EP1863754A1 - Method for preparing valienamine - Google Patents
Method for preparing valienamineInfo
- Publication number
- EP1863754A1 EP1863754A1 EP05821418A EP05821418A EP1863754A1 EP 1863754 A1 EP1863754 A1 EP 1863754A1 EP 05821418 A EP05821418 A EP 05821418A EP 05821418 A EP05821418 A EP 05821418A EP 1863754 A1 EP1863754 A1 EP 1863754A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- valienamine
- acarbose
- base
- hydroxide
- amberlite
- 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.)
- Withdrawn
Links
- XPHOBMULWMGEBA-VZFHVOOUSA-N valienamine Chemical compound N[C@H]1C=C(CO)[C@@H](O)[C@H](O)[C@H]1O XPHOBMULWMGEBA-VZFHVOOUSA-N 0.000 title claims abstract description 61
- XPHOBMULWMGEBA-UHFFFAOYSA-N Valienamine Natural products NC1C=C(CO)C(O)C(O)C1O XPHOBMULWMGEBA-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title claims abstract description 29
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims abstract description 75
- 229960002632 acarbose Drugs 0.000 claims abstract description 40
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 claims abstract description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical group [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 3
- 239000000920 calcium hydroxide Substances 0.000 claims description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 3
- 238000010494 dissociation reaction Methods 0.000 claims description 3
- 230000005593 dissociations Effects 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical group [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 3
- 235000019801 trisodium phosphate Nutrition 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 claims 3
- 150000004692 metal hydroxides Chemical class 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 abstract description 19
- 238000002360 preparation method Methods 0.000 abstract description 15
- 239000006227 byproduct Substances 0.000 abstract description 4
- 230000003467 diminishing effect Effects 0.000 abstract description 2
- 239000011541 reaction mixture Substances 0.000 description 28
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 27
- 239000003729 cation exchange resin Substances 0.000 description 26
- 229920001429 chelating resin Polymers 0.000 description 26
- 239000002585 base Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 150000001720 carbohydrates Chemical class 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 150000002016 disaccharides Chemical class 0.000 description 6
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 229930195482 Validamycin Natural products 0.000 description 4
- 235000014633 carbohydrates Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000006257 total synthesis reaction Methods 0.000 description 4
- JARYYMUOCXVXNK-IMTORBKUSA-N validamycin Chemical compound N([C@H]1C[C@@H]([C@H]([C@H](O)[C@H]1O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)CO)[C@H]1C=C(CO)[C@H](O)[C@H](O)[C@H]1O JARYYMUOCXVXNK-IMTORBKUSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 150000002772 monosaccharides Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- 235000012601 Euterpe oleracea Nutrition 0.000 description 1
- 244000207620 Euterpe oleracea Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- -1 NR R R (wherein R Chemical class 0.000 description 1
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 1
- 235000003650 acai Nutrition 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Chemical group 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical group 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical group OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DVUVKWLUHXXIHK-UHFFFAOYSA-N tetraazanium;tetrahydroxide Chemical compound [NH4+].[NH4+].[NH4+].[NH4+].[OH-].[OH-].[OH-].[OH-] DVUVKWLUHXXIHK-UHFFFAOYSA-N 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- valienamine The conventional synthetic methods of valienamine are divided into two types.
- the first type is a total synthesis of valienamine from carbohydrates, and the second type is a preparation of valienamine from validamycin or acarbose having a valienamine moiety therein. Disclosure of Invention Technical Problem
- NR R R (wherein R ,R , andR may be the same or different, and are independently alkyl group with a carbon number of 1 to 4) such as diisopropylethylamine, tripropylamine, triethylamine.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a method for preparing valienamine from acarbose or acarbose derivatives by using a base. The present invention provides an improved method for preparing valienamine compared to conventional preparation methods of valienamine by simplifying the reaction steps and diminishing byproducts.
Description
Description METHOD FOR PREPARING VALIENAMINE
Technical Field
[1] The invention relates to a method for preparing valienamine represented by the following formula (1). More particularly, the invention relates to a method for preparing valienamine from acarbose or acarbose derivatives by using a base.
[2]
[3] (1)
Background Art
[4] Valienamine is a core precursor used for preparing voglibose which is an effective hypoglycemics for treating diabetes, suppressing a sudden rise in blood sugar level after a meal [Carbohydrate Research, 140, 185 (1985); J. Med. Chem., 29, 1038 (1988); U.S. patent No. 4,701,559 (1987)].
[5] The conventional synthetic methods of valienamine are divided into two types. The first type is a total synthesis of valienamine from carbohydrates, and the second type is a preparation of valienamine from validamycin or acarbose having a valienamine moiety therein. Disclosure of Invention Technical Problem
[6] In the total synthesis of valienamine from carbohydrates, valienamine is economically prepared from carbohydrate sources such as D-glucose [Chem. Pharm. Bull., 36,4236 (1988); J. Org. Chem., 57, 3651 (1992)] and D-Xylose [J. Antibiot., 53, 430 (2000)]. However, the total synthesis is inadequate for mass production of valienamine since the synthesis reaction is too complicated due to its at least ten reaction steps.
[7] Therefore, a method for preparing valienamine from validamycin or acarbose, which are well known compounds having a valienamine moiety therein, was suggested in order to overcome the above-mentioned drawback of the total synthesis. For example, it is known that valienamine derivatives were prepared in a yield of about 36% to about 50% by reacting a validoxyamine derivative having benzyl protection group, which is prepared from validamycin, with NBS (N-bromosuccinimide) under a solvent such as DMF (dimethylformamide) or DMSO (dimethylsulfoxide) [Chemistry Letters, 725 (1989); J. Chem. Soc, Perkin Trans I, 3287 (1991)]. However, the method
also has some defects because a harmful reagent such as DMF, DMSO, and NBS is used as a solvent or an oxidizing agent, and various by-products are produced.
[8] As a solution to the above-mentioned problems, WO 2004/000782 describes a new method for preparing valienamine from acarbose or validamycin under a strong acid solvent of TFA (trifluoroacetic acid). The method is suitable for mass production compared to other conventional methods, but it also has drawbacks in that it uses a relatively expensive and harmful solvent such as TFA. Technical Solution
[9] Accordingly, the present inventors have developed a simple and economic process for preparing valienamine to minimize drawbacks of the prior arts. According to the present invention, valienamine can be easily obtained from acarbose or acarbose derivatives using a base, so the present invention is an economic method, which is suitable for the mass production of valienamine.
Advantageous Effects
[10] The object of the present invention is to provide a method for preparing valienamine from acarbose or acarbose derivatives using a base to solve the problems resulting from the conventional methods for preparing valienamine.
[11] To achieve said object, the present invention provides a method for preparing valienamine represented by the formula (1) from acarbose represented by the formula (2) or acarbose derivatives using a base.
[12]
[13] (1) [14]
[15] (2)
[16] Acarbose derivatives are compounds having one or more saccharides bonded to a valienamine backbone, and they are generally derivatives having monosaccharide or
disaccharide represented by the following formulas.
[17]
acarbose derivative (disacchaiide) (monosaccharide)
[18] According to the present invention, a low-priced reagent, a base, is used for preparing valienamine so the present invention is an economical method that is suitable for mass production. Best Mode for Carrying Out the Invention
[19] The method for preparing valienamine according to the present invention is schematized by the following reaction formula.
[20] Reaction formula 1 [21]
vaHeuainine
[22] In the present invention, various inorganic bases and organic bases may be used as a base, for example, it is not particularly limited, hydroxides, carbonates, bicarbonates, phosphates, organic amines, and the like.
[23] Suitable bases include hydroxides, e.g. alkali metal hydroxides such as sodium hydroxide (NaOH), potassium hydroxide (KOH), alkaline earth metal hydroxides such as calcium hydroxide (Ca(OH) ), barium hydroxide (Ba(OH) ), tetraammonium hydroxide such as tetramethylammonium hydroxide (NMe OH), tetraethylammonium
4 hydroxide (NEt OH); carbonates, e.g. metal carbonate (MCO ) (wherein M is alkali metals or alkaline earth metals) such as sodium carbonate (Na CO ), potassium carbonate (K CO ); bicarbonates, e.g. metal bicarbonate (MHCO ) such as sodium bicarbonate (NaHCO ), potassium bicarbonate (KHCO ) ; phosphates such as sodium phosphate tribasic (Na PO ), potassium phosphate tribasic (K PO ), sodium phosphate
dibasic (Na HPO ); and organic amines, e.g. NR R R (wherein R ,R , andR may be the same or different, and are independently alkyl group with a carbon number of 1 to 4) such as diisopropylethylamine, tripropylamine, triethylamine.
[24] A base strength may be considered to choose a suitable base among the various bases. In the present invention, the base strength is the most important factor to determine a reaction velocity and a reaction condition. If the base strength is higher, the reaction velocity is relatively faster. Generally, the base strength is indicated as a dissociation constant (pKa). For example, the pKa of hydroxyl group (OH ) is 15.7, the pKa of carboxyl group (CO ) is 10.3, the pKa of organic amine is 10, the pKa of triphosphate group (PO ) is 12.7, and the pKa of bicarbonate group (HCO ) is 6.4. In the present invention, it is preferable to use a base having pKa of at least 6, and it is more preferable to use a base having pKa of at least 10.
[25] An amount of the base is not particularly limited, but it is preferable to use an excess amount than that of acarbose or its derivatives. Preferably, an amount of the base is preferable to 5 or more equivalents of acarbose or its derivatives.
[26] Typically, a reaction solvent, e.g. water, or a mixture of water and a water-miscible organic solvent may be used for a smooth reaction of the reactants. A preferred water- miscible organic solvent is an alcohol such as methanol, ethanol, and ethylene glycol. An amount of the reaction solvent is not particularly limited, but it is preferable to use 5 times or more by weight of acarbose or its derivatives, and more preferable to use 5 times to 30 times by weight of acarbose or its derivatives. It is preferred that the reflux of the reaction mixture is carried out during the reaction. The preferred reaction temperature is 6O0C or higher, and the preferred reaction time is 12 hours or longer. The more preferred reaction temperature is 8O0C to 12O0C, and the more preferred reaction time is 24 hours to 72 hours.
[27] The resulting valienamine from the reaction mixture may be easily purified by a conventional purification method in the art. For example, an ion exchange resin may be used considering the physical properties of valienamine such as water-solubility. Moreover, the resulting valienamine may be further purified using a purification method such as crystallization.
[28] According to the present invention, a saccharide(s) combined with a backbone of acarbose are removed using a base, so acarbose derivatives, which are different only from the number of saccharides combined thereto as compared with acarbose, are subject to follow the same reaction path as acarbose. Therefore, the reaction conditions and the purification process of acarbose derivatives are substantially identical with those of acarbose as shown in the following reaction formula 2.
[29] Reaction formula 2
[30]
acarbose deiivative (disacchaiide) valie ua mine
acai bose deiivative (monosaccharide) valie iia mine
[31] In the reaction formula 2, the base may be the same defined as above.
[32] The present invention is further illustrated by the following examples, but these examples should not be construed as limiting the scope of the invention. Mode for the Invention
[33] Examples
[34] Example 1: Preparation of valienamine from acarbose (Is)
[35] Acarbose (1Og) and sodium hydroxide (9.3g) were added to water (20OmL) and then refluxed during 48 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (l.lg) was obtained.
[36] Hydrogen NMR spectrum of the resulting product (valienamine) was as follows:
[37] 1U NMR (D O, 300MHz) 3.35 (m,lH), 3.49(m,2H), 3.80-3.95 (m,2H), 4.02(d,lH),
5.61(d,lH)
[38] Example 2: Preparation of Valienamine from Acarbose (2)
[39] Acarbose (1Og) and potassium hydroxide (10.5g) were added to water (18OmL) and then refluxed during 48 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (1.Og) was obtained.
[40] Example 3: Preparation of Valienamine from Acarbose (3)
[41] Acarbose (1.Og) and calcium hydroxide (1.6g) were added to water (2OmL) and
then refluxed during 60 hours. The reaction mixture was cooled to room temperature, and then concentrated. The concentrated reaction mixture was purified with cation exc hange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG- 50). As a result, pure valienamine (0.12g) was obtained.
[42] Example 4: Preparation of Valienamine from Acarbose (4)
[43] Acarbose (1.Og) and barium hydroxide octahydrate (6.8g) were added to water
(2OmL) and then refluxed during 55 hours. The reaction mixture was cooled to room temperature, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.09g) was obtained.
[44] Example 5: Preparation of Valienamine from Acarbose (5)
[45] Acarbose (1.Og) and sodium carbonate (2.Og) were added to water (2OmL) and then refluxed during 72 hours. The reaction mixture was cooled to room temperature, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.08g) was obtained.
[46] Example 6: Preparation of Valienamine from Acarbose (6)
[47] Acarbose (1.Og) and sodium bicarbonate (1.8g) were added to water (2OmL) and then refluxed during 72 hours. The reaction mixture was cooled to room temperature, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.09g) was obtained.
[48] Example 7: Preparation of Valienamine from Acarbose Derivative (disaccharide)
Ol
[49] Acarbose derivative (disaccharide, 2.Og) and potassium hydroxide (2.Og) were added to water (4OmL) and then refluxed during 48 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.2g) was obtained.
[50] Example 8: Preparation of Valienamine from Acarbose Derivative (disaccharide)
(8)
[51] Acarbose derivative (disaccharide, 2.Og) and sodium hydroxide (1.6g) were added to water (4OmL) and then refluxed during 40 hours. The reaction mixture was cooled to room temperature, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.18g) was obtained.
[52] Example 9: Preparation of Valienamine from Acarbose (9)
[53] Acarbose (5g) and tetramethylammonium hydroxide (2Og) were added to water
(5OmL) and then refluxed during 40 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.4g) was obtained.
[54] Example 10: Preparation of Valienamine from Acarbose (10)
[55] Acarbose (2g) and potassium phosphate tribasic (9.8g) were added to water (2OmL) and then refluxed during 45 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.17g) was obtained.
[56] Example 11: Preparation of Valienamine from Acarbose (H)
[57] Acarbose (2g) and sodium phosphate tribasic (7.5g) were added to water (2OmL) and then refluxed during 48 hours. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.19g) was obtained.
[58] Example 12: Preparation of Valienamine from Acarbose (12)
[59] Acarbose (5g) and sodium phosphate dibasic (16.5g) were added to water (5OmL) and then refluxed during 4 days. The reaction mixture was cooled to room temperature, neutralized with IN hydrochloric acid solution, and then concentrated. The concentrated reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.35g) was obtained. [60] Example 13: Preparation of Valienamine from Acarbose Derivative (disaccharide)
(13)
[61] Acarbose (2g) and diisopropyl ethylamine (2OmL) were added to water (5mL) and then refluxed during 3 days. The reaction mixture was concentrated under reduced pressure and then diluted with water (5OmL). The resultant reaction mixture was purified with cation exchange resin (Amberlite IR- 120H) and weak acid cation exchange resin (Amberlite CG-50). As a result, pure valienamine (0.16g) was obtained. Industrial Applicability
[62] The conventional synthetic methods of valienamine are inadequate for mass production of the product since they are too complicated due to so many reaction steps and they produce many by-products. The present invention provides a method of preparing valienamine suitable for mass production by simplifying the reaction steps and diminishing byproducts. Moreover, the present invention uses a base for the reaction of acarbose or acarbose derivatives so it is a less harmful method in comparison with the conventional methods that uses harmful organic solvents.
Claims
(1)
[2] The method according to claim 1, wherein the base is selected from the group consisting of metal hydroxide, metal carbonate, and metal bicarbonate.
[3] The method according to claim 2, wherein the metal hydroxide is sodium hydroxide or potassium hydroxide.
[4] The method according to claim 2, wherein the metal hydroxide is calcium hydroxide or barium hydroxide.
[5] The method according to claim 2, wherein the metal carbonate is sodium carbonate or potassium carbonate.
[6] The method according to claim 2, wherein the metal bicarbonate is sodium bicarbonate or potassium bicarbonate. [7] The method according to claim 1, wherein the base is sodium phosphate tribasic or potassium phosphate tribasic. [8] The method according to claim 1, wherein the base is NR R R (in which R ,R , and R may be the same or different and are independently an alkyl group with a carbon number of 1 to 4) [9] The method according to claim 1, wherein a dissociation constant (pKa) of the base is at least 6. [10] The method according to claim 9, wherein the dissociation constant (pKa) of the base is at least 10.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20050021852 | 2005-03-16 | ||
| KR1020050036755A KR100593849B1 (en) | 2005-03-16 | 2005-05-02 | Method for preparing valienamine |
| PCT/KR2005/004093 WO2006107134A1 (en) | 2005-03-16 | 2005-12-02 | Method for preparing valienamine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1863754A1 true EP1863754A1 (en) | 2007-12-12 |
Family
ID=37073662
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP05821418A Withdrawn EP1863754A1 (en) | 2005-03-16 | 2005-12-02 | Method for preparing valienamine |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP1863754A1 (en) |
| WO (1) | WO2006107134A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5764648A (en) * | 1980-10-06 | 1982-04-19 | Takeda Chem Ind Ltd | N-substituted derivative of valienamine, its preparation, and alpha-glucosidase inhibitor |
| WO2004000782A1 (en) * | 2002-06-25 | 2003-12-31 | B T Gin., Inc. | Preparation method of valienamine from acarbose and/or acarbose derivatives using trifluoroacetic acid |
| WO2004108657A1 (en) * | 2003-06-11 | 2004-12-16 | B T Gin., Inc. | Preparation method of valienamine using solid catalysts |
-
2005
- 2005-12-02 EP EP05821418A patent/EP1863754A1/en not_active Withdrawn
- 2005-12-02 WO PCT/KR2005/004093 patent/WO2006107134A1/en active Application Filing
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| Title |
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| See references of WO2006107134A1 * |
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| WO2006107134A1 (en) | 2006-10-12 |
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