JP2011503053A - 2‐ヒドロキシ‐5‐フェニルアルキルアミノ安息香酸誘導体及びその塩の製造方法 - Google Patents
2‐ヒドロキシ‐5‐フェニルアルキルアミノ安息香酸誘導体及びその塩の製造方法 Download PDFInfo
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- trifluoromethylphenyl
- alkyl
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- 239000002253 acid Substances 0.000 title claims abstract description 19
- 150000003839 salts Chemical class 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims description 21
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 9
- UTMVACIBQLDZLP-UHFFFAOYSA-N crisdesalazine Chemical compound C1=C(O)C(C(=O)O)=CC(NCCC=2C=CC(=CC=2)C(F)(F)F)=C1 UTMVACIBQLDZLP-UHFFFAOYSA-N 0.000 claims description 9
- -1 phenylalkyl methanesulfonate Chemical compound 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- DOJLTJMICROPDO-UHFFFAOYSA-N 2-hydroxy-5-[2-[4-(trifluoromethyl)phenyl]ethylamino]benzoic acid;sulfuric acid Chemical compound OS(O)(=O)=O.C1=C(O)C(C(=O)O)=CC(NCCC=2C=CC(=CC=2)C(F)(F)F)=C1 DOJLTJMICROPDO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- MXUHMQZOATZRIK-UHFFFAOYSA-N methyl 5-amino-2-hydroxybenzoate Chemical compound COC(=O)C1=CC(N)=CC=C1O MXUHMQZOATZRIK-UHFFFAOYSA-N 0.000 claims description 2
- NCWMFABDCFTPPT-UHFFFAOYSA-N [N+](=O)([O-])[C]O Chemical compound [N+](=O)([O-])[C]O NCWMFABDCFTPPT-UHFFFAOYSA-N 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- HGKLFYLYWZXWPO-UHFFFAOYSA-N sulfo benzoate Chemical compound OS(=O)(=O)OC(=O)C1=CC=CC=C1 HGKLFYLYWZXWPO-UHFFFAOYSA-N 0.000 claims 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 abstract description 4
- 239000005711 Benzoic acid Substances 0.000 abstract description 2
- 235000010233 benzoic acid Nutrition 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 0 CC(C)(CC(C)(C)OS(C)(=O)=O)c1c(*)c(C*=*)c(C)c(*)c1* Chemical compound CC(C)(CC(C)(C)OS(C)(=O)=O)c1c(*)c(C*=*)c(C)c(*)c1* 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- NTURQZFFJDCTMZ-UHFFFAOYSA-N 1-(2-bromoethyl)-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(CCBr)C=C1 NTURQZFFJDCTMZ-UHFFFAOYSA-N 0.000 description 2
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229960004909 aminosalicylic acid Drugs 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- QQUGTTJYNYXZSW-UHFFFAOYSA-N 1-(3-bromopropyl)-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(CCCBr)C=C1 QQUGTTJYNYXZSW-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- YFZHODLXYNDBSM-UHFFFAOYSA-N 1-ethenyl-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(C=C)C=C1 YFZHODLXYNDBSM-UHFFFAOYSA-N 0.000 description 1
- UCHCAUUKJXSNAT-UHFFFAOYSA-N 1-nitro-4-prop-2-enylbenzene Chemical compound [O-][N+](=O)C1=CC=C(CC=C)C=C1 UCHCAUUKJXSNAT-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- CNPMUNGRAGQUIG-UHFFFAOYSA-N S(=O)(=O)(O)O.S(=O)(=O)(O)O.CC=1C(=C(C(=O)O)C=C(C1)NCCC1=CC=C(C=C1)C(F)(F)F)O Chemical compound S(=O)(=O)(O)O.S(=O)(=O)(O)O.CC=1C(=C(C(=O)O)C=C(C1)NCCC1=CC=C(C=C1)C(F)(F)F)O CNPMUNGRAGQUIG-UHFFFAOYSA-N 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
Abstract
Description
下記反応式1に従って2‐ヒドロキシ‐5‐[2‐(4‐トリフルオロメチルフェニル)エチルアミノ]安息香酸を製造した。
50Lのガラス反応器に7.00kgのメチル5‐アミノサリチレート(41.9mol)、11.23kgの化合物A(2‐(4‐トリフルオロメチルフェニル)エチルメタンスルホネート、41.9mol)、5.11kgのトリエチルアミン(50.6mol)、及び26Lのトルエンを窒素保護下で入れて混合した。混合物を撹拌して約70〜80℃で約28〜32時間反応させた。反応が始まって20時間後から4時間毎に反応器からサンプルを採り、HPLCで反応の終結可否を判断した。化合物Aの濃度が0.5%以下であれば、反応が終結したと評価した。その後、反応混合物を45℃に冷却して20Lのロータリーエバポレーター(rotary evaporator)に移し、約0.09MPaの真空、60〜75℃の条件でトルエンが除去されるまで濃縮して黒いオイル状の産物(22.31kg)を得た。それをエタノールに溶解し、50%の硫酸を用いて酸性化させた。混合物は、十分に沈殿させるため、10℃以下に冷却した。濾過後、50%のエタノールで洗浄して13.99kgの化合物B(メチル2‐ヒドロキシ‐5‐[2‐(4‐トリフルオロメチルフェニル)エチルアミノ]ベンゾエート)硫酸化物(sulfate)を得た(乾燥基準で74.8%、HPLC純度90.73%)。収率は58.4%であった。
窒素保護下で、得られた硫酸化物11.6kg(乾燥基準で9.04kg、21.1mol)を98%の硫酸13.2kg (sulfuric acid、132mol)、36Lの精製水及び8.2kgの酢酸(136.7mol)の混合物内で95〜100℃で27時間加水分解した。HPLCでサンプルを分析し、化合物Bの濃度が1%以下であれば、反応が終結したと判断した。その後、反応混合物を10〜20℃に冷却して濾過した。ケーキを6Lの精製水で3回洗浄して10.98kgの化合物C(2‐ヒドロキシ‐5‐[2‐(4‐トリフルオロメチルフェニル)エチルアミノ]安息香酸)の硫酸化物を得た(乾燥基準で69.4%、HPLC純度97.67%)。収率は94.2%であった。
段階IIで得た10.94kgの化合物Cの硫酸化物、30Lの無水エタノール及び7.5Lの精製水を撹拌して50〜65℃に加熱した後、透明な溶液が得られるまで50%の硫酸溶液を滴下した。溶液を濾過し、徐々に10℃以下に冷却した。濾過後、8.77kgの化合物Cの硫酸化物が得られた(乾燥基準で79.0%)。
得られた硫酸化物に15Lの50%エタノールを混合し、25%アンモニア水溶液を用いてpHを3.0〜3.5に調節した。混合物を濾過した後、ケーキを熱い精製水、エタノール、熱い精製水の順で十分洗浄して9.96kgの精製された産物を得た(乾燥基準で58.5%)。その後、得られた産物を55〜65℃の温度で少なくとも0.085Mpaの真空でLOD(Loss on Drying)が0.1%以下になるまで約24時間乾燥した。最終的に5.48kgの2‐ヒドロキシ‐5‐[2‐(4‐トリフルオロメチルフェニル)エチルアミノ]安息香酸(HPLC純度99.6%)が得られ、収率は84.7%であった。
製造された2‐ヒドロキシ‐5‐[2‐(4‐トリフルオロメチルフェニル)エチルアミノ]安息香酸の1H‐NMRスペクトル分析結果を下記表1に、IR吸収スペクトル分析結果を下記表2にそれぞれ示した。
Claims (8)
- 下記化学式1で表されるフェニルアルキルメタンスルホネートと下記化学式2で表されるアルキル5‐アミノサリチレートとを反応させ、下記化学式3で表されるアルキル2‐ヒドロキシ‐5‐フェニルアルキルアミノベンゾエートを製造する段階を含むことを特徴とする、下記化学式4で表される2‐ヒドロキシ‐5‐フェニルアルキルアミノ安息香酸誘導体またはその塩を製造する方法。
- 前記化学式1で表されるフェニルアルキルメタンスルホネートと化学式2で表されるアルキル5‐アミノサリチレートとの反応温度が60〜90℃であることを特徴とする請求項1に記載の方法。
- 前記方法が、化学式3で表されるアルキル2‐ヒドロキシ‐5‐フェニルアルキルアミノベンゾエートを硫酸水溶液を含む溶媒下で加水分解して2‐ヒドロキシ‐5‐フェニルアルキルアミノ安息香酸硫酸化物(sulfate)を形成する段階を含むことを特徴とする請求項1に記載の方法。
- 前記方法が、形成された2‐ヒドロキシ‐5‐フェニルアルキルアミノ安息香酸硫酸化物をpH3〜3.5に調節して精製する段階を含むことを特徴とする請求項3に記載の方法。
- 前記2‐(4‐トリフルオロメチルフェニル)エチルメタンスルホネートとメチル5‐アミノサリチレートとの反応温度が70〜80℃であることを特徴とする請求項5に記載の方法。
- 前記方法が、メチル2‐ヒドロキシ‐5‐[2‐(4‐トリフルオロメチルフェニル)エチルアミノ]ベンゾエートを硫酸水溶液を含む溶媒に溶解させた後、加水分解して2‐ヒドロキシ‐5‐[2‐(4‐トリフルオロメチルフェニル)エチルアミノ]安息香酸硫酸化物を形成する段階を含むことを特徴とする請求項5に記載の方法。
- 前記方法が、形成された2‐ヒドロキシ‐5‐[2‐(4‐トリフルオロメチルフェニル)エチルアミノ]安息香酸硫酸化物をpH3〜3.5に調節して精製する段階を含むことを特徴とする請求項7に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2007-0114660 | 2007-11-12 | ||
KR1020070114660A KR100852962B1 (ko) | 2007-11-12 | 2007-11-12 | 2-하이드록시-5-페닐알킬아미노벤조산 유도체 및 이의 염의제조방법 |
PCT/KR2008/006432 WO2009064084A2 (en) | 2007-11-12 | 2008-10-30 | Manufacturing method of 2-hydroxy-5-phenylalkylaminobenzoic acid derivatives and their salts |
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JP2011503053A true JP2011503053A (ja) | 2011-01-27 |
JP5649971B2 JP5649971B2 (ja) | 2015-01-07 |
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KR101646701B1 (ko) * | 2009-12-29 | 2016-08-08 | 주식회사 지엔티파마 | 에틸아미노 벤조산 유도체의 치료 용도 |
CN102617338B (zh) * | 2012-02-29 | 2014-02-05 | 常州市阳光药业有限公司 | 对三氟甲基水杨酸的制备方法 |
CN102617383A (zh) * | 2012-03-20 | 2012-08-01 | 横店集团家园化工有限公司 | 索法地尔晶型、制备方法及包含索法地尔晶体的无菌粉末 |
CN112479912A (zh) * | 2020-12-08 | 2021-03-12 | 浙江普洛家园药业有限公司 | 2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型及其制备方法 |
CN112409201B (zh) * | 2020-12-08 | 2022-10-25 | 浙江普洛家园药业有限公司 | 2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸的制备方法 |
CN113735726A (zh) * | 2021-08-09 | 2021-12-03 | 浙江理工大学 | 一种2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸钠及其制备方法 |
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CA2705496C (en) | 2016-12-06 |
AU2008321691A1 (en) | 2009-05-22 |
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CN101874016A (zh) | 2010-10-27 |
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AU2008321691B2 (en) | 2013-05-23 |
US8686185B2 (en) | 2014-04-01 |
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