1103738-17-5|(3AS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid| Ambeed

Structure of 1103738-17-5

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 1103738-17-5 ] Purity: 91% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 1103738-17-5 ]

CAS No. :	1103738-17-5
Formula :	C₈H₁₂O₆
M.W :	204.18
SMILES Code :	O=C([C@H](O1)[C@@H](O)[C@@]2([H])[C@]1([H])OC(C)(C)O2)O
MDL No. :	MFCD16877045
InChI Key :	YQQLEMAYGCQRAW-CXXDYQFHSA-N
Pubchem ID :	57558238

Safety of [ 1103738-17-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1103738-17-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	0
Fraction Csp3	0.88
Num. rotatable bonds	1
Num. H-bond acceptors	6.0
Num. H-bond donors	2.0
Molar Refractivity	42.57
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	85.22 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.49
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	-0.16
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-0.69
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-0.99
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.7
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	-0.21

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.94
Solubility	23.5 mg/ml ; 0.115 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.17
Solubility	13.7 mg/ml ; 0.0669 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.87
Solubility	1520.0 mg/ml ; 7.43 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.66 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.95

Application In Synthesis of [ 1103738-17-5 ]

* 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.

Downstream synthetic route of [ 1103738-17-5 ]

[ 1103738-17-5 ] Synthesis Path-Downstream 1~36

1
[ 110-91-8 ]
[ 1103738-17-5 ]
[ 2158-02-3 ]

Yield	Reaction Conditions	Operation in experiment
64%	With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In tetrahydrofuran;	To a solution of <strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> (5.0 g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20 C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20 C. for an additional 6 h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X *2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), delta 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).

References: [1]Patent: US2012/172320,2012,A1 .

2
[ 110-91-8 ]
[ 1103738-17-5 ]
[ 1103738-19-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In tetrahydrofuran; at 20℃; for 6.5h;	To a solution of <strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> (5.0 g, 24.5 mmol) in THF (100 ML, 20×) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20 C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20 C. for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2× ×2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4: 1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), delta 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
64%		To a solution of <strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> (5.0 g, 24.5 mmol) in THF (100 mL, 20×) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20 C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20 C. for an additional 6 h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2× ×2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), delta 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H)
64%		6. EXAMPLES Aspects of this invention can be understood from the following examples.6.1. Synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2.3-d][13]dioxol-5-yl)(morpholino)methanone To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose (504.40 g, 3.360 mol), acetone (5L, reagent grade) and anhydrous MgSO4 powder (811.23g, 6.740 mol / 2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24C over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt% water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23g, 86% yield, 96.7 area% pure by GC). 1H NMR (400 MHz, DMSO-d6)delta1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 - 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 13C NMR (101MHz, DMSO-d6) delta26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73. To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHC03 (33.0g, 3.0 equiv), NaBr (2.8g, 20 mol%) and TEMPO (0.40g, 2 mol%) at 20C. The mixture was cooled to 0-5C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid (<strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong>) as a yellow solid (21.0g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J= 3.2 Hz, 1H), 4.72 d, J= 3.2 Hz, 1H), 4.53 (d, J= 3.2 Hz, 1H), 4.38 (d, J= 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H). To a solution of <strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> (5.0g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20C for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), 8 6.02 (d, J= 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J= 3.2 Hz, 1H), 4.58 (d, J= 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).

64%		To a solution of Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired 24 morpholine amide (64%) as a white solid. 1H NMR (CDCl3), delta 6.02 (d, J = 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J = 3.2 Hz, 1H), 4.58 (d, J = 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
51.5%		in room temperature,2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (137 g, 426.7 mmol)With N-methylmorpholine (48 mL, 440 mmol)(3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro [2,3-d] [1,3] dioxolane-5-carboxylic acid 1d (58.0 g, 284 mmol)In tetrahydrofuran (1000 mL)After stirring at room temperature for 30 minutes,Morpholine (38 mL, 436 mmol) was added,Stir for 8 hours.The solid was removed by filtration,Washed with tetrahydrofuran (200 mL x 3)The filtrate was collected and concentrated under reduced pressure. Purification by silica gel column chromatography [petroleum ether / ethyl acetate (v / v) = 2/1]The title compound 1e was obtained as a white solid (40.0 g, 51.5%).
48%	With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In tetrahydrofuran; at 20℃; for 12h;	To a suspension of 183 (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxole-5-carboxylic acid (9.0 g, 44.2 mmol) and 185 HBTU (25.1 g, 66.3 mmol, N,N,N?,N?-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate) in 13 tetrahydrofuran was added 186 4-methylmorpholine (7.3 mL, 66.3 mmol) at room temperature. After 1 hour, to the mixture was added 187 morpholine (5.8 mL, 66.3 mmol) at room temperature. After 12 hours, the resulting mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo and the crude material was purified by silica gel column chromatography to obtain the 188 title compound (5.8 g, 48%) as a yellow solid. 1H NMR (400 MHz, CD3OD) delta 6.01 (d, J=3.6 Hz, 1H), 5.10 (s, 1H), 4.59 (d, J=2.4 Hz, 1H), 4.57 (d, J=3.6 Hz, 1H), 4.47 (d, J=2.4 Hz, 1H), 3.85-3.62 (m, 6H), 3.53-3.49 (m, 2H), 1.49 (s, 3H), 1.33 (s, 3H). [M+H]+ 274.

References: [1]Patent: US2009/30198,2009,A1 .Location in patent: Page/Page column 8.
[2]Patent: US2010/16422,2010,A1 .Location in patent: Page/Page column 4.
[3]Patent: EP2332947,2011,A1 .Location in patent: Page/Page column 6-7.
[4]Patent: EP2661256,2018,B1 .Location in patent: Paragraph 0091.
[5]Patent: CN106892948,2017,A .Location in patent: Paragraph 0195; 0196; 0197; 0198.
[6]Patent: US2019/169174,2019,A1 .Location in patent: Paragraph 0359; 0360.

3
[ 110-91-8 ]
[ 1103738-17-5 ]
[ 1103738-20-0 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile;Industry scale;	A solution of the diol (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol in acetonitrile (5.38 kg, 65% w/w, 3.50 kg active, 18.40 mol), acetonitrile (10.5 L) and TEMPO (28.4 g, 1 mol %) were added to a solution of K2HPO4 (0.32 kg, 1.84 mol) and KH2PO4 (1.25 kg, 9.20 mol) in water (10.5 L). A solution of NaClO2 (3.12 kg, 80% w/w, 27.6 mole, 1.50 eq) in water (7.0 L) and a solution of K2HPO4 (2.89 kg, 0.90 eq) in water (3.0 L) were prepared with cooling. Bleach (3.0 L, approximate 6% household grade) was mixed with the K2HPO4 solution. Approximately 20% of the NaClO2 solution (1.6 L) and bleach/K2HPO4 solution (400 mL, 1 mol %) were added. The remainders of the two solutions were added simultaneously. The reaction mixture turned dark red brown and slow exotherm was observed. The addition rate of the NaClO2 solution was about 40 mL/min (3-4 h addition) and the addition rate for the bleach/K2HPO4 solution was about 10-12 mL/min (10 hr addition) while maintaining the batch at 15-25 C. Additional charges of TEMPO (14.3 g, 0.5 mol %) were performed every 5-6 hr until the reaction went to completion (usually two charges are sufficient). Nitrogen sweep of the headspace to a scrubber with aqueous was performed to keep the green-yellowish gas from accumulating in the vessel. The reaction mixture was cooled to <10 C. and quenched with Na2SO3 (1.4 kg, 0.6 eq) in three portions over 1 hr. The reaction mixture was then acidified with H3PO4 until pH reached 2.0-2.1 (2.5-2.7 L) at 5-15 C. The layers were separated and the aqueous layer was extracted with acetonitrile (10.5 L ×3). The combined organic layer was concentrated under vacuo (100-120 torr) at <35 C. (28-32 C. vapor, 45-50 C. bath) to low volume (6-7 L) and then flushed with acetonitrile (40 L) until KF of the solution reached <1% when diluted to volume of about 12-15Lwith acetonitrile. Morpholine (1.61 L, 18.4 mol, 1.0 eq) was added over 4-6 h and the slurry was aged overnight under nitrogen. The mixture was cooled to 0-5 C. and aged for 3 hours then filtered. The filter cake was washed with acetonitrile (10 L). Drying under flowing nitrogen gave 4.13 kg of the morpholine salt of (<strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> as a white solid (92-94% pure based on 1H NMR with 1,4-dimethoxybenzene as the internal standard), 72-75% yield corrected for purity. 1H NMR (D2O) delta 5.96 (d, J=3.6 Hz, 1H), 4.58 (d, J=3.6 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.30 (d, J=3.2 Hz, 1H), 3.84 (m, 2H), 3.18 (m, 2H), 1.40 (s, 1H), 1.25 (s, 1H). 13H NMR (D2O) delta 174.5, 112.5, 104.6, 84.2, 81.7, 75.0, 63.6, 43.1, 25.6, 25.1.
	In acetonitrile;Inert atmosphere;	A solution of the diol (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol in acetonitrile (5.38 kg, 65% w/w, 3.50 kg active, 18.40 mol), acetonitrile (10.5 L) and TEMPO (28.4 g, 1 mol %) were added to a solution of K2HPO4 (0.32 kg, 1.84 mol) and KH2PO4 (1.25 kg, 9.20 mol) in water (10.5 L). A solution of NaClO2 (3.12 kg, 80% w/w, 27.6 mole, 1.50 eq) in water (7.0 L) and a solution of K2HPO4 (2.89 kg, 0.90 eq) in water (3.0 L) were prepared with cooling. Bleach (3.0 L, approximate 6% household grade) was mixed with the K2HPO4 solution. Approximately 20% of the NaClO2 solution (1.6 L) and bleach/K2HPO4 solution (400 mL, 1 mol %) were added. The remainders of the two solutions were added simultaneously. The reaction mixture turned dark red brown and slow exotherm was observed. The addition rate of the NaClO2 solution was about 40 mL/min (3-4 h addition) and the addition rate for the bleach/K2HPO4 solution was about 10-12 mL/min (10 hr addition) while maintaining the batch at 15-25 C. Additional charges of TEMPO (14.3 g, 0.5 mol %) were performed every 5-6 hr until the reaction went to completion (usually two charges are sufficient). Nitrogen sweep of the headspace to a scrubber with aqueous was performed to keep the green-yellowish gas from accumulating in the vessel. The reaction mixture was cooled to <10 C. and quenched with Na2SO3 (1.4 kg, 0.6 eq) in three portions over 1 hr. The reaction mixture was then acidified with H3PO4 until pH reached 2.0-2.1 (2.5-2.7 L) at 5-15 C. The layers were separated and the aqueous layer was extracted with acetonitrile (10.5 L×3). The combined organic layer was concentrated under vacuo (100-120 torr) at <35 C. (28-32 C. vapor, 45-50 C. bath) to low volume (6-7 L) and then flushed with acetonitrile (40 L) until KF of the solution reached <1% when diluted to volume of about 12-15 L with acetonitrile. Morpholine (1.61 L, 18.4 mol, 1.0 eq) was added over 4-6 h and the slurry was aged overnight under nitrogen. The mixture was cooled to 0-5 C. and aged for 3 hours then filtered. The filter cake was washed with acetonitrile (10 L). Drying under flowing nitrogen gave 4.13 kg of the morpholine salt of (<strong>[1103738-17-5](3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid</strong> as a white solid (92-94% pure based on 1H NMR with 1,4-dimethoxybenzene as the internal standard), 72-75% yield corrected for purity. 1H NMR (D2O) delta 5.96 (d, J=3.6 Hz, 1H), 4.58 (d, J=3.6 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.30 (d, J=3.2 Hz, 1H), 3.84 (m, 2H), 3.18 (m, 2H), 1.40 (s, 1H), 1.25 (s, 1H). 13H NMR (D2O) delta 174.5, 112.5, 104.6, 84.2, 81.7, 75.0, 63.6, 43.1, 25.6, 25.1

References: [1]Patent: US2009/30198,2009,A1 .Location in patent: Page/Page column 8.
[2]Patent: US2010/16422,2010,A1 .Location in patent: Page/Page column 4-5.

4
[ 114861-22-2 ]
[ 1103738-17-5 ]

Yield	Reaction Conditions	Operation in experiment
79%	With trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide;2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In methanol; water; acetone; at 0 - 20℃; for 24h;	To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0 g, 131 mmol) in acetone (375 mL, 15×) and H2O (125 mL, 5×) was added NaHCO3 (33.0 g, 3.0 equiv), NaBr (2.8 g, 20 mol %) and TEMPO (0.40 g, 2 mol %) at 20 C. The mixture was cooled to 0-5 C. and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20 C. for 24h. Methanol (20 mL) was added and the mixture was stirred at 20 C. for 1 h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2×). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12× ×3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5×) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0 g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J=3.2 Hz, 1H), 4.72 d, J=3.2 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.38 (d, J=3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H).
79%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In water; acetone; at 0 - 20℃;Product distribution / selectivity;	To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0 g, 131 mmol) in acetone (375 mL, 15×) and H2O (125 mL, 5×) was added NaHCO3 (33.0 g, 3.0 equiv), NaBr (2.8 g, 20 mol %) and TEMPO (0.40 g, 2 mol %) at 20 C. The mixture was cooled to 0-5 C. and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20 C. for 24 h. Methanol (20 mL) was added and the mixture was stirred at 20 C. for 1 h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2×). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12× ×3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5×) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0 g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J=3.2 Hz, 1H), 4.72 d, J=3.2 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.38 (d, J=3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H)
79%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In water; acetone; at 0 - 20℃;	6. EXAMPLES Aspects of this invention can be understood from the following examples.6.1. Synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2.3-d][13]dioxol-5-yl)(morpholino)methanone To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose (504.40 g, 3.360 mol), acetone (5L, reagent grade) and anhydrous MgSO4 powder (811.23g, 6.740 mol / 2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24C over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt% water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23g, 86% yield, 96.7 area% pure by GC). 1H NMR (400 MHz, DMSO-d6)delta1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 - 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 13C NMR (101MHz, DMSO-d6) delta26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73. To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHC03 (33.0g, 3.0 equiv), NaBr (2.8g, 20 mol%) and TEMPO (0.40g, 2 mol%) at 20C. The mixture was cooled to 0-5C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J= 3.2 Hz, 1H), 4.72 d, J= 3.2 Hz, 1H), 4.53 (d, J= 3.2 Hz, 1H), 4.38 (d, J= 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H). To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20C for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), 8 6.02 (d, J= 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J= 3.2 Hz, 1H), 4.58 (d, J= 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).

79%		To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHCO3 (33.0g, 3.0 equiv), NaBr (2.8g, 20 mol%) and TEMPO (0.40g, 2 mol%) at 20C. The mixture was cooled to 0-5C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J = 3.2 Hz, 1H), 4.72 d, J = 3.2 Hz, 1H), 4.53 (d, J = 3.2 Hz, 1H), 4.38 (d, J = 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H).
77.2%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In methanol; water; acetone; at 0 - 30℃; for 25h;	in room temperature,(3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2,2-dimethyl-3a, 5,6,6a-tetrahydrofuro [2,3-d] [1,3] Oxepin-6-ol 1c (70.0 g, 368 mmol)Was dissolved in a mixed solvent of acetone and water (v / v = 5 / 2,1400 mL)Sodium bicarbonate (93 g, 1.11 mol),Sodium bromide (7.6 g, 74 mmol)And tetramethylpiperidine nitrogen oxide (1.2 g, 7.7 mmol) were successively added to the above solution.Cooling to 0 ,Sucralyl isocyanuric acid (86.0 g, 370 mmol) was added in portions,Stirred at room temperature for 24 hours,Then methanol (60 mL) was added,Stirring was continued for 1 hour.The solid was removed by filtration and washed with acetone (200 mL x 3). The filtrates were combined and the organic solvent was concentrated under reduced pressure. The residue was extracted with ethyl acetate (800 mL x 4). The solvent was concentrated under reduced pressure and acetone (400 mL) ,Filtration, vacuum concentration,The title compound was obtained as a reddish brown oil (58.0 g, 77.2%).
58%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In N,N-dimethyl-formamide; at 20℃; for 12h;	To a solution of ((3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,2- d] [1 Was added TEMPO (0.24 g, 1.5 mmol) to a solutionof 3-bromopyridin-3-yl] The mixture was cooled to 0 [deg.] C and then trichloroisocyanuric acid (17.8 g, 76.7 mmol) was added in portions. The suspensionwas stirred at room temperature for 12 hours. Methanol (2.0 mL) was added and themixture was stirred at room temperature for 2 hours. The mixture was filtered andwashed with acetone (2 x 20 mL wash). The organic solvent was removed in vacuo, theaqueous layer was extracted with EtOAc and the organic layer was concentrated invacuo. Acetone was added and the mixture was filtered. The filtrate was concentrated togive the title compound (9.0 g, 58%) as a light yellow solid.
58%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In water; acetone; at 0 - 20℃; for 12h;	To a solution of (178 (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-ol (14.6 g, 76.7 mmol), 39 NaHCO3 (19.3 g, 230.3 mmol), and 180 NaBr (1.6 g, 15.4 mmol) in 42 acetone/9 water (120 mL/40 mL) was added 181 TEMPO (0.24 g, 1.5 mmol) at room temperature. The mixture was cooled to 0 C., and then 182 trichloroisocyanuric acid (17.8 g, 76.7 mmol) was added in small portions. The suspension was stirred at room temperature for 12 hours. 170 Methanol (2.0 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and washed with acetone (twice, 20 mL per wash). The organic solvent was removed in vacuo, the aqueous layer was extracted with EtOAc, and the organic layer was concentrated in vacuo. Acetone was added thereto and the mixture was filtered. The filtrate was concentrated to obtain the desired 183 acid (9.0 g, 58%) as a light yellow solid. 1H NMR (400 MHz, CD3OD) delta 5.98 (d, J=3.6 Hz, 1H), 4.71 (d, J=3.2 Hz, 1H), 4.51 (d, J=3.6 Hz, 1H), 4.36 (d, J=3.6 Hz, 1H), 1.45 (s, 3H), 1.31 (s, 3H).
	With sodium hypochlorite; sodium chlorite; dipotassium hydrogenphosphate; potassium dihydrogenphosphate;2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In water; acetonitrile; at 15 - 25℃;Industry scale;Product distribution / selectivity;	A solution of the diol (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol in acetonitrile (5.38 kg, 65% w/w, 3.50 kg active, 18.40 mol), acetonitrile (10.5 L) and TEMPO (28.4 g, 1 mol %) were added to a solution of K2HPO4 (0.32 kg, 1.84 mol) and KH2PO4 (1.25 kg, 9.20 mol) in water (10.5 L). A solution of NaClO2 (3.12 kg, 80% w/w, 27.6 mole, 1.50 eq) in water (7.0 L) and a solution of K2HPO4 (2.89 kg, 0.90 eq) in water (3.0 L) were prepared with cooling. Bleach (3.0 L, approximate 6% household grade) was mixed with the K2HPO4 solution. Approximately 20% of the NaClO2 solution (1.6 L) and bleach/K2HPO4 solution (400 mL, 1 mol %) were added. The remainders of the two solutions were added simultaneously. The reaction mixture turned dark red brown and slow exotherm was observed. The addition rate of the NaClO2 solution was about 40 mL/min (3-4 h addition) and the addition rate for the bleach/K2HPO4 solution was about 10-12 mL/min (10 hr addition) while maintaining the batch at 15-25 C. Additional charges of TEMPO (14.3 g, 0.5 mol %) were performed every 5-6 hr until the reaction went to completion (usually two charges are sufficient). Nitrogen sweep of the headspace to a scrubber with aqueous was performed to keep the green-yellowish gas from accumulating in the vessel. The reaction mixture was cooled to <10 C. and quenched with Na2SO3 (1.4 kg, 0.6 eq) in three portions over 1 hr. The reaction mixture was then acidified with H3PO4 until pH reached 2.0-2.1 (2.5-2.7 L) at 5-15 C. The layers were separated and the aqueous layer was extracted with acetonitrile (10.5 L ×3). The combined organic layer was concentrated under vacuo (100-120 torr) at <35 C. (28-32 C. vapor, 45-50 C. bath) to low volume (6-7 L) and then flushed with acetonitrile (40 L) until KF of the solution reached <1% when diluted to volume of about 12-15Lwith acetonitrile. Morpholine (1.61 L, 18.4 mol, 1.0 eq) was added over 4-6 h and the slurry was aged overnight under nitrogen. The mixture was cooled to 0-5 C. and aged for 3 hours then filtered. The filter cake was washed with acetonitrile (10 L). Drying under flowing nitrogen gave 4.13 kg of the morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid as a white solid (92-94% pure based on 1H NMR with 1,4-dimethoxybenzene as the internal standard), 72-75% yield corrected for purity. 1H NMR (D2O) delta 5.96 (d, J=3.6 Hz, 1H), 4.58 (d, J=3.6 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.30 (d, J=3.2 Hz, 1H), 3.84 (m, 2H), 3.18 (m, 2H), 1.40 (s, 1H), 1.25 (s, 1H). 13H NMR (D2O) delta 174.5, 112.5, 104.6, 84.2, 81.7, 75.0, 63.6, 43.1, 25.6, 25.1.
	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In water; acetone; at 0 - 20℃; for 24h;	Step-Ill: To a stirred solution of (3aS,5S,6R,6aS)-5-hydroxymethyl-2,2-dimethyl- tetrahydro-furo[2,3-d][1 ,3]dioxol-6-ol (30 g, 157 mmol) in acetone (450 ml) and water (150 ml) was added sodium bicarbonate (39.8 g, 473 mmol), sodium bromide (3.25 g, 31 mmol) and TEMPO (490 mg, 3.1 mmol) at 20 C. The mixture was cooled to 0-5 C and solid trichloroisocyanuric acid (TCCA, 36.69 g, 157 mmol) was then added in portions. After stirring for 24 h at room temperature, methanol (25 ml) was added stirred for additional 1 h. The white suspension was formed. This was filtered, washed with acetone (50 ml X 2). The volatiles were evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (300 ml X 3) and combined organic layers were concentrated to thick oily mixture with some solid residue. This was taken in acetone and filtered. The filtrate was concentrated to give 25 g of (3aS,5R,6S,6aS)-6- hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1 ,3]dioxole-5-carboxylic acid as a yellow solid. 1H NMR (400 MHz, CD3OD): delta 1.30 (s, 3H), 1.44 (s, 3H), 4.35 (d, J = 2.8 Hz, 1 H), 4.50 (d, J = 2.0 Hz, 1 H), 4.69 (d, J = 3.6 Hz, 1 H), 5.97 (d, J = 3.2 Hz, 1 H).
	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; In water; acetonitrile; at 30 - 50℃;	Compound 3 (100 g, 525.8 mmol) was dissolved in a mixed solution of acetonitrile (380 mL) and water (190 mL), and 2,2,6,6-tetramethylpiperidine oxide (0.2-0.7 eq) was added.And iodobenzene diacetate (1.0-5.0 eq),The reaction mixture was stirred at 30-50 120-180 minutes, and extracted three times with ethyl acetate (500mL / times) and concentrated under reduced pressure to give a brown oily crude product (93.6g, 87%) ethyl acetate solution was concentrated.

References: [1]Patent: US2009/30198,2009,A1 .Location in patent: Page/Page column 7-8.
[2]Patent: US2010/16422,2010,A1 .Location in patent: Page/Page column 4.
[3]Patent: EP2332947,2011,A1 .Location in patent: Page/Page column 6-7.
[4]Patent: EP2661256,2018,B1 .Location in patent: Paragraph 0090.
[5]Patent: CN106892948,2017,A .Location in patent: Paragraph 0192; 0193; 0194.
[6]Patent: KR101770302,2017,B1 .Location in patent: Paragraph 0334; 0335.
[7]Patent: US2019/169174,2019,A1 .Location in patent: Paragraph 0357; 0358.
[8]Patent: US2009/30198,2009,A1 .Location in patent: Page/Page column 8.
[9]Patent: WO2012/140596,2012,A1 .Location in patent: Page/Page column 54-55.
[10]Patent: CN109824687,2019,A .Location in patent: Paragraph 0042-0047.

5
[ 609-06-3 ]
[ 1103738-17-5 ]

References: [1]Patent: EP2332947,2011,A1 .
[2]Patent: WO2012/140596,2012,A1 .
[3]Patent: CN106892948,2017,A .
[4]Patent: EP2661256,2018,B1 .
[5]Patent: CN109824687,2019,A .

6
[ 1103738-17-5 ]
(3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2,3,4,5-tetraol [ No CAS ]

References: [1]Patent: EP2332947,2011,A1 .
[2]Patent: EP2661256,2018,B1 .

7
[ 1103738-17-5 ]
[ 1103738-30-2 ]

References: [1]Patent: EP2332947,2011,A1 .
[2]Patent: CN108675976,2018,A .
[3]Patent: EP2661256,2018,B1 .

8
[ 131156-47-3 ]
[ 1103738-17-5 ]

References: [1]Patent: WO2012/140596,2012,A1 .
[2]Patent: CN106892948,2017,A .
[3]Patent: CN109824687,2019,A .

9
[ 1103738-17-5 ]
(2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[[(2R)-thiiran-2-yl]methoxy]phenyl]methyl]phenyl]-6-methylthiotetrahydropyran-3,4,5-triol [ No CAS ]