本發(fā)明涉及兩類(lèi)阿比特龍衍生物的合成方法。屬于有機(jī)化合物的制備技術(shù)領(lǐng)域。

背景技術(shù)：

從埃及教科書(shū)中記載開(kāi)始以來(lái)，癌癥一直是一種棘手的疾病。如今，盡管生物學(xué)和醫(yī)學(xué)方面取得了巨大的進(jìn)步，但癌癥的發(fā)病率依然持續(xù)增加，已經(jīng)達(dá)到了流行的程度。預(yù)計(jì)從2012年到未來(lái)二十年其將從記錄的1400萬(wàn)例病例增加到2200萬(wàn)例。在現(xiàn)代醫(yī)學(xué)出現(xiàn)之前，通過(guò)用刀切割處理腫瘤，用熾熱鐵灼燒，熏蒸等來(lái)治療癌癥。現(xiàn)在，手術(shù)，放射治療，化療，免疫治療，靶向治療，激素治療和干細(xì)胞移植用于成功的治療癌癥。2016年1月ca公布了中國(guó)和美國(guó)最新的癌癥數(shù)據(jù)統(tǒng)計(jì)。這些數(shù)據(jù)顯示，癌癥仍然是威脅患者生命的重大疾病。因此，對(duì)于癌癥的認(rèn)識(shí)、預(yù)防和治療已刻不容緩。

前列腺癌是全球老年男性中最常見(jiàn)的腫瘤疾病，尤其在歐美等西方國(guó)家更為普遍，2012年，相關(guān)數(shù)據(jù)顯示，前列腺癌是導(dǎo)致美國(guó)男性死亡的第二大原因，僅次于肺癌。盡管在中國(guó)、韓國(guó)、印度等亞洲國(guó)家，前列腺癌的發(fā)病率目前遠(yuǎn)低于歐美國(guó)家，但是隨著中國(guó)人口老齡化的加劇，前列腺癌的危害也呈上升趨勢(shì)。調(diào)查結(jié)果顯示，從1990至2010年這20多年里，前列腺癌的發(fā)病率在我國(guó)增長(zhǎng)了10多倍，醫(yī)學(xué)研究人員表明前列腺癌對(duì)人類(lèi)健康的威脅將愈演愈烈。

前列腺癌是男性最常見(jiàn)的惡性腫瘤，在全球范圍內(nèi)的發(fā)病率及死亡率分別位列男性惡性腫瘤的第2位及第6位。目前，用于治療前列腺癌的臨床藥物主要有多西他賽、亮丙瑞林、戈舍瑞林、卡巴他賽、provenge(sipuleucel-t)、醋酸阿比特龍酯和enzalutamide(mdv3100,xtandi)等。其中2011年4月上市的醋酸阿比特龍酯是當(dāng)前治療去勢(shì)抵抗性前列腺癌的主流藥物，2015年，醋酸阿比特龍酯的銷(xiāo)售額將達(dá)6億美元。據(jù)biomedtracker預(yù)測(cè)，醋酸阿比特龍酯銷(xiāo)售峰值為26億美元(2021年)。醋酸阿比特龍酯是阿比特龍的前藥，在肝臟內(nèi)去乙?；玫交钚猿煞职⒈忍佚垼苁骨傲邢侔┗颊唧w內(nèi)前列腺特異性抗原水平顯著下降。之所以采用醋酸阿比特龍酯作為阿比特龍的前藥，是因?yàn)榘⒈忍佚埶苄詷O差，改造成醋酸阿比特龍酯后，水溶性有所改善，但依然屬于難溶(<1mg/ml)。因醋酸阿比特龍酯其水溶性差，市場(chǎng)僅以片劑銷(xiāo)售，其他劑型仍為空白。這需要增加劑量來(lái)提高療效，導(dǎo)致用藥成本急劇上升，毒副作用加強(qiáng)。

多數(shù)酯類(lèi)化合物能被體內(nèi)的脂酶降解，因此通過(guò)構(gòu)建酯類(lèi)前體藥物，調(diào)整藥物脂水分配系數(shù)，提高藥物生物利用度，進(jìn)而提高藥效、降低藥物毒性。該技術(shù)已成功用于多種臨床藥物，如：1)鹽酸伐昔洛韋(新)是阿昔洛韋與纈氨酸形成的酯類(lèi)前體藥物，口服后在體內(nèi)轉(zhuǎn)化為阿昔洛韋，抗病毒作用、機(jī)制和過(guò)程與阿昔洛韋一樣。在體內(nèi)的抗病毒活性?xún)?yōu)于阿昔洛韋，毒性很低；2)阿德福韋酯是阿德福韋的雙新特戊酰氧基甲醇酯，在體內(nèi)水解為阿德福韋后發(fā)揮抗病毒作用；3)鹽酸伊立替康，是羥喜樹(shù)堿的酯，屬前藥，溶于水；4)依托泊苷磷酸酯是依托泊苷的4′位酚羥基上引入磷酸酯結(jié)構(gòu)得到的衍生物，溶于水，為前藥，給藥后迅速水解生成依托泊苷而發(fā)揮作用；5)貝諾酯是阿司匹林和對(duì)乙酰氨基酚的酯化產(chǎn)物，是前藥，體內(nèi)水解生成兩者起作用。應(yīng)用藥物酯化技術(shù)，對(duì)先導(dǎo)化合物阿比特龍的羥基進(jìn)行酯化，季銨鹽化，能增強(qiáng)藥物與水的親和作用，提高藥物的水溶性。本發(fā)明對(duì)阿比特龍進(jìn)行化學(xué)結(jié)構(gòu)改造，引入親水的結(jié)構(gòu)單元，制備能經(jīng)脂酶降解的一系列阿比特龍前體藥物。

以阿比特龍為先導(dǎo)化合物，制備可被丁酰膽堿酯酶降解釋放阿比特龍的電正性的兩親性類(lèi)陽(yáng)離子脂質(zhì)體阿比特龍前體藥物，并增強(qiáng)藥物水溶性。所制備的陽(yáng)離子脂質(zhì)體前體藥物β-n-甲基-n¹,n¹-二正烷基氨基甲酸-py-n-甲基-阿比特龍酯和β-n-甲基-n¹,n¹-二正烷基氨基甲酸阿比特龍酯均具有良好的水溶解性。其水溶液具有結(jié)構(gòu)穩(wěn)定性好、粒度尺寸適中、粒徑分布窄、表面電荷適中、制備成本低廉等優(yōu)點(diǎn)，能滿足藥物高效、安全轉(zhuǎn)運(yùn)應(yīng)具備的基本要求，是治療去勢(shì)抵抗性前列腺癌的潛在藥物。

技術(shù)實(shí)現(xiàn)要素：

本發(fā)明的目的是提供合成成本低、操作容易的兩種阿比特龍前體藥物的合成方法。

本發(fā)明提供的一系列阿比特龍前體藥物的合成方法，包括如下步驟：

（1）以乙二胺為原料，分析純甲醇為溶劑，三乙胺為敷酸劑，二碳酸二叔丁酯為胺基保護(hù)劑，經(jīng)?；磻?yīng)和分離純化處理得到黃色液體(2-氨基乙基)氨基甲酸叔丁酯；

（2）以乙酸乙酯為溶劑，無(wú)水碳酸鉀為催化劑，(2-氨基乙基)氨基甲酸叔丁酯與正烷基溴發(fā)生取代反應(yīng)，經(jīng)相應(yīng)的分離純化處理得到白色固體(2-(n¹,n¹-二正烷基)乙基)氨基甲酸叔丁酯；

（3）以二氯甲烷為溶劑，(2-(n¹,n¹-二正烷基)乙基)氨基甲酸叔丁酯與三氟乙酸反應(yīng)脫去叔丁氧羰基，經(jīng)相應(yīng)的分離純化處理得到白色固體n¹,n¹-二正烷基-1,2-二胺；

（4）以阿比特龍為原料，二氯甲烷為溶劑，三乙胺為敷酸劑，4-二甲氨基吡啶為催化劑，n,n-羰基二咪唑?yàn)轷；瘎?，?jīng)?；磻?yīng)和分離純化處理得到白色固體咪唑氨基甲酸阿比特龍酯

（5）以四氫呋喃為溶劑，六磷酸苯并三唑-1-基-氧基三吡咯烷基磷為縮合試劑，步驟(4)得到的咪唑氨基甲酸阿比特龍酯與步驟(3)得到的n¹,n¹-二正烷基-1,2-二胺發(fā)生縮合反應(yīng)，經(jīng)相應(yīng)的分離純化處理得到淡黃色液體β-n¹,n¹-二正烷基氨基甲酸阿比特龍酯；

（6）以丙酮為反應(yīng)溶劑，步驟(5)得到的β-n¹,n¹-二正烷基氨基甲酸阿比特龍酯與碘甲烷進(jìn)行季銨鹽化反應(yīng)，經(jīng)相應(yīng)的分離純化處理得淡黃色粉末狀固體β-n-甲基-n¹,n¹-二正烷基氨基甲酸-py-n-甲基-阿比特龍酯；

（7）以丙酮的反應(yīng)溶劑，步驟(2)得到的(2-(n¹,n¹-二正烷基)乙基)氨基甲酸叔丁酯與碘甲烷進(jìn)行季銨鹽化反應(yīng)，經(jīng)相應(yīng)的分離提純處理得到白色固體(2-(n-甲基-n¹,n¹-二正烷基)乙基)氨基甲酸叔丁酯；

（8）以二氯甲烷為溶劑，(2-(n-甲基-n¹,n¹-二正烷基)乙基)氨基甲酸叔丁酯與三氟乙酸反應(yīng)脫去叔丁氧羰基，經(jīng)相應(yīng)的分離純化處理得到黃色液體n-甲基-n¹,n¹-二正烷基-1,2-二胺；

（9）以阿比特龍為原料，吡啶為溶劑，4-二甲氨基吡啶為催化劑，對(duì)硝基氯甲酸苯酯為?；瘎?，4-二甲氨基吡啶為催化劑，經(jīng)酰化反應(yīng)和分離純化處理得到白色固體4-硝基苯碳酸阿比特龍酯；

（10）以四氫呋喃為溶劑，三乙胺做催化劑，步驟(9)得到的4-硝基苯碳酸阿比特龍酯與步驟(8)得到的n-甲基-n¹,n¹-二正烷基-1,2-二胺發(fā)生偶聯(lián)反應(yīng)，經(jīng)相應(yīng)的分離純化處理得到白色固體β-n-甲基-n¹,n¹-二正烷基氨基甲酸阿比特龍酯。

本發(fā)明方法的主要優(yōu)點(diǎn)是成本低廉并且操作容易，能高效制備不同結(jié)構(gòu)的一系列阿比特龍前體藥物體。

附圖說(shuō)明

附圖1為兩種阿比特龍前體藥物的合成路線。

具體實(shí)施方式

下面結(jié)合實(shí)施例進(jìn)一步闡述本發(fā)明的內(nèi)容，但這些實(shí)施例并不限制本發(fā)明的保護(hù)范圍。各阿比特龍衍生物的合成路線如圖1所示。

實(shí)施例1.β-n-甲基-n¹,n¹-二正庚烷基氨基甲酸-py-n-甲基-阿比特龍酯納米顆粒的制備：

于100.0ml茄形瓶中加入乙二胺(1.9g,33.3mmol)，用甲醇(50.0ml)將其溶解，攪拌作用下加入三乙胺(10.1g,100.0mmol),將二碳酸二叔丁酯(7.3g,33.3mmol)溶于甲醇(60.0ml)中，然后逐滴加入，加畢，常溫反應(yīng)，tlc(v乙酸乙酯:v甲醇=5:1)監(jiān)測(cè)反應(yīng)至無(wú)明顯變化。濃縮，有白色固體析出，加水洗滌三次，抽濾，濃縮濾液得黃色液體化合物(2-氨基乙基)氨基甲酸叔丁酯(3.0g,56.6%)。¹hnmr(500mhz,cdcl3):δ(ppm)5.01(s,1h,ch2nhco),3.12-3.11(d,2h,nhch2ch2nh2),2.75-2.73(m,2h,nhch2ch2nh2),1.39(s,9h,(ch3)3c),1.25(s,2h,nhch2ch2nh2);¹³cnmr(125mhz,cdcl3):δ(ppm)156.3(1c,conhch2),79.2(1c,(ch3)3c),43.5(1c,nhch2ch2nh2),41.9(1c,nhch2ch2nh2),28.5(3c,(ch3)3c)。

在100.0ml圓底燒瓶中加入化合物(2-氨基乙基)氨基甲酸叔丁酯(0.3g,6.2mmol)，用乙酸乙酯溶解，攪拌作用下加入無(wú)水k2co3(6.9g,25mmol)、1-溴庚烷(3.5g,25mmol)。反應(yīng)混合物在70^oc下回流反應(yīng)48h，tlc(v石油醚:v乙酸乙酯=5:1)監(jiān)測(cè)反應(yīng)至原料基本反應(yīng)完全。過(guò)濾，濃縮。經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得白色固體(2-(n¹,n¹-二正庚基)乙基)氨基甲酸叔丁酯(0.7g,58.3%)。¹hnmr(500mhz,cdcl3):δ(ppm)5.01(s,1h,nhch2ch2),3.14-3.13(d,2h,nhch2ch2),2.49-2.47(m,2h,nhch2ch2),2.39-2.36(m,4h,n(ch2ch2)2),1.44(s,9h,(ch3)3c),1.42-1.39(m,4h,n(ch2ch2)2),1.37-1.27(m,16h,2ch2ch2(ch2)4ch3),0.88(t,6h,2ch2ch2(ch2)9ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.3(1c,conhch2),79.0(1c,(ch3)3c),54.0(2c,n(ch2ch2)2),53.2(1c,nhch2ch2nh2),38.4(1c,nhch2ch2nh2,32.0,29.4,27.6,27.2,22.8(8csomesignalswereoverlapped,2och2(ch2)4ch3),28.6((ch3)3c),14.2(2c,2ch2ch2(ch2)4ch3)。

在50.0ml圓底燒瓶中，加入化合物(2-(n¹,n¹-二庚基)乙基)氨基甲酸叔丁酯(2.0g,6.1mmol)，用無(wú)水二氯甲烷(25.0ml)溶解，攪拌作用下，滴加三氟乙酸(6.0ml)常溫下磁力攪拌。tlc(v乙酸乙酯:v石油醚=5:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。用koh(0.1mol/l)溶液調(diào)ph到7.0-8.0，有機(jī)相用無(wú)水na2so4干燥，過(guò)濾，濃縮，經(jīng)柱層析(洗脫劑：v乙酸乙酯:v甲醇=5:1)分離純化得淡黃色固體n¹,n¹-二庚基-1,2-二胺(1.1g,68.8%)。¹hnmr(500mhz,cdcl3):δ(ppm)2.75(s,2h,h2nch2ch2n),2.51-2.48(m,2h,h2nch2ch2n),2.40-2.37(m,4h,n(ch2(ch2)4ch3)2),1.40(s,4h,n(ch2ch2)2),1.24(s,16h,2ch2ch2(ch2)4ch3),0.87(t,6h,2ch2ch2(ch2)13ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)55.8(2c,n(ch2ch2)2),54.2(1c,nhch2ch2nh2),39.1(1c,nhch2ch2nh2),32.9,29.7,29.7,29.6,29.6,29.3,27.5,27.0,22.7(28csomesignalswereoverlapped,2och2(ch2)4ch3),14.1(2c,2ch2ch2(ch2)4ch3)。

在100ml的圓底燒瓶中加入藥物阿比特龍(0.1g,0.286mmol)，用二氯甲烷溶解，磁力攪拌，滴加三乙胺(0.4ml,3.5mmol),攪拌10min，加入n,n'-羰基二咪唑(0.4g,3.5mmol)，dmap(20.0mg,0.2mmol),回流反應(yīng)。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。用水和二氯甲烷進(jìn)行萃取，合并有機(jī)相，并用無(wú)水na2so4干燥。過(guò)濾，濃縮，經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=2:1)分離純化，得到白色固體化合物咪唑氨基甲酸阿比特龍酯(230.0mg,92.0%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.61-7.04(m,7h,py-h,im-h),5.98(s,1h,c16-h),5.47-5.46(d,1h,c6-h,j=5.0hz),4.72(s,1h,c1-h),2.51-1.20(m,17h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h),1.11(s,3h,c13-ch3),1.04(s,3h,c10-ch3);¹³cnmr(125mhz,cdcl3):δ(ppm)151.7,148.2,148.0,139.1,137.2,133.8,133.0,130.6,129.3,123.4(13c,im-co,py-c,im-c,c16,c17,c5,c6,),78.7(1c,c1),57.5,50.3,47.4,38.0,36.8,36.8,35.3,31.9,31.6,30.5,27.7,20.9(13c,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,clch2co),19.3(1c,c10-ch3),16.7(1c,c13-ch3)。

在50.0ml圓底燒瓶中，加入化合物n¹,n¹-二庚基-1,2-二胺(0.2g,0.4mmol)、咪唑氨基甲酸阿比特龍酯(0.2g,0.4mmol)，用四氫呋喃溶解，攪拌作用下，加入六磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.4g,0.6mmol)，回流反應(yīng)。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失，濃縮反應(yīng)液。柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得淡黃色液體β-n¹,n¹-二庚基氨基甲酸阿比特龍酯(190.0mg,48.7%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.61-7.19(m,4h,py-h),5.98(s,1h,c16-h,j=5.0hz),5.41-5.40(d,1h,c6-h,j=5.0hz),5.17(s,1h,conhch2),4.50(s,1h,c1-h),3.19-3.18(d,2h,conhch2ch2,j=5.0hz),2.50-2.48(m,2h,conhch2ch2),2.38-2.36(m,4h,ch2n(ch2)2),2.01-1.08(m,42h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)5ch3),1.06(s,3h,c13-ch3),1.03(s,3h,c10-ch3),0.87(t,6h,2ch2ch2(ch2)5ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.3,151.7,147.9,147.8,140.3,133.1,133.0,129.2,123.0,122.0(10c,conhch2,py-c,c17,c5,c16,c6),74.0(1c,c1),62.6(2c,n(ch2ch2)2),57.5,(1c,conhch2ch2),54.0,53.1,50.2,47.3,38.6,36.9,36.8,35.2,31.9,31.5,30.4,29.7,29.4,27.1,22.7,20.8(20c,somesignalswereoverlapped,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13c14,c15,conhch2ch2,2ch2(ch2)5ch3),19.3(1c,c10-ch3),16.6(1c,c13-ch3),14.4(2c,2ch2(ch2)5ch3)。

在25.0ml圓底燒瓶中，加入化合物β-n¹,n¹-二庚基氨基甲酸阿比特龍酯(0.3g,0.5mmol)，用丙酮溶解，加入ch3i(160.0μl,2.3mmol)，40^oc下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，加丙酮冷卻結(jié)晶，過(guò)濾，用丙酮淋洗，真空干燥得白色固體化合物β-n-甲基-n¹,n¹-二庚基氨基甲酸-py-n-甲基-阿比特龍酯(310.0mg,75.6%)。¹hnmr(500mhz,cdcl3):δ(ppm)9.13-8.03(m,4h,py-h),6.71(s,1h,c16-h),6.35(s,1h,conhch2),5.36(s,1h,c6-h),4.70(s,3h,py-n-ch3),4.41(s,1h,c1-h),3.68(d,4h,conhch2ch2),3.65(s,4h,conhch2ch2),3.42(s,3h,conhch2ch2nch3),3.28-1.22(m,38h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)5ch3),1.07(s,3h,c13-ch3),1.03(s,3h,c10-ch3),0.86(t,6h,2ch2(ch2)5ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.5,147.0,142.8,142.6,140.9,140.1,137.8,137.5,128.0,121.9(10c,conhch2,py-c,c17,c16,c5,c6),74.7(1c,c1),62.5(2c,n(ch2)2),60.2(1c,conhch2ch2),57.2,49.9,49.6,47.538.5,36.7,35.2,34.9,32.3,31.9,30.2,29.7,29.5,28.0,26.3,22.7,20.7(22c,somesignalswereoverlapped,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,py-n-ch3,conhch2ch2,conhch2ch2nch3,2ch2(ch2)5ch3),19.2(1c,c10-ch3),16.6(1c,c13-ch3),14.1(2c,2ch2(ch2)5ch3)。

實(shí)施例2.β-n-甲基-n¹,n¹-二辛基氨基甲酸-py-n-甲基-阿比特龍酯納米顆粒的制備：

在100.0ml圓底燒瓶中加入化合物(2-氨基乙基)氨基甲酸叔丁酯(4.0g,25.0mmol)，用乙酸乙酯溶解，攪拌作用下加入無(wú)水k2co3(13.8g,100.0mmol)、1-溴辛烷(19.3g,100.0mmol)。反應(yīng)混合物在70^oc下回流反應(yīng)48h，tlc(v石油醚:v乙酸乙酯=5:1)監(jiān)測(cè)反應(yīng)至原料基本反應(yīng)完全。過(guò)濾，濃縮。經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得白色固體(2-(n¹,n¹-二辛基)乙基)氨基甲酸叔丁酯(6.1g,58.9%)。¹hnmr(500mhz,cdcl3):δ(ppm)5.0(s,1h,nhch2ch2),3.13-3.12(d,2h,nhch2ch2),2.48-2.46(m,2h,nhch2ch2),2.38-2.35(m,4h,n(ch2ch2)2),1.43(s,9h,(ch3)3c),1.39-1.37(m,4h,n(ch2ch2)2),1.29-1.26(d,20h,2ch2ch2(ch2)5ch3),0.86(t,6h,2ch2ch2(ch2)5ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.1(1c,conhch2),78.8(1c,(ch3)3c),54.0(2c,n(ch2ch2)2),53.2(1c,nhch2ch2nh2),38.3(1c,nhch2ch2nh2),31.8,29.6,29.3,27.5,27.1,22.6(10csomesignalswereoverlapped,2och2(ch2)5ch3),28.4((ch3)3c),14.1(2c,2ch2ch2(ch2)5ch3)。

在50.0ml圓底燒瓶中，加入化合物(2-(n¹,n¹-二辛基)乙基)氨基甲酸叔丁酯(2.0g,4.1mmol)，用無(wú)水二氯甲烷(30.0ml)溶解，攪拌作用下，滴加三氟乙酸(6.1ml)常溫下磁力攪拌。tlc(v石油醚:v乙酸乙酯=5:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。用koh(0.1mol/l)溶液調(diào)ph到7.0-8.0，有機(jī)相用無(wú)水na2so4干燥，過(guò)濾，濃縮，經(jīng)柱層析(洗脫劑：v乙酸乙酯:v甲醇=5:1)分離純化得淡黃色固體n¹,n¹-二辛基-1,2-二胺(0.8g,52.0%)。¹hnmr(500mhz,cdcl3):δ(ppm)2.70-2.67(m,2h,h2nch2ch2n),2.43-2.41(m,2h,h2nch2ch2n),2.37-2.34(m,4h,n(ch2(ch2)13ch3)2),1.42-1.37(m,4h,n(ch2ch2)2),1.29-1.24(m,20h,2ch2ch2(ch2)5ch3),0.86(t,6h,2ch2ch2(ch2)5ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)57.3(2c,n(ch2ch2)2),54.4(1c,nhch2ch2nh2),39.9(1c,nhch2ch2nh2),32.8,29.5,29.3,27.5,27.2,22.6(10csomesignalswereoverlapped,2och2ch2(ch2)5ch3),14.0(2c,2ch2ch2(ch2)5ch3)。

在50.0ml圓底燒瓶中，加入化合物n¹,n¹-二辛基-1,2-二胺(0.2g,0.4mmol)、咪唑氨基甲酸阿比特龍酯(0.2g,0.4mmol)，用四氫呋喃溶解，攪拌作用下，加入六磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.4g,0.6mmol)，回流反應(yīng)。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得淡黃色液體β-n¹,n¹-二辛基氨基甲酸阿比特龍酯(210.0mg,52.7%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.61-7.19(m,4h,py-h),5.98(s,1h,c16-h,j=5.0hz),5.41-5.40(d,1h,c6-h,j=5.0hz),5.17(s,1h,conhch2),4.50(s,1h,c1-h),3.19-3.18(d,2h,conhch2ch2,j=5hz),2.50-2.48(m,2h,conhch2ch2),2.38-2.36(m,4h,ch2n(ch2)2),2.01-1.08(m,42h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)6ch3),1.06(s,3h,c13-ch3),1.03(s,3h,c10-ch3),0.87(t,6h,2ch2ch2(ch2)6ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.3,151.7,147.9,147.8,140.3,133.1,133.0,129.2,123.0,122.0(10c,conhch2,py-c,c16,c17,c5,c6),74.0(1c,c1),62.6(2c,n(ch2ch2)2),57.4,(1c,conhch2ch2),54.0,53.1,50.2,47.3,38.6,36.9,36.8,35.2,31.9,31.5,30.4,29.7,29.4,28.2,27.1,22.7,20.8(22c,somesignalswereoverlapped,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,conhch2ch2,2ch2(ch2)6ch3),19.3(1c,c10-ch3),16.6(1c,c13-ch3),14.4(2c,2ch2(ch2)6ch3)。

在25.0ml圓底燒瓶中，加入化合物β-n¹,n¹-二辛基氨基甲酸阿比特龍酯(0.4g,0.7mmol)，用丙酮溶解，加入ch3i(170.0μl,2.6mmol)，40^oc下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，加丙酮冷卻結(jié)晶，過(guò)濾，用丙酮淋洗，真空干燥得白色固體化合物β-n-甲基-n¹,n¹-二辛基氨基甲酸-py-n-甲基-阿比特龍酯(310.0mg,75.6%)。¹hnmr(500mhz,cdcl3):δ(ppm)9.13-8.03(m,4h,py-h),6.71(s,1h,c16-h),6.35(s,1h,conhch2),5.36(s,1h,c6-h),4.70(s,3h,py-n-ch3),4.41(s,1h,c1-h),3.68(d,4h,conhch2ch2),3.65(s,4h,conhch2ch2),3.42(s,3h,conhch2ch2nch3),3.28-1.22(m,42h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)6ch3),1.07(s,3h,c13-ch3),1.03(s,3h,c10-ch3),0.86(t,6h,2ch2(ch2)6ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.5,147.0,142.8,142.6,140.9,140.1,137.8,137.5,128.0,121.9(10c,conhch2,py-c,c17,c16,c5,c6),74.7(1c,c1),62.5(2c,n(ch2)2),60.2(1c,conhch2ch2),57.2,49.9,49.6,47.538.5,36.7,35.2,34.9,32.3,31.9,30.2,29.7,29.5,29.4,28.0,26.3,22.7,20.7(24c,somesignalswereoverlapped,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,py-n-ch3,conhch2ch2,conhch2ch2nch3,2ch2(ch2)6ch3),19.2(1c,c10-ch3),16.6(1c,c13-ch3),14.1(2c,2ch2(ch2)6ch3)。

實(shí)施例3.β-n-甲基-n¹,n¹-二癸基氨基甲酸-py-n-甲基-阿比特龍酯納米顆粒的制備：

在100.0ml圓底燒瓶中加入化合物咪唑氨基甲酸阿比特龍酯(4.0g,25.0mmol)，用乙酸乙酯溶解，攪拌作用下加入無(wú)水k2co3(13.8g,100.0mmol)、1-溴癸烷(22.1g,100.0mmol)。反應(yīng)混合物在70^oc下回流反應(yīng)48h，用tlc(v石油醚:v乙酸乙酯=5:1)監(jiān)測(cè)至原料不再變化。過(guò)濾，濃縮。經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得白色固體(2-(n¹,n¹-二癸基)乙基)氨基甲酸叔丁酯(1.0g,61.8%)。¹hnmr(500mhz,cdcl3):δ(ppm)5.0(s,1hnhch2ch2),3.14-3.13(d,2hnhch2ch2),2.49-2.47(m,2h,nhch2ch2),2.39-2.36(m,4h,n(ch2ch2)2),1.44(s,9h,(ch3)3c),1.40-1.38(m,4h,n(ch2ch2)2),1.30-1.26(d,36h,2ch2ch2(ch2)7ch3),0.88(t,6h,2ch2ch2(ch2)7ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.1(1c,conhch2),78.9(1c,(ch3)3c),54.0(2c,n(ch2ch2)2),53.2(1c,nhch2ch2nh2),38.3(1c,nhch2ch2nh2),31.9,29.7,29.6,29.3,27.5,27.1,22.7(14csomesignalswereoverlapped,2och2(ch2)7ch3),28.4((ch3)3c),14.1(2c,2ch2ch2(ch2)7ch3)。

在50.0ml圓底燒瓶中，加入化合物(2-(n¹,n¹-二癸基)乙基)氨基甲酸叔丁酯(2.0g,3.3mmol)，用無(wú)水二氯甲烷(30.0ml)溶解，攪拌作用下，滴加三氟乙酸(5.0ml)常溫下磁力攪拌。tlc(v石油醚:v乙酸乙酯=5:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。用koh(0.1mol/l,300.0ml)溶液洗三次,有機(jī)相用無(wú)水na2so4干燥，過(guò)濾，濃縮，經(jīng)柱層析(洗脫劑：v乙酸乙酯:v甲醇=5:1)分離純化得淡黃色固體n¹,n¹-二正癸基-1,2-二胺(0.9g,52.0%)。¹hnmr(500mhz,cdcl3):δ(ppm)2.71-2.69(m,2hh2nch2ch2n),2.45-2.43(m,2hh2nch2ch2n),2.39-2.36(m,4h,n(ch2(ch2)7ch3)2),1.43-1.39(m,4h,n(ch2ch2)2),1.30-1.25(s,52h,2ch2ch2(ch2)7ch3),0.87(t,6h,2ch2ch2(ch2)7ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)57.1(2c,n(ch2ch2)2),54.4(1c,nhch2ch2nh2),39.8(1c,nhch2ch2nh2),31.9,29.7,29.6,29.6,29.3,27.5,27.2,22.7(14csomesignalswereoverlapped,2och2ch2(ch2)7ch3),14.1(2c,2ch2ch2(ch2)7ch3)。

在50.0ml圓底燒瓶中，加入化合物n¹,n¹-二癸基-1,2-二胺(0.4g,0.8mmol)、化合物咪唑氨基甲酸阿比特龍酯(0.3g,0.6mmol)，用四氫呋喃溶解，攪拌作用下，加入六磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.5g,0.7mmol)，回流反應(yīng)。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。得淡黃色液體β-n¹,n¹-二癸基氨基甲酸阿比特龍酯(0.4g,52.9%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.61-7.19(m,4h,py-h),5.98(s,1h,c16-h,j=5.0hz),5.41-5.40(d,1h,c6-h,j=5.0hz),5.17(s,1h,conhch2),4.50(s,1h,c1-h),3.19-3.18(d,2h,conhch2ch2,j=5.0hz),2.50-2.48(m,2h,conhch2ch2),2.38-2.36(m,4h,ch2n(ch2)2),2.01-1.16(m,50h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)12ch3),1.08(s,3h,c13-ch3),1.02(s,3h,c10-ch3),0.84(t,6h,2ch2(ch2)12ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.3,151.7,147.9,147.8,140.3,133.1,133.0,129.2,123.0,122.0(10c,conhch2,py-c,c17,c16,c5,c6),74.0(1c,c1),62.6(2c,n(ch2ch2)2),57.5,(1c,conhch2ch2),54.0,53.1,50.2,47.3,38.6,38.5,36.9,36.8,35.2,31.9,31.8,31.5,30.4,29.7,29.6,29.4,28.2,27.5,27.1,22.7,20.8(34c,somesignalswereoverlapped,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,conhch2ch2,2ch2(ch2)12ch3),19.3(1c,c10-ch3),16.6(1c,c13-ch3),14.4(2c,2ch2(ch2)12ch3)。

在25.0ml圓底燒瓶中，加入化合物β-n¹,n¹-二癸基氨基甲酸阿比特龍酯(0.3g,0.6mmol)用丙酮溶解，加入ch3i(164.0μl,2.3mmol)，40^oc下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，加丙酮冷卻結(jié)晶，過(guò)濾，用丙酮淋洗，真空干燥得白色固體化合物β-n-甲基-n¹,n¹-二癸基氨基甲酸-py-n-甲基-阿比特龍酯(215.0mg,53.1%)。¹hnmr(500mhz,cdcl3):δ(ppm)9.11-8.03(m,4h,py-h),6.71(s,1h,c16-h),6.36(s,1h,conhch2),5.35(s,1h,c6-h),4.71(s,3h,py-n-ch3),4.40(s,1h,c1-h),3.66(d,4h,conhch2ch2),3.42(s,4h,conhch2ch2),3.28(s,3h,conhch2ch2nch3),2.35-1.21(m,50h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)8ch3),1.07(s,3h,c13-ch3),1.05(s,3h,c10-ch3),0.86(t,6h,2ch2(ch2)8ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.5,147.0,142.8,142.6,140.9,140.1,137.8,137.5,128.0,121.9(10c,conhch2,py-c,c17,c16,c5,c6),74.7(1c,c1),62.6(2c,n(ch2)2),60.2(1c,conhch2ch2),57.3(1c,c13),50.0,49.9,49.6,47.538.5,36.8,35.2,34.9,32.4,31.9,31.3,29.6,29.5,29.3,29.1,28.0,26.3,22.7,20.7(28c,somesignalswereoverlapped,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,py-n-ch3,conhch2ch2,conhch2ch2nch3,2ch2(ch2)8ch3),19.3(1c,c10-ch3),16.7(1c,c13-ch3),14.2(2c,2ch2(ch2)8ch3)。

實(shí)施例4.β-n-甲基-n¹,n¹-雙十二烷基氨基甲酸-py-n-甲基-阿比特龍酯納米顆粒的制備：

在100.0ml圓底燒瓶中加入化合物(2-氨基乙基)氨基甲酸叔丁酯(8.0g,50.0mmol)，用乙酸乙酯溶解，攪拌作用下加入無(wú)水k2co3(27.6g,200.0mmol)、月桂基溴(49.6g,200.0mmol)。反應(yīng)混合物在70^oc下回流反應(yīng)48h，用tlc(v石油醚:v乙酸乙酯=5:1)監(jiān)測(cè)至原料不再變化。過(guò)濾，濃縮。柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得白色固體(2-(n¹,n¹-雙十二烷基)乙基)氨基甲酸叔丁酯(15.6g,63.0%)。¹hnmr(500mhz,cdcl3):δ(ppm)5.0(s,1hnhch2ch2),3.14-3.13(d,2hnhch2ch2),2.49-2.47(m,2h,nhch2ch2),2.39-2.36(m,4h,n(ch2ch2)2),1.44(s,9h,(ch3)3c),1.40-1.38(m,4h,n(ch2ch2)2),1.31-1.26(d,36h,2ch2ch2(ch2)9ch3),0.88(t,6h,2ch2ch2(ch2)9ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.1(1c,conhch2),78.8(1c,(ch3)3c),54.0(2c,n(ch2ch2)2),53.2(1c,nhch2ch2nh2),34.0(1c,nhch2ch2nh2),32.8,31.9,29.7,29.6,29.4,28.8,28.4,28.2,27.5,27.1,22.7(18csomesignalswereoverlapped,2och2(ch2)9ch3),28.6((ch3)3c),14.2(2c,2ch2ch2(ch2)9ch3)。

在50.0ml圓底燒瓶中，加入化合物(2-(n¹,n¹-雙十二烷基)乙基)氨基甲酸叔丁酯(3.0g,6.0mmol)、用無(wú)水二氯甲烷(35.0ml)溶解，攪拌作用下，滴加三氟乙酸(7.0ml)常溫下磁力攪拌。tlc(v石油醚:v乙酸乙酯=5:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。用koh(0.1mol/l)溶液調(diào)ph到7.0-8.0，有機(jī)相用無(wú)水na2so4干燥，過(guò)濾，濃縮。經(jīng)柱層析(洗脫劑：v乙酸乙酯:v甲醇=5:1)分離純化得淡黃色固體n¹,n¹-雙十二烷基-1,2-二胺(1.2g,49.8%)。¹hnmr(500mhz,cdcl3):δ(ppm)2.74(s,2hh2nch2ch2n),2.50-2.46(m,2hh2nch2ch2n),2.40-2.36(m,4h,n(ch2(ch2)13ch3)2),1.41(s,4h,n(ch2ch2)2),1.23(s,36h,2ch2ch2(ch2)9ch3),0.86(t,6h,2ch2ch2(ch2)9ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)55.8(2c,n(ch2ch2)2),54.2(1c,nhch2ch2nh2),39.1(1c,nhch2ch2nh2),32.9,29.7,29.7,29.6,29.6,29.3,27.5,27.0,22.7(18csomesignalswereoverlapped,2och2ch2(ch2)9ch3),14.1(2c,2ch2ch2(ch2)9ch3)。

在50.0ml圓底燒瓶中，加入化合物n¹,n¹-雙十二烷基-1,2-二胺(0.3g,0.4mmol)、咪唑氨基甲酸阿比特龍酯(0.2g,0.4mmol)，用四氫呋喃溶解，攪拌作用下，加入六磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.4g,0.6mmol)，回流反應(yīng)。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得淡黃色液體β-n¹,n¹-雙十二烷基氨基甲酸阿比特龍酯(320.0mg,53.8%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.61-7.18(m,4h,py-h),5.98(s,1h,c16-h,j=5.0hz),5.41-5.40(d,1h,c6-h,j=5.0hz),5.17(s,1h,conhch2),4.50(s,1h,c1-h),3.19-3.18(d,2h,conhch2ch2,j=5.0hz),2.50-2.48(m,2h,conhch2ch2),2.38-2.36(m,4h,ch2n(ch2)2),2.01-1.15(m,58h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)10ch3),1.08(s,3h,c13-ch3),1.03(s,3h,c10-ch3),0.87(t,6h,2ch2(ch2)10ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.3(10c,conhch2,py-c,c17,c16,c5,c6),74.0(1c,c1),62.6(2c,n(ch2ch2)2),57.3,(1c,conhch2ch2),54.0,53.1,50.2,47.3,38.6,38.5,36.9,36.8,35.2,31.9,31.8,31.5,30.4,29.7,29.6,29.4,28.2,27.5,27.1,22.7,20.8(30c,somesignalswereoverlapped,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,conhch2ch2,2ch2(ch2)10ch3),19.3(1c,c10-ch3),16.6(1c,c13-ch3),14.4(2c,2ch2(ch2)10ch3)。

在25.0ml圓底燒瓶中，加入化合物β-n¹,n¹-雙十二烷基氨基甲酸阿比特龍酯(0.4g,0.7mmol)，用丙酮溶解，加入ch3i(160.3μl,2.3mmol)，40^oc下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，加丙酮冷卻結(jié)晶，過(guò)濾，用丙酮淋洗，真空干燥得白色固體化合物β-n-甲基-n¹,n¹-二正烷基氨基甲酸-py-n-甲基-阿比特龍酯(0.2g,42.6%)。¹hnmr(500mhz,cdcl3):δ(ppm)9.12-8.04(m,4h,py-h),6.72(s,1h,c16-h),6.37(s,1h,conhch2),5.36(s,1h,c6-h),4.72(s,3h,py-n-ch3),4.41(s,1h,c1-h),3.67(d,4h,conhch2ch2),3.43(s,4h,conhch2ch2),3.29(s,3h,conhch2ch2nch3),2.35-1.22(m,58h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)10ch3),1.06(s,3h,c13-ch3),1.02(s,3h,c10-ch3),0.85(t,6h,2ch2(ch2)10ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.6,147.0,142.8,142.6,140.9,140.1,137.9,137.5,128.0,121.9(10c,conhch2,py-c,c17,c16,c5,c6),74.8(1c,c1),62.6(2c,n(ch2)2),60.2(1c,conhch2ch2),57.3(1c,c13),50.0,49.9,49.6,47.538.5,36.8,36.7,35.2,34.9,32.4,31.9,31.3,30.2,29.6,29.5,29.5,29.3,29.2,29.1,28.0,26.3,22.7,22.5,20.7(32c,somesignalswereoverlapped,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,py-n-ch3,conhch2ch2,conhch2ch2nch3,2ch2(ch2)10ch3),19.3(1c,c10-ch3),16.7(1c,c13-ch3),14.2(2c,2ch2(ch2)10ch3)。

實(shí)施例5.β-n-甲基-n¹,n¹-雙十四烷基氨基甲酸-py-n-甲基-阿比特龍酯納米顆粒的制備：

在100.0ml圓底燒瓶中加入化合物(2-氨基乙基)氨基甲酸叔丁酯(8.0g,50.0mmol)，用乙酸乙酯溶解，攪拌作用下加入無(wú)水k2co3(27.6g,200.0mmol)、肉豆蔻基溴(55.2g,200.0mmol)。反應(yīng)混合物在70^oc下回流反應(yīng)48h，用tlc(v石油醚:v乙酸乙酯=5:1)監(jiān)測(cè)反應(yīng)至原料不再發(fā)生變化。過(guò)濾，濃縮。經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得白色固體(2-(n¹,n¹-雙十四烷基)乙基)氨基甲酸叔丁酯(17.1g,61.0%)。¹hnmr(500mhz,cdcl3):δ(ppm)5.0(s,1hnhch2ch2),3.14-3.13(d,2hnhch2ch2),2.49-2.47(m,2h,nhch2ch2),2.39-2.36(m,4h,n(ch2ch2)2),1.44(s,9h,(ch3)3c),1.40-1.38(m,4h,n(ch2ch2)2),1.30-1.26(d,44h,2ch2ch2(ch2)11ch3),0.88(t,6h,2ch2ch2(ch2)11ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.1(1c,conhch2),78.8(1c,(ch3)3c),54.0(2c,n(ch2ch2)2),53.2(1c,nhch2ch2nh2),34.0(1c,nhch2ch2nh2),32.8,31.9,29.7,29.6,29.4,28.8,28.4,28.2,27.5,27.1,22.7(22csomesignalswereoverlapped,2och2(ch2)12ch3),28.6((ch3)3c),14.2(2c,2ch2(ch2)12ch3)。

在50.0ml圓底燒瓶中，加入化合物(2-(n¹,n¹-雙十四烷基)乙基)氨基甲酸叔丁酯(3.5g,6.3mmol)、用無(wú)水二氯甲烷(30.0ml)溶解，攪拌作用下，滴加三氟乙酸(5.0ml)常溫下磁力攪拌。tlc(v石油醚:v乙酸乙酯=5:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。用koh(0.1mol/l)溶液調(diào)ph到7.0-8.0，有機(jī)相用無(wú)水na2so4干燥，過(guò)濾，濃縮。經(jīng)柱層析(洗脫劑：v乙酸乙酯:v甲醇=5:1)分離純化得淡黃色固體n¹,n¹-雙十四烷基-1,2-二胺(1.5g,51.0%)。¹hnmr(500mhz,cdcl3):δ(ppm)2.75(s,2hh2nch2ch2n),2.51-2.48(m,2hh2nch2ch2n),2.40-2.37(m,4h,n(ch2(ch2)11ch3)2),1.40(s,4h,n(ch2ch2)2),1.24(s,52h,2ch2ch2(ch2)11ch3),0.87(t,6h,2ch2ch2(ch2)11ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)55.8(2c,n(ch2ch2)2),54.2(1c,nhch2ch2nh2),39.1(1c,nhch2ch2nh2),32.9,29.7,29.7,29.6,29.6,29.3,27.5,27.0,22.7(28csomesignalswereoverlapped,2och2ch2(ch2)11ch3),14.1(2c,2ch2ch2(ch2)11ch3)。

在50.0ml圓底燒瓶中，加入化合物n¹,n¹-雙十四烷基-1,2-二胺(0.6g,0.8mmol)、化合物咪唑氨基甲酸阿比特龍酯(0.4g,0.8mmol)，用四氫呋喃溶解，攪拌作用下，加入六磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.6g,0.8mmol)，回流反應(yīng)。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。得淡黃色液體β-n¹,n¹-雙十四烷基氨基甲酸阿比特龍酯(0.6g,42.6%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.61-7.19(m,4h,py-h),5.98(s,1h,c16-h,j=5.0hz),5.41-5.40(d,1h,c6-h,j=5.0hz),5.17(s,1h,conhch2),4.50(s,1h,c1-h),3.19-3.18(d,2h,conhch2ch2,j=5.0hz),2.50-2.48(m,2h,conhch2ch2),2.38-2.36(m,4h,ch2n(ch2)2),2.01-1.16(m,66h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)12ch3),1.08(s,3h,c13-ch3),1.02(s,3h,c10-ch3),0.84(t,6h,2ch2(ch2)12ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.3,151.7,147.9,147.8,140.3,133.1,133.0,129.2,123.0,122.0(10c,conhch2,py-c,c17,c16,c5,c6),74.0(1c,c1),62.4(2c,n(ch2ch2)2),57.1,(1c,conhch2ch2),54.0,53.1,50.2,47.3,38.6,38.5,36.9,36.8,35.2,31.9,31.8,31.5,30.4,29.7,29.6,29.4,28.2,27.5,27.1,22.7,20.8(34c,somesignalswereoverlapped,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,conhch2ch2,2ch2(ch2)12ch3),19.3(1c,c10-ch3),16.6(1c,c13-ch3),14.4(2c,2ch2(ch2)12ch3)。

在25.0ml圓底燒瓶中，加入化合物β-n¹,n¹-雙十四烷基氨基甲酸阿比特龍酯(0.4g,0.7mmol)，用丙酮溶解，加入ch3i(174.3μl,2.8mmol)，40^oc下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，加丙酮冷卻結(jié)晶，過(guò)濾，用丙酮淋洗，真空干燥得白色固體化合物β-n-甲基-n¹,n¹-二正烷基氨基甲酸-py-n-甲基-阿比特龍酯(0.2g,40.0%)。¹hnmr(500mhz,cdcl3):δ(ppm)9.12-8.04(m,4h,py-h),6.72(s,1h,c16-h),6.37(s,1h,conhch2),5.36(s,1h,c6-h),4.72(s,3h,py-n-ch3),4.41(s,1h,c1-h),3.67(d,4h,conhch2ch2),3.43(s,4h,conhch2ch2),3.29(s,3h,conhch2ch2nch3),2.35-1.22(m,66h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)12ch3),1.08(s,3h,c13-ch3),1.06(s,3h,c10-ch3),0.87(t,6h,2ch2(ch2)12ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.5,147.0,142.8,142.6,140.9,140.1,137.8,137.5,128.0,121.9(10c,conhch2,py-c,c17,c16,c5,c6),74.7(1c,c1),62.6(2c,n(ch2)2),60.2(1c,conhch2ch2),57.3(1c,c13),50.0,49.9,49.6,47.5,38.5,36.8,36.7,35.2,34.9,32.4,31.9,31.3,30.2,29.6,29.5,29.5,29.3,29.2,29.1,28.0,26.3,22.7,22.5,20.7(36c,somesignalswereoverlapped,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,py-n-ch3,conhch2ch2,conhch2ch2nch3,2ch2(ch2)12ch3),19.3(1c,c10-ch3),16.7(1c,c13-ch3),14.2(2c,2ch2(ch2)12ch3)。

實(shí)施例6.β-n-甲基-n¹,n¹-二庚基氨基甲酸阿比特龍酯納米顆粒的制備：

在50.0ml圓底燒瓶中，加入化合物(2-(n¹,n¹-二庚烷基)乙基)氨基甲酸叔丁酯(2.0g,5.6mmol)，用丙酮溶解，加入無(wú)水k2co3(4.3g,31.2mmol)，ch3i(51.1μl,0.8mmol),常溫下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。過(guò)濾，濃縮，經(jīng)柱層析(洗脫劑：v乙酸乙酯:v甲醇=10:1)分離純化得黃色固體(2-(n-甲基-n¹,n¹-二庚烷基)乙基)氨基甲酸叔丁酯(2.1g,69.3%)。¹hnmr(500mhz,cdcl3):δ(ppm)5.99-5.98(1h,ch2nhco),3.66-3.63(m,4h,nhch2ch2),3.45-3.41(m,4h,n(ch2ch2)2),3.28(s,3h,nhch2ch2nch3),1.70(s,4h,n(ch2ch2)2),1.38(s,9h,(ch3)3c),1.34-1.25(m,16h,2ch2ch2(ch2)4ch3),0.85(t,6h,2ch2ch2(ch2)4ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.4(1c,conhch2),80.2(1c,(ch3)3c),62.7(2c,n(ch2ch2)2),60.5(1c,nhch2ch2nh2),49.6(1c,nhch2ch2nch3),35.1(1c,nhch2ch2nh2),31.5,28.8,26.2,22.5,22.5(8csomesignalswereoverlapped,2och2(ch2)4ch3),28.4((ch3)3c),14.0(2c,2ch2ch2(ch2)13ch3)。

在50.0ml圓底燒瓶中，加入化合物(2-(n-甲基-n¹,n¹-二庚基)乙基)氨基甲酸叔丁酯(4.0g,9.9mmol)，用無(wú)水二氯甲烷(30.0ml)溶解，攪拌作用下，滴加三氟乙酸(15.0ml)常溫下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)至原料點(diǎn)消失。用koh(0.1mol/l)溶液調(diào)ph到7.0-8.0，有機(jī)相用無(wú)水na2so4干燥，過(guò)濾，濃縮得淡黃色液體n-甲基-n¹,n¹-二庚基-1,2-二胺(1.1g,40.7%)。

在100ml的圓底燒瓶中加入藥物阿比特龍(0.5g,1.4mmol)，用吡啶溶解，磁力攪拌，加入對(duì)硝基氯甲酸苯酯(0.8g,4.2mmol)，dmap(0.5g,4.2mmol),常溫反應(yīng)。tlc(v石油醚:v乙酸乙酯=4:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。停止反應(yīng)，濃縮得黃色固體，加乙酸乙酯洗三次，濃縮濾液，經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=4:1)分離純化，得到白色固體化合物4-硝基苯碳酸阿比特龍酯(0.6g,80.6%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.61-7.20(m,8h,py-h,ph-h,),5.99(s,1h,c16-h),5.47-5.46(d,1h,c6-h,j=5.0hz),4.62(s,1h,c1-h),2.52-1.19(m17h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h),1.10(s3h,c13-ch3),1.05(s3h,c10-ch3);¹³cnmr(125mhz,cdcl3):δ(ppm)155.6(16c,py-c,ph-c,co,c5,c6,c16,c17,somesignalswereoverlapped),79.6(1c,c1),57.4,50.1,47.3,37.8,36.7,36.7,35.1,31.7,31.5,30.3,27.5,20.8(12c,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,somesignalswereoverlapped),19.2(1c,c10-ch3),16.5(1c,c13-ch3)。

在25.0ml圓底燒瓶中，加入化合物n-甲基-n¹,n¹-二庚烷基-1,2-二胺(0.2g,0.4mmol)、4-硝基苯碳酸阿比特龍酯(0.2g,0.4mmol)，用四氫呋喃溶解，攪拌作用下，滴加三乙胺(0.1ml)，40^oc下磁力攪拌。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得白色粉末狀固體β-n-甲基-n¹,n¹-二庚烷基氨基甲酸阿比特龍酯(180.0mg,52.7%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.61-7.23(m,5h,conhch2,py-h,),5.99(s,1h,c16-h),5.38(s,1h,c6-h),4.45(s,1h,c1-h),3.67(s,2h,conhch2ch2),3.67(s,2h,conhch2ch2),3.58(s,4h,n(ch2ch2c5h11)2),3.27(s,3h,conhch2ch2nch3),3.14-1.27(m,37h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)5ch3),1.05(s,3h,c13-ch3),1.03(s,3h,c10-ch3),0.86(t,6h,2ch2(ch2)5ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)157.0,151.5,147.5,140.1,133.7,133.0,129.2,123.0,121.9(10c,conhch2ch2,py-c,c17,c16,c5,c6),74.6(1c,c1),62.0(2c,n(ch2)2),60.5(1c,conhch2ch2),57.4(1c,c13),50.2,48.7,47.2,38.4,36.8,36.6,35.1,34.9,31.7,31.4,30.3,28.6,27.9,26.0,22.3,22.1,20.7,19.1(24c,somesignalswereoverlapped,conhch2ch2,conhch2ch2nch3,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,2ch2(ch2)5ch3),19.1(1c,c10-ch3),16.4(1c,c13-ch3),13.9(2c,2ch2(ch2)5ch3)。

實(shí)施例7.β-n-甲基-n¹,n¹-二辛基氨基甲酸阿比特龍酯納米顆粒的制備：

在50.0ml圓底燒瓶中，加入化合物(2-(n¹,n¹-二辛基)乙基)氨基甲酸叔丁酯(2.0g,5.2mmol)，用丙酮溶解，加入無(wú)水k2co3(4.2g,10.4mmol)和ch3i(1.3ml,20.8mmol)，常溫下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。過(guò)濾，濃縮，經(jīng)柱層析(洗脫劑：v乙酸乙酯:v甲醇=10:1)分離純化得黃色固體(2-(n-甲基-n¹,n¹-二辛基)乙基)氨基甲酸叔丁酯(1.5g,71.4%)。¹hnmr(500mhz,cdcl3):δ(ppm)6.10(s,1hch2nhco),3.69(m,4hnhch2ch2),3.49-3.43(m,4h,n(ch2ch2)2),3.31(s,3h,nhch2ch2nch3),1.73(m,4h,n(ch2ch2)2),1.43(s,9h,(ch3)3c),1.37-1.28(m,20h,2ch2ch2(ch2)5ch3),0.88(t,6h,2ch2ch2(ch2)5ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.4(1c,conhch2),80.1(1c,(ch3)3c),62.6(2c,n(ch2ch2)2),60.5(1c,nhch2ch2nh2),49.5(1c,nhch2ch2nch3),35.0(1c,nhch2ch2nh2),31.6,29.1,29.0,26.3,22.6,22.6,22.5(12csomesignalswereoverlapped,2och2(ch2)6ch3),28.5((ch3)3c),14.0(2c,2ch2ch2(ch2)5ch3)。

在50.0ml圓底燒瓶中，加入化合物(2-(n-甲基-n¹,n¹-二辛基)乙基)氨基甲酸叔丁酯(5.0g,12.5mmol)，用無(wú)水二氯甲烷(30.0ml)溶解，攪拌作用下，滴加三氟乙酸(15.0ml)常溫下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。用koh(0.1mol/l)溶液調(diào)ph到7.0-8.0,有機(jī)相用無(wú)水na2so4干燥，過(guò)濾，濃縮得淡黃色固體n-甲基-n¹,n¹-二辛基-1,2-二胺(1.5g,42.3%)。

在25.0ml圓底燒瓶中，加入化合物n-甲基-n¹,n¹-二辛基-1,2-二胺(0.3g,0.6mmol)、4-硝基苯碳酸阿比特龍酯(0.2g,0.4mmol)，用四氫呋喃溶解，攪拌作用下，滴加三乙胺(0.2ml),40^oc下磁力攪拌。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得白色固體β-n-甲基-n¹,n¹-二辛基氨基甲酸阿比特龍酯(0.3g,50.3%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.50-6.93(m,5h,py-h,conhch2),5.99(s,1h,c16-h),5.39(s,1h,c6-h),4.44(s,1h,c1-h),3.65(s,2h,conhch2ch2),3.52(s,2h,conhch2ch2),3.24(s,4h,n(ch2ch2c6h13)2),3.11(s,3h,conhch2ch2nch3),2.31-1.24(m,63h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)6ch3),1.04(s,3h,c13-ch3),1.02(s,3h,c10-ch3),0.86(t,6h,2ch2(ch2)6ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)157.3,151.5,147.5,140.2,134.3,129.7,129.2,123.0,121.9(10c,conhch2ch2,py-c,c17,c16,c5,c6),74.8(1c,c1),62.0(2c,n(ch2)2),60.9(1c,conhch2ch2),57.5(1c,c13),49.0,47.3,45.8,38.4,36.8,35.0,31.9,31.5,30.4,29.6,29.4,29.3,29.0,27.9,22.6,22.1,20.8,(26c,somesignalswereoverlapped,conhch2ch2,conhch2ch2nch3,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,2ch2(ch2)6ch3),19.2(1c,c10-ch3),16.4(1c,c13-ch3),14.2(2c,2ch2(ch2)6ch3)。

實(shí)施例8.β-n-甲基-n¹,n¹-二癸基氨基甲酸阿比特龍酯納米顆粒的制備：

在50.0ml圓底燒瓶中，加入化合物(2-(n¹,n¹-二癸基)乙基)氨基甲酸叔丁酯(2.0g,4.5mmol)，用丙酮溶解，加入無(wú)水k2co3(1.3g,9.0mmol)和ch3i(1.2ml,18.0mmol)，常溫下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。過(guò)濾，濃縮，經(jīng)柱層析(洗脫劑：v乙酸乙酯:v甲醇=10:1)分離純化得黃色固體(2-(n-甲基-n¹,n¹-二癸基)乙基)氨基甲酸叔丁酯(1.6g,77.4%)。¹hnmr(500mhz,cdcl3):δ(ppm)6.13(s,1hch2nhco),3.66(m,4hnhch2ch2),3.44-3.41(m,4h,n(ch2ch2)2),3.29(s,3h,nhch2ch2nch3),1.7(s,4h,n(ch2ch2)2),1.40(s,9h,(ch3)3c),1.35-1.24(m,28h,2ch2ch2(ch2)7ch3),0.86(t,6h,2ch2ch2(ch2)7ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.4(1c,conhch2),80.1(1c,(ch3)3c),62.6(2c,n(ch2ch2)2),60.6(1c,nhch2ch2nh2),49.5(1c,nhch2ch2nch3),35.1(1c,nhch2ch2nh2),31.9,31.8,29.5,29.4,29.4,29.3,29.2,29.2,26.3,22.6,22.5(28csomesignalswereoverlapped,2och2(ch2)8ch3),28.4((ch3)3c),14.1(2c,2ch2ch2(ch2)7ch3)。

在50.0ml圓底燒瓶中，加入化合物(2-(n-甲基-n¹,n¹-二癸基)乙基)氨基甲酸叔丁酯(4.0g,8.8mmol)，用無(wú)水二氯甲烷(30.0ml)溶解，攪拌作用下，滴加三氟乙酸(15.0ml)常溫下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。用koh(0.1mol/l)溶液調(diào)ph到7.0-8.0，有機(jī)相用無(wú)水na2so4干燥，過(guò)濾，濃縮得淡黃色固體n-甲基-n¹,n¹-二癸基-1,2-二胺(1.6g,53.3%)。

在25.0ml圓底燒瓶中，加入化合物n-甲基-n¹,n¹-二癸基-1,2-二胺(0.4g,0.6mmol)、4-硝基苯碳酸阿比特龍酯(0.3g,0.6mmol)，用四氫呋喃溶解，攪拌作用下，滴加三乙胺(0.2ml)，40^oc下磁力攪拌。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得白色固體β-n-甲基-n¹,n¹-二癸基氨基甲酸阿比特龍酯(0.4g,56.7%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.50-6.78(m,5h,py-h,conhch2),5.99(s,1h,c16-h),5.37(s,1h,c6-h),4.44(s,1h,c1-h),3.65(s,2h,conhch2ch2),3.52(s,2h,conhch2ch2),3.24(s,4h,n(ch2ch2c8h17)2),3.11(s,3h,conhch2ch2nch3),2.31-1.24(m,63h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)8ch3),1.04(s,3h,c13-ch3),1.02(s,3h,c10-ch3),0.86(t,6h,2ch2(ch2)8ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)157.1,151.4,147.5,140.2,134.3,129.7,129.2,123.0,121.9(10c,conhch2ch2,py-c,c17,c16,c5,c6),74.8(1c,c1),62.0(2c,n(ch2)2),60.9(1c,conhch2ch2),57.5(1c,c13),49.0,47.2,45.9,38.5,36.8,36.6,35.2,35.1,31.9,31.7,31.5,30.3,29.6,29.4,29.4,29.3,29.1,27.8,26.1,22.6,22.2,21.0,20.8,(23c,somesignalswereoverlapped,conhch2ch2,conhch2ch2nch3,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,2ch2(ch2)8ch3),19.3(1c,c10-ch3),16.6(1c,c13-ch3),14.3(2c,2ch2(ch2)8ch3)。

實(shí)施例9.β-n-甲基-n¹,n¹-雙十二烷基氨基甲酸阿比特龍酯納米顆粒的制備：

在50.0ml圓底燒瓶中，加入化合物(2-(n¹,n¹-雙十二烷基)乙基)氨基甲酸叔丁酯(2.0g,4.0mmol)，用丙酮溶解，加入無(wú)水k2co3(1.1g,8.0mmol)和ch3i(1.0ml,16.0mmol)，常溫下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。過(guò)濾，濃縮，經(jīng)柱層析(洗脫劑：v乙酸乙酯:v甲醇=10:1)分離純化得黃色固體(2-(n-甲基-n¹,n¹-雙十二烷基)乙基)氨基甲酸叔丁酯(1.6g,78.0%)。¹hnmr(500mhz,cdcl3):δ(ppm)6.05(s,1hch2nhco),3.66(m,4hnhch2ch2),3.43-3.40(m,4h,n(ch2ch2)2),3.29(s,3h,nhch2ch2nch3),1.69-1.67(m,4h,n(ch2ch2)2),1.41(s,9h,(ch3)3c),1.34-1.24(m,36h,2ch2ch2(ch2)9ch3),0.86(t,6h,2ch2ch2(ch2)9ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.3(1c,conhch2),80.1(1c,(ch3)3c),62.6(2c,n(ch2ch2)2),60.5(1c,nhch2ch2nh2),49.5(1c,nhch2ch2nch3),35.0(1c,nhch2ch2nh2),32.0,29.8,29.6,29.6,29.5,29.4,29.2,26.3,22.6,22.5(20csomesignalswereoverlapped,2och2(ch2)10ch3),28.5((ch3)3c),14.2(2c,2ch2ch2(ch2)9ch3)。

在50.0ml圓底燒瓶中，加入化合物(2-(n-甲基-n¹,n¹-雙十二烷基)乙基)氨基甲酸叔丁酯(4.0g,7.8mmol)，用無(wú)水二氯甲烷(30.0ml)溶解，攪拌作用下，滴加三氟乙酸(15.0ml)常溫下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。用koh(0.1mol/l)溶液調(diào)ph到7.0-8.0，有機(jī)相用無(wú)水na2so4干燥，過(guò)濾，濃縮得淡黃色固體n-甲基-n¹,n¹-雙十二烷基-1,2-二胺(1.5g,48.7%)。

在25.0ml圓底燒瓶中，加入化合物n-甲基-n¹,n¹-雙十二烷基-1,2-二胺(0.1g,0.2mmol)、4-硝基苯碳酸阿比特龍酯(0.1g,0.2mmol)，用四氫呋喃溶解，攪拌作用下，滴加三乙胺(0.1ml)，40^oc下磁力攪拌。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得白色固體β-n-甲基-n¹,n¹-二雙十二烷基氨基甲酸阿比特龍酯(120.0mg,66.7%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.50-6.76(m,5h,py-h,conhch2),5.99(s,1h,c16-h),5.37(s,1h,c6-h),4.44(s,1h,c1-h),3.65(s,2h,conhch2ch2),3.52(s,2h,conhch2ch2),3.24(s,4h,n(ch2ch2c5h11)2),3.11(s,3h,conhch2ch2nch3),2.31-1.24(m,63h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)10ch3),1.04(s,3h,c13-ch3),1.02(s,3h,c10-ch3),0.86(t,6h,2ch2(ch2)10ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)157.1,151.4,147.5,140.2,134.3,129.7,129.2,123.0,121.9(10c,conhch2ch2,py-c,c17,c16,c5,c6),74.8(1c,c1),62.0(2c,n(ch2)2),60.9(1c,conhch2ch2),57.5(1c,c13),49.0,47.3,45.8,38.4,36.8,36.7,35.2,35.0,31.9,31.8,31.5,30.4,29.6,29.4,29.3,29.3,29.0,27.9,26.1,22.6,22.1,21.0,20.8,(23c,somesignalswereoverlapped,conhch2ch2,conhch2ch2nch3,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,2ch2(ch2)10ch3),19.2(1c,c10-ch3),16.5(1c,c13-ch3),14.1(2c,2ch2(ch2)10ch3)。

實(shí)施例9.β-n-甲基-n¹,n¹-雙十四烷基氨基甲酸阿比特龍酯納米顆粒的制備：

在50.0ml圓底燒瓶中，加入化合物(2-(n¹,n¹-雙十四烷基)乙基)氨基甲酸叔丁酯(4.0g,7.2mmol)，用丙酮溶解，加入無(wú)水k2co3(1.8g,2.0mmol)和ch3i(1.8ml,28.8mmol)，常溫下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。過(guò)濾，濃縮，經(jīng)柱層析(洗脫劑：v乙酸乙酯:v甲醇=10:1)分離純化得黃色固體(2-(n-甲基-n¹,n¹-雙十四烷基)乙基)氨基甲酸叔丁酯(3.2g,78.0%)。¹hnmr(500mhz,cdcl3):δ(ppm)6.00(s,1hch2nhco),3.66(m,4hnhch2ch2),3.44-3.41(m,4h,n(ch2ch2)2),3.30(s,3h,nhch2ch2nch3),1.69-1.68(m,4h,n(ch2ch2)2),1.40(s,9h,(ch3)3c),1.34-1.25(m,44h,2ch2ch2(ch2)11ch3),0.85(t,6h,2ch2ch2(ch2)13ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)156.4(1c,conhch2),80.2(1c,(ch3)3c),62.7(2c,n(ch2ch2)2),60.6(1c,nhch2ch2nh2),49.6(1c,nhch2ch2nch3),35.1(1c,nhch2ch2nh2),32.0,29.8,29.7,29.7,29.6,29.5,29.4,29.2,26.3,22.7,22.6(28csomesignalswereoverlapped,2och2(ch2)12ch3),28.5((ch3)3c),14.2(2c,2ch2ch2(ch2)11ch3)。

在50.0ml圓底燒瓶中，加入化合物(2-(n-甲基-n¹,n¹-雙十四烷基)乙基)氨基甲酸叔丁酯(4.0g,7.0mmol)，用無(wú)水二氯甲烷(30.0ml)溶解，攪拌作用下，滴加三氟乙酸(15.0ml)常溫下磁力攪拌。tlc(v乙酸乙酯:v甲醇=10:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。用koh(0.1mol/l)溶液調(diào)ph到7.0-8.0,有機(jī)相用無(wú)水na2so4干燥，過(guò)濾，濃縮得淡黃色固體n-甲基-n¹,n¹-雙十四烷基-1,2-二胺(1.6g,50.7%)。

在50.0ml圓底燒瓶中，加入化合物n-甲基-n¹,n¹-雙十四烷基-1,2-二胺(0.4g,0.3mmol)、4-硝基苯碳酸阿比特龍酯(0.3g,0.3mmol)，用四氫呋喃溶解，攪拌作用下，滴加三乙胺(0.2ml)，40^oc下磁力攪拌。tlc(v石油醚:v乙酸乙酯=1:1)監(jiān)測(cè)反應(yīng)至原料點(diǎn)消失。濃縮，經(jīng)柱層析(洗脫劑：v石油醚:v乙酸乙酯=5:1)分離純化得白色固體β-n-甲基-n¹,n¹-二雙十四烷基氨基甲酸阿比特龍酯(0.4g,51.8%)。¹hnmr(500mhz,cdcl3):δ(ppm)8.51-4.78(m,5h,py-h,conhch2),5.98(s,1h,c16-h),5.36(s,1h,c6-h),4.43(s,1h,c1-h),3.64(s,2h,conhch2ch2),3.52(s,2h,conhch2ch2),3.23(s,4h,n(ch2ch2c5h11)2),3.10(s,3h,conhch2ch2nch3),2.30-1.23(m,63h,c2-h,c3-h,c4-h,c7-h,c8-h,c9-h,c11-h,c12-h,c14-h,c15-h,2ch2(ch2)10ch3),1.04(s,3h,c13-ch3),1.02(s,3h,c10-ch3),0.86(t,6h,2ch2(ch2)10ch3,j=6.5hz);¹³cnmr(125mhz,cdcl3):δ(ppm)157.1,151.4,147.5,140.2,134.3,129.7,129.2,123.0,121.9(10c,conhch2ch2,py-c,c17,c16,c5,c6),74.8(1c,c1),62.0(2c,n(ch2)2),60.9(1c,conhch2ch2),57.5,49.0,47.3,45.8,38.4,36.8,36.7,35.2,35.0,31.9,31.8,31.5,30.4,30.1,29.6,29.4,29.3,29.3,29.0,27.9,26.1,22.6,22.1,21.0,20.8,(38c,somesignalswereoverlapped,conhch2ch2,conhch2ch2nch3,c2,c3,c4,c7,c8,c9,c10,c11,c12,c13,c14,c15,2ch2(ch2)12ch3),19.2(1c,c10-ch3),16.5(1c,c13-ch3),14.1(2c,2ch2(ch2)12ch3)。