chiral separation

1
15 ?????? chiral separation
? ?????????????????????? ? ?????????????????? ?
????????????? ? ????????????????
2
COOH
COOH
??????????
?????
OH
HO
H
H
CH
CH
3
3
HOOC
COOH
H
H
H
C
CH
3
3
OH
HO
o
o
o
o
, mp 25.8 C
3.82
, mp 25.8 C
-3.82
,
????
d-?()-
,
l-?(-)-
????
?1 ?????????
3
1 ????????
??????????????????????????L.
Pasteur????????,????????????
???????????????????,????????L-??(D-??????????????
???????)? DNA???????D-??????L-????D-??????,???
??????????? ???,??D-??????????L-???,??????????
,???????????
4
 
?2??????????
Thalidomide
(???)
R-???????
??????
S-???
5
????(Thalidomide)
--------???????
?????,??????????????
50???,???????????????,???????
R-()-?????????? S-(-)-?????????
6
20??90???,??????,??????????????,?????,?????
????????,?????????????????????????????,???????????
???????????,?????????????? ??,????????????????
???????????
7
???(paclobutrazol)
-------- ???????
(2R,3R)-()- ????
(2S,3S)-(-)- ?????
???????????,????? ?????????
8
??????????
--------???????
? ????????????? ? ??????????????,??????????? ?
??????????????????,????????????
9
??????????
????????????????,????????????????????????????(
??????)?????????????????????????????????????????
?????????????,???????????????????
10
???????????
? ?????????? ? ????????????????????????????
????????
???????,??????????(???????????????????????????
??)????,?????????????
11
2 ??????????
???(chiral pool)
??
??????
?????
?????
???????,???????????????
??? ??? ?? ???
????
??
12
? ??????????????????????,????????????????
?????,?????????????????????????
?  ????????????????????????????????????
?  ????????????????????,??????????
13
3   ????????
?????????,????????,??????,???????????????????
?,???????(resolution)?????,??????????????,????????
????
14
3.1 ?????
? Pasteur???????? 1849?,Pasteur??????????,???
???????????27??????,????????????,???????????????
Pasteur?????,????????????????????????????????????

?3 ?????????
????????,?????????????,?????????
15
???????
??????????????????????????????,????,?????????
?????? ?????,??????,?????????????,???????????
??????,???????????????
?????????????,???????????????(??????????)???,?????
??(????)
??????????????,????????????
16
D,L?????????????????
80???
17
3.2 ?????
??????????????????????????????????????????????
?????,???,????????????,???????????????
1858?,Pasteur????????????????????????,???()-????
?????,?????????,??????????(-)-????????????????()-
???,????(-)-????
18
?5 D,L-?????????????

????????????????????????????,????????????????
?
19
???????????,?????????????? (1)???????????????
? (2)????,???,???????? (3)???????,?0
50?,pH???? (4)???,???,????????,???????
?????????????????????????????????????,??????????,?
???????????
20
3.3 ?????
????????????????????????
????????? ? ???????? ?
????? ? ?????? ? ??????
???????????????????
21
???????
?????????????????,?????????????,??????????????
(?????)????,??????????????????????????????????,???
??????????????????????????????????????????????????

?????? ?????? ??????????
22
()-????
D(-)-????????????,????????()-????????????????????
??????????????????(????, 1998 ,13(5)40)
23
????????????????????? ? ???
(1)????????????????????????????,??????????????????
? (2)???????????????????,?????????
(3)??????????????,???????????????????????(-)-B????
???90(???10?()-B),?????()-A?,??????????10????
()-A? (-)-B? (-)-A? ()-B?
(-)-A? (-)-B? ()-A? ()-B?
????
?
10
24

• (4)????????,??????
• ??????????
• ?????(-)-?????(-)-?????D-(-)-???? ????!
• ?????()-????()-????()-???-10-???L-()-?????
• ??????????????????????????,????????(???)???????
• ?????????????????????????????????

25
Dutch Resolution(??????)
99?9??????????????????,Vries T???????Dutch
Resolution???????????,???????????????????????????
,?????????????(families of resolving agents)
,??????????????????????????,??????????????????????
,???????????????????? ?? Vries T et. al.,
Angew. Chem. Int. Ed. 1998, 372349
26
3.4 ?????
??????????????????????????????????????????????
?,?????????????????????? ???,????????????,????
??????????????????????????????????????????????????
??????????,????,???????????????,???99??????
27
4 ????????
????????????????,??????/???????????????(????)
?????????,????????(?????????????????????????)?
???? ????????????????????????? ???/????????
28
4.1 ????????
?   ???? ???????????,?????????,?????????????
?????????? ?   ???????? ????????????????????
?,??????????????????????? ????????????????????
?????? ?   ????????
29
4.2 ??????

• 1) ???????
• ????????????,??????????,??????????????,???????
  ???????????,??????????????
• ???????????????????????????????????????,????
• ????????????????
• ???????????????????
• ???????????????

30
???????????????????,??????????????
?????????????????????,????????????????????????????
?????,??????? ?????????????????????????????,??
????,???????????????(????????)?
31
(-)-A(-)-B // ()-A(-)-B
?????
?????
????,???????????
????????Mosher??,??GC?HPLC???????????Mosher??????
????(Durabond DB-5 ,0.330 m?)?????4-???????Moshe
r?????????(Nucleosil 100-5?)???
32
2)   ????
??????????????????
??????????????,????????????????????
?????????????????????????????????,??????????
?????????,?????????,??????????
???,???????????,??????????????????????????????????
?????????????????????????
33

• ????????????,??????????????????????????(??????
  ??????????a???)?
• ??????????????
• ??????
• ??????
• ?????????-???????????????????????????????????
  ?,????????(????)?????????????????

34
??????
?????,???,???
(S)-???
(R)-??
?????,???,???
35
?????????????,????????????????????
????????????Pirkle???????????????,??????????????
?????????,???????????????????????????
??100????7000?????? ??????????????? ????????????
??100??
36
??????
???????????????????????????(CA),CA???????????
?????????????,??????????????????,?????????????????
?? ?????????????,????????????,?????????????CA?
?????????????????????????????,????????????????????
??????? ???CA???????????????????????????
37
TLC?????????

• ?D-10-?????????????????????,????GF254?????(2
  .510cm) 24???,??????(Labarol)?????(Batarock)????
  ????????
• Labarol CH2Cl2-CH3OH (6733),?D-?????6.8 mmol / L
  
• (b) Batarock CH2Cl2-CH3OH (6040),?D-?????6.8
  mmol / L
• (????,??, 1999 ,17216)

38
HPLC??????
????????OFLOXCIN,????????????(LEVOFLOXCIN),???C
ravit?
???d-phen, ??????????!
6 mmol/L l-phen CuSO415CH3OH
(pH3.5),Shim-Park PREP ODS (20mm25cm),
4.6mL/min, 293nm, 0.5ml15g/L ()-OFL
39
?????
???
40
?????????????
()-PSA????????????(-)-?????
15 mmol/Lß-CD 3 CH3CN 0.05 CF3COOH
0.30 mmol/L TM-ß-CD 16CH3CN 0.05CF3COOH
Nova-pak C18???
41
4.3 ??????
? ???? ? ?????? ? ?????
? ?????
42
(No Transcript)
43
(No Transcript)
44
4.3.1 ????

• GC?????????????????????GC?????????????????????
  ???????,???????????,????(10-8g),?????????????????
• ????????? gt 95???,????GC?HPLC???????(????)
• ???????(??????)
• ??????? (???)

45
????????????? ?  ????????????????????,??
????????????????????????????,???????????????? ?  ?
?????????????????????????????????????????????????
????????????????????????????????????
46
?  ?????????????????(Eu?Rh?Ni?Mn?Cu?)?????(??????
?,??????????????)????????????????????????(????)??,
???????????????????????????????????????????????? ?
 ?????????????????????????,??????????????????????
?????????????????,?????????,??????????????????????
???????????????????????????????????????????,??????
?????????
47
4.3.2 ??????
??????? ? ??????(Pirkle?????) ?
????????? ? ??? ? ?????? ? ???????????????
???????p-p????-???????????????????????????
48
??????(Pirkle?????)
??Illinois???W H Pirkle ?????,????Pirkle??????
(multiple-interaction)?????,????Brush-Type(??)????
????????,Pirkle?CSP??????????????????????????????C
SP???????????,????????????????????????? (1)p-??p-
???,????-????????(??????)? (2) ??????/??? (3) ????
?????????? (4)????????,????????????????????
49
Pirkle????????????CSP????????????????,???????
?(0.220)????????,???????????????????
???????????????? Pirkle?CSP???????????,??????
???,????????????????????,??????????,??????????????
??????????????????????????????????,??????????????
??
50
Chiral (S)-LEU (S)-NEA column, flow rate 1.0
mL/min, wavelength detection 275nm. Mobile phase
a) n-hexane/1,2-dichloroethane/ethanol (97.5
2.450.05,v/v/v) b) n-hexane/1,2-dichloroethane/e
thanol (86122,v/v/v)
51
?????????
?????
????D()-??????1,4-??????????????????????????
?????????????????,???????,????????????
?????????????????????,??????????????
??????????????????? ???????????,????????????
?????????Diacel????????????????
52
????,????CSP????????????????????(steric
fit)????,CSP?????????????,????????????????????????
????????????????????????????????????????
???CSP?????????????,?????,????????????????????????
?????????????,??????????/????????????????
??CSP???????,???????????????,???????????,??????,??
??,???????????????????????????????8085???OD?OJ?A
D?.
53
???????????1-????????
RH,Cl,Br,CH3
?????????????(CHIRACEL OB ,I.D.
4.6250mm)??1-?????1-?????2-?-1-?????2-?-1-???????
???,????????????????????????????(??????,1998,37(2)
309)
54
???????????????
???????CSP??????????? (1)??????????? (2)????
?? (3)????????? ????(imprinting)????????????
?????????(template)??,?????????????,?????????(sh
ape selectivity)??,????????????????
55
4.3.3 ?????
?????(CE)?20??90??????????????????????????????
?????????????? ? ???????????????? ?
??????????,?????
56
??????????? ??????????(?)

• ??????,?????????????,????????????????
• ?????????????????,???????,????????????,??????
  ????????
• ????????,???????????
• ????????
• ???????????????????
• ????????????????
• ?????????????????

57
?????????????????????????,??????????

• ??????????????
• ?????????
• ??????????????????????
• ?????????,???????????????,???,?????
• ???????,???????,???????
• ???????????,???????????????????

58
1) ????????
????????????????????????2) 2) ??
Kuhn????4??????18-?6-???(18C6H4)??????,?a??????,??
????????,????,phenylglycinol??????? 3) ???
Armstrong ???????????B????????????,?18????????????
???????????????????ristocetinA ,teicoplanin
,vancomycin????????????????,???????????????? 4)
??? ??????????????????????????,???????,???????
??????????
59
????????????????????????
????????????????????????
????????????,?pHlt7.00?????????,????????????
ß-CD??????,???????????pH???,???????ß-CD????????,??
????????? ?CM-ß-CD(???-)???????????????????????
,???????????? (???,??, 1998, 16(1)22)
60
(No Transcript)
61
Chlorthalidone ??? is a drug exhibiting diuretic
and hypertensive activity, but since it is
neutral, its enantiomers cannot be separated by
CZE using a neutral chiral selector. HPLC
Cyclobond I 2000 RSP column , CH3CN-70mM
triethylamine (595 v/v) adjusted to pH 4.1 with
acetic acid.
3 mm ODS, 50 mm I.D. capillary, 25.9cms packed,
52cms total length, Electrolyte
Acetonitrile/Phosphate buffer pH6.5, Ratio a)
1585, b) 2080, c) 2575, with 10mM HP- b -CD
( 1mM Na2 HPO4 , adjusted to pH6.5 with
concentrated H3PO4 ), Applied Voltage 15kV,
Detection at 220nm. ????
Fig. 16 The influence of acetonitrile on the
separation of enantiomers
62

• Electrolyte Acetonitrile/ Phosphate buffer
  pH6.5, Ratio
• 1585, b) 2080,
• 2575, d) 3070
• ( 5mM Na2HPO4 adjusted to pH6.5 with
  concentrated H3PO4 )

Fig. Separations at different acetonitrile
concentrations 5 mm HP b CD bonded silica
particles, 50 mm I.D. capillary, 27cms packed, 58
cms total length, Applied Voltage 15kV,
Detection at 220nm.
?????
63
4.4 ??????????
? ???????(SFC) ?HPLC??,????????????????????????G
C??,??????????????,????????????,??????????????????
??????????????? ? ???????(SMB)???????????????????
?,????????????????????92?Negawa
?????????????????????????????????,?????????,??????
????????????????????????????? ?
???????????????????,?????U-1????????????????(???,
???,????????,1999,20884-886)
64
5 ????????????

• ????????????
• ????????????????

65
5.1 ????????????
???????????????????????,?????????????????????
,???????????????????????(????????????????)????????
???????????????????????,???????????????????
??????????,??????????????????
??? ??? ???
66
   ????
???? ????
(????)
?????,?????(RSD gt 4) ? ??????????????? ?
??????????,???? ? ???????????
???????,?????????????????????????,?????????90?
67
     ?????
?????????,?e.e.?(enantiomeric excess)??
?
???????e.e. ??,????????????????????(????)
????????????????????????????????????????
68
??????????????
? ????? ?????(CDA)
????????(CLSA) ????(SA)
? ??????????????????? ? ???????????? ?
?????????????? ? ???(????,??,???)
Enantioselective analysis Enantioselective
assay
69
(No Transcript)
70
5.2 ?????????????
??????????????????,?????????????????????????
?????????????,????????????????????????????????????
????,?????????????????????????????,?????????????
71
  ???????????
?????????(??????)?????????????
?????????????????,?????????????????????????,??????
???D-???????????????????????????????
72
   ????????????
?????????????????,????????????????????????????
????D-?????????????????????????L-?????????????????
???,??L-???????????pH???(?????L-???)??????
73
?????????
?????????????????????????????????????????????
????????????????,?????????????????????????????????
????????,???????????????,????????????????????????
74
????
?1 ?????????????????????????? ?2 ??????????? ?3 
????????????????????? ?4 ????????3-??-2-2-??-1-?
???-2,3-??-1H-???-1-?
75
????????????
???????????????,???D-??????,L-???????????,
??????????L-???D-?????? gt 2 ?L-??,????????????
?GC,?D-????????0.1 ?L-????????,???D-???????????
76
??????????????????????
??????????,???????????L-???????????,?????L
-?????????????????D-?L-???????????????????????????
??,????????????????????????????????????,?????????
40????????(????,????,1987,15(9)786)
77
3-??-2-2-??-1-????-2,3-??-1H-???-1-?????????
?????????????,?????
???????????
(3R,1R)
(3S,1S)
Chiral (S)-LEU (S)-NEA, 1.0 mL/min, 254nm.
n-hexane/2-propanol (99 1,v/v)
(3S,1S)
(3R,1S)
78
 ????????????
??(??????) ???? ????????? ???(????) ????(?????????
) ??,??60 ????????????????
79
(No Transcript)