JP5612603B2 - ベータ−アセチルフラノシドの回収方法 - Google Patents
ベータ−アセチルフラノシドの回収方法 Download PDFInfo
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- JP5612603B2 JP5612603B2 JP2011542848A JP2011542848A JP5612603B2 JP 5612603 B2 JP5612603 B2 JP 5612603B2 JP 2011542848 A JP2011542848 A JP 2011542848A JP 2011542848 A JP2011542848 A JP 2011542848A JP 5612603 B2 JP5612603 B2 JP 5612603B2
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- acf
- mother liquor
- solvent
- distillation
- acetylfuranoside
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- 238000000034 method Methods 0.000 title claims description 35
- 239000002904 solvent Substances 0.000 claims description 19
- 238000004821 distillation Methods 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 239000012452 mother liquor Substances 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 7
- 230000006196 deacetylation Effects 0.000 claims description 7
- 238000003381 deacetylation reaction Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 238000011084 recovery Methods 0.000 claims description 7
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 229960004117 capecitabine Drugs 0.000 claims description 6
- 239000010409 thin film Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000012345 acetylating agent Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000013557 residual solvent Substances 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims 2
- 239000012141 concentrate Substances 0.000 claims 2
- FEOOHOXQNOVDKV-RKEPMNIXSA-N 1-[(3R,4S,5R)-2,3,4-trihydroxy-5-(hydroxymethyl)oxolan-2-yl]ethanone Chemical compound C(C)(=O)C1(O)[C@H](O)[C@H](O)[C@H](O1)CO FEOOHOXQNOVDKV-RKEPMNIXSA-N 0.000 claims 1
- MKMRBXQLEMYZOY-SOOFDHNKSA-N 5-deoxy-D-ribofuranose Chemical compound C[C@H]1OC(O)[C@H](O)[C@@H]1O MKMRBXQLEMYZOY-SOOFDHNKSA-N 0.000 claims 1
- NXEJETQVUQAKTO-ZBCCYFLUSA-N [(2r,3r,4r)-4,5-diacetyloxy-2-methyloxolan-3-yl] acetate Chemical compound C[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O NXEJETQVUQAKTO-ZBCCYFLUSA-N 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 7
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000000199 molecular distillation Methods 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical class O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 2
- 239000010408 film Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000001577 simple distillation Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- -1 acetyl halide Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 239000002894 chemical waste Substances 0.000 description 1
- 238000001944 continuous distillation Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000012958 reprocessing Methods 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
1つの実施態様において、本発明は、最初は分離されていないβ−ACFを、ACFの合成から残っている母液から回収するための方法を提供し、ここで、β−ACFは、少なくとも1つの蒸留方法及び少なくとも1つの化学反応ステップの組み合わせによって回収される。
a)ACFの最初の合成から残っている母液を残留溶媒が1%未満となるまで蒸発させて、残留α/β−ACFの含有量を約8〜15重量%から約25〜45重量%まで増加させ、続いて、約60〜80重量%まで蒸留し、そして、好適な溶媒を添加することによって、β−ACFを蒸留物から結晶化させ;
b)脱アセチル化及び続く再アセチル化により、ステップa)の母液中に残ったα/β−ACF混合物をβ−ACFに化学変換し、その後の好適な溶媒の添加によりβ−ACFを結晶化させ;
c)連続した(時計回りの)サイクル工程において、任意にステップa)及びb)を反復する。
定義
「母液」という用語は、本発明の方法の任意のステップにおいて主要反応生成物が残った出発材料又は副生成物の混合物から単離された後に残っている、出発材料又は副生成物の任意の残留混合物を意味する。特に、本明細書中で使用されるとおり、母液という用語は、上記のスキーム1によるACFの合成の後に残る混合物であって、さまざまな不純物及び副生成物とともに残余量のα/β−ACFを含むものを意味する。
上記のスキーム1によってβ−ACFを得るための化学的な標準的手順から残留する母液及び廃水流は、さまざまな不純物及び副生成物のほかに相当量のα/β−アセチルフラノシドを含む。
α/β−アセチルフラノシドのβ−アセチルフラノシドへの変換は、以下のスキーム2の方法にしたがって実施可能である:
蒸留
3000kgのアセチルフラノシド母液(α/β比が35:65)を、30〜80℃、及び5〜100mbarで、油(残留溶媒1%未満)となるまで蒸発させた(約1000kgの残油)。残油を、1〜3mbarの真空下、かつ200〜210℃の蒸気加熱温度において、連続薄膜蒸発装置中で蒸留して、(α/β−アセチルフラノシドを含む)609kgの蒸留物及び約400kgの残渣を得た。
1247kgの蒸留物(α/β比が35:65)を541Lのプロパン−2−オールに20〜25℃で溶解し、そして、−12℃〜−8℃に冷却した。得られた懸濁液を6時間攪拌して、結晶化を完結した。結晶化物(crystallizate)を単離して、冷プロパン−2−オールで洗浄した。
811kgのアセチルフラノシド母液(約250kgのα/β−アセチルフラノシド)を蒸留によって濃縮して、油性残渣(α/β比が60:40)を得た。そして、1060Lのメタノールを添加し、そして、−8℃に冷却した。127Lのナトリウムメトキシドを添加し、そして、3時間攪拌した。反応混合物を126Lの準濃塩酸(semi concentrated hydrochloric acid)で中和して、pH5.1とした。
Claims (4)
- 最初は分離されていない5−デオキシ−1,2,3−トリ−O−アセチル−D−リボフラノースのβアノマー体(β−ACF)を、5−デオキシ−1,2,3−トリ−O−アセチル−D−リボフラノース(ACF)の合成から残っている母液から回収する方法であって、前記β−ACFが、以下の連続的ステップ:
a)8〜15重量%のACFのαアノマー体とβアノマー体の混合物(α/β−ACF)を含有する前記ACFの最初の合成から残っている母液を、残留溶媒が1%未満となるまで蒸発させることにより、α/β−ACFを25〜45重量%含有する濃縮物を取得し、続いて、該濃縮物を蒸留して60〜80重量%のα/β−ACFを含有する蒸留物を取得し、そして次に、該蒸留物に溶媒を添加することによって、β−ACFを結晶化させ;
b)ステップa)の前記母液中に残ったα/β−ACFを脱アセチル化して5−デオキシリボフラノース(トリオール)を取得し、続いて該トリオールを再アセチル化してβ−ACFを取得し、その後の溶媒の添加によりβ−ACFを結晶化させ;
c)連続した(時計回りの)サイクル工程において、任意にステップa)及びb)を反復する、
によって回収される、前記方法。 - ステップa)における、60〜80重量%の蒸留物を取得する前記蒸留が、連続薄膜蒸発装置において、1〜3mbar及び200〜210℃の加熱温度で実施される、請求項1に記載の方法。
- ステップb)が、塩基の存在下でのα/β−ACFの前記脱アセチル化、続く酸による中和、そして、さらに続く塩基、触媒及びアセチル化剤の存在下での前記再アセチル化反応を含む、請求項1又は2に記載の方法。
- カペシタビンの製造の間に使用するための、請求項1〜3のいずれか1項に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09151384A EP2210895A1 (en) | 2009-01-27 | 2009-01-27 | Process for the recovery of beta-Acetylfuranoside |
EP09151384.6 | 2009-01-27 | ||
PCT/EP2010/050523 WO2010086247A1 (en) | 2009-01-27 | 2010-01-18 | Process for the recovery of beta-acetylfuranoside |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2012513970A JP2012513970A (ja) | 2012-06-21 |
JP5612603B2 true JP5612603B2 (ja) | 2014-10-22 |
Family
ID=40801987
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2011542848A Expired - Fee Related JP5612603B2 (ja) | 2009-01-27 | 2010-01-18 | ベータ−アセチルフラノシドの回収方法 |
Country Status (11)
Country | Link |
---|---|
US (2) | US20100190976A1 (ja) |
EP (2) | EP2210895A1 (ja) |
JP (1) | JP5612603B2 (ja) |
CN (2) | CN102245621A (ja) |
CA (1) | CA2748954C (ja) |
DK (1) | DK2391633T3 (ja) |
ES (1) | ES2535051T3 (ja) |
PL (1) | PL2391633T3 (ja) |
SG (1) | SG173113A1 (ja) |
SI (1) | SI2391633T1 (ja) |
WO (1) | WO2010086247A1 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2210895A1 (en) * | 2009-01-27 | 2010-07-28 | F. Hoffmann-La Roche AG | Process for the recovery of beta-Acetylfuranoside |
CN104017033B (zh) * | 2014-06-14 | 2016-08-17 | 济南尚博生物科技有限公司 | 一种制备糖苷的方法 |
CN112125938A (zh) * | 2020-09-26 | 2020-12-25 | 安徽金禾实业股份有限公司 | 一种从糖渣萃取三氯蔗糖-6-乙酯的方法 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1135258A (en) | 1979-06-15 | 1982-11-09 | Richard D'souza | Process for the preparation of 5'deoxy-5-fluorouridine |
DE3714473A1 (de) * | 1987-04-30 | 1988-11-10 | Basf Ag | Kontinuierliches verfahren zur epimerisierung von zuckern, insbesondere von d-arabinose zu d-ribose |
ITMI20032059A1 (it) | 2003-10-22 | 2005-04-23 | Clariant Lsm Italia Spa | Processo per la preparazione di doxifluridina. |
CN100383128C (zh) * | 2004-02-23 | 2008-04-23 | 上海迪赛诺医药发展有限公司 | N4-氧羰基胞嘧啶衍生物及制备方法与应用 |
WO2008080822A1 (en) * | 2006-12-29 | 2008-07-10 | F. Hoffmann-La Roche Ag | Epimerization methodologies for recovering stereo isomers in high yield and purity |
KR100908363B1 (ko) * | 2007-02-28 | 2009-07-20 | 한미약품 주식회사 | 트라이-O-아세틸-5-데옥시-β-D-라이보퓨라노즈의입체선택적 제조방법 및 이의 분리방법 |
EP2210895A1 (en) * | 2009-01-27 | 2010-07-28 | F. Hoffmann-La Roche AG | Process for the recovery of beta-Acetylfuranoside |
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2009
- 2009-01-27 EP EP09151384A patent/EP2210895A1/en not_active Withdrawn
-
2010
- 2010-01-18 CA CA2748954A patent/CA2748954C/en active Active
- 2010-01-18 WO PCT/EP2010/050523 patent/WO2010086247A1/en active Application Filing
- 2010-01-18 DK DK10700424.4T patent/DK2391633T3/en active
- 2010-01-18 SI SI201030937T patent/SI2391633T1/sl unknown
- 2010-01-18 EP EP10700424.4A patent/EP2391633B1/en active Active
- 2010-01-18 PL PL10700424T patent/PL2391633T3/pl unknown
- 2010-01-18 ES ES10700424.4T patent/ES2535051T3/es active Active
- 2010-01-18 CN CN2010800035320A patent/CN102245621A/zh active Pending
- 2010-01-18 JP JP2011542848A patent/JP5612603B2/ja not_active Expired - Fee Related
- 2010-01-18 CN CN201610288682.XA patent/CN106397503A/zh active Pending
- 2010-01-18 SG SG2011053337A patent/SG173113A1/en unknown
- 2010-01-20 US US12/690,167 patent/US20100190976A1/en not_active Abandoned
-
2012
- 2012-11-13 US US13/675,220 patent/US9580455B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
US20100190976A1 (en) | 2010-07-29 |
SI2391633T1 (sl) | 2015-06-30 |
US9580455B2 (en) | 2017-02-28 |
WO2010086247A1 (en) | 2010-08-05 |
US20130072674A1 (en) | 2013-03-21 |
DK2391633T3 (en) | 2015-05-11 |
EP2210895A1 (en) | 2010-07-28 |
CN102245621A (zh) | 2011-11-16 |
US20160333040A9 (en) | 2016-11-17 |
CA2748954A1 (en) | 2010-08-05 |
CN106397503A (zh) | 2017-02-15 |
EP2391633B1 (en) | 2015-03-18 |
ES2535051T3 (es) | 2015-05-04 |
SG173113A1 (en) | 2011-08-29 |
EP2391633A1 (en) | 2011-12-07 |
PL2391633T3 (pl) | 2015-08-31 |
CA2748954C (en) | 2017-01-03 |
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