侯大龍,曹穎迪,王恩思

(吉林大學(xué) 藥學(xué)院,長(zhǎng)春 130021)

?

研究簡(jiǎn)報(bào)

地拉韋啶的合成及晶體結(jié)構(gòu)

侯大龍,曹穎迪,王恩思

(吉林大學(xué) 藥學(xué)院,長(zhǎng)春 130021)

以煙酰胺、對(duì)硝基苯肼和丙酮酸乙酯等為原料合成目標(biāo)化合物地拉韋啶(C23H32N6O4S),并用核磁共振氫譜(1H NMR)和核磁共振碳譜(13C NMR)表征其結(jié)構(gòu),通過(guò)X射線單晶衍射確定其晶體結(jié)構(gòu).實(shí)驗(yàn)結(jié)果表明:該晶體屬于正交晶系,P212121空間群;晶體學(xué)數(shù)據(jù)為：a=1.096 9(4)nm,b=1.152 5(4)nm,c=1.951 0(7)nm,α=90°,β= 90°,γ=90°,V=2.468 5(15)nm3,Mr=488.61,Z=4,Dc=1.315 g/cm3,λ=0.071 073 nm,μ=0.172 mm-1,F(000)=1 040,R=0.040 7,wR=0.090 5;共收集14 875個(gè)衍射點(diǎn),其中4 851個(gè)為獨(dú)立衍射點(diǎn)(Rint=0.040 7),在I>2σ(I)時(shí)可觀察到4 099個(gè)衍射點(diǎn).

抗艾滋病藥物；地拉韋啶；晶體結(jié)構(gòu)

甲磺酸地拉韋啶的化學(xué)名稱為1-[3-[(1-甲基乙基)氨基]-2-吡啶]-4-[[5-[(甲磺?；?氨基]-1-氫-2-吲哚]羰基]哌嗪?jiǎn)渭谆撬猁}[1],為多晶型固體藥物,共有14種晶型[2-3],是用于治療艾滋病(HIV)感染的NNRTⅠ類藥物[4].文獻(xiàn)[5]以煙酰胺為原料合成了關(guān)鍵中間體2-(1-哌嗪基)-3-[(1-甲基乙基)氨基]吡啶(Ⅱ),以對(duì)硝基苯肼和丙酮酸乙酯為原料合成了關(guān)鍵中間體5-硝基吲哚-2-羧酸(Ⅲ),在草酰氯作用下,由Ⅲ生產(chǎn)酰氯,并與中間體Ⅱ縮合得到地拉韋啶.本文采用該方法合成地拉韋啶,并進(jìn)行X射線單晶衍射實(shí)驗(yàn),獲得了地拉韋啶的單晶結(jié)構(gòu)及參數(shù).

1 儀器與試劑

用UNITY-600型(美國(guó)Varian公司)核磁共振儀測(cè)定樣品的核磁共振氫譜(1H NMR)和核磁共振碳譜(13C NMR),TMS為內(nèi)標(biāo);用Vario EL型元素分析儀(德國(guó)Elementar公司)進(jìn)行元素分析;用電噴霧質(zhì)譜儀(美國(guó)LCQ公司)測(cè)定樣品的質(zhì)譜;用AXS D8型高分辨率單晶衍射儀(德國(guó)Bruker公司)測(cè)試樣品的單晶結(jié)構(gòu).試劑和溶劑均為國(guó)產(chǎn)分析純.

2 實(shí) 驗(yàn)

2.1 化合物的合成 地拉韋啶(3)和甲磺酸地拉韋啶(4)的合成路線如圖1所示.

圖1 地拉韋啶和甲磺酸地拉韋啶的合成路線Fig.1 Synthesis route of delavirdine and methylsulfonic acid-delavirdine

參照文獻(xiàn)[6]方法,先將1.0 g(3.9 mmol)化合物1、6 mL四氫呋喃(THF)、0.7 g(4.3 mmol)N,N′-羰基二咪唑(CDI)和1.0 g(4.7 mmol)化合物2進(jìn)行合成反應(yīng),得粗產(chǎn)品1.6 g,再用二甲基亞砜重結(jié)晶得1.3 g白色固體化合物3,收率70%,m.p.223～225 ℃.1H NMR(600 MHz,CDCl3),δ：1.18(d,J=6.6 Hz,6H,2×CH3),2.87(s,3H,CH3),3.02(brs,4H,2×CH2),3.60～3.61(m,1H,CH),3.94(brs,4H,2×CH2),4.48(d,J=7.8 Hz,1H,NH),6.84(s,1H,吲哚—H),6.92～6.93(m,1H,吡啶—H),7.11(dd,J=9.0 Hz,2.4 Hz,1H,吲哚—H),7.38(d,J=9.0 Hz,1H,吲哚—H),7.48(s,1H,吲哚—H),7.56 (m,1H,吡啶—H),9.35(s,1H,SO2—NH),11.64(s,吲哚—NH);13C NMR(150 MHz,DMSO-d6),δ:22.1,22.1,38.3,39.9,42.7,44.3,48.6,103.6,112.1,114.2,116.4,119.3,119.6,126.8,130.2,130.8,130.0,133.5,133.9,135.7,149.5,161.8.

2.2 單晶培養(yǎng) 將10.0 g化合物3溶解于50.0 mL甲醇中,加熱至45 ℃,攪拌,加入10.0 mL二氯甲烷至完全溶解,趁熱過(guò)濾,待濾液自然冷卻至室溫后,取0.5 mL濾液,加入0.25 mL丙酮,將溶液置于1 mL封口的青霉素瓶中,開(kāi)小孔靜置析晶,7 d后得到白色針狀晶體.

將10.0 g化合物4溶解于50.0 mL甲醇中,加熱至45 ℃,攪拌至完全溶解,趁熱過(guò)濾,待濾液冷卻至室溫后,取0.5 mL濾液,加入0.25 mL丙酮,將該混合液置于1 mL封口的青霉素瓶中,開(kāi)小孔靜置析晶,7 d后得到白色針狀晶體.該晶體為甲醇溶劑化地拉韋啶晶體,未得到甲磺酸地拉韋啶晶體.

2.3 結(jié)構(gòu)測(cè)定 選擇白色晶體3(0.25 mm×0.14 mm×0.11 mm)進(jìn)行X射線單晶衍射實(shí)驗(yàn).在單晶衍射儀上用經(jīng)石墨單色器單色化的MoKα射線(λ=0.071 073 nm),在2.56°≤θ≤23.51°(-13≤h≤8,-14≤k≤14,-23≤l≤24)內(nèi)以ω/2θ模式掃描,在185(2)K溫度下共收集14 875個(gè)衍射點(diǎn),其中4 851個(gè)為獨(dú)立衍射點(diǎn)(Rint=0.040 7),對(duì)4 099個(gè)可觀測(cè)衍射點(diǎn)(I>2σ(I))進(jìn)行結(jié)構(gòu)測(cè)定和修正.晶體結(jié)構(gòu)經(jīng)直接法解析,各參數(shù)經(jīng)全矩陣最小二乘法修正至收斂,所有計(jì)算均用SHELXL-97[8]程序完成,可得:R=0.040 7,wR=0.090 5(w=1/[σ2(Fo2)+(0.050 5P)2+0.226 1P]；P=(Fo2+2Fc2)/3),S=1.010,(Δ/σ)max=0,(Δρ)max=366 e/nm3,(Δρ)min=-323 e/nm3.

選擇白色晶體4(0.35 mm×0.19 mm×0.21 mm)進(jìn)行X射線單晶衍射實(shí)驗(yàn).在單晶衍射儀上用經(jīng)石墨單色器單色化的MoKα射線(λ=0.071 073 nm),在2.57°≤θ≤23.52°(-13≤h≤13,-14≤k≤13,-21≤l≤24)內(nèi)以ω/2θ模式掃描,在185(2)K溫度下共收集14 889個(gè)衍射點(diǎn),其中4 852個(gè)為獨(dú)立衍射點(diǎn)為(Rint=0.055 5),對(duì)3 630個(gè)可觀測(cè)衍射點(diǎn)(I>2σ(I))進(jìn)行結(jié)構(gòu)測(cè)定和修正.晶體結(jié)構(gòu)經(jīng)直接法解析,各參數(shù)經(jīng)全矩陣最小二乘法修正至收斂,所有計(jì)算均用SHELXL-97[8]程序完成,可得:R=0.048 1,wR=0.091 1(w=1/[σ2(Fo2)+(0.045 5P)2];P=(Fo2+2Fc2)/3),S=1.004,(Δ/σ)max=0,(Δρ)max=286 e/nm3,(Δρ)min=-272 e/nm3.

3 結(jié)果與討論

3.1 化合物3的晶體結(jié)構(gòu) 化合物3單晶的部分鍵長(zhǎng)與鍵角分別列于表1和表2.由于P-π共軛效應(yīng),因此2N—4C鍵(0.138 0(3)nm),3N—5C鍵(0.142 3(3)nm)、4N—13C鍵(0.135 3(3)nm),6N—18C鍵(0.144 8(3)nm)、5N—14C鍵(0.138 0(3)nm)和5N—21C鍵(0.136 7(3)nm)均短于典型的C—N鍵(0.147 nm)和正常的2N—6C鍵(0.146 5(2)nm)、3N—9C鍵(0.146 0(3)nm)、3N—11C鍵(0.148 4(3)nm)、4N—10C鍵(0.147 1(3)nm)及4N—12C鍵(0.147 2(23)nm).1O—13C的鍵長(zhǎng)為0.123 2(3)nm,是雙鍵.1O—13C—4N和1O—13C—14C的鍵角分別為122.7(2)°,118.2(2)°.化合物3的晶體結(jié)構(gòu)如圖2所示,其氫鍵的鍵長(zhǎng)和鍵角列于表3,非氫原子坐標(biāo)和熱參數(shù)列于表4,分子晶胞結(jié)構(gòu)如圖3所示.

表1 化合物3的部分鍵長(zhǎng)Table 1 Selected bond lengths of compound 3

表2 化合物3的部分鍵角Table 2 Selected bond angles of compound 3

圖2 地拉韋啶分子和溶劑化的甲醇分子晶體結(jié)構(gòu)Fig.2 Crystal structure of solvated methanol and delavirdine

圖3 地拉韋啶分子和溶劑化的甲醇分子晶胞結(jié)構(gòu)Fig.3 Packing diagram of solvated methanol and delavirdine

表3 化合物3氫鍵的鍵長(zhǎng)和鍵角Table 3 Hydrogen bond lengths and bond angle of compound 3

3.2 化合物4的晶體結(jié)構(gòu) 將化合物4的單晶進(jìn)行X射線衍射實(shí)驗(yàn),結(jié)果表明,單晶為甲醇溶劑化的地拉韋啶單晶,未得到甲磺酸地拉韋啶單晶.這可能是由于甲磺酸地拉韋啶為強(qiáng)酸弱堿鹽,當(dāng)甲醇為溶劑時(shí),甲磺酸易于分離所致.

表4 化合物3的非氫原子坐標(biāo)(×104 nm2)和熱參數(shù)Ueq(×10 nm2)Table 4 Atomic coordinates (×104 nm2)and the equivalent thermal parameters Ueq(×10 nm2)of compound 3

[1] Palmer J R,Romero D L,Aristoff P A,et al.Diaromatic Substituted Compounds as Anti HIV-1 Agents：US,005563142A [P].1996-10-08.

[2] Bergren M S,Chao R S,Meulman P A,et al.Solid Phase of Delavirdine Mesylate [J].J Pharm Sci,1996,85(8):834-841.

[3] Havens J L,Smith D P,Bergren M S,et al.Crystal Forms of 1-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl] Pioerazine:US,6452007B1 [P].2002-09-17.

[4] 周婷,謝藍(lán).HIV非核苷類逆轉(zhuǎn)錄酶抑制劑研究進(jìn)展 [J].藥學(xué)學(xué)報(bào),2004,39(8):666-672.(ZHOU Ting,XIE Lan.Progress in HIV Non-nucleoside Reverse Transcriptase Inhibitors NNRTls [J].Acta Pharmaceutica Sinica,2004,39(8):666-672.)

[5] 寧兆倫,燕方龍,賀麗鵬,等.新型抗艾滋病藥物地拉韋啶的合成 [J].吉林大學(xué)學(xué)報(bào):理學(xué)版,2006,44(1):118-122.(NING Zhaolun,YAN Fanglong,HE Lipeng,et al.Synthesis of a New Anti-Aids Drug Delavirdine Mesylate [J].Journal of Jilin University:Science Edition,2006,44(1):118-122.)[6] Perrault W R,Shephard K P,LaPean L A,et al.Production Scale Synthesis of the Non-nucleoside Reverse Transcriptase Inhibitor Atevirdine Mesylate [J].Organic Process Research &Development,1997,1(2):106-116.

[7] Romero D L,Morge R A,Biles C,et al.Discovery Synthesis and Bioactivity of Bis(heteroaryl)Piperazinesl.A Novel Class of Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors [J].J Med Chem,1994,37(7):999-1014.

[8] Sheldrick G M.SHELXS 97.Program for the Solution of Crystal Structure [CP].G?ttingen,Germany:University of G?ttingen,1997.

(責(zé)任編輯：?jiǎn)?凝)

SynthesisandCrystalStructureofDelavirdine

HOU Dalong,CAO Yingdi,WANG Ensi

(CollegeofPharmacy,JilinUniversity,Changchun130021,China)

The title compound delavirdine (C23H32N6O4S)has been synthesized from nicotinamide,4-nitrophenylhydrazine and ethyl pyruvate.It was characterized by means of1H NMR and13C NMR.Its crystal and molecular structures were determined by X-ray diffractometry.It belongs to the orthorhombic system,with space groupP212121witha=1.096 9(4)nm,b=1.152 5(4)nm,c=1.951 0(7)nm,α=90°,β=90°,γ=90°,V=2.468 5(15)nm3,Mr=488.61,Z=4,Dc=1.315 g/cm3,λ=0.071 073 nm,μ=0.172 mm-1,F(000)=1 040,the finalR=0.040 7 andwR=0.090 5.A total of 14 875 reflections were collected,of which 4 851 were independent (Rint=0.040 7)and 4 099 were observed withI>2σ(I).

anti-HIV-1 drug；delavirdine；crystal structure

10.13413/j.cnki.jdxblxb.2015.03.40

2014-08-27.

侯大龍(1989—),男,漢族,碩士研究生,從事藥物化學(xué)的研究,E-mail:h812616318@126.com.通信作者：王恩思(1955—),男,漢族,博士,教授,博士生導(dǎo)師,從事天然藥物合成及綠色化學(xué)的研究,E-mail:wangss@jlu.edu.cn.

O613

：A

：1671-5489(2015)03-0568-04