150609-95-3

Basic information

• Product Name: Diacetonefructose chlorosulfate
• Synonyms: 2,3:4,5-BIS-O-(1-METHYLETHYLIDENE)-BD-FRUCTOPYRANOSE CHLOROSULFATE;2,3:4,5-bis-o-(1-methylethylidene)-b-d-fructopyranose sulfonyl chloride;Diacetonefructose chlorosulfate;FRUTOPYRANOSE SULFURYL CHLORIDE;2,3:4,5-bis-O-(1-methylethylidene)-b-D-Fructopyranose;2,3:4,5-bis-O-(1-Methylethylidene)-1-chlorosulfate β-D-Fructopyranose;2,3:4,5-Bis-O-(1-methylethylidene)-b-D-fructopyranose sulfonyl chloride(Diacetonefructose chlorosulfate);(3aS,5aR,8aR,8bS)-3a-(chlorosulfonyloxymethyl)-2,2,7,7-tetramethyl-5,5a,8a,8b-tetrahydrodi[1,3]dioxolo[4,5-a:5',3'-d]pyran
• CAS NO: 150609-95-3
• Molecular Formula: C₁₂H₁₉ClO₈S
• Molecular Weight: 358.79
• Product Categories: Pharmaceutical Intermediates
• Mol File: 150609-95-3.mol

Chemical Properties

• Boiling Point: 406.3 °C at 760 mmHg
• Flash Point: 199.5 °C
• Appearance: /
• Density: 1.371 g/cm³
• Vapor Pressure: 1.93E-06mmHg at 25°C
• Refractive Index: 1.489
• Storage Temp.: Hygroscopic, -20°C Freezer, Under inert atmosphere
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• CAS DataBase Reference: Diacetonefructose chlorosulfate(CAS DataBase Reference)
• NIST Chemistry Reference: Diacetonefructose chlorosulfate(150609-95-3)
• EPA Substance Registry System: Diacetonefructose chlorosulfate(150609-95-3)

Safety Data

• Hazardous Substances Data: 150609-95-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Diacetonefructose chlorosulfate is used as an intermediate for the synthesis of Topiramate-d12 (T540252), which is a deuterated form of Topiramate. Topiramate is a medication used as an anticonvulsant, helping to control seizures in patients with epilepsy. The compound also serves as an impurity in the production of Topiramate (T540250), which is the non-deuterated version of the drug.

InChI:InChI=1/C12H19ClO8S/c1-10(2)18-7-5-16-12(6-17-22(13,14)15)9(8(7)19-10)20-11(3,4)21-12/h7-9H,5-6H2,1-4H3/t7-,8-,9+,12+/m1/s1

Synthetic route

2,3;4,5-di-O-isopropylidene-β-D-fructopyranose (20880-92-6) → 2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3)

Conditions	Yield
With sulfuryl dichloride In dichloromethane; toluene at -5 - 20℃; for 6h; Temperature; Reagent/catalyst; Inert atmosphere;	95.9%
With pyridine; sulfuryl dichloride In 1,2-dichloro-ethane at -20 - 25℃; for 2 - 7h; Product distribution / selectivity;	94%
With pyridine; sulfuryl dichloride In dichloromethane; toluene at -10 - 20℃; for 3h; Temperature;	93.7%

D-fructose (7660-25-5) → 2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: zinc(II) chloride / 2 h / 58 °C 2: sulfuryl dichloride; 1H-imidazole / dichloromethane / 2.5 h / 0 °C / Molecular sieve View Scheme

2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3) → topiramate (97240-79-4)

Conditions	Yield
With ammonia In tetrahydrofuran; hexane at 20℃; for 3h; Solvent; Temperature;	96.7%
With ammonia In tetrahydrofuran; Petroleum ether at 20℃; for 3h; Solvent;	95.2%
With pyridine; SULFAMIDE In 5,5-dimethyl-1,3-cyclohexadiene at 128 - 133℃; for 3h;	91.1%

2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3) → 2,3;4,5-di-O-isopropylidene-β-D-fructopyranose (20880-92-6)

Conditions	Yield
With ammonia In dichloromethane at 20 - 30℃; Temperature; Solvent;	90.7%

benzylamine (100-46-9) + 2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3) → N-benzyl topiramate

Conditions	Yield
In tetrahydrofuran at 23℃; for 24h;	76%

N-butylamine (109-73-9) + 2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3) → Butyl-sulfamic acid (3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyl-tetrahydro-bis[1,3]dioxolo[4,5-b;4',5'-d]pyran-3a-ylmethyl ester

Conditions	Yield
In tetrahydrofuran for 2h; Heating;	67%

ethylamine (75-04-7) + 2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3) → N-ethyl topiramate

Conditions	Yield
In tetrahydrofuran 1.) -78 deg C, 60 min, 2.) 23 deg C, 2 h;	59%

2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3) → 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose azidosulfate (106881-35-0)

Conditions	Yield
With pyridine; sodium azide In acetonitrile at 25 - 30℃; for 14h;

1-amino-2-propene (107-11-9) + 2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3) → N-allyl-2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate

Conditions	Yield
With triethylamine In tetrahydrofuran at 20 - 50℃; for 4.16667h;

2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3) → N-hydroxy-2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate

Conditions	Yield
With hydroxylamine hydrochloride; potassium carbonate In tetrahydrofuran; water at 20℃; for 12.17h;

(4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (236406-15-8) + 2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3) → C26H38N2O10S (1187321-63-6)

Conditions	Yield
Stage #1: (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester With triethylamine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester In tetrahydrofuran at 20℃; for 1.25h;

2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3) → C18H32N2O8S (1187321-64-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / tetrahydrofuran / 0.5 h / 20 °C 1.2: 1.25 h / 20 °C 2.1: hydrogen / 5%-palladium/activated carbon / ethanol / 0.33 h View Scheme

2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid ester (150609-95-3) → C25H40N4O9S (1187320-28-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / tetrahydrofuran / 0.5 h / 20 °C 1.2: 1.25 h / 20 °C 2.1: hydrogen / 5%-palladium/activated carbon / ethanol / 0.33 h 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 3 h / 65 °C View Scheme

Upstream product

• 7660-25-5 D-fructose 
• 20880-92-6 2,3;4,5-di-O-isopropylidene-β-D-fructopyranose 

Downstream Products

• 20880-92-6 2,3;4,5-di-O-isopropylidene-β-D-fructopyranose 
• 1187321-63-6 C₂₆H₃₈N₂O₁₀S 
• 106881-35-0 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose azidosulfate 
• 97240-79-4 topiramate 

Relevant articles and documents

Crystal form of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate

The invention belongs to the technical field of medicines and in particular relates to a crystal form I of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate. The invention further relates to a preparation method and application of the crystal form in preparing topiramate. The crystal form I of the 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate, whichis provided by the invention, is high in purity, the content of a single impurity 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose is less than 0.15%, the yield of topiramate prepared from thecrystal form I of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate is 92% or greater, the HPLC (high performance liquid chromatography) purity is greater than 99.85%, the content of the single impurity 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose is less than 0.06%, and the content of a single impurity of a condensation compound is smaller than 0.08%.

Crystal form of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphate

The invention belongs to the technical field of pharmaceuticals, and particularly relates to a crystal form A of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphate. The invention further relates to a preparation method of the 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphate and the purpose of the 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphate to preparation of Topiramate. The crystal form A of the prepared 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphate is high in purity, single-impurity 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose is smaller than 0.11%, the yield of the Topiramate prepared from the crystal form A of the 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphateis 92% or above, the HPLC purity is greater than 99.90%, the single-impurity 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose is smaller than 0.03%, and single impurities of a condensation compound are smaller than 0.05%.

Preparation method of high-purity topiramate

The invention discloses a preparation method of high-purity topiramate. The preparation method comprises the following steps: (1) performing reflux reaction on D-fructose and acetone in a dehydratingagent, centrifuging, then performing low-temperature reaction under a 4A molecular sieve-sulfuryl chloride-acid binding agent system, filtering and performing organic layer vacuum distillation; (2) dissolving a reaction product obtained in the step (1) by using a solvent, then introducing ammonia gas, stirring for 4-8 hours at a room temperature, vacuum-pumping for 0.5 h, increasing the temperature of reaction liquid, refluxing for 1 h, then slowly reducing the temperature to below 10 DEG C, crystallizing for 4 h, centrifuging and washing a filter cake with a solvent; (3) pressurizing a reaction product obtained in the step (2), increasing the temperature and dissolving, reducing the temperature to 65 DEG C, adding a small amount of topiramate seed crystals with a respective purity of morethan 99 percent, continuously reducing the temperature to 5 DEG C, crystallizing for 6 h, centrifuging and washing a filter cake with a low-temperature solvent to obtain the high-purity topiramate. The topiramate produced by the preparation method disclosed by the invention has the advantages of being abundant and cheap in raw material, low in cost, high in yield, high in purity, great in industrial value, low in pollution and the like.

Preparation method of high-purity topiramate

The invention discloses a preparation method of high-purity topiramate. Under the condition of dissolving the topiramate into an organic solvent, a proper concentration of alkali is added, so that the topiramate slat forms solid to be separated out in the solvent; the solid is dissolved into water, and is acidified into a weak acidic state; the solid is a topiramate coarse product; the topiramate coarse product is recrystallized to obtain the high-purity topiramate. The preparation method of the high-purity topiramate has the advantages that the purity reaches 99.90 percent or higher; under the condition that the product purity reaches 99.9 percent or higher, the yield of the product keeps unchanged; no additional excessive cost is added. The operation is convenient; the process is safe; the industrial production is easy.

Synthesis technology of topiramate

The invention provides a synthesis technology of topiramate and relates to the technical field of drug synthesis. The synthesis technology of the topiramate comprises the following steps that (1) diacetone fructose and sulfonyl chloride are esterified under the alkalescence environment to obtain chlorosulfonate ester; (2) the chlorosulfonate ester is aminated in a mixed solvent of tetrahydrofuran/dichloromethane, and a crude topiramate product is obtained; (3) refining is conducted: the crude topiramate product is subjected to recrystallization, and refined topiramate is obtained; the method for preparing the topiramate is safe and easy to operate, multistep recrystallization is avoided, the cost is reduced, the production technology is simplified, and the method is suitable for industrial large scale production.

PROCESS FOR THE PREPARATION AND PURIFICATION OF TOPIRAMATE

A process for the preparation of topiramate in an one pot reaction comprises the following steps: A) reacting 2,3:4, 5 -bis -O- { 1-methylethylidene) -β-D-f ructopyranose with sulfurylchloride in xylene in the presence of an organic or inorganic base to form 2,3:4, 5-bis-O- (1-methylethylidene) -β-D-f ructopyranose sulfuryl chloride, B) adding a second organic solvent to the mixture obtained in step A) C) reacting the mixture obtained in step B) with ammonia to form topiramate.

NOVEL DERIVATIVES OF ACYL CYANOPYRROLIDINES

A compound of formula (I) or a tautomeric form, regioisomer, stereoisomer, solvate, N-oxide or pharmaceutically acceptable salts thereof; wherein 'a' - is selected from the group consisting of substituted or unsubstituted heterocycloalkyl ring and substituted or unsubstituted carbohydrate moiety y is a member selected from -O-, -CO-, -S02-, aminoalkyl or formula (II) wherein, Rw is hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl; x is a member selected from -0-, -S-, -SO-, -S02-, CONR10, NR10CO and -NRd-, or x and y together represent a chemical bond; Z is selected from -CH-, -N-. t is an integer selected from O to 4; with the provisos that when 'a' is substituted or unsubstituted heterocycloalkyl ring then 't' is not O and when y = -CO-, x is not NRd.

Process for the preparation of sulfamate derivatives

An improved process for the preparation of sulfamate derivatives such as topiramate is provided comprising (a) reacting an alcohol with sulfuryl chloride in the presence of an amine base and in a first halogenated hydrocarbon solvent selected from the group consisting of aliphatic halogenated hydrocarbon solvents having 1 to 12 carbon atoms and at least three halogen atoms, aliphatic halogenated hydrocarbon solvents having 2 to 12 carbon atoms and less than three halogen atoms, aromatic halogenated hydrocarbon solvents having 6 to 18 carbon atoms and mixtures thereof to produce a chlorosulfate intermediate and (b) reacting the chlorosulfate intermediate with an amine of the formula R1NH2, wherein R1 is hydrogen or an alkyl from 1 to 4 carbon atoms, in a second halogenated hydrocarbon solvent selected from the group consisting of aliphatic halogenated hydrocarbon solvents having 1 to 12 carbon atoms and at least three halogen atoms, aliphatic halogenated hydrocarbon solvents having 2 to 12 carbon atoms and less than three halogen atoms, aromatic halogenated hydrocarbon solvents having 6 to 18 carbon atoms and mixtures thereof.

CONTINUOUS PROCESS FOR THE PREPARATION OF FRUCTOPYRANOSE SULFAMATE DERIVATIVES

The present invention is directed to a continuous process for the preparation of fructopyranose sulfamate derivatives of the general formula (I) wherein R1, R3, R4, R5, R6 and X are as herein defined. The present invention is further directed to a continuous process for the preparation of Topiramate.

PROCESS AND PRODUCT

A process of preparing topiramate of the formula (I) which comprises the following reaction steps and topiramate prepared thereby, compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.