CA2620902A1 - Novel method of extraction of 6-o-protected trichlorogalactose from the chlorinated mass - Google Patents
Novel method of extraction of 6-o-protected trichlorogalactose from the chlorinated mass Download PDFInfo
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- CA2620902A1 CA2620902A1 CA002620902A CA2620902A CA2620902A1 CA 2620902 A1 CA2620902 A1 CA 2620902A1 CA 002620902 A CA002620902 A CA 002620902A CA 2620902 A CA2620902 A CA 2620902A CA 2620902 A1 CA2620902 A1 CA 2620902A1
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- tgs
- dmf
- organic solvent
- ester
- acetate
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- 238000000605 extraction Methods 0.000 title claims abstract description 9
- WSELJKAMVUHMJP-PUZYILPLSA-N (2s,3r,4s,5r)-2,3-dichloro-2,3,4,5,6-pentahydroxyhexanoyl chloride Chemical compound OC[C@@H](O)[C@H](O)[C@@](O)(Cl)[C@](O)(Cl)C(Cl)=O WSELJKAMVUHMJP-PUZYILPLSA-N 0.000 title 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 96
- 238000000034 method Methods 0.000 claims abstract description 32
- 235000019408 sucralose Nutrition 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 239000000284 extract Substances 0.000 claims abstract description 12
- FACOTAQCKSDLDE-YKEUTPDRSA-N [(2R,3R,4R,5R,6R)-6-[(2R,3S,4S,5S)-2,5-bis(chloromethyl)-3,4-dihydroxyoxolan-2-yl]oxy-3-chloro-4,5-dihydroxyoxan-2-yl]methyl acetate Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](COC(=O)C)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 FACOTAQCKSDLDE-YKEUTPDRSA-N 0.000 claims abstract description 7
- 238000002955 isolation Methods 0.000 claims abstract description 6
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 6
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 4
- 239000012266 salt solution Substances 0.000 claims abstract description 3
- 230000002378 acidificating effect Effects 0.000 claims abstract 2
- 230000020176 deacylation Effects 0.000 claims abstract 2
- 238000005947 deacylation reaction Methods 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000000243 solution Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 238000005660 chlorination reaction Methods 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 150000003511 tertiary amides Chemical class 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002002 slurry Substances 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- 125000000217 alkyl group Chemical group 0.000 claims 3
- 238000010438 heat treatment Methods 0.000 claims 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 238000002360 preparation method Methods 0.000 claims 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- 102000004190 Enzymes Human genes 0.000 claims 1
- 108090000790 Enzymes Proteins 0.000 claims 1
- AFHCRQREQZIDSI-OVUASUNJSA-N [(2r,3s,4s,5r,6r)-6-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl benzoate Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](COC(=O)C=2C=CC=CC=2)O1 AFHCRQREQZIDSI-OVUASUNJSA-N 0.000 claims 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 229910017053 inorganic salt Inorganic materials 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- AFHCRQREQZIDSI-UHFFFAOYSA-N sucrose-6-benzoate Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC(=O)C=2C=CC=CC=2)O1 AFHCRQREQZIDSI-UHFFFAOYSA-N 0.000 claims 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 abstract description 6
- 239000004376 Sucralose Substances 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000000638 solvent extraction Methods 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000006196 deacetylation Effects 0.000 description 3
- 238000003381 deacetylation reaction Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 238000000622 liquid--liquid extraction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000003445 sucroses Chemical class 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 241000244489 Navia Species 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000005257 alkyl acyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- -1 sucrose Chemical class 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Extraction Or Liquid Replacement (AREA)
Abstract
A process is described for extraction of 6- acyl - 4,1~, 6~
trichlorogalactosucrose abbreviated as TGS-6-ester from a process stream containing one or more of TGS-6-ester and impurities including DMF, requiring DMF removal, comprising neutralization of the process stream, adjustment of pH
thereafter to acidic side, preferably between 5 to 7, followed by extraction with a partially miscible or immiscible organic solvent, optional concentration of the organic solvent extract, extraction of the organic solvent extracts with saturated aqueous salt solution to remove dimethylformamide (DMF) and isolation of TGS-6-acetate in a pure fraction which can be subjected to deacylation at alkaline pH to form TGS.
trichlorogalactosucrose abbreviated as TGS-6-ester from a process stream containing one or more of TGS-6-ester and impurities including DMF, requiring DMF removal, comprising neutralization of the process stream, adjustment of pH
thereafter to acidic side, preferably between 5 to 7, followed by extraction with a partially miscible or immiscible organic solvent, optional concentration of the organic solvent extract, extraction of the organic solvent extracts with saturated aqueous salt solution to remove dimethylformamide (DMF) and isolation of TGS-6-acetate in a pure fraction which can be subjected to deacylation at alkaline pH to form TGS.
Description
TITLE
TRICHLOROGALAC-TOSE FROM THE CHLORINATED MASS
TECHNICAL FIELD
The present invention relates to a novel process and a novel strategy for purification of the sucrose-6-ester free from amide such as dimethylformamide (DMF) by direct extraction from the reaction mixture in process for production of chlorinated compounds including sucrose, 1'-6'-Dich(oro-1'-6'-D I D EOXY-(i-Fructofuranasyl-4-ch Ioro-4-deoxy-galactopyranoside.
BACKGROUND OF THE INVENTION
Prior art literature describes the synthetic scheme to produce the 1'-6'-Dichloro-1'-6'-DI DEOXY-P-Fructofuranasyl-4-chloro-4-deoxy-galactopyranoside i.e. 4,1', 6' trichlorogalactosucrose (abbreviated as TGS), starting from sucrose. In one of the embodiments one could protect the 6t" position of the sucrose molecule before submitting it to the chlorination reaction. Chlorination of the sucrose-6-acetate, or any other equivalent sucrose-6-ester, could be carried out using any of the conventional Vilsmeier reagents prepared from phosphorus oxychloride, phosphorus pentachloride, phosgene or [Bis(trichioromethyl) carbonate]
and solvents like DMF or dimethylacetamide. The difficulty in these reactions is the isolation of the product in the protected or deprotected form free from the solvent such as DMF used during the reaction. Various methods are reported in the patent literature wherein the reaction mixture is first quenched in an aqueous alkali solution, which could be either I
subjected to steam stripping to remove only the DMF (Navia et al US
patent nos. 5530106 and 5498709) or by removing all the water and the solvent in a suitable drier [Ratnam et al (2005)a (WO/2005/090374 i.e.
PCT/IN2004/000142 and Ratnam et al (2005)b (WO/2005/090376) i.e.
PCT/IN20041000064). Both the methods have one drawback that during the de-protection process where the pH of the quenched mass goes up to 9 to 11, there is considerable loss in the DMF. Also if the DMF is not totally removed from the reaction mass it is carried over till the crystallization stage and hinders the crystallization process.
The present invention relates to a novel process and a novel strategy for isolation of the 6-protected trichlorogalactosucrose derivatives from the reaction mixtures obtained from the chlorination of the 6-acyl sucrose. The acyl group could be an aromatic acyl group like benzoyl, substituted aromatic acyl group such as paramethoxy benzoyl group or alkyl acyl group namely acetyl group. The 6-protected-trichlorogalactosucrose derivative could be deprotected by conventional alkaline hydrolysis to produce the desired trichlorogalactosucrose.
SUMMARY OF THE INVENTION
One embodiment of this invention relates to protecting DMF as well as TGS-6-ester from destruction by adjusting the pH of the neutralized chlorinated reaction mixture to pH 5 to 7, then extracting the same by immiscible or partially immiscible organic solvents, washing the organic solvent extract with saturated aqueous salt solution to achieve removal of DMF and recovery of the extracted organic ingredients from the organic solvent extract by applying appropriate method of purification including but not limited to solvent extraction, column chromatography and the like.
The TGS-6-ester isolated either in crude or pure form is de-esterified at alkaline pH and TGS formed is isolated by applying one or more of a purification process.
DETAILED DESCRIPTION OF THE INVENTION
In the present embodiment a process has been developed wherein after the chlorination reaction the pH of reaction mass is adjusted to about 5 to 7 by hydroxides or carbonates of alkali, alkaline earth metals or even with alkoxides of alkali or alkaline earth metals. The neutralized mass is analyzed by TLC and it was seen that there was practically no deacetylation observed from 6-acetyl TGS (TGS-6-acetate) to TGS. The mass is then extracted with water immiscible or sparingly miscible solvents such as ethyl acetate, methyl ethyl ketone, dichloromethane, etc.
All the 6-acyl trichlorogalactosucrose (TGS-6-ester) along with other chlorinated sucrose derivatives comes into the organic solvent layer.
The organic extract is concentrated to 50 % of its initial volume and is washed with saturated sodium chloride aqueous solution in order to remove DMF extracted in the organic layer. The ratio of saturated sodium chloride solution to organic extract is maintained between 1:5 to 1:7 The washing was repeated for 5 to 10 cycles It has been seen that the DMF, which is more water soluble, is retained back into the aqueous layer. Thus this methodology also gives an innovative process to remove the DMF
from the reaction mixture, which is rather difficult to get rid off.
TRICHLOROGALAC-TOSE FROM THE CHLORINATED MASS
TECHNICAL FIELD
The present invention relates to a novel process and a novel strategy for purification of the sucrose-6-ester free from amide such as dimethylformamide (DMF) by direct extraction from the reaction mixture in process for production of chlorinated compounds including sucrose, 1'-6'-Dich(oro-1'-6'-D I D EOXY-(i-Fructofuranasyl-4-ch Ioro-4-deoxy-galactopyranoside.
BACKGROUND OF THE INVENTION
Prior art literature describes the synthetic scheme to produce the 1'-6'-Dichloro-1'-6'-DI DEOXY-P-Fructofuranasyl-4-chloro-4-deoxy-galactopyranoside i.e. 4,1', 6' trichlorogalactosucrose (abbreviated as TGS), starting from sucrose. In one of the embodiments one could protect the 6t" position of the sucrose molecule before submitting it to the chlorination reaction. Chlorination of the sucrose-6-acetate, or any other equivalent sucrose-6-ester, could be carried out using any of the conventional Vilsmeier reagents prepared from phosphorus oxychloride, phosphorus pentachloride, phosgene or [Bis(trichioromethyl) carbonate]
and solvents like DMF or dimethylacetamide. The difficulty in these reactions is the isolation of the product in the protected or deprotected form free from the solvent such as DMF used during the reaction. Various methods are reported in the patent literature wherein the reaction mixture is first quenched in an aqueous alkali solution, which could be either I
subjected to steam stripping to remove only the DMF (Navia et al US
patent nos. 5530106 and 5498709) or by removing all the water and the solvent in a suitable drier [Ratnam et al (2005)a (WO/2005/090374 i.e.
PCT/IN2004/000142 and Ratnam et al (2005)b (WO/2005/090376) i.e.
PCT/IN20041000064). Both the methods have one drawback that during the de-protection process where the pH of the quenched mass goes up to 9 to 11, there is considerable loss in the DMF. Also if the DMF is not totally removed from the reaction mass it is carried over till the crystallization stage and hinders the crystallization process.
The present invention relates to a novel process and a novel strategy for isolation of the 6-protected trichlorogalactosucrose derivatives from the reaction mixtures obtained from the chlorination of the 6-acyl sucrose. The acyl group could be an aromatic acyl group like benzoyl, substituted aromatic acyl group such as paramethoxy benzoyl group or alkyl acyl group namely acetyl group. The 6-protected-trichlorogalactosucrose derivative could be deprotected by conventional alkaline hydrolysis to produce the desired trichlorogalactosucrose.
SUMMARY OF THE INVENTION
One embodiment of this invention relates to protecting DMF as well as TGS-6-ester from destruction by adjusting the pH of the neutralized chlorinated reaction mixture to pH 5 to 7, then extracting the same by immiscible or partially immiscible organic solvents, washing the organic solvent extract with saturated aqueous salt solution to achieve removal of DMF and recovery of the extracted organic ingredients from the organic solvent extract by applying appropriate method of purification including but not limited to solvent extraction, column chromatography and the like.
The TGS-6-ester isolated either in crude or pure form is de-esterified at alkaline pH and TGS formed is isolated by applying one or more of a purification process.
DETAILED DESCRIPTION OF THE INVENTION
In the present embodiment a process has been developed wherein after the chlorination reaction the pH of reaction mass is adjusted to about 5 to 7 by hydroxides or carbonates of alkali, alkaline earth metals or even with alkoxides of alkali or alkaline earth metals. The neutralized mass is analyzed by TLC and it was seen that there was practically no deacetylation observed from 6-acetyl TGS (TGS-6-acetate) to TGS. The mass is then extracted with water immiscible or sparingly miscible solvents such as ethyl acetate, methyl ethyl ketone, dichloromethane, etc.
All the 6-acyl trichlorogalactosucrose (TGS-6-ester) along with other chlorinated sucrose derivatives comes into the organic solvent layer.
The organic extract is concentrated to 50 % of its initial volume and is washed with saturated sodium chloride aqueous solution in order to remove DMF extracted in the organic layer. The ratio of saturated sodium chloride solution to organic extract is maintained between 1:5 to 1:7 The washing was repeated for 5 to 10 cycles It has been seen that the DMF, which is more water soluble, is retained back into the aqueous layer. Thus this methodology also gives an innovative process to remove the DMF
from the reaction mixture, which is rather difficult to get rid off.
The crude TGS-6-acetate could be isolated from ethyl acetate extract. It is then purified by either extractive purification using solvents or purifying the product by column chromatography using silanized silica gel. The purified could be isolated and deactylated either in an aqueous alkaline solution or in alcoholic alkoxide solution to give the desired trichlorogalactosucrose.
In an another strategy after the solvent extraction of the neutralized reaction mass, concentration and saturated sodium chloride washings, the impure TGS-6-ester could be deacetylated first to afford the crude trichlorogalactosucrose which is subsequently purified by either extractive purification method or by column chromatography using silanized silica gel.
Once the pure TGS is obtained from either extractive or chromatographic purification, it is crystallized by using solvent mixtures like ethyl acetate /
dichloromethane, methanol / ethyl acetate, butyl acetate /
dichloromethane or methanol / butyl acetate.
The examples given below are only illustrations of preferred embodiment of this invention. They shall in no way be construed to limit the scope of the invention by the actual chemicals used, by the actual reaction conditions used and the like. This invention is applicable to one or more of a process of production of TGS-6-acetate or TGS wherein DMF is a component of the process stream / Reaction Mixture and is required to be removed for making next process step possible more efficiently. Any adaptation or modification of the embodiments described here or new embodiments that are within the scope of the claims, that are obvious to a person skilled in the art, are considered as within the scope of this specification. Similarly, any mention of singular is also meant to cover its pleural also unless the context does not permit so. If the said singular word refers to a generic term / name, it also encompasses ail the specific examples of that kind, uniess the context does not permit so.
Thus, "a solvent" covers use of all known solvents, of one or more of them, either singly, or in combination as a mixture or as used successively and "a process of purification" encompasses one or more or all the known processes applicable in the context.
Further, mention of any ester group in general, including "acyl" or in specific including "acetyl" or "acetate" shafl be construed to include every chemical equivalent to that group.
Example 1 Tertiary amide removal from extracted neutralized mass by NaCI
washings and subsequent purification by extractive purification 80 kg of sucrose-6-acetate was chlorinated by the Vilsmeier reagent generated by PC15 (252.8 kg) and DMF (480 kg). After chlorination, the reaction mass was neutralized in water and calcium hydroxide slurry was used for adjusting the pH to 6.8. The total volume after neutralization was 3500 L. After neutralization the pH was then adjusted to 5.0 using dilute HCI.
The neutralized mass was filtered through the filter press to remove extraneous solids in the solution. Then the solution was subjected to Packed column Liquid-Liquid extraction using 1:3.5 times of ethyl acetate.
The layers were separated and the respective layers were analyzed for TGS-6-acetate content by HPLC and DMF content by GC. It was found that 93% of the 6-0-acetyl TGS was extracted into the organic layer and DMF content was found to be 1.87%.
The organic layer was then concentrated to 50% and was treated with 1:0.1 times of saturated NaCI solution. The layers were separated and five such washings were carried out. The DMF in the extract was reduced to less than 0.5%. The organic layer was then further concentrated for complete removal of ethyl acetate.
The syrup obtained was diluted to 1:2 times with water and then the pH
] 0 was adjusted to 9.0 using sodium hydroxide. The Deacetylation was monitored by TLC and after stirring for 4-5 hrs, the deacetylation was completed.
.The mass was filtered and neutralized with 30% Hydrochloric acid to a pH
of 7.0 - 7.5.
The deacetylated aqueous layer was taken for extractive purification for removal of polar and non polar impurities. Partial extraction of the neutralized mass was performed with 1: 0.25 v/v of 1:1 mixture of ethyl acetate and cyclohexane so as to remove the majority of the non-polar impurities. The aqueous layer was saturated with sodium chloride and the TGS was extracted back in to ethyl acetate.
The ethyl acetate extract was concentrated under vacuum to thick syrupy mass to which three times its volume of methanol was added.. Then the TGS was precipitated by addition of 1:3 times of ethyl acetate and slow removal of inethanoi by distillation. The crystallized product was 98.9%
pure and the yield obtained was 45% from the chlorination stage.
In an another strategy after the solvent extraction of the neutralized reaction mass, concentration and saturated sodium chloride washings, the impure TGS-6-ester could be deacetylated first to afford the crude trichlorogalactosucrose which is subsequently purified by either extractive purification method or by column chromatography using silanized silica gel.
Once the pure TGS is obtained from either extractive or chromatographic purification, it is crystallized by using solvent mixtures like ethyl acetate /
dichloromethane, methanol / ethyl acetate, butyl acetate /
dichloromethane or methanol / butyl acetate.
The examples given below are only illustrations of preferred embodiment of this invention. They shall in no way be construed to limit the scope of the invention by the actual chemicals used, by the actual reaction conditions used and the like. This invention is applicable to one or more of a process of production of TGS-6-acetate or TGS wherein DMF is a component of the process stream / Reaction Mixture and is required to be removed for making next process step possible more efficiently. Any adaptation or modification of the embodiments described here or new embodiments that are within the scope of the claims, that are obvious to a person skilled in the art, are considered as within the scope of this specification. Similarly, any mention of singular is also meant to cover its pleural also unless the context does not permit so. If the said singular word refers to a generic term / name, it also encompasses ail the specific examples of that kind, uniess the context does not permit so.
Thus, "a solvent" covers use of all known solvents, of one or more of them, either singly, or in combination as a mixture or as used successively and "a process of purification" encompasses one or more or all the known processes applicable in the context.
Further, mention of any ester group in general, including "acyl" or in specific including "acetyl" or "acetate" shafl be construed to include every chemical equivalent to that group.
Example 1 Tertiary amide removal from extracted neutralized mass by NaCI
washings and subsequent purification by extractive purification 80 kg of sucrose-6-acetate was chlorinated by the Vilsmeier reagent generated by PC15 (252.8 kg) and DMF (480 kg). After chlorination, the reaction mass was neutralized in water and calcium hydroxide slurry was used for adjusting the pH to 6.8. The total volume after neutralization was 3500 L. After neutralization the pH was then adjusted to 5.0 using dilute HCI.
The neutralized mass was filtered through the filter press to remove extraneous solids in the solution. Then the solution was subjected to Packed column Liquid-Liquid extraction using 1:3.5 times of ethyl acetate.
The layers were separated and the respective layers were analyzed for TGS-6-acetate content by HPLC and DMF content by GC. It was found that 93% of the 6-0-acetyl TGS was extracted into the organic layer and DMF content was found to be 1.87%.
The organic layer was then concentrated to 50% and was treated with 1:0.1 times of saturated NaCI solution. The layers were separated and five such washings were carried out. The DMF in the extract was reduced to less than 0.5%. The organic layer was then further concentrated for complete removal of ethyl acetate.
The syrup obtained was diluted to 1:2 times with water and then the pH
] 0 was adjusted to 9.0 using sodium hydroxide. The Deacetylation was monitored by TLC and after stirring for 4-5 hrs, the deacetylation was completed.
.The mass was filtered and neutralized with 30% Hydrochloric acid to a pH
of 7.0 - 7.5.
The deacetylated aqueous layer was taken for extractive purification for removal of polar and non polar impurities. Partial extraction of the neutralized mass was performed with 1: 0.25 v/v of 1:1 mixture of ethyl acetate and cyclohexane so as to remove the majority of the non-polar impurities. The aqueous layer was saturated with sodium chloride and the TGS was extracted back in to ethyl acetate.
The ethyl acetate extract was concentrated under vacuum to thick syrupy mass to which three times its volume of methanol was added.. Then the TGS was precipitated by addition of 1:3 times of ethyl acetate and slow removal of inethanoi by distillation. The crystallized product was 98.9%
pure and the yield obtained was 45% from the chlorination stage.
Example 2 Tertiary amide removal from extracted neutralized mass by NaCI
washings and subsequent. purification by column chromatography 80 kg of sucrose-6-acetate was chlorinated by the Vilsmeier reagent generated by PCI5. (252.8 kg) and DMF (480 kg). After chlorination, the reaction mass was neutralized using 30% sodium hydroxide solution and then the pH was again brought back to 5.0 by addition of dilute HCI. The total volume of the filtered solution was found to be 3200L. Then the solution was filtered to remove extraneous solids and was subjected to Packed column Liquid-Liquid extraction using 1:3.5 times of ethyl acetate.
The organic layer was then concentrated to 50% and was treated with 1:0.1 times of saturated NaCI solution. The layers were separated and five such washings were carried out. The DMF in the extract was reduced to less than 0.5%. The organic layer was then further concentrated for complete removal of ethyl acetate.
The aqueous concentrate syrup obtained was loaded on to a SS column packed with Silanized hydrophobic silica. The quantity of silanized silica gel taken was 10 times the quantity of the aqueous concentrate taken for separation. The mobile phase used to separate the TGS from other chlorinated sucrose derivatives was aqueous buffer at pH 11Ø
The pure product fractions collected from the column chromatographic process were pooled together and concentrated by reverse osmosis membrane system up to a level of 30% concentration of TGS solution.
Then the syrupy solution was extracted into ethyl acetate and was subjected to vacuum concentration and crystallization.
washings and subsequent. purification by column chromatography 80 kg of sucrose-6-acetate was chlorinated by the Vilsmeier reagent generated by PCI5. (252.8 kg) and DMF (480 kg). After chlorination, the reaction mass was neutralized using 30% sodium hydroxide solution and then the pH was again brought back to 5.0 by addition of dilute HCI. The total volume of the filtered solution was found to be 3200L. Then the solution was filtered to remove extraneous solids and was subjected to Packed column Liquid-Liquid extraction using 1:3.5 times of ethyl acetate.
The organic layer was then concentrated to 50% and was treated with 1:0.1 times of saturated NaCI solution. The layers were separated and five such washings were carried out. The DMF in the extract was reduced to less than 0.5%. The organic layer was then further concentrated for complete removal of ethyl acetate.
The aqueous concentrate syrup obtained was loaded on to a SS column packed with Silanized hydrophobic silica. The quantity of silanized silica gel taken was 10 times the quantity of the aqueous concentrate taken for separation. The mobile phase used to separate the TGS from other chlorinated sucrose derivatives was aqueous buffer at pH 11Ø
The pure product fractions collected from the column chromatographic process were pooled together and concentrated by reverse osmosis membrane system up to a level of 30% concentration of TGS solution.
Then the syrupy solution was extracted into ethyl acetate and was subjected to vacuum concentration and crystallization.
Claims (3)
1. A process of production of 1'-6'-Dichloro-1'-6'-DIDEOXY-.beta.-Fructofuranasyl-4-chloro-4-deoxy-galactopyranoside abbreviated as TGS, or 6- acyl - 4,1', 6' trichlorogalactosucrose abbreviated as TGS-6-ester comprising a process stream containing one or more of TGS-6-ester, DMF, one or more of an inorganic salt, one or more of an organic salt, one or more of a caramelization product, one or more of an enzyme and the like, wherein isolation of TGS-6-ester is achieved comprising one or more of a step of:
a. adjustment of pH of the said process stream after neutralization to acidic side, preferably between 5 to 7, b. extraction of the process stream of step (a.) of this claim with a partially miscible or immiscible organic solvent comprising one or more of ethyl acetate, butyl acetate, methyl ethyl ketone, dichloromethane, toluene, cyclohexane, chloroform, and the like, c. optional concentration of the organic solvent extract of step (b.) of this claim, d. extraction, for one or more number of times, of the organic solvent extract of step (b) or (c.) of this claim with saturated aqueous salt solution to remove dimethylformamide (DMF) until content of residual DMF in the said organic solvent extract reduces appreciably, preferably to 0.5% or less, e. subjecting the organic solvent extract at the end of step (d.) of this claim for isolation of TGS-6-acetate, or subjecting TGS-6-acetate formed, after or before isolation and purification, to deacylation at alkaline pH to form TGS.
a. adjustment of pH of the said process stream after neutralization to acidic side, preferably between 5 to 7, b. extraction of the process stream of step (a.) of this claim with a partially miscible or immiscible organic solvent comprising one or more of ethyl acetate, butyl acetate, methyl ethyl ketone, dichloromethane, toluene, cyclohexane, chloroform, and the like, c. optional concentration of the organic solvent extract of step (b.) of this claim, d. extraction, for one or more number of times, of the organic solvent extract of step (b) or (c.) of this claim with saturated aqueous salt solution to remove dimethylformamide (DMF) until content of residual DMF in the said organic solvent extract reduces appreciably, preferably to 0.5% or less, e. subjecting the organic solvent extract at the end of step (d.) of this claim for isolation of TGS-6-acetate, or subjecting TGS-6-acetate formed, after or before isolation and purification, to deacylation at alkaline pH to form TGS.
2. A process of step I wherein a. the ester group of the said TGS-6-ester comprises an alkyl or an aryl group, preferably an acetate or a benzoate, b. the said organic solvent used for extraction of the said process stream is ethyl acetate.
3. A process of claim 1 or 2 wherein the said process stream is a neutralized chlorination reaction mixture produced by steps comprising:
a. preparing a Vilsmeier Reagent of general formula HCIC=N + R2 ]Cl- where R represents an alkyl group, typically a methyl or ethyl group, by one or more of a method of its preparation by reacting a tertiary amide, preferably DMF, with an acid chloride or [Bis(trichloromethyl) carbonate] (C3O3Cl6) or carbonyl chloride (COCl2) or thionyl chloride (SOCl2) including a method of reacting DMF with Phosphorus Pentachloride or ethanedioyl chloride with DMF, or b. preparing a Vilsmeier Reagent of formula [HPOCl2.O.C.sup+=N.sup+.R2] Cl- where R
represents an alkyl group, typically a methyl or ethyl group-by one or more of a method of its preparation by reacting a tertiary amide, preferably DMF, with phosphorus oxychloride, c. reacting sucrose-6-ester solution, preferably a sucrose-6-acetate or sucrose-6-benzoate solution, made preferably in DMF, with the said Vilsmeier reagent of the step (a.) or (b.) of this claim, d. heating the reaction mass to around 85°C, and maintaining the same for a period of time, preferably for about 60 minutes, e. then further heating to around 100°C, and maintaining the same for a period of time, preferably for about 5 hours, and f. then further heating to around 115°C and maintaining the same for a period of time, preferably for around 90 minutes, g. cooling the chlorinated mass to lower temperature, preferably around 60°C, h. neutralizing the said cooled chlorinated mass with an alkali, preferably by calcium hydroxide slurry in water, to around pH
7Ø
a. preparing a Vilsmeier Reagent of general formula HCIC=N + R2 ]Cl- where R represents an alkyl group, typically a methyl or ethyl group, by one or more of a method of its preparation by reacting a tertiary amide, preferably DMF, with an acid chloride or [Bis(trichloromethyl) carbonate] (C3O3Cl6) or carbonyl chloride (COCl2) or thionyl chloride (SOCl2) including a method of reacting DMF with Phosphorus Pentachloride or ethanedioyl chloride with DMF, or b. preparing a Vilsmeier Reagent of formula [HPOCl2.O.C.sup+=N.sup+.R2] Cl- where R
represents an alkyl group, typically a methyl or ethyl group-by one or more of a method of its preparation by reacting a tertiary amide, preferably DMF, with phosphorus oxychloride, c. reacting sucrose-6-ester solution, preferably a sucrose-6-acetate or sucrose-6-benzoate solution, made preferably in DMF, with the said Vilsmeier reagent of the step (a.) or (b.) of this claim, d. heating the reaction mass to around 85°C, and maintaining the same for a period of time, preferably for about 60 minutes, e. then further heating to around 100°C, and maintaining the same for a period of time, preferably for about 5 hours, and f. then further heating to around 115°C and maintaining the same for a period of time, preferably for around 90 minutes, g. cooling the chlorinated mass to lower temperature, preferably around 60°C, h. neutralizing the said cooled chlorinated mass with an alkali, preferably by calcium hydroxide slurry in water, to around pH
7Ø
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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IN1048/MUM/2005 | 2005-08-30 | ||
IN1048MU2005 | 2005-08-30 | ||
PCT/IN2006/000329 WO2007052305A2 (en) | 2005-08-30 | 2006-08-29 | Novel method of extraction of 6-o-protected trichlorogalac tose from the chlorinated mass |
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CA2620902A1 true CA2620902A1 (en) | 2007-05-10 |
Family
ID=38006313
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CA002620902A Abandoned CA2620902A1 (en) | 2005-08-30 | 2006-08-29 | Novel method of extraction of 6-o-protected trichlorogalactose from the chlorinated mass |
Country Status (5)
Country | Link |
---|---|
CN (1) | CN101253188A (en) |
CA (1) | CA2620902A1 (en) |
GB (1) | GB2443146A (en) |
WO (1) | WO2007052305A2 (en) |
ZA (1) | ZA200801751B (en) |
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GB2469157B (en) * | 2009-03-30 | 2011-07-06 | John Kerr | Process for removing dimethylamine during sucralose production |
GB2551591B (en) | 2016-06-23 | 2019-08-07 | Tate & Lyle Tech Ltd | Liquid-liquid extraction of DMF |
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US5530106A (en) * | 1993-03-12 | 1996-06-25 | Mcneil-Ppc, Inc. | Recovery of sucralose intermediates |
US5498709A (en) * | 1994-10-17 | 1996-03-12 | Mcneil-Ppc, Inc. | Production of sucralose without intermediate isolation of crystalline sucralose-6-ester |
US20060205936A1 (en) * | 2005-03-14 | 2006-09-14 | Sl Laboratories, Llc | Chlorination of Sucrose-6-esters |
-
2006
- 2006-08-29 WO PCT/IN2006/000329 patent/WO2007052305A2/en active Application Filing
- 2006-08-29 GB GB0803649A patent/GB2443146A/en not_active Withdrawn
- 2006-08-29 CN CNA2006800313211A patent/CN101253188A/en active Pending
- 2006-08-29 CA CA002620902A patent/CA2620902A1/en not_active Abandoned
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GB0803649D0 (en) | 2008-04-02 |
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WO2007052305A2 (en) | 2007-05-10 |
CN101253188A (en) | 2008-08-27 |
ZA200801751B (en) | 2009-10-28 |
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