CN109369720A - 一种合成替诺福韦类似物的方法 - Google Patents
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical class OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 34
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- 125000002015 acyclic group Chemical group 0.000 claims abstract description 12
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- 238000006366 phosphorylation reaction Methods 0.000 claims abstract description 10
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- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 8
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种合成替诺福韦类似物的方法,属于医药中间体合成技术领域。采用α‑嘌呤取代羧酸1和醇2为原料,加入溶剂、碱、酸酐,以手性(S)‑BTM为催化剂,反应后得到手性非环嘌呤核苷3,反应的对映选择性好,收率中等至优秀。手性非环嘌呤核苷3在硼氢化钠条件下还原得到手性单醇非环嘌呤核苷4,接着磷酸化反应生成替诺福韦类似物5。本发明原料易得,操作简单,为替诺福韦(Tenofovir)类似物的合成提供了一种新途径。
Description
技术领域
本发明涉及一种合成替诺福韦(Tenofovir)类似物的方法,属于医药中间体合成技术领域。
背景技术
手性非环核苷和其磷酸酯因其重要的抗病毒活性而受到越来越多的关注,比如替诺福韦是一种新型核苷酸类逆转录酶抑制剂,可有效对抗多种病毒,用于治疗病毒感染性疾病。同时替诺福韦Tenofovir前体磷酸化药物Tenofovir alafenamide2016年获FDA批准用于治疗乙肝病毒感染具有显著疗效。因此,开发一种合成替诺福韦(Tenofovir)类似物的方法具有较大的应用前景和意义。
传统合成替诺福韦的方法主要有以下两种。一种是以腺嘌呤及其衍生物为原料,用NaH或n-BuLi去质子后,加入TfOCH2P(O)(OEt)2或MsOCH2P(O)(OEt)2进行磷酸化得到替诺福韦的磷酸酯,然后加入三甲基溴硅烷,用乙腈作溶剂, 50o回流得到替诺福韦。另一种是以6-氯嘌呤取代的丙烯酸乙酯为原料,在金属铑的作用下,催化加氢得到6-氯嘌呤取代的丙酸乙酯,接着用硼氢化钠在甲醇溶剂中发生还原反应得到相应的醇,随后用NaH去质子后,加入 TfOCH2P(O)(OEt)2进行磷酸化得到相应的磷酸酯,最后进行氨化反应制得替诺福韦类似物。
以上方法中,腺嘌呤衍生物中间体的合成成本较高并且过程复杂。因此选用廉价易得的羧酸为原料来制备替诺福韦类似物的方法,具有很好的价值。
发明内容
为了克服上述缺陷,本发明采用α-嘌呤取代的羧酸1和醇2为原料,在手性催化剂作用下,反应后得到手性非环嘌呤核苷3。手性非环嘌呤核苷3在硼氢化钠条件下还原得到手性单醇非环嘌呤核苷4,接着磷酸化反应生成替诺福韦类似物5。为合成替诺福韦类似物提供了一种简便、廉价、高效的途径。
一种合成替诺福韦类似物的方法,其特征在于:包括如下操作:以α-嘌呤取代羧酸1和醇2为原料,加入溶剂、碱、酸酐,在手性催化剂存在下,反应后得到手性非环嘌呤核苷3,接着还原反应生成非环嘌呤核苷4,随后磷酸化反应得到替诺福韦类似物5。反应方程式如下:
其中:R1选自:二甲氨基、二乙胺基、二丙氨基、氨基、吡咯、哌啶、吗啉、甲氧基、乙氧基、苄氧基、丙硫基、Ph或Cl;R2选自:甲基、乙基、正丙基、异丙基或正丁基;R3选自:氨基或Cl;R选自:(1-Np)2CH、异丙基、 Ph2CH或Ph。
进一步地,在上述技术方案中,所述手性催化剂选自手性氮杂卡宾、手性 4-氨基吡啶、(S)-BTM或(R)-HBTM。催化剂分别对应具体结构如下:
进一步地,在上述技术方案中,第一步中,酸酐选自特戊酸酐、苯甲酸酐、乙酸酐或Boc酸酐。
进一步地,在上述技术方案中,第一步中,溶剂选自二氯甲烷、甲苯、乙腈或N,N-二甲基甲酰胺。
进一步地,在上述技术方案中,第一步中,碱选自二异丙基乙基胺、碳酸氢钠、三乙胺或三乙烯二胺(简称DABCO)。
进一步地,在上述技术方案中,第一步反应温度选自为-20℃至40℃。
进一步地,在上述技术方案中,第一步催化剂用量选自2%-5%。
进一步地,在上述技术方案中,第二步还原反应采用硼氢化钠或四氢铝锂还原剂在甲醇溶剂中进行。
进一步地,在上述技术方案中,第三步磷酸化反应采用NaH或n-BuLi去质子后,接着与TfOCH2P(O)(OEt)2或MsOCH2P(O)(OEt)2进行反应。
发明有益效果:
本发明反应原料易得,产物立体选择性高,反应后得到手性非环核苷类化合物3,收率中等至优秀。手性非环嘌呤核苷3在硼氢化钠条件下还原得到手性单醇非环嘌呤核苷4,接着磷酸化反应得到替诺福韦类似物5,为替诺福韦 (Tenofovir)类似物的合成提供了一种新途径。
具体实施方式
实施例1
aUnless otherwise noted,1a(0.1mmol),2a(0.12mmol),and catalyst(2mol%)were added in a test tube.Then,Piv2O(0.36mmol),i-Pr2NEt(0.48mmol)and solvent(1mL)were added and the reaction was performed for 4days.NR=No Reaction.bIsolated yield based on 1a.cDetermined by chiral HPLC analysis.dC3(5mol%),DMF(1mL),4days.
在反应条件的筛选过程中,首先考察了不同手性催化剂对反应的影响(entries1-4),最终确定了C3为最佳催化剂。同时考虑溶剂、温度和催化剂用量对反应的影响,最终选用DMF做溶剂,反应温度为15℃,催化剂用量为5mol%。
反应条件的考察(以entry 13为例):
在反应管内,将特戊酸酐(73μL,0.36mmol,3.6equiv),N,N-二异丙基乙基胺(79μL,0.48mmol,4.8equiv)依次加入到溶有6-二乙胺基嘌呤取代的丙酸1a (26.3mg,0.1mmol)的DMF(1mL)溶剂中,将反应管置于15℃的油浴中。然后将手性催化剂C3(1.3mg,5mol%)和二萘-1-甲醇2a(34.1mg,0.12mmol,1.2 equiv)依次加入到反应液中,15℃下搅拌4天。通过TLC检测,终止反应后,用水/乙酸乙酯(1:3)萃取。合并有机相,用无水硫酸钠干燥有机相并真空浓缩。然后通过柱层析获得目标化合物3aa收率93%,96%ee。
在其它条件固定的情况下,仅考察不同碱对反应的影响,反应方程式如下:
aUnless otherwise noted,1a(0.1mmol),2a(0.12mmol),and C3(5mol%)wereadded in a test tube.Then,Piv2O(0.36mmol),base(0.48mmol)and DMF(1mL) wereadded and the reaction was performed for 4days.NR=No Reaction.bIsolatedyield based on 1a.cDetermined by chiral HPLC analysis.
实施例2:
在反应管内,将特戊酸酐(73μL,0.36mmol,3.6equiv),N,N-二异丙基乙基胺(79μL,0.48mmol,4.8equiv)依次加入到溶有6-氨基嘌呤取代的丙酸1d(20.7 mg,0.1mmol)的DMF(2mL)溶剂中,将反应管置于-20℃的低温泵中。然后将手性催化剂C3(1.3mg,5mol%)和二萘-1-甲醇2a(34.1mg,0.12mmol,1.2equiv)依次加入到反应液中,-20℃下搅拌8天。通过TLC检测,终止反应后,用水/乙酸乙酯(1:3)萃取。合并有机相,用无水硫酸钠干燥有机相并真空浓缩。然后通过柱层析获得目标化合物3da收率68%,95%ee。
3da White solid;32.2mg,68%yield,95%ee.HPLC CHIRALCEL IE,n-hexane/2-propanol=40/60,flow rate=1.0mL/min,λ=256nm,retention time:10.717min(minor),12.400min(major).m.p.:165.8-166.6℃.[α]D 25.0=4.6(c=0.20,CH2Cl2). TLC:Rf=0.26(dichloro methane:methanol=20:1).1H NMR(600MHz,CD3OD)δ=8.35(s,1H),8.28(s,1H),8.06(s,1H),7.92-7.79(m,7H),7.50-7.31(m,7H), 7.26-7.22(m,2H),5.58(q,J=7.2Hz,1H),1.91(d,J=7.2Hz,3H).13C NMR(150 MHz,CDCl3)δ=169.5,155.2,152.4,150.0,139.3,134.0,133.94,133.92,133.7, 131.1,131.0,129.63,129.58,129.2,129.1,127.0,126.9,126.17,126.15,126.10, 126.09,125.32,125.28,123.3,123.2,119.3,73.4,52.3,18.0.HRMS:exact mass calcd for C29H24N5O2(M+H)+requires m/z474.1925,found m/z 474.1922.
实施例3:
在反应管内,将特戊酸酐(73μL,0.36mmol,3.6equiv),N,N-二异丙基乙基胺(79μL,0.48mmol,4.8equiv)依次加入到溶有6-吡咯烷基嘌呤取代的丙酸1e (26.1mg,0.1mmol)的DMF(1mL)溶剂中,将反应管置于15℃的油浴中。然后将手性催化剂C3(1.3mg,5mol%)和二萘-1-甲醇2a(34.1mg,0.12mmol,1.2 equiv)依次加入到反应液中,15℃下搅拌4天。通过TLC检测,终止反应后,用水/乙酸乙酯(1:3)萃取。合并有机相,用无水硫酸钠干燥有机相并真空浓缩。然后通过柱层析获得目标化合物3ea收率69%,95%ee。
实施例4:
在反应管内,将特戊酸酐(73μL,0.36mmol,3.6equiv),N,N-二异丙基乙基胺(79μL,0.48mmol,4.8equiv)依次加入到溶有6-吗啉基嘌呤取代的丙酸1h (27.7mg,0.1mmol)的DMF(1mL)溶剂中,将反应管置于15℃的油浴中。然后将手性催化剂C3(1.3mg,5mol%)和二萘-1-甲醇2a(34.1mg,0.12mmol,1.2 equiv)依次加入到反应液中,15℃下搅拌4天。通过TLC检测,终止反应后,用水/乙酸乙酯(1:3)萃取。合并有机相,用无水硫酸钠干燥有机相并真空浓缩。然后通过柱层析获得目标化合物3ha,收率72%,95%ee。
3ha White solid;39.1mg,72%yield,95%ee.HPLC CHIRALCEL IE,n-hexane/2-propanol=70/30,flow rate=0.8mL/min,λ=256nm,retention time:27.267min(minor),28.537min(major).m.p.:97.1-97.3℃.[α]D 25.0=-4.8(c=0.46,CH2Cl2). TLC:Rf=0.35(petroleum:ethyl acetate=1:1).1H NMR(400MHz,CDCl3)δ= 8.42(s,1H),8.30(s,1H),7.99-7.81(m,7H),7.53-7.28(m,8H),5.55(q,J=7.6Hz, 1H),4.29(s,4H),3.83(t,J=4.8Hz,4H),1.86(d,J=7.6Hz,3H).13C NMR(100 MHz,CDCl3)δ=169.8,154.0,152.5,151.0,137.0,134.1,134.01,133.95,133.8, 131.1,131.0,129.6,129.5,129.14,129.05,126.92,126.90,126.2,126.11,126.05, 125.32,125.28,123.34,123.25,119.8,73.3,67.2,52.1,45.7,17.9.HRMS:exact mass calcd for C33H29N5O3Na(M+Na)+requiresm/z 566.2163,found m/z 566.2160.
实施例5:
在反应管内,将特戊酸酐(73μL,0.36mmol,3.6equiv),N,N-二异丙基乙基胺(79μL,0.48mmol,4.8equiv)依次加入到溶有6-甲氧基嘌呤取代的丙酸1i(22.2 mg,0.1mmol)的DMF(2mL)溶剂中,将反应管置于0℃的低温泵中。然后将手性催化剂C3(1.3mg,5mol%)和二萘-1-甲醇2a(34.1mg,0.12mmol,1.2equiv) 依次加入到反应液中,0℃下搅拌8天。通过TLC检测,终止反应后,用水/乙酸乙酯(1:3)萃取。合并有机相,用无水硫酸钠干燥有机相并真空浓缩。然后通过柱层析获得目标化合物3ia收率73%,92%ee。
实施例6:
在反应管内,将特戊酸酐(73μL,0.36mmol,3.6equiv),N,N-二异丙基乙基胺(79μL,0.48mmol,4.8equiv)依次加入到溶有6-丙硫基嘌呤取代的丙酸1l(26.6 mg,0.1mmol)的DMF(2mL)溶剂中,将反应管置于0℃的低温泵中。然后将手性催化剂C3(1.3mg,5mol%)和二萘-1-甲醇2a(34.1mg,0.12mmol,1.2equiv) 依次加入到反应液中,0℃下搅拌8天。通过TLC检测,终止反应后,用水/乙酸乙酯(1:3)萃取。合并有机相,用无水硫酸钠干燥有机相并真空浓缩。然后通过柱层析获得目标化合物3la收率87%,82%ee。
3la White solid;46.3mg,87%yield,82%ee.HPLC CHIRALCEL OD-H,n-hexane/2-propanol=70/30,flow rate=0.6mL/min,λ=256nm,retention time:15.057min(major),20.393min(minor).m.p.:130.8-131.7℃.[α]D 25.0=-10.1(c= 1.11,CH2Cl2).TLC:Rf=0.36(petroleum:ethyl acetate=2:1)[UV].1H NMR(400 MHz,CDCl3)δ=8.60(s,1H),8.43(s,1H),8.06(s,1H),7.94-7.82(m,6H),7.52- 7.27(m,8H),5.54(q,J=7.2Hz,1H),3.37(t,J=7.2Hz,2H),1.90-1.81(m,5H), 1.09(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3):169.3,161.8,152.0,148.3, 141.0,134.00,133.95,133.9,133.6,131.2,131.03,130.97,129.63,129.61,129.2, 129.1,127.0,126.2,126.1,125.30,125.27,123.2,73.5,52.4,30.8,23.0,17.9,13.6. HRMS:exact mass calcd forC32H29N4O2S(M+H)+requires m/z 533.2006,found m/z 533.2002.
实施例7:
在反应管内,将特戊酸酐(73μL,0.36mmol,3.6equiv),N,N-二异丙基乙基胺(79μL,0.48mmol,4.8equiv)依次加入到溶有6-氯嘌呤取代的丙酸1n(22.6mg, 0.1mmol)的DMF(2mL)溶剂中,将反应管置于-20℃的低温泵中。然后将手性催化剂C3(1.3mg,5mol%)和二萘-1-甲醇2a(34.1mg,0.12mmol,1.2equiv)依次加入到反应液中,-20℃下搅拌8天。通过TLC检测,终止反应后,用水/乙酸乙酯(1:3)萃取。合并有机相,用无水硫酸钠干燥有机相并真空浓缩。然后通过柱层析获得目标化合物3na收率77%,89%ee。
实施例8:
在反应管内,将特戊酸酐(73μL,0.36mmol,3.6equiv),N,N-二异丙基乙基胺(79μL,0.48mmol,4.8equiv)依次加入到溶有6-二甲胺基-2-氯嘌呤取代的丙酸 1q(26.9mg,0.1mmol)的DMF(1mL)溶剂中,将反应管置于15℃的油浴中。然后将手性催化剂C3(1.3mg,5mol%)和二萘-1-甲醇2a(34.1mg,0.12mmol,1.2 equiv)依次加入到反应液中,15℃下搅拌4天。通过TLC检测,终止反应后,用水/乙酸乙酯(1:3)萃取。合并有机相,用无水硫酸钠干燥有机相并真空浓缩。然后通过柱层析获得目标化合物3qa收率84%,98%ee。
3qa White solid;45.0mg,84%yield,98%ee.HPLC CHIRALCEL ID,n-hexane/2-propanol=40/60,flow rate=1.0mL/min,λ=256nm,retention time:11.185min(minor),16.337min(major).m.p.:173.7-174.1℃.[α]D 25.0=-46.8(c=0.51,CH2Cl2).TLC:Rf=0.29(petroleum:ethyl acetate=1:1).1H NMR(400MHz,CDCl3)δ=8.40 (s,1H),7.98-7.82(m,7H),7.54-7.38(m,7H),7.34-7.29(m,1H),5.52(q,J=7.6 Hz,1H),3.80-3.10(m,6H),1.82(d,J=7.6Hz,3H).13C NMR(150MHz,CDCl3)δ=169.8,155.3,154.0,151.8,136.9,134.04,134.02,133.9,133.7,131.1,131.0,129.6, 129.5,129.2,129.1,127.00,126.95,126.3,126.12,126.09,126.06,125.43,125.41, 123.3,123.2,118.8,73.4,52.0,39.5,38.1,18.0.HRMS:exact mass calcd for C31H26ClN5O2Na(M+Na)+requires m/z 558.1667,found m/z 558.1669.
实施例9:
在反应管内,将特戊酸酐(73μL,0.36mmol,3.6equiv),N,N-二异丙基乙基胺(79μL,0.48mmol,4.8equiv)依次加入到溶有6-二乙胺基嘌呤取代的异戊酸1s (29.1mg,0.1mmol)的DMF(1mL)溶剂中,将反应管置于15℃的油浴中。然后将手性催化剂C3(1.3mg,5mol%)和二萘-1-甲醇2a(34.1mg,0.12mmol,1.2 equiv)依次加入到反应液中,15℃下搅拌4天。通过TLC检测,终止反应后,用水/乙酸乙酯(1:3)萃取。合并有机相,用无水硫酸钠干燥有机相并真空浓缩。然后通过柱层析获得目标化合物3sa收率64%,93%ee。
实施例10:
根据实施例2-9中的反应条件,仅仅将反应底物进行改变(除非特别说明)a,得到如下反应结果:
aUnless otherwise noted,reaction conditions were as follows:1(0.1mmol),2a(0.12 mmol),C3(5mol%),Piv2O(0.36mmol)and i-Pr2NEt(0.48mmol)in DMF(1mL) at 15℃for 4days.Isolated yields are reported.The ee values weredetermined by chiral HPLC analysis.bIn DMF(2mL)at-20℃for 8days.cIn DMF(2mL)at0℃ for 8days.
实施例11:
在反应管内,加入手性非环核苷化合物3aa(52.9mg,0.1mmol,96%ee)和 1mL甲醇,将反应置于0℃,然后将溶于1mL甲醇的硼氢化钠(22.7mg,0.6 mmol,6equiv)滴加到反应体系中。通过TLC检测,待反应完全,用饱和氯化铵淬灭反应。然后用二氯甲烷进行萃取,合并有机相,用无水硫酸钠干燥有机相并真空浓缩,柱层析(二氯甲烷/甲醇=20:1)获得目标化合物4aa(收率82%, 95%ee)。反应方程式如下:
4aa Colorless oil;20.4mg,82%yield,95%ee.HPLC CHIRALCEL OD-H,n-hexane/2-propanol=80/20,flow rate=0.6mL/min,λ=256nm,retention time:8.463min(major),11.213min(minor).[α]D 25.0=-22.0(c=0.17,CH2Cl2).TLC:Rf =0.29(二氯甲烷/甲醇=20:1).1H NMR(600MHz,CDCl3)δ=8.26(s,1H),7.74 (s,1H),5.40(s,1H),4.63-4.59(m,1H),4.14-3.84(m,6H),1.60(d,J=7.2Hz, 3H),1.29(t,J=7.2Hz,6H).13C NMR(150MHz,CD3OD)δ=155.0,152.8,151.2, 139.7,120.6,65.2,54.2,44.3,17.0,13.9.HRMS:exact mass calcd for C12H20N5O (M+H)+requires m/z 250.1662,found m/z250.1665.
实施例12:
在反应管内,加入手性非环核苷化合物3da(47.3mg,0.1mmol,95%ee)和 1mL甲醇,将反应置于0℃,然后将溶于1mL甲醇的硼氢化钠(22.7mg,0.6 mmol,6equiv)滴加到反应体系中。通过TLC检测,待反应完全,用饱和氯化铵淬灭反应。然后用二氯甲烷进行萃取,合并有机相,用无水硫酸钠干燥有机相并真空浓缩。最后通过柱层析(二氯甲烷/甲醇=20:1)获得化合物4da(收率78%, 96%ee)。
然后将化合物4da溶于DMF溶液中,将正丁基锂的四氢呋喃溶液(1M)滴加到此溶液中,将反应搅拌5分钟后,将三氟甲磺亚磷酸乙酯的四氢呋喃溶液滴加到反应体系中,室温下搅拌48h。终止反应后,反应液用50%的醋酸淬灭,然后用二氯甲烷萃取三次,合并有机相,用无水硫酸钠干燥有机相并真空浓缩。然后通过柱层析(10%甲醇的氯仿溶液)获得目标化合物5da。反应方程式如下:
4da White solid;15.1mg,78%yield,96%ee.HPLC CHIRALCEL ID,n-hexane/2-propanol=30/70,flow rate=1.0mL/min,λ=256nm,retention time:9.820min(minor),14.285min(major).m.p.:189.4-190.3℃.[α]D 25.0=8.2(c=0.16,CH2Cl2). TLC:Rf=0.31(二氯甲烷/甲醇=10:1).1H NMR(400MHz,DMSO-d6)δ=8.15(s, 1H),8.12(s,1H),7.17(s,2H),5.04(s,1H),4.62-4.56(m,1H),3.83-3.76(m,1H), 3.71-3.65(m,1H),1.48(d,J=6.8Hz,3H).13C NMR(150MHz,DMSO-d6)δ= 155.9,152.0,149.4,139.8,119.0,63.4,52.6,16.7.HRMS:exact mass calcd for C8H12N5O(M+H)+requires m/z 194.1036,foundm/z 194.1037.
5da 1H NMRδ=8.27(s,1H),7.93(s,1H),6.39(br s,2H,exch.with D2O),4.85(m,1H),4.00-3.70(m,8H),1.59(d,J=7.0Hz,3H),1.21(t,J=7.0Hz,6H).13C NMRδ=155.6,152.5,149.6,139.4,119.4,74.8(d,JCP=9.9Hz),65.2(d,JCP=166 Hz),62.3(d,JCP=6.5Hz),50.5,17.0,16.3(d,JCP=5.6Hz).31P NMRδ=20.1. Anal.Calcd forC13H22N5O4P:C,45.48;H,6.46;N,20.39.Found:C,45.23;H,6.40; N,20.19.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明原理的范围下,本发明还会有各种变化和改进,这些变化和改进均落入本发明保护的范围内。
Claims (10)
1.一种合成替诺福韦类似物的方法,经过三步反应完成,反应方程式如下:
其特征在于,包括如下步骤:以α-嘌呤取代羧酸1和醇2为原料,加入溶剂、碱、酸酐,在手性催化剂存在下,反应后得到手性非环嘌呤核苷3,接着还原反应生成非环嘌呤核苷4,随后磷酸化反应得到替诺福韦类似物5。
2.根据权利要求1中一种合成替诺福韦类似物的方法,其特征在于:R1选自:二甲氨基、二乙胺基、二丙氨基、氨基、吡咯、哌啶、吗啉、甲氧基、乙氧基、苄氧基、丙硫基、Ph或Cl;R2选自:甲基、乙基、正丙基、异丙基或正丁基;R3选自:氨基或Cl;R选自:(1-Np)2CH、异丙基、Ph2CH或Ph。
3.根据权利要求1或2中一种合成替诺福韦类似物的方法,其特征在于:所述手性催化剂选自(S)-BTM或(R)-HBTM。
4.根据权利要求1或2中一种合成替诺福韦类似物的方法,其特征在于:所述酸酐选自特戊酸酐、苯甲酸酐、乙酸酐或Boc酸酐。
5.根据权利要求1或2中一种合成替诺福韦类似物的方法,其特征在于:所述溶剂选自二氯甲烷、甲苯、乙腈或N,N-二甲基甲酰胺。
6.根据权利要求1或2中一种合成替诺福韦类似物的方法,其特征在于:所述碱选自:二异丙基乙基胺、碳酸氢钠、三乙胺或三乙烯二胺。
7.根据权利要求1或2中一种合成替诺福韦类似物的方法,其特征在于:反应温度选自-20℃至40℃。
8.根据权利要求1或2中一种合成替诺福韦类似物的方法,其特征在于:催化剂用量选自2%-5%。
9.根据权利要求1或2中一种合成替诺福韦类似物的方法,其特征在于:还原反应采用硼氢化钠或四氢铝锂还原剂在甲醇溶剂中进行。
10.根据权利要求1或2中一种合成替诺福韦类似物的方法,其特征在于:磷酸化反应采用NaH或n-BuLi去质子后,接着与TfOCH2P(O)(OEt)2或MsOCH2P(O)(OEt)2进行反应。
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