[ CAS No. 874638-80-9 ] {[proInfo.proName]}

Name: 874638-80-9|((2R,3R,4R)-3-(Benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl benzoate|97%
Brand: Ambeed
SKU: A123043
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Product Details of [ 874638-80-9 ]

CAS No. :	874638-80-9	MDL No. :	MFCD17677380
Formula :	C₂₀H₁₇FO₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OUKYMZJNLWKCSO-JXXFODFXSA-N
M.W :	372.34	Pubchem ID :	42625091
Synonyms :

Safety of [ 874638-80-9 ]

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:

Application In Synthesis of [ 874638-80-9 ]

* 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.

Upstream synthesis route of [ 874638-80-9 ]
Downstream synthetic route of [ 874638-80-9 ]

[ 874638-80-9 ] Synthesis Path-Upstream 1~20

1
[ 879551-04-9 ]
[ 98-88-4 ]
[ 874638-80-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	at 20℃; for 0.333333 h;	The compound of Example 3 (60 mg, 0.16 mmol) was dissolved in anhydrous pyridine (1 mL) and enzoyl chloride (0.3 mL) was added. The resulting reaction mixture was stirred at room temperature for 20 min, water added (1 mL), stirred for 20 min, diluted with ethyl acetate (5 mL), washed with water (2 mL) and IM HCl (2 mL x 3), and dried with sodium sulfate. Upon filtration and concentration, the residue was purified by silica gel column chromatography (hexanes: ethyl acetate = 10:1) to give 3,5-di-O-benzoyl-2-deoxy-2-fluoro-D-ribono- γ-latone as a white solid (118 mg, 87percent). 1H NMR (CDCl3) δ (ppm) 8.08 (m, 2H, aromatic), 7.99 (m, 2H, aromatic), 7.63 (m, IH, aromatic), 7.58 (m, IH, aromatic), 7.49 (m, 2H, aromatic), 7.43 (m, 2H, aromatic), 5.51 (dd, IH, J = 7.2, 17.6 Hz, H-3), 5.00 (m, IH, H-4), 4.78 (dd, IH, J = 3.6, 12.8 Hz5 H-5), 4.59 (dd, IH, J = 5.2, 12.8 Hz, H-5'), 1.75 (d, 3H, J = 23.6 Hz, CH3-2)
86%	With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12 h;	Three-necked flask were sequentially added CompoundVI(2.5g, 15mmol) and CH₂Cl₂(25mL), and stirred to dissolve slowly added DMAP (180mg, 1.5mmol) and benzoyl chloride (5.3g, 37.7mmol).System down to below 0 , followed by the slow dropwise addition of triethylamine (6.1g, 60mmol).After the addition was complete the reaction system naturally warmed to room temperature 12 hours, then added dropwise to quench the reaction 1MHCl.The organic phase was separated, the aqueous phase with CH₂Cl₂Extracted twice (2 × 20mL).The combined organic phases, the organic phase was washed with water (30 mL) and saturated brine (30 mL), then dried over anhydrous sodium sulfate.The residue was filtered and concentrated under reduced pressure was purified by silica gel column chromatography (heptane / ethyl acetate, 10: 1) to give a white solidVII(4.8g, 86percent).
84.2%	With dmap; triethylamine In acetonitrile at 5 - 20℃; for 2 h;	To the oily substance 6, 100 m of acetonitrile was added and the mixture was cooled to 5 to 8 ° C. 18.6 g of benzoyl chloride, 0.55 g of DMAP and 20 ml of triethylamine were added and the mixture was stirred at 15 to 20 ° C for 2 hours, 100 mℓ of ethyl acetate was added thereto and stirred for 30 minutes. The filter cake was washed with ethyl acetate, and the filtrate was washed successively with 80 ml of water, 100 ml of saturated sodium bicarbonate solution and 100 ml of saturated brine, and then the organic phase was concentrated under reduced pressure. 150 ml of isopropanol was added to the residue and the mixture was gradually cooled to -1 to 3 ° C for 4 hours in 3 hours. The mixture was filtered and the filter cake was washed with isopropanol and dried at 62 to 65 ° C under reduced pressure to give 15.8 g of a target Compound 1, yield 84.2percent, purity 98.8percent.

84%	With dmap; triethylamine In acetonitrile at 20 - 25℃; for 4 h; Inert atmosphere	Under nitrogen, acetonitrile (160 mL), DMAP (0.74 g, 0.006 mol) and benzoyl chloride (51.6 g, 0.365 mol) were added to a solution of compound of formula IX (20 g, 0.122 mol) and cooled to about 20 ° C. Triethylamine (37.0 g, 0.365 mol) was added at a controlled temperature not higher than 40 ° C. Add finished, cooled to 20-25 ° C, the reaction was stirred for 4 hours. The reaction was completed, cooled to 0-5 ° C, add water (lOOmL) quenched. Ethyl acetate (300 mL) was added and the organic phase was separated. The aqueous phase was extracted once more with ethyl acetate (150 mL). The combined organic phases were washed with saturated sodium bicarbonate and brine respectively, dried and concentrated. The resulting crude product is recrystallized from isopropanol to give the intermediate of formula I.
83.9%	With dmap; triethylamine In tetrahydrofuran at 0 - 40℃; for 2 h;	(3R,4R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one (25.5 g, 0.155 mol) obtained from example 3 was dissolved in 200 ml of THF. 4-(Dimethylamino)- pyridine (8.3 g, 0.067 mol) and triethylamine (35 g, 0.35 mol) were added and the reaction mixture was cooled to 0°C. Benzoyl chloride (46.7 g, 0.33 mol) was added, and the mixture was warmed to 35-40 °C in the course of 2 hrs. Upon completion of the reaction (TLC check) water (100 ml) was charged and the mixture was stirred for 30 min. Phases were separated and to the aqueous phase methyl-tert-butyl ether (100 ml) was added and the mixture was stirred for 30 min. Phases were separated and the organic phase was washed with saturated NaCl solution (100 ml). The combined organic phases were dried over Na₂SC>4 (20 g) filtered and the filtrate was evaporated to dryness. The residue was taken up in i-propanol (250 ml) and the mixture was warmed to 50 °C and stirred for 60 min, then cooled down to 0°C and further stirred for 60 min. The solid was filtered and the wet cake was washed with i-propanol (50 ml) and then dried under vacuum. The title compound ((3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran- 2-yl)methyl benzoate (48.3 g, 83.9 percent yield) was obtained. 'H-NMR (CDCI₃, 400 MHz): 58.10 (d, 7=7.6 Hz, 2H), 8.00 (d, 7=7.6 Hz, 2H), 7.66 (t, 7=7.6 Hz, IH), 7.59 (t, 7=7.6 Hz, IH), 7.50 (m, 2H), 7.43 (m, 2H), 5.53 (dd, 7=17.6, 5.6 Hz, IH), 5.02 (m, IH), 4.77 (dd, 7=12.8, 3.6 Hz, IH), 4.62 (dd, 7=12.8, 5.2 Hz, IH), 1.77(d, 7=23.2 Hz, 3H).
82.6%	With dmap; triethylamine In tetrahydrofuran at 0 - 40℃; for 2 h;	(3R,4R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one(19)(25.4 g, 0.154 mol) obtained from example 3 was dissolved in 200 ml ofTHF. 4-(dimethylamino)pyridine(8.2 g, 0.066 mol) and triethylamine (35 g, 0.35 mol) were added and the reaction mixturewas cooled to 0 'C. Benzoyl chloride (46.0 g, 0.33 mol) was added, and the mixture was warmed to35-40 'C in the course of2 hs. Upon completion of the reaction, water (100 mL) was charged andthe mixture was stirred for 30 min. Phases were separated and to the aqueous phase methyl-tertbutylether (100 mL) was added and the mixture was stirred for 30 min. Phases were separated andthe organic phase was washed with saturated NaCl solution (100 mL). The combined organicphases were dried over Na2S04 (20 g) filtered and the filtrate was evaporated to dryness. Theresidue was taken up in iso-propanol (250 mL) and the mixture was warmed to 50 'C and stirred for60 min, then cooled down to 0 'C and further stirred for 60 min. The solid was filtered and the wetcake was washed with i-propanol (50 mL) and then dried under vacuum. The title compound( (3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran- 2-yl)methyl benzoate ( 4 7.5 g,82.6percent yield) was obtained. 'H-NMR (CDCl3, 400 MHz): 8.10 (d, 7=7.6 Hz, 2H), 8.00 (d, 7=7.6Hz, 2H), 7.66 (t, 7=7.6 Hz, 1H), 7.59 (t, 7=7.6 Hz, 1H), 7.50 (m, 2H), 7.43 (m, 2H), 5.53 (dd, 7=17.6,5.6 Hz, 1H), 5.02 (m, 1H), 4.77 (dd, 7=12.8, 3.6 Hz, 1H), 4.62 (dd, 7=12.8, 5.2 Hz, 1H), 1.77(d,7=23.2 Hz, 3H).
70.7%	With dmap; triethylamine In acetonitrile at 10 - 40℃;	Step 4; - To the residue from step 3 containing 28 was added MeCN (35 kg) and ca. 15L was distilled out under atmospheric pressure. The reaction mixture was cooled to ca. 10⁰C and then benzoyl chloride (8.27 kg) and DMAP (0.14 kg) are added. TEA (5.84 kg) was added slowly to the reaction mixture while cooling to maintain temperature below 4O⁰C. The batch was aged at ca. 20⁰C and the progress of the benzoylation is monitored by HPLC. <n="16"/>After completion of the reaction, EtOAc (30 kg) was added to the mixture and the resulting suspension is stirred for about 30 min. The reaction mixture was filtered through a CELITE.(R). pad (using a nutsche filter) to remove inorganic salts. The solid cake was washed with EtOAc (38 kg). The combined filtrate and washes were washed successively with water (38 kg), saturated NaHCψ₃ solution (40 kg) and saturated brine (44 kg). The organic phase was polish-filtered (through a cartridge filter) and concentrated under modest vacuum to minimum volume. IPA (77 kg) was added to the concentrate and ca. 25 L of distillate was collected under modest vacuum allowing the infernal batch temperature to reach ca 75°C at the end of the distillation. The remaining solution was then cooled to ca. 5°C over 5 h and optionally aged overnight. The precipitate was filtered and washed with of cold (ca. 5°C) IPA (24 kg). The product was dried under vacuum at 60-70⁰C to afford 6.63 kg (70.7percent theory of 10 which was 98.2percent pure by HPLC.
61.2%	at 0 - 20℃; for 0.75 h;	Compound 66-7 (110 g) was dissolved in anhydrous pyridine (1 L). Benzoyl chloride (200 mL, 1.67 mol) was added slowly at 0-5° C. The mixture was stirred at ambient temperature for 45 mins. The reaction was quenched with ice and MeOH to form a precipitate. After filtration, the filtrate was washed with MeOH to give 66-8 (200 g, 61.2percent) as a white solid.
60%	at 0 - 20℃; for 24 h;	2-Deoxy-2-fluoro-2-C-methyl-D-ribono-l,4-lactone (200mg, 1.219mmol) was dissolved in anhydrous pyridine (2.4ml) and cooled to O⁰C under an atmosphere of argon. Benzoyl chloride (353μl, 3.05mmol) was added dropwise over 5min. The solution was allowed to warm to room temperature and stirred for 4h. Benzoyl chloride (142μl, 1.219mmol) was added dropwise and the mixture was stirred for 16h after which time a further portion of benzoyl chloride (142μl, 1.219mmol) was added. Having stirred the solution for a further 3h, a final portion of benzoyl chloride (142μl, 1.219mmol) was added and left for a further Ih. T.l.c. (ethyl acetate/heptane, 2:3) indicated complete conversion of the starting material (R_f 0.16) to faintly stained, but UV active products (Rf 0.67, 0.63). The reaction was quenched with water (ImI) and the solids dissolved. After stirring at room temperature for 5min crystals precipitated from the solution which were filtered and washed with water (2ml x 2) and found by <n="27"/>t.l.c. to contain two UV active components and pyridine. The dried, sticky solid (400mg) was therefore dissolved in dichloromethane (10ml) and subjected to a IM HCl_aq (4ml x 2) wash. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The crude off-white residue (340mg) was purified by flash column chromatography (pre-adsorbed onto silica from dichloromethane, eluted with ethyl acetate/heptane, 1:4) to give 3,5-di-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D- jribono-l,4-lactone (272mg, 60percent) as fine, white needles.Data for SjS-di-benzoyl^-deoxy^-fluoro^-C-methyl-D-ribono-l^-lactone C_2OHi₇FO₆ 372.34SmOl^"1; R_f = 0.62, ethyl acetate/heptane, 2:3; m.p. : 123-125°C; [α]_D²⁰ : +102.943 (c, 0.8728 in CH₃CN); v_max (thin film) : 1793cm^"1 (O=O, α-fluoro- γ-lactone), 1733cm^"1, 1717cm^"1 (C=O, Bz); ¹H NMR δ_H (400 MHz, CD₃CN) : 1.74 (3H, d, JH,F 24.1, CH₃), 4.62 (IH, dd, J_{5 A}- 12.7, J₅,₄ 5.6, H-5), 4.75 (IH, dd, Jy,₅ 12.7, Js- _A 3.5, H-5'), 5.07 (IH, ddd, J_4j3 7.2, J₄₎₅ 5.6, J₄,y 3.5, H-4), 5.62 (IH, dd, ³J_H,_F 17.7, J₃,4 7.2, H-3); 7.48, 7.55 (4H, 2 x t, 4 x H_meta), 7.64, 7.70 (2H, 2 x t, 2 x H_para), 8.01, 8.09 (4H, 2 x t, 4 x H_ortho); ¹³C NMR δ_c (100 MHz, CD₃CN) : 18.88 (d, ²J_C,_F 24.5, CH₃), 63.51 (C-5), 73.07 (d, ²J_C,_P 14.6, C-3), 78.84 (C-4), 92.61 (d, ¹Jc_1F 185.6, C-2), 129.51, 130.53 (2 x C_ipso), 129.64, 129.78 (2 x C_meta), 130.43, 130.76 (2 x C_olλo), 134.46, 135.00 (2 x C_para), 166.22, 166.63 (2 x CO₂Bz), 170.64 (d, ²Jc₁F 21.0, C=O); ¹⁹F NMR δ_F (376 MHz, CD₃CN) : -164.77 (IF, m, ³J_F>H 24.4, F). NMR assignments confirmed using COSY, HMQC, HMBC and nOe experiments; Mass Spec m/z (ESI- ) : 373.1 ([M+Hf, 50percent), 390.2 ([M+NH₄]⁺, 100percent); HPLC (272ntn) R₄ = 6.17 (98percent); Microanalysis : C_2OH_nFO₆ calculated C 64.51percent, H 4.60percent, found C 64.56percent, H 4.66percent.
51.2%	With dmap; triethylamine In ethyl acetate at -5℃; for 2 h;	Compound V-1 (2.56 g) was dissolved in 50 mL of ethyl acetate, and then adding triethylamine (8.75 mL, 4eq) and 4-dimethylaminopyridine (DMAP) (0.75g, 0.4 eq.). Benzoyl chloride (5.45 mL, 3eq) was slowly added dropwise at the temperature of −5 ° C.5° C. The reaction completed two hours later indicating by TLC, the solid was filtered, and the filter cake was washed with 20 mL of ethyl acetate to give 3 g white flocculent solid Compound VI-1. HPLC purity was 97.5percent. Yield: 51.2percent. ¹HNMR(300 MHz, DMSO-d6) δ1.68 (d,3H, J=24.2 Hz), 4.62-4.74 (m, 2H), 5.11-5.15 (m, 1H), 5.76 (dd, 1H, J=7.0, 18.4 Hz), 7.46 (m, 2H), 7.55 (m, 2H), 7.62 (m, 1H), 7.70 (m, 1H), 7.93 (m, 2H), 8.06 (m, 2H), 8.08 (m, 2H).
48.4%	With dmap; triethylamine In acetonitrile at 10 - 30℃; for 5 h; Large scale	8) Into the reactor. add the above-mentioned oily matter, 360L acetonitrile, stirring 20 minutes, the reaction liquid cooling to 10 °C, and into the reaction system, add 4-dimethylaminopyridine, control temperature to below 10 °C. Slowly add dropwise 82.7 kg benzoyl chloride. After dropwise addition is complete, heat up to 20 °C, control temperature at 25-30 °C slowly add dropwise 74.2 kg triethylamine, dropping complete, maintain temperature and react for 5 hours. Reaction is completed. the reaction liquid centrifugal, the filtrate is concentrated under reduced pressure to remove the 2/3 of the acetonitrile, cake 200L washing twice ethyl acetate, the combined organic phase, the organic phase for respectively 200L purified water, 200L saturated sodium bicarbonate, 200L saturated salt is washed with water, dried with anhydrous sodium sulfate, 45 - 50 °C lower concentrated under reduced pressure to dry, to obtain a yellow solid of about 70 kg, residue by adding 300L methanol heated to 30 - 35 °C stirring 2 hours, the temperature slowly drops to 0 - 5 °C stirring 2 hours, cooling crystallization, filtration, 50 - 60 °C decompression drying shall be 3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-methyl-D-ribono-γ-lactone 101 kg, yield: 48.4percent, purity in ethyl (E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methyl-2-propenoate idea, product purity 98.7percent.
5.49 g	With pyridine In acetonitrile at 20℃; for 2 h; Cooling with ice	Represented by the formula [6a] obtained above (2R)-2-fluoro-2-C-methyl-D-Ribono-γ-lactone 7.55g (46.0mmol), acetonitrile 46ml (1.0L / mol) and pyridine 8.37g (105.8mmol, 2.30eq) was added, and benzoyl chloride 14.17g (100. 8mmol, 2.19eq) is added to under ice-cooling, and the mixture was stirred at room temperature for 2 hours. It was added to the reaction-terminated liquid water 180ml under ice-cooling, followed by stirring at room temperature for 10 minutes, and extracted with ethyl acetate 350 ml, and collected organic layers were washed with 5percent aqueous sodium hydrogencarbonate solution 100ml, and washed with 5percent brine 100ml , the following formula by which concentrated under reduced pressure, and dried under vacuum [1a]: Shown in (2R)-2-fluoro-2-C-methyl-D-Ribono-γ-lactone 1a It was obtained 5.49g

Reference： [1] Patent: WO2006/31725, 2006, A2, . Location in patent: Page/Page column 13; 30-31
[2] Patent: CN105418547, 2016, A, . Location in patent: Paragraph 0019; 0020
[3] Patent: CN106146433, 2016, A, . Location in patent: Paragraph 0009; 0025
[4] Patent: CN107573304, 2018, A, . Location in patent: Paragraph 0120-0124
[5] Patent: WO2014/108525, 2014, A1, . Location in patent: Page/Page column 18
[6] Patent: WO2018/32356, 2018, A1, . Location in patent: Page/Page column 37; 38
[7] Patent: WO2008/45419, 2008, A1, . Location in patent: Page/Page column 14-15
[8] Patent: US2014/179627, 2014, A1, . Location in patent: Paragraph 0511
[9] Patent: WO2007/75876, 2007, A2, . Location in patent: Page/Page column 17; 25-26
[10] Patent: US2015/284351, 2015, A1, . Location in patent: Paragraph 0074-0076
[11] Patent: CN106083773, 2016, A, . Location in patent: Paragraph 0030; 0055
[12] Journal of Organic Chemistry, 2009, vol. 74, # 17, p. 6819 - 6824
[13] Patent: US2013/72699, 2013, A1, . Location in patent: Paragraph 0073; 0074
[14] Patent: JP2015/13851, 2015, A, . Location in patent: Paragraph 0113; 0114; 0115

2
[ 729596-46-7 ]
[ 874638-80-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: With pyridine; trifluoromethylsulfonic anhydride In dichloromethane at -40 - 20℃; for 1 h; Stage #2: With fluorosulfonyl fluoride; triethylamine tris(hydrogen fluoride); triethylamine In acetonitrileCooling with ice	The intermediate I-1 (0.74g, 2mmoL) dissolved in 10 ml methylene chloride, adding pyridine (0.18 ml, 2 . 2mmoL, 1 . 1eq), -40 ° C stirring, then slowly adding trifluoromethyl sulfonic anhydride (0.37 ml, 2 . 2mmoL, 1 . 1eq), after dripping, slowly to room temperature, is continuously stirred for 1 hour. Added to the reaction solution 1.5mLDMSO, stir at room temperature, TLC monitoring after the reaction is complete, concentrated reaction fluid to the surface of the small volume, in the reaction system are sequentially added acetonitrile (15 ml), triethylamine three hydrofluoric acid salt (0.49 ml, 3mmoL, 1.5eq) and triethylamine (1.40 ml, 10mmoL, 5eq), stirring under the conditions of ice, at this temperature into the sulfuryl fluoride gas. TLC monitoring after the reaction is complete, evaporate the solvent, precipitation reddish brown color solid, water and methanol is obtained after beating 0.59g white solid, yield 78percent, purity 98.0percent.

Reference： [1] Patent: CN105693661, 2016, A, . Location in patent: Paragraph 0112; 0113; 0114; 0115
[2] Tetrahedron Letters, 2015, vol. 56, # 29, p. 4345 - 4348
[3] Tetrahedron Letters, 2015, vol. 56, # 29, p. 4345 - 4348
[4] Patent: CN105693661, 2016, A,
[5] Patent: CN105693661, 2016, A,
[6] Patent: CN105693661, 2016, A,
[7] Patent: CN105693661, 2016, A,

3
[ 492-30-8 ]
[ 98-88-4 ]
[ 874638-80-9 ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: With triethylamine In dichloromethaneCooling with ice Stage #2: With pyridine; trifluoromethylsulfonic anhydride In dichloromethane at -40 - 20℃; for 1 h; Stage #3: With triethylamine tris(hydrogen fluoride); triethylamine In acetonitrileCooling with ice	The 2-C-methyl-D- ribotide -1,4-lactone (0.32g, 2mmoL) suspended in 10 ml methylene chloride, under the condition of ice bath, dripping benzoyl chloride (0.46 ml, 4mmoL, 2eq). Is omitted, then slowly dripped into triethylamine (0.61 ml, 4 . 4mmoL, 2 . 2eq), at least 1 hour drop end, reaction sleepovers. Pyridine is added to the reaction system (0.18 ml, 2 . 2mmoL, 1 . 1eq), -40 ° C stirring, then slowly adding trifluoromethyl sulfonic anhydride (0.37 ml, 2 . 2mmoL, 1 . 1eq), after dripping, slowly to room temperature, is continuously stirred for 1 hour. Added to the reaction solution 1.5mLDMSO, stir at room temperature, TLC monitoring after the reaction is complete, concentrated reaction fluid to the surface of the small volume, added to the reaction system in acetonitrile (12 ml), triethylamine three hydrofluoric acid salt (0.49 ml, 3mmoL, 1.5eq) and triethylamine (1.40 ml, 10mmoL, 5eq), stirring under the conditions of ice, at this temperature into the sulfuryl fluoride gas. TLC monitoring after the reaction is complete, evaporate the solvent, by adding 20 ml of water, the room temperature is arranged to separate out reddish brown solid. Filtering, after drying, is obtained after beating with methanol 0.42g gray solid, yield 58percent.

Reference： [1] Patent: CN105693661, 2016, A, . Location in patent: Paragraph 0116; 0117; 0118; 0119

4
[ 74-88-4 ]
[ 874638-80-9 ]

Yield	Reaction Conditions	Operation in experiment
3.5 g	With Selectfluor In N,N-dimethyl-formamide at -40 - 20℃; for 1 h;	Under nitrogen, the crude product obtained in the previous step (7.4g, 50.6mmol), acetonitrile (140mL), DMAP (0.83g, 7.0mmol) and benzoyl chloride (49.3g, 350mmol) into the reaction flask, cooled to ice bath 0 -5 , dropwise addition of triethylamine (35.5g, 350mmol), dropwise addition, naturally warmed to room temperature for 30min, added ethyl acetate (150 mL), water (150g) was stirred for 30min, standing stratified The organic layer was collected, washed with saturated sodium bicarbonate solution (60mL), saturated brine (60mL) the organic phase was washed, layers were separated and the organic layer was dried with sodium sulfate, filtered, concentrated to dryness under reduced pressure to 60 deg.] C, isopropanol was added (200 mL), warmed to 80 deg.] C, stirred for 10min, cooled to 0 -10 , crystallization 1h, filtered and the filter cake was washed with a little cold isopropanol, dried under reduced pressure to 50 deg.] C to afford compound 34a / 35a ( 20.8g, three-step total yield of 23.3percent). Under nitrogen, the 34a / 35a of the mixture (7.16g, 20mmol) and methylene chloride (200 mL) into the reaction flask, stirred and dissolved.Cooled to 0 , was slowly added dropwise triethylamine (9.4mL, 70mmol), dropwise addition of tert-butyldimethylsilyl triflate (8.46g, 32mmol), completion of the dropping, the reaction mixture was stirred at 0 30min, the reaction was added 200mL of water to quench the reaction, standing layer, the aqueous phase was extracted three times with dichloromethane, the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, the resulting product was dissolved in N, N- dimethylformamide (200 mL) in.Cooling down -40 , iodomethane (5.68g, 40mmol).After addition was complete, warmed to room temperature, the reaction was stirred for 1h, the reaction was added 300mL of water to quench the reaction, and extracted three times with ethyl acetate (3 x 300 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness and the resulting crude product was recrystallized from isopropanol to give a white solid compound 1a (3.5g, 47percent).

Reference： [1] Patent: CN105566406, 2016, A, . Location in patent: Page/Page column 0132; 0133

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[ 98-88-4 ]
[ 874638-80-9 ]
[ 1157884-58-6 ]

Reference： [1] Patent: JP2015/13851, 2015, A, . Location in patent: Paragraph 0128; 0129; 0130

6
[ 98-88-4 ]
[ 874638-80-9 ]

Reference： [1] Patent: WO2006/31725, 2006, A2, . Location in patent: Page/Page column 12

7
[ 93635-76-8 ]
[ 874638-80-9 ]

Reference： [1] Patent: US2013/72699, 2013, A1,
[2] Patent: US2014/179627, 2014, A1,
[3] Patent: CN106146433, 2016, A,
[4] Patent: CN106366057, 2017, A,

8
[ 98-88-4 ]
[ 874638-80-9 ]

Reference： [1] Tetrahedron Letters, 2015, vol. 56, # 29, p. 4345 - 4348
[2] Tetrahedron Letters, 2015, vol. 56, # 29, p. 4345 - 4348
[3] Patent: CN105693661, 2016, A,
[4] Patent: CN105693661, 2016, A,
[5] Patent: CN105693661, 2016, A,
[6] Patent: CN105693661, 2016, A,
[7] Patent: CN105693661, 2016, A,
[8] Patent: CN105693661, 2016, A,

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[ 492-30-8 ]
[ 874638-80-9 ]

10
[ 98-88-4 ]
[ 874638-80-9 ]

Reference： [1] Tetrahedron Asymmetry, 2009, vol. 20, # 3, p. 305 - 312

11
[ 130606-67-6 ]
[ 874638-80-9 ]

Reference： [1] Patent: US2014/179627, 2014, A1,
[2] Patent: CN106146433, 2016, A,

12
[ 879551-01-6 ]
[ 874638-80-9 ]

Reference： [1] Patent: US2014/179627, 2014, A1,
[2] Patent: CN106146433, 2016, A,

13
[ 1351925-17-1 ]
[ 874638-80-9 ]

Reference： [1] Patent: US2013/72699, 2013, A1,

14
[ 1033394-83-0 ]
[ 874638-80-9 ]

Reference： [1] Patent: US2013/72699, 2013, A1,

15
[ 1616508-45-2 ]
[ 874638-80-9 ]

Reference： [1] Patent: WO2014/108525, 2014, A1,

16
[ 1616508-57-6 ]
[ 874638-80-9 ]

Reference： [1] Patent: WO2014/108525, 2014, A1,

17
[ 81997-76-4 ]
[ 874638-80-9 ]

Reference： [1] Patent: CN105418547, 2016, A,

18
[ 127642-52-8 ]
[ 874638-80-9 ]

Reference： [1] Patent: CN106083773, 2016, A,

19
[ 98-88-4 ]
[ 874638-80-9 ]
[ 1157884-58-6 ]

Reference： [1] Tetrahedron Asymmetry, 2009, vol. 20, # 3, p. 305 - 312

20
[ 874638-80-9 ]
[ 1294481-82-5 ]

Reference： [1] Patent: JP2015/227337, 2015, A,

[ 874638-80-9 ] Synthesis Path-Downstream 1~8

1
[ 879551-04-9 ]
[ 98-88-4 ]
[ 874638-80-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With pyridine at 20℃; for 0.333333h;	4; 6.f The compound of Example 3 (60 mg, 0.16 mmol) was dissolved in anhydrous pyridine (1 mL) and enzoyl chloride (0.3 mL) was added. The resulting reaction mixture was stirred at room temperature for 20 min, water added (1 mL), stirred for 20 min, diluted with ethyl acetate (5 mL), washed with water (2 mL) and IM HCl (2 mL x 3), and dried with sodium sulfate. Upon filtration and concentration, the residue was purified by silica gel column chromatography (hexanes: ethyl acetate = 10:1) to give 3,5-di-O-benzoyl-2-deoxy-2-fluoro-D-ribono- γ-latone as a white solid (118 mg, 87%). 1H NMR (CDCl3) δ (ppm) 8.08 (m, 2H, aromatic), 7.99 (m, 2H, aromatic), 7.63 (m, IH, aromatic), 7.58 (m, IH, aromatic), 7.49 (m, 2H, aromatic), 7.43 (m, 2H, aromatic), 5.51 (dd, IH, J = 7.2, 17.6 Hz, H-3), 5.00 (m, IH, H-4), 4.78 (dd, IH, J = 3.6, 12.8 Hz5 H-5), 4.59 (dd, IH, J = 5.2, 12.8 Hz, H-5'), 1.75 (d, 3H, J = 23.6 Hz, CH3-2)
86%	With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h;	7 Example 7 Three-necked flask were sequentially added CompoundVI(2.5g, 15mmol) and CH2Cl2(25mL), and stirred to dissolve slowly added DMAP (180mg, 1.5mmol) and benzoyl chloride (5.3g, 37.7mmol).System down to below 0 , followed by the slow dropwise addition of triethylamine (6.1g, 60mmol).After the addition was complete the reaction system naturally warmed to room temperature 12 hours, then added dropwise to quench the reaction 1MHCl.The organic phase was separated, the aqueous phase with CH2Cl2Extracted twice (2 × 20mL).The combined organic phases, the organic phase was washed with water (30 mL) and saturated brine (30 mL), then dried over anhydrous sodium sulfate.The residue was filtered and concentrated under reduced pressure was purified by silica gel column chromatography (heptane / ethyl acetate, 10: 1) to give a white solidVII(4.8g, 86%).
84.2%	With dmap; triethylamine In acetonitrile at 5 - 20℃; for 2h;	1 Example 1 To the oily substance 6, 100 m of acetonitrile was added and the mixture was cooled to 5 to 8 ° C. 18.6 g of benzoyl chloride, 0.55 g of DMAP and 20 ml of triethylamine were added and the mixture was stirred at 15 to 20 ° C for 2 hours, 100 mℓ of ethyl acetate was added thereto and stirred for 30 minutes. The filter cake was washed with ethyl acetate, and the filtrate was washed successively with 80 ml of water, 100 ml of saturated sodium bicarbonate solution and 100 ml of saturated brine, and then the organic phase was concentrated under reduced pressure. 150 ml of isopropanol was added to the residue and the mixture was gradually cooled to -1 to 3 ° C for 4 hours in 3 hours. The mixture was filtered and the filter cake was washed with isopropanol and dried at 62 to 65 ° C under reduced pressure to give 15.8 g of a target Compound 1, yield 84.2%, purity 98.8%.

84%	With dmap; triethylamine In acetonitrile at 20 - 25℃; for 4h; Inert atmosphere;	12F Synthesis of intermediate (I) Under nitrogen, acetonitrile (160 mL), DMAP (0.74 g, 0.006 mol) and benzoyl chloride (51.6 g, 0.365 mol) were added to a solution of compound of formula IX (20 g, 0.122 mol) and cooled to about 20 ° C. Triethylamine (37.0 g, 0.365 mol) was added at a controlled temperature not higher than 40 ° C. Add finished, cooled to 20-25 ° C, the reaction was stirred for 4 hours. The reaction was completed, cooled to 0-5 ° C, add water (lOOmL) quenched. Ethyl acetate (300 mL) was added and the organic phase was separated. The aqueous phase was extracted once more with ethyl acetate (150 mL). The combined organic phases were washed with saturated sodium bicarbonate and brine respectively, dried and concentrated. The resulting crude product is recrystallized from isopropanol to give the intermediate of formula I.
83.9%	With dmap; triethylamine In tetrahydrofuran at 0 - 40℃; for 2h;	4 Preparation of ((3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2- yl)methyl benzoate (3R,4R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one (25.5 g, 0.155 mol) obtained from example 3 was dissolved in 200 ml of THF. 4-(Dimethylamino)- pyridine (8.3 g, 0.067 mol) and triethylamine (35 g, 0.35 mol) were added and the reaction mixture was cooled to 0°C. Benzoyl chloride (46.7 g, 0.33 mol) was added, and the mixture was warmed to 35-40 °C in the course of 2 hrs. Upon completion of the reaction (TLC check) water (100 ml) was charged and the mixture was stirred for 30 min. Phases were separated and to the aqueous phase methyl-tert-butyl ether (100 ml) was added and the mixture was stirred for 30 min. Phases were separated and the organic phase was washed with saturated NaCl solution (100 ml). The combined organic phases were dried over Na2SC>4 (20 g) filtered and the filtrate was evaporated to dryness. The residue was taken up in i-propanol (250 ml) and the mixture was warmed to 50 °C and stirred for 60 min, then cooled down to 0°C and further stirred for 60 min. The solid was filtered and the wet cake was washed with i-propanol (50 ml) and then dried under vacuum. The title compound ((3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran- 2-yl)methyl benzoate (48.3 g, 83.9 % yield) was obtained. 'H-NMR (CDCI3, 400 MHz): 58.10 (d, 7=7.6 Hz, 2H), 8.00 (d, 7=7.6 Hz, 2H), 7.66 (t, 7=7.6 Hz, IH), 7.59 (t, 7=7.6 Hz, IH), 7.50 (m, 2H), 7.43 (m, 2H), 5.53 (dd, 7=17.6, 5.6 Hz, IH), 5.02 (m, IH), 4.77 (dd, 7=12.8, 3.6 Hz, IH), 4.62 (dd, 7=12.8, 5.2 Hz, IH), 1.77(d, 7=23.2 Hz, 3H).
82.6%	With dmap; triethylamine In tetrahydrofuran at 0 - 40℃; for 2h;	17 Example 17: preparation of ((3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetra hydro furan-2- yl)methyl benzoate (3R,4R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one(19)(25.4 g, 0.154 mol) obtained from example 3 was dissolved in 200 ml ofTHF. 4-(dimethylamino)pyridine(8.2 g, 0.066 mol) and triethylamine (35 g, 0.35 mol) were added and the reaction mixturewas cooled to 0 'C. Benzoyl chloride (46.0 g, 0.33 mol) was added, and the mixture was warmed to35-40 'C in the course of2 hs. Upon completion of the reaction, water (100 mL) was charged andthe mixture was stirred for 30 min. Phases were separated and to the aqueous phase methyl-tertbutylether (100 mL) was added and the mixture was stirred for 30 min. Phases were separated andthe organic phase was washed with saturated NaCl solution (100 mL). The combined organicphases were dried over Na2S04 (20 g) filtered and the filtrate was evaporated to dryness. Theresidue was taken up in iso-propanol (250 mL) and the mixture was warmed to 50 'C and stirred for60 min, then cooled down to 0 'C and further stirred for 60 min. The solid was filtered and the wetcake was washed with i-propanol (50 mL) and then dried under vacuum. The title compound( (3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran- 2-yl)methyl benzoate ( 4 7.5 g,82.6% yield) was obtained. 'H-NMR (CDCl3, 400 MHz): 8.10 (d, 7=7.6 Hz, 2H), 8.00 (d, 7=7.6Hz, 2H), 7.66 (t, 7=7.6 Hz, 1H), 7.59 (t, 7=7.6 Hz, 1H), 7.50 (m, 2H), 7.43 (m, 2H), 5.53 (dd, 7=17.6,5.6 Hz, 1H), 5.02 (m, 1H), 4.77 (dd, 7=12.8, 3.6 Hz, 1H), 4.62 (dd, 7=12.8, 5.2 Hz, 1H), 1.77(d,7=23.2 Hz, 3H).
70.7%	With dmap; triethylamine In acetonitrile at 10 - 40℃;	4.4 Step 4; - To the residue from step 3 containing 28 was added MeCN (35 kg) and ca. 15L was distilled out under atmospheric pressure. The reaction mixture was cooled to ca. 100C and then benzoyl chloride (8.27 kg) and DMAP (0.14 kg) are added. TEA (5.84 kg) was added slowly to the reaction mixture while cooling to maintain temperature below 4O0C. The batch was aged at ca. 200C and the progress of the benzoylation is monitored by HPLC. After completion of the reaction, EtOAc (30 kg) was added to the mixture and the resulting suspension is stirred for about 30 min. The reaction mixture was filtered through a CELITE pad (using a nutsche filter) to remove inorganic salts. The solid cake was washed with EtOAc (38 kg). The combined filtrate and washes were washed successively with water (38 kg), saturated NaHCθ3 solution (40 kg) and saturated brine (44 kg). The organic phase was polish-filtered (through a cartridge filter) and concentrated under modest vacuum to minimum volume. IPA (77 kg) was added to the concentrate and ca. 25 L of distillate was collected under modest vacuum allowing the infernal batch temperature to reach ca 75°C at the end of the distillation. The remaining solution was then cooled to ca. 5°C over 5 h and optionally aged overnight. The precipitate was filtered and washed with of cold (ca. 5°C) IPA (24 kg). The product was dried under vacuum at 60-700C to afford 6.63 kg (70.7% theory of 10 which was 98.2% pure by HPLC.
61.2%	With pyridine at 0 - 20℃; for 0.75h;	48 Example 48 Compound 66-7 (110 g) was dissolved in anhydrous pyridine (1 L). Benzoyl chloride (200 mL, 1.67 mol) was added slowly at 0-5° C. The mixture was stirred at ambient temperature for 45 mins. The reaction was quenched with ice and MeOH to form a precipitate. After filtration, the filtrate was washed with MeOH to give 66-8 (200 g, 61.2%) as a white solid.
61.2%	With pyridine at 0 - 20℃; for 0.75h;	1 Compound 66-7 (1 10 g) was dissolved in anhydrous pyridine (1 L). Benzoyl chloride (200 ml_, 1.67 mol) was added slowly at 0-5°C. The mixture was stirred at ambient temperature for 45 mins. The reaction was quenched with ice and MeOH to form a precipitate. After filtration, the filtrate was washed with MeOH to give 66-8 (200 g, 61.2%) as a white solid.
60%	With pyridine at 0 - 20℃; for 24h;	5; IV.iv; III.A.iv; III.B.iv 2-Deoxy-2-fluoro-2-C-methyl-D-ribono-l,4-lactone (200mg, 1.219mmol) was dissolved in anhydrous pyridine (2.4ml) and cooled to O0C under an atmosphere of argon. Benzoyl chloride (353μl, 3.05mmol) was added dropwise over 5min. The solution was allowed to warm to room temperature and stirred for 4h. Benzoyl chloride (142μl, 1.219mmol) was added dropwise and the mixture was stirred for 16h after which time a further portion of benzoyl chloride (142μl, 1.219mmol) was added. Having stirred the solution for a further 3h, a final portion of benzoyl chloride (142μl, 1.219mmol) was added and left for a further Ih. T.l.c. (ethyl acetate/heptane, 2:3) indicated complete conversion of the starting material (Rf 0.16) to faintly stained, but UV active products (Rf 0.67, 0.63). The reaction was quenched with water (ImI) and the solids dissolved. After stirring at room temperature for 5min crystals precipitated from the solution which were filtered and washed with water (2ml x 2) and found by t.l.c. to contain two UV active components and pyridine. The dried, sticky solid (400mg) was therefore dissolved in dichloromethane (10ml) and subjected to a IM HClaq (4ml x 2) wash. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The crude off-white residue (340mg) was purified by flash column chromatography (pre-adsorbed onto silica from dichloromethane, eluted with ethyl acetate/heptane, 1:4) to give 3,5-di-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D- jribono-l,4-lactone (272mg, 60%) as fine, white needles.Data for SjS-di-benzoyl^-deoxy^-fluoro^-C-methyl-D-ribono-l^-lactone C2OHi7FO6 372.34SmOl"1; Rf = 0.62, ethyl acetate/heptane, 2:3; m.p. : 123-125°C; [α]D20 : +102.943 (c, 0.8728 in CH3CN); vmax (thin film) : 1793cm"1 (O=O, α-fluoro- γ-lactone), 1733cm"1, 1717cm"1 (C=O, Bz); 1H NMR δH (400 MHz, CD3CN) : 1.74 (3H, d, JH,F 24.1, CH3), 4.62 (IH, dd, J5 A- 12.7, J5,4 5.6, H-5), 4.75 (IH, dd, Jy,5 12.7, Js- A 3.5, H-5'), 5.07 (IH, ddd, J4j3 7.2, J4)5 5.6, J4,y 3.5, H-4), 5.62 (IH, dd, 3JH,F 17.7, J3,4 7.2, H-3); 7.48, 7.55 (4H, 2 x t, 4 x Hmeta), 7.64, 7.70 (2H, 2 x t, 2 x Hpara), 8.01, 8.09 (4H, 2 x t, 4 x Hortho); 13C NMR δc (100 MHz, CD3CN) : 18.88 (d, 2JC,F 24.5, CH3), 63.51 (C-5), 73.07 (d, 2JC,P 14.6, C-3), 78.84 (C-4), 92.61 (d, 1Jc1F 185.6, C-2), 129.51, 130.53 (2 x Cipso), 129.64, 129.78 (2 x Cmeta), 130.43, 130.76 (2 x Colλo), 134.46, 135.00 (2 x Cpara), 166.22, 166.63 (2 x CO2Bz), 170.64 (d, 2Jc1F 21.0, C=O); 19F NMR δF (376 MHz, CD3CN) : -164.77 (IF, m, 3JF>H 24.4, F). NMR assignments confirmed using COSY, HMQC, HMBC and nOe experiments; Mass Spec m/z (ESI- ) : 373.1 ([M+Hf, 50%), 390.2 ([M+NH4]+, 100%); HPLC (272ntn) R4 = 6.17 (98%); Microanalysis : C2OHnFO6 calculated C 64.51%, H 4.60%, found C 64.56%, H 4.66%.
51.2%	With dmap; triethylamine In ethyl acetate at -5℃; for 2h;	10 Compound V-1 (2.56 g) was dissolved in 50 mL of ethyl acetate, and then adding triethylamine (8.75 mL, 4eq) and 4-dimethylaminopyridine (DMAP) (0.75g, 0.4 eq.). Benzoyl chloride (5.45 mL, 3eq) was slowly added dropwise at the temperature of -5 ° C.5° C. The reaction completed two hours later indicating by TLC, the solid was filtered, and the filter cake was washed with 20 mL of ethyl acetate to give 3 g white flocculent solid Compound VI-1. HPLC purity was 97.5%. Yield: 51.2%. 1HNMR(300 MHz, DMSO-d6) δ1.68 (d,3H, J=24.2 Hz), 4.62-4.74 (m, 2H), 5.11-5.15 (m, 1H), 5.76 (dd, 1H, J=7.0, 18.4 Hz), 7.46 (m, 2H), 7.55 (m, 2H), 7.62 (m, 1H), 7.70 (m, 1H), 7.93 (m, 2H), 8.06 (m, 2H), 8.08 (m, 2H).
48.4%	With dmap; triethylamine In acetonitrile at 10 - 30℃; for 5h; Large scale;	8 8) Into the reactor. add the above-mentioned oily matter, 360L acetonitrile, stirring 20 minutes, the reaction liquid cooling to 10 °C, and into the reaction system, add 4-dimethylaminopyridine, control temperature to below 10 °C. Slowly add dropwise 82.7 kg benzoyl chloride. After dropwise addition is complete, heat up to 20 °C, control temperature at 25-30 °C slowly add dropwise 74.2 kg triethylamine, dropping complete, maintain temperature and react for 5 hours. Reaction is completed. the reaction liquid centrifugal, the filtrate is concentrated under reduced pressure to remove the 2/3 of the acetonitrile, cake 200L washing twice ethyl acetate, the combined organic phase, the organic phase for respectively 200L purified water, 200L saturated sodium bicarbonate, 200L saturated salt is washed with water, dried with anhydrous sodium sulfate, 45 - 50 °C lower concentrated under reduced pressure to dry, to obtain a yellow solid of about 70 kg, residue by adding 300L methanol heated to 30 - 35 °C stirring 2 hours, the temperature slowly drops to 0 - 5 °C stirring 2 hours, cooling crystallization, filtration, 50 - 60 °C decompression drying shall be 3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-methyl-D-ribono-γ-lactone 101 kg, yield: 48.4%, purity in ethyl (E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methyl-2-propenoate idea, product purity 98.7%.
24 g	With pyridine at 0 - 20℃; for 0.5h;
	With pyridine at 20℃; for 0.5h; Cooling with ice;	1 Example 1 [0073]The whole of the above-obtained crude product (regarded as 660 μmol) was mixed with 2.45 g (31.0 mmol, 47.0 eq) of pyridine, followed by adding thereto 750 mg (5.34 mmol, 8.09 eq) of benzoyl chloride under ice cooling. The resulting liquid was stirred for 30 minutes at room temperature. To the thus-obtained reaction-terminated liquid, 2 mL of water was added under ice cooling. The reaction-terminated liquid was further stirred for 10 minutes at room temperature and concentrated under reduced pressure. The concentration residue was admixed with 10 mL of saturated aqueous sodium hydrogencarbonate solution and extracted with 20 mL of ethyl acetate. The recovered aqueous layer was again extracted with 20 mL of ethyl acetate. The recovered organic layers were combined. The combined organic layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure and dried under vacuum. There was thus obtained a crude product of (2R)-2-fluoro-2-C-methyl-D-ribono-γ-lactone of the following formula.It was confirmed by 19F-NMR quantification analysis (internal standard method) of the crude product that the target compound of the above formula was contained in an amount of 380 μmol. The total yield from the 1,2-diol substrate was 38%.[0074]The 19F-NMR analysis results of the crude product are indicated below. 19F-NMR [standard material: C6F6, deuterated solvent: CDCl3] δ ppm: -5.44 (m, 1F).
5.49 g	With pyridine In acetonitrile at 20℃; for 2h; Cooling with ice;	11 Represented by the formula [6a] obtained above (2R)-2-fluoro-2-C-methyl-D-Ribono-γ-lactone 7.55g (46.0mmol), acetonitrile 46ml (1.0L / mol) and pyridine 8.37g (105.8mmol, 2.30eq) was added, and benzoyl chloride 14.17g (100. 8mmol, 2.19eq) is added to under ice-cooling, and the mixture was stirred at room temperature for 2 hours. It was added to the reaction-terminated liquid water 180ml under ice-cooling, followed by stirring at room temperature for 10 minutes, and extracted with ethyl acetate 350 ml, and collected organic layers were washed with 5% aqueous sodium hydrogencarbonate solution 100ml, and washed with 5% brine 100ml , the following formula by which concentrated under reduced pressure, and dried under vacuum [1a]: Shown in (2R)-2-fluoro-2-C-methyl-D-Ribono-γ-lactone 1a It was obtained 5.49g
1.6 g	With dmap; triethylamine In dichloromethane at -5℃; for 2h; Inert atmosphere;	2.2.3. Preparation of 3,5-Di-O-benzoyl-2-deoxy-2-chloro-2-C-methyl-D-ribono-γ-lactone 5a General procedure: To a 50 mL three-necked flask equipped with a nitrogen inlet, a magnet stirrer and a thermometer was charged with 4a (740 mg, 4.10 mmol, 1.0 eq.) and DMAP (200 mg, 1.64 mmol, 0.4 eq.), after three times vacuum/nitrogen cycle, DCM (10 mL) was charged followed by triethylamine (2.3 mL, 16.4 mol, 4.0 eq.). The reactor was cooled to an internal temperature of -5°C followed by adding benzoyl chloride (1.4 mL, 12.40 mmol, 3.0 eq.) slowly with the internal temperature not higher than 5°C and reaction mixture was stirred at -5°C for 2h. The insoluble substance was filtered and washed by DCM (10 mL). The combined organic phase was washed by water (10 mL) and brine (10 mL), then dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (petroleum ether/dichloromethane, from 5/1 to 1/2) to give product 5a as white solid (1.29 g, 3.32 mol, 81% yield).

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2006/31725, 2006, A2 Location in patent: Page/Page column 13; 30-31
[2]Current Patent Assignee: WISDOM PHARMACEUTICAL - CN105418547, 2016, A Location in patent: Paragraph 0019; 0020
[3]Current Patent Assignee: CHANGZHOU PHARMACEUTICAL FACTORY CO., LTD. - CN106146433, 2016, A Location in patent: Paragraph 0009; 0025
[4]Current Patent Assignee: PHARMARESOURCES SHANGHAI CO LTD - CN107573304, 2018, A Location in patent: Paragraph 0120-0124
[5]Current Patent Assignee: GILEAD SCIENCES INC - WO2014/108525, 2014, A1 Location in patent: Page/Page column 18
[6]Current Patent Assignee: PHARMARESOURCES SHANGHAI CO LTD - WO2018/32356, 2018, A1 Location in patent: Page/Page column 37; 38
[7]Current Patent Assignee: ROCHE HOLDING AG - WO2008/45419, 2008, A1 Location in patent: Page/Page column 14-15
[8]Current Patent Assignee: JOHNSON & JOHNSON INC - US2014/179627, 2014, A1 Location in patent: Paragraph 0511
[9]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2021/209419, 2021, A1 Location in patent: Page/Page column 35-36
[10]Current Patent Assignee: MERCK & CO INC - WO2007/75876, 2007, A2 Location in patent: Page/Page column 17; 25-26
[11]Current Patent Assignee: TOPHARMAN SHANGHAI CO., LTD.; Shanghai Institute of Materia Medica (in: CAS); CHINESE ACADEMY OF SCIENCES - US2015/284351, 2015, A1 Location in patent: Paragraph 0074-0076
[12]Current Patent Assignee: HANGZHOU HUINUO MEDICINE TECH - CN106083773, 2016, A Location in patent: Paragraph 0030; 0055
[13]Location in patent: experimental part Wang, Peiyuan; Chun, Byoung-Kwon; Rachakonda, Suguna; Du, Jinfa; Khan, Noshena; Shi, Junxing; Stec, Wojciech; Cleary, Darryl; Ross, Bruce S.; Sofia, Michael J. [Journal of Organic Chemistry, 2009, vol. 74, # 17, p. 6819 - 6824]
[14]Current Patent Assignee: CENTRAL GLASS CO LTD - US2013/72699, 2013, A1 Location in patent: Paragraph 0073; 0074
[15]Current Patent Assignee: CENTRAL GLASS CO LTD - JP2015/13851, 2015, A Location in patent: Paragraph 0113; 0114; 0115
[16]Liu, He; Yang, Wenjiao; Zheng, Shaojiu; He, Yang; Wang, Guan; Qin, Hongjian; Zhu, Fuqiang; Jiang, Xiangrui; Shen, Jingshan; Gong, Xudong [Tetrahedron Letters, 2022, vol. 95]

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[ 874638-80-9 ]

Reference： [1]Patent: US2013/72699,2013,A1
[2]Patent: US2014/179627,2014,A1
[3]Patent: CN106146433,2016,A
[4]Patent: CN106366057,2017,A

3
[ 874638-80-9 ]
[ 817204-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 2,2,2-trifluoroethanol; sodium bis(2-methoxyethoxy)aluminium dihydride / toluene; acetic acid butyl ester / -20 - -15 °C 1.2: -20 - 20 °C 2.1: tin(IV) chloride / dichloromethane / 20 h / 30 - 80 °C / 1875.19 Torr / Sealed tube 2.2: 18 - 25 °C
	Multi-step reaction with 3 steps 1.1: sodium bis-(2-methoxyethoxy) (2,2,2,trifluoroethoxy) aluminum hydride / toluene; acetic acid butyl ester / -20 - -15 °C 2.1: tetrabutylammomium bromide; sulfuryl dichloride / toluene; acetic acid butyl ester / 1 h / -20 - 0 °C 3.1: tin(IV) chloride / dichloromethane / 20 h / 75 - 80 °C / 1875.19 Torr 3.2: 18 - 25 °C
	Multi-step reaction with 3 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride / dichloromethane / -20 - -15 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / toluene / 1 h / -5 - 0 °C 3: tin(IV) chloride; N,O-bis-(trimethylsilyl)-acetamide / acetonitrile / Reflux

	Multi-step reaction with 2 steps 1.1: Red-Al(OCH₂CF₃) / dichloromethane / 0.5 h / -10 °C 1.2: 16 h / -10 - 20 °C 2.1: ammonium sulfate / chlorobenzene / 1.5 h / 20 °C 2.2: 10 h / 70 °C
	Multi-step reaction with 3 steps 1: diisobutylaluminium hydride / dichloromethane / 2.5 h / Inert atmosphere 2: N-chloro-succinimide; triphenylphosphine / dichloromethane / 1 h / 0 - 15 °C / Inert atmosphere 3: tin(IV) chloride / chlorobenzene / 75 °C
	Multi-step reaction with 3 steps 1.1: aluminium / dichloromethane; 2,2,2-trifluoroethanol; toluene / 0 - 10 °C 2.1: triphenylphosphine; diethylazodicarboxylate / toluene / 0 - 30 °C 3.1: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane / chlorobenzene / 90 - 100 °C 3.2: 65 - 70 °C
	Multi-step reaction with 3 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene; dichloromethane; 2,2,2-trifluoroethanol / -15 - -10 °C 2: tetrabutylammomium bromide / toluene; dichloromethane; 2,2,2-trifluoroethanol / -40 - 0 °C 3: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane; tin(IV) chloride / chlorobenzene / 85 - 135 °C / Reflux
	Multi-step reaction with 3 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride; 1,1,1,3,3,3-hexamethyl-disilazane / dichloromethane / -18 °C / Inert atmosphere 2.1: oxalyl dichloride / chlorobenzene / 2 h / 15 - 40 °C 3.1: chlorobenzene / 0.25 h / 23 °C 3.2: 18 h / 50 - 60 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2013/178571, 2013, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - US2013/324709, 2013, A1
[3]Current Patent Assignee: NANTONG CHANGYOO PHARMATECH; NANTONG CHANGYOU PHARMACEUTICAL TECHNOLOGY - CN104610404, 2016, B
[4]Current Patent Assignee: ANHUI BIOCHEM UNITED PHARMACEUTICAL CO., LTD. - CN103848876, 2016, B
[5]Current Patent Assignee: FUZHOU XINGCHEN PHARAMCEUTICAL - CN106810515, 2017, A
[6]Current Patent Assignee: ZHEJIANG A & F UNIVERSITY - CN106905398, 2017, A
[7]Current Patent Assignee: CHANGZHOU PHARMACEUTICAL FACTORY CO., LTD. - CN109422789, 2019, A
[8]Current Patent Assignee: JIANGSU ALPHARM PHARMACEUTICAL GROUP - CN113354700, 2021, A

4
[ 874638-80-9 ]
[ 817204-32-3 ]
(2R,3R,4R,5S)-5-(4-benzoylamino-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: lithium tri-t-butoxyaluminum hydride / tetrahydrofuran / -20 °C / Inert atmosphere 2.1: dmap / 1.5 h / -20 °C / Inert atmosphere 3.1: N,O-bis-(trimethylsilyl)-acetamide / chlorobenzene / 2 h / 80 °C 3.2: 16 h / 65 °C

Reference： [1]Maiti, Munmun; Maiti, Mohitosh; Rozenski, Jef; De Jonghe, Steven; Herdewijn, Piet [Organic and Biomolecular Chemistry, 2015, vol. 13, # 18, p. 5158 - 5174]

5
[ 492-30-8 ]
[ 874638-80-9 ]

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 4345 - 4348
[2]Tetrahedron Letters,2015,vol. 56,p. 4345 - 4348
[3]Patent: CN105693661,2016,A
[4]Patent: CN105693661,2016,A
[5]Patent: CN105693661,2016,A
[6]Patent: CN105693661,2016,A
[7]Patent: CN105693661,2016,A
[8]Patent: CN105693661,2016,A

6
[ 492-30-8 ]
[ 98-88-4 ]
[ 874638-80-9 ]

Yield	Reaction Conditions	Operation in experiment
58%		The 2-C-methyl-D- ribotide -1,4-lactone (0.32g, 2mmoL) suspended in 10 ml methylene chloride, under the condition of ice bath, dripping benzoyl chloride (0.46 ml, 4mmoL, 2eq). Is omitted, then slowly dripped into triethylamine (0.61 ml, 4 . 4mmoL, 2 . 2eq), at least 1 hour drop end, reaction sleepovers. Pyridine is added to the reaction system (0.18 ml, 2 . 2mmoL, 1 . 1eq), -40 ° C stirring, then slowly adding trifluoromethyl sulfonic anhydride (0.37 ml, 2 . 2mmoL, 1 . 1eq), after dripping, slowly to room temperature, is continuously stirred for 1 hour. Added to the reaction solution 1.5mLDMSO, stir at room temperature, TLC monitoring after the reaction is complete, concentrated reaction fluid to the surface of the small volume, added to the reaction system in acetonitrile (12 ml), triethylamine three hydrofluoric acid salt (0.49 ml, 3mmoL, 1.5eq) and triethylamine (1.40 ml, 10mmoL, 5eq), stirring under the conditions of ice, at this temperature into the sulfuryl fluoride gas. TLC monitoring after the reaction is complete, evaporate the solvent, by adding 20 ml of water, the room temperature is arranged to separate out reddish brown solid. Filtering, after drying, is obtained after beating with methanol 0.42g gray solid, yield 58percent.

Reference： [1]Patent: CN105693661,2016,A .Location in patent: Paragraph 0116; 0117; 0118; 0119

7
[ 874638-80-9 ]
[ 879551-04-9 ]

Yield	Reaction Conditions	Operation in experiment
95.3%	With methanesulfonic acid In ethanol for 5h; Reflux;	1-8 Example 4 This embodiment provides a method for preparing (3R, 4R, 5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-one, which is the same as in Example 1. Basically the same, the difference is: adding 89.5eq of methanesulfonic acid; finally drying to obtain 210g of white solid (yield 95.3%, purity 99.5%).
	With sodium methylate In methanol at 20℃; for 2h;	1 ((2R, 3R, 4R) 3(benzoyloxy) 4fluoro4methyl5oxotetrahydrofuran2yl)benzoate (1a, 44.50g, 119.5mmol) inanhydrous methanol It was suspended in (240mL). Methanol (2.3mL, 10mmol, 8.3mol%) and a catalytic amount of 25 wt%sodium methoxide in, was added at room temperature. After 2 hours, the reaction was complete as indicated by TLC (20%EtOAc in hexanes). After concentration under reduced pressure, the residue mixture of ethyl ether and hexane (1: 2v / v) totriturated with (200 mL), the crude intermediate lactone, yielded a. The solid was collected by filtration, rinsed with hexanes (3× 40mL). The crude intermediate round bottom flask dried 1L loaded, was dissolved in anhydrous THF (500mL). 4chlorobenzoylchloride (46mL, 358mmol) was added at room temperature. The mixture was cooled in an icewaterbath and thenwas added triethylamine (100mL, 717mmol). The cloudy mixture was stirred at room temperature overnight. The reaction byadding water (60 mL) is stopped, after which the solution was concentrated under reduced pressure. The residue was dilutedwith ethyl acetate (200 mL), washed with water, brine (each 2 × 100mL). The organic layer was concentrated under reducedpressure, (in hexane, 20% EtOAc) and the residue was purified by column chromatography to afford the product as a fluffysolid in pale yellow. Dry the product (0.2mmHg, 50 ° C, 2 hours),

Reference： [1]Current Patent Assignee: SUZHOU KAIYUAN MINSHENG SCI TECH - CN111825641, 2020, A Location in patent: Paragraph 0020-0044
[2]Current Patent Assignee: GILEAD SCIENCES INC - JP2015/227337, 2015, A Location in patent: Paragraph 0213

8
[ 874638-80-9 ]
[ 1190307-88-0 ]

Reference： [1]Patent: CN103848876,2016,B
[2]Patent: CN106905398,2017,A

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(2S,3R)-Ethyl 3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,3-dihydroxy-2-methylpropanoate

[ 817204-32-3 ]

(2R,3R,4R,5R)-5-(4-Benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate

[ 1190307-88-0 ]

(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

[ 62062-65-1 ]

(S)-Isopropyl 2-aminopropanoate hydrochloride

[ 26661-13-2 ]

N-(2-Oxo-1,2-dihydropyrimidin-4-yl)benzamide

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Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
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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

[ CAS No. 874638-80-9 ] {[proInfo.proName]}

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[ 874638-80-9 ] Synthesis Path-Upstream 1~20

[ 874638-80-9 ] Synthesis Path-Downstream 1~8

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