一类γ-氨基丁酸衍生物的制备方法

一类
γ-氨基丁酸衍生物的制备方法
技术领域
1.本发明涉及一种新的菲尼布特、巴氯芬及咯利普兰的合成方法。


背景技术：

2.γ-aminobutyric acids(gaba)药物主要有咯利普兰(英文名：rolipram)，菲尼布特(英文名：phenibut)和巴氯芬(英文名：baclofen)。以上三种药物都是γ-氨基丁酸衍生物，其中咯利普兰和菲尼布特是神经类药物，用于治疗哮喘、关节炎、亨廷顿氏(huntington
′
s)病，阿尔茨海默症和多发性硬化症等，可以在大脑中更好地调节过度兴奋和焦虑。巴氯芬具有松弛骨骼肌的作用，主要用于缓解脊髓肿瘤、横贯型脊髓炎、脊髓外伤、运动神经元病、脑血管病、脑膜炎、颅脑外伤引起的骨骼肌痉挛。目前该类化合物的合成受到广泛关注，已经发展出多种合成方法，但其中多利用过渡金属做催化剂，价格昂贵，步骤复杂，且很多方法中应用到了定量的手性助剂。因此，开发该类化合物的新合成方法是十分必要的。


技术实现要素：

3.本发明要解决的技术问题是：提供一种操作方法简单、底物易制得的γ-氨基丁酸衍生物的制备方法，以解决现有技术中存在的问题。
4.本发明的技术方案是：一类γ-氨基丁酸衍生物的制备方法，反应式如下：
[0005][0006]
，其中r为苯基对位上的h、cl或为苯基间位上的烷氧基和对位上的羟基同时取代，r1为芳香族取代基。
[0007]
具体包含以下步骤：(1)0℃-30℃，碱性条件下，式1所示的化合物与ii所示的硫酚类化合物经氮杂环卡宾类催化剂反应生成式iii所示的中间体；(2)在甲醇作溶剂的条件下，步骤(1)中所得iii所示的中间体在硫酸的作用下进行反应，反应结束后得到甲酯类产物4；(3)步骤(2)中所得产物与硼氢化钠和氯化镍混合，溶于甲醇中，室温下反应得到5；(4)步骤(3)中5再经过盐酸水解的条件，得到产物：菲尼布特和巴氯芬。
[0008]
所述的氮杂环卡宾类催化剂为
[0009]
所述步骤(1)的碱性条件为k2co3，cs2co3，na2co3，et3n，dabco，dmap，dipea，quinecldine或dabco。
[0010]
所述步骤(1)反应在有机溶剂条件下进行，所述有机溶剂为thf,dcm,etoac,mtbe,toluene,xylene。
[0011]
本发明的有益效果：本发明方法操作简单，步骤少而明确，底物易制备，反应条件温和，产率高，立体选择性高，便于手性合成咯利普兰，菲尼布特和巴氯芬。
具体实施方式
[0012]
通过下列实施例可以进一步说明本发明，实施例是为了说明而非限制本发明的。本领域的任何普通技术人员都能够理解这些实施例不以任何方式限制本发明，可以对其做适当的修改和数据变换而不违背本发明的实质和偏离本发明的范围。
[0013]
除非另有说明，化学品均购自商业化产品并且不用经进一步纯化。薄层色谱分析(tlc)使用(hsgf 254)硅胶板。硅胶柱层析使用青岛海洋硅胶(200-300目)。tlc显色采用uv光(254nm)。1hnmr图谱使用bruker 400核磁共振仪表征，1h nmr为400mhz,13c nmr为100mhz,以d-cdc13为溶剂。化学位移的单位是ppm,耦合常数的单位是hz。
[0014]
高效液相色谱图使用waters厂家的的高效液相色谱仪。
[0015]
(1)制备手性氰基化合物的合成路线：
[0016][0017]
制备实施方法和条件如下：
[0018]
分别称取0.10mmol氰基醛1、0.12mmol芳香族硫酚2、0.01mmol氮杂环卡宾催化剂，0.02mmol三乙烯二胺做碱，并加入100mg分子筛。加入配有磁力搅拌子的10ml schlenk反应管中，加入2ml甲苯做溶剂，使反应体系充分混合均匀。于30℃水浴中充分搅拌反应11小时，tlc监测反应完毕后，将整个反应体系通过湿法上样，经过柱层析分离，使用石油醚:
乙酸乙酯＝6:1的洗脱剂得到目标化合物，称量后计算相应的产率，化合物通过熔点仪，旋光仪，核磁共振仪nmr，高分辨质谱仪hrms和高效液相色谱仪hplc予以表征。
[0019]
对合成的化合物实验表征如下：
[0020]
s-(对甲苯基)(r)-3-氰基-3-苯基丙烷硫代酸酯
[0021]
取代基r1为苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow solid,83％yield,38.6mg,m.p.94-96℃.
[0022]
[α]
25d
＝-15.1(c＝0.4in chcl3).
[0023]1h nmr(400mhz,cdcl3)δ7.45
–
7.36(m,5h),7.28
–
7.24(d,j＝1.07hz,4h),4.42
–
4.36(t,j＝7.32hz,1h),3.38
–
3.31(dd,j＝16.13,7.75hz,1h),3.21
–
3.14(dd,j＝16.19,6.96hz,1h),2.41
–
2.39(s,3h).
[0024]
13
c nmr(101mhz,cdcl3)δ193.9,140.4,134.5,134.1,130.3,129.4,128.7,127.5,122.9,119.6,47.9,33.1,21.4.
[0025]
hrms(esi,m/z):masscalcd.for c
17h16
nos
+
[m+h]
+
,282.0947；found 282.0943.hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.5ml/min,254nm),rt1(major)＝36.2min,rt2(minor)＝42.8min；95:5er.
[0026]
s-(对甲苯基)(r)-3-氰基-3-(4甲基苯基)丙烷硫代酸酯
[0027]
取代基r1为4-甲基苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow solid,85％yield,25.1mg m.p.99-101℃.
[0028]
[α]
25d
＝-61.3(c＝0.6in chcl3).
[0029]1h nmr(400mhz,cdcl3)δ7.37
–
7.31(m,2h),7.25
–
7.20(s,4h),7.12
–
7.04(m,2h),4.39
–
4.32(t,j＝7.28hz,1h),3.34
–
3.27(dd,j＝16.14,7.25hz,1h),3.16
–
3.09(dd,j＝16.16,7.35hz,1h),2.40
–
2.35(s,3h).
[0030]
13
c nmr(101mhz,cdcl3)δ193.8,163.9,161.5,140.5,134.4,130.3,129.9,129.9,129.4,129.3,122.7,119.4,116.5,116.2,47.8,32.3,21.4.
[0031]
19
f nmr(377mhz,cdcl3)δ-112.65.
[0032]
hrms(esi,m/z):mass calcd.for c
18h17
nnaos
+
[m+h]
+
,318.0923；found 318.0927.hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝27.4min,rt2(minor)＝30.1min；96:4er.
[0033]
s-(对甲苯基)(r)-3-氰基-3-(4-甲氧基苯基)丙烷硫代酸酯
[0034]
取代基r1为4-甲氧基苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；white solid,92％yield,28.6mg.m.p.168-170℃.；
[0035]
[α]
25d
＝-71.5(c＝0.6in chcl3).
[0036]1h nmr(400mhz,cdcl3)δ7.40
–
7.35(m,1h),7.26
–
7.20(s,4h),7.17
–
7.14(dt,j＝7.64,1.34hz,1h),7.11
–
7.04(m,2h),4.40
–
4.34(t,j＝7.25hz,1h),3.35
–
3.29(dd,j＝16.23,7.43hz,1h),3.18
–
3.11(dd,j＝16.20,7.12hz,1h),2.40
–
2.36(s,3h).
[0037]
13
c nmr(101mhz,cdcl3)δ194.0,159.7,140.3,134.4,130.3,128.7,126.0,122.9,119.8,114.6,55.4,48.1,32.3,21.4.
[0038]
hrms(esi,m/z):mass calcd.for c
18h17
nnao2s
+
[m+na]
+
,334.0872；found 334.0872.
[0039]
hplc analysis (chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝44.2min,rt2(minor)＝47.3min；96:4er.
[0040]
s-(对甲苯基)(r)-3-氰基-3-(4叔丁基苯基)丙烷硫代酸酯
[0041]
取代基r1为4-叔丁基苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；white solid,85％yield,28.7mg,m.p.81-82℃.
[0042]
[α]
25d
＝-37.0(c＝0.6in chcl3).
[0043]1h nmr(400mhz,cdcl3)δ7.45
–
7.41(d,j＝8.43hz,2h),7.33
–
7.24(m,6h),4.39
–
4.34(dd,j＝8.06,6.67hz,1h),3.37
–
3.30(dd,j＝16.23,8.09hz,1h),3.19
–
3.13(dd,j＝16.23,6.66hz,1h),2.42
–
2.39(s,3h),1.36
–
1.33(s,9h).
[0044]
13
c nmr(101mhz,cdcl3)δ194.0,151.8,140.3,134.5,131.0,130.3,127.1,126.3,122.9,119.7,47.9,34.7,32.6,31.3,21.4.
[0045]
hrms(esi,m/z):mass calcd.for c
21h23
nnaos
+
[m+na]
+
,360.1393；found 360.1393.
[0046]
hplc analysis(chiralcel od-h；25℃,ipa/hexane＝10/90,0.5ml/min,254nm),rt1(major)＝44.4min,rt2(minor)＝59.3min；97:3er.
[0047]
s-(对甲苯基)(r)-3-氰基-3-(4氟苯基)丙烷硫代酸酯
[0048]
取代基r1为4-叔丁基苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow oil,84％yield,yield,26.6mg.
[0049]
[α]
25d
＝-35.9(c＝0.5in chcl3).
[0050]1h nmr(400mhz,cdcl3)δ7.37
–
7.31(m,2h),7.25
–
7.20(s,4h),7.12
–
7.04(m,2h),4.39
–
4.32(t,j＝7.28hz,1h),3.34
–
3.27(dd,j＝16.14,7.25hz,1h),3.16
–
3.09(dd,j＝16.16,7.35hz,1h),2.40
–
2.35(s,3h).
[0051]
13
c nmr(101mhz,cdcl3)δ193.8,162.7(d,j＝248.46hz),140.5,134.4,130.3,129.9(d,j＝3.51hz),129.4(d,j＝8.37hz),129.3,122.7,119.4,116.4(d,j＝22.02hz),47.8,32.3,21.4.
[0052]
19
f nmr(377mhz,cdcl3)δ-112.65.
[0053]
hrms(esi,m/z):mass calcd.for c
17h14
fnnaos
+
[m+na]
+
,322.0672；found 322.0668.
[0054]
hplc analysis(chiralcelad-h；25℃,ipa/hexane＝05/95,0.5ml/min,254nm),rt1(major)＝41.8min,rt2(minor)＝51.7min；92:8er.
[0055]
s-(对甲苯基)(r)-3-氰基-3-(4氯苯基)丙烷硫代酸酯
[0056]
取代基r1为4-氯苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；white solid,84％yield,26.5mg,m.p.104-106℃.
[0057]
[α]
25d
＝-11.6(c＝0.4in chcl3).
[0058]1h nmr(400mhz,cdcl3)δ7.40
–
7.34(d,j＝8.55hz,2h),7.32
–
7.28(d,j＝8.53hz,2h),7.25
–
7.19(s,4h),4.39
–
4.31(t,j＝7.25hz,1h),3.34
–
3.27(dd,j＝16.22,7.23hz,1h),3.16
–
3.09(dd,j＝16.23,7.28hz,1h),2.41
–
2.34(s,3h).
[0059]
13
c nmr(101mhz,cdcl3)δ193.7,140.5,134.8,134.4,132.6,130.3,129.5,128.9,122.7,119.2,47.7,32.4,21.4.
[0060]
hrms(esi,m/z):mass calcd.for c
17h14
clnnaos
+
[m+na]
+
,338.0377；found 338.0377.
[0061]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝36.0min,rt2(minor)＝45.6min；86:14er.
[0062]
s-(对甲苯基)(r)-3-氰基-3-(4溴苯基)丙烷硫代酸酯取代基r1为4-溴苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow solid,88％yield,88％yield,31.7mg,m.p.94-96℃.
[0063]
[α]
25d
＝-76.3(c＝0.5in chcl3).
[0064]1h nmr(400mhz,cdcl3)δ7.58
–
7.53(d,j＝8.47hz,2h),7.29
–
7.25(d,j＝2.87hz,6h),4.39
–
4.33(t,j＝7.25hz,1h),3.37
–
3.30(dd,j＝16.26,7.20hz,1h),3.19
–
3.12(dd,j＝16.27,7.33hz,1h),2.42
–
2.38(s,3h).
[0065]
13
c nmr(101mhz,cdcl3)δ193.7,140.5,134.4,133.1,132.5,130.3,129.2,122.9,122.6,119.1,47.6,32.5,21.4.
[0066]
hrms(esi,m/z):mass calcd.for c
17h14
brnnaos
+
[m+na]
+
,381.9872；found 381.9869.
[0067]
hplc analysis (chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝42.6min,rt2(minor)＝52.7min；80:20er.
oil,85％yield,25.4mg.
[0085]
[α]
25d
＝-26.5(c＝0.8in chcl3).
[0086]1h nmr(400mhz,cdcl3)δ7.40
–
7.35(m,1h),7.26
–
7.20(s,4h),7.17
–
7.14(dt,j＝7.64,1.34hz,1h),7.11
–
7.04(m,2h),4.40
–
4.34(t,j＝7.25hz,1h),3.35
–
3.29(dd,j＝16.23,7.43hz,1h),3.18
–
3.11(dd,j＝16.20,7.12hz,1h),2.40
–
2.36(s,3h).
[0087]
13
c nmr(101mhz,cdcl3)δ193.7,163.0(d,j＝244.42hz),140.5,136.4(d,j＝7.52hz),134.4,131.0(d,j＝8.34hz),130.3,123.2(d,j＝2.99hz),122.7,119.0,115.8(d,j＝20.87hz),114.8(d,j＝22.92hz).47.6,32.7,21.4.
[0088]
19
f nmr(377mhz,cdcl3)δ-110.93.
[0089]
hrms(esi,m/z):mass calcd.for c
17h14
fnnaos
+
[m+na]
+
,322.0672；found 322.0671.
[0090]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝39.2min,rt2(minor)＝45.6min；92:8er.
[0091]
s-(对甲苯基)(r)-3-氰基-3-(3氯苯基)丙烷硫代酸酯
[0092]
取代基r1为3-氯苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow solid,85％yield,28.6mg,m.p.99-101℃.
[0093]
[α]
25d
＝-9.8(c＝0.4in chcl3).
[0094]1h nmr(400mhz,cdcl3)δ7.41
–
7.32(m,3h),7.30
–
7.24(m,5h),4.40
–
4.34(t,j＝7.28hz,1h),3.37
–
3.30(dd,j＝16.23,7.44hz,1h),3.20
–
3.13(dd,j＝16.25,7.13hz,1h),2.42
–
2.38(s,3h).
[0095]
13
c nmr(101mhz,cdcl3)δ193.7,140.5,136.0,135.2,134.5,130.6,130.3,129.0,127.8,125.7,122.7,119.0,47.6,32.7,21.4.
[0096]
hrms(esi,m/z):mass calcd.for c
17h14
clnnaos
+
[m+na]
+
,338.0377；found 338.0369.
[0097]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝36.0min,rt2(minor)＝45.6min；86:14er.
[0098]
s-(对甲苯基)(r)-3-氰基-3-(2氟苯基)丙烷硫代酸酯
[0099]
取代基r1为2-氟苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow oil,93％yield,27.8mg.
[0100]
[α]
25d
＝-42.6(c＝0.6in chcl3).
[0101]1h nmr(400mhz,cdcl3)δ7.48
–
7.43(td,j＝7.64,1.76hz,1h),7.39
–
7.33(m,1h),7.26
–
7.16(m,5h),7.14
–
7.08(m,1h),4.59
–
4.54(dd,j＝8.23,6.15hz,1h),3.34
–
3.28(dd,
j＝16.33,8.21hz,1h),3.24
–
3.17(dd,j＝16.33,6.18hz,1h),2.38
–
2.36(s,3h).
[0102]
13
c nmr(101mhz,cdcl3)δ193.5,160.0(d,j＝248.66hz),140.4,134.5,130.8(d,j＝8.33hz),130.3,129.5(d,j＝3.06hz),125.0(d,j＝3.64hz),122.8,121.3(d,j＝13.74hz),118.5,116.2(d,j＝21.03hz),45.8,27.6,21.4.
[0103]
19
f nmr(377mhz,cdcl3)δ-116.94.
[0104]
hrms(esi,m/z):mass calcd.for c
17h14
fnnaos
+
[m+na]
+
,322.0672；found 322.0668.
[0105]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝48.8min,rt2(minor)＝65.7min；91:9er.
[0106]
s-(对甲苯基)(r)-3-氰基-3-(2甲基苯基)硫代丙酸酯
[0107]
取代基r1为2-甲基苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；white solid,88％yield,27.4mg,m.p.108-109℃.
[0108]
[α]
25d
＝-31.8(c＝0.4in chcl3).
[0109]1h nmr(400mhz,cdcl3)δ7.41
–
7.36(dd,j＝7.60,1.68hz,1h),7.35
–
7.29(ddd,j＝8.16,7.49,1.71hz,1h),7.28
–
7.25(s,1h),7.23
–
7.18(d,j＝8.20hz,2h),7.00
–
6.94(td,j＝7.52,1.11hz,1h),6.93
–
6.88(dd,j＝8.32,1.11hz,1h),4.65
–
4.51(dd,j＝8.28,6.03hz,1h),3.90
–
3.85(s,3h),3.28
–
3.16(m,2h),2.38
–
2.33(s,3h).
[0110]
13
c nmr(101mhz,cdcl3)δ194.2,156.3,140.1,134.5,130.2,130.1,129.0,123.2,122.1,121.1,119.6,111.0,55.6,45.5,28.5,21.4.
[0111]
hrms(esi,m/z):mass calcd.for c
18h17
nnao2s
+
[m+na]
+
,334.0872；found 334.0884.
[0112]
hplc analysis(chiralcel od-h；25℃,ipa/hexane＝15/85,0.6ml/min,254nm),rt1(major)＝49.2min,rt2(minor)＝79.0min；90:10er.
[0113]
s-(对甲苯基)(r)-3-氰基-3-(3,5-(二甲基)苯基)硫代丙酸酯
[0114]
取代基r1为3,5-二甲基苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow solid,82％yield,25.4mg,m.p.103-104℃.
[0115]
[α]
25d
＝-37.1(c＝0.8in chcl3).
[0116]1h nmr(400mhz,cdcl3)δ7.27
–
7.21(m,4h),7.03
–
6.89(d,j＝7.29hz,3h),4.31
–
4.23(dd,j＝8.04,6.65hz,1h),3.32
–
3.24(dd,j＝16.08,8.06hz,1h),3.14
–
3.07(dd,j＝16.07,6.64hz,1h),2.40
–
2.36(s,3h),2.35
–
2.29(s,6h).
[0117]
13
c nmr(101mhz,cdcl3)δ194.0,140.3,139.1,134.5,134.0,130.2,125.2,123.0,119.8,48.0,33.0,21.4,21.3.
[0118]
hrms(esi,m/z):mass calcd.for c
19h19
nnaos
+
[m+na]
+
,332.1080；found 332.1078.
[0119]
hplc analysis(chiralcel if；25℃,ipa/hexane＝05/95,0.5ml/min,254nm),rt1(major)＝35.7min,rt2(minor)＝43.2min；96:4er.
[0120]
s-(对甲苯基)(r)-3-氰基-3-(3,4,-(二甲氧基)苯基)硫代丙酸酯
[0121]
取代基r1为3,4-二甲氧基苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow solid,90％yield,30.7mg,m.p.121-122℃.
[0122]
[α]
25d
＝-23.1(c＝0.6in chcl3).
[0123]1h nmr(400mhz,cdcl3)δ7.28
–
7.23(d,j＝1.08hz,4h),6.95
–
6.83(m,3h),4.37
–
4.31(t,j＝7.35hz,1h),3.93
–
3.88(d,j＝1.72hz,6h),3.35
–
3.28(dd,j＝16.03,7.51hz,1h),3.19
–
3.12(dd,j＝16.07,7.17hz,1h),2.42
–
2.37(s,3h).
[0124]
13
c nmr(101mhz,cdcl3)δ194.0,149.4,149.2,140.4,134.4,130.3,126.4,122.9,119.8,119.8,111.5,110.3,56.0,56.0,48.0,32.7,21.4.
[0125]
hrms(esi,m/z):mass calcd.for c
19h19
nnao3s+[m+na]
+
,364.0978；found 364.0980.
[0126]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝70.8min,rt2(minor)＝77.4min；97:3er.
[0127]
s-(对甲苯基)(r)-3-氰基-3-(胡椒基)硫代丙酸酯
[0128]
取代基r1为胡椒基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow solid,86％yield,28.0mg,m.p.125-127℃.
[0129]
[α]
25d
＝-36.0(c＝0.4in chcl3).
[0130]1h nmr(400mhz,cdcl3)δ7.26
–
7.20(m,4h),6.88
–
6.70(m,3h),6.01
–
5.97(s,2h),4.31
–
4.24(t,j＝7.31hz,1h),3.31
–
3.24(dd,j＝16.13,7.38hz,1h),3.14
–
3.07(dd,j＝16.14,7.23hz,1h),2.40
–
2.35(s,3h).
[0131]
13
c nmr(101mhz,cdcl3)δ193.9,148.4,147.9,140.4,134.4,130.3,127.6,122.9,121.1,119.6,108.8,107.8,101.6,48.0,32.8,21.4.
[0132]
hrms(esi,m/z):mass calcd.for c
18h15
nnao3s
+
[m+na]
+
,348.0665；found 348.0664.
[0133]
hplcanalysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.5ml/min,254nm),rt1(major)＝87.9min,rt2(minor)＝95.7min；96:4er.
[0134]
s-(对甲苯基)(r)-3-氰基-3-(3-(环戊氧基)-4-甲氧基苯基)丙烷硫代丙酸酯取代基r1为3-(环戊氧基)-4-甲氧基苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow solid,81％yield,32.0mg,m.p.107-108℃.
[0135]
[α]
25d
＝-61.9(c＝0.4in chcl3).
[0136]1h nmr(500mhz,cdcl3)δ7.26
–
7.16(s,4h),6.90
–
6.80(m,3h),4.80
–
4.73(tt,j＝6.30,3.04hz,1h),4.33
–
4.25(t,j＝7.34hz,1h),3.88
–
3.81(s,3h),3.32
–
3.24(dd,j＝16.00,7.42hz,1h),3.16
–
3.08(dd,j＝16.04,7.26hz,1h),2.43
–
2.35(s,3h),1.98
–
1.81(m,6h),1.64
–
1.57(m,2h).
[0137]
13
c nmr(101mhz,cdcl3)δ194.0,150.2,148.1,140.3,134.4,130.2,126.2,122.9,119.8,119.6,113.9,112.2,80.6,56.1,48.1,32.8,32.7,32.7,24.1,21.4.
[0138]
hrms(esi,m/z):mass calcd.for c
23h25
nnao3s
+
[m+na]
+
,418.1447；found 418.1447.
[0139]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝49.4min,rt2(minor)＝40.0min；96:4er.
[0140]
s-(对甲苯基)(r)-3-氰基-3-(3，4，5-三甲氧基苯基)丙烷硫代丙酸酯
[0141]
取代基r1为3，4，5-三甲氧基苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow solid,94％yield,34.9mg,m.p.116-118℃.
[0142]
[α]
25d
＝-184.3(c＝0.4in chcl3).
[0143]1h nmr(400mhz,cdcl3)δ7.29
–
7.24(d,j＝9.32hz,4h),6.60
–
6.53(s,2h),4.36
–
4.30(t,j＝7.32hz,1h),3.92
–
3.83(d,j＝8.20hz,9h),3.37
–
3.29(dd,j＝16.08,7.67hz,1h),3.21
–
3.13(dd,j＝16.06,7.01hz,1h),2.43
–
2.37(s,3h).
[0144]
13
c nmr(101mhz,cdcl3)δ194.0,153.8,140.5,138.0,134.4,130.3,129.6,122.8,119.5,104.4,60.9,56.3,48.0,33.3,21.4.
[0145]
hrms(esi,m/z):c20h
21
nnao4s
+
[m+na]
+
,394.1083；found 394.1092.
[0146]
hplc analysis(chiralcel ib；25℃,ipa/hexane＝10/90,0.8ml/min,254nm),rt1(major)＝32.8min,rt2(minor)＝53.6min；96:4er.
[0147]
s-(对甲苯基)(r)-3-氰基-3-(1，1'-联苯基)丙烷硫代丙酸酯
[0148]
取代基r1为1，1'-联苯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow solid,92％yield,32.9mg,m.p.97-98℃.
[0149]
[α]
25d
＝-46.3(c＝0.4in chcl3).
[0150]1h nmr(500mhz,cdcl3)δ7.65
–
7.54(dd,j＝14.00,7.69hz,4h),7.49
–
7.35(m,5h),7.28
–
7.21(m,5h),4.45
–
4.38(t,j＝7.29hz,1h),3.39
–
3.32(dd,j＝16.19,7.62hz,1h),3.23
–
3.16(dd,j＝16.23,6.99hz,1h),2.42
–
2.33(s,3h).
[0151]
13
c nmr(101mhz,cdcl3)δ193.9,141.7,140.4,140.1,134.5,133.0,130.3,128.9,128.0,127.9,127.8,127.1,122.9,119.5,47.9,32.7,21.4.
[0152]
hrms(esi,m/z):mass calcd.for c
23h19
nnaos
+
[m+na]
+
,380.1080；found 380.1074.
[0153]
hplc analysis(chiralcel od-h；25℃,ipa/hexane＝20/80,0.6ml/min,254nm),rt1(major)＝31.5min,rt2(minor)＝47.8min；96:4er
[0154]
s-(对甲苯基)(r)-3-氰基-3-(1萘基)丙烷硫代丙酸酯
[0155]
取代基r1为1-萘基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow solid,90％yield,29.7mg,m.p.84-85℃.
[0156]
[α]
25d
＝-16.3(c＝0.4in chcl3).
[0157]1h nmr(500mhz,cdcl3)δ7.97
–
7.84(m,3h),7.75
–
7.69(d,j＝6.12hz,1h),7.63
–
7.48(m,3h),7.28
–
7.22(q,j＝8.48,8.08hz,4h),5.16
–
5.08(dd,j＝9.23,4.97hz,1h),3.46
–
3.38(dd,j＝16.26,9.25hz,1h),3.32
–
3.24(dd,j＝16.31,4.99hz,1h),2.44
–
2.34(s,3h).
[0158]
13
c nmr(101mhz,cdcl3)δ194.2,140.4,134.5,134.1,130.3,129.7,129.6,129.5,127.4,126.4,126.0,125.5,122.9,121.9,119.6,47.1,30.3,21.4.
[0159]
hrms(esi,m/z):mass calcd.for c
21h17
nnaos
+
[m+na]
+
,354.0923；found 354.0917.
[0160]
hplc analysis (chiralcel ig； 25 ℃, ipa/hexane ＝ 10/90, 0.6 ml/min, 254 nm), rt
1 (major)＝61.9min,rt2(minor)＝67.1min；94:6er.
[0161]
s-(对甲苯基)(r)-3-氰基-3-(1-甲基-吲哚基)丙烷硫代丙酸酯
[0162]
取代基r1为1-甲基-吲哚基,r2为4-甲基苯基，制备实施方法和条件同实施例i；brown solid,86％yield,28.8mg,m.p.127-128℃.
[0163]
[α]
25d
＝-90.5(c＝0.4in chcl3).
[0164]1h nmr(500mhz,cdcl3)δ7.65
–
7.59(d,j＝8.00hz,1h),7.35
–
7.26(m,2h),7.24
–
7.15(m,5h),7.12
–
7.07(d,j＝0.60hz,1h),4.66
–
4.58(ddd,j＝7.54,6.75,0.68hz,1h),3.78
–
3.73(s,3h),3.38
–
3.25(m,2h),2.38
–
2.34(s,3h).
[0165]
13
c nmr(101mhz,cdcl3)δ194.3,140.2,137.3,134.5,130.2,127.5,125.4,123.2,122.5,120.0,119.8,118.5,109.9,107.2,46.9,32.9,24.9,21.4.
[0166]
hrms(esi,m/z):mass calcd.for c
20h18
n2naos
+
[m+na]
+
,357.1032；found 357.1031.
[0167]
hplc analysis(chiralcel as-h；25℃,ipa/hexane＝30/70,0.6ml/min,254nm),rt1(major)＝50.4min,rt2(minor)＝58.2min；96:4er.
[0168]
s-(对甲苯基)(r)-3-氰基-3-(1-噻吩)丙烷硫代丙酸酯取代基r1为1-噻吩,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow oil,83％yield,23.9mg.
[0169]
[α]
25d
＝-8.7(c＝0.4in chcl3).
[0170]1h nmr(400mhz,cdcl3)δ7.31
–
7.22(m,5h),7.12
–
7.08(dt,j＝3.56,1.07hz,1h),7.01
–
6.96(dd,j＝5.17,3.56hz,1h),4.70
–
4.62(td,j＝7.25,0.83hz,1h),3.39
–
3.33(dd,j＝16.25,7.35hz,1h),3.27
–
3.21(dd,j＝16.25,7.13hz,1h),2.39
–
2.37(s,3h).
[0171]
13
c nmr(101mhz,cdcl3)δ193.5,140.4,135.8,134.4,130.3,127.3,127.0,126.2,122.8,118.7,48.0,28.3,21.4.
[0172]
hrms(esi,m/z):mass calcd.for c
15h13
nnaos
2+
[m+na]
+
,310.0331；found 310.0330.
[0173]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.5ml/min,254nm),rt1(major)＝42.9min,rt2(minor)＝46.3min；75:25er.
[0174]
s-(对甲苯基)(r)-3-氰基-3-(1-环己烯基)丙烷硫代丙酸酯取代基r1为1-环己烯基,r2为4-甲基苯基，制备实施方法和条件同实施例i；yellow soild,47％yield,13.4mg,m.p.68-70℃.
[0175]
[α]
25d
＝-11.4(c＝0.4in chcl3).
[0176]1h nmr(400mhz,cdcl3)δ7.33
–
7.18(m,4h),5.89
–
5.75(d,j＝1.08hz,1h),3.74
–
3.60(t,j＝7.40hz,1h),3.08
–
2.95(m,2h),2.44
–
2.33(s,3h),2.14
–
1.97(m,4h),1.73
–
1.66(t,j＝6.05hz,2h),1.59
–
1.56(t,j＝1.73hz,2h).
[0177]
13
c nmr(101mhz,cdcl3)δ194.1,140.3,134.4,130.2,130.0,127.8,123.1,119.3,44.2,35.0,25.9,25.2,22.4,21.7,21.4.
[0178]
hrms(esi,m/z):mass calcd.for c
17h19
nnaos
+
[m+na]
+
,308.1080；found 308.1078.
[0179]
hplc analysis(chiralcel as3rcd；25℃,ammonium bicarbonate/acetonitrile＝30/70,0.6ml/min,254nm),rt1(major)＝7.8min,rt2(minor)＝7.0min；80:20er.
[0180]
s-(4-甲氧基苯基)(r)-3-氰基-3-苯基硫代丙酸酯
[0181]
取代基r1为苯基,r2为4-甲氧基苯基，制备实施方法和条件同实施例i；yellow solid,88％yield,26.2mg,m.p.112-114℃.
[0182]
[α]
25d
＝-46.6(c＝0.6in chcl3).
[0183]1h nmr(400mhz,cdcl3)δ7.45
–
7.36(m,5h),7.30
–
7.27(m,2h),6.99
–
6.93(d,j＝8.78hz,2h),4.42
–
4.36(t,j＝7.35hz,1h),3.87
–
3.83(s,3h),3.37
–
3.30(dd,j＝16.15,7.77hz,1h),3.19
–
3.13(dd,j＝16.16,6.93hz,1h).
[0184]
13
c nmr(101mhz,cdcl3)δ194.5,161.0,136.1,134.1,129.4,128.7,127.5,119.6,117.0,115.1,55.4,47.8,33.1.
[0185]
hrms(esi,m/z):mass calcd.for c
17h16
no2s
+
[m+na]
+
,298.0896；found 298.0902.
[0186]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝57.9min,rt2(minor)＝67.7min；96:4er.
[0187]
s-(4-氟苯基)(r)-3-氰基-3-苯基硫代丙酸酯取代基r1为苯基,r2为4-氟苯基，制备实施方法和条件同实施例i；yellow solid,87％yield,24.8mg,m.p.83-84℃.
[0188]
[α]
25d
＝-38.7(c＝0.6in chcl3).
[0189]1h nmr(400mhz,cdcl3)δ7.46
–
7.33(m,7h),7.18
–
7.11(m,2h),4.42
–
4.35(dd,j＝7.89,6.83hz,1h),3.39
–
3.32(dd,j＝16.18,7.96hz,1h),3.22
–
3.15(dd,j＝16.15,6.80hz,1h).
[0190]
13
c nmr(101mhz,cdcl3)δ193.4,163.8(d,j＝251.05hz),136.6(d,j＝8.72hz),133.9,129.4,128.8,127.5,121.6(d,j＝3.50hz),119.5,116.8(d,j＝3.50hz),48.0,33.1.
[0191]
19
f nmr(377mhz,cdcl3)δ-110.05.
[0192]
hrms(esi,m/z):mass calcd.for c
16h12
fnnaos
+
[m+na]
+
,308.0516；found 308.0515.
[0193]
hplc analysis (chiralcel ia； 25 ℃, ipa/hexane ＝ 05/95, 0.7 ml/min, 254 nm), rt
1 (major)＝30.6min,rt2(minor)＝35.6min；93:7er.
[0194]
s-(3-甲基苯基)(r)-3-氰基-3-苯基硫代丙酸酯
[0195]
取代基r1为苯基,r2为3-甲基苯基，制备实施方法和条件同实施例i；yellow solid,86％yield,24.2mg,m.p.95-97℃.
[0196]
[α]
25d
＝-78.2(c＝0.6in chcl3).
[0197]1h nmr(400mhz,cdcl3)δ7.42
–
7.34(m,5h),7.32
–
7.27(t,j＝7.50hz,1h),7.25
–
7.21(m,1h),7.21
–
7.12(m,2h),4.39
–
4.33(dd,j＝7.87,6.84hz,1h),3.35
–
3.28(dd,j＝16.15,7.87hz,1h),3.17
–
3.11(dd,j＝16.17,6.83hz,1h),2.37
–
2.34(s,3h).
[0198]
13
c nmr(101mhz,cdcl3)δ193.6,139.4,135.0,134.1,131.5,130.8,129.4,129.2,128.7,127.5,126.0,119.5,48.0,33.1,21.3.
[0199]
hrms(esi,m/z):mass calcd.for c
17h15
nnaos
+
[m+na]
+
,304.0767；found 304.0763.
[0200]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝28.3min,rt2(minor)＝34.6min；95:5er.
[0201]
s-(2-甲基苯基)(r)-3-氰基-3-苯基硫代丙酸酯
[0202]
取代基r1为苯基,r2为2-甲基苯基，制备实施方法和条件同实施例i；yellow solid,81％yield,22.8mg,m.p.98-99℃.
[0203]
[α]
25d
＝-10.6(c＝0.4in chcl3).
[0204]1h nmr(400mhz,cdcl3)δ7.46
–
7.32(m,8h),7.27
–
7.22(m,1h),4.43
–
4.36(t,j＝7.43hz,1h),3.39
–
3.33(dd,j＝15.95,7.71hz,1h),3.23
–
3.17(dd,j＝15.93,7.20hz,1h),2.30
–
2.23(s,3h).
[0205]
13
c nmr(101mhz,cdcl3)δ192.9,142.1,135.8,134.0,131.0,130.6,129.4,128.7,127.5,126.8,119.5,47.9,33.2,20.6.
[0206]
hrms(esi,m/z):mass calcd.for c
17h15
nnaos
+
[m+na]
+
,304.0767；found 304.0766.
[0207]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝27.7min,rt2(minor)＝30.3min；94:6er.
[0208]
s-(2-甲氧基苯基)(r)-3-氰基-3-苯基硫代丙烷酸酯
[0209]
取代基r1为苯基,r2为2-甲氧基苯基，制备实施方法和条件同实施例i；yellow solid,74％yield,22.0mg,m.p.104-106℃.
[0210]
[α]
25d
＝-41.1(c＝0.5in chcl3).
[0211]1h nmr(400mhz,cdcl3)δ7.48
–
7.34(m,7h),7.04
–
6.97(m,2h),4.44
–
4.37(t,j＝7.32hz,1h),3.86
–
3.83(s,3h),3.40
–
3.33(dd,j＝16.23,7.75hz,1h),3.23
–
3.16(dd,j＝16.22,6.91hz,1h).
[0212]
13
c nmr(101mhz,cdcl3)δ192.7,159.2,136.6,134.2,132.3,129.3,128.6,127.5,121.2,119.6,114.6,111.7,56.0,47.7,33.0.
[0213]
hrms(esi,m/z):mass calcd.for c
17h15
nnao2s
+
[m+na]
+
,320.0716；found 320.0728.
[0214]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝44.3min,rt2(minor)＝51.2min；94:6er.
[0215]
s-(2,6-二甲基苯基)(r)-3-氰基-3-苯基硫代丙酸酯
[0216]
取代基r1为苯基,r2为2，6-二甲基苯基，制备实施方法和条件同实施例i；yellow solid,78％yield,23.0mg,m.p.88-90℃.
[0217]
[α]
25d
＝-28.2(c＝0.8in chcl3).
[0218]1h nmr(400mhz,cdcl3)δ7.46
–
7.36(m,5h),7.29
–
7.24(m,1h),7.21
–
7.13(d,j＝7.55hz,2h),4.44
–
4.37(t,j＝7.49hz,1h),3.39
–
3.33(dd,j＝15.78,7.55hz,1h),3.26
–
3.19(dd,j＝15.79,7.39hz,1h),2.44
–
2.10(s,6h).
[0219]
13
c nmr(101mhz,cdcl3)δ192.4,142.8,134.0,130.4,129.4,128.7,128.4,127.6,125.9,119.6,47.9,33.2,21.6.
[0220]
hrms(esi,m/z):mass calcd.for c
18h17
nnaos
+
[m+na]
+
,318.0923；found 318.0929.
[0221]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝42.7min,rt2(minor)＝50.1min；94:6er.
[0222]
s-(萘基)(r)-3-氰基-3-苯基硫代丙烷酸酯取代基r1为苯基,r2为萘基，制备实施方法和条件同实施例i；white solid,81％yield,25.7mg,m.p.104-105℃.
[0223]
[α]
25d
＝-50.2(c＝0.8in chcl3).
[0224]1h nmr(400mhz,cdcl3)δ7.94
–
7.84(m,4h),7.61
–
7.54(ddd,j＝7.10,4.65,1.75hz,2h),7.46
–
7.38(q,j＝4.59,3.63hz,6h),4.45
–
4.39(dd,j＝7.83,6.87hz,1h),3.44
–
3.37(dd,j＝16.16,7.90hz,1h),3.26
–
3.20(dd,j＝16.19,6.81hz,1h).
[0225]
13
c nmr(101mhz,cdcl3)δ193.6,134.6,134.1,133.5,133.5,130.6,129.4,129.1,128.7,128.1,127.9,127.5,127.5,126.8,123.7,119.6,48.1,33.1.
[0226]
hrms(esi,m/z):mass calcd.for c
20h15
nnaos
+
[m+na]
+
,340.0767；found 340.0768.
[0227]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.6ml/min,254nm),rt1(major)＝64.5min,rt2(minor)＝71.9min；94:6er.
[0228][0229]
methyl(r)-3-cyano-3-(3-(cyclopentyloxy)-4-methoxyphenyl)propanoate(5)
[0230]
purificationby flash column chromatography on silica gel(petroleum ether/ethyl acetate＝10/1).white solid,91％yield,2.51g,m.p.98-99℃.
[0231]1h nmr(400mhz,cdcl3)δ6.90
–
6.81(m,3h),4.81
–
4.74(tt,j＝6.39,3.12 hz,1h),4.27
–
4.19(dd,j＝8.04,6.85 hz,1h),3.86
–
3.81(s,3h),3.76
–
3.68(s,3h),3.04
–
2.96(dd,j＝16.51,8.10 hz,1h),2.87
–
2.79(dd,j＝16.51,6.84 hz,1h),1.98
–
1.80(m,6h),1.67
–
1.56(m,2h).
[0232]
13
c nmr(101mhz,cdcl3)δ169.8,150.1,148.1,126.6,120.2,119.5,113.8,112.2,80.6,56.1,52.3,40.0,32.8,32.8,32.7,24.1.
[0233]
hrms(esi,m/z):mass calcd.for c
17h21
nnao
4+
[m+na]
+
,326.1363；found 326.1364.
[0234]
(r)-rolipram(6)
[0235]
purificationby flash column chromatography on silica gel(dichloromethane/methanol＝20/1).white solid,86％yield,2.2g,m.p.133-134℃.
[0236]
[α]
25d
＝-30.7(c＝0.6 in chcl3).
[0237]1h nmr(400mhz,cdcl3)δ6.84
–
6.75(m,3h),6.69
–
6.50(s,1h),4.81
–
4.74(tt,j＝5.79,3.46hz,1h),3.86
–
3.81(s,3h),3.79
–
3.73(ddd,j＝9.30,8.07,1.04hz,1h),3.67
–
3.59(m,1h),3.42
–
3.35(dd,j＝9.47,7.35hz,1h),2.75
–
2.67(dd,j＝16.89,8.90hz,1h),2.51
–
2.44(dd,j＝16.88,8.94hz,1h),1.95
–
1.81(m,6h),1.67
–
1.56(m,2h).
[0238]
13
c nmr(101mhz,cdcl3)δ177.9,149.2,147.9,134.6,118.8,113.9,112.2,80.6,56.2,49.8,40.0,38.2,32.8,24.0.
[0239]
hrms(esi,m/z):mass calcd.for c
16h21
nnao
3+
[m+na]
+
,298.1414；found 298.1415.
[0240]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.5ml/min,254nm),rt1(major)＝18.1min,rt2(minor)＝22.5min；95:5er.
[0241]
methyl(r)-3-cyano-3-phenylpropanoate(7)
[0242]
purificationby flash column chromatography on silica gel(petroleum ether/ethyl acetate＝5/1).white solid,87％yield,56.9mg,m.p.92-94℃.
[0243]
[α]
25d
＝15.6(c＝0.6in chcl3).
[0244]1h nmr(400mhz,cdcl3)δ7.40
–
7.32(m,5h),4.32
–
4.26(dd,j＝8.39,6.52hz,1h),3.70
–
3.67(s,3h),3.04
–
2.97(dd,j＝16.67,8.38hz,1h),2.87
–
2.81(dd,j＝16.68,6.58hz,1h).
[0245]
13
c nmr(101mhz,cdcl3)δ169.7,134.5,129.3,128.6,127.4,120.0,52.3,39.7,33.1.
[0246]
hrms(esi,m/z):mass calcd.for c
11h11
nnao
2+
[m+na]
+
,212.0682；found 212.0685.
[0247]
hplc analysis(chiralcelad-h；25℃,ipa/hexane＝05/95,0.5ml/min,254nm),rt1(major)＝33.8min,rt2(minor)＝37.2min；95:5er.
[0248]
methyl(r)-3-(4-chlorophenyl)-3-cyanopropanoate(8)
[0249]
purificationby flash column chromatography on silica gel(petroleum ether/ethyl acetate＝5/1).yellow solid,90％yield,77.8mg,m.p.93-95℃.
[0250]
[α]
25d
＝10.2(c＝0.6in chcl3).
[0251]1h nmr(400mhz,cdcl3)δ7.41
–
7.35(m,2h),7.34
–
7.29(m,2h),4.32
–
4.25(t,j＝7.41hz,1h),3.75
–
3.69(s,3h),3.05
–
2.99(dd,j＝16.66,7.75hz,1h),2.87
–
2.80(dd,j＝16.69,7.07hz,1h).
[0252]
13
c nmr(101mhz,cdcl3)δ169.4,134.8,132.9,129.5,128.8,119.5,52.5,39.7,32.6.
[0253]
hrms(esi,m/z):mass calcd.for c
11h10
clnnao
2+
[m+na]
+
,246.0292；found 246.0288.
[0254]
hplc analysis(chiralcel ad-h；25℃,ipa/hexane＝05/95,0.5ml/min,254nm),rt1(major)＝33.9min,rt2(minor)＝40.1min；87:13er.
[0255]
(2)手性氰基化合物的gaba衍生物合成研究：
[0256]
得到目标化合物，称量后计算相应的产率，化合物通过熔点仪，旋光仪，核磁共振仪nmr，高分辨质谱仪hrms和高效液相色谱仪hplc予以表征。
[0257]
由化合物3a和3f转化为化合物(r)-phenibut和(r)-baclofen的制备方法
[0258][0259]
在一个配有磁力搅拌子的100ml茄形瓶中加入3a(2.81g,10.0mmol)或3f(3.16g,10.0mmol)，加入30ml甲醇使其溶解，再加入2ml浓硫酸于室温下搅拌，tlc监测至反应完毕，将反应体系冷却到0℃，加水稀释并用乙酸乙酯萃取，利用无水硫酸钠干燥。旋干得到粗产品后，通过柱层析分离，洗脱剂极性石油醚:乙酸乙酯＝10:1得到目标化合物7和8，分别是87％和90％的收率。
[0260]
在一个配有磁力搅拌子的50ml茄形瓶中加入化合物7(1.66g,8.68mmol)或8(2.00g,9.00mmol)并溶于20ml甲醇中，加入5.0equiv硼氢化钠(1.72g,45.00mmol)，在室温下搅拌一小时，tlc监测至反应完毕。利用饱和氯化铵溶液淬灭，经无水硫酸钠干燥，旋干得到粗产品后，通过柱层析分离，洗脱剂极性石油醚:乙酸乙酯＝5:1以85％和90％的收率得到相应的目标化合物，之后将化合物加入6nhcl中，在100℃条件下回流18小时，浓缩干燥后得到目标化合物(r)-菲尼布特(收率83％)和(r)-巴氯芬(收率79％)。
[0261]
(r)菲尼布特
[0262]
purificationby flash column chromatography on silica gel(petroleum ether/ethyl acetate＝5/1).white solid,83％yield,1.4g.
[0263]
[α]
25d
＝-20.6(c＝0.6in h2o).
[0264]1h nmr(300mhz,d2o)d 2.65(dd,1h,j 15.8and 8.8hz),2.75(dd,1h,j 15.8and 5.3hz),3.10-3.30(m,3h),7.26-7.36(m,5h).
[0265]
13
c nmr(75mhz,d2o)d 40.7,42.4,46.3,130.3,130.8,131.8,140.8,177.9.
[0266]
hrms(esi,m/z):mass calcd.for c
10h14
no
2+
[m+h]
+
,180.1019；found 180.1020.
[0267]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.5ml/min,254nm),rt1(major)＝24.8min,rt2(minor)＝28.0min；95:5er.
[0268]
(r)巴氯芬
[0269]
purificationby flash column chromatography on silica gel(petroleum ether/ethyl acetate＝5/1).white solid,79％yield,1.2g.
[0270]
[α]
25d
＝-9.1(c＝0.6in h2o).
[0271]1h nmr(300mhz,d2o)d 2.73(dd,1h,j 16.4and 8.8hz),2.86(dd,1h,j 16.4and 5.9hz),3.20-3.48(m,3h),7.33(d,2h,j 8.8hz),7.43(d,2h,j 8.8hz).
[0272]
13
c nmr(75mhz,d2o)d 38.4,39.6,43.8,129.4,129.6,133.5,137.1,175.5.
[0273]
hrms(esi,m/z):mass calcd.for c
10h13
clno
2+
[m+h]
+
,214.0629；found 214.0630.
[0274]
hplc analysis(chiralcel ad-h；25℃,ipa/hexane＝05/95,0.5ml/min,254nm),rt1(major)＝18.9min,rt2(minor)＝20.2min；87:13er.
[0275]
由化合物3q转化为化合物6的制备方法
[0276][0277]
在一个配有磁力搅拌子的100ml茄形瓶中加入3q(3.60g,13.5mmol)，加入30ml甲
醇使其溶解，再加入2ml浓硫酸于室温下搅拌，tlc监测至反应完毕，将反应体系冷却到0℃，加水稀释并用乙酸乙酯萃取，利用无水硫酸钠干燥。旋干得到粗产品后，通过柱层析分离，洗脱剂极性石油醚:乙酸乙酯＝10:1以91％的收率得到目标化合物5。
[0278]
在一个配有磁力搅拌子的50ml茄形瓶中加入化合物5(2.76g,8.25mmol)并溶于20ml甲醇中，加入5.0equiv硼氢化钠(1.56g,41.21mmol)，在室温下搅拌一小时，tlc监测至反应完毕。利用饱和氯化铵溶液淬灭，经无水硫酸钠干燥，旋干得到粗产品后，通过柱层析分离，洗脱剂极性石油醚:乙酸乙酯＝20:1以86％的收率得到目标化合物6。
[0279]
(r)咯利普兰
[0280]
white solid,86％yield,2.2g,m.p.133-134℃.
[0281]
[α]
25d
＝-30.7(c＝0.6in chcl3).
[0282]1h nmr(400mhz,cdcl3)δ6.84
–
6.75(m,3h),6.69
–
6.50(s,1h),4.81
–
4.74(tt,j＝5.79,3.46hz,1h),3.86
–
3.81(s,3h),3.79
–
3.73(ddd,j＝9.30,8.07,1.04hz,1h),3.67
–
3.59(m,1h),3.42
–
3.35(dd,j＝9.47,7.35hz,1h),2.75
–
2.67(dd,j＝16.89,8.90hz,1h),2.51
–
2.44(dd,j＝16.88,8.94hz,1h),1.95
–
1.81(m,6h),1.67
–
1.56(m,2h).
[0283]
hrms(esi,m/z):mass calcd.for c
16h21
nnao
3+
[m+na]
+
,298.1414；found 298.1415.
[0284]
hplc analysis(chiralcel ia；25℃,ipa/hexane＝05/95,0.5ml/min,254nm),rt1(major)＝18.1min,rt2(minor)＝22.5min；95:5er.

技术特征：
1.一类γ-氨基丁酸衍生物的制备方法，其特征在于：反应式如下：，其中r为苯基对位上的h、cl或为苯基间位上的烷氧基和对位上的羟基同时取代，r1为芳香族取代基。2.根据权利要求1所述的一类γ-氨基丁酸衍生物的制备方法，其特征在于：具体包含以下步骤：(1)0℃-30℃，碱性条件下，式1所示的化合物与ii所示的硫酚类化合物经氮杂环卡宾类催化剂反应生成式iii所示的中间体；(2)在甲醇作溶剂的条件下，步骤(1)中所得iii所示的中间体在硫酸的作用下进行反应，反应结束后得到甲酯类产物4；(3)步骤(2)中所得产物与硼氢化钠和氯化镍混合，溶于甲醇中，室温下反应得到5；(4)步骤(3)中5再经过盐酸水解的条件，得到产物：菲尼布特和巴氯芬。3.根据权利要求2所述的一类γ-氨基丁酸衍生物的制备方法，其特征在于：所述的氮杂环卡宾类催化剂为4.根据权利要求2所述的一类γ-氨基丁酸衍生物的制备方法，其特征在于：所述步骤(1)的碱性条件为k2co3，cs2co3，na2co3，et3n，dabco，dmap，dipea，quinecldine或dabco。5.根据权利要求2所述的一类γ-氨基丁酸衍生物的制备方法，其特征在于：所述步骤(1)反应在有机溶剂条件下进行，所述有机溶剂为thf,dcm,etoac,mtbe,toluene,xylene。

技术总结
本发明公开了一类γ-氨基丁酸衍生物的制备方法，其特征在于：反应式如下：，其中R为苯基对位上的H、Cl或为苯基间位上的烷氧基和对位上的羟基同时取代，R1为芳香族取代基。基。


技术研发人员：郑鹏程 王青云 吴树权 池永贵
受保护的技术使用者：贵州大学
技术研发日：2023.06.05
技术公布日：2023/8/31