32384-65-9

Usage

Uses

2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone is an antidiabetic agent and an intermediate of Dapagliflozin (D185370). 2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone acts as a reagent in the synthesis of trans-cyclohexane-bearing C-glucose as sodium glucose co-transporter 2 inhibitors.

Reference

Guo, C.; Hu, M.; DeOrazio, R. J.; Usyatinsky, A.; Fitzpatrick, K.; Zhang, Z. J.; Maeng, J. H.; Kitchen, D. B.; Tom, S.; Luche, M.; Khmelnitsky, Y.; Mhyre, A. J.; Guzzo, P. R.; Liu, S., The design and synthesis of novel SGLT2 inhibitors: C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties. Bioorg. Med. Chem. 2014, 22, 3414-3422. S Thirumalai Rajan; Eswaraiah, S., Process for the preparation of (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxylphenyl)methyl]phenyl]-D-glucitol and its solvate thereof. US Patent 2015, WO 2015/132803 A2. Hrapchak, M.; Latli, B.; Wang, X. J.; Lee, H.; Campbell, S.; Song, J. J.; Senanayake, C. H., Synthesis of empagliflozin, a novel and selective sodium-glucose co-transporter-2 inhibitor, labeled with carbon-14 and carbon-13. J. Label. Compd. Radiopharm. 2014, 57, 687-694. Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi, E.; Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.; Kimata, H.; Nakayama, K.; Tsuda-Tsukimoto, M., Discovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus. J. Med. Chem. 2010, 53, 6355-6360.

Chemical Properties

Pale yellow oil

Upstream product

• 75-77-4 chloro-trimethyl-silane 
• 90-80-2 D-Glucono-1,5-lactone 
• 999-97-3 1,1,1,3,3,3-hexamethyl-disilazane 
• 1335-57-5 3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one 
• 15892-28-1 (3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-one 
• 18156-74-6 1-(Trimethylsilyl)imidazole 

Downstream Products

• 1000878-02-3 C₁₄H₂₀O₆ 
• 714269-57-5 (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 
• 1030825-21-8 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methyl-phenyl)-D-glucopyranoside 
• 914922-82-0 1-C-(4-chlorophenyl)-2,3,4,6-tetrakis-O-(trimethylsilyl)hexopyranose 
• 960494-15-9 C₃₃H₅₇ClO₇Si₄ 

Relevant academic research and scientific papers

SYNTHETIC ROUTES TO HIGHER-CARBON SUGARS. REACTION OF LACTONES WITH 2-LITHIO-1,3-DITHIANE

The per(trimethylsilyl) ether of D-glucono-1,5-lactone reacted with 2-lithio-1,3-dithiane to give, after removal of protecting groups, a 62 percent yield of 1-C-(1,3-dithian-2-yl)-α-D-glucopyranose (3) as a single tautomer; this product is formally a derivative of a 7-carbon, 1,2-dicarbonyl sugar.The crystalline 2,3,4,6-tetraacetate (4) of 3 was readily obtained, again as a single tautomer, and forcing conditions of acetylation led to the acyclic, enol hexaacetate in admixture with the cyclic pentaacetate (6) of 3.Desulfurization of the tetraacetate 4 with Raney nickel gave 1-deoxy-D-gluco-heptulose as its α-pyranose 3,4,5,7-tetraacetate, whereas similar desulfurization of the pentaacetate 6 was accompanied by removal of the tertiary acetoxyl group, providing stereospecific access to the C-β-D-glucosyl compound 2,6-anhydro-1-deoxy-D-glycero-D-gulo-heptitol as its 3,4,5,7-tetraacetate.To explore the effects of chain substituents on the tautomeric behavior of the lacton-derived adducts, the simple lactones 5-pentanolide, 4-butanolide, and 4-pentanolide were made to react with 2-lithio-1,3-dithiane, and the tautomeric compositions of the products wre examined before and after acetylation.This work establishes preparative access to 1,2-dicarbonyl sugars, higher ketoses, and C-glycosyl compounds from readily available lactone precursors.

Synthesis of unlabelled and stable-isotope–labelled glucuronide metabolites of dapagliflozin and synthesis of stable-isotope–labelled dapagliflozin

Two regioisomeric glucuronide metabolites of dapagliflozin (BMS-512148) were synthesized and used to elucidate the structures of dapagliflozin metabolites observed in human urine samples. The structures of the synthetic metabolites were assigned by heteronuclear multiple-bond correlation, ROESY, and total correlation spectroscopy experiments. Analogues of these metabolites containing carbon-13 as a stable label were also prepared for use as internal standards for the analysis of urine samples obtained from patients participating in clinical studies.

Synthesis method and application of 1-methyl glucose

The invention discloses a synthesis method and application of 1-methyl glucose. The synthesis method comprises the following steps: dissolving gluconic acid delta-lactone in THF, adding N-methylmorpholine and TMSCl, reacting to obtain TMS-protected gluconic acid delta-lactone, dissolving the TMS-protected gluconic acid delta lactone in anhydrous THF, treating with methyl lithium or methyl magnesium bromide, reacting to obtain TMS-protected 1-methyl glucose, dissolving the TMS-protected 1-methyl glucose in acetonitrile-water, and removing TMS protection by adding H strong cation exchangeresin to obtain 1-methyl glucose. The effect of applying 1-methyl glucose to cigarette perfuming is mainly to improve the aroma quality and aroma quantity, reduce irritation and purify the aftertaste.

Preparation method and preparation of C-glycoside derivative

The invention relates to a preparation method of a co-crystal containing (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl)-4-chlorphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and L-proline, and a pharmaceutical preparation of the co-crystal. A preparation method is low in impurity content, high in yield and especially suitable for preparation of the pharmaceutical preparation. The preparation obtained by using the co-crystal prepared by the method has good stability and dissolubility, and can effectively achieve the curative effects of treating diabetes mellitus and reducing blood sugar as an SGLT-2 inhibitor drug; the pharmaceutical composition can meet the requirements of clinical medication and has good safety.

Telescoped lithiation, C-arylation and methoxylation in flow-batch hybrid toward the synthesis of canagliflozin

We report a highly efficient three-step flow-batch hybrid procedure for the synthesis of a key canagliflozin intermediate. The telescoped process provides exquisite control over an exothermic and mixing sensitive lithiation and subsequent C-arylation within a microstructured flow reactor. Methoxylation reagents are then added in flow, before reaching completion in a batch vessel. The flow process afforded the target intermediate in 76% yield, with a throughput of 26.8 g/h.

Method for synthesizing diabetes medicine by D - gluconic acid - δ δ-lactone

The invention discloses a method for synthesizing a diabetes drug by D - gluconic acid - δ δ-lactone. To the technical field of drug synthesis, D - glucose acid - δ δ-lactone is used as a raw material, and then subjected to catalytic hydrogenation and bromination reaction through three-silyl protecting reaction, then condensed with 5 - bromo -2 - chloro -4’ - ethoxy diphenyl methane, and finally, trimethyl silicon-based protection is removed. To the method for synthesizing the diabetes medicine by D - gluconic acid - δ δ-lactone, D - gluconic acid - δ δ-lactone is adopted as the starting raw material, the reaction process is simple, the intermediate is easy to purify, and the raw materials used in the reaction are easily obtained. The reaction process is more mild than the prior art. The yield of the final product can reach 95.89% or above, and the purity can reach 99.5% or more.

Preparation method and application of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone

The invention relates to the technical field of medicine, in particular to a preparation method and application of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-gluconolactone. According to the preparation method, D-gluconolactone and hexamethyldisilazane react in an ionic liquid, cations in the ionic liquid are alkyl imidazolium ions, and anions in the ionic liquid are hexafluorophosphate radicals, tetrafluoroborate radicals, tetrachloroaluminate radicals or chloride ions. The ionic liquid is stable during high-temperature distillation, the solvent after reaction can be recycled, the preparation methodhas few reaction steps, atom economy is high, and operation conditions are easy to control. The preparation method can be used for preparing canagliflozin.

Preparation method for polyhydroxy carbohydrate compound

The invention discloses a preparation method and post-treatment method for a trimethylsilyl protecting group of a polyhydroxy carbohydrate compound. According to the preparation method, a reaction occurs by taking the polyhydroxy carbohydrate compound as a raw material, dichloromethane, tetrahydrofuran, methylbenzene and methyl tert-butyl ether as solvents and a halogen elementary substance or a halogen-containing trimethyl reagent as a catalyst; then a protecting group compound is added, and the temperature is controlled to be 0-60 DEG C; and finally, an adsorbent is added into a reaction solution, and filtering is performed to obtain the product. The simple-to-operate preparation method for the trimethylsilyl protecting groups on polyhydroxy saccharide and a polyhydroxy natural product has the advantages that the raw and auxiliary materials are few; the cost is low; post-treatment is simple; a way of post-treatment with water is avoided; and the used catalyst is completely removed byadopting the multi-pore activated carbon and multi-pore ion resin, thus guaranteeing the stability increase of the product.

Preparation method of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone

The present invention provides a preparation method of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone. The method comprises the following steps: dropwise adding trimethylchlorosilane into a system of tetrahydrofuran and N-methylmorpholine, adding glucolactone in batches after dropwise adding of the trimethylchlorosilane, and then adding 4-dimethyl pyridine for reaction so as to obtain the 2, 3,4, 6-tetra-O-trimethylsilyl-D-glucolactone. Compared with the prior art, the preparation method disclosed by the invention has the advantages that the requirements on the feeding temperature and the feeding time during reaction are wider, the quality controllable range is widened, the process repeatability is good, the requirement on the cooling of production equipment is reduced, and the preparation method has great advantages in the aspects of product purity and impurity compound IV control.

A Concise and Efficient Synthesis of Dapagliflozin

A concise and efficient synthesis of the SGLT-2 inhibitor dapagliflozin (1) has been developed. This route involves ethyl C-aryl glycoside 9 as the key intermediate, which is easily crystallized and purified as the crystalline n-propanol solvate with high purity (>98.5%). The tetra-O-unprotected compound 9 could be directly reduced to crude dapagliflozin with high diastereoselectivity. The final pure API product 1 was isolated and purified with high purity (>99.7%). The process has been implemented on a multikilogram scale.