JP2008545648A - Process for producing 6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane - Google Patents
Process for producing 6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane Download PDFInfo
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- JP2008545648A JP2008545648A JP2008512210A JP2008512210A JP2008545648A JP 2008545648 A JP2008545648 A JP 2008545648A JP 2008512210 A JP2008512210 A JP 2008512210A JP 2008512210 A JP2008512210 A JP 2008512210A JP 2008545648 A JP2008545648 A JP 2008545648A
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- variolamine
- hydroxymethyl
- trihydroxy
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- 238000000034 method Methods 0.000 title claims abstract description 23
- FTAQFNFNHWVZOF-UHFFFAOYSA-N 6,7,8-trihydroxy-5-(hydroxymethyl)-4-oxa-2-azabicyclo[3.3.1]nonan-3-one Chemical compound C1C2NC(=O)OC1(CO)C(O)C(O)C2O FTAQFNFNHWVZOF-UHFFFAOYSA-N 0.000 title abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 17
- 231100000252 nontoxic Toxicity 0.000 claims description 16
- 230000003000 nontoxic effect Effects 0.000 claims description 16
- -1 C 1 -C 4 alkyl Inorganic materials 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- KWSLGOVYXMQPPX-UHFFFAOYSA-N 5-[3-(trifluoromethyl)phenyl]-2h-tetrazole Chemical compound FC(F)(F)C1=CC=CC(C2=NNN=N2)=C1 KWSLGOVYXMQPPX-UHFFFAOYSA-N 0.000 claims description 10
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims description 10
- 229910001379 sodium hypophosphite Inorganic materials 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 229940120503 dihydroxyacetone Drugs 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 claims description 3
- MDCWDBMBZLORER-UHFFFAOYSA-N triphenyl borate Chemical compound C=1C=CC=CC=1OB(OC=1C=CC=CC=1)OC1=CC=CC=C1 MDCWDBMBZLORER-UHFFFAOYSA-N 0.000 claims description 3
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 17
- 239000013078 crystal Substances 0.000 description 16
- 238000005695 dehalogenation reaction Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 6
- HWPJDWBYAZGNTJ-UHFFFAOYSA-N 4,5,6-trihydroxy-1-(hydroxymethyl)-2-oxa-4-azabicyclo[3.3.1]nonan-3-one Chemical compound C1CC2(CC(C1O)(N(C(=O)O2)O)O)CO HWPJDWBYAZGNTJ-UHFFFAOYSA-N 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- SVXYAZRXGDKVFH-UHFFFAOYSA-N C1C2C(C(C(C1(OC(=O)N2Br)CO)O)O)O Chemical compound C1C2C(C(C(C1(OC(=O)N2Br)CO)O)O)O SVXYAZRXGDKVFH-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 108010028144 alpha-Glucosidases Proteins 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- VDLOJRUTNRJDJO-ZYNSJIGGSA-N (1s,2s,3r,4s,5s)-5-amino-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetrol Chemical compound N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O VDLOJRUTNRJDJO-ZYNSJIGGSA-N 0.000 description 1
- FMEHIMDNLRASDU-UHFFFAOYSA-N 1-azabicyclo[3.3.1]nonane Chemical compound C1CCN2CCCC1C2 FMEHIMDNLRASDU-UHFFFAOYSA-N 0.000 description 1
- RAUBSVOEEKRVQV-UHFFFAOYSA-N 2-oxa-4-azabicyclo[3.3.1]nonane Chemical compound C12OCNC(CCC1)C2 RAUBSVOEEKRVQV-UHFFFAOYSA-N 0.000 description 1
- LSAHZMCCMCYVKC-UHFFFAOYSA-N 9-bromo-6,7,8-trihydroxy-5-(hydroxymethyl)-4-oxa-2-azabicyclo[3.3.1]nonan-3-one Chemical compound O1C(=O)NC2C(O)C(O)C(O)C1(CO)C2Br LSAHZMCCMCYVKC-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- OGZPHBBHLBKSAZ-GCJQMDKQSA-N NC(O[C@](CO)(CC[C@@H]([C@H]1O)O)[C@H]1O)=O Chemical compound NC(O[C@](CO)(CC[C@@H]([C@H]1O)O)[C@H]1O)=O OGZPHBBHLBKSAZ-GCJQMDKQSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- XPHOBMULWMGEBA-UHFFFAOYSA-N Valienamine Natural products NC1C=C(CO)C(O)C(O)C1O XPHOBMULWMGEBA-UHFFFAOYSA-N 0.000 description 1
- VDLOJRUTNRJDJO-UHFFFAOYSA-N Valiolamine Natural products NC1CC(O)(CO)C(O)C(O)C1O VDLOJRUTNRJDJO-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940038597 peroxide anti-acne preparations for topical use Drugs 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229910000083 tin tetrahydride Inorganic materials 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 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 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/02—Monosaccharides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/45—Monoamines
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの製造方法、及びこれを利用したバリオールアミンまたはその誘導体の製造方法が提供される。 Process for producing 6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane, and variolamine or derivative thereof using the same A manufacturing method is provided.
Description
本発明は、６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの製造方法に関する。また、本発明は、これを利用したバリオールアミン（valiolamine）またはその誘導体の製造方法に関する。 The present invention relates to a method for producing 6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane. The present invention also relates to a method for producing valiolamine or a derivative thereof using the same.
バリオールアミンは、その化学名が（１Ｓ）−（１（ＯＨ），２，４，５／１，３）−５−アミノ−１−Ｃ−（ヒドロキシメチル）−１，２，３，４−シクロヘキサンテトロールであり、α−グルコシダーゼ（α-glucosidase）に対する抑制活性を有する（米国特許第４，４４６，３１９号明細書）。また、バリオールアミンのＮ−置換された誘導体、例えばＮ−（１，３−ジヒドロキシ−２−プロピル）バリオールアミンもα−グルコシダーゼ抑制活性を有する（米国特許第４，７０１，５５９号明細書）。バリオールアミン及びＮ−（１，３−ジヒドロキシ−２−プロピル）バリオールアミンは、過血糖症状及び糖尿病、肥満及び高脂血症のような過血糖症により誘発される各種疾病の予防及び治療に有用である。バリオールアミン及びＮ−（１，３−ジヒドロキシ−２−プロピル）バリオールアミンは、下記化学式（Ｉａ）及び（Ｉｂ）と示される。
米国特許第４，４４６，３１９号明細書は、バリエナミン（valienamine）から得た９−ブロモ−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナン（下記反応式１で、化学式（ＩＩＩ）の化合物）の脱ハロゲン化を行って６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナン（下記反応式１で、化学式（ＩＩ）の化合物）を得る段階、及び化学式（ＩＩ）の化合物を加水分解する段階を含むバリオールアミンの製造方法を開示する。また、米国特許第４，７０１，５５９号明細書は、バリオールアミンまたはその無毒性塩と、ジヒドロキシアセトンとを反応させることを含むＮ−（１，３−ジヒドロキシ−２−プロピル）バリオールアミンの製造方法を開示する。米国特許第４，４４６，３１９号明細書及び第４，７０１，５５９号明細書に開示された全体工程は、下記反応式１で表す：
反応式１
Reaction formula 1
化学式（ＩＩＩ）の化合物の脱ハロゲン化を行うために、米国特許第４，４４６，３１９号明細書及び第４，７０１，５５９号明細書は、いくつかの方法を開示している：（１）水素化ホウ素ナトリウムのようなアルカリ金属水素化ホウ素（alkali metal boron hydride）のような、金属水素化物複合体（metal hydride complex）を使用した脱ハロゲン化；（２）パラジウムカーボンのような遷移金属触媒を使用した触媒的還元過程による脱ハロゲン化；（３）（ｎ−Ｃ４Ｈ９）３ＳｎＨのような有機スズ水素化物を使用した脱ハロゲン化；（４）リチウムアルミニウム水素化物のようなアルミニウム水素化物のアルカリ金属錯体（complexes）を使用した脱ハロゲン化；（５）亜鉛及び塩酸を使用した脱ハロゲン化；及び（６）電気分解的還元（electrolytic reduction）による脱ハロゲン化。 US Pat. Nos. 4,446,319 and 4,701,559 disclose several methods for dehalogenating compounds of formula (III): (1 ) Dehalogenation using a metal hydride complex such as an alkali metal boron hydride such as sodium borohydride; (2) Transition metals such as palladium carbon dehalogenation by catalytic reduction process using a catalyst; (3) (n-C 4 H 9) 3 dehalogenation using an organic tin hydride such as SnH; (4), such as lithium aluminum hydride Dehalogenation using alkali metal complexes of aluminum hydride; (5) Dehalogenation using zinc and hydrochloric acid; and (6) Electrolytic reduction. eduction).
しかし、前記方法（１）及び（４）は、水素ガスが発生するので、非常な爆発性を有する。また、前記生成物（すなわち、化学式（ＩＩ）の化合物）を分離するために、活性炭を使用したカラムクロマトグラフィのための特殊な製造装置を必要とするので、産業的規模の量産に適さない。 However, the methods (1) and (4) are very explosive because hydrogen gas is generated. Further, in order to separate the product (that is, the compound of the chemical formula (II)), a special production apparatus for column chromatography using activated carbon is required, which is not suitable for mass production on an industrial scale.
前記方法（２）は、非常な爆発性を有し、水素化反応器のような特殊な製造装置を必要とする。 The method (2) is very explosive and requires special production equipment such as a hydrogenation reactor.
前記方法（３）で使われる有機スズ水素化物は、環境ホルモンの一つであり、生成物に残留する可能性がある。従って、前記方法（３）は、医薬品またはその合成中間体の製造に適さない。 The organotin hydride used in the method (3) is one of environmental hormones and may remain in the product. Therefore, the method (3) is not suitable for producing a pharmaceutical product or a synthetic intermediate thereof.
前記方法（５）及び（６）も、特殊な製造装置を必要とするので、産業的規模の量産に適さない。 The methods (5) and (6) are also not suitable for industrial-scale mass production because they require special production equipment.
本発明は、安全であって産業的規模の量産に適用されうる化学式（ＩＩＩ）の化合物、すなわち９−ブロモ−６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの脱ハロゲン化方法を提供する。 The present invention is a compound of the formula (III) that is safe and applicable to mass production on an industrial scale, namely 9-bromo-6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2 A method for dehalogenation of oxa-4-azabicyclo [3.3.1] nonane is provided.
本発明は、亜リン酸塩誘導体をラジカル−還元剤として使用することにより、産業的規模の量産に適用できる、化学式（ＩＩＩ）の化合物の脱ハロゲン化方法を提供する。 The present invention provides a method for dehalogenating a compound of formula (III), which can be applied to mass production on an industrial scale by using a phosphite derivative as a radical-reducing agent.
本発明の一様態により、化学式（ＩＩＩ）の化合物を化学式（ＩＶ）の化合物と反応させることを含む、化学式（ＩＩ）の化合物の製造方法が提供される：
本発明の他の様態により、前記製造方法から得られた化学式（ＩＩ）の化合物を加水分解することを含む、バリオールアミンまたはその無毒性塩の製造方法が提供される。 According to another aspect of the present invention, there is provided a method for producing variolamine or a non-toxic salt thereof, comprising hydrolyzing a compound of the formula (II) obtained from the above production method.
本発明のさらに他の様態により、前記製造方法から得られた化学式（ＩＩ）の化合物を加水分解してバリオールアミンまたはその無毒性塩を得る段階と、前記バリオールアミンまたはその無毒性塩をジヒドロキシアセトンと反応させる段階とを含む、Ｎ−（１，３−ジヒドロキシ−２−プロピル）バリオールアミンまたはその無毒性塩の製造方法が提供される。 According to still another aspect of the present invention, a step of hydrolyzing a compound of the formula (II) obtained from the above production method to obtain variolamine or a non-toxic salt thereof, And a method for producing N- (1,3-dihydroxy-2-propyl) variolamine or a non-toxic salt thereof, comprising a step of reacting with dihydroxyacetone.
本発明の一具現例による化学式（ＩＩ）の化合物の製造方法は、下記反応式２により、化学式（ＩＩＩ）の化合物を化学式（ＩＶ）の化合物と反応させることを含む：
反応式２
Reaction formula 2
化学式（ＩＩＩ）の化合物は、公知の方法（例えば、米国特許第４，４４６，３４９号明細書）を利用して製造でき、化学式（ＩＶ）の化合物は、商業的に得ることができる。 The compound of the formula (III) can be produced by using a known method (for example, US Pat. No. 4,446,349), and the compound of the formula (IV) can be obtained commercially.
本発明の製造方法において、化学式（ＩＶ）の化合物は、ラジカル−還元剤として使われる。化学式（ＩＶ）の化合物は、非常に安全であり、取扱いが容易である。また、化学式（ＩＶ）の化合物は、生成物、すなわち化学式（ＩＩ）の化合物を分離する段階で、使われた溶媒と共に容易に除去されうる。また、化学式（ＩＶ）の化合物を使用した脱ハロゲン化は、通常の製造装置で行うことができるので、産業的規模の量産に容易に適用できる。 In the production method of the present invention, the compound of formula (IV) is used as a radical-reducing agent. The compound of formula (IV) is very safe and easy to handle. Also, the compound of formula (IV) can be easily removed together with the solvent used in the step of separating the product, that is, the compound of formula (II). Moreover, since the dehalogenation using the compound of the chemical formula (IV) can be performed with a normal production apparatus, it can be easily applied to mass production on an industrial scale.
化学式（ＩＶ）の化合物は、次亜リン酸（hypophosphorous acid）、次亜リン酸ナトリウム（sodium hypophosphite）、亜リン酸ジメチル（dimethyl phosphite）及び亜リン酸ジエチル（diethyl phosphite）を含む。このうち、次亜リン酸ナトリウムが望ましく使われる。化学式（ＩＶ）の化合物の量は、化学式（ＩＩＩ）の化合物１ｅｑ．に対して約１〜１０ｅｑ．、望ましくは１〜２ｅｑ．の範囲でありうる。 Compounds of formula (IV) include hypophosphorous acid, sodium hypophosphite, dimethyl phosphite and diethyl phosphite. Of these, sodium hypophosphite is preferably used. The amount of the compound of the chemical formula (IV) is adjusted according to the compound 1 eq. About 1 to 10 eq. , Desirably 1-2 eq. Range.
化学式（ＩＩＩ）の化合物と化学式（ＩＶ）の化合物との反応は、ラジカル反応の開始剤、例えばα，α’−アゾビスイソブチロニトリル（α,α’-azobisisobutyronitrile）のようなアゾ化合物類、過酸化ベンゾイル（benzoylperoxide）のような過酸化物類、またはトリフェニルボレート（triphenylborate）などの存在下で行うことが可能である。前記開始剤は、化学式（ＩＩＩ）の化合物に対して触媒量で使われうる。 The reaction of the compound of formula (III) with the compound of formula (IV) is a radical reaction initiator, for example, azo compounds such as α, α'-azobisisobutyronitrile. It can be carried out in the presence of peroxides such as benzoylperoxide or triphenylborate. The initiator may be used in a catalytic amount relative to the compound of formula (III).
また、化学式（ＩＩＩ）の化合物と化学式（ＩＶ）の化合物との反応は、水、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、アセトニトリル、メタノールまたはエタノールのようなＣ１−Ｃ５アルコール、テトラヒドロフランのようなエーテル類、アセトンまたはメチルエチルケトンのようなケトン類、酢酸メチルまたは酢酸エチルのようなエステル類、トルエンのようなベンゼン類、及びそれらの混合物からなる群から選択された溶媒中で行うことが可能である。それらのうち、水とＣ１−Ｃ５アルコールとの混合溶媒が望ましく使われうる。 Also, the reaction of the compound of formula (III) with the compound of formula (IV) is carried out by reacting C 1 − such as water, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, methanol or ethanol. C 5 alcohols, ethers such as tetrahydrofuran, ketones such as acetone or methyl ethyl ketone, esters such as methyl acetate or ethyl acetate, benzenes such as toluene, and selected from the group consisting of mixtures thereof solvent Can be done in. Among them, a mixed solvent of water and C 1 -C 5 alcohol can be used preferably.
化学式（ＩＩＩ）の化合物と化学式（ＩＶ）の化合物との反応は、窒素及びアルゴンのような不活性ガス下で行われうる。また、前記反応は、４０〜１００℃または使われた溶媒の還流温度で、約３〜５時間行われうる。 The reaction of the compound of formula (III) with the compound of formula (IV) can be carried out under an inert gas such as nitrogen and argon. In addition, the reaction may be performed at 40 to 100 ° C. or the reflux temperature of the solvent used for about 3 to 5 hours.
前記のような製造方法によって得られた化学式（ＩＩ）の化合物は、公知の方法（例えば、米国特許第４，４４６，３１９号明細書及び／または第４，７０１，５５９号明細書）により、バリオールアミンまたはその無毒性塩及び／またはＮ−（１，３−ジヒドロキシ−２−プロピル）バリオールアミンまたはその無毒性塩に転換されうる。 The compound of formula (II) obtained by the above production method can be obtained by a known method (for example, US Pat. No. 4,446,319 and / or 4,701,559). It can be converted to variolamine or its non-toxic salt and / or N- (1,3-dihydroxy-2-propyl) variolamine or its non-toxic salt.
例えば、化学式（ＩＩ）の化合物を加水分解し、バリオールアミンまたはその無毒性塩に転換させることができる。また、ジヒドロキシアセトンのようなケトン化合物を使用して前記バリオールアミンまたはその無毒性塩の還元的アルキル化を行うことにより、バリオールアミンのＮ−置換された誘導体またはその無毒性塩を得ることができる。 For example, the compound of formula (II) can be hydrolyzed and converted to variolamine or a non-toxic salt thereof. Also, an N-substituted derivative of variolamine or a nontoxic salt thereof can be obtained by performing reductive alkylation of the variolamine or nontoxic salt thereof using a ketone compound such as dihydroxyacetone. Can do.
従って、本発明の他の様態により、前記製造方法から得られた化学式（ＩＩ）の化合物を加水分解することを含むバリオールアミンまたはその無毒性塩の製造方法が提供される。 Therefore, according to another aspect of the present invention, there is provided a method for producing variolamine or a non-toxic salt thereof comprising hydrolyzing the compound of formula (II) obtained from the above production method.
また、本発明のさらに他の様態により、前記製造方法から得られた化学式（ＩＩ）の化合物を加水分解し、バリオールアミンまたはその無毒性塩を得る段階と、前記バリオールアミンまたはその無毒性塩をジヒドロキシアセトンと反応させる段階とを含む、Ｎ−（１，３−ジヒドロキシ−２−プロピル）バリオールアミンまたはその無毒性塩の製造方法が提供される。 Further, according to still another aspect of the present invention, the compound of the formula (II) obtained from the production method is hydrolyzed to obtain variolamine or a non-toxic salt thereof; Reacting the salt with dihydroxyacetone, and a method for producing N- (1,3-dihydroxy-2-propyl) variolamine or a non-toxic salt thereof.
以下、本発明を実施例を介してさらに具体的に説明する。しかし、下記実施例は、例示を目的に提供されたものであり、本発明がそれらのみによって制限されるものではない。 Hereinafter, the present invention will be described more specifically through examples. However, the following examples are provided for illustrative purposes, and the present invention is not limited thereto.
参照実施例１．
９−ブロモ−６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナン
９．３ｇのＮ−（ベンジルオキシカルボニル）バリエナアミンの水溶液２００ｍｌと、５．３ｇの臭素水溶液２５０ｍｌとを同時に５〜１０℃に冷却された水１００ｍｌに約１時間にわたって滴加した。前記反応混合物を同じ温度で１．５時間さらに撹拌し、炭酸水素ナトリウム水溶液でｐＨ６に調節した後、酢酸エチルで洗浄した。前記水溶液を減圧濃縮した後、残滓をＭＣＩ Ｇｅｌ ＣＨＰ ２０Ｐカラム（三菱化学工業（株）、６００ｍｌ）でクロマトグラフィを行った。溶離液を濃縮した。得られた残滓を結晶化して濾過し、標題化合物６．５ｇを得た。
1H NMR (D2O, 400MHz) δ 4.70 (1H, s), 4.30 (1H, d, J 9.6 Hz), 4.14 (1H, d, J 9.6 Hz), 4.07 (1H, d, J 13.2 Hz), 3.93-3.87 (2H, m), 3.69-3.59 (1H, m)
Reference Example 1
9-bromo-6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane 9.3 g N- (benzyloxycarbonyl) 200 ml of an aqueous solution of varienaamine and 250 ml of a 5.3 g aqueous bromine solution were simultaneously added dropwise to 100 ml of water cooled to 5 to 10 ° C. over about 1 hour. The reaction mixture was further stirred at the same temperature for 1.5 hours, adjusted to pH 6 with aqueous sodium bicarbonate solution, and then washed with ethyl acetate. The aqueous solution was concentrated under reduced pressure, and the residue was chromatographed on an MCI Gel CHP 20P column (Mitsubishi Chemical Industry Co., Ltd., 600 ml). The eluent was concentrated. The resulting residue was crystallized and filtered to obtain 6.5 g of the title compound.
1 H NMR (D 2 O, 400 MHz) δ 4.70 (1H, s), 4.30 (1H, d, J 9.6 Hz), 4.14 (1H, d, J 9.6 Hz), 4.07 (1H, d, J 13.2 Hz) , 3.93-3.87 (2H, m), 3.69-3.59 (1H, m)
実施例１．
６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナン
４００ｍｌの水及び３００ｍｌのメタノールの混合溶媒中の１００ｇの９−ブロモ−６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの懸濁液に、１．１ｇのα，α’−アゾビスイソブチロニトリル及び４６．２ｇの次亜リン酸ナトリウムを加えた。前記反応混合物を８０〜８５℃で３時間撹拌後、５０〜６０℃に冷却した。前記反応混合物を濾過して不溶物を除去し、濾液を減圧濃縮した。５００ｍｌのメタノールを得られた残滓に加え、３０分間還流した。前記反応混合物を室温で１時間撹拌し、濾過した。得られた結晶を減圧乾燥して白色結晶の標題化合物６７ｇを得た。
1H NMR (D2O, 400MHz) δ 3.82 (1H, d, J 12.4 Hz), 3.69-3.63 (3H, m), 3.60 (1H, d, J 9.2 Hz), 3.49 (1H, t, J 9.2 Hz), 2.15 (1H, dd, J 14.4, 4.4 Hz), 1.94 (1H, dd, J 14.4, 2.0 Hz)
Example 1.
6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane 100 g of 9 in a mixed solvent of 400 ml water and 300 ml methanol -To a suspension of bromo-6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane, 1.1 g of α, α'-Azobisisobutyronitrile and 46.2 g of sodium hypophosphite were added. The reaction mixture was stirred at 80 to 85 ° C. for 3 hours and then cooled to 50 to 60 ° C. The reaction mixture was filtered to remove insoluble matters, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue and refluxed for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and filtered. The obtained crystals were dried under reduced pressure to give 67 g of the title compound as white crystals.
1 H NMR (D 2 O, 400 MHz) δ 3.82 (1H, d, J 12.4 Hz), 3.69-3.63 (3H, m), 3.60 (1H, d, J 9.2 Hz), 3.49 (1H, t, J 9.2 Hz), 2.15 (1H, dd, J 14.4, 4.4 Hz), 1.94 (1H, dd, J 14.4, 2.0 Hz)
実施例２．
６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナン
４００ｍｌの水中の１００ｇの９−ブロモ−６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの懸濁液に、１．１ｇのα，α’−アゾビスイソブチロニトリル及び４６．２ｇの次亜リン酸ナトリウムを加えた。前記反応混合物を８０〜８５℃で３時間撹拌後、５０〜６０℃に冷却した。前記反応混合物を濾過して不溶物を除去し、濾液を減圧濃縮した。５００ｍｌのメタノールを得られた残滓に加え、３０分間還流した。前記反応混合物を室温で１時間撹拌し、濾過した。得られた結晶を減圧乾燥して白色結晶の標題化合物６８．３ｇを得た。
Example 2
6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane 100 g 9-bromo-6,7,8 in 400 ml water -To a suspension of trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane, 1.1 g of α, α'-azobisisobutyro Nitrile and 46.2 g sodium hypophosphite were added. The reaction mixture was stirred at 80 to 85 ° C. for 3 hours and then cooled to 50 to 60 ° C. The reaction mixture was filtered to remove insoluble matters, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue and refluxed for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and filtered. The obtained crystals were dried under reduced pressure to obtain 68.3 g of the title compound as white crystals.
実施例３．
６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナン
４００ｍｌのエタノール中の１００ｇの９−ブロモ−６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの懸濁液に、１．１ｇのα，α’−アゾビスイソブチロニトリル及び４６．２ｇの次亜リン酸ナトリウムを加えた。前記反応混合物を８０〜８５℃で３時間撹拌した。 溶媒の一部を減圧蒸留して除去した。前記反応混合物を室温で１時間撹拌し、濾過した。得られた結晶を減圧乾燥して白色結晶の標題化合物５８.１ｇを得た。
Example 3
6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane 100 g of 9-bromo-6,7,400 ml in 400 ml of ethanol To a suspension of 8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane was added 1.1 g of α, α′-azobisisobutyrate. Ronitrile and 46.2 g of sodium hypophosphite were added. The reaction mixture was stirred at 80-85 ° C. for 3 hours. A part of the solvent was removed by distillation under reduced pressure. The reaction mixture was stirred at room temperature for 1 hour and filtered. The obtained crystals were dried under reduced pressure to obtain 58.1 g of the title compound as white crystals.
実施例４．
６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナン
４００ｍｌの水及び３００ｍｌのエタノールの混合溶媒中の１００ｇの９−ブロモ−６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの懸濁液に、１．１ｇのα，α’−アゾビスイソブチロニトリル及び４６．２ｇの次亜リン酸ナトリウムを加えた。前記反応混合物を８０〜８５℃で３時間撹拌後、５０〜６０℃に冷却した。前記反応混合物を濾過して不溶物を除去し、濾液を減圧濃縮した。５００ｍｌのメタノールを得られた残滓に加え、３０分間還流した。前記反応混合物を室温で１時間撹拌し、濾過した。得られた結晶を減圧乾燥して白色結晶の標題化合物７１ｇを得た。
Example 4
6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane 100 g of 9 in a mixed solvent of 400 ml water and 300 ml ethanol -To a suspension of bromo-6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane, 1.1 g of α, α'-Azobisisobutyronitrile and 46.2 g of sodium hypophosphite were added. The reaction mixture was stirred at 80 to 85 ° C. for 3 hours and then cooled to 50 to 60 ° C. The reaction mixture was filtered to remove insoluble matters, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue and refluxed for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and filtered. The obtained crystals were dried under reduced pressure to obtain 71 g of the title compound as white crystals.
実施例５．
６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナン
４００ｍｌのアセトニトリル中の１００ｇの９−ブロモ−６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの懸濁液に、１．１ｇのα，α’−アゾビスイソブチロニトリル及び４６．２ｇの次亜リン酸ナトリウムを加えた。前記反応混合物を８０〜８５℃で３時間撹拌した。溶媒の一部を減圧蒸留して除去した。前記反応混合物を室温で１時間撹拌し、濾過した。得られた結晶を減圧乾燥して白色結晶の標題化合物６０ｇを得た。
Example 5 FIG.
6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane 100 g 9-bromo-6,7,400 ml in 400 ml acetonitrile To a suspension of 8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane was added 1.1 g of α, α′-azobisisobutyrate. Ronitrile and 46.2 g of sodium hypophosphite were added. The reaction mixture was stirred at 80-85 ° C. for 3 hours. A part of the solvent was removed by distillation under reduced pressure. The reaction mixture was stirred at room temperature for 1 hour and filtered. The obtained crystals were dried under reduced pressure to obtain 60 g of the title compound as white crystals.
実施例６．
６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナン
４００ｍｌの水中の１００ｇの９−ブロモ−６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの懸濁液に、１．１ｇのα，α’−アゾビスイソブチロニトリル及び４０．６ｇの亜リン酸ジメチルを加えた。前記反応混合物を８０〜８５℃で４時間撹拌後、５０〜６０℃に冷却した。前記反応混合物を濾過して不溶物を除去し、濾液を減圧濃縮した。５００ｍｌのメタノールを得られた残滓に加え、濾過した。得られた結晶を減圧乾燥して白色結晶の標題化合物５７.６ｇを得た。
Example 6
6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane 100 g 9-bromo-6,7,8 in 400 ml water -To a suspension of trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane, 1.1 g of α, α'-azobisisobutyro Nitrile and 40.6 g of dimethyl phosphite were added. The reaction mixture was stirred at 80 to 85 ° C. for 4 hours and then cooled to 50 to 60 ° C. The reaction mixture was filtered to remove insoluble matters, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue and filtered. The obtained crystals were dried under reduced pressure to obtain 57.6 g of the title compound as white crystals.
実施例７．
６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナン
４００ｍｌの水中の１００ｇの９−ブロモ−６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの懸濁液に、１．１ｇのα，α’−アゾビスイソブチロニトリル及び３９．１ｇの次亜リン酸ナトリウムを加えた。前記反応混合物を８０〜８５℃で４時間撹拌後、５０〜６０℃に冷却した。前記反応混合物を濾過して不溶物を除去し、濾液を減圧濃縮した。５００ｍｌのメタノールを得られた残滓に加え、濾過した。得られた結晶を減圧乾燥して白色結晶の標題化合物６１ｇを得た。
Example 7
6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane 100 g 9-bromo-6,7,8 in 400 ml water -To a suspension of trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane, 1.1 g of α, α'-azobisisobutyro Nitrile and 39.1 g sodium hypophosphite were added. The reaction mixture was stirred at 80 to 85 ° C. for 4 hours and then cooled to 50 to 60 ° C. The reaction mixture was filtered to remove insoluble matters, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue and filtered. The obtained crystals were dried under reduced pressure to give 61 g of the title compound as white crystals.
実施例８．
６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナン
４００ｍｌの水中の１００ｇの９−ブロモ−６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの懸濁液に、１．１ｇのα，α’−アゾビスイソブチロニトリル及び４６．２ｇの次亜リン酸ナトリウムを加えた。前記反応混合物を４０〜５０℃で５時間撹拌した。前記反応混合物を濾過して不溶物を除去し、濾液を減圧濃縮した。５００ｍｌのメタノールを得られた残滓に加え、濾過した。得られた結晶を減圧乾燥して白色結晶の標題化合物５４ｇを得た。
Example 8 FIG.
6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane 100 g 9-bromo-6,7,8 in 400 ml water -To a suspension of trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane, 1.1 g of α, α'-azobisisobutyro Nitrile and 46.2 g sodium hypophosphite were added. The reaction mixture was stirred at 40-50 ° C. for 5 hours. The reaction mixture was filtered to remove insoluble matters, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue and filtered. The obtained crystals were dried under reduced pressure to obtain 54 g of the title compound as white crystals.
本発明は、安全であって産業的規模の量産に適用できる、９−ブロモ−６，７，８−トリヒドロキシ−１−（ヒドロキシメチル）−３−オキソ−２−オキサ−４−アザビシクロ［３．３．１］ノナンの脱ハロゲン化方法を提供する。また、本発明は、バリオールアミンまたはＮ−（１，３−ジヒドロキシ−２−プロピル）バリオールアミンの製造方法を提供する。 The present invention is 9-bromo-6,7,8-trihydroxy-1- (hydroxymethyl) -3-oxo-2-oxa-4-azabicyclo [3, which is safe and applicable to mass production on an industrial scale. 3.1] A method for dehalogenation of nonane is provided. The present invention also provides a method for producing variolamine or N- (1,3-dihydroxy-2-propyl) variolamine.
Claims (8)
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| KR1020050044964A KR100956490B1 (en) | 2005-05-27 | 2005-05-27 | A process for preparing pseudo-aminosugars using new dehalogenation reagent |
| KR10-2005-0044964 | 2005-05-27 | ||
| PCT/KR2006/001764 WO2006126790A1 (en) | 2005-05-27 | 2006-05-11 | Processes for preparing 6,7,8-trihydroxy-1-(hydroxymethyl)-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane |
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| CN101830814A (en) * | 2010-05-13 | 2010-09-15 | 浙江钱江生物化学股份有限公司 | Method for separating and purifying intermediate product of Valienamine bromide in effective Valiolamine synchronizing process |
| CN103145650B (en) * | 2013-03-15 | 2016-03-23 | 浙江医药股份有限公司新昌制药厂 | A kind of preparation method of (-)-effective mildew enamine pentaacetate epoxide |
| CN108276298A (en) * | 2017-12-29 | 2018-07-13 | 山东新华制药股份有限公司 | The preparation process of voglibose impurity vinyl voglibose |
| CN116239498B (en) * | 2023-05-11 | 2023-07-21 | 北京元延医药科技股份有限公司 | Method for preparing clenbuterol intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57179174A (en) * | 1981-04-28 | 1982-11-04 | Takeda Chem Ind Ltd | Novel aminocyclitol and its preparation |
| JPH0238580B2 (en) * | 1981-06-02 | 1990-08-31 | Takeda Chemical Industries Ltd | BARIOORUAMINNONNCHIKANJUDOTAI * SONOSEIZOHOOYOBYOTO |
| JPH0380561A (en) * | 1989-08-23 | 1991-04-05 | Seiko Epson Corp | Semiconductor device provided with battery unit |
| JP2000198796A (en) * | 1998-11-02 | 2000-07-18 | Ajinomoto Co Inc | Production of nucleic acid derivative |
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| DE3166093D1 (en) | 1981-01-05 | 1984-10-18 | Takeda Chemical Industries Ltd | N-substituted pseudo-aminosugars, their production and use |
| US4446319A (en) * | 1981-04-28 | 1984-05-01 | Takeda Chemical Industries, Ltd. | Aminocyclitols and their production |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57179174A (en) * | 1981-04-28 | 1982-11-04 | Takeda Chem Ind Ltd | Novel aminocyclitol and its preparation |
| JPH0238580B2 (en) * | 1981-06-02 | 1990-08-31 | Takeda Chemical Industries Ltd | BARIOORUAMINNONNCHIKANJUDOTAI * SONOSEIZOHOOYOBYOTO |
| JPH0380561A (en) * | 1989-08-23 | 1991-04-05 | Seiko Epson Corp | Semiconductor device provided with battery unit |
| JP2000198796A (en) * | 1998-11-02 | 2000-07-18 | Ajinomoto Co Inc | Production of nucleic acid derivative |
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| JP2011530487A (en) * | 2008-08-08 | 2011-12-22 | ▲無▼▲錫▼▲薬▼▲興▼▲医▼▲薬▼科技有限公司 | Substances and methods for the stereoselective synthesis of variolamines |
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| JP4954201B2 (en) | 2012-06-13 |
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