手性药物合成举例之一

O H3C OH HC CH3 CH Cl 3 O H3C O O O NH3 EtOH H3C O NH2 OH CH3 CH3 Et3N H3C O Cl Cl O HN O OH CH3 CH3 F Cl DAST CH2Cl2 H3C O CH3 CH3 O N O H3C O 2.5 mol/L H2SO4 O HN O OH CH CH3 3 Cl F Mn CH3 CH3 F Cl
SO2Cl2 CH2Cl2
Cl
O OH
HNO3 CH2Cl2
Cl
O OH NO2
Cl
O O NO2 O
1) HCl, C3H7OH 2) KOH, EtOH
Cl
O O NO2
OH
PhCOCl CH2Cl2
O Cl O O NO2 O O O N N H O 1) Resolution (+)-camphorsulfonic acid 2) Benzoylaziridine 3) KOH, EtOH 4) HCl, EtOH NH2 O H2-Pd/C, EtOH O O HCl O
O HN(CH2CH2Cl)2 HCl PhCl
O O N N
OH HCl F
HCl
H N O
Implitapide : 降血脂
CH3 N H3C N O N H OH
CH3 N H3C NH2 i-PrCH2CH2ONO HCl CH3 N Pd heat H3C NH I H3C
CH3 CH3 N Cl NH2-NH2 H3C CH3 heat N NH NH2 O H3C N N H
SOCl2 tol
CH3
H N O CH3
BuBr K2CO3 N H
CH3
H N O CH3
1) (S,S)-tartaric acid 2) ) H C l 3
CH3
结
晶
N
H N O CH3
异
丙
醇
N
2
路
线
NH2 NaNO2 HO O N H COOCH2Ph AcOH, AcONa HO O N H
OMe
OMe NH2 O NaBH3CN
OMe N O F
BBr3
Rotigotine : 抗帕金森症
OH
Me2SO4 NaOH OMe
OMe 1) Na/EtOH 2) HCl/H2O OMe H N
O
1) PrNH2 2) H2/Pt
OH H N
CH3
1) L-DBTA 2) Resolution
O OH OH O LiAlH4 H N N Ac2O
O O N O
H2N N
O N O H2, Pd/C
H N
O N O
N
1) L-(+)tartaric acid Mother liquors 2) crystallization
1) NaOH 2) D-(-)tartaric acid 3) crystallization 4) NaOH
O O O
R1 N
R2
HO
R1 N O OH
R2
N
CH3 CH3 O HN
HCl
F N CH3 CH3 O HN
HO 1) NaOH 2) Ca(Ac)2
O O OH
F
N
CH3 CH3 O
Ca2+
HN
2
Moxifloxacin Hydrochloride 盐酸莫西沙星：喹诺酮类抗菌药
O F HN N OMe O OH HCl
cis-racemic H N N H2, Pd/C H N NH
(s,s)-isomer
O F F OMe O F F OMe CH3 F O O O F Cl KO
O
O O CH3 F F OMe NH2
O
O O CH3 CH(OEt)3 Ac2O
Et3N
F
O F F OMe F
O O NH CH3
1) HOBT, EDC 2) Chormatography
瑞伐托酯: 支气管扩张药
O O OH S O
N
CH3
O O Cl OH S LDA CH3 OH S CH3 MeOH H2SO4
O O S CH3 CH3 HO
N
NaH
O O S
N (CH2O)n NaH CH3
O O S
H N chromatography over SiO2 CH3 OH
N H
COOCH2Ph
N
EtOH
Belaperidone 抗精神病
O H F MgCl THF OH HCl Cl F tol F HN F HCl acetone hv resolution HN I O OH HBr N H N O Br II F H2N
COOCH3 NH2
H2N ClCOOCH3 K2CO3 COOCH3 NHCOOCH3
CH3 N CH3
F CH3 N CH3
CH3 O CF 3 Ph Cl O
F CH3 O CF 3 Ph NC O OH O HPLC
F CH3 O CF 3 Ph NC O OH O
CH3 N CH3
CH3 N CH3
t-BuOK
F NC O N CH3 CH3
O CH3 B O Br Na2CO3 H2O2 H3C HN OH O Br CH3 NaH
CH3 N N
O
OH H3C O N
O
CH3 N N
CH3
Robalzotan : 抗抑郁药
OMe NH2 O OMe Br2 O Br Ph N O F Ph Pd/C HCOONH4 F O OH N O F O HCl OH N O F F SOCl2 F O Cl N O F NH3 O (CF3SO2)2O F3C S O O N O F NH2 N O CO, MeOH Pd(OAc)2 O O OMe N O NH2 PhCH2Br K2CO3 Br O OMe N Ph Ph
CH3
1) NaF 2) H+
O O F F OMe N O OH F H N NH 1) Base 2) HCl HN N OMe
O OH HCl
Flesinoxan Hydrochloride :抗高血压
O O N N F H N O HCl OH
O OH Epichlorohydrine K2CO3, DMF
手性药物合成举例
Lanperisone Hydrochloride 盐酸兰砒立松 ： 肌肉松弛药
O N F3 C CH3 HCl
CHO F3C
EtMgBr F3C
OH CH3
CrO3 H2SO4 F3 C
O CH3
Ac O HN HCHO HCl F3C CH3 N
H N
COOH D-maleic acid
O O OH
O O HN N
O
O N
O OHC 3 O CH3 CH3
Pd/C, H2
O H3C N
H N
OH C 3 O CH3 CH3 I
CH3 O HO OMe
p-TsCl Et3N TsO
CH3 O OMe CH3 O TsO OH C 3 O CH3 CH3 NaOH TsO
CH3 O OH H3C
3+
O catalyst H3C O
O
CH CH3 3
F
Atorvastatin Calcium 阿托发他汀钙 ： 降血脂药
HO O O OH F CH 3 N CH 3 O HN Ca2+
2 R1 N O
O HO NC
OEt H 3C O
R1 N
LDA R2 R1=OMe, R2 =Me HO NC
SOCl2 TsO
CH3 O II Cl
O
O Et3N NH2
t-BuOK I+II
O H3C N
N
H3C
O
O CH3 N H O H3C N N O OH C 3 O CH3 CH3 HCl H3C O
O CH3 N H O N H3C O O N OH HCl
左布比卡因 ：局部麻醉药
1
路
线
CH3 HO O NH2 N H CH3
H3C O CH3 O O OCH2Ph
H3C
O OH
TsCl Pyr
H3C
O OTs
NaH
AcOH
H3C O
H3C O
OH OCH2Ph HO O OCH2Ph O O OH TsCl Et3N DMAP TsO O OCH2Ph OTs H2 Pd/C
TsO O OH
OTs
K2CO3
OTs I
O O N O Br HO O NaH
CH3
HBr
H N
CH3
OMe CH3 N S
OMe
OH
HO O
Se3N/BH3
OH OH
Talampanel ：抗癫痫药
CH3 O CH3 O2N OH CHO O O O CH3
O O
chiral reduction
O O
O O2/NaOH DMF/DMSO O
CH3 O OH H2N
H N
CH3 O CH3 O O N OH H N
NO2 O CH3 MsCl
NO2
NO2 CH3 O N N Pd/C CH3 O O N N O CH
3
CH3 O O N OMs H N O CH3 NaOH O O
CH3
NO2
NO2
NH2
Tonabersat : 抗偏头痛
OAc DCC COOCH2Ph CH3 NH2 CH3 OH K2CO3 TsCl H N O CH3 OTs K2CO3 CH3 H N O CH3 N H COOCH2Ph
OAc CH3 H N CH3 O
N H
COOCH2Ph
CH3
CH3
H N O CH3
BuBr K2CO3 N H
CH3
H N O CH3
O
R2
Et 2BOMe NaBH 4
R1 HO HO NC O N R2
H 3 C OMe H3C OMe H3 C H3 C O O O
R1 N R2 H 2, Ra-Ni
R1 H 3C H 3C O O O N R2
MeSO 3H
NC
NH 2
F OO CH3 CH3 O HN heat F
H3C H3C
O N O O
O O N2H4
O H2N O O II O O I+II O N H O O HCl
Escitalopram Oxalate 抗抑郁
1
路
线
NC MgBr NC O O F F NC OMgBr CH3 OMgCl N CH3 NC AcOH OH OH O OMgBr
NC
OMgBr ClMg O
O O S
N F3COOH
OH
CH3
O
N HPLC O S CH3 O
O O OH S O
N
OH
SiO2
CH3
盐酸咪达普利 ： 抗高血压
H3C
O
O CH3 N H O N H3C t-BuOH ICH OH C 3 O CH3 CH3 K2CO3 O H3C N O O N OH HCl
O O HN N
F O I+II N H N O N
孟鲁司特钠 抗过敏
O Cl N H BrMg CH2 tol/THF Cl N OH CH2
Br H3C O O DMF Pd(OAc)2 Cl N H3C O O OH Cl N H3C MeSO2Cl (i-Pr)2NEt Cl tol acetonitrile N H3C HO O O OSO2Me I CH3 MeMgCl CeCl3/THF OH Cl N H3C HO O CDIB THF
CH3
OH OH CN
(i-Pr)2SO or SOCl2 CH2Cl2
O S O O COOH
NaCN CH2Cl2 HO
CN MeSO2Cl MeSO2O
CN
MeCOSK
NaOH Ac S tol H2O
II HS
O
OH
1)BuLi I+II 2) H N Cl N
S
H3C HO
CH3
MKC-242 抗抑郁
Br H3C H3C O OH t-BuOH DCC H3C O O t-Bu t-BuOK O O t-Bu
NBS, AIBN
Br
O O t-Bu II CH3 H2SO4 H3C N O O t-Bu N N O OH
CH3 t-BuOK I+II H3C N
CH3 N H2N OH H3C N O N H OH
O O N3
O O H2 Pd/C O N F O N NH2 Ac2O N F
O N
O
H N O
CH3
Lisofylline :促造血药
O H3C B H3C O Br OH OH O B O Br CH2Cl2 BuLi
Cl O B O
Cl Br Li
ZnCl2
Cl O B O Br
MeMgBr
或
HCl O N HCl CH3
F3C
Linezolid 吗啉噁酮 ：抗菌药
NO2 NH O F F O H N PhCH2OCOCl NaHCO3 O N F NO2 (i-Pr)2EtN N F HCO2NH4 Pd/C O O O COOCH2Ph H3C BuLi O O O MeSO2Cl Et3N O N F O N OMs NaN3 N F N O N F O O N OH N F NH2