CN101514163B - Optically pure Sibutramine and process for preparing salt derivative thereof - Google Patents
Optically pure Sibutramine and process for preparing salt derivative thereof Download PDFInfo
- Publication number
- CN101514163B CN101514163B CN2009100383648A CN200910038364A CN101514163B CN 101514163 B CN101514163 B CN 101514163B CN 2009100383648 A CN2009100383648 A CN 2009100383648A CN 200910038364 A CN200910038364 A CN 200910038364A CN 101514163 B CN101514163 B CN 101514163B
- Authority
- CN
- China
- Prior art keywords
- sibutramine
- optically pure
- tartrate
- resolving agent
- preparation technology
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
- C07C209/88—Separation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation process of optically pure Sibutramine. In the process, chiral O,O'-diaryl formacyl tartaric acid is taken as a resolving agent to resolve Sibutramine raceme to obtain diastereomer salt thereof; and the diastereomer salt is separated, alkalized and extracted to obtain optically pure levorotatory Sibutramine or optically pure dextrorotatory Sibutramine. The invention further discloses a preparation process of a salt derivative of the optically pure Sibutramine, and the optically pure Sibutramine obtained by the process is combined with an acid compound to form the salt derivative of the optically pure Sibutramine. The preparation process of the optically pure Sibutramine is characterized by high resolving efficiency, simple and practical process, short resolving cycle and the like; and the used resolving agent can be recovered and recycled. Furthermore, the salt derivative of the optically pure Sibutramine prepared by the invention can expand Sibutramine application scope.
Description
Technical field
The present invention relates to the preparation technology of optically pure Sibutramine and salt derivative thereof, belong to the organic synthesis field.
Background technology
Sibutramine, chemistry N-{1-[1-(4-chloro-phenyl-) cyclobutyl by name]-the 3-methyl butyl }-N, there is a chiral carbon atom in N '-dimethylamine in the molecular structure, be the main component of present novel slimming medicine Sibutramine Hydrochloride.Sibutramine hydrochloride is a kind of novel slimming medicine of being researched and developed out by U.S. Knoll drugmaker, has good absorption, the characteristics such as determined curative effect.After the Sibutramine hydrochloride listing, successively have about 1,000 ten thousand people to use this product, sales volume also increases with 50% annual growth, becomes to be popular in American-European best-selling slimming medicine.But this medicine all is to use with the form of raceme clinically at present, and the listing of chirality Sibutramine hydrochloride is not yet arranged.There are some researches show, Sibutramine hydrochloride may cause serious untoward reaction with the raceme form administration.2000, the people such as Stanley [Eur.J.Pharm.acol.397,93 (2000)] carry out the pharmacologically active experiment by two kinds of enantiomorphs to Sibutramine hydrochloride, reported that two kinds of enantiomorphs have different pharmacologically actives, wherein R type ratios of the isomers S type isomer and racemic modification have stronger pharmacologically active at curative effect on obesity.In addition, United States Patent (USP) [US 6,552,087 (2003)] has reported that the chirality sibutramine also has good effect at aspects such as treatment melancholia and Parkinson's diseases.
The people such as Radhakrishna [J.Pharm.Biomed.Anal.22,627 (2000)] utilize chiral chromatography and capillary electrophoresis that sibutramine is carried out chiral separation, can effectively obtain the chirality sibutramine, but chromatogram and kapillary method only are confined to microseparation, can't use in the actual industrial production.Qun K.Fang[Tetrahedron:Asymmetry 10,4477 (1999)] at first reported the use dibenzoyl tartaric acid as resolving agent, utilize Split Method that this compound is carried out chiral separation.Chinese patent [CN 1554333A (2003)] has also been reported similar approach subsequently; use dibenzoyl tartaric acid, the two pairs of methyl benzoyl tartrate and tartrate as resolving agent (wherein preferred dibenzoyl tartaric acid); e.e. value can reach 99.5%, and yield is 28%.The people such as Tan Sishi [meticulous and specialty chemicals, 15,19 (2007)] also utilize D-camphor-10-sulfonic acid as chiral resolving agent, sibutramine is carried out chemistry split, and obtaining optical purity is the chirality sibutramine of 97%e.e., and yield is 23.5%.But the resolving agent cost that the method is used is higher, and it is not high to split efficient.Although Split Method is fit to the suitability for industrialized production optically pure Sibutramine very much, these two kinds of methods of having reported at present do not have good circulation ratio, can't form effective sibutramine resolution process.
Summary of the invention
The object of the present invention is to provide a kind of effective optically pure Sibutramine preparation technology, this technique can become the racemate resolution of sibutramine optically pure left-handed sibutramine and dextrorotation sibutramine, and has good yield.
Another object of the present invention is to provide multiple optically pure Sibutramine salt derivative, in order to expand the scope of application of sibutramine.
The preparation technology of optically pure Sibutramine of the present invention; adopt the O of chirality; O '-two sweet-smelling formacyl tartrate splits the sibutramine racemic modification as resolving agent; obtain its diastereoisomeric salt; this diastereoisomeric salt is separated, after alkalization, extract and obtain optically pure left-handed sibutramine or dextrorotation sibutramine.
The preparation technology of optically pure Sibutramine of the present invention may further comprise the steps:
(1) O of a kind of configuration of employing, O '-two sweet-smelling formacyl tartrate splits the sibutramine racemic modification as resolving agent, and the resolution reaction resultant is filtered;
(2) filter cake is carried out recrystallization, then alkalize, obtain a kind of optically pure Sibutramine of configuration with organic solvent extraction;
(3) mother liquor is alkalized, use organic solvent extraction, recycle the O of another kind of configuration, O '-two sweet-smelling formacyl tartrate carries out the optically pure Sibutramine that recrystallization obtains another kind of configuration.
The preparation technology of optically pure Sibutramine of the present invention also comprises the resolving agent recycling step: behind alkalization, organic solvent extraction, water is carried out acidifying, resolving agent is separated out, filter, reclaim.
In the present invention; described O; O '-two sweet-smelling formacyl tartrate comprises O; the single-substituted formyl radical tartrate of O '-two, O; O '-two disubstituted benzene formyl radical tartrate and O; O '-two Multi substituted benzenes formyl radical tartrate, wherein substituting group is alkyl, alkoxyl group, carbonyl, ester group, halogen, nitro or the sulfo group etc. of C1-C20.
In the present invention, described O, O '-two sweet-smelling formacyl tartrate is O preferably, O '-di-p-methoxy benzoyl tartrate, O, O '-two p-nitrophenyl formyl radical tartrate and O, the adjacent chlorobenzene formacyl tartrate of O '-two.
In the present invention, the O of chirality, the mol ratio of O '-two sweet-smelling formacyl tartrate and sibutramine racemic modification is 1: 4-1: 1.
In the present invention, described fractionation is to carry out in one or more the mixed solvent in ester class (manthanoate, acetic ester, propionic ester, butyric ester etc.), alcohols (methyl alcohol, ethanol, propyl alcohol, Virahol etc.), ketone (acetone, butanone etc.), alkanes (normal hexane etc.), ethers (sherwood oil, ether etc.), chloride class (chloroform, methylene dichloride etc.) and aromatics (benzene,toluene,xylene etc.) solvent.
In the present invention, described alkalization is to carry out in the solution such as sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus, and the pH value of alkalization is 9-14.
In the present invention, described acidifying be in the inorganic acid solutions such as hydrochloric acid, sulfuric acid, nitric acid or the organic acid soln such as acetic acid in carry out, the pH value of acidifying is 1-4.
The preparation technology of optically pure Sibutramine salt derivative of the present invention is that the prepared optically pure Sibutramine of the present invention is combined with acid compounds, forms the optically pure Sibutramine salt derivative.
In the present invention, the described combination with acid compounds is to carry out in water or organic solvent, and described organic solvent is selected from one or more the mixed solvent in ethers, alcohols, ester class and the ketones solvent; Described acid compounds comprises hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, toxilic acid, fumaric acid and tartrate etc.
The preparation technology of optically pure Sibutramine of the present invention and salt derivative thereof has the following advantages:
(1) the present invention uses chirality O, O '-two sweet-smelling formacyl tartrate is as resolving agent, splits sibutramine and directly obtains single enantiomer salt, only needs recrystallization once or twice can obtain the enantiomer salt of high-optical-purity, fractionation efficient is high, the technique simple possible;
(2) formation that is fit to enantiomer salt of the solvent system that uses of the present invention with separate, the formation crystallization velocity is fast, and yield improves nearly twice than method in the past, and optimal yield can reach more than 40%, greatly improved fractionation efficient and shortened the cycle, the cycle that generally splits can finish in 1 day;
(3) in the present invention, to isolate sibutramine opticity enantiomorph and chirality O, the sibutramine enantiomorph solution of gained uses another configuration resolving agent crystallization to reclaim after the O '-two sweet-smelling formacyl tartrate, can obtain another configuration optically pure Sibutramine, remaining solution can be recycled in this technological process;
(4) the chirality O of the present invention's use, O '-two sweet-smelling formacyl tartrate resolving agent, can be by the convenient preparation of natural, cheap chirality tartrate, can conveniently separate simultaneously obtain opticity enantiomorph sibutramine after, the recovery resolving agent reuses, reduce the resolving agent use cost, improve value of the product, increased the competitiveness of product in market;
(5) the present invention utilizes multiple organic and mineral acid, is combined with optically pure Sibutramine in the mixing solutions of water and organic solvent, and the optically pure Sibutramine salt derivative of convenient preparation various features has been expanded the scope of application of this product.
Embodiment
Among the following embodiment, the yield of the product all sibutramine raceme raw material in this embodiment calculates as benchmark.
Embodiment one:
The sibutramine racemies that take by weighing 2.1 grams are put into the 250mL round-bottomed bottle and are dissolved in the 100mL ethyl acetate, add 3.22 gram O, and the adjacent chlorobenzene formacyl of O '-two-L-TARTARIC ACID resolving agent stirs, and reflux stirs half an hour, and crystal dissolves gradually, and solution becomes is transparent.Leave standstill or stir be cooled to room temperature after, filter, filtration cakes torrefaction gets the O of 2.3 gram white powder crystal-dextrorotation sibutramines, the adjacent chlorobenzene formacyl of O '-two-L-TARTARIC ACID salt.Optical purity is 86.25%e.e., and yield is 43.98%.
Embodiment two:
The sibutramine racemies that take by weighing 2.1 grams are put into the 50mL round-bottomed bottle and are dissolved in 20mL 1, and the 2-ethylene dichloride adds 3.22 gram O, and the adjacent chlorobenzene formacyl of O '-two-L-TARTARIC ACID resolving agent stirs, and reflux stirs half an hour, and crystal dissolves gradually, and solution becomes is transparent.Leave standstill or stir be cooled to room temperature after, filter, filtration cakes torrefaction gets the O of 2.0 gram white powder crystal-dextrorotation sibutramines, the adjacent chlorobenzene formacyl of O '-two-L-TARTARIC ACID salt.Optical purity is 80.29%e.e., and yield is 38.28%.
Embodiment three:
The sibutramine racemies that take by weighing 2.1 grams are put into the 500mL round-bottomed bottle and are dissolved in 120mL acetone, add 3.38 gram O, and O '-two p-nitrophenyl formyl radical-L-TARTARIC ACID resolving agent stirs, and crystal dissolves gradually, and solution becomes is transparent.Add the 120mL normal hexane, the mixed post-heating return stirring of solution becomes half an hour, leave standstill be cooled to room temperature after, filter, filtration cakes torrefaction gets the O of 2.25 gram white powder crystal-dextrorotation sibutramines, O '-two p-nitrophenyl formyl radical-L-TARTARIC ACID salt.Optical purity is 90.09%e.e., and yield is 43.02%.
Embodiment four:
The sibutramine racemies that take by weighing 2.1 grams are put into the 250mL round-bottomed bottle and are dissolved in 60mL ethanol, add 3.13 gram O, and O '-di-p-methoxy benzoyl-L-TARTARIC ACID resolving agent stirs, and crystal dissolves gradually, and solution becomes is transparent.Add the 60mL sherwood oil, the mixed post-heating return stirring of solution becomes half an hour, leave standstill be cooled to room temperature after, filter, filtration cakes torrefaction gets the O of 2.5 gram white powder crystal-dextrorotation sibutramines, O '-di-p-methoxy benzoyl-L-TARTARIC ACID salt.Optical purity is 80.88%e.e., and yield is 47.80%.
Embodiment five:
The sibutramine racemies that take by weighing 2.1 grams are put into the 250mL round-bottomed bottle and are dissolved in 60mL ethanol, add 3.13 gram O, and O '-di-p-methoxy benzoyl-L-TARTARIC ACID resolving agent stirs, and crystal dissolves gradually, and solution becomes is transparent.Add the 60mL normal hexane, the mixed post-heating return stirring of solution becomes half an hour, leave standstill be cooled to room temperature after, filter, filtration cakes torrefaction gets the O of 2.25 gram white powder crystal-dextrorotation sibutramines, O '-di-p-methoxy benzoyl-L-TARTARIC ACID salt.Optical purity is 90.36%e.e., and yield is 43.02%.
Embodiment six:
Get the O of the dextrorotation sibutramine of arbitrary 80%e.e.-91%e.e. among the embodiment one to five; O '-two sweet-smelling formacyls-L-TARTARIC ACID salt 2 grams; add 100ml acetone and 150ml sherwood oil and carry out recrystallization, filter and obtain white crystal 1.57 grams, the recrystallization yield is 78.5%.Add sodium hydroxide solution again, transfer to pH=9-14, with 3 * 50ml ethyl acetate extraction, merge organic phase, use anhydrous sodium sulfate drying, be spin-dried for solvent and obtain dextrorotation sibutramine 0.63 gram, optical purity is 99%e.e..Water transfers to pH=1-2 with acid, and resolving agent is separated out, and filters recycling use.The resolving agent rate of recovery is more than 90%.
Embodiment seven:
Get the O of the dextrorotation sibutramine of arbitrary 80%e.e.-91%e.e. among the embodiment one to five, O '-two sweet-smelling formacyls-L-TARTARIC ACID salt 2 grams adds the 25ml Virahol and carries out recrystallization, filters and obtains white crystal 1.82 grams, and the recrystallization yield is 91%.Add sodium hydroxide solution again, transfer to pH=9-14, with 3 * 50ml ethyl acetate extraction, merge organic phase, use anhydrous sodium sulfate drying, be spin-dried for solvent and obtain dextrorotation sibutramine 0.72 gram, optical purity is 99%e.e..Water transfers to pH=1-2 with acid, and resolving agent is separated out, and filters recycling use.The resolving agent rate of recovery is more than 90%.
Embodiment eight:
Get the mother liquor solvent evaporated that filtration stays among the embodiment one to five, add alkali aqueous solution and transfer to pH=9-14, with 3 * 50ml ethyl acetate extraction, merge organic phase, use anhydrous sodium sulfate drying, be spin-dried for solvent recuperation and obtain sibutramine 1.16 grams, yield is 55.2%.Water transfers to pH=1-2 with acid, and resolving agent is separated out, and filters recycling use.The resolving agent rate of recovery is more than 90%.
Embodiment nine:
Get and reclaim 1.16 gram sibutramines and the 1.6 gram O that obtain in the experimental example eight, O '-two sweet-smelling formacyls-D-tartrate mixes, and difference recrystallization twice in the 40mL Virahol filters and obtains white crystal 2.02 grams, and the recrystallization yield is 70%.Add sodium hydroxide solution again, transfer to pH=9-14, with 3 * 50ml ethyl acetate extraction, merge organic phase, use anhydrous sodium sulfate drying, be spin-dried for solvent and obtain left-handed sibutramine 0.8 gram, optical purity is 99%e.e..Water transfers to pH=1-2 with acid, and resolving agent is separated out, and filters recycling use.The resolving agent rate of recovery is more than 90%.
Embodiment ten:
The sibutramine racemies that take by weighing 2.1 grams are put into the 250mL round-bottomed bottle and are dissolved in the 100mL ethyl acetate, add 3.22 gram O, and the adjacent chlorobenzene formacyl of O '-two-D-tartrate resolving agent stirs, and reflux stirs half an hour, and crystal dissolves gradually, and solution becomes is transparent.Leave standstill or stir be cooled to room temperature after, filter, filtration cakes torrefaction gets the O of 2.3 gram white powder crystal-left-handed sibutramines, the adjacent chlorobenzene formacyl of O '-two-D-tartrate.Optical purity is 86.25%e.e., and yield is 43.98%.
Embodiment 11:
The sibutramine racemies that take by weighing 2.1 grams are put into the 50mL round-bottomed bottle and are dissolved in 20mL 1, and the 2-ethylene dichloride adds 3.22 gram O, and the adjacent chlorobenzene formacyl of O '-two-D-tartrate resolving agent stirs, and reflux stirs half an hour, and crystal dissolves gradually, and solution becomes is transparent.Leave standstill or stir be cooled to room temperature after, filter, filtration cakes torrefaction gets the O of 2.0 gram white powder crystal-left-handed sibutramines, the adjacent chlorobenzene formacyl of O '-two-D-tartrate.Optical purity is 80.29%e.e., and yield is 38.28%.
Embodiment 12:
The sibutramine racemies that take by weighing 2.1 grams are put into the 500mL round-bottomed bottle and are dissolved in 120mL acetone, add 3.38 gram O, and O '-two p-nitrophenyl formyl radical-D-tartrate resolving agent stirs, and crystal dissolves gradually, and solution becomes is transparent.Add the 120mL normal hexane, the mixed post-heating return stirring of solution becomes half an hour, leave standstill be cooled to room temperature after, filter, filtration cakes torrefaction gets the O of 2.25 gram white powder crystal-left-handed sibutramines, O '-two p-nitrophenyl formyl radical-D-tartrate.Optical purity is 90.09%e.e., and yield is 43.02%.
Embodiment 13:
The sibutramine racemies that take by weighing 2.1 grams are put into the 250mL round-bottomed bottle and are dissolved in 60mL ethanol, add 3.13 gram O, and O '-di-p-methoxy benzoyl-D-tartrate resolving agent stirs, and crystal dissolves gradually, and solution becomes is transparent.Add the 60mL sherwood oil, the mixed post-heating return stirring of solution becomes half an hour, leave standstill be cooled to room temperature after, filter, filtration cakes torrefaction gets the O of 2.5 gram white powder crystal-left-handed sibutramines, O '-di-p-methoxy benzoyl-D-tartrate.Optical purity is 80.88%e.e., and yield is 47.80%.
Embodiment 14:
The sibutramine racemies that take by weighing 2.1 grams are put into the 250mL round-bottomed bottle and are dissolved in 60mL ethanol, add 3.13 gram O, and O '-di-p-methoxy benzoyl-D-tartrate resolving agent stirs, and crystal dissolves gradually, and solution becomes is transparent.Add the 60mL normal hexane, the mixed post-heating return stirring of solution becomes half an hour, leave standstill be cooled to room temperature after, filter, filtration cakes torrefaction gets the O of 2.25 gram white powder crystal-left-handed sibutramines, O '-di-p-methoxy benzoyl-D-tartrate.Optical purity is 90.36%e.e., and yield is 43.02%.
Embodiment 15:
Get the O of the left-handed sibutramine of arbitrary 80%e.e.-91%e.e. among the embodiment ten to 14; O '-two sweet-smelling formacyls-D-tartrate 2 grams; add 100ml acetone and 150ml sherwood oil and carry out recrystallization, filter and obtain white crystal 1.57 grams, the recrystallization yield is 78.5%.Add sodium hydroxide solution again, transfer to pH=9-14, with 3 * 50ml ethyl acetate extraction, merge organic phase, use anhydrous sodium sulfate drying, be spin-dried for solvent and obtain left-handed sibutramine 0.63 gram, optical purity is 99%e.e..Water transfers to pH=1-2 with acid, and resolving agent is separated out, and filters recycling use.The resolving agent rate of recovery is more than 90%.
Embodiment 16:
Get the O of the left-handed sibutramine of arbitrary 80%e.e.-91%e.e. among the embodiment ten to 14, O '-two sweet-smelling formacyls-D-tartrate 2 grams adds the 25ml Virahol and carries out recrystallization, filters and obtains white crystal 1.82 grams, and the recrystallization yield is 91%.Add sodium hydroxide solution again, transfer to pH=9-14, with 3 * 50ml ethyl acetate extraction, merge organic phase, use anhydrous sodium sulfate drying, be spin-dried for solvent and obtain left-handed sibutramine 0.72 gram, optical purity is 99%e.e..Water transfers to pH=1-2 with acid, and resolving agent is separated out, and filters recycling use.The resolving agent rate of recovery is more than 90%.
Embodiment 17:
Get the mother liquor solvent evaporated that filtration stays among the embodiment ten to 14, add alkali aqueous solution and transfer to pH=9-14, with 3 * 50ml ethyl acetate extraction, merge organic phase, anhydrous sodium sulfate drying is spin-dried for solvent recuperation and obtains sibutramine 1.16 grams, and yield is 55.2%.Water transfers to pH=1-2 with acid, and resolving agent is separated out, and filters recycling use.The resolving agent rate of recovery is more than 90%.
Embodiment 18:
Get and reclaim 1.16 gram sibutramines and the 1.6 gram O that obtain in the experimental example 17, O '-two sweet-smelling formacyls-L-TARTARIC ACID mixes, and difference recrystallization twice in the 40mL Virahol filters and obtains white crystal 2.02 grams, and the recrystallization yield is 70%.Add sodium hydroxide solution again, transfer to pH=9-14, with 3 * 50ml ethyl acetate extraction, merge organic phase, use anhydrous sodium sulfate drying, be spin-dried for solvent and obtain dextrorotation sibutramine 0.8 gram, optical purity is 99%e.e..Water transfers to pH=1-2 with acid, and resolving agent is separated out, and filters recycling use.The resolving agent rate of recovery is more than 90%.
Embodiment 19:
Get optical purity dextrorotation sibutramine 0.558 gram among the embodiment six, seven and 18, add the hydrochloric acid diethyl ether solution of 5ml 1N, stir half an hour under the room temperature after, be spin-dried for solvent, drying under reduced pressure obtains optical purity dextrorotation sibutramine hydrochloride solid 0.63 gram.Salify yield 100%.
Embodiment 20:
Get optical purity dextrorotation sibutramine 0.558 gram among the embodiment six, seven and 18, be dissolved in the ethyl acetate, agitation and dropping 0.2mL acetic acid, stir half an hour under the room temperature after, be spin-dried for solvent, drying under reduced pressure obtains optical purity dextrorotation sibutramine acetate solid 0.67 gram.Salify yield 100%.
Embodiment 21:
Get left-handed sibutramine 0.558 gram of optical purity among the embodiment nine, 15 and 16, add the hydrochloric acid diethyl ether solution of 5ml 1N, stir half an hour under the room temperature after, be spin-dried for solvent, drying under reduced pressure obtains the left-handed sibutramine hydrochloride of optical purity solid 0.63 gram.Salify yield 100%.
Embodiment 22:
Get left-handed sibutramine 0.558 gram of optical purity among the embodiment nine, 15 and 16, be dissolved in the ethyl acetate, agitation and dropping 0.2mL acetic acid, stir half an hour under the room temperature after, be spin-dried for solvent, drying under reduced pressure obtains the left-handed sibutramine acetate of optical purity solid 0.67 gram.Salify yield 100%.
Claims (1)
1. the preparation technology of an optically pure Sibutramine, it is characterized in that: the O that adopts chirality, O '-two sweet-smelling formacyl tartrate splits the sibutramine racemic modification as resolving agent, obtain its diastereoisomeric salt, this diastereoisomeric salt is separated, after alkalization, extract and obtain optically pure left-handed sibutramine or dextrorotation sibutramine;
Described preparation technology may further comprise the steps:
⑴ adopt a kind of O of configuration, and O '-two sweet-smelling formacyl tartrate splits the sibutramine racemic modification as resolving agent, and the resolution reaction resultant is filtered;
⑵ carry out recrystallization to filter cake, then alkalizes, and obtains a kind of optically pure Sibutramine of configuration with organic solvent extraction;
⑶ alkalize to mother liquor, uses organic solvent extraction, recycles the O of another kind of configuration, and O '-two sweet-smelling formacyl tartrate carries out the optically pure Sibutramine that recrystallization obtains another kind of configuration;
Wherein, described O, O '-two sweet-smelling formacyl tartrate comprises O, O '-di-p-methoxy benzoyl tartrate, O, O '-two p-nitrophenyl formyl radical tartrate and O, the adjacent chlorobenzene formacyl tartrate of O '-two.
2. preparation technology according to claim 1 is characterized in that, also comprises the resolving agent recycling step: behind alkalization, organic solvent extraction, water is carried out acidifying, resolving agent is separated out, filter, reclaim.
3. preparation technology according to claim 1 and 2, it is characterized in that: described O, the mol ratio of O '-two sweet-smelling formacyl tartrate and described sibutramine racemic modification is 1:4-1:1.
4. preparation technology according to claim 1 and 2 is characterized in that: described fractionation is to carry out in one or more the mixed solvent in ester class, alcohols, ketone, alkanes, ethers, chloride class and aromatic solvents.
5. preparation technology according to claim 1 and 2, it is characterized in that: described alkalization is to carry out in sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate or potassium bicarbonate solution, the pH value of alkalization is 9-14.
6. preparation technology according to claim 2, it is characterized in that: described acidifying is to carry out in inorganic acid solution or in the organic acid soln, the pH value of acidifying is 1-4.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100383648A CN101514163B (en) | 2009-04-02 | 2009-04-02 | Optically pure Sibutramine and process for preparing salt derivative thereof |
| PCT/CN2009/071508 WO2010111844A1 (en) | 2009-04-02 | 2009-04-28 | The method of preparing optically pure sibutramine and its derivative salts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100383648A CN101514163B (en) | 2009-04-02 | 2009-04-02 | Optically pure Sibutramine and process for preparing salt derivative thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101514163A CN101514163A (en) | 2009-08-26 |
| CN101514163B true CN101514163B (en) | 2013-04-24 |
Family
ID=41038798
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100383648A Expired - Fee Related CN101514163B (en) | 2009-04-02 | 2009-04-02 | Optically pure Sibutramine and process for preparing salt derivative thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101514163B (en) |
| WO (1) | WO2010111844A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497145B (en) * | 2013-10-10 | 2016-01-27 | 南昌大学 | A kind of preparation technology of optical purity E2020 |
| CN104151171B (en) * | 2014-08-14 | 2016-07-27 | 六安佳诺生化科技有限公司 | The method of optical voidness R-1-naphthalene ethylamine is prepared in a kind of fractionation |
| CN108976164A (en) * | 2018-06-20 | 2018-12-11 | 南通常佑药业科技有限公司 | The preparation method of chiral piperidine amine compounds and the recovery method of chiral resolving agent |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1554333A (en) * | 2003-12-26 | 2004-12-15 | 复旦大学 | Use of dextro sibutramine and its corresponding salt in preparing fat-reducing medicine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19518988A1 (en) * | 1995-05-29 | 1996-12-05 | Basf Ag | Use of aryl substituted cyclobutylalkylamines to treat obesity |
| US6552087B1 (en) * | 1999-03-19 | 2003-04-22 | Abbott Gmbh & Co. Kg | Therapeutic agent comprising (+)-sibutramine |
-
2009
- 2009-04-02 CN CN2009100383648A patent/CN101514163B/en not_active Expired - Fee Related
- 2009-04-28 WO PCT/CN2009/071508 patent/WO2010111844A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1554333A (en) * | 2003-12-26 | 2004-12-15 | 复旦大学 | Use of dextro sibutramine and its corresponding salt in preparing fat-reducing medicine |
Non-Patent Citations (4)
| Title |
|---|
| .1999,第10卷4477-4480. * |
| Qun K. Fang等.First preparation of enantiomerically pure sibutramine and its major metabolite, and determination of their absolute configuration by single crystal X-ray analysis.< * |
| QunK.Fang等.Firstpreparationofenantiomericallypuresibutramineanditsmajormetabolite and determination of their absolute configuration by single crystal X-ray analysis.<Tetrahedron: Asymmetry>.1999 |
| Tetrahedron: Asymmetry> * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101514163A (en) | 2009-08-26 |
| WO2010111844A1 (en) | 2010-10-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102249998B (en) | Method for preparing cisatracurium besylate | |
| CZ2004131A3 (en) | Process for preparing racemic citalopram | |
| CN101514163B (en) | Optically pure Sibutramine and process for preparing salt derivative thereof | |
| CN102453011A (en) | Preparation method of high-purity naringenin | |
| CN103193779A (en) | Eszopiclone preparation method | |
| JP2009541291A (en) | Crystalline duloxetine hydrochloride | |
| CN102850347A (en) | Resolution method for pyrazole derivative or salt thereof | |
| CN103288801A (en) | Preparation method for high-purity esomeprazole sodium | |
| CN102010327B (en) | Splitting method of (+/-)-2-(3-benzoyl)-phenylpropionic acid | |
| CN100478327C (en) | L-dopa methyl ester hydrochloride preparation method | |
| CN103467350B (en) | (S) preparation method of-AzeOH | |
| CN109988083B (en) | Preparation method of high-optical-purity escitalopram oxalate intermediate S-configuration diol | |
| CN103804234A (en) | Synthetic method of alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile | |
| CN104876812B (en) | Process for preparing sertraline hydrochloride intermediates and impurities | |
| CN103497145B (en) | A kind of preparation technology of optical purity E2020 | |
| CN102977077A (en) | Method for preparing dabigatran etexilate intermediate | |
| CN103044361B (en) | Preparation method of (2R,3S)-epoxidation amino-benzene butane | |
| CN106349144A (en) | Preparation method of (S)-oxiracetam intermediate | |
| CN102757367A (en) | Splitting process of racemic ethyl benzene sulfonic acid | |
| CN108404979B (en) | Thiourea-proline chiral catalyst and synthesis method and application thereof | |
| KR101001646B1 (en) | Method of preparing r-+-lansoprazole and intermediate used therein | |
| CN105130972A (en) | Emtricitabine benzoate, preparation method thereof, and method of preparing emtricitabine from emtricitabine benzoate | |
| CN101037411B (en) | Splitting method of tetrahydroisoquinoline racemes | |
| CN105085243A (en) | Preparing method of (S)-(-)-4-bromine mandelic acid | |
| CN107628983B (en) | Apremilast of high chiral purity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: GUANGZHOU JINKUI TRADE CO., LTD. Free format text: FORMER OWNER: GUANGZHOU HUIHONG BIOPHARMACEUTICAL TECHNOLOGY CO., LTD. Effective date: 20120604 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20120604 Address after: 510630, Room 201, building C, Huajing Software Park, 69 West Zhongshan Road, Tianhe District, Guangdong, Guangzhou, China Applicant after: GUANGZHOU HUIHONG BIO-MEDICAL TECHNOLOGY CO.,LTD. Address before: 510630, Room 201, building C, 89 West Zhongshan Road, Tianhe District, Guangdong, Guangzhou Applicant before: Guangzhou Huihong Biopharmaceutical Technology Co., Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130424 Termination date: 20150402 |
|
| EXPY | Termination of patent right or utility model |