TWI549953B - ７－環戊基－２－（５－哌－１－基－吡啶－２－基胺基）－７ｈ－吡咯并［２，３－ｄ］嘧啶－６－羧酸二甲醯胺之鹽類及其製備方法 - Google Patents

７－環戊基－２－（５－哌－１－基－吡啶－２－基胺基）－７ｈ－吡咯并［２，３－ｄ］嘧啶－６－羧酸二甲醯胺之鹽類及其製備方法 Download PDF

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TWI549953B
TWI549953B TW100140959A TW100140959A TWI549953B TW I549953 B TWI549953 B TW I549953B TW 100140959 A TW100140959 A TW 100140959A TW 100140959 A TW100140959 A TW 100140959A TW I549953 B TWI549953 B TW I549953B
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約翰 文盛 卡里尼
陳國平
鮑金 高格
普瑞莎德 科特斯瓦瑞 卡帕
維夏爾 塞西納
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諾華公司
亞士德醫療股份有限公司
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Description

7-環戊基-2-(5-哌 -1-基-吡啶-2-基胺基)-7H-吡咯并[2,3-D]嘧啶-6-羧酸二甲醯胺之鹽類及其製備方法
本發明係關於：(1)製備7-環戊基-2-(5-哌-1-基-吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲醯胺及其鹽類之方法；(2)7-環戊基-2-(5-哌-1-基-吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲醯胺之新穎鹽類；(3)包含該等之醫藥組合物；及(4)使用該等之治療方法。
式(I)之7-環戊基-2-(5-哌-1-基-吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲醯胺
及其合成具體描述於WO 2010/020675 A1，實例74中。WO 2010/020675揭示式(I)化合物具有寶貴的藥理學性質且例如可作為：(1)細胞週期調節蛋白依賴性激酶(特定言之，係選自CDK1、CDK2、CDK3、CDK4、CDK5、CDK6及CDK9之細胞週期蛋白依賴性激酶)之抑制劑；及(2)肝醣合成酶激酶-3(GSK-3)的調節劑及/或抑制劑。
WO 2010/020675並未揭示或提議7-環戊基-2-(5-哌-1-基-吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲醯胺之琥珀酸鹽。
本發明係關於7-環戊基-2-(5-哌-1-基-吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲醯胺之琥珀酸鹽。該琥珀酸鹽係具有式(II)的結構
本發明亦關於一種製備式(II)化合物之方法。
本發明進一步係關於一種製備式(I)化合物之方法。
本發明進一步亦係關於一種製備式(III)化合物之方法：
本發明進一步亦係關於一種製備式(IV)化合物之方法：
本發明進一步係關於醫藥組合物，該醫藥組合物含有式(II)之鹽及至少一種醫藥上可接受之載劑、稀釋劑、媒劑或賦形劑。
本發明亦關於一種治療對細胞週期調節蛋白依賴性激酶(特定言之，選自CDK1、CDK2、CDK3、CDK4、CDK5、CDK6及CDK9之細胞週期調節蛋白激酶)之抑制具有反應之疾病的方法，該方法包括將治療上有效量的式(II)化合物投與需此治療之個體之步驟。
本發明係關於7-環戊基-2-(5-哌-1-基-吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲醯胺之琥珀酸鹽。
該琥珀酸鹽具有式(II)結構：
7-環戊基-2-(5-哌-1-基-吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲醯胺之琥珀酸鹽可以是非水合物、水合物或其混合物之形式。
在一個實施例中，該琥珀酸鹽大於99.9%係非水合物之形式。
在一個實施例中，該琥珀酸鹽大於99%係非水合物之形式。
在一個實施例中，該琥珀酸鹽大於97%係非水合物之形式。
在一個實施例中，該琥珀酸鹽大於95%係非水合物之形式。
在一個實施例中，該琥珀酸鹽大於90%係非水合物之形式。
7-環戊基-2-(5-哌-1-基-吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲醯胺之琥珀酸鹽之非水合物形式具有良好的安定性、非吸濕性及良好的溶解性。
本發明亦關於一種製備式(I)化合物及式(II)化合物的方法：
本發明進一步關於一種製備式(III)化合物之方法。
相較之前製造式(III)化合物的方法，本發明方法將式(III)化合物之總體產率從4%提高至30%。此外，本改良方法不需要先前方法所需之五個管柱純化步驟。
本發明亦進一步關於製備式(IV)化合物之方法：
在本發明之式(IV)化合物(即A2)合成中，發展出使用正丁醇為溶劑將A2d中的氯取代為A2c的簡易方法。此方法可以提高產率且免掉了式(IV)化合物為進一步加工之層析純化作用。
總之，本發明發展出用以製造起始物質A1(式(III)化合物)、A2(式(IV)化合物)、游離鹼A4(式(I)化合物)及琥珀酸鹽A6(式(II)化合物)之可放大生產規模、更安全、更簡單、產率更高及成本效益更高之方法。相較先前的合成方法，該總體步驟縮短合成步驟且將總產率自0.9%提升至12%。
本發明進一步關於醫藥組合物，該醫藥組合物包含式(II)之鹽及至少一種醫藥上可接受之載劑、稀釋劑、媒劑或賦形劑。
本發明亦關於一種治療對細胞週期調節蛋白依賴性激酶(特定言之，選自CDK1、CDK2、CDK3、CDK4、CDK5、CDK6及CDK9之細胞週期調節蛋白依賴性激酶)之抑制具有反應之疾病的方法，該方法包括將治療上有效量的式(II)化合物投與需此治療之個體之步驟。
此對細胞週期調節蛋白依賴性激酶之抑制具有反應的疾病包括(但不限於)乳癌、泌尿生殖癌、肺癌、胃腸癌、表皮樣癌、黑色素瘤、卵巢癌、胰腺癌、神經母細胞瘤、頭及/或頸癌或膀胱癌、或更廣泛意義上的腎臟、腦或胃癌；白血病、增生、胃癌、結腸癌、喉癌、淋巴系統癌、生殖泌尿道癌、骨癌、前列腺癌、小細胞型肺癌、神經膠質瘤癌、結腸直腸癌、腎癌、上皮癌、肝癌、食道癌、造血系統癌、淋巴瘤、骨髓瘤、甲狀腺濾泡狀癌；源自間葉的腫瘤，例如纖維肉瘤或橫紋肌肉瘤；中樞或周圍神經系統的腫瘤，例如星形細胞瘤、神經母細胞瘤、神經膠質瘤或神經鞘瘤；黑色素瘤；精原細胞瘤；畸胎瘤；骨肉瘤；著色性乾皮病；角化棘皮瘤；甲狀腺濾泡狀癌；卡波西氏(Kaposi's)肉瘤、慢性淋巴細胞白血病、外套細胞淋巴瘤、大B細胞淋巴瘤。
「治療上有效量」係意欲表明本發明之鹽投與有需要之個體時，足以藉由抑制細胞週期調節蛋白依賴性激酶之活性緩解病情而達到治療效果之量。在治療上具有效果之本發明特定化合物的量會隨著諸如病情及其嚴重度、有需要個體的本身狀態等因素而變化，該量可由此技術中一般具有技能的技術人員例行性地決定。
「至少一種醫藥上可接受之載劑、稀釋劑、媒劑或賦形劑」可輕易地由此技術中一般具有技能之技術人員選定，且由所欲投藥方式決定。適宜的投藥方式的說明性實例包括經口、經鼻、非經腸、局部、經皮、及經直腸。本發明之醫藥組合物可為熟悉此項技藝者認為適合之任何醫藥形式。適宜的醫藥形式包括固體、半固體、液體、或凍乾之調配物，如錠劑、粉末、膠囊、栓劑、懸浮液、脂質體、及噴霧劑。
現在將以參考下列實例來說明本發明之特定實施例。應了解揭示此等實例僅為說明本發明且不應以任何方式限制本發明之範疇。
實例1　製備化合物A1(即式(III)化合物)
根據下列合成流程圖製備化合物A1(即式(III)化合物，2-氯-7-環戊基-N,N-二甲基-7H-吡咯并[2,3-d])嘧啶-6-羧醯胺)。
各步驟之細節提供於下列步驟1.1至1.4中。步驟1.5係選擇性的純化步驟。
1 .1　5-溴-2-氯-N-環戊基嘧啶-4-胺(A1f)
將250 g(1.097 mol，140.4 mL，1.0 eq.)之5-溴-2,4-二氯嘧啶(A1h)及1127 g(1250 mL)之乙酸乙酯進料至5 L的經氮沖洗且適當配備之4-頸圓底燒瓶中。在20℃溫度下攪拌該內容物並添加283.5 g(2.194 mol，382.0 mL，2.0 eq.)之N,N-二異丙基乙胺。60分鐘內添加溶解於1127 g(1250 mL)乙酸乙酯中之102.8 g(1.207 mol，119 mL，1.1 eq.)環戊胺溶液。觀察到從18℃至36℃之放熱現象。將該溶液加熱至40℃。保持此溫度至少達6小時或直至以HPLC分析法確認所有起始物質(A1h)皆耗盡的時候。將所得漿液冷卻至25℃且添加500 g(500 mL)的水，攪拌該內容物15分鐘，並讓相分離。移除底層(水性)且使用500 g(500 mL)水再一次沖洗有機層。攪拌該樣品達15分鐘，且讓相分離。移除底層(水性)。使該有機相濃縮至(大氣壓)體積為1500 mL(批料溫度=82℃)。添加684 g(1 L)庚烷且將其再濃縮至體積為1500 mL(批料溫度=85℃)。再次，添加684 g(1 L)庚烷且將其再濃縮至體積為1500 mL(批料溫度=96℃)。使該樣品冷卻至50℃並加入晶種。繼續冷卻至4℃且將該溫度保持在4℃達1小時。將固體過濾且使用137 g(200 mL)冷庚烷(4℃)沖洗濾餅一次。在50℃溫度下乾燥該等固體達16小時，以提供259.0 g(經校正88.0%)呈白色結晶固體狀、mp=95-96℃之化合物A1f。
1.2　3-[2-氯-4-(環戊胺基)嘧啶-5-基]丙-2-炔-1-醇(A1d)
將200 g(0.723 mol，1.0 eq.)之5-溴-2-氯-N-環戊基嘧啶-4-胺(A1f)及2303 g(2600 mL)之四氫呋喃進料至5 L的經氮沖洗、適當配備之4-頸圓底燒瓶中。攪拌該混合物，將其加熱至回流(67℃)，且收集200 mL餾份。使該樣品冷卻至25℃，並添加52.7 g(0.940 mol，55.6 mL，1.3 eq.)之炔丙醇(A1e)、570.3 g(1.808 mol，2.5 eq.)之三水四丁基氟化銨及25.4 g(0.036 mL，0.05 eq.)之雙(三苯基膦)二氯化鈀。攪拌該樣品且將其加熱至回流(67℃)且在此溫度下保持達2小時或直至以HPLC分析法確認剩餘5至7%的起始物質(A1f)的時候。將該樣品冷卻至25℃且在減壓(100 mbar，最大內部溫度30℃)下濃縮至體積為1150 mL，以移除四氫呋喃。進料541 g(600 mL)之乙酸乙酯。再次使該樣品在減壓(100 mbar，最大內部溫度30℃)下濃縮至體積為1150 mL，以移除殘留的四氫呋喃。添加2706 g(3000 mL)之乙酸乙酯及溶於1500 g(1500 mL)水之63 g重碳酸鈉溶液。在25℃溫度下攪拌該樣品達10分鐘且讓相分離。使用1500 g(1500 mL)水將有機相(頂部)沖洗一次。攪拌該樣品達10分鐘且讓相分離。在減壓(100 mbar，最高內部溫度30℃)下使該有機相(頂部)濃縮至體積為625 mL，以移除乙酸乙酯。將1582 g(2000 mL)之丙酮添加至該濃縮物中。攪拌該樣品，將其加熱至回流(58℃)且在此溫度下保持30分鐘。然後使其冷卻至40℃且經以矽藻土過濾墊過濾加以澄清化。使用158 g(200 mL，2 x每次沖洗100 mL)之丙酮沖洗該燒瓶及濾餅兩次。在減壓(100 mbar，最大內部溫度30℃)下使該樣品濃縮至體積為460 mL。然後使其冷卻至4℃且在此溫度下維持1小時。將固體過濾且使用158 g(2×100 mL)之冰冷丙酮(4℃)沖洗濾餅兩次。在50℃溫度下乾燥該固體達16小時，以提供85.6 g(經校正47.4%)呈棕黃色結晶固體狀、mp=162-163℃之化合物A1d。
1.3　(2-氯-7-環戊基-7H-吡咯并[2,3-d]嘧啶-6-基)甲醇(A1c)
將100 g(純度：98%，0.389 mol，1.0 eq.)之3-(2-氯-4-(環戊基胺基)嘧啶-5-基)丙-2-炔-1-醇(A1d)、880 g(1000 mL)之過氧化游離四氫呋喃及753 g(856 mL)之四丁基氟化銨(1.0 M THF溶液)進料至5 L之乾燥及經氮沖洗之4-頸圓底燒瓶中。在25℃溫度下攪拌該內容物達10分鐘，且然後將溶液加熱至60℃。保持此溫度達1.5小時直至以HPLC分析法確認起始物質(A1d)2.5±0.5%。使所得溶液冷卻至低於30±3℃，且在減壓下進行蒸餾以移除THF。添加79 g(100 mL)之2-丙醇。攪拌該樣品達15分鐘，且然後在30分鐘內緩慢添加1000 g(1000 mL)水。在20±3℃溫度下攪拌該樣品達30分鐘且然後過濾。使用200 g(2×100 mL)水沖洗濾餅兩次。在50℃溫度下乾燥固體達16小時，以提供棕黃色、結晶固體狀、mp=174-176℃之化合物A1c。
1.4　2-氯-7-環戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-羧醯胺(A1)
將97.3 g之氰化鈉、2,500 g之(2-氯-7-環戊基-7H-吡咯并[2,3-d]嘧啶-6-基)甲醇(A1c)、16,680 g(19.5 L)之二甲胺、A1a(2.0 M THF溶液)、及28,320 g(30.0 L)之無水N,N-二甲基甲醯胺進料至乾燥、經氮沖洗之ACE-100 L反應器中。在20±3℃溫度下攪拌該混合物達15分鐘。然後添加2.06 kg之二氧化錳(IV)。將深色漿液攪拌30分鐘且每隔30分鐘分三份添加12.36 kg之二氧化錳(IV)(第一份：2.06 kg；第二份：4.12 kg；及第三份：6.18 kg)。添加最後一份之後，保持該樣品達1小時且然後添加6.18 kg之二氧化錳(IV)。保持該樣品達1小時。然後抽取該反應混合物樣本。若以HPLC分析法確認起始物質(A1c)1.0±0.5%，則認為該反應完全。然後將該反應混合物經以矽藻土墊過濾以移除二氧化錳(IV)。然後使用23 L之乙酸乙酯漂洗該反應器及濾餅。在減壓(45±3℃，20 mbar)下將濾液與餾份合併以移除THF、二甲胺及乙酸乙酯。在減壓(70±5℃，5 mbar)下進一步蒸餾該樣品以移除DMF。使用35 L之乙酸乙酯稀釋該濃縮物。使用硫酸亞鐵水溶液(在14 L的水中含1 kg FeSO4‧7H2O)、15 L的水及最後使用15 L之10% NaCl水溶液沖洗所得之深色溶液。每次沖洗後讓相分離。蒸餾(45℃，50 mbar)有機相以共沸方式移除水。所得之粗製A1(2,788 g深色黏稠半固體殘餘物)可直接用於隨後的步驟。
1.5　步驟：自粗製A1分離出純A1
可視需要藉由下列之方法1或2來純化源自步驟1.4之粗製A1。
方法-1：
將10 g之粗製A1及9 mL 1-丙醇溫和地加熱直至獲得均質深色溶液。將該溶液冷卻至25±3℃且緩慢添加30至40 mL己烷。將樣品加入晶種並攪拌直至觀察到結晶。另外緩慢地添加50至60 mL己烷。所添加之己烷總體積約90 mL。在22±3℃溫度下保持該漿液達2小時，然後使其冷卻至4℃且另外保持2小時。將固體過濾。根據需要使用己烷沖洗燒瓶及濾餅。在50℃溫度及50 mbar壓力下乾燥該濾餅，以提供6.35 g淡棕黃色結晶固體狀之純化A1。回收率：63.5%
方法2：
製備溶於10 mL EtOAc之10 g之粗製A1溶液，且將其裝載至100 g矽膠床上。使用300 mL EtOAc/己烷(2/8)洗脫該管柱且丟棄洗脫液。然後使用800 mL EtOAc/己烷(5/5)洗脫該管柱且收集洗脫液(#2)以便分離產物。將洗脫液(#2)濃縮至稀油狀。緩慢添加100 mL己烷且在22±3℃溫度下攪拌樣品達2小時。將該樣品冷卻至4℃並額外保持2小時。將固體過濾。根據需要使用己烷沖洗燒瓶及濾餅。在50℃溫度及50 mbar壓力下乾燥該濾餅，以提供6.05 g淡棕黃色結晶固體狀之純化A1。回收率係60.5%。
實例2　製備化合物A2(即式(IV)化合物，第三丁基4-(6-胺基吡啶-3-基)哌 -1-羧酸酯)：
根據下列合成流程圖製備化合物A2(即式(IV)化合物，第三丁基4-(6-胺基吡啶-3-基)哌-1-羧酸酯)。
各步驟的細節係提供於下列步驟2.1至2.4中。
2.1　1-(6-硝基吡啶-3-基)哌 鹽酸鹽(A2b)
將1392 g(8.78 mol，1.0 eq.)之5-氯-2-硝基吡啶(A2d)、1512 g(17.56 mol，2.0 eq.)之哌(A2c)及11,340 g(14,000 mL)之正丁醇進料至22 L的經氮沖洗、適當配備之4-頸圓底燒瓶。攪拌所得懸浮液且將其加熱至95℃。保持此溫度達至少24小時或直至以HPLC分析法確認剩餘起始物質A2d2%(面積標準化)。將所得漿液在1小時內冷卻至25℃。將固體經以聚丙烯濾墊過濾。使用總量為2267 g(2×1300 mL)之乙酸異丙酯沖洗濾餅兩次。在60℃溫度下乾燥該固體達16小時，以提供1769 g(82.3%，未經校正)黃色結晶固體狀及mp>230℃的A2b。
2.2　第三丁基4-(6-硝基吡啶-3-基)哌 -1-羧酸酯(A2a)
將589 g(2.41 mol，1.0 eq.)之1-(6-硝基吡啶-3-基)哌鹽酸鹽(A2b)進料至22 L的經氮沖洗、適當配備之4-頸圓底燒瓶中。製備溶於10,223 g(11,500 mL)四氫呋喃之630.5 g(2.89 mol，1.2 eq.)二碳酸二-第三丁酯之溶液，且將其進料至該燒瓶中。攪拌所得懸浮液且使其冷卻至8±3℃。將499 g(3.61 mol，1.5 eq.)之碳酸鉀進料至5 L的經氮沖洗、適當配備之4-頸圓底燒瓶中。將3,600 g(3,600 mL)水添加至該5 L燒瓶中。攪拌後獲得溶液。使此溶液冷卻至25±3℃且在30分鐘內將其移至反應混合物中。在整個添加過程中，批料溫度保持在12±3℃。將該混合物加熱至22±3℃，且在此溫度下另外保持1小時或直至以TLC分析法確認不再顯現起始物質(A2b)。該2-相混合物經以250 g之矽藻土濾墊過濾。使用總量為800 g(2×450 mL)之四氫呋喃沖洗濾餅兩次。使該沖洗物與濾液合併。讓相分離且丟棄水相(底部)。在減壓(100 mbar，內部最大溫度40℃)下使濾液濃縮成黏稠的糊狀物。
將此完整過程再重複兩次。該等從所有三回合所得之濃縮物合併在22 L經氮沖洗及適當配備之4-頸圓燒瓶中。將4,719 g(6,900 mL)之庚烷添加至該等濃縮批料中。攪拌該樣品且在減壓(100 mbar，內部最大溫度40℃)下使其濃縮成黏稠的糊狀物。此外，將3,146 g(4,600 mL)之庚烷添加至該濃縮批料中。在37±3℃溫度下攪拌所得懸浮液達1小時；使其冷卻至22±3℃並維持15分鐘。將固體經以聚丙烯濾墊過濾，且使用615 g(2×450 mL)之庚烷將其沖洗兩次。在55℃溫度下利用氮清掃將該固體乾燥達16小時，以提供2,088 g(93.8%)之黃色、結晶固體狀及mp=173-174℃之化合物A2a。
2.3　第三丁基4-(6-胺基吡啶-3-基)哌 -1-羧酸酯(A2)
將68 g(0.22 mol)之第三丁基4-(6-硝基吡啶-3-基)哌-1-羧酸酯(A2a)、6.8 g 10%鈀碳、50%含水量觸媒及807 g(1020 mL)之甲醇進料至2.5 L經氮沖洗之厚壁帕爾(Parr)瓶。使用氮(ca. 30 psi)將反應器惰化三次，以便每次惰化時排散反應混合物上方的空氣。利用氫(ca. 30 psi)加壓該容器兩次，以便每次加壓時排散反應混合物上方的空氣。利用氫將該反應器加壓至45 psi。啟動振盪器電動機。該反應係放熱反應。溫度會在15分鐘內從19℃上升至54℃，在此期間氫氣的攝入會停止。讓混合物在1小時內冷卻至30℃，此時將振盪器停止。使用如上文所述之氮(惰化反應器)置換掉氫氣。藉由通過10 g矽藻土過濾墊過濾來移除觸媒。將此完整過程再重複一次，將兩次所得之濾液合併並進料至乾淨的3 L 4-頸圓底燒瓶中。
2.4　產物分離
攪拌源自步驟2.3之濾液且在減壓(50 mbar，最大內部溫度40℃)下使其濃縮成粘稠的糊狀物。將190 g(250 mL)之第三丁基甲醚進料至殘餘物中。再次攪拌該樣品且在減壓(50 mbar，最大內部溫度30℃)下使其濃縮成粘稠的糊狀物。將342 g(500 mL)之庚烷進料至殘餘物中且在22±3℃溫度下攪拌所得懸浮液達15分鐘。將固體過濾且使用68 g(100 mL)之庚烷沖洗濾餅。在50℃溫度下乾燥該固體達16小時，以提供112.3 g(93.4%)棕黃色盤狀及mp=124-126℃之化合物A2。
實例3　製備7-環戊基-2-(5-哌 -1-基-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲醯胺(即式(I)化合物)：
根據下列合成流程圖製備化合物A4即式(I)化合物，7-環戊基-2-(5-哌-1-基-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲醯胺)。
各步驟之細節係提供於下列步驟3.1至3.2中。
3.1　第三丁基4-(6-(7-環戊基-6-(二甲基胺甲醯基)-7H-吡咯并[2,3-d]嘧啶-3-基)哌 -1-羧酸酯(A3)：
將43.9 g(0.15 mol，1.0 eq.)之2-氯-7-環戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-羧醯胺(源自以上步驟1.4之粗製A1)、45.9 g(0.165 mL，1.1 eq.)之第三丁基4-(6-胺基吡啶-3-基)哌-1-羧酸酯(A2)、0.67 g(3.0 mmol，0.02 eq.)乙酸鈀(II)、3.73 g(6.0 mmol，0.04 eq.)之(±)2,2'-雙(二苯基膦基)-1,1'-聯二萘、±BINAP(2,2'-雙(二苯基膦基)-1,1'-聯二萘)及275 g(344 mL)之4-甲基-2-戊酮進料至3 L之經氮沖洗之阿爾戈(Argonaut)反應器系統中。攪拌所得懸浮液並將其加熱至40±3℃。以5至10份分量於15分鐘內加入73.3 g(0.225 mol，1.5 eq)之碳酸銫。攪拌所得懸浮液且將其加熱至100±3℃。保持此溫度達3小時或直至以HPLC分析法確認剩餘起始物質(A1)2%(面積標準化)。使用加工操縱控制來檢查反應進程。使樣品冷卻至70±3℃且在5分鐘內添加344 g(344 mL)水。使樣品冷卻至50±3℃且在此溫度下維持30分鐘。在30分鐘內添加353 g(516 mL)之庚烷，且攪拌該樣品達2小時。然後使該混合物冷卻至22±3℃且維持至少4小時(停頓點)。固體經以聚丙烯濾墊過濾。使用24 g(30 mL)之4-甲基-2-戊酮與41 g(60 mL)庚烷之冰冷混合物(4℃)沖洗濾餅。在60℃溫度下乾燥該等固體直至HSGC PSC顯示有機溶劑1%，以提供72.6 g棕黃色、固體狀、mp=215-217℃(dec.)之A3。
3.2　7-環戊基-N,N-二甲基-2-(5-(哌 -1-基)吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧醯胺(A4)
將67.4 g(0.126 mol，1.0 eq.)之第三丁基4-(6-(7-環戊基-6-(二甲基胺甲醯基)-7H-吡咯并[2,3-d]嘧啶-2-基胺基吡啶-3-基)哌-1-羧酸酯(A3)及329 g(380 mL)之甲苯進料至3 L之經氮沖洗之阿爾戈反應器系統。攪拌懸浮液且使其冷卻至12±3℃。在30分鐘內添加138 g(126 mL，6.0 eq.)之6 N鹽酸水溶液，保持批料溫度15±3℃。將所得之2-相溶液加熱至25±3℃，且在此溫度下保持達30分鐘或直至以HPLC分析法確認剩餘起始物質(A3)2%(面積標準化)。利用加工操縱控制來檢查反應進程。添加250 g(250 mL)之1 N鹽酸水溶液且將混合物攪拌5分鐘。2-相反應混合物經以25 g矽藻土濾墊過濾。讓相分離。將水相(含有產物)進料至2 L之4-頸圓底燒瓶(如根據裝置入口4所描述之配備)且使其冷卻至15±3℃。緩慢添加62 g(41 mL)之50%氫氧化鈉水溶液，將pH值調節至3.2±0.3，在整個添加過程中使批料溫度保持在27±3℃。添加16.4 g矽-硫醇官能化矽膠。在50±3℃溫度下攪拌漿液達3小時。濾出樹脂，使用50 mL水漂洗燒瓶及濾餅。將漂洗物與濾液合併。將該濾液轉移回燒瓶中，且添加16.4 g矽-硫醇官能化矽膠。在50±3℃溫度下攪拌漿液達3小時。濾出矽膠。使用50 mL水漂洗該燒瓶及濾餅。將漂洗物與濾液合併。將該濾液轉移回燒瓶中，且再添加16.4 g矽-硫醇官能化矽膠。在50±3℃溫度下攪拌漿液達3小時。濾出矽膠。使用50 mL水漂洗該燒瓶及濾餅。使漂洗物與濾液合併。將該濾液進料至3L之經沖洗之阿爾戈反應器系統且使其冷卻至15±3℃。緩慢添加17 g(18 mL)之50%氫氧化鈉水溶液，將pH值調節至12.5±0.5，以使產物(批料體積=900 mL，最大容積)沉澱。在22±3℃溫度下攪拌該樣品達至少6小時。將固體經以聚丙烯濾墊過濾。使用340 g(4×85 mL)水沖洗濾餅四次直至沖洗物之pH值9。在60℃溫度下乾燥該等固體達至少16小時或直至LOD1%，以提供45.7 g(84.9%，未經校正)呈棕黃色固體狀、mp=194-195℃之化合物A4。
實例4　7-環戊基-2-(5-哌 -1-基-吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲基醯胺(即化合物A6，式(II)化合物)之琥珀酸鹽的製備：
根據下列合成流程圖製備化合物A6(即式(II)化合物，7-環戊基-N,N-二甲基-2-(5-(哌-1-基)吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧醯胺琥珀酸酯)。
將11.16 g(0.0945 mol，1.05 eq.)之琥珀酸(A5)及245 g(312 mL)之2-丙醇進料至1 L之經氮沖洗之4-頸圓底燒瓶中。攪拌懸浮液且將其加熱至65±3℃，以獲得透明溶液。該溶液在溫熱時經玻璃纖維濾紙過濾。將濾液保持在30±3℃，用於添加至A4。將39.11 g(0.09 mol,1.0 eq)7-環戊基-N,N-二甲基-2-(5-(哌-1-基)吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧醯胺(A4)及1115g(1420 mL)2-丙醇進料至2 L之經氮沖洗之4-頸圓底燒瓶中。攪拌所得懸浮液且將其加熱至80±3℃，獲得渾濁黃色溶液。將該溶液冷卻至70±3℃並經25 g矽藻土墊過濾。將該溫熱、經過濾之A4溶液轉移至3 L之經氮沖洗之阿爾戈反應器系統中，且再加熱至80±3℃。在1小時內添加琥珀酸/2-丙醇溶液，整個添加過程保持80±3℃。在已添加80%琥珀酸溶液後，在批料中加入晶種。在該添加完成後，該樣品在80±3℃攪拌1小時且在1小時內冷卻至20±3℃，保持30分鐘，且將固體過濾。使用78 g(100 mL)之2-丙醇洗濾餅。該固體在60℃乾燥至少16小時或直至LOD1%，提供47.16g(94.9%，經校正)化合物A6，呈黃色結晶固體，mp=202-203℃。
實例5　式(II)化合物在90% RH下之物理形式特徵：
將實例4所得化合物A6暴露於兩種水氣循環(0-90-0% RH)，以瞭解其吸濕性質。表1及圖1顯示在各循環中，化合物A6在90% RH吸收達2%的水分，此反映其在高濕度條件下之低吸濕行為。在各循環中亦觀察到水分吸收之驟升在90% RH的條件下，且吸附行為與解吸附行為之差異反映水合物形式的形成係發生於90% RH之條件下。圖2、3及4顯示化合物A6暴露至90% RH時物理形式改變，觀察到不同晶形與吸熱轉變，其顯示在約100℃重量損失3%，在暴露於90% RH之後兩種形式均轉化成水合物形式。
在90% RH下，約7.35%之實例4中所得化合物A6會從非水合物形式轉化成水合物形式。
實例6　式(II)化合物在90% RH下之物理形態特性
將在實例4所得化合物A6暴露於0-80-0% RH之水氣循環中，以確認90%RH下所觀察的形態轉變不會發生於80% RH的時候。表2及圖5顯示化合物A6在80% RH下吸收達0.5%的水分，此反映其在80% RH下幾乎非吸濕行為。圖5及6顯示，反映為非水合物形式的式(II)化合物暴露於最高至80% RH中之物理形態的安定性。由於原藥料及藥品在75% RH下之物理形態的安定性是令人滿意的，因此式(II)化合物(非水合物)係適於發展的。
在80% RH下，僅約0.52%之實例4所得化合物A6會從非水合物形式轉化成水合物形式。
實例7　溶解度：
非水合物形式在水中之溶解度為30 mg/mL。相反地，水合物形式的溶解度明顯地較低且係低於0.5 mg/mL。
圖1顯示式(II)化合物之動態蒸汽吸附(DVS)等溫曲線圖(0-90-0%相對濕度(RH)循環)。
圖2顯示在式(II)化合物之DVS後之X-光粉末繞射(XRPD)(0-90-0% RH循環)。
圖3顯示在DVS後之式(II)化合物之差式掃描量熱法(DVS)(0-90-0% RH循環)。
圖4顯示在DVS後之式(II)化合物之熱重分析(TGA)(0-90-0% RH循環)。
圖5顯示式(II)化合物之DVS等溫曲線圖(0-80-0% RH循環)。
圖6顯示在式(II)化合物之DVS後之XRPD(0-80-0% RH循環)。
(無元件符號說明)

Claims (6)

  1. 一種7-環戊基-2-(5-哌-1-基-吡啶-2-基胺基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲基醯胺之琥珀酸鹽。
  2. 如請求項1之鹽，其中該鹽具有式(II)
  3. 如請求項1之鹽，其係非水合物形式。
  4. 如請求項1之鹽，其係水合物形式。
  5. 一種醫藥組合物，其包含：(a)治療上有效量的如請求項1至4中任一項之鹽；及(b)至少一種醫藥上可接受之載劑、稀釋劑、媒劑或賦形劑。
  6. 一種如請求項1至4中任一項之鹽之用途，其係用於製造供治療對細胞週期調節蛋白依賴性激酶活性之抑制具有反應之疾病的醫藥。
TW100140959A 2010-11-10 2011-11-09 ７－環戊基－２－（５－哌－１－基－吡啶－２－基胺基）－７ｈ－吡咯并［２，３－ｄ］嘧啶－６－羧酸二甲醯胺之鹽類及其製備方法 TWI549953B (zh)

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Families Citing this family (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY33227A (es) 2010-02-19 2011-09-30 Novartis Ag Compuestos de pirrolopirimidina como inhibidores de la cdk4/6
US20120115878A1 (en) * 2010-11-10 2012-05-10 John Vincent Calienni Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof
EP2726074B1 (en) 2011-07-01 2018-04-04 Novartis AG Combination therapy comprising a cdk4/6 inhibitor and a pi3k inhibitor for use in the treatment of cancer
EP2934515B1 (en) * 2012-12-20 2018-04-04 Novartis AG A pharmaceutical combination comprising binimetinib
WO2015180642A1 (en) * 2014-05-28 2015-12-03 Shanghai Fochon Pharmaceutical Co Ltd Certain protein kinase inhibitors
CN105294737B (zh) * 2014-07-26 2019-02-12 广东东阳光药业有限公司 Cdk类小分子抑制剂的化合物及其用途
PL3218005T3 (pl) 2014-11-12 2023-05-02 Seagen Inc. Związki oddziałujące z glikanami i sposoby ich zastosowania
WO2016091221A1 (zh) * 2014-12-12 2016-06-16 苏州晶云药物科技有限公司 吡咯并[2,3-d]嘧啶化合物的盐及盐的新晶型
CN105111215B (zh) * 2014-12-12 2019-06-18 苏州晶云药物科技股份有限公司 一种周期蛋白依赖性激酶抑制剂的晶型及其制备方法
US10138250B2 (en) 2014-12-12 2018-11-27 Crystal Pharmatech Co., Ltd. Salt of pyrrolo[2,3-D]pyrimidine compound and novel polymorph of salt
WO2016151501A1 (en) 2015-03-25 2016-09-29 Novartis Ag Pharmaceutical combinations
WO2016155670A1 (zh) * 2015-04-01 2016-10-06 苏州晶云药物科技有限公司 一种cdk抑制剂和mek抑制剂的共晶及其制备方法
CN115554257A (zh) 2015-04-16 2023-01-03 诺华股份有限公司 瑞博西尼片剂
CN105037236B (zh) 2015-06-04 2017-07-28 苏州明锐医药科技有限公司 瑞博西尼中间体及其制备方法
EP3340990B1 (en) * 2015-08-28 2019-09-25 Novartis AG Pharmaceutical combinations comprising (a) the cyclin dependent kinase 4/6 (cdk4/6) inhibitor lee011 (=ribociclib), and (b) the epidermal growth factor receptor (egfr) inhibitor erlotinib, for the treatment or prevention of cancer
EP3156406A1 (en) 2015-10-14 2017-04-19 ratiopharm GmbH Crystalline forms of ribociclib free base
IL302822A (en) 2015-11-12 2023-07-01 Seagen Inc Compounds interacting with glycans and methods of use
CN106749259B (zh) * 2015-11-19 2019-02-01 华东师范大学 一种环戊基嘧啶并吡咯类化合物的合成方法
CN107266451B (zh) * 2016-04-07 2021-12-31 上海医药工业研究院 瑞布昔利布中间体的制备方法
JP6927548B2 (ja) 2016-05-07 2021-09-01 シャンハイ フォチョン ファーマシューティカル カンパニー リミテッド ある種のタンパク質キナーゼ阻害剤
CA3034875A1 (en) 2016-08-23 2018-03-01 Eisai R&D Management Co., Ltd. Combination therapies for the treatment of hepatocellular carcinoma
WO2018051280A1 (en) * 2016-09-15 2018-03-22 Dr. Reddy’S Laboratories Limited Process for preparation of ribociclib, its acid addition salts
CN106478641B (zh) * 2016-10-09 2018-07-24 杭州科巢生物科技有限公司 瑞博西尼中间体的合成方法
WO2018094143A1 (en) 2016-11-17 2018-05-24 Siamab Therapeutics, Inc. Glycan-interacting compounds and methods of use
CN108314686A (zh) * 2017-01-18 2018-07-24 西南民族大学 一种新颖的Ribociclib制备方法
BR112019018043A2 (pt) 2017-03-03 2020-04-07 Seattle Genetics Inc método de tratamento de câncer, e, conjugado de anticorpo-fármaco
WO2018170447A1 (en) 2017-03-16 2018-09-20 Eisai R&D Management Co., Ltd. Combination therapies for the treatment of breast cancer
CN108586356B (zh) * 2017-03-16 2021-02-19 杭州科巢生物科技有限公司 瑞博西尼新中间体及其制备瑞博西尼的合成方法
CN108623599A (zh) * 2017-03-17 2018-10-09 西南民族大学 一种快速合成Ribociclib方法
CN106928236B (zh) * 2017-05-06 2019-05-31 山东君瑞医药科技有限公司 一种瑞博西尼的合成工艺
CN109206373B (zh) * 2017-07-07 2022-02-15 上海医药工业研究院 一种帕博昔布中间体5-溴-2-氯-4-环戊基氨基嘧啶的制备工艺
WO2019019959A1 (zh) * 2017-07-27 2019-01-31 苏州晶云药物科技股份有限公司 瑞博西尼的单琥珀酸盐晶型及其制备方法和用途
EP3672968B1 (en) 2017-08-25 2023-11-01 Assia Chemical Industries Ltd Solid state form of ribociclib succinate
CN111433375A (zh) 2017-08-31 2020-07-17 诺华股份有限公司 选择针对癌症患者的治疗的方法
CN111164085B (zh) 2017-09-29 2023-04-04 杭州领业医药科技有限公司 瑞博西林的共晶和瑞博西林单琥珀酸盐的共晶、其制备方法、组合物和用途
JP7100125B2 (ja) * 2017-10-27 2022-07-12 フレゼニウス・カビ・オンコロジー・リミテッド リボシクリブおよびその塩の改善された調製のためのプロセス
WO2019111160A1 (en) * 2017-12-04 2019-06-13 Sun Pharmaceutical Industries Limited Crystalline forms of ribociclib succinate
US11111250B2 (en) 2017-12-22 2021-09-07 Shilpa Meicare Limited Polymorphs of Ribociclib mono succinate
IN201741000072A (zh) * 2017-12-29 2018-07-06
CN107936029B (zh) * 2018-01-08 2020-06-30 南京奇可药业有限公司 一种合成瑞博西尼的方法
CN110016024B (zh) * 2018-01-09 2021-09-03 南京药石科技股份有限公司 一种合成cdk4/6双重抑制剂的关键中间体及其制备方法和应用
WO2019142206A1 (en) * 2018-01-20 2019-07-25 Natco Pharma Limited An improved process for the preparation of ribociclib succinate and its novel crystalline forms thereof
WO2019150181A1 (en) * 2018-02-05 2019-08-08 Biophore India Pharmaceuticals Pvt Ltd Improved process for the preparation of 7-cyclopentyl-n, n-dimethyl-2-(5-(piperazin-1-yl) pyridin-2-ylaminuteso)-7h-pyrrolo[2,3-d] pyrimidine-6-carboxamide succinate (ribociclib succinate) and its crystalline forms thereof
WO2019166987A1 (en) * 2018-02-28 2019-09-06 Sun Pharmaceutical Industries Limited A process for the preparation of ribociclib and its intermediates
WO2019167068A1 (en) 2018-03-01 2019-09-06 Cipla Limited Novel polymorphs of ribociclib succinate
CA3043066A1 (en) 2018-05-14 2019-11-14 Apotex Inc. Processes for the preparation of ribociclib and intermediates thereof
TWI675662B (zh) 2018-05-17 2019-11-01 中化合成生技股份有限公司 瑞博西尼琥珀酸鹽（Ｒｉｂｏｃｉｃｌｉｂ ｓｕｃｃｉｎａｔｅ ｓａｌｔ）晶型Ｂ、Ｃ及Ｄ與其衍生物，以及其等之製造方法與藥物組合物
CA3048036A1 (en) 2018-07-02 2020-01-02 Apotex Inc Novel crystalline form of ribociclib succinate
CN110156793B (zh) * 2018-07-13 2022-01-14 安礼特（上海）医药科技有限公司 瑞博西尼单琥珀酸盐新晶型及制备方法
WO2020084389A1 (en) 2018-10-23 2020-04-30 Lupin Limited Ribociclib intermediate and process for preparation thereof
CN111100128B (zh) * 2018-10-26 2022-09-06 广安凯特制药有限公司 一种瑞博西尼中间产品的合成方法及其中间体化合物
JPWO2020130125A1 (ja) 2018-12-21 2021-11-04 第一三共株式会社 抗体−薬物コンジュゲートとキナーゼ阻害剤の組み合わせ
CN109400612A (zh) * 2018-12-24 2019-03-01 重庆三圣实业股份有限公司 一种瑞博西尼的制备方法及其产品和用途
WO2020152629A1 (en) 2019-01-23 2020-07-30 Novartis Ag New crystalline forms of a succinate salt of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine -6-carboxylic acid dimethylamide
WO2020225827A1 (en) 2019-05-08 2020-11-12 Mylan Laboratories Limited Novel polymorphs of ribociclib succinate
CN112010857B (zh) * 2019-05-30 2021-11-05 常州制药厂有限公司 一种瑞博西尼单丁二酸盐的晶型
WO2021038590A1 (en) 2019-08-30 2021-03-04 Mylan Laboratories Limited Novel polymorph of ribociclib succinate
JP2023525100A (ja) 2020-05-12 2023-06-14 ノバルティス アーゲー Ｃｒａｆ阻害剤を含む治療的組み合わせ
WO2022207788A2 (en) 2021-04-01 2022-10-06 Krka, D.D., Novo Mesto Process for the preparation of ribociclib and pharmaceutically acceptable salts thereof
CN113636973B (zh) * 2021-09-07 2023-04-07 山东铂源药业股份有限公司 一种4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯的工业化制备方法
WO2023107525A1 (en) 2021-12-10 2023-06-15 Eli Lilly And Company Cdk4 and 6 inhibitor in combination with fulvestrant for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in patients previously treated with a cdk4 and 6 inhibitor
WO2023114264A1 (en) 2021-12-15 2023-06-22 Eli Lilly And Company Combination for treatment of high-risk metastatic hormone-sensitive prostate cancer
TW202329977A (zh) 2022-01-25 2023-08-01 瑞士商諾華公司 瑞博西尼藥物組成物
WO2024049926A1 (en) 2022-08-31 2024-03-07 Arvinas Operations, Inc. Dosage regimens of estrogen receptor degraders
CN117069663B (zh) * 2023-08-31 2023-12-26 四川维亚本苑生物科技有限公司 一种瑞博西尼中间体v的合成方法及瑞博西尼的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006008545A2 (en) * 2004-07-22 2006-01-26 Astex Therapeutics Limited Thiazole and isothiazole derivatives as protein kinase inhibitors
WO2007140222A2 (en) * 2006-05-26 2007-12-06 Novartis Ag Pyrrolopyrimidine compounds and their uses
WO2010020675A1 (en) * 2008-08-22 2010-02-25 Novartis Ag Pyrrolopyrimidine compounds as cdk inhibitors

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI992711A1 (it) 1999-12-27 2001-06-27 Novartis Ag Composti organici
CA2470044C (en) 2001-12-20 2010-12-14 Osi Pharmaceuticals, Inc. Pyrrolopyrimidine a2b selective antagonist compounds, their synthesis and use
CN102060806A (zh) 2003-09-11 2011-05-18 iTherX药品公司 细胞因子抑制剂
PL1713806T3 (pl) * 2004-02-14 2013-09-30 Irm Llc Związki i kompozycje jako inhibitory kinaz białkowych
WO2006091737A1 (en) * 2005-02-24 2006-08-31 Kemia, Inc. Modulators of gsk-3 activity
EP1910218A1 (en) 2005-07-22 2008-04-16 Qualcomm Mems Technologies, Inc. Mems devices having support structures and methods of fabricating the same
WO2007075783A2 (en) * 2005-12-22 2007-07-05 Wyeth Substituted isoquinoline-1,3(2h,4h)-diones, 1-thioxo-1,4-dihydro-2h-isoquinoline-3-ones and 1,4-dihydro-3(2h)-isoquinolones and use thereof as kinase inhibitor
AR081331A1 (es) 2010-04-23 2012-08-08 Cytokinetics Inc Amino- pirimidinas composiciones de las mismas y metodos para el uso de los mismos
US20120115878A1 (en) 2010-11-10 2012-05-10 John Vincent Calienni Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006008545A2 (en) * 2004-07-22 2006-01-26 Astex Therapeutics Limited Thiazole and isothiazole derivatives as protein kinase inhibitors
WO2007140222A2 (en) * 2006-05-26 2007-12-06 Novartis Ag Pyrrolopyrimidine compounds and their uses
WO2010020675A1 (en) * 2008-08-22 2010-02-25 Novartis Ag Pyrrolopyrimidine compounds as cdk inhibitors

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