CN107474017A - 一种不对称烯丙基化反应合成手性n1‑烯丙基嘧啶的方法 - Google Patents
一种不对称烯丙基化反应合成手性n1‑烯丙基嘧啶的方法 Download PDFInfo
- Publication number
- CN107474017A CN107474017A CN201710756439.0A CN201710756439A CN107474017A CN 107474017 A CN107474017 A CN 107474017A CN 201710756439 A CN201710756439 A CN 201710756439A CN 107474017 A CN107474017 A CN 107474017A
- Authority
- CN
- China
- Prior art keywords
- chiral
- allyl
- pyrimidines
- reaction
- synthesis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
- B01J2531/0266—Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL"
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/822—Rhodium
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Saccharide Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种不对称烯丙基化反应合成手性N1‑烯丙基嘧啶的方法,属于不对称合成领域。以N3‑保护的嘧啶和烯丙基碳酸酯为原料,以[Rh(COD)Cl]2为催化剂,DTBM‑Segphos或DTBM‑MeOBIPHEP为手性配体,反应后得到手性N1‑烯丙基嘧啶,收率中等至优秀。
Description
技术领域
本发明涉及手性非环嘧啶的合成方法,具体涉及一种不对称烯丙基化反应合成手性N1-烯丙基嘧啶的方法,属于有机化学中的不对称合成领域。
背景技术
手性非环嘧啶类化合物具有广泛的生理活性,比如(S)-西多福韦对巨细胞病毒(CMV)、单纯疱疹病毒(HSV)和带状疱疹病毒(VZV)等有很强的抑制活性。其他的手性非环核苷如:(S)-FPMPT、(S)-willardiine、(S)-HPMPA和(R)-Tenofovir具有不同的药物活性。同时,非环核苷的绝对构型对其活性具有非常大的影响。例如:西多福韦S构型的活性要高于R构型;FPMPA的S构型抗HIV病毒活性的IC50值为1.85μM而R构型不具有抗HIV病毒活性。
目前,手性嘧啶核苷的合成方法主要是通过手性诱导的方法,选用嘧啶同手性底物反应构筑手性嘧啶核苷。其特点都需要选用手性的反应底物。通常,手性底物相对难以制备并且成本较高。相对来说,选用低成本的,廉价易得的非手性烯丙基试剂来制备手性N1-烯丙基嘧啶的方法,还尚未有所报道。
发明内容
为了克服上述缺陷,本发明采用嘧啶和消旋的烯丙基碳酸酯为原料,在金属铑和手性双磷配体的共同作用下合成手性N1-烯丙基嘧啶衍生物。该方法为手性非环嘧啶类化合物提供了一种简便、廉价、高效的合成方法。
一种不对称烯丙基化反应合成手性N1-烯丙基嘧啶的方法,其特征在于,包括如下操作:以N3-保护的嘧啶1和消旋的烯丙基碳酸酯2为原料,加入溶剂,在铑催化剂和手性配体存在下,反应得到手性N1-烯丙基嘧啶3。反应方程式如下:
进一步地,在上述技术方案中,R1选自:取代芳烃、链状烷基、环烷基;R2选自:H、CH3、F、Cl、Br、I、CF3;Pg选自:Boc、Bz。
进一步地,在上述技术方案中,所述铑催化剂选自[Rh(COD)Cl]2;所述手性配体选自DTBM-Segphos或DTBM-MeOBIPHEP,每种配体都包括R型和S型两种,配体具体结构如下:
进一步地,在上述技术方案中,所述嘧啶1、烯丙基碳酸酯2、[Rh(COD)Cl]2和手性配体的摩尔比为1:1-2:0.02-0.04:0.02-0.08。
进一步地,在上述技术方案中,反应溶剂选自1,2-二氯乙烷、四氢呋喃、二氯甲烷、氯仿。
进一步地,在上述技术方案中,反应温度选自50℃至100℃。
进一步地,在上述技术方案中,整个反应过程需要惰性气体保护下操作,惰性气体优选氮气。
在上述反应条件下,经过反应纯化后,对于不同的底物分离收率43%-93%。
发明有益效果:
本发明为手性N1-烯丙基嘧啶提供了一种简便、廉价、高效的合成方法,反应原料易得,产物结构丰富,产物立体选择性高,反应后得到手性N1-烯丙基嘧啶3,收率中等至优秀。
具体实施方式
实施例1
a Entry 1,Conditions A:1a(0.2mmol,1.0equiv),cinnamyl carbonate 2b(0.2mmol)[Ir(COD)Cl]2(2mol%)and L1(4mol%),tetrahydrofuran(THF)(0.2mL),K3PO4(1.0equiv.)50℃,N2,12h.b Entries 2-10,Conditions B:1a(0.2mmol,1.0equiv),cinnamyl carbonate 2b(0.2mmol)[Rh(COD)Cl]2(3mol%)and Ligand(6mol%),DCE(0.2M),80℃,N2,12h.c The ratio determined form crude 1H NMR.d Yields ofisolated product.e The ee values were determined by chrial-phase HPLCanalysis.
在反应条件的筛选过程中,首先考察了金属Ir与金属Rh对反应的影响(entries1-2)。同时通过对照不同配体对反应的影响,确定了配体L9和L10为最佳配体。
反应条件的考察:在10mL的真空管中,加入N3-Bz保护的胸腺嘧啶(46.1mg,0.2mmol),[Rh(COD)Cl2](2.9mg,0.006mmol)和(R)-DTBM-Segphos(14.2mg,0.012mmol)。通过氮气置换3次,使得反应管中充满氮气,然后在氮气流下,加入碳酸酯2b,加入1mL的1,2-二氯乙烷。密封反应管,将反应管置于80℃的油浴锅中反应12小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3ab收率85%,ee值98%。
在其它条件固定的情况下,仅考察催化剂和配体的用量对反应的影响,以1a和2b反应生成3ab为例,反应方程式如下:
1%mmol[Rh(COD)Cl2]2%(R)-DTBM-Segphos yield:28%-35%;ee:92%-94%
2%mmol[Rh(COD)Cl2]4%(R)-DTBM-Segphos yield:68%-73%;ee:95%-97%
3%mmol[Rh(COD)Cl2]6%(R)-DTBM-Segphos yield:84%-89%;ee:97%-98%
4%mmol[Rh(COD)Cl2]8%(R)-DTBM-Segphos yield:85%-88%;ee:93%-96%
在其它条件固定的情况下,仅考碳酸酯的用量对反应的影响,以1a和2b反应生成3ab为例,反应方程式如下:
0.2mmol 1a,0.2mmol 2b yield:60%-63%;ee:91-93%
0.2mmol 1a,0.3mmol 2b yield:75%-81%;ee:96-98%
0.2mmol 1a,0.4mmol 2b yield:85%-89%;ee:97-98%
0.2mmol 1a,0.5mmol 2b yield:84%-88%;ee:95-97%
0.2mmol 1a,0.6mmol 2b yield:86%-89%;ee:94-96%
实施例2:
在10mL的真空管中,加入N3-Bz保护的胸腺嘧啶(46.1mg,0.2mmol),[Rh(COD)Cl2](2.9mg,0.006mmol)和(R)-DTBM-Segphos(14.2mg,0.012mmol)。通过氮气置换3次,使得反应管中充满氮气,然后在氮气流下,加入碳酸酯2b(82.4mg,0.4mmol),加入1mL的1,2-二氯乙烷。密封反应管,将反应管置于80℃的油浴锅中反应12小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3ab,收率84%,ee值98%。产物3aa-3ib的制备参照化合物3ab的合成及后处理方法。
实施例3:
在10mL的真空管中,加入5-I-N3-Bz保护的胸腺嘧啶(68.4mg,0.2mmol),[Rh(COD)Cl2](2.9mg,0.006mmol)和(R)-DTBM-Segphos(14.2mg,0.012mmol)。通过氩气置换3次,使得反应管中充满氩气,然后在氮气流下,加入碳酸酯2b(82.4mg,0.4mmol),加入1mL的1,2-二氯乙烷。密封反应管,将反应管置于80℃的油浴锅中反应12小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3cb,收率83%,ee值95%。
代表性化合物表征数据如下:
3cb Light yellow oil.[α]D 27=-115.4°(c=0.92,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol=70/30,flow rate=0.8mL/min,temperature=25℃,λ=254nm,retention time:8.532min,10.263min.1H NMR(600MHz,CDCl3)δ7.87(d,J=7.6Hz,2H),7.64(t,J=7.4Hz,1H),7.57(s,1H),7.48(t,J=7.8Hz,2H),7.32(m,2H),7.29-7.25(m,2H),6.43(d,J=4.7Hz,1H),6.16(m,1H),5.55(d,J=10.4Hz,1H),5.15(d,J=16.8Hz,1H),2.30(s,3H).13C NMR(151MHz,CDCl3)δ167.7,158.9,149.6,146.2,137.4,135.4,133.9,133.8,131.8,131.1,130.5,129.5,129.4,127.7,126.8,120.1,67.7,58.7,19.2.HRMS(ESI):m/z calcd.For C21H17IN2NaO3[M+Na]+495.0176,found m/z 495.0177.
实施例4:
在10mL的真空管中,加入N3-Bz保护的胸腺嘧啶(46.1mg,0.2mmol),[Rh(COD)Cl2](2.9mg,0.006mmol)和(R)-DTBM-MeOBIPHEP(16.0mg,0.012mmol)。通过氮气置换3次,使得反应管中充满氮气,然后在氮气流下,加入碳酸酯2b(82.4mg,0.4mmol),加入1mL的1,2-二氯乙烷。密封反应管,将反应管置于80℃的油浴锅中反应12小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3ab,收率62%,ee值87%。
实施例5:
在10mL的真空管中,加入N3-Bz保护的胸腺嘧啶(46.1mg,0.2mmol),[Rh(COD)Cl2](2.9mg,0.006mmol)和(R)-DTBM-Segphos(14.2mg,0.012mmol)。通过氮气置换3次,使得反应管中充满氮气,然后在氮气流下,加入碳酸酯2b(82.4mg,0.4mmol),加入1mL的二氯甲烷。密封反应管,将反应管置于50℃的油浴锅中反应12小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3ab,收率55%,ee值85%。
实施例6:
在10mL的真空管中,加入5-CF3-N3-Bz保护的胸腺嘧啶(56.8mg,0.2mmol),[Rh(COD)Cl2](1.9mg,0.004mmol)和(R)-DTBM-Segphos(9.5mg,0.008mmol)。通过氮气置换3次,使得反应管中充满氮气,然后在氮气流下,加入碳酸酯2b(82.4mg,0.4mmol),加入1mL的1,2-二氯乙烷。密封反应管,将反应管置于90℃的油浴锅中反应12小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3gb,收率69%,ee值93%。
代表性化合物表征数据如下:
3gb Colorless oil.[α]D 27=-100.9°(c=1.01,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol=70/30,flow rate=0.8mL/min,temperature=25℃,λ=254nm,retention time:6.251min,6.954min.1H NMR(600MHz,CDCl3)δ7.88(d,J=7.7Hz,2H),7.66(m,2H),7.50(t,J=7.4Hz,2H),7.36–7.29(m,2H),7.29–7.23(m,2H),6.49(d,J=4.2Hz,1H),6.21–6.13(m,1H),5.59(d,J=10.2Hz,1H),5.16(d,J=16.8Hz,1H),2.31(s,3H).13CNMR(151MHz,CDCl3)δ167.2,157.4,148.9,142.2,142.1,137.2,135.5,133.3,133.3,131.8,130.9,130.4,129.6,129.4,127.4,126.9,122.5,120.6,105.1,104.9,58.9,19.1.HRMS(ESI):m/z calcd.For C22H17F3N2NaO3[M+Na]+437.1083,found m/z 437.1077.
实施例7:
在10mL的真空管中,加入N3-Bz保护的胸腺嘧啶(46.1mg,0.2mmol),[Rh(COD)Cl2](1.9mg,0.004mmol)和(R)-DTBM-MeOBIPHEP(10.7mg,0.008mmol)。通过氮气置换3次,使得反应管中充满氮气,然后在氮气流下,加入碳酸酯2b(82.4mg,0.4mmol),加入1mL的甲苯。密封反应管,将反应管置于100℃的油浴锅中反应20小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3ab,收率51%,ee值79%。
实施例8:
在10mL的真空管中,加入N3-Bz保护的胸腺嘧啶(46.1mg,0.2mmol),[Rh(COD)Cl2](3.8mg,0.008mmol)和(R)-DTBM-Segphos(18.8mg,0.016mmol)。通过氮气置换3次,使得反应管中充满氮气,然后在氮气流下,加入碳酸酯2a(76.8mg,0.4mmol),加入1mL的1,2-二氯乙烷。密封反应管,将反应管置于80℃的油浴锅中反应4小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3aa,收率71%,ee值85%。
代表性化合物表征数据如下:
3aa Colorless oil.[α]D 27=-79.4°(c=1.65,CH2Cl2).HPLC CHIRALCEL IDH,n-hexane/2-propanol=70/30,flow rate=0.8mL/min,temperature=25℃,λ=254nm,retention time:29.150min,32.663min.1H NMR(600MHz,CDCl3)δ7.91(d,J=7.8Hz,2H),7.63(t,J=7.2Hz,1H),7.48(t,J=7.5Hz,2H),7.43(t,J=7.2Hz,2H),7.41–7.36(m,1H),7.32(d,J=7.8Hz,2H),7.02(s,1H),6.39(d,J=4.2Hz,1H),6.23–6.16(m,1H),5.54(d,J=10.8Hz,1H),5.26(d,J=16.8Hz,1H),1.90(s,3H).13C NMR(151MHz,CDCl3)δ169.1,162.8,150.2,137.5,136.8,135.1,134.1,131.7,130.5,129.3,129.2,128.9,128.2,120.6,111.0,77.2,60.2,12.8.HRMS(ESI):m/z calcd.For C21H18N2NaO3[M+Na]+369.1210,foundm/z 369.1209.
实施例9:
在10mL的真空管中,加入N3-Bz保护的胸腺嘧啶(46.1mg,0.2mmol),[Rh(COD)Cl2](2.9mg,0.006mmol)和(R)-DTBM-MeOBIPHEP(16.0mg,0.012mmol)。通过氮气置换3次,使得反应管中充满氮气,然后在氮气流下,加入碳酸酯2b(82.4mg,0.4mmol),加入1mL的1,2-二氯乙烷。密封反应管,将反应管置于100℃的油浴锅中反应4小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3ab,收率67%,ee值94%。
实施例10:
在10mL的真空管中,加入N3-Bz保护的胸腺嘧啶(46.1mg,0.2mmol),[Rh(COD)Cl2](2.9mg,0.006mmol)和(R)-DTBM-Segphos(14.2mg,0.012mmol)。通过氮气置换3次,使得反应管中充满氮气,然后在氮气流下,加入碳酸酯2d(82.4mg,0.4mmol),加入1mL的氯仿。密封反应管,将反应管置于70℃的油浴锅中反应4小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3ad,收率63%,ee值75%。
代表性化合物表征数据如下:
3ad Light yellow oil.[α]D 27=-127.9°(c=1.46,CH2Cl2).HPLC CHIRALCELIDH,n-hexane/2-propanol=70/30,flow rate=0.8mL/min,temperature=25℃,λ=254nm,retention time:29.607min,34.183min.1H NMR(600MHz,CDCl3)δ7.92(d,J=7.7Hz,2H),7.63(t,J=7.1Hz,1H),7.48(t,J=7.3Hz,2H),7.22(s,4H),7.04(s,1H),6.35(d,J=4.3Hz,1H),6.23–6.14(m,1H),5.51(d,J=10.2Hz,1H),5.25(d,J=16.8Hz,1H),2.37(s,3H),1.89(s,3H).13C NMR(151MHz,CDCl3)δ169.1,162.9,150.2,138.8,137.6,135.1,134.2,133.8,131.8,130.5,130.3,130.0,129.3,128.6,128.2,120.1,110.9,60.0,21.3,12.8.HRMS(ESI):m/z calcd.For C22H20N2NaO3[M+Na]+383.1366,found m/z 383.1364.
实施例11:
在10mL的真空管中,加入N3-Bz保护的胸腺嘧啶(46.1mg,0.2mmol),[Rh(COD)Cl2](0.9mg,0.002mmol)和(R)-DTBM-Segphos(4.8mg,0.004mmol)。通过氮气置换3次,使得反应管中充满氮气,然后在氮气流下,加入碳酸酯2b(82.4mg,0.4mmol),加入1mL的1,2-二氯乙烷。密封反应管,将反应管置于80℃的油浴锅中反应24小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3ab,收率52%,ee值92%。
实施例12:
在10mL的真空管中,加入N3-Bz保护的胸腺嘧啶(46.1mg,0.2mmol),[Rh(COD)Cl2](2.9mg,0.006mmol)和(R)-DTBM-Segphos(14.2mg,0.012mmol)。通过氮气置换3次,使得反应管中充满氦气,然后在氦气流下,加入碳酸酯2b(82.4mg,0.4mmol),加入0.5mL的1,2-二氯乙烷。密封反应管,将反应管置于80℃的油浴锅中反应12小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3ab,收率89%,ee值89%。
实施例13:
在10mL的真空管中,加入N3-Bz保护的胸腺嘧啶(46.1mg,0.2mmol),[Rh(COD)Cl2](2.9mg,0.006mmol)和(R)-DTBM-Segphos(14.2mg,0.012mmol)。通过氮气置换3次,使得反应管中充满氮气,然后在氮气流下,加入碳酸酯2b(41.2mg,0.2mmol),加入1mL的1,2-二氯乙烷。密封反应管,将反应管置于80℃的油浴锅中反应24小时。用TLC跟踪反应,终止反应后,加入乙酸乙酯/水进行萃取,无水硫酸钠干燥有机相,真空浓缩有机相,然后经柱层析获得目标化合物3ab,收率51%,ee值88%。
代表性化合物表征数据如下:
3ab:Light yellow oil.[α]D 27=-131.9°(c=1.78,CH2Cl2).HPLC CHIRALCEL ID,n-hexane/2-propanol=70/30,flow rate=0.8mL/min,temperature=25℃,λ=254nm,retention time:24.178min,27.350min.1H NMR(600MHz,CDCl3)δ7.90(d,J=7.8Hz,2H),7.63(t,J=7.8Hz,1H),7.48(t,J=8.4Hz,2H),7.30–7.26(m,4H),6.97(s,1H),6.45(d,J=4.8Hz,1H),6.17(m,1H),5.51(d,J=10.8Hz,1H),5.14(d,J=15.6,1H),2.30(s,3H),1.88(s,3H).13C NMR(151MHz,CDCl3)δ169.0,162.9,149.9,137.6,137.4,135.1,134.7,134.4,131.8,131.6,130.5,129.3,129.2,128.0,126.6,119.1,110.7,57.8,19.3,12.8.HRMS(ESI):m/z calcd.For C22H20N2NaO3[M+Na]+383.1366,found m/z 383.1371.
根据实施例1中的反应条件,仅仅将反应底物进行改变,得到如下反应结果:
Claims (6)
1.一种不对称烯丙基化反应合成手性N1-烯丙基嘧啶的方法,其特征在于,包括如下步骤:以N3-保护嘧啶1和消旋的烯丙基碳酸酯2为原料,加入溶剂,在铑催化剂和手性配体存在下,反应得到手性N1-烯丙基嘧啶3,反应方程式如下:
R1选自:取代芳烃、链状烷基或环烷基;R2选自:H、CH3、F、Cl、Br、I或CF3;Pg选自:Boc或Bz。
2.根据权利要求1中一种不对称烯丙基化反应合成手性N1-烯丙基嘧啶的方法,其特征在于:所述铑催化剂选自[Rh(COD)Cl]2;所述手性配体选自DTBM-Segphos或DTBM-MeOBIPHEP。
3.根据权利要求1中一种不对称烯丙基化反应合成手性N1-烯丙基嘧啶的方法,其特征在于:反应溶剂选自1,2-二氯乙烷、四氢呋喃、二氯甲烷或氯仿。
4.根据权利要求1中一种不对称烯丙基化反应合成手性N1-烯丙基嘧啶的方法,其特征在于:所述嘧啶1、烯丙基碳酸酯2、[Rh(COD)Cl]2和手性配体的摩尔比为1:1-2:0.02-0.04:0.04-0.08。
5.根据权利要求1中一种不对称烯丙基化化反应合成手性N1-烯丙基嘧啶的方法,其特征在于:反应温度选自50-100℃。
6.根据权利要求1中一种不对称烯丙基化反应合成手性N1-烯丙基嘧啶的方法,其特征在于:整个反应过程需要在惰性气体保护下操作。。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710756439.0A CN107474017B (zh) | 2017-08-29 | 2017-08-29 | 一种不对称烯丙基化反应合成手性n1-烯丙基嘧啶的方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710756439.0A CN107474017B (zh) | 2017-08-29 | 2017-08-29 | 一种不对称烯丙基化反应合成手性n1-烯丙基嘧啶的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107474017A true CN107474017A (zh) | 2017-12-15 |
CN107474017B CN107474017B (zh) | 2020-07-10 |
Family
ID=60603027
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710756439.0A Active CN107474017B (zh) | 2017-08-29 | 2017-08-29 | 一种不对称烯丙基化反应合成手性n1-烯丙基嘧啶的方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107474017B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112759595A (zh) * | 2021-03-05 | 2021-05-07 | 河南师范大学 | 不对称烯丙基化反应合成手性非环核苷的方法 |
-
2017
- 2017-08-29 CN CN201710756439.0A patent/CN107474017B/zh active Active
Non-Patent Citations (2)
Title |
---|
CHANGKUN LI ET AL.: "Rhodium-Catalyzed dynamic kinetic asymmetric allylation of phenols and 2-hydroxypyridines", 《CHEM. EUR. J.》 * |
P. ANDREW EVANS ET AL.: "Regioselective and enantiospecific rhodium-catalyzed allylic amination with thymine: synthesis of a new conformationally rigid nucleoside", 《CHEM. COMMUN.》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112759595A (zh) * | 2021-03-05 | 2021-05-07 | 河南师范大学 | 不对称烯丙基化反应合成手性非环核苷的方法 |
CN112759595B (zh) * | 2021-03-05 | 2023-01-20 | 河南师范大学 | 不对称烯丙基化反应合成手性非环核苷的方法 |
Also Published As
Publication number | Publication date |
---|---|
CN107474017B (zh) | 2020-07-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9440965B2 (en) | Process for the synthesis of benzothiadiazole compounds | |
CN105859774B (zh) | 一种膦苯类化合物的制备方法 | |
CN108659041B (zh) | 基于四甲基螺二氢茚骨架的膦配体化合物及其中间体和制备方法与用途 | |
US10913756B2 (en) | Phosphoramidate compound and preparation method and crystal thereof | |
CN113527303B (zh) | 一种瑞德西韦母核中间体的制备工艺 | |
CN107698590A (zh) | 一种不对称[3+2]环化反应合成手性五元碳环嘌呤核苷的方法 | |
Duan et al. | Synthesis of new alkoxy/sulfonate-substituted carbene precursors derived from [2.2] paracyclophane and their application in the asymmetric arylation of aldehydes | |
CN108675943A (zh) | 一种沙库巴曲关键中间体的制备方法 | |
CN114014872A (zh) | 青蒿琥酯衍生物及其制备方法和应用 | |
Widhalm et al. | A modular approach to a new class of phosphinohydrazones and their use in asymmetric allylic alkylation reactions | |
CN114380675A (zh) | 一种可见光诱导卤代芳烃与苯酚化合物反应合成芳基酚的方法 | |
EP2537839B1 (en) | B-dihydrofuran deriving compound, method for producing b-dihydrofuran deriving compound or b-tetrahydrofuran deriving compound, b -glycoside compound, method for producing b-glycoside compound, and method for producing 4'-ethynyl d4t and analogue compounds thereof | |
CN113416150B (zh) | 一种洛铂中间体的合成方法 | |
CN108314655B (zh) | 一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法 | |
CN107474017A (zh) | 一种不对称烯丙基化反应合成手性n1‑烯丙基嘧啶的方法 | |
CN105985258B (zh) | 一种苯甲酰胺化合物的制备方法及其中间体 | |
CN104098607A (zh) | 含三环己基膦的单膦单氮杂环卡宾镍(ii)配合物及其应用 | |
CN107032972B (zh) | 具有2’-羟基查尔酮结构Diels-Alder产物的制备方法 | |
CN108467408B (zh) | 一种具有羟基苯基官能团的二芳基磷化合物及其制备方法 | |
CN109776295B (zh) | 一种邻位含二氟亚甲基的芳基碘化合物及制备方法 | |
CN101759601B (zh) | 利用过渡金属配合物制备手性α-非天然氨基酸的方法 | |
CN101445481B (zh) | 硫代2,6-吡啶二甲酰胺骨架的钳形硫代酰胺配体及其络合物和用途 | |
EP1151987B1 (en) | Optically active fluorinated binaphthol derivative | |
CN108840829A (zh) | 一种4-芳基-1,3,5-三嗪-2-酮类化合物的制备方法 | |
CN107936034B (zh) | 苄氧基二苯并[b,f]噁庚英环丙烯酸类化合物与中间体及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |