TWI724031B - 製備1-(4-甲烷磺醯基-2-三氟甲基-苄基)-2-甲基-1h-吡咯并[2,3-b]吡啶-3-基-乙酸之方法 - Google Patents
製備1-(4-甲烷磺醯基-2-三氟甲基-苄基)-2-甲基-1h-吡咯并[2,3-b]吡啶-3-基-乙酸之方法 Download PDFInfo
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- TWI724031B TWI724031B TW105131422A TW105131422A TWI724031B TW I724031 B TWI724031 B TW I724031B TW 105131422 A TW105131422 A TW 105131422A TW 105131422 A TW105131422 A TW 105131422A TW I724031 B TWI724031 B TW I724031B
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- GFPPXZDRVCSVNR-UHFFFAOYSA-N 2-[2-methyl-1-[[4-methylsulfonyl-2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-b]pyridin-3-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC=CN=C2N1CC1=CC=C(S(C)(=O)=O)C=C1C(F)(F)F GFPPXZDRVCSVNR-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 81
- 150000001875 compounds Chemical class 0.000 claims description 74
- 239000003054 catalyst Substances 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 52
- 239000002904 solvent Substances 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 36
- 229940126062 Compound A Drugs 0.000 claims description 33
- 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 claims description 33
- 239000002253 acid Substances 0.000 claims description 31
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 26
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 24
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 19
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 16
- 239000003638 chemical reducing agent Substances 0.000 claims description 13
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 11
- 229940011051 isopropyl acetate Drugs 0.000 claims description 10
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 10
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
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- 229910052763 palladium Inorganic materials 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 4
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- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
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Abstract
本發明係關於合成[1-(4-甲烷磺醯基-2-三氟甲基-苄基)-2-甲基-1H-吡咯并[2,3-b]吡啶-3-基]-乙酸之新穎方法及該等方法中所用的中間體。
Description
本發明係關於合成1-(4-甲烷磺醯基-2-三氟甲基-苄基)-2-甲基-1H-吡咯并[2,3-b]吡啶-3-基-乙酸之新穎方法及該等方法中所用的中間體。
醫藥活性化合物1-(4-甲烷磺醯基-2-三氟甲基-苄基)-2-甲基-1H-吡咯并[2,3-b]吡啶-3-基-乙酸(「化合物A」)係表現於Th2淋巴球(「CRTh2」)上之G-蛋白偶聯趨化介素受體同源分子之拮抗劑,其用於治療若干病症,例如氣喘及異位性皮膚炎。化合物A具有以下化學結構:[1-(4-甲烷磺醯基-2-三氟甲基-苄基)-2-甲基-1H-吡咯并[2,3-b]吡啶-3-基]-乙酸 在頒佈於2011年5月10日的美國專利號7,666,878中提及化合物A、合成化合物A之方法及使用化合物A治療各種病症之方法,其內容係全文以引用的方式併入本文中。 儘管已知製造化合物A之方法,但本發明首次揭示具有更少步驟、具有更高產率且對化合物A具有更高選擇性之製造化合物A之方法。本發明主要經由使用σ遷移重排實現該等特徵,該σ遷移重排更詳細地闡述於下文中。上述優點例示於以下實例中。
本發明係關於具有下式之化合物:2-(1-{[4-甲烷磺醯基-2-(三氟甲基)苯基]甲基}-2-甲基-1H-吡咯并[2,3-b
]吡啶-3-基)乙酸甲酯 此化合物係合成化合物A之中間體。 本發明亦係關於具有下式之化合物:3-[2-({[4-甲烷磺醯基-2-(三氟甲基)苯基]甲基}胺基)吡啶-3-基]丙-2-炔-1-醇 此化合物可用作合成式C8化合物及化合物A二者之中間體。 本發明亦係關於具有下式之化合物:3-溴-N-{[2-甲烷磺醯基-4-(三氟甲基)苯基}吡啶-2-胺 此化合物可用於合成化合物C6及化合物A二者。 本發明亦係關於製備C4之方法。該方法包含在酸、較佳對甲苯磺酸、三氟乙酸、三氯乙酸或草酸存在下,使下式化合物(其中R1係選自由Br或NH2
組成之群)與下式化合物(其中R1係選自由醛或胺組成之群)反應。當化合物C1之R1係NH2
且C2之R1係醛時,形成下式化合物:3-溴-N-{[2-甲烷磺醯基-4-(三氟甲基)苯基]亞甲基}吡啶-2-胺 然後在溶劑、較佳甲苯及甲醇之混合物及硼氫化鈉(NaBH4
)存在下將化合物C3轉化為化合物C4。當化合物C1之R1係Br且C2之R1係NH2
時,由於不形成化合物C3,因此無需該轉化。 本發明亦係關於製造化合物C6之方法。該方法包含在觸媒、一或多種溶劑、配體及鹼存在下,使式C4化合物與下式化合物反應。較佳觸媒包括基於鈀之觸媒(例如乙酸鈀)及銅觸媒(例如碘化銅),或鈀觸媒(例如炭載鈀或乙酸鈀,或氯化鈀)。較佳配體係三苯基膦。較佳溶劑包括乙醇、甲苯及乙酸異丙酯。較佳鹼包括三級胺(如三乙胺)或無機鹼(如碳酸鉀)。 本發明亦係關於製造化合物C8之方法。該方法包含在催化量之酸及溶劑存在下使化合物C6與下式化合物反應,其中R1及R2各自獨立地係C1
-C6
烷基,其可相同或不同且X係Y-Z,其中Y係N、S、SO2
或O且Z係H、O或C1
-C6
烷基。有機酸例如乙酸、丙酸或特戊酸以及路易斯酸蒙脫石或固定化酸或酸性氧化鋁係用於該轉化之勝任觸媒。溶劑可係任一溶劑,然而有機溶劑(例如甲基異丁基酮)係較佳的。 在酸及鹼存在下經由皂化將所得化合物C8轉化為化合物A。較佳地,酸係強酸(例如鹽酸)。較佳鹼係強鹼(例如氫氧化鈉)。皂化後,分離且純化化合物A。 上文所概述之步驟之順序可整合至製造化合物A之整體方案中。此一整合製程通常包括在本文所述之適宜反應條件下進行以下步驟: (a) 使化合物C1與C2反應形成C4; (b) 使化合物C4與化合物C5反應形成C6; (c) 使化合物C6與化合物C7反應形成C8;及 (d) 將化合物C8轉化為化合物A。 本發明亦揭示製備C6之方法,其包含(a)在觸媒、還原劑及一或多種溶劑存在下使下式化合物與下式化合物反應。在一實施例中,觸媒係炭載鈀。在另一實施例中,觸媒係氯化鈀。在又一實施例中,觸媒係乙酸鈀。在另一實施例中,觸媒係碘化銅。其他實施例使用有機酸。 可用於上述方法中之適宜溶劑包括乙醇、甲苯(toluene)、甲苯(toluol)、乙酸異丙酯及其混合物。該等溶劑之任一者或其組合可與上述觸媒中之任一者結合使用。舉例而言,炭載鈀可與乙醇、甲苯(toluene)、甲苯(toluol)、乙酸異丙酯及其混合物結合使用。類似地,氯化鈀可與乙醇、甲苯(toluene)、甲苯(toluol)、乙酸異丙酯及其混合物結合使用。乙酸鈀亦可與乙醇、甲苯(toluene)、甲苯(toluol)、乙酸異丙酯及其混合物結合使用。與其他觸媒一樣,氧化銅及有機酸可與溶劑乙醇、甲苯(toluene)、甲苯(toluol)、乙酸異丙酯及其混合物結合使用。 本發明亦揭示將強酸添加至C4、C5與上述觸媒中之任一者之混合物中之步驟(例如,強鹼可與炭載鈀、氯化鈀、乙酸鈀、碘化銅及有機酸中之任一者一起使用)。強酸(例如特戊酸)亦可在任一溶劑存在下存在。如上所述,溶劑可係乙醇、甲苯(toluene)、甲苯(toluol)、乙酸異丙酯及其混合物之任一組合,與上述任一觸媒組合。 或者,可將強鹼添加至C4、C6、觸媒、強酸(若存在)及溶劑中任一者(若存在)之混合物中。 在又一實施例種,可將還原劑(例如NaBH4或三苯基膦)添加至溶劑、鹼、觸媒及酸之任何組合之混合物中。 本發明亦包含製備C8之方法,其包含在觸媒及溶劑存在下,使下式化合物與下式化合物反應。在一些實施例中,觸媒係有機酸。在較佳實施例中,觸媒係特戊酸。在較佳實施例中,溶劑係甲基異丁基酮。在尤佳實施例中,溶劑甲基異丁基酮及強酸特戊酸一起使用。 本發明亦係關於製備下式化合物之方法:[1-(4-甲烷磺醯基-2-三氟甲基-苄基)-2-甲基-1H-吡咯并[2,3-b]吡啶-3-基]-乙酸 其包含 (a) 在酸存在下使下式化合物(其中R1係選自由Br或NH2
組成之群)與下式化合物(其中R1係選自由醛或胺組成之群)反應, 以形成下式化合物(b) 在觸媒、還原劑及一或多種溶劑存在下使式C4化合物與下式化合物反應以形成下式化合物(c) 在觸媒及溶劑存在下使式C6化合物與下式化合物(其中R1及R2各自獨立地係C1
-C6
烷基,其可相同或不同,且X係Y-Z,其中Y係N、S、SO2
或O且Z係H、O或C1
-C6
烷基)反應 以形成下式化合物或使式C6化合物與下式化合物反應以形成下式化合物(d)藉由在強鹼存在下皂化C8將式C8化合物轉化為化合物A。 在一實施例中,上述步驟(a)中之酸可係1-對甲苯磺酸、三氟乙酸、三氯乙酸及草酸中之任一者。 在又一實施例中,步驟(b)中之觸媒可係炭載鈀、氯化鈀、乙酸鈀、碘化銅及有機觸媒中之任一者。熟習此項技術者應理解,關於步驟(a)之上述酸中之任一者可與此段落中所述觸媒中之任一者一起使用。 在又一實施例中,步驟(b)中之溶劑係乙醇、甲苯(toluene)、甲苯(toluol)、乙酸異丙酯及其混合物中之任一者。應理解,此步驟中所述溶劑中之任一者可與先前段落中所列觸媒或酸中之任一者以任一組合使用。 本發明亦揭示其中步驟(b)進一步包含將強酸添加至C4、C5及觸媒之混合物中之實施例。在又一實施例中,步驟(b)進一步包含將強鹼添加至C4、C5及觸媒之混合物中。熟習此項技術者應理解,強酸或強鹼可與先前段落中所述溶劑、觸媒或其他酸中之任一者一起使用。 在又一實施例中,步驟(b)中之還原劑係三苯基膦。熟習此項技術者應理解,還原劑可與任一先前列舉之觸媒、酸或強酸一起使用。 在另一實施例中,步驟(c)中之觸媒係有機酸(例如特戊酸)。熟習此項技術者應理解,還原劑可與任一先前列舉之觸媒、酸或還原劑一起使用。
在以下論述中,所提及化合物C1-C8及化合物A係如上文對其所定義而定義。本發明化合物及方法繪示於以下所示之反應方案中: 反應方案 ( 續 ) 本發明當前方案藉由將重排反應應用於游離炔丙醇C6有利地增加化合物A之產率及選擇性。此方案使得可在較溫和條件下實施C6至C8之σ遷移重排並建立閉環體系。 製程方案以胺基吡啶C1與醛C2之縮合開始;去除水形成亞胺中間體C3。反應係在一或多種溶劑存在下進行。溶劑可係業內已知之任一適宜溶劑。較佳溶劑係有機溶劑(例如甲苯)。反應係在酸觸媒、較佳對甲苯磺酸一水合物存在下發生。可使用其他觸媒,例如H3
PO4
、 H2
SO4
、SiO2
、對甲苯磺酸吡啶鎓、AlOxH+
(其中x係0至4之整數)、三氟乙酸、三氯乙酸、草酸、酒石酸、馬來酸及富馬酸。適宜反應溫度條件係自100℃至140℃,其中110℃至135℃之範圍較佳。捕獲並除去反應期間形成之任何水。 然後將C3還原為化合物C4。該轉化係在溶劑及還原劑存在下達成。可使用任一溶劑,然而較佳溶劑係有機溶劑,尤佳溶劑係甲醇、甲苯(toluene)、甲苯(toluol)、異丙基酮及其混合物。適宜還原劑包括膦、三苯基膦、NaBH4
、LiAlH4
或業內已知之其他試劑(例如矽烷)。適宜反應溫度條件係自40℃至60℃,其中50℃至56℃之範圍較佳。通常產率係大於90%,且C4之純度係約99%。 或者,藉由在觸媒(例如乙醯丙酮鈀)、鹼(例如碳酸鉀)及配體(例如BINAP)存在下在高沸點溶劑(如茴香醚)中,過渡金屬催化之2,3-二溴-吡啶C1與苄基胺C2交叉偶合(胺化) (如上述方案中所示)製備中間體C4,得到46%之高純度(>98%) C4。適宜反應溫度條件係自110℃至180℃,其中150℃至160℃之範圍較佳。 在寬範圍條件下使用觸媒、配體、鹼及溶劑達成C4與炔丙醇C5薗頭耦合(Sonogashira coupling)製造丙炔基衍生物C6。較佳觸媒包括任一鈀源,例如炭載鈀(Pd/C觸媒)、或鈀鹽,例如乙酸鈀或氯化鈀;及作為第二觸媒之任一銅源,例如碘化亞銅(CuI)或氯化銅(CuCl)。且較佳鹼包括三級胺(例如三乙胺)或無機鹼(例如碳酸鉀)。較佳配體包括三苯基膦。適宜溶劑包括乙醇、異丙醇、第三丁醇、乙酸乙酯、乙酸異丙酯、乙酸丁酯、環戊基甲醚、四氫呋喃、二甲基甲醯胺、甲苯、二甲苯、枯烯及其組合。在強酸及強鹼存在下實施反應後處理。較佳實例包括鹽酸、氫氧化銨及氫氧化鈉。適宜反應溫度條件係自70℃至110℃,其中75℃至85℃之範圍較佳。通常產率係在75%及以上之範圍內;純度通常大於98%。 在最重要步驟中,在催化量弱酸(如乙酸、丙酸、特戊酸、乙酸酐、蒙脫石、固定化酸或酸性氧化鋁)存在下、在一或多種溶劑存在下,利用C7處理C6以經由重排反應提供甲基酯C8。適宜溶劑包括有機溶劑;較佳溶劑係甲基異丁基酮。較佳觸媒包括乙酸及特戊酸。適宜反應溫度條件係自120℃至180℃,其中140℃至150℃之範圍較佳。通常產率係在75%及以上之範圍內;純度通常大於99%。或者,可在適宜可加壓設備(例如連續式反應器及諸如此類)存在下採用高達300℃之高溫。另外,若使用原乙酸三乙酯代替C7,則形成化合物A之乙酯類似物(未示出)。 然後在強酸及強鹼存在下經由皂化將C8轉化為化合物A。較佳酸係鹽酸且較佳鹼係氫氧化鈉。適宜反應溫度條件係自40℃至80℃,其中50℃至55℃之範圍較佳。通常產率係在75%及以上之範圍內;純度通常大於99%。為獲得期望之多形體或結晶形式,根據業內熟知技術將化合物A重結晶。實驗實例
以下實驗實例說明本發明方法且不意欲限制如以下申請專利範圍所界定之本發明範圍。實例 1a : C4 (3- 溴 -N
-{[4- 甲烷磺醯基 -2-( 三氟甲基 ) 苯基 ]- 甲基 } 吡啶 -2- 胺 ) 之製備 在對甲苯磺酸一水合物(0.78 g,4 mmol)之酸催化下,將36.5 g (210 mmol) C1(2-胺基-3-溴吡啶)及50.5 g (200 mmol) C2 (4-甲烷磺醯基-2-(三氟甲基)苯甲醛)在500 ml甲苯中在145℃之溫度下在Dean-Stark裝置中回流。捕獲所形成之水;最少15小時後反應完成。將熱溶液冷卻至50℃之內部溫度(「IT」)且添加40 ml甲醇。在2小時內分4份添加硼氫化鈉(8 g,200 mmol)。此外,將懸浮液加熱5小時。在此期間形成氫氣。接下來,在10分鐘內添加100 ml水且藉由添加100 ml水及14 g乙酸之混合物控制pH,以調整pH至約6。將反應混合物再攪拌1小時。然後分離各相且利用200 ml水洗滌甲苯相。然後過濾甲苯相;在減弱真空下蒸餾出450 g甲苯。向所得溶液中添加150 ml異丙醇,同時將溶液加熱至85℃。在2小時內將溶液冷卻至IT=0℃-5℃且在IT 50℃下添加晶種。過濾所得懸浮液。利用60 ml冷異丙基酮/庚烷(1:1體積比)洗滌殘餘物2次以形成C4 (3-溴-N
-{[4-甲烷磺醯基-2-(三氟甲基)苯基]甲基}吡啶-2-胺)。將濕C4在烘箱中在50℃之溫度下乾燥12小時。分離77.1 g (94.2%)之白色物質。經計算產率係94.2%。純度大於99%。實例 1b : C4 之製備 在100 ml圓底燒瓶(t=g)中,將2,3-二溴吡啶(1 g,4.221 mmol)、(4-(甲基磺醯基)-2-(三氟甲基)苯基)甲胺(1.3 g,5,133 mmol)及K2
CO3
(1.8 g,13.024 mmol)懸浮於茴香醚(20 ml)中得到棕色懸浮液。添加BINAP (0.5 g,0.803 mmol)及乙醯丙酮鈀(II) (0.2 g,0.891 mmol)。將反應混合物加熱至155℃,保持3 h。在t=3 h (m+1=408/410)時,LCMS顯示反應完成。將反應混合物過濾,利用DCM洗滌沈澱。將反應混合物濃縮,且將粗產物添加至矽膠(100 g)柱中,且用EtOAc/庚烷(0%-70%)溶析。經分離之C4產率係0.79 g (46%)。實例 2 : C6 (3-[2-({[4- 甲烷磺醯基 -2-( 三氟甲基 ) 苯基 ]- 甲基 } 胺基 ) 吡啶 -3- 基 ] 丙 -2- 炔 -1- 醇 ) 之製備 在15 L雙夾套容器中,將1.8 kg C4 (3-溴-N
-{[4-甲烷磺醯基-2-(三氟甲基)苯基]甲基}吡啶-2-胺)、0.91 kg碳酸鉀及0.17 kg三苯基膦懸浮於6.5 kg甲苯中。在替代實施例中,可用甲苯(toluene)代替甲苯(toluol)。添加0.31 kg炔丙醇(C5)及0.3 kg乙醇。用氮有效惰性化(三倍減壓至低於100毫巴,隨後用氮再加壓至1巴)後,添加乙酸鈀(4.9 g)及碘化亞銅(41.9 g)在乙醇(0.7 kg)中之漿液。用氮再次惰性化(條件同上文所述)後,將溫度增加至75℃。不斷攪拌混合物直至轉化率高於98%為止(藉由HPLC之製程中控制來檢查)。老化隨觸媒活性及裝載量而變。在此情況下,1 mol%乙酸鈀需要約10-14 h。然後,藉由過濾除去固體且利用甲苯與乙醇(9:1重量比)之混合物(總重量2.5 kg)沖洗容器及吸濾器(nutsche)。將澄清濾液裝填至第二容器,利用水(12.6 kg)及乙醇(0.8 kg)稀釋且利用濃鹽酸(0.6 kg)使其呈酸性。在50℃下攪拌30分鐘後,分離各相。將下層水相(含有C6鹽酸鹽)轉移於罐中,同時利用乙醇鹽酸(1.8 kg水、0.3 kg乙醇及90 g HCl 37%)混合物再次萃取剩餘有機相。除去有機相且利用乙醇清洗容器後,經由精濾器(polishing filter)再次裝填水相且利用更多乙醇(6.4 kg)稀釋。藉由添加苛性鈉(0.9 kg)使pH呈鹼性,同時保持溫度在50℃-60℃之間。然後用C6 (30 g在乙醇/水3:7中之漿液)加晶種後,將溶液陳化2 h且在4 h內冷卻至0℃。藉由過濾分離所得產物。利用3:7乙醇/水(3 kg)及水(6 kg)洗滌濕濾餅,且在真空下(60℃,<10毫巴)乾燥以得到呈灰白色固體之C6。近似產量係1.7 kg。所估計產率百分比係約90%且純度大於99%。實例 3a : 化合物 A 之製備 C8 之製造 :
將化合物C6 (3-[2-({[4-甲烷磺醯基-2-(三氟甲基)-苯基]甲基}胺基)吡啶-3-基]丙-2-炔-1-醇) (1000 g,2600 mmol)溶解於甲基異丁基酮(MIBK,1000 ml)、625 g (5200 mmol) C7 (原乙酸三甲氧基酯)及特戊酸(213 g,存於甲基異丁基酮中50%)之混合物中。將混合物在2 h內在1-4巴之N2
超壓下加熱至140℃。反應期間形成甲醇且藉由壓力調節閥將其自容器中除去。4 h後,添加第二份甲基異丁基酮、C7 (313 g,2605 mmol)及特戊酸(106 g,存於甲基異丁基酮中50%)且將混合物在145℃下在1.1-1.3巴之N2
超壓下加熱6 h。所得產物係C8 (2-(1-{[4-甲烷磺醯基-2-(三氟甲基)苯基]甲基}-2-甲基-1H-吡咯并[2,3-b
]吡啶-3-基)乙酸甲酯)之溶液。轉化率經量測係99%且產率係84%。轉化為化合物 A :
將所得溶液在真空下在100℃/200毫巴及水(6000 ml)下濃縮。將氫氧化鈉溶液(1734 g,30%,13 mol)添加至混合物中且在50℃加熱4 h。將溶液在100℃/100毫巴下再次蒸餾。在50℃下分離各相且用甲基異丁基酮(2000 ml)萃取水相。再次分離各相並在50℃下過濾水相。向濾液中加入甲基異丁基酮(5000 ml)且用鹽酸(963 g,37%,9.8 mol)分2份中和水溶液至pH 4-4.5。將各相加熱至80℃且分離有機相。添加水(1000 ml)以洗滌有機相且相分離後,將有機相冷卻至70℃。將化合物A之晶種及庚烷(1000 ml)一起加入。將所得懸浮液攪拌30分鐘,隨後在3 h內進一步冷卻至0℃。將懸浮液在0℃下攪拌3 h且然後藉助吸濾器過濾。首先用預冷HPTF/甲基異丁基酮(1000 g,5:1)洗滌濾餅,然後用丙酮/水(1000 g,1:2)洗滌且最後用水(1000 g)洗滌。將濕化合物A在烘箱中在60℃及真空下乾燥8 h以分離804 g化合物A。轉化率經計算係99%;產率係79%。實例 3b : 化合物 A 之製備 C8 之製造
:將化合物C6 (3-[2-({[4-甲烷磺醯基-2-(三氟甲基)-苯基]甲基}胺基)吡啶-3-基]丙-2-炔-1-醇) (20 g,52 mmol)溶解於甲基異丁基酮(MIBK,125 g)、25.3 g (156 mmol) 1,1,1-三乙氧基乙烷及乙酸(0.625 g,10 mmol)之混合物中。將混合物在40分鐘內在1-4巴之N2
超壓下加熱至140℃。反應期間形成乙醇且藉由壓力調節閥將其自容器中除去。3.5 h後,添加第二份乙酸(0.625 g)且將混合物在140℃下在1-4巴之N2
超壓下加熱3.5 h。所得產物係2-(1-{[4-甲烷磺醯基-2-(三氟甲基)苯基]甲基}-2-甲基-1H-吡咯并[2,3-b
]吡啶-3-基)乙酸乙酯之溶液且轉化率經量測為98%且產率90%。過濾溶液且加入40 g MIBK。將溶液加熱至IT=80℃且在3 h內冷卻至IT=20℃。在65℃之IT下加晶種。在IT 20℃下分離中間體C8且用40 g MIBK洗滌且在烘箱中在IT=60℃/20毫巴下乾燥。轉化為化合物 A :
將中間體C8在真空下在100℃/200毫巴及水(6000 ml)下濃縮。將氫氧化鈉溶液(1734 g,30%,13 mol)添加至混合物中且在50℃加熱4 h。將溶液在100℃/100毫巴下再次蒸餾。在50℃下分離各相且用甲基異丁基酮(2000 ml)萃取水相。再次分離各相並在50℃下過濾水相。向濾液中加入甲基異丁基酮(5000 ml)且用鹽酸(963 g,37%,9.8 mol)分2份中和水溶液至pH 4-4.5。將各相加熱至80℃且分離有機相。添加水(1000 ml)以洗滌有機相且相分離後,將有機相冷卻至70℃。將化合物A之晶種及庚烷(1000 ml)一起加入。將所得懸浮液攪拌30分鐘,隨後在3 h內進一步冷卻至0℃。將懸浮液在0℃下攪拌3 h且然後藉助吸濾器過濾。首先用預冷HPTF/甲基異丁基酮(1000 g,5:1)洗滌濾餅,然後用丙酮/水(1000 g,1:2)洗滌且最後用水(1000 g)洗滌。將濕化合物A在烘箱中在60℃及真空下乾燥8 h分離804 g化合物A。轉化率經計算係99%;產率係79%。實例 3c : 化合物 A 之替代性製備 將5 g (3-[2-({[4-甲烷磺醯基-2-(三氟甲基)-苯基]甲基}胺基)吡啶-3-基]丙-2-炔-1-醇)、甲基異丁基酮(MIBK,50 ml)及1,1-二甲氧基-N,N-二甲基乙胺一起置於200 ml反應器中且在100℃下攪拌15 h。藉由添加鹽酸(15 ml)酸化混合物且在100℃下維持攪拌15 h。然後添加水(25 ml),且溫度降至50℃。加入苛性鈉(約15 ml)以將pH設置為12左右。然後,相分離及用水(10 ml)第二次萃取後,用甲基異丁基酮(25 ml)稀釋經合併水相且在80℃下用鹽酸酸化至pH 4。將混合物冷卻至70℃、加晶種且在2 h內冷卻至0℃。在0℃下陳化2 h後,過濾收集結晶固體,用甲基異丁基酮(10 ml)及水(10 ml)洗滌,且在真空下在60℃下乾燥直至恆定重量為止。得到2.93 g。
Claims (20)
- 如請求項2之方法,其中該觸媒係選自由炭載鈀、氯化鈀、乙酸鈀、碘化銅及有機觸媒組成之群。
- 如請求項2或3之方法,其中該等溶劑係選自由乙醇、甲苯、乙酸異丙 酯及其混合物組成之群。
- 如請求項2或3之方法,其進一步包含(b)將強酸添加至C4、C5及該觸媒之混合物中。
- 如請求項2或3之方法,其進一步包含(c)將強鹼添加至C4、C6及該觸媒之混合物中。
- 如請求項2或3之方法,其中該還原劑係三苯基膦。
- 如請求項8之方法,其中該觸媒係有機酸。
- 如請求項9之方法,其中該有機酸係特戊酸。
- 如請求項8至10中任一項之方法,其中該溶劑係甲基異丁基酮。
- 一種製備下式化合物
- 如請求項12之方法,其中步驟(a)中之該酸係選自由1-對甲苯磺酸、三氟乙酸、三氯乙酸及草酸組成之群。
- 如請求項12或13之方法,其中步驟(b)中之該觸媒係選自由炭載鈀、 氯化鈀、乙酸鈀、碘化銅及有機觸媒組成之群。
- 如請求項12或13之方法,其中步驟(b)中之該等溶劑係選自由乙醇、甲苯、乙酸異丙酯及其混合物組成之群。
- 如請求項12或13之方法,其中步驟(b)進一步包含將強酸添加至C4、C5及該觸媒之混合物中。
- 如請求項12或13之方法,其中步驟(b)進一步包含將強鹼添加至C4、C6及該觸媒之混合物中。
- 如請求項12或13之方法,其中步驟(b)中之該還原劑係三苯基膦。
- 如請求項12或13之方法,其中步驟(c)中之該觸媒係有機酸。
- 如請求項19之方法,其中該有機酸係特戊酸。
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WO2019011337A1 (zh) * | 2017-07-14 | 2019-01-17 | 苏州科睿思制药有限公司 | Qaw-039的晶型及其制备方法和用途 |
CN110467612B (zh) * | 2018-05-09 | 2020-09-25 | 新发药业有限公司 | 一种前列腺素d2受体抑制剂化合物的简便制备方法 |
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JP2018535248A (ja) | 2018-11-29 |
US10508110B2 (en) | 2019-12-17 |
US20180273530A1 (en) | 2018-09-27 |
CN108137503A (zh) | 2018-06-08 |
RU2744976C1 (ru) | 2021-03-17 |
PL3356329T3 (pl) | 2020-10-19 |
CA2998278A1 (en) | 2017-04-06 |
TW201718502A (zh) | 2017-06-01 |
SI3356329T1 (sl) | 2020-08-31 |
IL257558A (en) | 2018-04-30 |
EP3356329B1 (en) | 2020-04-15 |
AU2019253796A1 (en) | 2019-11-14 |
AU2016330264A1 (en) | 2018-03-22 |
EP3356329A1 (en) | 2018-08-08 |
JP6839715B2 (ja) | 2021-03-10 |
WO2017056001A1 (en) | 2017-04-06 |
DK3356329T3 (da) | 2020-07-13 |
PT3356329T (pt) | 2020-07-15 |
IL257558B (en) | 2021-01-31 |
AU2019253796B2 (en) | 2021-01-21 |
JO3712B1 (ar) | 2021-01-31 |
AR106195A1 (es) | 2017-12-20 |
CN108137503B (zh) | 2021-06-15 |
ES2805307T3 (es) | 2021-02-11 |
KR20180058724A (ko) | 2018-06-01 |
HK1250713A1 (zh) | 2019-01-11 |
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