TWI358408B - New process for the synthesis of strontium ranelat - Google Patents
New process for the synthesis of strontium ranelat Download PDFInfo
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- TWI358408B TWI358408B TW097136693A TW97136693A TWI358408B TW I358408 B TWI358408 B TW I358408B TW 097136693 A TW097136693 A TW 097136693A TW 97136693 A TW97136693 A TW 97136693A TW I358408 B TWI358408 B TW I358408B
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- salt
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- 238000000034 method Methods 0.000 title claims description 16
- 230000015572 biosynthetic process Effects 0.000 title claims description 5
- 238000003786 synthesis reaction Methods 0.000 title claims description 5
- 229910052712 strontium Inorganic materials 0.000 title 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 title 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000001308 synthesis method Methods 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 229940079488 strontium ranelate Drugs 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 238000007127 saponification reaction Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 2
- XXUZFRDUEGQHOV-UHFFFAOYSA-J strontium ranelate Chemical compound [Sr+2].[Sr+2].[O-]C(=O)CN(CC([O-])=O)C=1SC(C([O-])=O)=C(CC([O-])=O)C=1C#N XXUZFRDUEGQHOV-UHFFFAOYSA-J 0.000 claims 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims 1
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 claims 1
- DVVGIUUJYPYENY-UHFFFAOYSA-N 1-methylpyridin-2-one Chemical compound CN1C=CC=CC1=O DVVGIUUJYPYENY-UHFFFAOYSA-N 0.000 claims 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
- 230000007704 transition Effects 0.000 claims 1
- 238000009834 vaporization Methods 0.000 claims 1
- 230000008016 vaporization Effects 0.000 claims 1
- WJKLKWHUBHCSFS-UHFFFAOYSA-N 5-[bis(carboxymethyl)amino]-3-(carboxymethyl)-4-cyanothiophene-2-carboxylic acid;strontium Chemical class [Sr].[Sr].OC(=O)CN(CC(O)=O)C=1SC(C(O)=O)=C(CC(O)=O)C=1C#N WJKLKWHUBHCSFS-UHFFFAOYSA-N 0.000 description 12
- -1 Diterpenoid salt Chemical class 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000002309 gasification Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- PMGGFTVJVZZSFU-UHFFFAOYSA-L 1-methyl-1-[[2-[2-[4-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-1,3-dioxolan-2-yl]ethyl]-1,3-dioxolan-4-yl]methyl]pyrrolidin-1-ium;diiodide Chemical class [I-].[I-].C1OC(CCC2OC(C[N+]3(C)CCCC3)CO2)OC1C[N+]1(C)CCCC1 PMGGFTVJVZZSFU-UHFFFAOYSA-L 0.000 description 2
- 229930004069 diterpene Natural products 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- PUNXVEAWLAVABA-UHFFFAOYSA-N 1,2,3,4-tetrahydroanthracene;1,2,5,6-tetrahydroanthracene Chemical compound C1=CC=C2C=C(CCCC3)C3=CC2=C1.C1=CCCC2=C1C=C1CCC=CC1=C2 PUNXVEAWLAVABA-UHFFFAOYSA-N 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 150000000703 Cerium Chemical class 0.000 description 1
- PGBFYLVIMDQYMS-UHFFFAOYSA-N Methyl thiophene-2-carboxylate Chemical compound COC(=O)C1=CC=CS1 PGBFYLVIMDQYMS-UHFFFAOYSA-N 0.000 description 1
- 101100496858 Mus musculus Colec12 gene Proteins 0.000 description 1
- YMGLHCFGJKCKRZ-UHFFFAOYSA-N P.[Sr++] Chemical compound P.[Sr++] YMGLHCFGJKCKRZ-UHFFFAOYSA-N 0.000 description 1
- XBDYBAVJXHJMNQ-UHFFFAOYSA-N Tetrahydroanthracene Natural products C1=CC=C2C=C(CCCC3)C3=CC2=C1 XBDYBAVJXHJMNQ-UHFFFAOYSA-N 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- DJSXNILVACEBLP-UHFFFAOYSA-N ranelic acid Chemical compound OC(=O)CN(CC(O)=O)C=1SC(C(O)=O)=C(CC(O)=O)C=1C#N DJSXNILVACEBLP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/42—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Inorganic Compounds Of Heavy Metals (AREA)
Description
1358408 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種合成式⑴之雷奈酸鳃鹽（str〇ntium ranelate)：
或5-[雙（羧甲基）胺基]-3-羧甲基_4_氰基噻吩甲酸之二锶 鹽及其水合物之方法。 【先前技術】 雷奈酸鰓鹽具有極有價值之藥理學及治療特性、尤其顯 著的抗骨質疏鬆特性，從而使此化合物適用於治療骨病。 雷奈酸㈣、其製備及其治療用途已描述於歐洲專利說 明書g P (L 415』51中》
專利說明書EP 0 415 δ50描述雷奈酸鳃鹽之三種合成方 所述第二種方法由以下步驟組成：在水性醇系介質中在 回流下加熱式（Ila)之四乙酯：
(Ha) 與氫氧化鈉且接著蒸餾去乙醇及大部分水以藉由沈澱分 134522.doc 1358408 離式（Ilia)之四鈉鹽： Na+ -OX Na+
-CXC
Na+ ana) CO，- Na+ 接著使式（Ilia)化合物與氣化鰓於水中反應以得到雷奈 酸锶鹽，藉由過濾將其分離。 然而，當在對彼第二種方法所述之條件下操作時，本申 請者僅以小於70%產率獲得雷奈酸錄鹽。 【發明内容】 本申請者已開發出一種工業合成方法’其使得以極佳產 率及以極佳純度獲得雷奈酸鰓鹽成為可能。 更特定言之，本發明係關於一種合成式⑴之雷奈酸锶鹽 之方法，其以式（II)化合物起始：
(II) 其中可相同或不同之R及R，各自表千古 曰衣不直鏈或分支鏈（CrC6) 烷基，較佳曱基， 使該式(II)化合物在代至⑽。。之溫度下於水中或水 機溶劑之混合物中與氫氧化鈉或氫氧化鉀反應， 以得到式（III)之鹽： 134522.doc (III)， 1358408 A+
-0,C A* -o,c
CN 、co2- A+ A+ 其中A表示Na或K， 於水與有機溶劑 使該式（III)之鹽在Ot;至10(rC2溫度下 之混合物中，與氯化鎇反應，
分離後得到雷奈酸锶鹽或其水合物之一。 舉例而5，可提及之有機溶劑為四氫呋喃、丙酮、2-曱 / 氫夫南一甲亞碾、乙腈'N-甲基吡咯啶酮，及醇 系溶劑，諸如甲醇、乙醇、異丙醇及異丁醇。 令人驚訝地，使用.氣化锶進行鹽轉化之步驟中，有機溶 劑的存在可能大幅增加產率。 氫氧化納或氫氧化鉀之量較佳為大於或等於4莫耳/莫耳 式（II)化合物。 皂化反應之溫度較佳為20°C至70。(3。 根據本發明之一實施例，式（111)之鹽在與氣化锶反應前 先分離。 根據另一實施例，式（III)之鹽的溶液在用於與氯化鰓反 應前先淨化。 根據另一實施例，式（III)之鹽的溶液係原樣用於與氣化 錄反應。 氣化鰓之量較佳大於或等於2莫耳/莫耳式（11)化合物。 與氣化锶反應之溫度較佳為20°C至50。(：。 134522.doc 1358408 在本發明之方法中，較佳藉由過濾分離雷奈酸锶鹽。較 佳在藉由喊分離雷奈酸錄鹽之後進行—或多侧水、用 有機溶劑或用水/有機溶劑混合物洗滌之步驟且在其後進 行乾燥步驟》 A表示K之式（III)化合物之特定實例式（nib)之鉀鹽：
(nib) 為適用作化學或醫藥工業中、尤其合成雷奈酸鰓鹽及其水 合物中之合成中間物的新穎化合物，且由此其形成本發明 之組成部分。 【實施方式】 以下實例說明本發明。 實例1 : 5-丨雙（羧甲基）胺基】_3_羧甲基_4_氱基-2-噻吩甲酸 • 之二勰鹽 在20-25°C下，向裝有溫度探針及葉輪之800 ml反應器中 裂入50 g 5-[雙（2-甲氧基_2-側氧基乙基）-胺基]-4-氰基-3-(2-曱氧基-2-側氧基乙基）·2_噻吩甲酸甲酯及75 ml四氫呋 喃。 開始授拌且接著向該反應器中裝入預先使用22.9 g NaOH及2 16 ml水製備之氫氧化鈉水溶液。 保持攪拌反應混合物4至6小時。 134522.doc 1358408 添加預先使用73.9 g SrCh及340 ml水製備之氯化鏍水溶 液。 在20°C至25°C下保持攪拌20小時。 懸浮液緩慢變得更加明顯（精細黃色懸浮液）。 經1 00 mm直徑之3號玻璃料過濾（極快速過濾）且立即用 2x50 ml水洗滌穿過該玻璃料。 於真空中自產物移除揮發性組份歷時30分鐘。於通風烘 箱中在30°C下乾燥。 藉此以93.8°/。之產率獲得雷奈酸锶鹽。 實例2 : 5_[雙（羧甲基）胺基】-3-羧甲基氱基_2_噻吩甲酸 之二锶鹽 所使用之方法為實例1中所述之方法，四氫咬喃由丙酮 替代。 藉此以92.6%之產率獲得雷奈酸锶鹽。 實例3 : 5-[雙（羧曱基）胺基】-3-羧甲基_4_氰基噻吩曱酸 之二勰鹽 所使用之方法為實例1中所述之方法，氫氧化鈉由321 ^ KOH替代。 在與氣化锶反應前淨化式（IIIb)之斜鹽的溶液。 藉此以94%之產率獲得雷奈酸鳃鹽。 實例4: 5-[雙（鼓甲基）胺基]_3，甲基_4基_2_嘆吩甲酸 之二锶鹽 所使用之方法為實例1中所诚夕士、土 卜 只1MT尸/7遴之方法，四氫呋喃由異丙 醇替代。 134522.doc •10- 1358408 藉此以94.8°/。之產率獲得雷奈酸锶鹽。 實例5 : 5-丨雙（羧甲基）胺基卜3_羧甲基_4_氟基-2-噻吩甲酸 之二鏍鹽 在20-25°C下，向裝有溫度探針及葉輪之800 ml反應器中 裝入22.9 g NaOH及500…水。開始攪拌且向該反應器中裝 入50 g 5-[雙（2-甲氧基_2-側氧基乙基）-胺基]-4·氰基-3-(2-甲氧基-2-側氧基乙基）-2-嘆吩甲酸甲酯。 經30分鐘將混合物加熱至7〇〇c且在彼溫度下維持25分 鐘’且接著在70°C下經孔隙率4及75 mm直徑之玻璃料淨化 且用5 0 m 1水沖洗。 將上述澄清橘黃色濾液再裝入80〇 ml反應器中。 將反應混合物冷卻至20°C，且添加75 ml乙醇且接著經 15分鐘添加73·9 g SrCl2於137 ml水中之預先製備溶液。 在20°C至25°C下攪拌2小時。 懸浮液緩慢變得更加明顯（均勻黃色懸浮液）。 經100 mm直徑之3號玻璃料過濾（瞬時過濾）且立即用 2x250 ml水經該玻璃料再過濾。於通風烘箱中在3〇〇c下乾 燥。 藉此以94¼之產率獲得雷奈酸锶鹽。 實例6 : 5-丨雙（羧甲基）胺基】_3_羧甲基_4_氡基2噻吩甲酸 之二勰鹽 步称A . 5-[雙（羧甲基）胺基]缓甲基_4_氰基_2噻吩甲酸 之鉀鹽（式（111b)化合物) 在20-25°C下，向裝有溫度探針及葉輪之8〇〇 ml反應器中 134522.doc • 11 - 1358408 裝入 40.4 g KOH及 225 ml水。 開始攪拌且接著向該反應器中裝入60 g 5-[雙（2_曱氧基· 2-側氧基乙基）-胺基]-4 -氰基-3-(2-甲氧基-2·側氧基乙基）_ 2-噻吩甲酸曱酯及50 ml水。
經30分鐘將反應混合物加熱至55_6〇〇c且保持授拌2小 時。在60°C下進行淨化且接著將反應混合物冷卻至2〇_ 25°C。在40°C下於真空中乾燥。將20〇 mi乙酸乙酯及2〇 ml 甲醇添加至藉此獲得之殘餘物中。攪拌8小時。過濾所獲 得之懸浮液。真空移除產物中揮發性組份3〇分鐘。於通風 烘箱中在30°C下乾燥。 步驟B : 5-[雙（緩曱基）胺基]_3_緩甲基冬氣基如塞吩甲酸 之二鋇鹽 向62.0 g前述步驟中獲得之鉀鹽中添加乃…四氫呋读及 216如水’且接著添加預先使用73.9 g SrClA 340 m】水製 備之氣化链水溶液。
在20°C至25°C下攪拌2〇小時。 懸浮液緩慢變得更加明顯。經 于尺加4顯。經I00 mm直徑之3號玻螭 過遽且立即㈣2x5G ml水洗㈣過該玻瑪料。 於真空中自產物移除揮發性組份料3Q 箱中在30t：下乾燥。 郵洪 134522.doc 12·
Claims (1)
1358408 第097136693號專利申請案 中文申請專利範圍替換本方 .申請專利範圍替換本---、申請專利範圍〒年/ •弓修(更〉正本
1. 一種合成式⑴之雷奈酸錄鹽（strontium ranelate)
及其水合物之方法， 其係藉使式（II)化合物：
其中可相同或不同之R及R'各自表示直鏈或分支鏈（Cr C6)烷基， 在0°c至1 oo°c之溫度下，於水中或水與有機溶劑之混 合物中，與氫氧化納或氫氧化鉀反應，
以得到式（III)之鹽：
(III)， 其中A表示Na或K，其中該有機溶劑選自四氫呋喃、丙 酮、2-甲基-四氫呋喃、二甲亞颯、乙腈、N-甲基吡洛啶 酮，及醇系溶劑，諸如曱醇、乙醇、異丙醇及異丁醇， 使該式（III)之鹽在o°c至100°c之溫度下，與氣化鰓反 134522-1000726.doc 丄 1/¾. · 應， 分離後得到雷奈酸鳃鹽或其水合物之一， ： 其特徵在於使該式⑽之鹽與氯化链反應之步驟⑽ ： 水與有機溶劑之混合物中進行，其令該有機溶劑選自四 氫咳。南、丙嗣'2-甲基-四氫。夫喊、二甲亞砜、乙腈、ν· 甲基吡咯啶酮，及醇系溶劑，諸如子醇、乙醇、異丙醇 及異丁醇。 2·如凊求項1之合成方法，其中氫氧化鈉或氫氧化鉀之量 0 大於或等於4莫耳/莫耳式（II)化合物。 3·如凊求項1或2之合成方法，其中針對該式（11)化合物之 ' 皂化反應之溫度為20°C至70。(：。 4.如請求項1或2之合成方法，其中該式（in)之鹽在與氯化 總反應前先分離。 5‘如請求項1或2之合成方法，其中該式（III)之鹽的溶液在 用於與氯化錕反應前先淨化。 6·如請求項1或2之合成方法，其中該式（III)之鹽的溶液係 ® 原樣用於與氣化鏍反應。 7·如請求項1或2之合成方法，其中氯化链之量大於或等於 2莫耳/莫耳式（η)化合物。 8·如請求項1或2之合成方法，其中針對該式（ΠΙ)化合物之 鹽轉化反應之溫度為20°C至501。 9.如請求項1或2之合成方法，其中該雷奈酸銘鹽係藉由過 渡分離。 134522-1000726.doc ·2· ^ ⑧ 1358408
10. 如請求項9之合成方法，其中該過濾步驟之後進行一或 多個洗滌步驟及一個乾燥步驟。 11. 如請求項1或2之合成方法，其中R及R’各自表示甲基。 134522-1000726.doc
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| EP2346846A1 (en) * | 2008-09-29 | 2011-07-27 | Ratiopharm GmbH | Anhydrate and hydrate forms of strontium ranelate |
| HU228820B1 (en) | 2010-01-14 | 2013-05-28 | Richter Gedeon Nyrt | Process for the preparation of distrontium ranelate |
| IT1398542B1 (it) * | 2010-03-05 | 2013-03-01 | Chemelectiva S R L | Processo per la preparazione di un polimorfo |
| WO2011110597A1 (de) | 2010-03-11 | 2011-09-15 | Azad Pharmaceutical Ingredients Ag | Verfahren zur herstellung von strontiumranelat |
| WO2011124992A1 (en) * | 2010-03-24 | 2011-10-13 | Actavis Group Ptc Ehf | Substantially pure strontium ranelate |
| US20110275834A1 (en) * | 2010-05-06 | 2011-11-10 | Divi's Laboratories, Limited | Polymorph of strontium ranelate and a process for its preparation |
| WO2012046251A2 (en) * | 2010-10-08 | 2012-04-12 | Glenmark Generics Limited | Novel form of ranelic acid |
| CZ2011320A3 (cs) * | 2011-05-30 | 2012-12-12 | Zentiva, K.S. | Stabilní krystalická forma X stroncium ranelátu |
| CN102391247B (zh) * | 2011-09-20 | 2016-12-28 | 浙江华海药业股份有限公司 | 一种雷尼酸锶水合物晶形k及其制备方法 |
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