TWI496781B - 製備{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯之方法及其使用作為醫藥活性化合物之純化 - Google Patents
製備{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯之方法及其使用作為醫藥活性化合物之純化 Download PDFInfo
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Description
本發明係關於一種製備式(I)之{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯之方法。
本發明另關於一種用於純化使用作為醫藥活性化合物之式(I)化合物粗產物之方法,其中為了純化,以中間物形式分離出{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷(1:1),即式(II)化合物
或於此純化製程中以中間物形式產生,若適當,以混合物形式存在。
式(I)化合物係用作可溶鳥苷酸環化酶之激活劑,並可使用作為預防及/或治療心血管疾病之藥劑,例如用於治療高血壓及心衰竭、穩定型及不穩定型心絞痛、周邊及心臟血管疾病、心律不整、用於治療血栓栓塞疾病及局部缺血如心肌梗塞、中風、暫時性腦缺血、末梢血流失調、預防術後再狹窄如血栓溶解後血管成形術、經皮腔內血管成形術(PTA)、冠狀動脈氣球擴張術(PTCA)、繞道及用於治療動脈硬化、氣喘症及尿殖系統疾病如(例如)***肥大、***障礙、女性性功能障礙、骨鬆症、青光眼、肺性高血壓、胃輕癱及失禁。
式(I)化合物之製備及其純化原則上係已知的。WO 03/095451描述藉由下列途徑製備式(I)化合物。
在此,起初藉由催化氫化作用***出式(III)之2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-[(E)-苯基二氮烯基]嘧啶-4,6-二胺,並以式(IV)之2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4,5,6-嘧啶三胺三鹽酸鹽形式分離出所得三胺基化合物。然後此三鹽酸鹽與式(V)之氯甲酸甲酯在溶劑吡啶中反應,以獲得式(VI)之4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基胺基甲酸甲酯。或者,ChemMedChem 2009,4,853-865描述該三胺基化合物係以三鹽酸鹽形式分離出,然後藉以NaHCO3
水溶液萃取產生HCl-游離鹼,且該游離鹼與式(V)之氯甲酸甲酯在溶劑吡啶中反應以獲得式(VI)化合物。式(VI)化合物然後與式(VII)之甲基碘在鹼的存在下反應,獲得式(I)化合物之粗產物。該式(I)化合物之粗產物係根據WO 03/095451之實例8的實驗程序及ChemMedChem 2009,4,853-865之類似描述藉由下列程序純化:以二氯甲烷/THF研製該粗產物、中間藉由過濾分離出經二氯甲烷/THF研製之產物、分離固體與甲醇一起沸騰、中間藉由過濾分離出與甲醇一起沸騰之固體、在活性碳的存在下將固體溶於二噁烷、二氯甲烷與甲醇之混合物中、經由矽藻土或塞利特矽藻土(Celite)藉由過濾去除活性碳、濃縮過濾溶液至乾、以甲醇研製濃縮至乾之固體、藉由過濾分離出經甲醇研製之固體並(WO 03/095451之實例8或ChemMedChem 2009,4,853-865中未描述,但客觀上需要)乾燥之。或者,可藉由製備型色層分析術(RP-HPLC)以不佳產率純化經濃縮乾燥之式(I)化合物之粗產物。
此合成及純化具有許多極不利於大規模工業實行之缺點。特別係以式(IV)之三鹽酸鹽形式分離出該三胺基化合物時確實如此。氫氯酸之添加需要防酸工業設備,且該步驟之產率不令人滿意地僅為理論之59.3%(參見,例如WO 03/095451之實例8A)。式(IV)之三胺基化合物或對應HCl-游離鹼在溶劑吡啶中進行反應同樣係不利的。僅可藉由完全蒸發反應混合物分離出式(IV)化合物,其對工業規模係不利的(參見,例如WO 03/095451之實例5)。在相當大的規模下,此等步驟一般產生極大問題如反應以極大規模進行時,由於實質較長之熱應力而膠黏或熱分解。根據WO 03/095451之實例5的實驗程序藉於二乙基醚中沸騰的方式純化式(VI)產物亦有許多缺點。因為二乙基醚之高易燃性,此步驟僅可以更高的工業支出費用來實行。
然而,特別不利的係式(I)粗產物之純化方法。一種有效的純化是使用作為醫藥活性化合物之必要條件。所述經由RP HPLC之純化,即色層分析純化為一種實驗室方法,以工業規模實行之係非常昂貴的。此外,僅為29%之所述式(I)粗產物之合成步驟及其純化的產率是非常低的。替代製備及純化方法非常複雜。其包括總計分離固體5次(濃縮至乾2次及過濾3次)而且如上已提及般以工業規模濃縮至乾係非常不利的。總之,當進行化學步驟時,分離固體5次之數目對以工業規模製備及純化醫藥活性化合物而言係極不利的。
因此,目標係提供一種安全且亦可有利地以工業規模進行並可以高產率及高純度和醫藥上可接受品質提供活性化合物之簡化方法。
令人驚訝地,吾人現已發現一種製備式(I)之{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯之方法,
及其使用作為醫藥活性化合物之純化。此式(I)化合物之粗產物之新穎方法及純化在下列各點上係不同於迄今已知之方法:
-催化氫化式(III)化合物之後,以式(VIII)之游離鹼形式分離出該三胺基化合物而中間無形成鹽,
-式(VI)化合物之製備係利用氯甲酸甲酯或二碳酸二甲酯作為試劑以無吡啶製程進行,
-式(VI)化合物係以本身已知方式利用甲基化試劑轉化成式(I)粗產物;使用作為醫藥活性化合物之式(I)粗產物之純化係經由化合物{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷(1:1),即式(II)化合物作為分離中間物或以混合物形式產生的方式進行
憑藉此等差異,可克服迄今已知方法之缺點並以高產率及高純度和醫藥上可接受品質獲得活性化合物。
根據本發明用於製備式(I)化合物之方法及經由式(II)中間物之純化係詳細描述於下。
催化氫化式(III)化合物
根據本發明方法之第一步驟係始於催化氫化式(III)化合物。
此可在雷尼(Raney)鎳或工業界慣用Pt/碳或Pd/碳觸媒的存在下進行。較佳係使用Pt/碳或Pd/碳。N,N-二甲基甲醯胺(DMF)、N,N-二甲基乙醯胺(DMA)或N-甲基-2-吡咯啶酮(NMP),較佳係DMF係用作溶劑。
氫化條件係溫度40-80℃,較佳係50-70℃,壓力:2-90巴,較佳係5-70巴之氫氣,氫化時間:1-72小時,較佳係3-36小時。
藉由過濾去除觸媒之後,產物係由C1
-C4
-醇,較佳係甲醇或乙醇及/或水中沉澱。較佳係使用甲醇、異丙醇或乙醇與水之混合物。
在本發明背景中,C1
-C4
-醇係具有1至4個碳原子之直鏈或分支醇。下列可者可以舉例方式或較佳實例方式提及:甲醇、乙醇、正丙醇、異丙醇、正丁醇及第三丁醇。此定義亦可應用於下文所用之C1
-C4
-醇。
亦可在沉澱前先去除部分溶劑,根據本發明部分蒸餾去除0-80%,較佳係40-70%之溶劑。
依此方式獲得之濕潤產物係在較低壓力下乾燥:此獲得式(VIII)產物(相當於式(IV)之游離鹼)。
然後式(VIII)產物例如與式(V)之氯甲酸甲酯以新穎的無吡啶製程進行反應以獲得式(VI)產物。
用於該反應之溶劑係C1
-C4
-醇,較佳係乙醇、甲醇、異丙醇,特佳係異丙醇。
以所用式(VIII)化合物計,氯甲酸甲酯之用量係1.0至3.0當量,較佳係從1.0至2.0當量。
可能反應溫度係0-75℃,較佳係15-50℃。
反應期間,在反應混合物中形成形成式(IX)化合物之鹽酸鹽,即式(VI)產物之鹽酸鹽。此式(IX)產物係以含HCl產物形式分離出,並藉由鹼的添加***成式(VI)產物或其甚至可在分離前藉由鹼的添加***,因此直接分離出式(VI)產物。
根據本發明較佳係在分離之前藉由鹼的添加***出式(IX)產物並直接分離出式(VI)之游離鹼。
根據本發明,適合的鹼係所有pKB高於式(I)化合物之pKB之鹼。可能提及之實例係鹼金屬及鹼土金屬之氫氧化物、碳酸鹽及磷酸鹽、含氮有機鹼,如三烷基胺、胍或脒。可能提及之實例係氫氧化鋰、氫氧化鈉、氫氧化鉀、氫氧化銣、氫氧化銫、氫氧化鎂、氫氧化鈣、氫氧化鍶、氫氧化鋇、碳酸鋰、碳酸鈉、碳酸鉀、碳酸銣、碳酸銫、碳酸鎂、碳酸鈣、碳酸鍶及碳酸鋇、磷酸鈉及磷酸鉀、具有直鏈、環狀或分支C1
-C20
-烷基之三烷基胺及環狀或開環胍或脒。根據本發明較佳係三乙基胺、三丙基胺、二異丙基乙基胺、三丁基胺、二環己基乙基胺、環己基二甲基胺、環己基二乙基胺、三異辛基胺、三癸基胺、三-十二碳基胺、三-十六碳基胺、N-甲基嗎福啉、DBU、DBN、四甲基胍等。特佳係三乙基胺、三丁基胺、二異丙基乙基胺、N-甲基嗎福啉、DBU、DBN。
鹼之用量以所用式(V)之氯甲酸甲酯計係1.0至2.0當量,較佳係從1.0至1.5當量。
與鹼反應之可能反應溫度係0-100℃,較佳係15-70℃。
式(VI)產物係以懸浮液形式存在,並藉由過濾分離之。以C1
-C4
-醇清洗之並在較低壓力下以慣用方式乾燥。
在根據本發明另一種方法中,式(VIII)產物係與式(X)之二碳酸二甲酯反應以獲得式(VI)產物。此反應不需使用任何鹼,例如吡啶。
用於此反應之溶劑係C1
-C4
-醇,較佳係乙醇、甲醇、異丙醇,特佳係異丙醇。
二碳酸二甲酯之用量以所用式(VIII)化合物計係1.0至3.0當量,較佳係從1.0至2.0當量。
可能反應溫度係0-65℃,較佳係15-40℃。
式(VI)之產物沉澱並藉由過濾方式分離之。以C1
-C4
-醇清洗之並在較低壓力下以慣用方式乾燥。
與二碳酸二甲酯反應時,直接獲得式(VI)產物。因此不需另外添加鹼。
兩種方法,即式(VIII)化合物與氯甲酸甲酯反應,並接著以鹼使式(IX)之鹽酸鹽***,或式(VIII)化合物與二碳酸二甲酯反應皆提供類似式(VI)產物之品質,因此源自這兩種方法之式(VI)產物皆可以相同方式用於進一步轉化成式(I)產物。
根據本發明偏好使用這兩種方法。
式(VI)化合物可形成溶劑合物或含溶劑固體形式,例如含甲醇、含乙醇或含異丙醇之固體形式。因此,當式(IX)之鹽酸鹽***成式(VI)產物,或以二碳酸二甲酯直接合成式(VI)產物時,可獲得使用作為溶劑之C1
-C4
-醇的溶劑合物。該溶劑合物在乾燥式(VI)產物期間亦係安定的,其不會完全分解且明顯無顯著溶劑殘留物,即,例如所提C1
-C4
-醇之殘留物,因此留在式(VI)產物中。另一方面,式(VI)產物並不需在太熱之溫度下乾燥,因為其在太高之溫度下可能分解形成副產物。
因此,根據本發明較佳係在不超過110°之產物溫度下,特佳係在不超過100°之產物溫度下乾燥以鹼***式(IX)之鹽酸鹽或以二碳酸二甲酯直接合成得到之式(VI)產物。在此,任何以溶劑合物形式存在之C1
-C4
-醇殘留物特佳係留在式(VI)產物中,並使用此形式之式(VI)產物製備式(II)中間物或式(I)產物。根據本發明,式(VI)產物極特佳係包含範圍從0至13%之異丙醇殘留溶劑。
依此方式獲得之式(VI)產物係以本身已知方式,例如根據WO 03/095451或ChemMedChem 2009,4,853-865中任一描述與甲基化劑Me-X反應以獲得包含高量式(I)化合物之粗產物。
根據本發明所用之甲基化劑Me-X係甲基碘、硫酸二甲酯、甲苯磺酸甲酯等並以甲基碘或硫酸二甲酯為佳。
根據本發明,純化式(I)粗產物以使用作為醫藥活性化合物。為此,起初形成包含高量之式(II)化合物中間物之混合物。
為此,令式(I)粗產物溶於DMSO中,若適當,在選自酮、醚、酯或醇之群之醫藥上可接受之簡單溶劑的存在下進行。此等可能提及之溶劑實例係:甲醇、乙醇、異丙醇、1-丁醇、2-丁醇、乙酸乙酯、乙酸異丙酯或乙酸丙酯、乙酸丁酯、第三丁基甲基醚、二異丙基醚、丙酮、甲基乙基酮、甲基異丁基酮等。較佳係乙醇、異丙醇、乙酸乙酯、異酸異丙酯、乙酸丁酯、甲基乙基酮、甲基異丁基酮;特佳係乙酸乙酯。亦可使用此等溶劑之混合物。
以式(I)粗產物之使用量計,DMSO之添加量係100至750重量%,較佳係從150至500重量%。
若適當,以式(I)粗產物之使用量計,活性碳可以0.25至35重量%,較佳係從0.5至20重量%之量加入此混合物中。
為形成溶液,將混合物加熱至40-120℃,較佳係50-100℃。
為形成式(I)之醫藥上可接受產物必須過濾該溶液。該過濾必須獨立於是否添加活性碳地進行。
除了DMSO之外,加入式(I)粗產物溶液中,即過濾前所用之醫藥上可接受溶劑之量,以DMSO計為25至200重量%,較佳係40至100重量%。
該過濾係趁熱進行,該溫度係40-120℃,較佳係50-100℃。
過濾後,將醫藥上可接受溶劑,較佳係如上相同之溶劑加入熱濾液中。此導致式(II)產物結晶。
過濾前後,溶劑之總量以DMSO計係從200至1500重量%,較佳係400-1200重量%。
添加溫度係30-110℃,較佳係35-90℃。
在分離含有高量式(II)化合物之固體之前,為使沉澱完全,將混合物冷卻至0-35℃之溫度範圍,較佳係冷卻至(例如)20-30℃之周遭溫度。
利用慣用分離裝置如Nutsche管或離心機進行分離。為去除母液,分離期間以醫藥上可接受溶劑,較佳係如上相同之溶劑清洗分離物。
DMSO再溶解之後,該分離物包含高量之式(II)產物。此外,小量之式(I)產物通常亦可直接沉澱而不與DMSO形成溶劑合物。亦可能形成不同化學計量之溶劑合物或形成無固定化學計量之溶劑加成物。此外,DMSO亦可以未鍵結形式如附著殘留溶劑般存在。分離物中DMSO之含量通常係10至25重量%,較佳係12-17重量%。根據本發明,式(II)產物特佳係以此混合物形式形成並用於製備式(I)純化產物。
現可乾燥依此方式獲得之式(II)產物,或者以含有溶劑殘留物,即附著DMSO及沉澱溶劑之濕潤形式用於轉化成式(I)純化產物。
式(II)化合物係新穎的。其可如下工作實例所述般以純形式製得並可經分析特徵化。
對於醫藥用途,必須自式(II)產物或含有高量式(II)化合物之混合物中去除DMSO。
為此,式(II)產物或含有高量式(II)產物之分離混合物係在選自酮、醚、酯或醇之群之醫藥上可接受溶劑中沸騰。此等可能提及之溶劑實例係:甲醇、乙醇、異丙醇、1-丁醇、2-丁醇、乙酸乙酯、乙酸異丙酯或乙酸丙酯、乙酸丁酯、第三丁基甲基醚、二異丙基醚、丙酮、甲基乙基酮、甲基異丁基酮等。較佳係乙醇、異丙醇、乙酸乙酯、乙酸異丙酯、乙酸丁酯、甲基乙基酮、甲基異丁基酮。亦可使用此等溶劑之混合物。特佳係使用乙酸乙酯或乙酸乙酯與乙醇之混合物。
沸騰係在所提溶劑迴流下或若適當在稍高壓力下進行。該溫度係50-150℃,較佳係80-120℃。
根據本發明方法相較於先前技術提供顯著優勢。特別令人驚訝地係中間無形成式(IV)化合物(三鹽酸鹽),直接分離式(VIII)化合物(游離鹼)可使產率顯著增加,並同時使工業實施更加簡單(無防酸設備部件)。
然後,式(VIII)化合物可以新穎無吡啶製程,以氯甲酸甲酯或二碳酸二甲酯轉化成式(VI)化合物。此等新穎製程非常簡單並可以最少之工業花費進行。反應後,式(VI)產物係以固體形式懸浮存在,並可藉由過濾無蒸發步驟地分離。所得產率非常高。
另外,令人驚訝地係用於醫藥用途之式(I)粗產物的純化特別可藉由再溶解於含DMSO溶劑混合物的方式進行,且該新穎式(II)化合物在此步驟中係以中間物形式,若適合在混合物中以高比例獲得。藉由此步驟,去除所有不純物,除了小量殘留物之外,因此在藉由簡單沸騰去除DMSO含量之後,留下高純度之式(I)固體。此固體一般係無色至極輕微黃色且分析純度(HPLC)明顯高於98重量%,其對醫藥用途而言係極為有利。
該製程在技術上可安全地進行並可以工業規模製造。其可有彈性地適合工廠之現有設備使用。在特佳具體實施例中,純化式(I)粗產物時,中間分離式(II)產物或含有高量式(II)化合物之混合物係在努茨(Nutsch)過濾乾燥器中進行。接著藉將溶劑直接加入努茨過濾乾燥器中並或無中間乾燥式(II)產物的方式自努茨過濾乾燥器中以中間物形式分離出式(II)產物中去除DMSO。此可避免公開操作式(II)產物之固體及相關污染風險。
縮寫及首字母縮寫:
abs. 絕對
cat. 催化
CI 化學電離(MS中)
d 天
TLC 薄層色層分析術
DMF 二甲基甲醯胺
DMSO 二甲基亞碸
ee 鏡像異構物過量
EI 電子撞擊電離(MS中)
ent 鏡像異構物/鏡像異構物純度
eq 當量
ESI 電噴灑離子化(MS中)
GC-MS 氣相色層分析耦合質譜術
重量% 重量百分率
h 小時
HPLC 高壓、高效液相色層分析術
conc. 濃度
LC-MS 液相色層分析耦合質譜術
min 分鐘
MS 質譜術
NMR 核磁共振光譜法
Ph 苯基
Rf
滯留指數(TLC中)
Rt
滯留時間(HPLC中)
RT 室溫
體積/體積 (溶液之)體積相對於體積之比例
aq 水性、水溶液
下列實例說明本發明,但本發明不限於該等實例。
實例1
2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4,5,6-嘧啶三胺(VIII)之製備
在高壓釜中,使1100克之式(III)化合物懸浮於5.4公升之DMF中。加入44克之慣用水濕潤(約50%)5%Pd/碳觸媒,並在以氮氣惰化,並施加氫氣之後,於65巴之氫氣壓力及約60℃之內部溫度下氫化密封之高壓釜約18小時。冷卻至約25℃、排氣及惰性化之後,去除高壓釜之內容物,以650毫升之DMF清洗之。
合併依此相同方式進行之三種反應物,濾掉舊觸媒,以1.1公升之DMF清洗濾餅並在較低壓力下濃縮濾液至約其質量之三分之一。依序將8.25公升之甲醇及8.25公升之水計量送入約6.5公斤之殘留物中,令其完全結晶,使懸浮液冷卻至約5℃並濾掉固體和以甲醇/水(1:1體積)清洗之。在50℃及較低壓力下乾燥產物。重量為2415克,其相當於理論之91.8%。式(VIII)目標產物(游離鹼)之含量係>98面積%或>97重量%。最顯著之不純物係DMF(約0.8重量%)及水(約0.5重量%)。
實例2
4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基胺基甲酸甲酯(VI)之製備
起初將3063克之式(VIII)化合物及30.7公升之工業級異丙醇裝入反應容器中。隨攪拌在20-25℃下計量裝入1641克之二碳酸二甲酯並在此溫度下攪拌混合物22小時。抽氣濾掉沉澱產物,以工業級異丙醇清洗之並在50℃及較低壓力下乾燥之。所得產物之重量係3748克或理論之105.9%。式(I)產物特別包含約4.7%實際上乾燥無法去除之異丙醇(部分以異丙醇溶劑合物存在),且分析含量係89.5重量%(HPLC)。以此含量計,產率係理論之94.8%。
實例3
2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4,5,6-嘧啶三胺(VIII)之製備
起初將300克之式(III)化合物、1600毫升之DMF及60克之水濕潤雷尼(Raney)鎳裝入高壓釜中並在惰性化後,在60℃之內部溫度及65巴之氫氣壓力下氫化約18小時。冷卻並排氣後,濾掉舊觸媒並以100毫升之DMF清洗之。在較低壓力下濃縮濾液至534.5克並在35-40℃下將750毫升之甲醇計量送入殘留物中,冷卻後,然後在0-5℃下將750毫升之水計量送入殘留物中。濾掉固體並在50℃及較低壓力下乾燥之。重量為219.7克或理論之91.8%。
實例4
4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基胺基甲酸甲酯(VI)之製備
起初將1.50公斤之式(VIII)化合物裝入反應容器中14.25公升之異丙醇裏,並隨攪拌將混合物加熱至35℃。在30分鐘內以穩定速率計量送入531克之氯甲酸甲酯,以750毫升之異丙醇清洗之並在35℃下攪拌混合物16小時。然後將混合物加熱至50℃並在50℃下隨著攪拌計量送入3.85公升之甲醇及606克之三乙基胺,以450毫升之甲醇清洗之。然後在50℃下攪拌混合物1小時,冷卻至RT並在RT下攪拌1小時。抽氣濾掉懸浮固體,各以3.0公升之異丙醇/甲醇(4:1)清洗2次,並以3.0公升之異丙醇清洗一次並抽乾之。在50℃下乾燥濕潤產物1小時,然後在100℃下真空乾燥箱中乾燥22小時。所得產物之重量係1.793公斤或理論之103.3%。式(VI)產物包含6.45%實際上乾燥無法去除之異丙醇(部分以異丙醇溶劑合物存在),且分析含量係87.9重量%(HPLC)。以此含量計,產率係理論之90.8%。
對照實例5
4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基(甲基)胺基甲酸甲酯(I)之製備
(依本身已知方式根據WO 03/095451之實例8的第二程序甲基化)
在20-25℃下,令1630克之式(VI)化合物懸浮於16.3公升之THF中。令懸浮液冷卻至-6至-4℃並計量送入3480克之1M雙(三甲基矽基)鈉醯胺溶液。攪拌混合物並計量送入596克之甲基碘。短暫攪拌混合物並令其緩慢溫熱至約5℃。在此溫度下攪拌混合物直到反應結束(約4小時)。以4.1公升之強度15%的氯化銨溶液清洗反應混合物4次。蒸發濃縮有機相至殘留物為約6.4公斤並將溫度調整至約25℃。濾掉沉澱固體,以總計3公升之THF清洗之並在50℃及較低壓力下乾燥之。此獲得1112克之式(I)粗產物。此相當於理論之75.2%的產率。
實例6
由4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基(甲基)胺基甲酸甲酯(I)與{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷(II)組成並具高量之式(II)產物之混合物的製備
在100℃下將9.0克已以類似對照實例5之方式製得之式(I)粗產物溶於16毫升之DMSO中。(在此實驗室實驗內免除此時必須進行以獲得醫學上可接受產物品質之過濾澄清化)。然後令混合物冷卻至75℃,加入110毫升之乙酸乙酯並令混合物緩慢冷卻至約25℃。濾掉沉澱固體,以總計28毫升之乙酸乙酯清洗,並在50℃及較低壓力下乾燥之。該重量係9.6克或理論之90.0%。
實例7
純化4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基(甲基)胺基甲酸甲酯(I)之製備
令上述實例6中所製得之所有式(II)產物量在135毫升之乙酸乙酯中迴流(約78℃)下攪拌1小時並冷卻至約25℃。抽氣濾掉固體,以總計36毫升之乙酸乙酯清洗之並在較低壓力下乾燥之。該重量係7.6克或理論之93.8%。產物之含量明顯高於98重量%(HPLC)。作為溶劑之乙酸乙酯係以約0.2%之量存在。DMSO含量係低於0.1%。
實例8
以中間分離出含有高量之{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷(II)之濕潤產物的混合物製備純化4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基(甲基)胺基甲酸甲酯(I)
在約96℃下將193.5克已以類似對照實例5之方式製得之式(I)粗產物溶於344毫升之DMSO及172毫升之乙酸乙酯中。然後加入19.4克之活性碳及172毫升之乙酸乙酯並攪拌熱混合物。然後過濾熱混合物以去除活性碳,以172毫升之乙酸乙酯清洗。將濾液之溫度調整至78℃並緩慢加入1850毫升之乙酸乙酯。在約2-3小時內,將混合物冷卻至約25℃並濾掉固體,以總計772公升之乙酸乙酯清洗之。令混合物中包含高量之式(II)化合物之濕潤產物懸浮於2900毫升之乙酸乙酯中,迴流加熱1小時並冷卻至約25℃。抽氣過濾固體,以總計774公升之乙酸乙酯清洗,並在50℃及較低壓力下乾燥之。所得重量係155.1克或起始物之80.2%。產物之含量明顯高於98重量%(HPLC)。關於溶劑,實際上僅乙酸乙酯及DMSO以小量存在。
實例9
{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷(II)之製備及分析特徵化
在約94℃下將14.8克已以類似對照實例5之方式製得之式(I)粗產物溶於28.9克之DMSO及11.85克之乙酸乙酯中。然後加入1.5克之活性碳Norit A-Supra及另一份11.85克之乙酸乙酯,迴流攪拌(88-90℃)混合物1小時,然後過濾熱混合物以去除活性碳。藉由溫熱至約78℃再度溶解部分已沉殿之固體,然後令該溶液緩慢冷卻。在RT下抽氣過濾沉澱固體,各以50毫升之乙酸乙酯清洗3次,並在乾燥箱中30℃下乾燥18小時。此獲得9.2克或理論之52.5%的式(II)化合物淡黃色結晶粉末。
HPLC:99.90面積%(無考慮DMSO)
DMSO(GC):14.7重量%
1
H-NMR(400MHz,於DMF-d7
中):d=2.59(s,約6H,DMSO之2 CH3
),3.13(s,3H,N-CH3
),3.58+3.67(兩個s,3H,於O-CH3
之受阻旋轉),5.91(s,2H,-CH2
-),6.53(s,4H,-NH2
),7.05-7.40(m,5H,o-氟苯甲基取代基之4個芳族H及於吡啶環上吡啶氮之間位的1H),8.60(dd,吡啶環上吡啶氮之鄰位的1H),9.12(dd,吡啶環上吡啶氮之對位的1H)。
元素分析:
Claims (4)
- 一種製備式(I)之{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯之方法,其特徵在於a)藉由催化氫化***式(III)之2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-[(E)-苯基二氮烯基]嘧啶-4,6-二胺,並無中間形成鹽地分離出式(VIII)之2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4,5,6-嘧啶三胺,
- 一種製備式(I)之{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯之方法,其特徵在於a)藉由催化氫化***式(III)之2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-[(E)-苯基二氮烯基]嘧啶-4,6-二胺,並無中間形成鹽地分離出式(VIII)之2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4,5,6-嘧啶三胺,
- 一種純化式(I)之{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯之方法,其特徵在於將根據申請專利範圍第1或2項之方法所獲得之式(I)化合物之粗產物溶於二甲基亞碸中,並分離出所得式(II)之{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷,接著藉於醫藥上可接受溶劑中沸騰再次去除該二甲基亞碸。
- 一種下式(II)之{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷
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2010
- 2010-11-22 MY MYPI2017001426A patent/MY180184A/en unknown
- 2010-11-22 PE PE2017002307A patent/PE20180203A1/es unknown
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