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CAS No. : | 122111-01-7 | MDL No. : | MFCD08458308 |
Formula : | C19H14F2O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SHHNEUNVMZNOID-HUUCEWRRSA-N |
M.W : | 376.31 | Pubchem ID : | 9821015 |
Synonyms : |
|
Chemical Name : | ((2R,3R)-3-(Benzoyloxy)-4,4-difluoro-5-oxotetrahydrofuran-2-yl)methyl benzoate |
Num. heavy atoms : | 27 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.21 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 87.06 |
TPSA : | 78.9 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.9 cm/s |
Log Po/w (iLOGP) : | 2.81 |
Log Po/w (XLOGP3) : | 3.79 |
Log Po/w (WLOGP) : | 3.47 |
Log Po/w (MLOGP) : | 2.83 |
Log Po/w (SILICOS-IT) : | 3.26 |
Consensus Log Po/w : | 3.23 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.43 |
Solubility : | 0.0141 mg/ml ; 0.0000374 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.14 |
Solubility : | 0.00272 mg/ml ; 0.00000723 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -5.46 |
Solubility : | 0.0013 mg/ml ; 0.00000344 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.65 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
34% | Heating / reflux; Dean and Stark apparatus | The experiment was repeated with quantities as given in example 1, method A. The residue obtained, after benzoylation, was analyzed by HPLC, which indicated erythrose 82percent, threose 8percent and the hydroxy acid 10percent. This mixture was dissolved in toluene 500moi and transferred into a 1 lit three-necked round bottom flask fitted with a stirrer, Dean and Stark apparatus carrying a condenser and a stopper. p-Tolunesulfonic acid, 2gms was added and the mixture was stirred at reflux and the water collected azeotropically. When the water collection had ceased, the reaction mixture was analyzed by HPLC. An aliquot was transferred into a test tube, cooled to about 60 C and washed with hot water 60 °C. Toluene layer was separated and concentrated and the residue was subject to HPLC analysis. The product indicated erythrose 90percent and threose 10percent. The hydroxy acid was absent. The reaction mixture was cooled to about 60 °C and hot water (60 °C) 100ml was added and the mixture was stirred for 15 minutes. Toluene layer was separated and concentrated under reduced pressure at 60 °C. The residue was taken in 350ml toluene and warmed to about 50 C. To the stirred solution hexane 350ml was added dropwise. At the end of the addition, the mixture was cooled first to 25 °C and subsequently to about 10 C to 15 C. The cooled mixture was stirred at 10 °C to 15 °C for about an hour. The solid was filtered, washed with a 1: 1 (v/v) mixture of toluene and hexane. The solid was dried at 60 °C. It showed HPLC purity of 99.8percent in erythrose, having mp 120-121 °C [a] 25o= +47. 8. ° Yield 50 gms (34percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.5% | Example-lPreparation of 2J-Deoxy-21,21-difluoro-3,5-bisbenzoyloxy-D-ribose trichloroacetimidate (Compound of formula Ia)Step-1: Preparation of lactol, viz. 21-Deoxy-21,21-difluoro-D-ribofuranose-3,5- dibenzoate (Compound of formula W) Sodium bis(2-methoxyethoxy)aluminium hydride (Vitride; 70% in toluene; 80 ml; 0.287 mol) was added slowly to a solution of 21-deoxy-21,21-difluoro-3,5- dibenzoate-1-oxoribose (III; 100 gm; 0.265 mol) in dry tetrahydofuran cooled to -30C under an atmosphere of nitrogen . After the addition, the reaction mixture was agitated at the same temperature for lhr and quenched by the addition of 6N hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The organic layer was separated and washed with 5% sodium bicarbonate solution followed by water. Concentration of the organic layer under reduced pressure gave lOOgm ( 99.5%) of the title compound as an oil.1H NMR (CDCl3, delta): 5.6 (m, H-I, IH), 5.45 - 5.32 (br, H-3, IH), 4.7 (m, H-4, IH),4.65 (br, H-5, 2H), 3.6 (s, IH5OH). | |
84% | With lithium tri-t-butoxyaluminum hydride; In tetrahydrofuran; diethyl ether; at -78℃; for 1h;Inert atmosphere; | A solution of 2-deoxy-d-erythro-pentafuranos-1-ulose-3,5-dibenzoate 1 (5.00 g, 0.013 mmol) in anhydrous THF (40 mL) and anhydrous diethyl ether (10 mL) was cooled to -78 C and lithium tri(tert-butoxy)aluminium hydride (14.58 mL, 1.0 M in THF) was added dropwise. The reaction mixture was stirred for 1 h at -78 C and was quenched by the slow addition of methanol (3.2 mL). The reaction mixture was allowed to warm to rt and then ethyl acetate (162 mL) was added. The organic phase was washed with equal volumes of saturated NaHCO3 solution and brine, and the organic layer was dried on Na2SO4 and concentrated to give a thick oil as a mixture of anomers (4.14 g, 84%). 19F NMR (CDCl3, 471 MHz): delta -108.97, -109.50, -123.19, -123.70, -124.93, -125.46. 1H NMR of major (55%) anomer (CDCl3, 500 MHz): delta 8.14-7.99 (4H, m, Bz), 7.66-7.55 (m, 2H, Bz), 7.51-7.39 (m, 4H, Bz), 5.81-5.73 (m, 1H, H-3), 5.52-5.49 (m, 1H, H-1), 4.82-4.58 (m, 3H, H-4, H-5), 3.66 (s, 1H, OH). 1H NMR of minor (45%) anomer (CDCl3, 500 MHz): delta 8.14-7.99 (m, 4H, Bz), 7.66-7.55 (m, 2H, Bz), 7.51-7.39 (m, 4H, Bz), 5.55-5.49 (m, 1H, H-3), 5.40-5.35 (m, 1H, H-1), 4.77-4.60 (m, 2H, H-5), 4.51-4.45 (m, 1H, H-4), 3.93 (s, 1H, OH). 13C NMR (CDCl3, 126 MHz): delta 63.46, 64.57 (C-5), 71.52 (dd, J1C-F = 16.4 Hz, J2C-F = 28.4 Hz, C-3), 72.15 (dd, J1C-F = 17.9 Hz, J2C-F = 36.3 Hz, C-3), 76.82, 79.25 (C-4), 95.84 (dd, J1C-F = 23.7 Hz, J2C-F = 37.0 Hz, C-1), 96.10 (dd, J1C-F = 23.2 Hz, J2C-F = 42.1 Hz, C-1), 121.29 (dd, J1C-F = 254.4 Hz, J2C-F = 263.9 Hz, C-2), 121.77 (dd, J1C-F = 248.4 Hz, J2C-F = 272.4 Hz, C-2), 127.15, 127.63, 128.45, 128.52, 128.62, 128.66 (Ph), 129.38 (?ipso? Ph), 129.80, 130.07, 130.11, 133.37, 133.43, 133.91, 134.00 (Ph), 165.31, 165.59, 166.59, 166.65 (CO). |
76% | Example 605: <n="103"/>Part A:According to a modification of a literature procedure (Chou. T. S1 et at. Synthesis 1992, 565) a solution of lactone 605A (10.0 g, 26.6 mmol) in dry diethylether (80 mL) and dry THF (30 mL) under argon atmosphere, was stirred at rt for 10 min. Then lithium tri-te/t-butoxy aluminum hydride (8.25 g, 32.4 mmol) was added in 3 portions. The mixture was stirred at rt for 1 h and then quenched with methanol (20 mL) slowly, followed by 1 N HCI solution (100 mL). The aqueous layer was separated, extracted with DCM (3 x 50 mL), and the combined organic layers were washed with satd. NaHCO3 solution (50 mL) and brine (2 x 50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, 30% ethyl acetate/hexanes) to afford 605B (7.64 g; 76%) as an oil. HPLC-MS tR = 1.92 min (UV2S* nm); mass calculated for formula C19Hi6F2O6 378.09, observed LCMS m/z 401.0 (M+Na) and 361.0 (M-OH, oxonium ion). |
In a 2 lit four-necked round bottom flask fitted with a stirrer, condenser carrying a guard tube, addition funnel carrying a nitrogen inlet system and thermometer socket, was taken 2-deoxy-2, 2-difluoro-D-erythropentofuranose-1-ulose-3, 5- dibenzoate 100gms, and THF 1 lit. The solution was cooled to about-20 C under stirring. Vitride, 60ml (65% w/w in toluene), was taken in the addition funnel and added dropwise into the flask at such a rate so as to maintain the mass temperature at-20 C. After the addition, the reactor mixture was stirred at-20 C for 1 hour. TLC (Mobile phase-Ethyl acetate: Pet. Ether: 2: 8) was checked for completion of the reaction. HPLC analysis in Zarboax CN using hexane + isopropyl alcohol 92ml + 8ml indicated the product as two peaks. On completion, the reaction mixture was allowed to warm upto 0 C and treated with methane), 15m !. Later 10% aqueous hydrochloric acid, 300ml, was added into the reaction mass and stirred for 30min. The organic layer was separated. | ||
With sodium tetrahydroborate; In tetrahydrofuran; at 2℃; for 3h;Product distribution / selectivity; | 100 g of <strong>[122111-01-7]2-deoxy-D-erythro-2,2-difluoro-pentafuranos-1-ulose-3,5-dibenzoate</strong> (0.266 mole) was dissolved in a 2 L round-bottom flask in 650 ml of tetrahydrofuran and cooled to 2 C., after which 3.20 g of NaBH4 (0.084 mole) was added. The suspension was stirred for 3 h, then a sample was taken and monitored by HPLC. After completion, the reaction was stopped by addition of 500 ml of brine and concentrated HCl to pH 2 (about 7 ml). The mixture was stirred for 10 minutes, then the aqueous phase was separated at room temperature; the organic phase was washed with 500 ml of brine, added with a further 500 ml of brine and the biphasic system was evaporated to remove THF; when an oil suspended in water was obtained, 500 ml of CH2Cl2 were added thereto. The mixture was stirred for 15 minutes, then the aqueous phase was separated and extracted again with 150 ml of CH2Cl2, then the combined organic phases were concentrated to give an oil (107 g). HPLC analysis showed purity of 75%; the calculated yield was 90%. Part of the oil was subjected to silica gel chromatography (eluent: 6:4 ethyl acetate-hexane) to give 3.0 g of pure lactol and 300 mg of impurity. | |
100 g of <strong>[122111-01-7]2-deoxy-D-erythro-2,2-difluoro-pentafuranos-1-ulose-3,5-dibenzoate</strong> (0.266 mole) was dissolved in a 2 L round-bottom flask in 650 ml of tetrahydrofuran and cooled to 2C, after which 3.20 g of NaBH4 (0.084 mole) was added. The suspension was stirred for 3h, then a sample was taken and monitored by HPLC. After completion, the reaction was stopped by addition of 500 ml of brine and concentrated HCl to pH 2 (about 7 ml). The mixture was stirred for 10 minutes, then the aqueous phase was separated at room temperature; the organic phase was washed with 500 ml of brine, added with a further 500 ml of brine and the biphasic system was evaporated to remove THF; when an oil suspended in water was obtained, 500 ml of CH2Cl2 were added thereto. The mixture was stirred for 15 minutes, then the aqueous phase was separated and extracted again with 150 ml of CH2Cl2, then the combined organic phases were concentrated to give an oil (107 g). HPLC analysis showed purity of 75%; the calculated yield was 90%. Part of the oil was subjected to silica gel chromatography (eluent: 6:4 ethyl acetate-hexane) to give 3.0 g of pure lactol and 300 mg of impurity. | ||
8.36 g | With lithium tri-t-butoxyaluminum hydride; In tetrahydrofuran; diethyl ether; at -78℃; | To a solution of <strong>[122111-01-7]3,5-di-O-benzoyl-2,2-deoxy-2,2-difluoro-D-arabinofuran-1-one</strong> 15 (8.0 g, 21.2 mmol) in THF/Et2O4/1 (80 mL) at -78 oC was added dropwise LiAl(OtBu)3H (42.5 mL, 42.5 mmol, 2eq). The reaction mixturewas stirred at -78 oC for 2h before addition of 12 mL of anhydrousMeOH. The reaction mixture was allowed to reach rt before addition of AcOEt (80mL). The organic phase was washed with NaHCO3 sat (140 mL) and theaqueous phases were extracted with AcOEt (140 mL). The combined organic phaseswere washed with NaHCO3 sat (200 mL) and dried over MgSO4.Solvents were evaporated to dryness to give 16 as a colorless oil (8. 36 g) which was used without furtherpurification in the next step. |
100.5 g | With lithium tri-t-butoxyaluminum hydride; In tetrahydrofuran; at -78 - 20℃; for 2h;Inert atmosphere; | To a stirred solution of 84-1 (100.0 g, 265.9 mmol) in dry THF (1000 mL) was added Li(O-t-Bu)3AlH (318.9 mL, 318.9 mmol) at -78 C. under N2. The mixture was stirred at -78 C. for 1 h and then at R.T for 1 h. The reaction mixture was cooled to -50 C. and quenched with ice and a saturated NH4Cl solution. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to afford the l?- OH derivative (100.5 g) as a white solid. |
With lithium tri-(tert-butoxy)aluminum hydride; In tetrahydrofuran; at -78 - 20℃; for 2h;Inert atmosphere; | To a stirred solution of compound 16-1 (100.0 g, 265.9 mmol) in dry THF (1000 mL) was added Li(O-t-Bu)3AlH (318.9 mL, 318.9 mmol) at -78 C. under N2. The mixture was stirred at -78 C. for 1 hour and then at R.T. for an additional 1 hour. The reaction mixture was cooled to -50 C. and quenched with ice and a saturated NH4Cl solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to afford the crude product (100.5 g) as a white solid, which was dissolved in dry DCM (600 mL). To the mixture was added dropwise NEt3 (110 mL) and MsCl (45.5 g, 298.0 mmol) at 0 C., and the reaction mixture was stirred at R.T. for 2 hour, quenched with ice water at 0 C., and extracted with DCM. The organic layer was dried over Na2SO4, concentrated and purified on silica gel column to afford compound 16-2 (113.4 g, yield 93.9%) as a white solid. | |
With 2,2,2-trifluoroethanol; sodium bis(2-methoxyethoxy)aluminium dihydride; In acetic acid butyl ester; toluene; at -15 - -10℃; for 12h;Inert atmosphere; | To a Red-Al (3.5M in toluene, 9.87 mL, 34.55 mmol, 1.30 equiv.) solution in tolene (20 mL) at 10 ~ 15 C, CF3CH2OH (2.70 mL,37.20 mmol, 1.40 equiv.) was added dropwise. The resulting solution was warmed to RT and transferred into another solution of 8[8] (10.00 g, 26.57 mmol, 1.00 equiv.) in n-butyl acetate (30 mL) and toluene (10 mL) at 10 ~ 15 C. The mixture was stirred at this temperature for 12 h, treated with TBAB (100 mg, 0.31 mmol, 0.01equiv.), and then with SO2Cl2 (17.50 mL, 216.55 mmol, 8.15 equiv.).The resulting solution was stirred at RT for 12 h, quenched by addition of sodium citrate (45 g), water (150 mL), and n-butyl acetate(100 mL), and the pH of the mixture was brought to 7e8 with2 N aq. NaOH. The organic phase was separated, washed with brine,dried over sodium sulfate, concentrated, and purified by flash chromatography on silica gel (10:1, 60e90 C petroleum ether eEtOAc) to give 10a [10b] (colorless oil, 6.54 g, 16.48 mmol, 62%,alpha: beta 1: 0.39). | |
With oxygen; sodium bis(2-methoxyethoxy)aluminium dihydride; In 2,2,2-trifluoroethanol; acetic acid butyl ester; toluene; at -10 - 15℃; for 12h;Inert atmosphere; | Under anhydrous and anaerobic conditions,The red aluminum reagent (3.5M toluene solution, 9.87mL, 34.55mmol) was dissolved in toluene (20mL), and the temperature of the reaction system was controlled to between -10 C and 15 C.Trifluoroethanol (2.70 mL, 37.20 mmol) was slowly added dropwise thereto. After the dropwise addition was completed,Naturally warm to room temperature to obtain a colorless and clear solution; under anhydrous oxygen and nitrogen,Take raw material 9 (10.00g, 26.57mmol) into the reaction flask, add butyl acetate (30mL) and toluene (10mL) to it, and control the temperature of the reaction system to between -10 C and 15 C.The colorless and clear solution prepared above was slowly added dropwise thereto, and after the dropwise addition was completed,After the temperature is controlled from -10 C to 15 C for 12 hours, the raw materials are completely reacted and intermediate 10 is formed.While maintaining the temperature at -10 C to 15 C, TBAB (100mg, 0.31mmol) was added to the reaction solution, and sulfonyl chloride (17.50mL, 216.55mmol) was slowly added dropwise.The system was left to react at room temperature for 12 hours.To the reaction solution were added sodium citrate (45 g), water (150 mL) and butyl acetate (100 mL).Adjust the pH to 7-8 with 2N sodium hydroxide solution, separate the organic layer,Washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate,Column chromatography (PE: EA (v: v) = 10: 1) separated 7b (6.54 g, 16.48 mmol) as a colorless oil, yield: 62%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine;dmap; In ethyl acetate; at 60 - 65℃; for 6h;Product distribution / selectivity; | The residue, obtained above, was dissolved in ethyl acetate, 500m1 and transferred into a 2 lit four-necked flask fitted with a stirrer, condenser carrying a guard tube, an addition funnel carrying a nitrogen bubbling system and a stopper. 4-Dimethyl amino pyridine, 10.3gms and pyridine, 86ml, were charged into the flask. Benzoyl chloride, 112mut was dissolved in ethyl acetate, 500ml, and charged into the addition funnel. The reaction mixture was warmed to about 60 C to 65 C under stirring and the solution of benzoyl chloride was added into the flask dropwise in about 3 hours. After the addition, the reaction mixture was stirred at 60 C to 65 C for about 3 hours and then cooled to 25 C to 30 C and filtered through a bed of hyflow. Then the hyflow bed was washed with ethyl acetate, 200ml. The combined ethyl acetate extract was washed with 10% hydrochloric acid, 300ml, 10% sodium bicarbonate solution, 300ml, saturated sodium chloride solution, 300moi and finally dried over anhydrous sodium sulphate. The ethyl acetate solution was filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane, 150ml and transferred into a three-necked round bottom flask fitted with a stirrer, addition funnel and a thermometer socket. Hexane, 300moi was charged into the addition funnel and this was added dropwise into the stirred dichloromethane solution. After the addition, the solution was stirred at 25 C to 30 C for about 1 hour, when solid started precipitating out. The reaction mixture was then cooled to about 10 C to 15 C and stirred at that temperature for about one hour. The solid was filtered, washed with a mixture of dichloromethane and hexane at 10 C to yield 30 gms of title compound having mp 116-118 C [a] 25p= +40 (C=1.0, CHC13) The solid was checked for its purity by HPLC [Zorbax CN 4.6x25 cm : eluent, hexane/1-PrOH (92: 8)]. It was about 85% pure in the D-erythro, about 8% of threo and 7% of an unknown substanceMethod B The experiment was repeated as given under Method A. After the benzoylation the residue was crystallized from isopropyl alcohol to give 35gms of the title compound in 24% yield., having mp 115-116 C [a] 25p= +39 (C=1.0, CHC13) HPLC analysis (Zorbax CN 4.6x25 cm: eluent, hexane/1-PrOH (92: 8) flowrate, 5ml/min UV 254) indicated the product in 83% rich in D-erythro 8% D-threo and about 9% unknown compound.; EXAMPLE 3 Preparation of pure 2-deoxy-D-erythro pento furanose-1-ulose-3, 5-dibenzoate Method A The experiment was repeated with quantities as given in example 1, method A. The residue obtained, after benzoylation, was analyzed by HPLC, which indicated erythrose 82%, threose 8% and the hydroxy acid 10%. This mixture was dissolved in toluene 500moi and transferred into a 1 lit three-necked round bottom flask fitted with a stirrer, Dean and Stark apparatus carrying a condenser and a stopper. p-Tolunesulfonic acid, 2gms was added and the mixture was stirred at reflux and the water collected azeotropically. When the water collection had ceased, the reaction mixture was analyzed by HPLC. An aliquot was transferred into a test tube, cooled to about 60 C and washed with hot water 60 C. Toluene layer was separated and concentrated and the residue was subject to HPLC analysis. The product indicated erythrose 90% and threose 10%. The hydroxy acid was absent. The reaction mixture was cooled to about 60 C and hot water (60 C) 100ml was added and the mixture was stirred for 15 minutes. Toluene layer was separated and concentrated under reduced pressure at 60 C. The residue was taken in 350ml toluene and warmed to about 50 C. To the stirred solution hexane 350ml was added dropwise. At the end of the addition, the mixture was cooled first to 25 C and subsequently to about 10 C to 15 C. The cooled mixture was stirred at 10 C to 15 C for about an hour. The solid was filtered, washed with a 1: 1 (v/v) mixture of toluene and hexane. The solid was dried at 60 C. It showed HPLC purity of 99.8% in erythrose, having mp 120-121 C [a] 25o= +47. 8. Yield 50 gms (34%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; at 45 - 50℃; for 3h; | The product, as obtained in example 1 method A, 20gms, was charged into a 500ml three-necked round bottom flask fitted with a stirrer, condenser and a stopper. A solution of 4N hydrochloric acid, 200ml was also charged in the flask and the reaction mixture was stirred at 45 C to 50 C for about 3 hours and on cooling a solid precipitated out. The solid was filtered and dried. The product, on HPLC analysis, was matching with the retention time of the unknown compound found along with the product of formula IV and the purity was 99%. The compound was characterized by IR'HNMR, MS and elemental analysis m p 104. 5 C-106. 5 C [a] D25 +30. 71 (C=1, MeOH) Elemental analysis as Cl9Hl6F207 Calculated C 57.90 ; H 4.10 Found C 57.85 ; H 4.12 IR (KBr, cm~1) 3351,1761, 1694,1451, 1286,1266, 1146,1091 714 NMR (DMSOD6) 8 4.25 (M, 2H, C-5), 4.378 (m, 1 H, C-4), 5.88 (m, 1 H, C-3) 7.513 (m. 6H, Ar-H), 7.96 (m, 4H, Ar-H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | toluene-4-sulfonic acid; In toluene;Heating / reflux; Dean and Stark apparatus;Product distribution / selectivity; | The experiment was repeated with quantities as given in example 1, method A. The residue obtained, after benzoylation, was analyzed by HPLC, which indicated erythrose 82%, threose 8% and the hydroxy acid 10%. This mixture was dissolved in toluene 500moi and transferred into a 1 lit three-necked round bottom flask fitted with a stirrer, Dean and Stark apparatus carrying a condenser and a stopper. p-Tolunesulfonic acid, 2gms was added and the mixture was stirred at reflux and the water collected azeotropically. When the water collection had ceased, the reaction mixture was analyzed by HPLC. An aliquot was transferred into a test tube, cooled to about 60 C and washed with hot water 60 C. Toluene layer was separated and concentrated and the residue was subject to HPLC analysis. The product indicated erythrose 90% and threose 10%. The hydroxy acid was absent. The reaction mixture was cooled to about 60 C and hot water (60 C) 100ml was added and the mixture was stirred for 15 minutes. Toluene layer was separated and concentrated under reduced pressure at 60 C. The residue was taken in 350ml toluene and warmed to about 50 C. To the stirred solution hexane 350ml was added dropwise. At the end of the addition, the mixture was cooled first to 25 C and subsequently to about 10 C to 15 C. The cooled mixture was stirred at 10 C to 15 C for about an hour. The solid was filtered, washed with a 1: 1 (v/v) mixture of toluene and hexane. The solid was dried at 60 C. It showed HPLC purity of 99.8% in erythrose, having mp 120-121 C [a] 25o= +47. 8. Yield 50 gms (34%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
toluene-4-sulfonic acid; In toluene;Heating / reflux; Dean and Stark apparatus;Product distribution / selectivity; | 100gms of solid obtained as given under example 2 was charged into a 2 lit three-necked round bottom flask fitted with a stirrer, Dean Stark apparatus carrying a condenser and thermometer socket. Toluene, 600mut, was added along with p-toluenesulfonic acid, 2gm and the mixture was stirred to reflux. Water formed was collected by azeotropic distillation. When the water collection had ceased, the reaction mixture was cooled to 60 C and washed with hot water (60 C, 300ml). Toluene layer was separated and concentrated under reduced pressure at <60 C. Subsequently the residue was taken in toluene, 350moi and warmed to about 40 C to 50 C and hexane, 350ml, was added dropwise. After the addition, the mixture was cooled to 25 C under stirring and then cooled to 10 C to 15 C. It was stirred at 10 C to 15 C for one hour, the solid was filtered, washed with a mixture of toluene-hexane (1: 1), dried at 60 C to give the product >99% rich in the erythrose, which showed [a] 25D +48 (C=1, CHC13) mp = 121-122C. |
Yield | Reaction Conditions | Operation in experiment |
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Example 1:Preparation of 2-deoxy-D-erythro-2,2-difluoro-ribofuranose-3, 5-dibenzoate:<strong>[122111-01-7]2-deoxy-D-erythro-2,2-difluoro-pentafuranos-1-ulose-3,5-dibenzoate</strong> (20Og) was dissolved in (2 L) of tetrahydrofuran in a 5L round bottom flask. (0.2L) of vitride (70% solution in toluene) was added between -50 to -700C. The reaction was continued for 60 minutes. On completion, reaction was arrested by adding methanol (0.24L) followed by hydrolysis with 7% HCI (1.3L). After stirring for -30 min the aqueous layer was separated at RT. The aqueous layer was repeatedly extracted with Ethyl acetate (0.8 L X 2). The collected organic layer was washed with brine (0.5 L X 2) and 5% aqueous NaHCO3 (0. 5 L X2) followed by brine (0.5 L X 2). The organic layer was concentrated under vacuum to get thick oil (0.2kg). | ||
With lithium tri-t-butoxyaluminum hydride; In tetrahydrofuran; diethyl ether; at 20℃; for 1.5h;Inert atmosphere; | LiAlH(OtBu)3 (10.2 g, 40.0 mmol) was added portion-wise with stirring over 40 min to lactone 16 (10.0g, 26.6 mmol) in Et2O and THF (1:1, 110 mL) and the resulting suspension allowed to warm to roomtemperature. After 1.5 h, MeOH (20 mL) was added dropwise with stirring and the mixture diluted withEt2O (200 mL) and washed sequentially with aqueous HCl (1.0 M; 200 mL), saturated aqueous NaHCO3(150 mL), saturated aqueous Rochelle?s salt (2 × 200 mL) and H2O (200 mL). The organic layer wasdried (MgSO4) and rotary evaporated to yield 3,5-di-O-benzoyl-2-deoxy-2,2-difluoro-D-ribofuranose(17) (10.0 g, 99.8%) as a colorless oil containing a 1.0 : 1.6 mixture of anomers | |
With sodium tetrahydroborate; zinc(II) chloride; tert-butyl alcohol; In tetrahydrofuran; ethyl acetate; at 15℃; | Ethyl acetate 45mL,Tetrahydrofuran 15mL added to the reaction flask,10 g of 2-deoxy-2,2-difluoro-D-erythro-pentofuranos-1-one-3,5-dibenzoate was added,Anhydrous zinc chloride 1.8,Stirring to dissolve,Tert-butanol 2g,Temperature below 15 sodium borohydride 0.67g,The reaction is for 1 to 1.5 hours.The reaction is completed,Add dilute hydrochloric acid 40mL,Stir for 10 minutes,Static stratification,Abandoned water layer,The organic layer was saturated brine 20mL,Saturated aqueous sodium bicarbonate 20mL wash,Dried over anhydrous magnesium sulfate, filtered,concentrate,2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoate 10 g,alpha / beta = 3.7,Yield 100%. |
Yield | Reaction Conditions | Operation in experiment |
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With dmap; In ethyl acetate; at 60 - 65℃; for 6.25h; | EXAMPLE 16 This example describes the preparation of 2-deoxy-2,2-difluoro-D-erythro-pentofuranos-1-ulose-3,5-dibenzoate. 3,5-dihydroxy-2,2-difluoro-D-erythro-pentofuranos-1-ulose, obtained by Process A, (4.3 g, 0.0245 mol) was dissolved under nitrogen at 60 C. in dry ethyl acetate (70 ml). Anhydrous pyridine (7.9 ml, 0.098 mol, 4.0 equiv.) and 4-(dimethy-lamino)pyridine (DMAP) (0.73 g, 0.0061 mol, 0.25 equiv.) were added to the solution. Then, benzoyl chloride (7.2 g, 0.051 mol, 2.1 equiv.) in ethyl acetate (20 ml) was added drop-wise to the mixture at 60 C. for 15 minutes and the reaction mixture was heated at 60-65 C. for 6 hours. The mixture was then cooled to 0-5 C. and pyridinium hydrochloride was collected by filtration and washed witl cold ethyl acetate (3×10 ml). The filtrate was cooled at 0 C. for 2 hours and an additional portion of pyridinium hydrochloride was collected by filtration. The solvent was removed to dryness under reduced pressure to obtain a colorless semisolid crude product. The crude product was dissolved in dry toluene (20 ml) under heating and the mixture was cooled to ambient temperature and kept at 5-10 C. for 3 hours. A colorless precipitate was collected by filtration, washed with a mixture of 1:2 toluene:n-hexane (3×10 ml) and dried at 50 C. overnight to give 6.5 g of 2-Deoxy-2,2-difluoro-D-erythro-pentofuranos-1-ulose-3,5-dibenzoate, having a purity of 99.72% (by HPLC). The solvents were removed to dryness under reduced pressure and the thus obtained residue was slurried in toluene (10 ml) at ambient temperature for 4 hours. A colorless precipitate was then collected by filtration, washed with a 1:2 toluenie:n-hexanie mixture (3×5 ml) and dried at 50 C. overnight to yield an additional 0.7 g of the product, having a purity of 99.12% (by HPLC). Total yield. 7.2 g, 78.1% from the dicyclohexylammonium salt. Overall yield [from the compound of fonnula (IV)]: 40.1%; mp 120-121 C., [alpha]D20.5+69.67 (c=1.0, acetonitrile). 1H NMR (DMSO-d6): delta=4.81 (m, 2 H, H-5), 5.43 (q, 1 H, H-4), 6.12 (m, 1 H, H-3), 7.45-7.78 (m, 6 Harom), 7.97 (m, 2 Harom), 8.08 (m, 2 Harom). 13C NMR (DMSO-d6): delta=63.04 (C-5), 69.23 (C-3, JC-F=26.5, 30.0 Hz), 77.72 (C-4, JC-F=5.6 Hz), 111.95 (C-2, JC-F=258, 260 Hz), 127.7, 128.75, 128.88, 128.96, 129.30, 129.80, 133.69, 134.40(Carom), 163.04 (C-1,JC-F=32, 34 Hz), 164.36 [OC(O)Ph], 165.17 [OC(O)Ph]. GC/MS (CI): m/z[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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3 (RS)-2, 2-difluoro-3- (2, 2-dimethyldioxalan-4-yl) propionate 100gms was charged into a 2 lit three-necked round bottom flask fitted with a stirrer, condenser and a stopper. Water 300ml was charged into the flask, followed by p-toluenesulfonic acid, 2gms. The reaction mixture was stirred at 75C to 80C for 3 hours. Subsequently toluene, 600ml, was charged into the flask and the set up was fitted with a Dean and Stark apparatus. The reaction mixture was stirred to reflux and water was distilled off as an azeotrope. Toluene, equivalent to the volume distilled off, was replaced into the flask. This process was continued until the distillation of the water was completed. The reaction mixture was cooled to about 60 C and hot water (60 C) 600mut, was added and the reaction mixture was stirred for 15 minutes. Toluene extract was separated and concentrated under reduced pressure at 60 C. The residue was dissolved in ethyl acetate and subjected to benzoylation as given in example 1, method A. The residue, after distillation of ethyl acetate, was dissolved in toluene 350ml and warmed to and 50 C and to the stirred toluene solution at 50 C, hexane, 350moi, was added dropwise from dropping funnel. After the addition, the solution was cooled to about 25 C under stirring. Subsequently, the solution was slowly cooled to 10 C to 15 C, maintained for one hour and the solid was filtered. The solid was washed with 1: 1 (v/v) toluene-hexane mixture and dried at 60 C to yield 50 gms of product. The HPLC purity of the compound was >99% of erythrose with mp120-121C and [alphaJ25o= +47. 8. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; In ethyl acetate; at 25 - 60℃;Inert atmosphere; | The residue obtained in Example 3 was dissolved in 50 ml of ethylacetate at 25-35C and 8 ml of pyridine was added to it. The reaction mass was heated to 600C and then a mixture of 10 ml of benzoyl chloride and 50 ml of ethylacetate was added slowly for 3 hours. The reaction mixture was maintained at about 60 0C for about 3 hours under nitrogen atmosphere. The reaction mixture cooled to 25-300C and stirred for 3 hours. 2 gm of activated charcoal was added to the mixture and cooled the contents to about 5 C. The charcoal was removed by filtration and the filtrate was passed over anhydrous sodium sulfate. The final organic layer was distilled completely to obtain a semi solid material.10 ml of dichloromethane and 50 ml of isopropyl alcohol was added to the above obtained material and cooled to about 10 0C. The solution was stirred for 2 hours for solid precipitation. The solid was filtered and dried to obtain 6 gm of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
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To a 3L four-necked round bottom flask 82g of ethyl~3-(2,2-dimethyl-1 ,3- dioxolan-4-yl)-2,2-difluoro-3-hydroxy propionate having 75% of required R isomer was charged, and acetonitrile (820ml) and water (26ml) and pyridinium trifluoroacetate (14.76g) were added to it and the reaction mixture was heated to reflux. The reaction mixture was stirred at reflux temperature for 3 hours. Mixture of Acetonitrile and water was azeotropically distilled completely to give oil. Ethyl acetate (90ml) was added in the reaction mass and subjected to distillation atNTP. The obtained oil was dissolved in ethyl acetate (328ml), dry pyridine (96ml) was added followed by 4, 4'-dimethyl aminopyridine (9.52g). The mixture was <n="17"/>heated to 65C under N2 atmosphere. Solution of benzoyl chloride (96ml) in ethyl acetate (255ml) was added drop wise over 3 hours at 650C. The reaction was stirred at 650C for another 3 hours and then cooled to room temperature (25- 300C) and stirred for another 3 hours. The reaction mass was cooled to 0-50C and stirred for another 1 hour and filtered. The filtrate was concentrated under vacuum at 35C to yield 160 g oil. Oil so obtained was taken into 164ml ethyl acetate followed by distillation to get a thick mass to which 61.5 ml ethyl acetate was then added under stirring and contents were cooled to 0-50C followed by keeping for half an hour. Diisopropyl ether (205ml) was then added to the contents and continued further for 10-15 min. Product so obtained is filtered off washed with diisopropyl ether and dried under vacuum at 40-45C. Yield (53.3g), HPLC purity of +99.5%, DSC thermogram has shown the endotherm in the range of 121-125C (peak at 123.69), Figure 1. | ||
Example EPreparation & isolation of 2-deoxy-D-erythro-2,2-difluoro-pentafuranos-1- ulose-3,5-dibenzoate:To a 3L four-necked round bottom flask 9Og of ethyl-3-(2,2-dimethyl-1 ,3- dioxolan-4-yl)-2,2-difluoro-3-hydroxy propionate having 75% of required R isomer was charged, and acetonitrile (900ml) and water (29ml) and pyridinium para toluene sulphonate (19.6g) were added to it and the reaction mixture was heated to reflux. The reaction mixture was stirred at reflux temperature for 12 hours. Mixture of Acetonitrile and water was azeotropically distilled completely to give oil. Ethyl acetate (100ml) was added in the reaction mass and subjected to distillation at NTP. The obtained oil was dissolved in ethyl acetate (360ml), dry pyridine (105ml) was added followed by 4, 4'-dimethyl aminopyridine (10.44g). The mixture was heated to 650C under N2 atmosphere. Solution of benzoyl chloride (105ml) in ethyl acetate (260ml) was added drop wise over 3 hours at 65C. The reaction was stirred at 65C for another 3 hours and then cooled to room temperature (25-3O0C) and stirred for another 3 hours. The reaction mass was cooled to 0-5C and stirred for another 1 hour and filtered. The filtrate was concentrated under vacuum at 35C to yield 16O g oil. Oil so obtained was taken <n="18"/>into 170ml ethyl acetate followed by distillation to get a thick mass to which 61.5 ml ethyl acetate was then added under stirring and contents were cooled to 0- 50C followed by keeping for half an hour. Diisopropyl ether (210ml) was then added to the contents and continued further for 10-15 min. Product so obtained is filtered off washed with diisopropyl ether and dried under vacuum at 40-450C. Yield (59g), HPLC purity of +99.5%. DSC thermogram has shown endotherm in the range of 121-1250C (peak at 123.15) Figure 2.Example F Procedure in example E was repeated with 162 g (Erythro:Threo) ethyl-3-(2,2-dimethyl-1 ,3-dioxolan-4-yl)-2,2-difluoro-3-hydroxy propionate resulting in to 290 g oil. Thick oil so obtained is taken into 300ml ethylene dichloride followed by distillation under vacuum at 55-600C to get a thick mass to which 122 ml ethylene dichloride was then added under stirring and contents were cooled to 0- 50C followed by keeping for half an hour. Diisopropyl ether (400ml) was then added to the contents and continued further for10-15 min. Product so obtained was filtered off washed with diisopropyl ether and dried under vacuum at 40- 45C. Yield (105.3g), HPLC purity of +99.5 % & more, DSC thermogram has shown endotherm in the range of 121-125C (peak at 123.19) Figure 3. The present invention has following advantages: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; aluminum isopropoxide; In isopropyl alcohol; toluene; at 5 - 30℃; for 1.5h; | 37.6 g (0.10 mol) of the compound of formula I, <strong>[122111-01-7]2-deoxy-2,2-difluoro-D-erythro-1-furanose-3,5-dibenzoyl ester</strong>, was added to a clean reactor.Add 500 mL of toluene and 5 mL of isopropyl alcohol, and then start to cool down to below 5 C.The temperature was controlled and a mixed catalytic system of 30.6 g (0.15 mol) of aluminum isopropoxide and 16.8 g (0.15 mol) of potassium t-butoxide was added.After the addition is completed, the mixture is heated, heated, and the temperature is controlled at 25 C to 30 C for 1.5 h.The central control sample can be used for HPLC detection of the purity of the intermediate compound II to 99.1%.After the reaction is over, go directly to the next reaction.Slowly lower the reaction system to 0 to 5 C,Control the temperature and start slowly adding dropwise 12.6 g (0.11 mol) of methylsulfonyl chloride.After the completion of the dropwise addition, the temperature is slowly raised and the temperature is controlled at 25 C to 30 C for the incubation reaction for 2.5 h.The purity of the methanesulfonyl ester of the gemcitabine intermediate of the compound of formula III was determined by HPLC to be 98%.After the reaction is completed, the temperature of the control system is below 30 C, and the pH is adjusted to 10-8 by adding 10% by mass of hydrochloric acid. After stabilization, it is allowed to stand for 30 min, and the layers are separated, and anhydrous sodium sulfate is added to the collected organic phase toluene layer. 2 g of stirring was dried for 30 min, then filtered.The collected filtrate is distilled under reduced pressure to remove the solvent.After shrinking to dryness, 100 mL of methanol was added to the residue, and the beating treatment was carried out for 1 hour.Then, slowly lowering the temperature to 0 to 5 C for crystallization treatment for 1 h, filtering, and drying the filter cake.Obtaining the corresponding dry product of the formula III compound gemcitabine intermediate mesylate 41.5g,The content was 99.7% and the molar yield was 91%. | |
With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 25 - 30℃; for 3h; | 150 liters of tetrahydrofuran solvent was added to the reactor at room temperature, and then <strong>[122111-01-7]2-deoxy-2,2-difluoro-D-erythro-1-furanose-3,5-dibenzoyl ester</strong> 20 g ( 0.054 mol),2.0 g (0.054 mol) of sodium borohydride and the PPO-CBS supported catalyst recovered in Example 1, and further added 0.2 g of a new PPO-CBS supported catalyst.Then, under stirring, 6 g of methanol is slowly added dropwise, and the controlled temperature during the dropwise addition is between 25 C and 30 C;After the addition is completed, continue to control the temperature at about 25 C for 3.0 hours.After the reaction was completed, the pH of the hydrochloric acid-adjusting system was added dropwise to the reaction solution, and the mixture was stirred for 10 minutes.Filtration, recovery of solid PPO-CBS supported catalyst can be applied, the filtrate is allowed to stand for 30min, and then the organic phase is collected in layers;The aqueous layer can be extracted twice with 50 mL of tetrahydrofuran.The organic phase was combined and washed with a saturated aqueous solution of sodium hydrogencarbonate (50 mL), and the mixture was allowed to stand, and the organic phase (tetrahydrofuran layer) was collected, and 10 g of anhydrous sodium sulfate was added to the collected organic phase, and then filtered.The collected filtrate was subjected to distillation under reduced pressure to remove the solvent.Obtained 18.4 g of 2-deoxy-2,2-difluoro-D-erythro-3,5-dibenzoate as a yellow oily liquid.The total purity was 98.6% and the alpha-isomer purity was 96.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.3 g | With pyridine; dmap; In ethyl acetate; at 20℃; for 12h;Reflux; | Add 250g of absolute ethanol to another clean reactor,40 g of ethyl 2,2-difluoro-D-erythro-3-hydroxy-(2,2-dimethyl-1,3-dioxolan-4-yl)propanoate, 18 g of concentrated hydrochloric acid, then,The heating is slowly heated to a reflux state for the incubation reaction for 12 hours.Distillation under reduced pressure, concentration is completed, and the temperature is lowered to about 20 C.Add 250g of ethyl acetate to the reactor, stir and dissolve evenly.Then, 23 g of pyridine and 1.7 g of DMAP were added, and 45 g of benzoyl chloride was added dropwise.During the dropping process, the temperature is controlled below 20 C, and the addition is completed.Then slowly heat up to reflux for 12 hours, after the end of the heat, then cool to 0 C,And control the temperature at 0 ~ 5 C, suction filtration, the filtrate is distilled under reduced pressure,When a large amount of solids precipitates, stop the distillation and start to cool down. When the temperature drops to 0 to 5 C,Filtering,The solid product of the compound of formula IV, 2-deoxy-2,2-D-erythro-pentanose-1-one-3,5-dibenzoate, 58.3 g was obtained in a yield of 98.5% and a content of 99.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium tri-t-butoxyaluminum hydride In tetrahydrofuran at -78℃; for 3h; Overall yield = 89.7 percent; Overall yield = 33.9 g; | 1 Example 1 Add 37.6 g (0.1 mol) of 2-deoxy-2,2-difluoro-D-erythro-1-furanulose-3,5-dibenzoate (compound 2) to 200 g of anhydrous tetrahydrofuran,Then add 110mL (0.11mol) lithium tri-tert-oxybutylaluminum hydride tetrahydrofuran solution (1mol/L) at -78°C,Carry out the reduction reaction for 3h,After the reaction is over, add 15 mL of methanol to the resulting product to quench,Concentrate tetrahydrofuran, add 400mL dichloromethane,Use 160mL NaHCO3 with a mass concentration of 5%,Wash with 60 mL of sodium chloride aqueous solution with a mass concentration of 20% and 160 mL of water to separate the organic layer;The obtained organic layer is evaporated to dryness,Obtain 37.2 g of the concentrate (containing compound 3 and compound 9, compound 3 includes two configurations of 3a with a cyclic hemiacetal structure and 3b with a ring-opened aldehyde structure);The content of compound 3 (3a+3b) measured by HPLC external standard is: 91.0%, equivalent pure yield: 33.9g, HPLC purity is 91.5%;Yield: 89.7%, the HPLC purity of compound 9 is 6.6%,External standard content 2.5g; |
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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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