) was added di-tert-butyl dicarbonate (DBDC, 873 mg, 4.0 mmol). The resulting mixture was stirred at room temperature for 72 hours. Water (20 ml) was added and the mixture was extracted with dichloromethane (100 mL). The organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2S04, and concentrated to dryness under reduced pressure. The residue was purified by silicagel flash chromatography (using a mixture of methanol and dichloromethane in a gradient gradually ranging from 0% to 20% methanol) to give the title compound as white solid (1 .28 g, 88%). (0594) 1H NMR (300 MHz, CDCI3) delta: 7.59 (d, J=7.4 Hz, 1 H, Ar-H), 7.03 (br., 1 H, NH), 6.32 (br., 1 H, NH), 6.27 (t, J=9.4 Hz, 1 H, H-1 '), 5.79 (d, J = 7.4 Hz, 1 H, Ar-H), 5.79(m, IH, H-3'), 4.95 (m, 1 H, H-4'), 4.03 (m, 1 H, H-5'), 3.70 (m, 1 H, H-5') 1 .43 (s, 9H, CH3) ppm. |
67% | With sodium carbonate; In tetrahydrofuran; water; at 20℃; | At room temperature, to a mixed solution of the compound 61501d (20 g) in tetrahydrofuran (200 ml) and water (100 ml) was added 35.4 g of sodium carbonate, followed by 17.5 g of di-tert-butyl dicarbonate, and the mixture was stirred at room temperature until the completion of the reaction. The mixture was subjected to extraction three times with ethyl acetate (3x200 ml), each time with 200 ml of ethyl acetate, and ethyl acetate was combined, washed with saline and dried with anhydrous sodium sulfate. After the solvent was eliminated by distillation, the residue was purified by silica gel chromatography (2.5% to 10% methanol/dichloromethane) to give 18 g of the compound 61501c with a yield of 67%. |
67% | With sodium carbonate; In tetrahydrofuran; water; at 20℃; | At room temperature, to a mixed solution of the compound 61501d (20 g) in tetrahydrofuran (200 ml) and water (100 ml) was added sodium carbonate (35.4 g), followed by di-tert-butyl dicarbonate (17.5 g), and the mixture was stirred at room temperature until the completion of the reaction. The mixture was subjected to extraction with ethyl acetate (3×200 ml), and ethyl acetate was combined, washed with saline and dried with anhydrous sodium sulfate. After the solvent was eliminated by evaporation, the residue was purified by silica gel chromatography (2.5% to 10% methanol/dichloromethane) to give 18 g of the compound (61501c) with a yield of 67%. |
0.6 g | With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 48h; | The operation of the experiment: Gemcitabine (<strong>[95058-81-4]gemcitabine</strong>, 0.60g, 2mmol), Na2CO3 (1.06g), 40 ml dioxane, 40 ml water, di-tert-butyl dicarbonate (DBDC, 0.44g, 2mmol) were stirred at room temperature for 48 hours. Add 20 ml water, for 2 × 300 ml ethyl acetate extraction, Na2SO4Drying, concentrated under reduced pressure. Rapid column chromatography (CH2Cl2Ethyl acetate - - EtOH 1:1: 0.02) get the 3'-O-(N-tert-butoxycarbonyl)<strong>[95058-81-4]gemcitabine</strong> (0.60g). |
18 g | With sodium carbonate; In tetrahydrofuran; water; at 20℃; | At room temperature, to a solution of the compound 61501d (20 g) in a mixed solution of 200 ml of tetrahydrofuran and 100 ml of water, 35.4 g of sodium carbonate was added, and then 17.5 g of di-tert-butyl dicar13bonate was added, and the mixture was stirred at room temperature until the reaction was complete. The mixturewas extracted three times with ethyl acetate, each time with200 ml of ethyl acetate. The ethyl acetate phases werecombined, washed with saline and dried over anhydroussodium sulfate. After the solvent was eliminated by distil-lation, 18 g of the compound 61501c was obtained via silicagel column chromatography (mobile phase: methanol/dichioromethane (the proportion of methanol increased from2.5% to 10%, gradient elution). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide; N,N-dimethyl-formamide at 55℃; for 24h; | 2 Compound 12: N-(1-((4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide jOO165 To a stirred solution of gemcitabine (0.22 g. 0.84 rnrnol) in DMF/DMSO (3:1) (4 mL) was added NMtvi (85 mg, 0.84 rnrnol), HOBt (114 mg, 0.84 rnrnol), EDC1.HC1 (0.21 g, 1.09 mrnol) and carboxyl acid (1.1 eq.) at room temperature and stirred for 24 hours at 55 °C. The reaction mixture was cooled to it then added 10 mL H20 slowly. The mixture was extracted with ethyl acetate (3 X 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated on rotary evaporator to get the crude product which was purified with silica gel column chromatography (1-10%) methanol in DCM and then purified by preparative HPLC using 30-100% water /acetonitrile solvent system. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In N,N-dimethyl-formamide; at 50℃; for 18h; | 3.85 g (1.5 eq.) of Boc-anhydride was added to a solution of 2.24 g (11.2 mmol) of 4-amino-i -((2R,4R,5R)-3, 3-difluoro-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2- yl)-1H-pyrimidine-2-one (5(1)) in 8 ml of dimethylformamide. The reaction mixture was heated at 500 C. for 18 h. In order to decompose the excess of Boc2O 8 ml of water was added, the reaction mixture was cooled to room temperature, at stirring 16 ml of water was added. The suspension was filtered, the solid on filter was washed with watet The obtained tert-butyl [1 -((2R,4R,5R)-3,3-difluoro-4-hydroxy- 5-hydroxymethyl-tetrahydro-thran-2-yl)-2-oxo-i ,2-dihy- dro-pyrimidin-4-yl]-carbamate (5(2)) was dried in vacuo.Yield is 3.65 g (86%). HPLC of purity (UV254) was 98.3%. ?H NMR (DMSO-D6, 300 MHz) oe 1.46 (s, 9H), 3.6-3.9 (m, 2H), 4.18 (m, 1H), 5.29 (bt s, 1H), 6.16 (t, J=7.5 Hz, 1H),6.30 (d, J=6.6 Hz, 1H), 7.06 (d, J=7.8, 1H), 8.18 (d, J=7.8 Hz, 1H), 10.52 (s, 1H). |
86% | In N,N-dimethyl-formamide; at 50℃; for 18h; | 3.58g(1.5eq. ) Boc- Anhydride added into 2.24g (11.2mmol) of 4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl)-1H-pyrimidin-2-one (5(1)) in in the solution of Dimethylformamide 8ml. The reaction mixturewas heated at 50 C for 18h. for Decompose excess of Boc2O, add 8mlof water, The reaction mixture was cooled at room temperature and while stirring 16ml of water was added. Thesuspension was filtered and the solid was washed with water on the filter.Vacuum drying to give [1-((2R4R5R)-3,3- Difluoro-4-hydroxy-5-hydroxy-methyl -tetrahydro - furan-2-yl)-2- Oxo-1,2-dihydro - pyrimidin-4-yl] - tert-Butyl carbamate(5(2)). Yield is 3 65g(86 % ). HPLC purity (UV254) is 98. 3 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | To a solutioncooled at -5 C of trisnorsqualenic acid-d6 (1) (31.5 mg,0.077 mmol) in dry THF (0.6 mL) was sequentially added triethylamine(60 mg, 0.23 mmol) and ethyl chloroformate(10 mg, 0.093 mmol). The reaction mixture was stirred for30 min at this temperature and a solution of <strong>[95058-81-4]gemcitabine</strong> base(60.6 mg, 0.23 mmol) in DMF (2 mL) was added. The reactionmixture was stirred for 4 days at 20 C and concentrated underreduced pressure. The residue was directly chromatographedover silica gel eluting with cyclohexane/AcOEt 4:1 followed byneat AcOEt to provide GemSQ-d6 (3) as a colorless oil(36.0 mg, 72%). 1H NMR (CDCl3, 400 MHz) delta 9.15 (br s, 1H,NHCO), 8.10 (d, J = 7.5 Hz, 1H, H-6), 7.47 (d, J = 7.5 Hz, 1H,H-5), 6.18 (t, J = 7.4 Hz, 1H, H-1?), 5.20-5.06 (m, 5H, =CH),4.55-4.41 (m, 1H, H-3?), 4.15-3.95 (m, 3H, H-4?, H-5?, OH),3.91 (d, 1H, J = 10.8 Hz, H-5?), 2.55 (2H, t, J = 7.6 Hz,CH2CON), 2.32 (2H, t, J = 7.4 Hz, CH2CH2CON), 2.10-1.91(m, 16H, =CCH2CH2C(CH3)), 1.60 (3H, s, =C(CH3)), 1.59 (s,6H, =C(CH3)), 1.58 (3H, s, =C(CH3)); 13C NMR (CDCl3, 75MHz) delta 173.6 (C, CONH), 163.1 (C, C-4), 155.8 (C, C-2),145.6 (CH, C-6), 135.3 (C, (CH3)C= CH2(CH3)C=), 135.0 (2C,CH2(CH3)C=), 132.8 (C, CH2(CH3)C=), 131.2 (C, (CD3)2C=),126.0 (CH, HC=), 124.5 (2CH, HC=), 124.4 (2 HC=), 122.5(CF2, t, J = 258 Hz, C-2?), 97.8 (CH, C-5), 81.8 (CH, C-4?),69.3 (CH, m, C-3?), 60.0 (CH2, C-5?), 39.9 (2CH2), 39.7 (CH2), 36.7 (CH2, NHCOCH2CH2), 34.5 (CH2, NHCOCH2CH2), 29.8(CH2), 28.4 (2CH2), 27.0 (CH2), 26.9 (2CH2), 26.8 (2CH2),16.2 (2CH3), 16.1 (CH3), 16.0 (CH3); IR (film, cm-1) nu:3500-3000 (broad), 2979, 2932, 2872, 2852, 2222, 2191, 1724,1683, 1660, 1618, 1561, 1494, 1433, 1397, 1383, 1365, 1337,1320, 1312, 1272, 1206, 1194, 1134, 1086, 1069, 1051, 915,893, 813, 787, 738; HRMS-ESI-: calcd for C36H46D6N3O5F2:650.4257; found: 650.4230. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | S18: To a suspension of 2'-Deoxy-2',2'-difluorocytidine (0.526 g, 1.998 mmol) in THF (13.32 ml) at 0C under nitrogen, was dropwise added via syringe a 1M THF solution of t- butylmagnesium chloride (4.00 mL, 4.00 mmol), and the resulting mixture was stirred at the same temperature for 30 min. A solution of S7 (1.770 g, 4.00 mmol) in THF (13.32 mL) at 0 C was added dropwise via syringe, the mixture was allowed to warm to rt and was stirred for another 24 hrs. The reaction was cooled to 0C and carefully quenched with sat. aq. NH4C1. The mixture was concentrated by rotary evaporation, and the obtained solid was redissolved in MeOH and filtered through a plug of Celite, rinsing the plug with MeOH. The filtrate was concentrated by rotary evaporation, and automated flash chromatography (40 g column, 0 to 15% gradient of MeOH in DCM) gave S18 (0.620 g, 58%) as a brown foam, as a diastereomeric mixture. 1H NMR (400 MHz, CD3OD, diastereomeric mixture) delta 7.60 (dd, J = 26.1 Hz, 7.4 Hz, 1H), 7.43 - 7.30 (m, 2H), 7.31 - 7.12 (m, 3H), 6.26 (q, J = 7.7 Hz, 1H), 5.92 (dd, J= 21.2 Hz, 7.2 Hz, 1H), 4.97 (m, 1H), 4.60 - 4.30 (m, 2H), 4.29 - 4.15 (m, 1H), 4.10 (m, 1H), 3.88 (m, 1H), 1.33 (t, J = 8.0 Hz, 3H), 1.22 (m, 6H);13C NMR (100 MHz, CD3OD, diastereomeric mixture) delta 174.61, 174.57, 174.35, 174.30, 167.18, 154.42, 152.15, 152.08, 142.62, 142.52, 139.86, 130.84, 130.20, 126.30, 124.17, 121.49, 121.44, 80.45, 70.18, 69.95, 66.90, 65.69, 51.88, 51.72, 21.97, 21.94, 21.91, 21.89, 21.85, 21.25, 21.19, 20.52, 20.45, 20.34, 20.26, 15.44;19F NMR (376 MHz, CD3OD) delta -118.20 (dd, J = 238.6 Hz, 73.5 Hz,), - 120.20 (d, J = 237.0 Hz);31P NMR (162 MHz, CD3OD) delta 3.81, 3.74; HRMS calcd. for C2iH2808N4F2P [M+H]+: 533.16073, found: 533.16038. | |
58% | S18: To a suspension of 2'-Deoxy-2',2'-difluorocytidine (0.526 g, 1.998 mmol) in THF (13.32 ml) at 0C under nitrogen, was dropwise added via syringe a 1M THF solution of t- butylmagnesium chloride (4.00 mL, 4.00 mmol), and the resulting mixture was stirred at the same temperature for 30 min. A solution of S7 (1.770 g, 4.00 mmol) in THF (13.32 mL) at 0 C was added dropwise via syringe, the mixture was allowed to warm to rt and was stirred for another 24 hrs. The reaction was cooled to 0C and carefully quenched with sat. aq. NH4C1. The mixture was concentrated by rotary evaporation, and the obtained solid was redissolved in MeOH and filtered through a plug of Celite, rinsing the plug with MeOH. The filtrate was concentrated by rotary evaporation, and automated flash chromatography (40 g column, 0 to 15% gradient of MeOH in DCM) gave S18 (0.620 g, 58%) as a brown foam, as a diastereomeric mixture. 1H MR (400 MHz, CD3OD, diastereomeric mixture) delta 7.60 (dd, J = 26.1 Hz, 7.4 Hz, 1H), 7.43 - 7.30 (m, 2H), 7.31 - 7.12 (m, 3H), 6.26 (q, J = 7.7 Hz, 1H), 5.92 (dd, J= 21.2 Hz, 7.2 Hz, 1H), 4.97 (m, 1H), 4.60 - 4.30 (m, 2H), 4.29 - 4.15 (m, 1H), 4.10 (m, 1H), 3.88 (m, 1H), 1.33 (t, J = 8.0 Hz, 3H), 1.22 (m, 6H); 13C NMR (100 MHz, CD3OD, diastereomeric mixture) delta 174.61, 174.57, 174.35, 174.30, 167.18, 154.42, 152.15, 152.08, 142.62, 142.52, 139.86, 130.84, 130.20, 126.30, 124.17, 121.49, 121.44, 80.45, 70.18, 69.95, 66.90, 65.69, 51.88, 51.72, 21.97, 21.94, 21.91, 21.89, 21.85, 21.25, 21.19, 20.52, 20.45, 20.34, 20.26, 15.44; 19F NMR (376 MHz, CD3OD) delta -118.20 (dd, J = 238.6 Hz, 73.5 Hz,), - 120.20 (d, J = 237.0 Hz); 31P NMR (162 MHz, CD3OD) delta 3.81, 3.74; HRMS calcd. for C2iH2808N4F2P [M+H]+: 533.16073, found: 533.16038. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; | S16: To a solution of 2'-deoxy-2',2'-difluorocytidine (0.526 g, 2.00 mmol) and imidazole (0.408 g, 6.00 mmol) in DMF (10 ml) was added TBS triflate (1.147 ml, 5.00 mmol) at 0C under argon. The resulting mixture was stirred at 0C for 2 hrs, then it was slowly warmed to rt and stirred overnight. After being partitioned between Et20 and water, the organic layer was separated and washed with H20 and brine, dried over Na2S04, filtered, and concentrated by rotary evaporation. Automated flash chromatography (24 g column, 0 to 12.5% gradient of MeOH in DCM) yielded S16 (0.71 g, 72%) as a clear colorless oil: 1H NMR (400 MHz, CDC13) delta 8.23 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 6.25 (dd, J = 10.4 Hz, 4.2 Hz, 1H), 5.97 (d, J = 7.6 Hz, 1H), 4.30 (m, 1H), 3.98 (m, 1H), 3.89 (m, 1H), 3.79 (dd, J= 11.8 Hz, 2.1 Hz, 1H), 0.93 (s, 9H), 0.90 (s, 9H), 0.11 (t, J = 4.1 Hz, 12H);13C NMR (100 MHz, CDCI3) delta 164.6, 154.6, 140.8, 121.9 (t, J = 259 Hz), 95.7, 84.1 (dd, J = 40 Hz, 24 Hz), 81.3 (d, J= 9 Hz), 77.2, 69.7 (dd, J = 28 Hz, 18 Hz), 60.1, 53.4, 25.8, 25.5, 18.3, 18.0, -4.8, -5.3, - 5.49, -5.52;19F NMR (376 MHz, CDC13) delta -115.95 (dd, J = 238.4 Hz, 12.1 Hz), -117.55 (dt, J = 239.1 Hz, 10.7 Hz); HRMS calcd. for C2iH4o04N3F2Si2[M+H]+: 492.25199, found: 492.25172. |
72% | With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;Inert atmosphere; | S16: To a solution of 2'-deoxy-2',2'-difluorocytidine (0.526 g, 2.00 mmol) and imidazole (0.408 g, 6.00 mmol) in DMF (10 ml) was added TBS triflate (1.147 ml, 5.00 mmol) at 0C under argon. The resulting mixture was stirred at 0C for 2 hrs, then it was slowly warmed to rt and stirred overnight. After being partitioned between Et20 and water, the organic layer was separated and washed with H20 and brine, dried over Na2S04, filtered, and concentrated by rotary evaporation. Automated flash chromatography (24 g column, 0 to 12.5% gradient of MeOH in DCM) yielded S16 (0.71 g, 72%) as a clear colorless oil: 1H NMR (400 MHz, CDCI3) delta 8.23 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 6.25 (dd, J = 10.4 Hz, 4.2 Hz, 1H), 5.97 (d, J = 7.6 Hz, 1H), 4.30 (m, 1H), 3.98 (m, 1H), 3.89 (m, 1H), 3.79 (dd, J= 11.8 Hz, 2.1 Hz, 1H), 0.93 (s, 9H), 0.90 (s, 9H), 0.11 (t, J = 4.1 Hz, 12H); 13C NMR (100 MHz, CDCI3) delta 164.6, 154.6, 140.8, 121.9 (t, J = 259 Hz), 95.7, 84.1 (dd, J = 40 Hz, 24 Hz), 81.3 (d, J= 9 Hz), 77.2, 69.7 (dd, J = 28 Hz, 18 Hz), 60.1, 53.4, 25.8, 25.5, 18.3, 18.0, -4.8, -5.3, - 5.49, -5.52; 19F NMR (376 MHz, CDC13) delta -115.95 (dd, J = 238.4 Hz, 12.1 Hz), -117.55 (dt, J = 239.1 Hz, 10.7 Hz); HRMS calcd. for C2iH4o04N3F2Si2 [M+H]+: 492.25199, found: 492.25172. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cytidine deaminase enzyme; In aq. phosphate buffer; at 37℃; for 0.0833333h;pH 7;Enzymatic reaction; | Comparative Example 8: Deamination of gemcitabine (compound 2) to uridine arabinoside A 70 mM solution of gemcitabine (495 mu) in 100 mM phosphate buffer at pH 7 was mixed with 5 L of cytidine deaminase enzyme solution containing >30 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 under UV-DAD (ultraviolet-diode array detection). The expected product was obtained in quantitative yield (>99% from the crude reaction). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | CyINC (8mg, 10mumol) was dissolved in DMSO (2.5mL), then TBTU (8mg, 25mumol) and DIEA (4muL, 20mumol) were added. After stirring for 0.5hat room temperature, <strong>[95058-81-4]gemcitabine</strong> (GEM, 5.2mg, 20mumol) was added and stirred for another 15h. The crude product was purified on a Prep-HPLC. TheCyINC-GEM was obtained as a blue solid (8mg, 75% yield). HRMS (ESI-TOF, negative mode): calculated Mr=890.2005 for C39H42F2N5O11S3-, found m/z=890.2013. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.6% | Gambogic Acid (500 mg, 0.71 mmol)Gemcitabine(169 mg, 0.64 mmol)Dissolved in dichloromethane (5.0 ml) at room temperature,Then, EDCI (150 mg, 0.78 mmol) was added to the mixture,And HOBT (105 mg, 0.78 mmol),After stirring for 30 minutes, TBTU (249 mg, 0.78 mmol) was added,The temperature was raised to 50 C and stirred for 5 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]Get orange-yellow amorphous powder326 mg,The yield was 52.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.7% | With ammonium hydroxide; In methanol; at 20℃; for 3h; | Under stirring at room temperature, the compound 4 (330.0g, 0.70 mol) was dissolved in 700.0 ml methanol. Add dropwise concentrated aqueous ammonia (100.0 ml, 28%, 15.0 mol/L). Stir the reaction for more than 3h. After the reaction, water 700.0 ml, decompression of the concentrated solution to the original volume of the 1/2 can be to remove methanol, adding ethyl acetate 500.0 ml, fully stirring 30min. Layered, separating the organic layer. The aqueous layer then adding ethyl acetate 200.0 ml extraction, separating the organic layer, the combined organic layer, adding activated carbon to decolorize, filtering. The filtrate is concentrated under reduced pressure, the residual solid obtained. The residual solid 200.0 ml isopropanol stirring and dissolving, slowly concentrated hydrochloric acid to adjust the pH to 3.5 - 3.7, temperature control in the 70 - 75 C stirring 30min, cooling to room temperature, stirring crystallization 3h above. Filtering to obtain white solid, vacuum oven drying, maintained at a temperature of 45 - 50 C, maintained in the vacuum degree of the 0.08 - 0.1 mpa, drying 6h above, obtain 153.8 g white solid, is compound 5, yield 82.7%. |
With sodium t-butanolate; In methanol; at 20℃; for 2h; | 2'-deoxy-2 ', 2'-difluoro-cytidine-3', 5'-benzoate (75.0g, 0.16mol, alpha-isomer content of 0.08%),Sodium tert-butoxide (33.6 g, 0.34 mol),Methanol (800ml) in 2L three-necked flask and mix well,Reaction at room temperature 2h,TLC detection reaction was completed,1M hydrochloric acid to adjust the pH to 7,Concentrate to dryness under reduced pressure,Water (1 L),Extraction with ethyl acetate impurity,After the ethyl acetate layer was backwash with a small amount of water,Merged water layer,Activated carbon bleaching,filter,Filtrate spin dry,Isopropyl alcohol (1 L) and concentrated hydrochloric acid (40 ml) were added to the residue,Heated to 70 C,After 30min incubation at room temperature overnight.filter,The filter cake was washed successively with cold isopropanol and n-hexane,dry,Gemcitabine hydrochloride 44.8g,Purity 99.5%alpha isomer content of 0.02%Yield 93.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.6% | Accurately measured 120.0 ml pyridine was added to a 1.0L three-necked round bottom flask equipped with a thermometer. Cool to 0-5 C. Slowly add dropwise 92.0 g phosphorus oxychloride. During the dropwise addition process, the temperature was controlled for not more than 10 C. After the dropwise addition is complete, stir the reaction for 1 hour. Compound 5 (131.5g, 0 . 50 mol) was dissolved in 150.0 ml in pyridine. Then slowly add dropwise to the above reaction solution. Within 2 hours the dropwise addition is complete. Naturally warm to room temperature. Stir the reaction overnight. After the reaction is finished, add 500.0 ml distilled water. Slowly add dropwise concentrated hydrochloric acid to adjust the pH to 3.0-4.0. Fully stir for 30min. filtered, the filter cake is washed with distilled water, vacuum cutter disk, maintained at a temperature of 45 - 50 C, maintained in the vacuum degree of the 0.08 - 0.1 mpa, drying 6h above, to obtain compound 1 of the crude product, obtained after using ethanol to recrystallize the 103.2 g compound 1a, yield 66.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With 4-methyl-morpholine; In acetonitrile; at 20℃; for 2h;Inert atmosphere; | Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-amino-l-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5- (hydroxymethyl)oxolan-2-yl]-l,2-dihydropyrimidin-2-one (200 mg, 0.66 mmol, 1.00 equiv) in CH3CN (2 mL), <strong>[638-41-5]pentyl chloroformate</strong> (126 mg, 0.84 mmol, 1.30 equiv), NMM (153.6 mg, 1.52 mmol, 2.40 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2x10 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 90 mg (31%) of pentyl N-[l-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2- oxo- 1,2-dihy drop yrimidin-4-yl] carbamate as a off-white solid. LC-MS: (ES, m/z): [M+H]+= 378. ^-NMR^OO MHz, d6-OMSO, ppm): d 10.81(br, 1H) , 8.23(d, /=7.8Hz,lH), 7.11(d,/=7.8Hz,lH), 6.31 (d, /=6.3Hz,lH) , 6.17 (t, /=7.5Hz,lH), 5.30 (t, /=5.5Hz, 1H), 4.20(m, 1H), 3.93-3.60(m, 3H), 1.69-1.23(m, 8H), 0.90(m, 3H). |
210 mg | triethylchlorosilane(0.76 ml, 4.5 mmol) was added to the solution2 ', 2'-difluoro-2'-Deoxycytidine(263 mg, 1 mmol) in anhydrous pyridine (10 ml)After stirring at room temperature for 1 hour, amyl chloroformate (0.86 ml, 6 mmol) was added,Stirring was continued for 3 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in a mixed solution of dichloromethane / methanol (20 ml / 5 ml)Trifluoroacetic acid (0.5 ml) was added and the mixture was stirred at room temperature for 1 hour.Washed with NaHCO3 and water, respectively,The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to give 210 mg of solid product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | The second step is the synthesis of CPT-SS-GEM in the followingprocedure. CPT-SS-OH (529 mg, 1 mmol) and triphosgene (110 mg,0.34 mmol) were dispersed in anhydrous DCM (50 mL), to which, DMAP (390 mg, 3.2 mmol) was added. The mixture was stirred at roomtemperature for 3 h. GEM (264 mg, 1 mmol) in DMF (10 mL) was addeddropwise. The solution was stirred at room temperature. The reactionprocess was monitored by TLC and stopped after the starting materialwas completely consumed. The reaction solution was diluted with DCM(200 mL) and washed with HCl (pH 1, 3×50 mL) and then with water(3×50 mL). The organic phase was dried with Na2SO4. After the solventwas removed under vacuum, CPT-SS-GEM was purified by silica gel column chromatography (DCM/MeOH=50:1 to 20:1 v/v) to give aslight yellow solid (396 mg, yield 50%). Reversed-phase high-performanceliquid chromatography (RP-HPLC) analysis showed that thepurity of CPT-SS-GEM was over 97.5% (Fig. S8). 1H NMR of CPT-SSGEM(400 MHz, DMSO-d6, delta, ppm, TMS):10.86 (s, 1H), 8.69 (s, 1H),8.20 (d, J=8 Hz, 1H), 8.17 (d, J=8 Hz, 1H), 7.86 (t, J=8 Hz, 1H),7.71 (t, J=8 Hz, 1H), 7.10 (s, 1H), 7.02 (d, J=8 Hz, 1H), 6.31 (d,J=8 Hz, 1H), 6.16 (t, J=8 Hz, 1H), 5.52 (s, 2H), 5.32 (s, 2H), 5.29 (t,J=8,4 Hz, 1H), 4.35 (dd, J=8, 4 Hz, 2H), 4.29 (t, J=8, 4 Hz, 2H),4.17 (t, J=4, 8 Hz, 1H), 3.89 (t, J=8 Hz, 1H), 3.80 (d, J=8 Hz, 1H),3.65 (m, J=8 Hz, 1H), 3.04 (t, J=8, 4 Hz, 2H), 2.98 (t, J=8, 4 Hz,2H), 2.18 (q, J=8, 4 Hz, 2H), 0.92 (t, J=8 Hz, 3H) (Fig. S1). ESI-MS(low resolution, positive mode): calculated for C35H33F2N2O12S2, m/z,818.15 [M+H]+, found 818.2214 [M+H]+ (Fig. S3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Following the same method, reduction non-cleavable CPT-CC-GEMwas synthesized as control Scheme 1. In the first step, 2-hydroxyethyldisulfide was replaced by 1, 6-hexanediol as the reduction non-cleavablelinker. After two steps of reaction and purification, a white yellowsolid was obtained (overall yield 40%). 1H NMR (400 MHz, DMSO-d6, delta,ppm, TMS):10.79 (s, 1H), 8.69 (s,1H), 8.21 (d, J=8 Hz, 1H), 8.17 (d,J=8 Hz, 1H), 8.12 (d, J=8 Hz, 1H), 7.87 (t, J=8 Hz, 1H), 7.71 (t,J=8 Hz, 1H), 7.06 (d, J=8 Hz, 2H), 6.33 (d, J=8 Hz, 1H), 6.17 (t,J=8, 4 Hz,1H), 5.52 (s, 2H), 5.33 (s, 2H), 5.29 (d, J=8 Hz, 1H), 4.18(d, J=8 Hz, 1H), 4.11 (t, J=8, 4 Hz, 2H), 3.97 (t, J=8, 4 Hz, 2H),3.89 (d, J=8 Hz, 1H), 3.81 (d, J=8 Hz, 1H), 3.65 (m, J=8, 4 Hz,1H), 2.17 (dd, J=8, 4 Hz, 2H), 1.55 (d, J=32 Hz, 4H), 1.30 (d,J=32 Hz, 4H), 0.91 (t, J=8 Hz, 3H) (Fig. S2). ESI-MS (low resolution,positive mode): calculated for C35H33F2N2O12S2, m/z, 782.72 [M+H]+, found 782.2446 [M+H]+ (Fig. S4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium carbonate / tetrahydrofuran; water / 20 °C 2.1: tetrahydrofuran / 1 h / 0 °C 2.2: 20 °C 3.1: trifluoroacetic acid / dichloromethane / 0 °C | ||
Multi-step reaction with 3 steps 1.1: sodium carbonate / tetrahydrofuran; water / 20 °C 2.1: tert-butylmagnesium chloride / tetrahydrofuran / 1 h / 0 °C 2.2: 20 °C 3.1: trifluoroacetic acid / dichloromethane / 0 °C | ||
Multi-step reaction with 3 steps 1: sodium carbonate / water; 1,4-dioxane / 72 h / Inert atmosphere 2: tert-butylmagnesium chloride / tetrahydrofuran / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 1.5 h / 0 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The camptothecin intermediate (CPT-SS) prepared in the first step, under the conditions of temperature ? 0 C and argon (Ar) reaching 5-10 Pa,4-dimethylaminopyridine (DMAP),Solid triphosgene is dissolved in anhydrous dichloromethane (DCM),The molar ratio of the above camptothecin intermediate (CPT-SS), 4-dimethylaminopyridine (DMAP), and solid triphosgene is 1:3:1/3, and is stirred at 0 C for 30 minutes in the dark. ,Then, a 2 times CPT molar amount of a solution of <strong>[95058-81-4]gemcitabine</strong> (GT) in N,N-dimethylformamide (DMF) was slowly added, and after stirring at room temperature for 24 hours in the dark,Purified by extraction and column chromatography to obtain a pure reduction-reactive drug-drug conjugate GT-CPT. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | 0.44 g (3 mmol) of adipic acid was dissolved in 15 ml of anhydrous dioxane, and after adding 0.25 g (2.5 mmol) of triethylamine, 0.28 g (2.4 mmol) of thionyl chloride was added dropwise, and vacuum nitrogen was added dropwise. Protected, refluxed at 110 C for 4 h, concentrated the reaction mixture under reduced pressure to give a pale yellow oil.Reconstituted with 10 ml of DMF. 0.78 g (3.2 mmol) of <strong>[95058-81-4]gemcitabine</strong> was added, and 0.19 g (1.5 mmol) of triethylamine was added dropwise thereto at room temperature, and the mixture was subjected to vacuum nitrogen-protection overnight, and the reaction was completed by TLC. The reaction mixture was concentrated under reduced pressure to give a red brown oil. Column chromatography gave a white solid in 61% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.1% | 0.52 g (3 mmol) of suberic acid was dissolved in 15 ml of anhydrous dioxane, and after adding 0.25 g (2.5 mmol) of triethylamine, 0.28 g (2.4 mmol) of thionyl chloride was added dropwise, and vacuum nitrogen was added dropwise. The mixture was refluxed at 110 C for 4 h. 0.78 g (3.2 mmol) of <strong>[95058-81-4]gemcitabine</strong> was added, and 0.19 g (1.5 mmol) of triethylamine was added dropwise thereto at room temperature, and the mixture was subjected to vacuum nitrogen-protection overnight, and the reaction was completed by TLC. The reaction mixture was concentrated under reduced pressure to give a red brown oil. Column chromatography gave a white solid in 69.1% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | 0.61 g (3 mmol) of sebacic acid was dissolved in 15 ml of anhydrous dioxane, and after adding 0.25 g (2.5 mmol) of triethylamine, 0.28 g (2.4 mmol) of thionyl chloride was added dropwise, and vacuum nitrogen was added dropwise. The mixture was refluxed at 110 C for 4 h. 0.78 g (3.2 mmol) of <strong>[95058-81-4]gemcitabine</strong> was added, and 0.19 g (1.5 mmol) of triethylamine was added dropwise thereto at room temperature, and the mixture was subjected to vacuum nitrogen-protection overnight, and the reaction was completed by TLC. The reaction mixture was concentrated under reduced pressure to give a red brown oil. Column chromatography gave a white solid in 53% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | 0.35 g (3 mmol) of succinic acid was dissolved in 15 ml of anhydrous dioxane.After adding 0.25 g (2.5 mmol) of triethylamine,0.28 g (2.4 mmol) of thionyl chloride was added dropwise.Drip the vacuum nitrogen protection,Reflow at 110 C for 4 h,The reaction mixture was concentrated under reduced pressure to give a pale yellow oil.Reconstituted with 10 ml of DMF.Add <strong>[95058-81-4]gemcitabine</strong> 0.78g (3.2mmol),Further, 0.19 g (1.5 mmol) of triethylamine was added dropwise at room temperature.Drip the vacuum nitrogen protection,The reaction was continued overnight and the reaction was complete by TLC. The reaction mixture was concentrated under reduced pressure to give a red brown oil. Column chromatography gave a white solid in 75% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | 0.35 g (3 mmol) of succinic acid was dissolved in 15 ml of anhydrous dioxane, and after adding 0.25 g (2.5 mmol) of triethylamine, 0.28 g (2.4 mmol) of thionyl chloride was added dropwise, and the vacuum nitrogen was added dropwise. The mixture was refluxed at 110 C for 4 h. 0.39 g (1.6 mmol) of <strong>[95058-81-4]gemcitabine</strong> was added, and 0.09 g (0.9 mmol) of triethylamine was added dropwise thereto at room temperature, and the mixture was subjected to vacuum nitrogen-protection overnight, and the reaction was completed by TLC. The reaction mixture was concentrated under reduced pressure to give a red brown oil. Column chromatography gave a white solid in 55% yield. | |
55% | With triethylamine; In 1,4-dioxane; at 60℃; | Succinic acid (0.708 g, 6 mmol) was dissolved in 10 mL 1, 4-dioxaneand heated to reflux. Sulfoxide chloride (0.72 g, 6 mmol) was addeddropwise, and the reaction was allowed to reflux 4 h. The solvent wasconcentrated under reduced pressure and residue was dissolved in10 mL DMF. Gem (0.78 g, 3 mmol) and stirred and triethylamine (TEA,0.3 g, 3 mmol) were then filled in the reaction flask and heated to 60 Covernight until TLC (thin layer chromatography) indicated completeconsumption of starting material. The solvent was then evaporated, andthe residue was purified by preparative HPLC. Yield of prodrug 5: 55%of a white powder. C13H24N3O7F2, MS (ESI): m/z = 464 [M + H+].The purity determined by HPLC was 98.3%.1H NMR (400 MHz, MeOD)delta 8.01 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 6.21 (t, J = 8.9 Hz, 1H), 5.87(d, J = 7.6 Hz, 1H), 5.29 (m, 1H), 4.44-4.24 (m, 3H), 2.72-2.49 (m,8H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17%; 63% | j00132J To a suspension of 11 (40 g, 152.0 mmol) in HIVIDS (73.46 g, 456.2 mmol) were added DMAP (1.8 g, 15.2 mmol) and TMSOTf (1.01 g, 4.56 mmol) at 0C. The resulting mixture was stirred at room temperature for 12h. Boc-anhydride (165 g, 760 mmol) was then added dropwise over a period of lh at 0 C. The resulting reaction mixture was stirred at room temperature for 16h and then methanol (400 mL) and TEA (200 mL) were added at 0Clh. The resulting reaction mixture was stirred at room temperature for 20h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (100and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude compound was purified by silica gel chromatography to afford 4a (35.0 g, 63 %) and(12 g, 17%) as off-white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.5% | With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 48h; | (1) Weigh 60 mg of <strong>[95058-81-4]gemcitabine</strong> and 106 mg of sodium carbonate in a round bottom flask. Add 4 mL of dioxane (measured in a 50 mL graduated cylinder) and 1 mL of distilled water (pipette removal). Place it on a magnetic stirrer and stir it to dissolve (the rotation speed can make the center of the reaction liquid vortex). At this time, (Boc)2O 44 mg is added. The reaction was carried out for 48 h at room temperature, and the reaction was completed to obtain a reaction liquid; Then, the reaction solution was extracted with ethyl acetate. The organic layer was separated and the organic layer was dried over anhydrous MgSO4 and filtered. The crude product was obtained by a solvent under reduced pressure, and purified by silica gel column chromatography eluting with methylene chloride:methanol (25:1, 40:1, 60:1) to give compound ML-B-1 (72.5%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Gemcitabine (131.5mg) and1,1'-carbonylbis(1,2,4-triazole) (82.1 mg) was dissolved in 10 mL of dichloromethane.The reaction was stirred at room temperature for 2 hours, then 10 mL of deionized water was added.The mixture was extracted with 50 mL of dichloromethane.The organic layer was washed three times with deionized water (10 mL x 3).Drying and concentration under reduced pressure gave a hydroxyl-activated <strong>[95058-81-4]gemcitabine</strong> intermediate.The intermediate product (71.6 mg) was added to 10 mL of dichloromethane in which hydroxymethyl parthenolide (52.8 mg) was dissolved at room temperature, and then catalyst pyridine (200 muL) was added thereto, and the reaction was stirred for 48 hours. 10 mL of deionized water was added and extracted with dichloromethane. The organic phase was washed three times with deionized water (10 mL×3), washed with 10 mL of saturated NaCI, dried over anhydrous sodium sulfate and filtered. :1) As an eluent, the crude product is purified by column chromatography.Finally, the solvent was removed by rotary evaporation to obtain 62.0 mg of the desired product.The yield was 56%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | A suspension of <strong>[95058-81-4]gemcitabine</strong> 1 (700 mg, 2.7 mmol) in dry pyridine (25 mL) was prepared and cooled to 4C in an ice bath. Trimethylsilylchloride (3.5 mL, 27 mmol) was added dropwise under an argon atmosphere and the mixture was left to stir at room temperature. After 1.5 h,the solution was cooled to 4C in an ice bath and benzyl chloroformate (2 mL, 14 mmol) was added dropwise. After 12 h the solution wascooled to 4C in an ice bath, methanol (24 mL) was added slowly and the reaction mixture was stirred at room temperature overnight. Then themixture was evaporated to dryness. The residue was treated with saturated sodium bicarbonate (20 mL) and it was extracted with ethylacetate (3 x 40 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness withrepeated coevaporation using toluene. The residue was dissolved in methanol and evaporated with silica gel (2 g). The crude product waspurified by silica gel column chromatography using dichloromethane-methanol (gradient from 100:1 to 10:1, v/v) as eluent to afford 18 (yield:961.6 mg, 91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca.70% | Folic acid (0.15 mmol) was dissolved in 60 ml of DMSO.Under the action of dehydrating agent DCC (3.0 mmol) and catalyst DMAP (3.0 mmol),The reaction was stirred at 0 C for 6 h; then gemcitabine was added at a molar ratio of <strong>[59-30-3]folic acid</strong> 1:3 (gemcitabine was dissolved in DMSO), and the temperature was raised from the ice bath to room temperature 25 C.Stir in the dark overnight, remove by-product by filtration, concentrate the filtrate, recrystallize from ice diethyl ether or isopropyl alcohol.Chromatography or preparative liquid phase purification,Lyophilized to obtain the tumor-targeting prodrug GEM-FA, C28H28F2N10O9, the theoretical MW is 686.5(yield about 70%), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Biotin (0.18 mmol) was dissolved in 60 ml of DMSO, and stirred under the action of dehydrating agent DCC (4.0 mmol) and catalyst DMAP (4.0 mmol) at 0 C for 6 h; then <strong>[95058-81-4]gemcitabine</strong> dissolved in DMSO, biotin and The molar ratio of <strong>[95058-81-4]gemcitabine</strong> is 1:3; the temperature is raised from the ice bath to room temperature 25 C, stirred overnight in the dark; the by-products are filtered off, the filtrate is concentrated, recrystallized from ice diethyl ether or isopropanol, chromatographed or purified in liquid phase. The <strong>[95058-81-4]gemcitabine</strong> prodrug GEM-B, C19H25F2N5O6S with tumor targeting ability can be obtained by lyophilization, the theoretical MW is 489.5 (yield about 70%), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: o(LLA)n-GEM or o(DLA)n-GEM was prepared by amidation of a carboxylic acid group on o(LLA)n or o(DLA)n and an amine group on a <strong>[95058-81-4]gemcitabine</strong> molecule. In general, direct hydrogenation of Bn-o(LLA)n or Bn-o(DLA)n was achieved over palladium on activated carbon (10 wt %) to afford o(LLA)n or o(DLA)n according to a previously published report (Yield: -90-99%, see Takizawa, K. el al ., J.Polym. Sci. A Polym. Chem., 2008, 46:5977-5990). Subsequently, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (1.5 eq.) and N-hydroxysuccinimide (NHS) (1.5 eq.) were added to a solution of o(LLA)n or o(DLA)n (1 eq.) in dry DMF and stirred at room temperature under argon for 2 hours. GEM (1 eq.) was dissolved in dry DMF and was added dropwise into the above mixture. The reaction mixture was stirred for 24 hours at room temperature under argon. The crude products were diluted with ethyl acetate (20-fold), washed with 0.5% w/v hydrochloric acid, saturated NaHC03, and brine solution. The organic layer was then collected, dried over MgS04 and filtered. Solvent was removed under reduced pressure and the resulting concentrate was purified via a CombiFlash Rf 4x system using gradient elution of hexane and ethyl acetate. The purified product was concentrated under reduced pressure to provide a white solid (Yield: 80% for o(LLA)6-GEM, 63% for O(DLA)6-GEM, 87% for o(LL A) 10-GEM, and 74% for o(DL A) 10-GEM). NMR of O(LLA)6-GEM (CDCh ,500MHz): d = 8.09 (d, =7.6 Hz, 1 H), 7.36 (br. s., 1 H), 6.20 (br. s.,1 H), 5.30 (s, 1 H), 5.14 - 5.29 (m, 5 H), 4.45 - 4.57 (m, 1 H), 4.37 (q, J=7A Hz, 1 H), 4.00 - 4.09 (m, 2 H), 3.92 (d, =l0.5 Hz, 1 H), 1.46 - 1.62 ppm (m, 18 H). ESI-TOF: m/z calcd C27H35F2N3O16 [M + H]+: 696.2058, found 696.2061; NMR of o(DLA)6-GEM (CDCh ,500MHz): d = 8.10 (d, =7.3 Hz, 1 H), 7.40 (br. s., 1 H), 6.17 (br. s., 1 H), 5.34 (d, J=1.1 Hz, 1 H), 5.10 - 5.31 (m, 5 H), 4.58 (br. s., 1 H), 4.37 (q, =6.8 Hz, 1 H), 3.99 - 4.09 (m, 2 H),3.92 (d, =l0.7 Hz, 1 H), 1.47 - 1.61 ppm (m, 18 H). ESI-TOF: m/z calcd C27H35F2N3O16 [M + H]+: 696.2058, found 696.2058; NMR of o(LLA)io-GEM (CDCh ,500MHz): d = 8.08 (d, =7.3 Hz, 1 H), 7.39 (d, J=5.9 Hz, 1 H), 6.19 (br. s., 1 H), 5.13 - 5.33 (m, 10 H), 4.54 (br. s., 1 H), 4.37 (q, =6.8 Hz, 1 H), 4.05 (d, J=l0.3 Hz, 2 H), 3.93 (d, =l0.0 Hz, 1 H), 1.46 - 1.63 ppm (m, 30 H). ESI-TOF: m/z calcd C39H51F2N3O24 [M + H]+: 984.2903, found984.2907; NMR of o(DL A) 10-GEM (CDCh ,500MHz): d = 8.04 (d, =8. l Hz, 1 H), 7.32 - 7.49 (m, 1 H), 6.18 (br. s., 1 H), 5.11 - 5.41 (m, 10 H), 4.56 - 4.70 (m, 1 H), 4.36 (d, J=63 Hz, 1 H), 4.02 - 4.09 (m, 2 H), 3.93 (d, J=l0.0 Hz, 1 H), 1.48 - 1.65 ppm (m, 30 H). ESI- TOF: m/z calcd C39H51F2N3O24 [M + H]+: 984.2903, found 984.2905. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | Gemcitabine base (1.052 g, 4 mmol) was dissolved in DMF (3 ml_), and added to a round bottom flask and sealed under nitrogen. Anhydrous pyridine (1 .62 ml_, 20 mmol) was added to the solution and stirred using a magnetic stirrer over an ice bath. Chlorotrimethylsilane (2.172 ml_, 20 mmol) was added to the solution dropwise and the reaction was stirred for 1 h. The product showed a positive ion m/Z of 408. N-Boc (Peg3)-chloroformate (4 mmol), a product obtained from reaction described in 8.1 , was added to the Gemcitabine solution. Anhydrous pyridine (1.62 ml_) was added and the reaction mixture was left to stir at room temperature for 1 h. The product showed a positive ion m/Z of 682.7. Pyridine salt was removed by filtration and the filtrate was evaporated to dryness. The residue was redissolved in DCM (5mL) and cooled to 4C. Trifluoroacetic acid (TFA, 5m L) was added to the DCM solution and stirred for 30 min at 4C and 1 h at room temperature. The product showed a positive ion (m/Z of 438.93). TFA and DCM were then evaporated under reduced pressure. The residue was redissolved in water and purified on preparative HPLC using a Reveleris C18 40 g. Water and water/ethanol (50/50) were used as solvent A and B, and using a linear gradient program from 100% solvent A to 100% solvent B. The right fractions were pooled and evaporated to dryness. To this product (0.876 g, 2 mmol), was added oleoyl succinimide, which was obtained from example 8.2. The pH of the reaction was adjusted to 7.5-8 by addition of triethylamine (0.7 ml_). The title compound was formed after 30 min reaction as confirmed by MS, showing the right MS +ve mode m/z: 703.14. The solvent was evaporated to dryness and the residue was redissolved inEthanol/Water and purified on a preparative HPLC using a Reveleris C18 40 g.Water/Ethanol (90/10) and ethanol were used as solvent A and B, and using a linear gradient program from 100% solvent A to 100% solvent B. The right fractions were pooled to obtain 450 mg of the pure compound with the total yield of 36%. ESI - MS (MeOH) +ve mode m/z: 703.14, 725.27, 1427.10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine; In 1,4-dioxane; at 60℃; | Succinic acid (0.35 g, 3 mmol) was dissolved in 10 mL 1, 4-dioxaneand heated to reflux. Sulfoxide chloride (0.36 g, 3 mmol) was addeddropwise, and the reaction was allowed to reflux 4 h. The solvent wasconcentrated under reduced pressure and residue was dissolved in10 mL DMF. Gem (0.78 g, 3 mmol) and stirred and triethylamine (TEA,0.3 g, 3 mmol) were then filled in the reaction flask and heated to 60 Covernight. The solvent was evaporated, and the residue was purified bycolumn chromatography on a silica gel, eluting with methanol in dichloromethane(gradient 5-10%). Yield of prodrug 1: 75% of a whitepowder. C13H19N3O5F2, MS (ESI): m/z = 364 [M + H+]. The puritydetermined by HPLC was 97.5%. 1H NMR (400 MHz, D2O) delta 7.73 (d,J = 7.8 Hz, 1H), 6.22 (t, J = 7.8 Hz, 1H), 6.17 (d, J = 7.8 Hz, 1H),4.57 (d, J = 12.7 Hz, 1H), 4.52-4.34 (m, 2H), 4.28 (m, 1H), 2.73 (dd,J = 7.1, 4.7 Hz, 2H), 2.68 (dd, J = 6.9, 4.3 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine; In 1,4-dioxane; at 60℃; | Adipic acid (0.44 g, 3 mmol) was dissolved in 10 mL 1, 4-dioxaneand heated to reflux. Sulfoxide chloride (0.36 g, 3 mmol) was addeddropwise, and the reaction was allowed to reflux 4 h. The solvent wasconcentrated under reduced pressure and residue was dissolved in10 mL DMF. Gem (0.78 g, 3 mmol) and stirred and triethylamine (TEA,0.3 g, 3 mmol) were then filled in the reaction flask and heated to 60 Covernight. The solvent was evaporated, and the residue was purified bycolumn chromatography on a silica gel, eluting with methanol in dichloromethane(gradient 5-10%). Yield of prodrug 2: 61% of off-whitepowder. C15H23N3O5F2, MS (ESI): m/z = 392 [M + H+]. The puritydetermined by HPLC was 97.2%. 1H NMR (400 MHz, DMSO) delta 11.00 (s,1H), 8.25 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 6.62 - 6.24 (m,1H), 6.17 (t, J = 7.5 Hz, 1H), 5.32 (s, 1H), 4.20 (dd, J = 21.4, 12.8 Hz,1H), 4.03 (q, J = 7.1 Hz, 1H), 3.93 - 3.85 (m, 1H), 3.81 (d,J = 12.6 Hz, 1H), 3.66 (dd, J = 12.7, 3.3 Hz, 1H), 2.96 (q, J = 7.2 Hz,2H), 2.42 (t, J = 6.9 Hz, 2H), 2.22 (t, J = 6.7 Hz, 2H), 1.99 (s, 1H),1.91 (s, 1H), 1.65-1.41 (m, 5H), 1.16 (dd, J = 12.5, 5.3 Hz, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.1% | With triethylamine; In 1,4-dioxane; at 60℃; | Suberic acid (0.52 g, 3 mmol) was dissolved in 10 mL 1, 4-dioxaneand heated to reflux. Sulfoxide chloride (0.36 g, 3 mmol) was addeddropwise, and the reaction was allowed to reflux 4 h. The solvent wasconcentrated under reduced pressure and residue was dissolved in10 mL DMF. Gem (0.78 g, 3 mmol) and stirred and triethylamine (TEA,0.3 g, 3 mmol) were then filled in the reaction flask and heated to 60 Covernight. The solvent was evaporated, and the residue was purified bycolumn chromatography on a silica gel, eluting with methanol in dichloromethane(gradient 5-10%). Yield of prodrug 3: 69.1% of offwhitepowder. C17H27N3O5F2, MS (ESI): m/z = 420 [M + H+]. Thepurity determined by HPLC was 96.2%. 1H NMR (400 MHz, DMSO) delta11.81 (s, 1H), 10.98 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.29 (d,J = 7.6 Hz, 1H), 6.32 (s, 1H), 6.17 (t, J = 7.5 Hz, 1H), 5.31 (s, 1H),4.27 - 4.12 (m, 1H), 3.96 - 3.85 (m, 1H), 3.81 (d, J = 12.2 Hz, 1H),3.66 (d, J=12.2 Hz, 1H), 3.03 (q, J=7.3 Hz, 1H), 2.40 (t, J=7.3 Hz,2H), 2.19 (t, J = 7.3 Hz, 2H), 1.59-1.44 (m, 4H), 1.27 (s, 4H), 1.17 (t,J = 7.3 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With triethylamine; In 1,4-dioxane; at 60℃; | Sebacic acid (0.61 g, 3 mmol) was dissolved in 10 mL 1, 4-dioxaneand heated to reflux. Sulfoxide chloride (0.36 g, 3 mmol) was addeddropwise, and the reaction was allowed to reflux 4 h. The solvent wasconcentrated under reduced pressure and residue was dissolved in10 mL DMF. Gem (0.78 g, 3 mmol) and stirred and triethylamine (TEA,0.3 g, 3 mmol) were then filled in the reaction flask and heated to 60 Covernight. The solvent was evaporated, and the residue was purified bycolumn chromatography on a silica gel, eluting with methanol in dichloromethane(gradient 5-10%). Yield of prodrug 4: 53% of off-whitepowder. C19H31N3O5F2, MS (ESI): m/z = 448 [M + H+]. The puritydetermined by HPLC was 97.6%. 1H NMR (400 MHz, DMSO) delta 11.81 (s,1H), 10.98 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H),6.32 (s, 1H), 6.17 (t, J = 7.5 Hz, 1H), 5.31 (s, 1H), 4.27 - 4.12 (m, 1H),3.96 - 3.85 (m, 1H), 3.81 (d, J = 12.2 Hz, 1H), 3.66 (d, J = 12.2 Hz,1H), 3.03 (q, J = 7.3 Hz, 1H), 2.40 (t, J = 7.3 Hz, 2H), 2.19 (t,J = 7.3 Hz, 2H), 1.59-1.44 (m, 4H), 1.27 (s, 4H), 1.17 (t, J = 7.3 Hz,1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate |
A157458[ 550-33-4 ]
(2R,3S,4R,5R)-2-(Hydroxymethyl)-5-(9H-purin-9-yl)tetrahydrofuran-3,4-diol
Reason: Gemcitabine, Antineoplastic,DNA damage
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. |
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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. |
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P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
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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. |
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P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
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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 | |
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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.
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