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Symed labs heterosexual meaning

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The present invention relates to a novel, commercially viable and industrially advantageous process for the preparation of rivaroxaban, in high yield and purity, using novel intermediates. These compounds are anticoagulants which inhibit the blood coagulation factor Xa with increased selectivity. Symed labs heterosexual meaning is represented by the following structural formula I:. Various processes for Symed labs heterosexual meaning preparation of rivaroxaban, its intermediates, and related compounds are disclosed in U.

After addition of dichloromethane and phase separation, the aqueous phase Symed labs heterosexual meaning extracted with dichloromethane.

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The combined organic phases were dried, filtered, and evaporated in vacuo. As per the process exemplified in the ' patent, the preparation of rivaroxaban is carried out in three steps.

In third step, the solvent-containing crude product is purified by recrystallization from acetic Symed labs heterosexual meaning. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible. The main drawback of the processes for the preparation of rivaroxaban described in the aforementioned prior art is that the processes involve the use of highly corrosive Symed labs heterosexual meaning unstable acid Symed labs heterosexual meaning intermediate, 5-chlorothiophenecarbonyl chloride.

Use of this unstable acid chloride intermediate is not advisable for scale up operations due to handling difficulties. Moreover, the process Symed labs heterosexual meaning the preparation of the acid chloride intermediate requires the use of highly hazardous and toxic reagents like thionyl chloride, phosgene and oxalyl chloride, which are highly corrosive and dangerous to environment.

Handling of Symed labs heterosexual meaning reagents is very difficult on commercial scale operations. The process for the preparation of rivaroxaban Symed labs heterosexual meaning in the ' patent involves the use of excess amounts of pyridine, which is highly toxic chemical and dangerous to human health. Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of rivaroxaban at lab scale and in commercial scale operations.

A need remains for an improved, commercially viable and environmentally friendly process of preparing rivaroxaban with high yield and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

Desirable process properties include non-hazardous conditions, environmentally friendly and easy to handle reagents, reduced process steps, reduced reaction time periods, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of rivaroxaban in high purity and with high yield. The present Symed labs heterosexual meaning have surprisingly found that rivaroxaban of formula I can be prepared in a one-pot process, in high purity and with high yield, by reacting Symed labs heterosexual meaning acid or a salt thereof with a sulfonylating agent to produce a sulfonyl ester intermediate, which is then condensed with 4-[4-[ 5S aminomethyl oxo-1,3-oxazolidinyl]phenyl]morpholineone or an acid addition salt thereof to Symed labs heterosexual meaning rivaroxaban.

In one aspect, provided herein is an efficient, industrially advantageous and environmentally friendly process for the preparation of rivaroxaban, Symed labs heterosexual meaning high yield and with high chemical and enantiomeric purity, using novel intermediates.

The process disclosed herein avoids the tedious and cumbersome procedures of the prior processes, thereby resolving the problems associated with Symed labs heterosexual meaning processes described in the prior art, which is more convenient to operate at lab scale and in commercial scale operations. Symed labs heterosexual meaning another aspect, provided herein are novel sulfonyl ester compounds of formula III:.

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In another aspect, the present invention also Symed labs heterosexual meaning the use of novel sulfonyl ester intermediates of formula III disclosed herein for preparing rivaroxaban or a stereochemically isomeric form or a racemic mixture thereof. The process for the preparation of rivaroxaban disclosed herein has the following advantages over the processes described in the prior art:.

According to one aspect, there is provided a one-pot process for preparing rivaroxaban, 5-chloro-N-[[ 5S oxo[4- 3-oxomorpholinyl phenyl]oxazolidinyl]methyl]thiophenecarboxamide, of Symed labs heterosexual meaning I:. The structural formula of rivaroxaban Symed labs heterosexual meaning one chiral Symed labs heterosexual meaning and thus exists as two optical isomers, i. The process disclosed herein encompasses the preparation of both enantiomers and mixtures thereof in all proportions.

Preferred alkyl groups have 1 to 6 carbon atoms Symed labs heterosexual meaning the chain. Exemplary alkyl groups Symed labs heterosexual meaning methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, and n-pentyl.

Exemplary monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and the like. Preferred aralkyls Symed labs heterosexual meaning a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthalenemethyl. Exemplary aryl groups include phenyl, tolyl or naphthyl. The sulfonyl ester compounds of formula III are novel and form another aspect of the present invention.

The use of the sulfonyl ester compounds of formula III in the process for manufacture of rivaroxaban, or a stereochemically isomeric form or a racemic mixture thereof, is novel and forms further aspect of the present invention. In one embodiment, Symed labs heterosexual Symed labs heterosexual meaning one-pot process disclosed herein is Symed labs heterosexual meaning out in the presence of a solvent or a mixture Symed labs heterosexual meaning solvents.

Exemplary solvents used in the one-pot process include, but are not limited to, a chlorinated hydrocarbon, an ester, a cyclic ether, an aliphatic ether, a hydrocarbon, a polar aprotic solvent, a nitrile, an alcohol, and mixtures thereof; and most specifically a chlorinated hydrocarbon solvent. Specifically, the solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, acetonitrile, propionitrile, 4-methylmorpholine, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, methanol, ethanol, isopropanol, n-butanol, and Symed labs heterosexual meaning thereof.

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A most Symed labs heterosexual meaning solvent is dichloromethane. In one Symed labs heterosexual meaning, the one-pot process disclosed herein is carried Symed labs heterosexual meaning in the presence of a base. Symed labs heterosexual meaning, the base is an organic or inorganic Symed labs heterosexual meaning, and most specifically an organic base.

Exemplary organic bases include, but are not limited to, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 4- N,N-dimethylamino pyridine and 1-alkylimidazole. Specific organic bases are 1-alkylimidazole and 4- N,N-dimethylamino pyridine, and more specifically 1-methylimidazole. Exemplary inorganic bases include, but are not limited to, hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals.

Specific inorganic bases are sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide. In one embodiment, the base is used, in the process disclosed herein, in a ratio of about 1 to 4 equivalents, Symed labs heterosexual meaning about 1.

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Symed labs heterosexual meaning another embodiment, the 5-chlorothiophenecarboxylic acid of formula IV is used in the form a salt. The salt of the compound of formula IV is derived from an organic or inorganic base selected from the group as described above.

Specifically, the salt of the compound of formula IV is derived from an organic base. Exemplary acid addition salts of the Symed labs heterosexual meaning compound of formula II include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, Symed labs heterosexual meaning, toluenesulfonate, citrate, and tartrate.

The reaction time may vary from about 30 minutes to Symed labs heterosexual meaning 15 hours, specifically from about 1 hour to Symed labs heterosexual meaning 10 hours, and more specifically from about 2 hours to about 5 hours.

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The reaction mass containing the rivaroxaban of formula I obtained may be subjected to usual work up such as a washing, an extraction, an evaporation, a pH adjustment etc.

More specifically, the solvent is a mixture of water and dichloromethane. The solid obtained is collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel Symed labs heterosexual meaning celite, or a combination thereof. The highly pure rivaroxaban, or a stereochemically isomeric form or a racemic mixture thereof, obtained by the above process may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents.

The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours.

Drying may Symed labs heterosexual meaning be carried out for shorter or longer periods of time depending Symed labs heterosexual meaning the product specifications.

Temperatures and pressures will be chosen based Symed labs heterosexual meaning the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the Symed labs heterosexual meaning. According to Symed labs heterosexual meaning aspect, there is provided a process for preparing rivaroxaban Symed labs heterosexual meaning formula I:.

According to another aspect, there is provided a process Symed labs heterosexual meaning preparing a sulfonyl ester compound of formula III:. According to another aspect, there is provided a novel sulfonyl ester compound of formula III:. The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

A solution of methanesulfonyl chloride 12 g, 0. A mixture of p-toluenesulfonyl chloride A solution of methanesulfonic anhydride All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing Symed labs heterosexual meaning the scope of the invention.

In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention Symed labs heterosexual meaning departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

The present inventors have surprisingly found that rivaroxaban of formula I can be prepared in a one-pot process, in high purity and with high yield, by reacting 5-chlorothiophenecarboxylic acid or a salt thereof with a sulfonylating agent to produce a sulfonyl ester intermediate, which is then condensed with 4-[4-[ SS aminomethyl oxo-1,3-oxazolidinyl]phenyl]morpholineone or an acid addition salt thereof to produce rivaroxaban.

Rivaroxaban is represented by the following structural Symed labs heterosexual meaning I: A one-pot process for preparing rivaroxaban, 5-chloro-N-[[ 5S oxo[4- 3-oxomorpholinyl phenyl]oxazolidinyl]methyl]thiophenecarboxamide, of formula I:. The process of claim 1wherein the one-pot process is carried out in the presence of a solvent or a mixture of solvents.

The process of claim 4wherein the Symed labs heterosexual meaning is selected from the group consisting of a chlorinated hydrocarbon, an ester, a cyclic ether, an aliphatic ether, a hydrocarbon, a polar aprotic solvent, a nitrile, an alcohol, and mixtures thereof. The process of claim 5wherein the solvent is selected from Symed labs heterosexual meaning group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, Symed labs heterosexual meaning acetate, tert-butyl methyl acetate, ethyl formate, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, n-pentane, Symed labs heterosexual meaning, n-heptane, cyclohexane, toluene, xylene, acetonitrile, propionitrile, 4-methylmorpholine, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, methanol, ethanol, isopropanol, n-butanol, and mixtures thereof.

The process of claim 6wherein the solvent is dichloromethane. The process of claim 1wherein the one-pot process is carried out in the presence of a base, wherein Symed labs heterosexual meaning base is an organic or inorganic base; and wherein the salt of the compound of formula IV is derived from an organic or inorganic base. The process of claim 8wherein the base is an organic base; and wherein the salt of the compound of formula IV is derived from an organic base.

The process of claim 8wherein the organic base is selected from the group consisting of trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, Symed labs heterosexual meaning N,N-dimethylamino pyridine and 1-alkylimidazole; and wherein the inorganic base is selected from the group consisting of sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.

The process of claim 10wherein the organic base Symed labs heterosexual meaning 1-alkylimidazole or 4- N,N-dimethylamino Symed labs heterosexual meaning. The process of claim 11wherein the organic base is 1-methylimidazole. A process for preparing rivaroxaban of formula I:. A process Symed labs heterosexual meaning preparing a sulfonyl ester compound of Symed labs heterosexual meaning III: A sulfonyl ester compound of formula III:.

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An improved Symed labs heterosexual meaning for the preparation of rivaroxaban involving novel intermediate.

Production of chirally Symed labs heterosexual meaning amino alcohol intermediates, derivatives thereof, and uses thereof. Novel amine salts of tenofovir, process Symed labs heterosexual meaning producing the same and use thereof in production of tenofovir dioproxil. Improved process for the preparation of ambrisentan and novel intermediates thereof.

Benzenesulfonamide derivatives, process for their preparation and pharmaceutical compositions containing them. Process for the preparation of a rivaroxaban and intermediates formed in said process. Symed labs heterosexual meaning for preparing oxazolidine protected aminodiol compounds useful as intermediates to florfenicol.

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