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DC LIU CHA ALKALOID

AI CNG
BM. DC LIU
TRNG AI HOC Y DC CN TH
Nguyn Ngoc Quynh
MC TIU HC TP
1. inh nghia, danh phap, cac tinh cht ly hoa,
trang thai t nhin cua alcaloid trong dc
liu.
2. Phn loai alkaloid theo cu truc hoa hoc.
3. Ph.phap chit xut, phn lp akc. t dc
liu.
4. Cac ph.phap thng dung inh tinh, inh
lng akc.
5. Cac ni dung chinh v 20* dc liu cha
alcaloid.
NI DUNG
1. Lich s, inh nghia, Danh phap
2. Cu truc Phn loai
3. Phn b trong t nhin
4. Tinh cht chung
5. Chit xut Phn lp
6. Kim nghim (inh tinh inh lng)
7. Cng dung
1.Lich s, inh nghia, Danh phap

Thc vt cht trung tinh, cht acid


binh thng
(mui, ng, cac cht chua . . .)

Thc vt cht co tinh kim bt thng

trai quy lut t nhin


1.Lich s, inh nghia, Danh phap
Fourcroy (1792)
Cht kim t Canhkina
Derosne (1803)
Mui thuc phin (narc +morphin)
Seguin
1.Lich s, inh nghia, Danh phap

Nm 1806

Friedrich Wilhelm Adam Sertrner


(1783 - 1841)
1.Lich s, inh nghia, Danh phap

AUX PHARMACIENS

PELLETIER & CAVENTOU


POUR
LEUR DECOUVERTE DE LA QUININE
1.Lich s, inh nghia, Danh phap
1805 Morphin Serturner

1817 Narcotin Robiquet

1818 Strychnin, Brucin Pelletier & Caventou

1819 Colchicin, Veratrin Meissner & Caventou

1820 Quinin, Caffein Runge; Pelletier & Caventou

1822 Emetin Pelletier & Magendie

1827 Coniin Giesecke; Geiger & Hess

1828 Nicotin Posselt & Reimann


1.Lich s, inh nghia, Danh phap
1831 Aconitin Mein; Geiger & Hess
1832 Codein Robiquet
1833 Atropin, Hyoscyamin Geiger & Hess
1833 Thebain Pelletier & Dumas
1842 Theobromin Woskresenky
1848 Papaverin Merck
1851 Cholin Babo & Hirschbrunn
1855 Cocain Gaedcke & Niemann (1860)
1870 Muscarin Schmiedeberg & Koppe
1875 Ergotinin C. Tanret . . .
1.Lich s, inh nghia, Danh phap
NH NGHA ALKALOID
1819 : C.F. Winhelm Meiner (Meissner; c)

ALKALOD

- hp cht hu c - co phan ng kim


- co cha Nit - t thc vt
Tuy nhin, sau o a tim thy

Phyllobates aurotaenia
Dendrobates pumilio Bufo bufo Salamanders

?!!?

batrachotoxin serotonin samanin


pumiliotoxin bufotenin, samandarin
bufotenidin
Tetraodon miurus Puffer Fish

Tetrodotoxin
Ascaris suum Claviceps purpurea Claviceps sorghi

Morphin Agroclavin Caffein


(J. Immun., 2000, Fitopatology Brasil,
165, pp. 339343) 28(4), 2003

(1168 278 ng/g giun) # 1 ppm !


Su bi (Glomeris marginata) Hai ly (Castor fiber)

Glomerin, homoglomerin (P)-castoramin


1.Lich s, inh nghia, Danh phap
NH NGHA ALKALOID
(Max Polonovski 1861 - 1939)
Max Polonovski (1910): Alkaloid la cac
Hp cht hu c, co phan ng kim.
Co cha N, a s co nhn di vong.
Thng t thc vt (i khi t ng vt).
Thng co dc tinh manh.
Cho phan ng vi cac thuc th chung cua
alkaloid.
1.Lich s, inh nghia, Danh phap
NH NGHA ALKALOID
Theo T. Lewis (1986) : Alkaloid la nhng hp cht hu c :
Cha Nit, co ngun gc thc vt, thng co di vong,
Thng co cu truc phc tap, thng co MW ln.
Co nhom ammoni bc 1, 2, 3; i khi bc 4
Rt it tan trong nc; tan c trong cn, Bz, Et2O,
CHCl3
Tao mau hay tao tua vi cac thuc th cua alkaloid,
Co tac dung dc ly manh,
c s dung rng ri trong y hoc lam thuc tri bnh,
Mt s co c tinh cao, ngay khi liu rt nh.
1.Lich s, inh nghia, Danh phap

Promethazin, Alimemazin...
cht tng hp
(tr cac cua alkaloid)

acid amin, histamin,


cht truyn thng
vitamin (B1, B2, B6 ...)

acid amin, histamin, kiu nucleosid


vitamin (B1, B2, B6 ...) (tr serotonin...)
1.Lich s, inh nghia, Danh phap
Danh php alkaloid
T tn thc vt
Strychnos strychnin - S. rotunda rotundin
Berberis berberin - R. serpentina serpentin
Stemona stemonin - T. baccata baccatin
T tac dung
Gy nn emetin - Nha c (tubo)curarin
Cht nn vomicin - Morpheus morphin
Ha nhit febrifugin - Atropos atropin
T tn ngi
- Pelletier pelletierin - Nicot nicotin
Morpheus

Morphine

Thalanos, Hypnos Icelus, Phantasus, Morpheus (Thn Gic m);


1.Lich s, inh nghia, Danh phap
Tip u ng :
nor / epi / iso / neo / pseudo + X + in.
(pseudoephedrin)
Tip vi ng :
X + idin / anin / alin / amidin (quinin /
quinidin)
2. Cu truc Phn loai
Phn loi alkaloid
1. Theo tac dung dc ly
2. Theo ho / chi thc vt
akc / ho Solanaceae / chi Atropa / chi Datura
3. Theo ngun acid amin : t tyr, tryp, orn,
lys, his ...
4. Theo ng sinh : pseudo-, proto-,
alc. thc
2. Cu truc Phn loai
Phn loi alkaloid theo sinh tng hp
1.Alkaloid thc (N t acid amin thuc di vong).
Hu nh lun kim; cha 1N / di vong
ai a s tn tai dang mui vi acid hu c
Co th dang t do (alk. base), dang N-oxid alkaloid
Mt s dang glycosid
Phn b hep, co hoat tinh sinh ly (thng c / CNS)
2. Protoalkaloid (N t acid amin khng cu thanh di
vng).
ephedrin, capsaicin, colchicin, hordenin, mescalin)
3. Pseudoalkaloid (N khng bt ngun t acid amin).
(cafein, coniin, aconitin, conessin, solanidin)
2. Cu truc Phn loai
Phn loi alkaloid
Theo cu truc hoa hoc
Alkaloid c chia thnh nhom co cng khung c
bn
Nhng khung c bn ny co cu truc n gin, ch
c 1 hay 2 vng
Trong mi nhom alkaloid c chia thnh nhng
nhom nh
Tng i logic v tin dung
Tuy nhin khng phn anh mi lin h gia cac
alkaloid trong cac taxon thc vt
Thng c cac nh hoa hoc s sung
2. Cu truc Phn loai
Phn loi alkaloid
6.Theo sinh & cu truc hoa hoc :
Cac nhom ln c xp thnh theo sinh
nguyn
Cac phn nhom chia theo cu truc hoa hoc
Khng khac nhiu vi phn loi hoa hoc. Tr
mt vi trng hp cng cu truc khc
sinh nguyn
Hin vn s dung nhiu. n gin v logic
hn, m bo tnh cht t nhin v ngun
gc.
alk. pyrol, pyrolidin,

alk. tropan, indol, indolin


alkaloid thc (N/vong)
alk. quinolin, isoquinolin...
alk. pyridin, piperidin...

alk. phenyl alkylamin


proto-alkaloid (N/nhanh)
alk. tropolon

alk. terpenoid, steroid


pseudo-alkaloid
(N khng t acid amin) alk. purin, peptid
2. Cu truc Phn loai
Phn loi alkaloid
1. Alkaloid thc
La nhom ln & quan trong nht (alkaloid chinh
thc)
Sinh nguyn : t cac acid amin (khac
pseudo-alkaloid)
Co N / nhn di vong (khac proto-
alkaloid)
c chia thanh nhiu nhom tuy nhn cn
ban
(pyrol, indol, tropan, quinolin, isoquinolin)
2. Cu truc Phn loai
Phn loi alkaloid
1. Alkaloid thc
1. Alkaloid pyrrol v pyrrolidin
2. Alkaloid pyrrolizidin
3. Alkaloid tropan
4. Alkaloid pyridin v piperidin
5. Alkaloid indol, indolin
6. Alkaloid indolizidin
7. Alkaloid quinolizidin
8. Alkaloid quinolein
9. Alkaloid iso-quinolein
10. Alkaloid quinazolin
11. Alkaloid imidazol
2. Cu truc Phn loai
Phn loi alkaloid
1. Alkaloid thc
1.1. alkaloid pyrrol va pyrrolidin

O O

N N N N N
H H Me Me
Me

pyrrol pyrrolidin hygrin cuscohygrin

1.2. alkaloid pyrrolizidin


HO CH2OH
N N

pyrrolizidin retronecin
Phn loi alkaloid
1. Alkaloid thc
1.3. alkaloid tropan

N OH N O N OH

tropanol (tropin) tropan scopanol (scopin)


COOH

N OH N OOC CH Ph
CH2OH
ecgonin hyoscyamin
COOMe

N OOC Ph
O N OOC CH Ph
CH2OH
cocain
(benzoyl) scopolamin
Phn loi alkaloid
1. Alkaloid thc
1.4. alkaloid pyridin va piperidin
COOMe

N
N
N N Me

pyridin nicotin arecolin

O O O

N N N
H Me H

piperidin lobelin isopelletierin


Phn loi alkaloid
1. Alkaloid thc
1.5. alkaloid indol, indolin (1)

COOH Me
N
NH2 Me
N N N

H H H

indol trytophan gramin

HO COOH

NH2 NH
N N N Me
H H H

indolin serotonin abrin

kiu indol alkylamin


Phn loi alkaloid
1. Alkaloid thc
1.5. alkaloid indol va indolin (2)

Me Me
N
Me
O
N N N N
H H Me Me

kiu eseran eserin

N
N
N H Me
N
H
harmin
kiu -carbolin
Phn loi alkaloid
1. Alkaloid thc
1.5. alkaloid indol va indolin (3)
COOH

N H N Me

N N

H H

kiu ergolin : ergolin acid lysergic

N N
MeO

N MeO N

O O O O

kiu strychnan : strychnin brucin


Phn loi alkaloid
1. Alkaloid thc
1.5. alkaloid indol va indolin (4)
kiu yohimban MeO N
N
OMe
H

O OOC OMe

OMe OMe OMe

reserpin

N N
N MeO N
H H
O O O

OMe OH OMe OMe

yohimbin ajmalicin
Phn loi alkaloid
1. Alkaloid thc
1.6. alkaloid indolizidin
OH OH
HO

N N
HO

indolizidin castanospermin

1.7. alkaloid quinolizidin

N
N

quinolizidin spartein
Phn loi alkaloid
1. Alkaloid thc
1.8. alkaloid quinolein

N N

quinolein acridin


HO HO
N N
R R

N N

quinin (R = OMe) quinidin (R = OMe)


cinchonin (R = H) cinchonidin (R = H)
Phn loi alkaloid
1. Alkaloid thc
1.9. alkaloid iso-quinolein (1)

N N

quinolein iso-quinolein

kiu benzyl isoquinolein,


kiu aporphin,
kiu morphinan,
kiu protoberberin,
kiu protopin,
kiu emetin, . . .
Phn loi alkaloid
1. Alkaloid thc
1.9. alkaloid iso-quinolein (2)

kiu benzyl isoquinolein

MeO MeO

N N Me
MeO MeO
OMe OMe

OMe OMe

papaverin laudanosin
Phn loi alkaloid
1. Alkaloid thc
1.9. alkaloid iso-quinolein (3)
kiu aporphin
MeO O

N R N Me N Me
MeO O

aporphin nuciferin / Sen roemerin / Binh vi

HO MeO

morphin O O
codein
N Me N Me
HO HO

kiu morphinan
Phn loi alkaloid
1. Alkaloid thc
1.9. alkaloid iso-quinolein (4)
MeO

N N
MeO
MeO

MeO

kiu protoberberin palmatin

O MeO

N N
O MeO
MeO MeO

MeO MeO

berberin rotundin
(tetrahydro palmatin)
Phn loi alkaloid
1. Alkaloid thc
1.9. alkaloid iso-quinolein (5)
kiu emetin
MeO

N
MeO

Et
CH2
OMe
H N

OMe

Ngoai ra con cac kiu

- bisbenzyl iQ, phtalid iQ,

- protopin, benzophenanthridin . . .
Phn loi alkaloid
1. Alkaloid thc
1.10. alkaloid quinazolin
O O
OH
N N
N N
O O
N N HO

-dichroin -dichroin
(Thng sn, Dichroa febrifuga Saxifragaceae)
1.11. alkaloid imidazol
Me Et
N N

N N O O
H H

imidazol pilocarpin
2. Cu truc Phn loai
Phn loi alkaloid
2. Proto-alkaloid
C sinh phat nguyn t acid amin ( decarboxyl)
Cu truc n gian; gp / ca thc vt ln ng vt
Thng l hp cht thm co N / mach nhanh
Mt s tac gia xp vao nhom amin thm ( alkaloid !)
Mt s tac gia lai coi cac amin thng la 1 dang
alkaloid.
Cac kiu proto-alkaloid thng gp
- kiu phenyl alkylamin (ephedrin, mescalin, capsaicin...)
- kiu tropolon (colchicin...)
- kiu indol n gian (serotonin, gramin, abrin...)
COOH COOH

NH2 NH2 NH2


HO HO

tyramin phenylalanin tyrosin

O
MeO
N
H
capsaicin
HO

OH
MeO

NH2
MeO N N
HO H Me HO Me Me
OMe

mescalin ephedrin hordenin


Nit co ngun t acid amin

COOH Me MeO
N
O
NH2 Me
N N MeO
N
H H
MeO H
tryptophan gramin
O
OMe

HO COOH

NH
colchicin
NH2
N N Me
H H

serotonin abrin
2. Cu truc Phn loai
Phn loi alkaloid
3. Pseudo-alkaloid
alkaloid kiu purin : theobromin, cafein, theophyllin
O O O
Me Me Me Me
N N N N N N

O N N O N N O N N

Me Me Me

alkaloid kiu steroid : conessin, solanidin,


OH N
N

N HO

conessin / Mc hoa trng solanidin / Solanaceae


2. Cu truc Phn loai
Phn loi alkaloid
3. Pseudo-alkaloid
kiu alkaloid terpenoid : aconitin, mesaconin, taxol

Paclitaxel = Taxol

kiu alkaloid peptid : ergotamin, ergocryptinin


2. Cu truc Phn loai
c im chung v cu truc

s Nit : - thng t 1 2 (i khi > 2 Nit


dimer)
Loai vong: - a s : di vong Nit
- mt s : vong carbon (protoalkaloid)
s vong: - t khi 1 vong duy nht (protoalkaloid)
- thng 2 5 vng
bc Nit: - thng la bc III (=N), bc II (NH)
thng co tinh kim; a s co pKa = 7 9.
2. Cu truc Phn loai
c im chung v cu truc
do m in ca Nit < Oxy
- lin kt N-H km phn cc hn lin kt O-H
- lin kt hydro N...H lng lo hn O...H
- alkaloid km phn cc hn alcol tng ng
im si ca alkaloid so vi alcol tng ng :
alcol > alk I > alk II > alk III > ether
tinh kim ca alkaloid so vi ammoniac :
NH4OH > alk IV > alk I > alk II > alk III (NR2)

pKa = 9,3 > tinh kim yu nht day


3.Phn b trong t nhin
Hin nay, a bit > 27.000 cu truc alkaloid / 6000 loai
thc vt (~20% thc vt bc cao).

Ch yu la thc vt bc cao, nganh hat kin.

It gp alk / nganh hat trn, nm & quyt thc vt.

Hu nh khng gp alk / TV bc thp (Ru, ia y, Tao)

Mt s ng vt, vi khun cung cha alkaloid.


(NAPRALERT, 2005) 27000

1975-2005 : 22.000 cht (02 alk / ngy)


(G.A. Cordell, 2001)
21200

(NAPRALERT, 1993)
16000

(Southon & Buckingham, 1989)


10000
1805-1975 : 5.000 cht (02 alk / thng)

5000
4000
2000
500 1000
300 400

1920 1930 1940 1950 1960 1970 1975 1990 1993 2001 2005
3.Phn b trong t nhin
Cac ho thc vt giau alkaloid
Apocynaceae Papaveraceae Fabaceae
Rutaceae Liliaceae Solanaceae
Amaryllidaceae MenispermaceaeRubiaceae
Loganiaceae Asteraceae Euphorbiaceae
Ranunculaceae Berberidaceae Cataceae
Cha tim thy alkaloid trong 4 b
Salicales, Fagales, Cucurbitales, Oleales
3.Phn b trong t nhin
Mt s (~ 800) alkaloid t ng vt
Mt s alkaloid t Nm (mushroom)
Mt s alkaloid t ngnh Ru (moss)
Mt s alkaloid t vi khun v vi nm
(fungus)
T Claviceps sorghi caffein (2003)
3.Phn b trong t nhin
S a dang va chuyn bit
Tom lai

trong 1 ho : co th gp nhiu nhom alkaloid.

cung 1 ho : hy vong co cac alkaloid cung nhom.

cung 1 chi : rt hy vong co cac alkaloid cung nhom.

cung 1 alk. : co th gp nhiu ho khac hn nhau.

Him khi alcaloid va tinh du ng thi hin din.


3.Phn b trong t nhin
Cac b phn cha alkaloid trong dc liu
Trong cy, alk. thng tp trung 1 s b phn nht inh

Hat : Ma tin, Ca dc Qua : Anh tuc, Tiu, t

La : Tra, Thuc la Hoa : Ca dc

Thn : Ma hoang R : Ba gac, Lu

V thn : Canhkina C : Binh vi, Bach b

Hanh : N hoang cung


3.Phn b trong t nhin

Berberin co trong 27 chi thuc >10 ho khac nhau :

1. Berberidaceae 6. Nandinaceae

2. Fumariaceae 7. Papaveraceae

3. Hydrastidaceae 8. Ranunculaceae

4. Juglandaceae 9. Rubiaceae, Fabaceae

5. Menispermaceae 0. Rutaceae
Trong ho Amaryllidaceae 30 chi co Lycorin

Amaryllis Crinum Haemanthus Pancratium

Ammocharis Curcoligo Hippeastrum Sprekelia

Brunsdonna Cyrtanthus Hymenocallis Sternbergia

Buphane Elisena Leucojum Ungernia

Calortemma Eucharis Lycoris Urceolina

Chlidanthus Eurycles Narciscus Valotta

Clivia Estephia Nerine Zephyranthes

Cooperia Galanthus
Caffein co trong nhiu cy

1. Tra (Camellia sinensis L., Theaceae)

2. C ph (Coffea spp., Rubiaceae)

3. Mate (Ilex paraguariensis,

Ilex vomitoria, Aquifoliaceae)

4. Guaran (Paullinia cupana, Sapindaceae)

5. Cola (Cola acuminata, Sterculiaceae)

6. Citrus (Citrus spp., Rutaceae; bao phn)


3.Phn b trong t nhin
Ham lng alkaloid :
Thay i theo iu kin dinh dng, sinh ly cua
cy
noi chung, [alkaloid] thng thp (# )
t alcaloid : di 1% (Wagner, 1996)
nhiu alcaloid : 1% (berberin: 2-3% /
Vang ng)

Vai trng hp c bit


- v thn Canhkina cha 6 10% alcaloid
- nha Thuc phin cha 20 30% alcaloid
3.Phn b trong t nhin
Ham lng alcaloid :

dang base dang mui dang glycosid


(# 0) (a s) (it)

vi acid v c (it)
vi acid hu c thng thng
vi acid hu c c bit
- acid meconic, tropic, aconitic
- acid gallic, tannic; tannin
4.Tinh cht chung
4.1. Ly tinh
kt tinh c
a s [C,H,O,N] rn / tO thng
mp ro rang
(tr arecolin; pilocarpidin)
(nu bn tO)

bay hi c,
a s [C,H, N] lng / tO thng
bn nhit,
(tr sempervirin, conessin)
ct ko c
4.Tinh cht chung
4.1. Ly tinh
- mui : thng khng mui
- vi : thng ng
(piperin, capsaicin cay; aconitin khng ng !!!)
- mau : thng khng mau
(berberin, palmatin, chelidonin: mau vang
jatrorrhizin mau cam, pyocyanin mau xanh)
- []D : thng ta trin
- pKa : thng t 7 9 (nn kim hoa v pH = pKa + 2)
4.Tinh cht chung
4.1. Ly tinh
1. co phn cc trung binh
- alk. base tan / dmhc co ph.cc trung binh n yu;
- nhng kho tan / cac dmhc qua km ph.cc nh EP, n6.
- p dng chit & tinh ch (kim hoa, bin alk. mui
alk. base, chit alk. base bng Bz, DCM, Cf, Et2O...)
2. co tinh kim
d bi ko vt trn ban si-gel pha thun (Si-OH).
khc phc : thm kim vao pha ng, vt s gon.
3. km bn (nht la khi + tO)
nn chit di dang alkaloid mui (bn hn)
4.Tinh cht chung
4.1. Ly tinh
alcaloid base : thng km tan / nc
d tan / dmhc km phcc
(tr cafein, nicotin, coniin, colchicin, spartein tan / nc)

alcaloid mui : d tan / nc


km tan / dmhc km ph.cc ( EP)
(tr berberin clorid, berberin nitrat km tan / nc
reserpin.HCl lai tan / CHCl3)

alcaloid phenol : dang base vn tan c / d.dich kim


(morphin, cephaelin)
4.Tinh cht chung
4.1. Ly tinh
Mt s alkaloid (ephedrin, cafein)
co th thng hoa c ap sut
thng
dung pp thng hoa tinh ch
(trn bt tra vi vi, un / cat),
4.Tinh cht chung
4.1. Ha tnh
Tinh kim
kim manh kim yu kim rt yu khng kim acid yu

colchicin
cafein arecaidin*
ricinin
nicotin A S codein guvacin**
ricinin
piperin isoguvacin
theobromin

alcaloid + acid mui tng ng


alcaloid + mui kim loai nng mui phc
alcaloid + thuc th chung ta hay mau
4.1. Ha tnh
Alkaloid base co tinh kim yu hn cac kim v c.

[alk mui] s giai phong ra [alk base]


bi Na2CO3, amoniac, M(OH)n

[alk.H]+.X + OH [alk] + (X/H2O)

Nu alkaloid co 2 Nit (2 chc base) :


- ca 2 N u co tinh kim : co th tao 2 loai mui.
Vi d : Quinin Q.HCl v Q.2HCl
- 1 N c tinh base qua yu : ch co th tao 1 loai mui.
Vi d : Strychnin (Str)2SO4
4.Tinh cht chung
4.1. Ha tnh
alcaloid (pKa) alcaloid (pKa) alcaloid (pKa)
berberin 2.5 pilocarpin 7.0 morphin 9.2 & 7.9
caffein 3.6 vinblastin 7.4 ammoniac 9.3
acid
4.8 heroin 7.6 -ephedrin 9.4
acetic
reserpin 6.6 scopolamin 7.7 ephedrin 9.6
quinin, brucin 7.8 amphetamin 9.9
quinidin,
7.9 atropin 10.2
codein
strychnin 8.3 nicotin 11.0 & 6.2
cocain 8.6
alcaloid %
pKa
alcaloid mui alcaloid base
100%

~90%

~75%

50% pH

~25%

~10%

(pKa 2) pKa (pKa + 2)

~99% la 50% la alc. mui ~99% la


alc. mui 50% la alc. base alc. base
Henderson Hasselbalch:

[base l.hp]
[alk. mui]+ + H2O pH = pKa + log
[acid]
Ka
[alk. base]
[alk. base] + H3O+ pH = pKa + log
[alk. mui]

[alk. base] = 100 [alk. mui] pH = pKa + 2


(> 99% dang alk. base; nu pH = pKa + 2)

[alk. mui] = 100 [alk. base] pH = pKa 2


(> 99% dang alk. mui; nu pH = pKa 2)
pH = pKa + 3 > 99.9% dang alk. base
pH = pKa 3 > 99.9% dang alk. mui

nu SKLM 1 alkaloid pH # pKa thi :


# 50% mu dang alk. base (km phn cc; Rf cao)
# 50% mu dang alk. mui (phn cc hn; Rf thp)

vt bi ko dai, co th tach thanh 2 nhom vt

cn thm kim n pH = pKa + (2 3)


SKLM alkaloid / Si-gel NP
vi pha ng co pH << [pKa 2]

alk.base, km phn cc hn, bi ko vt.

alk.mui, phn cc hn, vt gon hn.

Ngoi phn cc ca pha ng,


cn chu y n pH khi SKLM alkaloid !
4.2. Phan ng tao tua
tua v inh hinh tua tinh th

Valse-Mayer - AuCl3
Bouchardat - PtCl3
Bertrand (silico-tungstic) - acid picric (Hager)
- acid picrolinic
Reineckat - acid styphnic
Scheibler (ac. phospho-tungstic) - thth Marme
Sonnenschein (ac. phospho- (CdI2-KI)
molybdic)
thuc th thanh phn tao tua v inh hinh mau

Bouchardat KI + I2 nu, nu

Valse-
KI + HgI2 bng trng vng ng
Mayer

Dragendorff KI + BiI3 cam

Marm KI + CdI2 trng vng (co th k tinh)

Bertrand acid silicotungstic trng trng nga

Tannin acid tannic trng (tan / cn, AcOH, NH3)


4.2. Phan ng tao tua

alkaloid Valse-Mayer Bouchardat Dragendorff

quinin 8 ppm

morphin 400 ppm

caffein 100 ppm 1700 ppm


Trn vi phu (phan ng hoa m)

vi
ra bng ri + thuc th
ph Kt lun
cn tartric Bouchardat
u

1 khng ra co tua nu

2 co ra vn co tua nu

3 co ra khng con tua nu

- alcaloid va protein u cho ta vi th th Bouchardat


- alk. tan / cn tartric; protein khng tan / cn tartric.
thuc th thanh phn tao tua kt tinh

Vng clorid AuCl3. HCl


co mau thay i
tuy loai alkaloid
Platin clorid PtCl4. 2HCl

acid picric 2,4,6-trinitrophenol


c mu vng cam
acid styphnic 2,4,6-trinitroresorcin co hinh dang c trng
co im chay xac inh
acid picrolonic cua p-nitrobenzen
4.3. Phan ng vi thuc th c hiu (inh danh)

thuc th thanh phn Alkaloid s cho mau

Erdmann acid sulfo-nitric Conessin vng xanh luc

Frohde acid sulfo-molybdic Morphin tm

Mandelin acid sulfo-vanadic Strychnin tm xanh

Merke acid sulfo-selenic Codein xanh ngoc


Marquis sulfo-formol Morphin tim
Wasicky sulfo-PDAB Indol xanh tim n
HNO3 acid nitric . Brucin mau
4.3. Phan ng vi thuc th c hiu (inh danh)

Tac nhn: cac cht co tinh oxy-hoa manh

(acid sulfuric ., acid nitric ., sulfochromic...)

Mi trng thc hin : thng la khan.

Cho san phm mau kha chuyn bit, giup inh danh alk.

Mau thng km bn (quan sat nhanh)

Mau thay i tuy cac iu kin phan ng

(tO, pH va nht la mc tinh khit ca mu alkaloid).


4.4. Ph UV cua alkaloid
a s alkaloid : max 250 310 nm.
mt s alkaloid : max trong vung kha kin
max thay i theo pH m.trng (dang alk mui /
base)
c ng dung trong inh tinh, inh lng.

max UV cua mt s alkaloid


- berberin : 263 nm 345 nm.
- colchicin : 350 nm
- morphin : 285 2 (pH 4); 298 2 nm (pH 11)
- quinin : 281 2 v 331 2 nm
Ph UV ca morphin & codein (pH 4); morphin (pH 11)
5. Chit xut Phn lp
Nguyn tc chung
Alk la cac base yu, trong cy co th dang
- alk. mui vi acid hu c, v c (d chuyn dang)
- alk. phc hp bn vi tannin (kho chuyn dang)
Nu mun chit ngay di dang alk. mui :
Chit trc tip [Alc.H]+.X vi dung mi thich hp

Nu mun chit di dang alk. Base


cn dung kim (tr.binh / manh) tao phan ng :

[alk.H]+.X + OH [alk] + (X/H2O)


5. Chit xut Phn lp

Alk. mui / dc liu

ROH / H+ Dmhc / kim

Alk. mui / ROH Alk. base / dmhc

Dmhc / kim HOH / H+

Alk. base / dmhc Alk. mui / H2O

Thay i pH va dung mi
5. Chit xut Phn lp
5.1. CC PHNG PHP CHIT XUT ALKALOID
5.1.1. Chit dang alkaloid base

Bt dc liu
Lm m dc liu

Bt dc liu
Kim hoa
Chit bng dung mi km
phn cc
Dung mi cha
alkaloid Base
5. Chit xut Phn lp
5.1.2. Chit dang alcaloid base bay hi
nhit k va
b tip nc

hi nc si Alk base
ngng t

dc liu + kim
dung dich
acid loang
5. Chit xut Phn lp
5.1.3. Chit cac alcaloid base thng hoa
bong / khan lanh

phien knh

tinh the
Alkaloid chen nung

bot dc lieu
li amiant

R
5. Chit xut Phn lp
5.1. Chit dang alkaloid mui
Bt dc liu
Lm m dc liu

Bt dc liu
lam m
Chit bng dung mi cn,
cn acid, nc acid
Dung mi cha
alkaloid mui
PP. STAS OTTO (1850) Alk. mui / dc liu

Chit = cn acid C thu hi cn

ban u : Alk. mui / dich acid


cn - acid tartric
Lc vi Et2O B tap tan / Et2O
tap bng nc
Alk. mui / dich acid
dmhc l Et2O, CHCl3
+ Kim, Lc d.mi hu c

hin nay :
Alk. base / dmhc
acid thay i
C thu hi d.mi hu c
loai tap = dmhc / H+
dmhc thay i Cn Alkaloid base
5. Chit xut Phn lp
5.2. PHN LP V TINH CH

5.1. Loai b tap mau bng than hoat tinh


cn thm do t l C* it mt alkaloid.
5.2. Chuyn dang alk mui alk base
chon loai kim NH4OH, Na2CO3, NaOH, Ca(OH)2
chon pH thich hp (pH = pKa +2)
chon dmhc Bz, Et2O, DCM, Cf, Cf Et2O (3 : 1)
5.3. Chuyn dang alk base alk mui
chon loai acid (sulfuric, HCl, AcOH, tartric)
chon pH thich hp (pH = pKa 2)
chon dung mi (EtOH, MeOH, HOH)
5. Chit xut Phn lp
5.2. PHN LP V TINH CH

alk. base bc IV (berberin) Tan c


alk. phenolat (morphin) trong nc,
nicotin base, cafein base nn cch
phn lp
chuyn bit
5.5. Phng phap sc ky ct (SKC)

a. SKC hp ph

cht hph : Si-gel (15-40 hay 40-63 m)

co th nhi Si-gel vi d.dich m kim

mu nap : alcaloid base (it tap);

khai trin : hay dung CHCl3 MeOH

theo doi : SKLM / UV 254 nm hay /


Dragendorff

thu phn oan tinh khit, kt tinh alcaloid base.


5.5. Phng phap SKC

b. SKC ry phn t

Thng s dng pha tnh la Sephadex LH-20

Mu th : alk. base toan phn con ln tap / (Cf MeOH)

Khai trin vi MeOH, MeOH CHCl3

- cac hp cht co MW ln s ra trc

- cac hp cht co MW nh s ra sau.


5.5. Phng phap SKC
c. SKC trao i ion
c.1. vi ct Cationit

R H+

alcaloid
BH+ Cl H+ Cl (pH acid)
mui
R BH+

NH4+ OH HOH

R NH4+

B
alcaloid
base
c.2. vi ct Anionit

R OH

BH+ HOH
alcaloid
mui
Cl R Cl

B alcaloid
base

alcaloid kim yu s ra trc


alcaloid kim manh bi gi lai trn ct, ra sau
5.5. Phng phap SKC

d. SKC phn b ao

Thng dung pha tnh Diaion HP-20 (Mitsubishi).

Mu : alk. mui toan phn con it tap / (MeOH H2O)

Khai trin ct vi (H2O MeOH) (100 : 0 0 : 100)


5.6. Phng phap chit pha rn (SPE)
Thng dung chun bi mu cho HPLC, GC.

Dng c : ct SPE cha 100 1000 mg pha tnh (NP, RP)

Lng mu nap SPE = 5% lng pha tnh.

Khai trin bng dmi thich hp (tuy NP, RP)

- gi tap lai trn ct SPE, ch cho alkaloid ra

- loai tap ra trc, alkaloid s ra sau

5.7. Phng phap HPLC iu ch


thng dung phn lp, tinh ch 1 lng mu nh
(nghin cu cu truc, mu chun)
5.7. Phng phap HPLC iu ch
thng dung phn lp, tinh ch 1
lng mu nh
(nghin cu cu truc, mu chun)
Trn vi phu (phan ng hoa m)

vi
ra bng ri + thuc th
ph Kt lun
cn tartric Bouchardat
u

1 khng ra co tua nu

2 co ra vn co tua nu

3 co ra khng con tua nu

- alcaloid va protein u cho ta vi th th Bouchardat


- alk. tan / cn tartric; protein khng tan / cn tartric.
6. Kim nghim dc liu
6.1. nh tnh
6.1.1. Bng phng phap sc ky
Muc ch - co alkaloid ???
- co dc liu A, B, C ???
- co alkaloid x, y, z ???
- ham lng x, y, z ???
K thut
- SKLM (TLC; HP-TLC; p-TLC)
- HPLC (LC-UV; LC-PDA; LC-MS )
6. Kim nghim dc liu
6.1.1. Bng phng phap sc ky
6.1.1.1. Trn SKLM
Ban mng : Si-gel F254, RP-18 (Merck )
mu chm : alk base (it tap) / CHCl3 (chm vach)
dung mi : thng thm kim (hu c, v c) yu *
phat hin : UV 254 nm / Dragendorff / th th khac
Ch
* Thm kim n pH (pKa + 2)
* K thut thm kim
Dung mi thng thm kim yu (pH modifiers)
- NH4OH ( %), dimethyl formamid (DMF)
- diethylamin, triethylamin (DEA, TEA)
6. Kim nghim dc liu
6.1.1. Bng phng phap sc ky
6.1.1.1. Trn SKLM
Mu th
- thng la alkaloid base (toan phn, phn
oan)
- mu c hoa trong Bz, Cf, DCM.
Phat hin vt
6. Kim nghim dc liu
6.1.1. Bng phng phap sc ky
6.1.1.2. HPLC
Pha tinh
- ct phn b (Si-gel RP-18; RP-8), ct trao i ion
- ct hp phu (Si-gel ghep amin, cyano, diol)
Pha ng
- H2O, MeOH, AcCN, THF (co th thm m hu c, v
c)
Mu th : alkaloid base / MeOH
Detector : UV, RI, MS, NMR.
Kt qua : Sc ky (Rt); ph.
Hin rt th.dung, cn thit / .tinh, .lng, t.chun hoa)
6. Kim nghim dc liu
6.1. nh tnh
6.1.2. Bng phn ng hoa hoc
Bt Dc liu

a. NH4OH c H2SO4 2%
b. CHCl3

Alk base / CHCl3 Alk mui / nc acid

a. Lc vi H2SO4 2% a. NH4OH n pH 10-11


b. Ly lp nc acid b. Lc vi CHCl3

Alk mui / nc acid Alk base / CHCl3 SKLM

a. Th2 chung CHCl3


2
b. Th c hiu

cn Alkaloid base Th2 c hiu


6. Kim nghim dc liu
6.1. nh tnh
6.1.2. Bng phn ng hoa hoc
Bng thuc th chung va thuc th c
hiu
alkaloid phan ng mau alkaloid phan ng mau
Tropan Vitali-Morin Berberin Oxyberberin
Strychnin Sulfo-chromic Quinin Thaleoquinin
Brucin Cacothelin Quinin Erythroquinin
Cafein Murexid Quinin Huynh quang
6. Kim nghim dc liu
6.2. nh lng
Nguyn tc chung

alk. mui / dc liu


A B

alk. mui / d.mi alk. base / d.mi


thay i pH

tap tap
cn alk. base sach

1. p.phap cn 3. o quang
2. acid base 4. pp. sc ky
6. Kim nghim dc liu
6.2. nh lng
6.2.1.Phng phap cn

chit dang alk. acid hoc base

loai tap (cht bo, tannin )

i pH nhiu ln (chuyn dang)

alkaloid base

cn trc tip, gian tip


6. Kim nghim dc liu
6.2. nh lng
6.2.1.Phng phap cn

P b (kho cn)
cafein, nicotin

Bertrand

Bertrand.(alk)4

P ln (d cn) Palkaloid

(cn gian tip)


6. Kim nghim dc liu
6.2. nh lng
6.2.1. Ph.phap th tich

alk. base

acid tha
(HCl, H2SO4 loang)
kim

vi cac chi thi mau vng pH acid :


- methyl (4.2 6.3 vang)
- methyl cam (3.0 4.4 vang)
(co th + methylen xanh)
6. Kim nghim dc liu
6.2. nh lng
6.2.1. Ph.phap th tich (mi trng khan)
- nn: AcOH bng
- acid percloric tha
- chi thi mau: Tim tinh th
- ap dung: k ca alk. kim qua yu (cafein,
colchicin)
- chinh xac > ph.phap cn
tim tinh th : vang luc (acid) xanh luc
(tr.tinh) tim (kim)
6. Kim nghim dc liu
6.2. nh lng
6.2.1.Phng phap o mu
6.2.2.Phng phap HPLC
Thng kt hp vi nhiu cach ch.bi mu
(SPE, SPME)
vi nhiu detector khac nhau (UV, IR, RI, MS)
7. CNG DNG
La nhng cht chuyn hoa th cp, cht bai tit hoc la
san phm cui trong qua trinh chuyn hoa ca thc vt.
La nhng cht d tr Nit, tham gia vao chu trinh Nit
trong thc vt.
i khi la nhng cht tich luy dn t thc n (Kin ly
alk. t la cy; ch, Coc n kin ch, Coc co alk.)
La nhng cht bao v, chng cac sinh vt n thc vt.
La vu khi hoa hoc trong t v, cn trong qua trinh
sinh tn nht la ng vt (Ca, Coc, K nhng ...)
7. CNG DNG
Alkaloid thng co hoat tinh sinh hoc manh n rt manh
kha nhiu cht c s dng trong y hoc.
mt s cht dung lam cht c dung trong sn bn
(tubocurarin / Curar)
mt s cht qua c, khng dung trong y hoc
(Gelsemin trong L ngn).
nhiu cht co thm tac ng nguy hai n xa hi
(gy nghin, ma tuy, ao giac)

If Nature had any sense, She wouldnt make alkaloids !


(John Comforth)
7. CNG DNG

Khi thc vt co nhom alkaloid, thi tac dng ca dc liu


thng do nhom alk. (trong o thng do 1 alk. ch yu).
Trn h thn kinh
- kch thch TKTW : cafein, strychnin
- c ch TKTW : morphin, codein
- kich thich trc giao cam : ephedrin
- lit trc giao cam : yohimbin
- kich thich pho giao cam : pilocarpin
- lit pho giao cam :
7. CNG DNG
Trn cac c quan khac
- Gy t : cocain - Giam au : morphin

- Giam ho : Codein - Giam co tht : Papaverin

- Tri st rt : Quinin - Dit giun san : Arecolin

- Dit khun : Berberin, Emetin - Ha huyt ap : Reserpin

- Tri ung th : Taxol, Vincristin, Vinblastin, Vincamin


8. DC LIU C TH
1. Tn khoa hoc
2. B phn dng
3. Thnh phn hoa hoc
4. nh tnh v nh lng
5. Tac dung v cng dung
9 dc liu:
Thuc la, c c dc, thuc phin, bnh vi,
vng ng, m tin, ba gc, ch, mc hoa
trng.
khung Dc liu Hot cht
protoalkaloi 1. Ma hong ephedrin
d 2. Ti c colchicin
pyridin 3. Thuc la nicotin
hyoscin =
4. C c dc
scopolamin
tropan
5. Belladon hyoscyamin
6. Coca cocain
7. Thuc phin morphin, codein,
8. Bnh vi rotundin
isoquinolin
9. Hong lin berberin
10. Vng ng berberin
khung Dc liu Hot cht
quinolin 11. Canhkina quinin, cinchonin
12. M tin strychnin, brucin
indol 13. Ba gc serpentin, ajmalicin
14. Ca kha mch ergotamin
15. Ch Cafein
purin
16. C ph Cafein
17. Mc hoa trng conessin
steroid
18. C la x solanin
diterpenoid 19. u aconitin
khc 20. Bach b stemonin
Lu y

- Opium = Nha thuc phin = hn hp cac alkaloid

chit t nha qua Papaver somniferum

- Opiat = cac alkaloid t nhin ca qua Thuc phin

(morphin, codein ...)

- Opioid = cac cht t nhin hay tng hp,

co tac dng kiu morphin.

Thc t, cac cht giam au kiu morphin u la cac alk.


THUC PHIN
Papaver somniferum L.
Papaveraceae
Anh tuc, A Phin, A Phu dung, Papaver, Poppy.
c im thc vt
- Cy thao cao 0,71,5 m.
- L so le, La trn x rng ca tha, su;
- La gc x lng chim. Gc la m thn rt c bit
- Hoa mu 4, moc n c u canh, mau thay i.
- Hat nh va nhiu, mi qua co 2 3 van hat.
- Toan cy co nha m trng mau nu en / kh.khi
Cac th Thuc phin
Th nhn (var. glabrum): Th nh K
Hoa tim (trng), hat tim en (trng), qua cu rng.
Th trng (var. album): n , Iran, Trung .
Hoa trng, hat trng - vang nhat, qua hinh trng,
khng co l di u nhy.
Th en (var. nigrum): Trng ly hat Chu u.
La va cung hoa nhn, hoa tim, hat mau xam,
qua hinh cu phia di, co l trn mp u nhy.
Th lng cng (var. setigerum): Nam u.
Hoa tim, cung hoa ph y lng cng.
Crossant dOr Triangle dOr
Ngun gc
A. Thuc phin s dng lam thuc

n (banh 5 kg, 12 banh / thung).

Th Nh K (banh 2 kg), Kirghizstan, Nam T cu,

Iran va Ai cp (nay khng con san xut na).

Trung quc, Australia (Tasmania)

Phap, Ty ban nha, Ha lan, Scotland, Na uy, M v.v

cung trng mt lng nh vi mc ich chit alkaloid.


Ngun
gc
B. Thuc phin san xut bt hp phap

vng Ch thp vang (Pakistan, Afghanistan v Iran)

vng Tam gic vng (Lo, Myanmar v Thi Lan).

Vit Nam: Sn La, Lai Chu, Lao Cai, Hoa Binh,

Ha Giang, Lang Sn, Cao Bng

Hin nay a cm trng.


Thu hai
Thu nha (Opium)

- Rach qua mau xanh mau vang vao bui chiu,

- sau 812 gi cao ly nha, ong thanh banh.

- Nng sut: 10-15 kg nha / ha 50-70 kg nha / ha

Thu qua va hat

- Qua : dung chit alkaloid hay dung lam thuc.

- Hat : dung lam thc phm, dung p du.


qu Thuc phin
Nha Thuc phin ng thnh bnh
San lng nha
Hp phap (1987)
Toan cu # 1500 tn Opium # 170 T morphin
n # 45% (673 tn Opium # 74 tn morphin).

Bt hp phap (1989) # 3.400 tn Opium


- Afghanishtan 800 T, - Pakistan 130 T,
- Myanmar 2000 T, - Thi lan 50 T
- Lo 400 T,
San lng nha Opium (1980s)

Afghanist
Trung (1350 tn) 1265 tn
an
(vng Ch thp vng)
Pakistan 85 tn
Myanmar 2365 tn
ng Nam (2645 tn) Lo 210 tn
(vng Tam gic vng) Vit Nam 45 tn
Thi Lan 25 tn
Columbia 66 tn
Nam M (112 tn)
Mexico 46 tn
trn 4000 tn
Din tich trng Thuc phin (1990-2005, ngn ha)

250 ngn ha
250
R
L 200
200

150
150
M
100

50
A

1990 1995 2000 2005


Tai Afghanistan (theo s liu ca UNODC; 9/2007)

San lng nha Thuc phin

- nm 1997: 52% toan cu

- nm 2000: 70% ton cu

- nm 2006: 95% toan cu (6.724 tn; 143% / 2005).

Din tich trng Thuc phin

- 2005: 104.000 ha

- 2006: 165.000 ha (chim 17% din tich quc gia).


Din tich trng Thuc phin tai Myanmar,
(1990-2005, ngn hecta)

200

160 165.8
154.1 155.1
150

108.7
100 89.5
81.4
62.2
44.2
50 32.8

0
1990 1993 1997 2001 2003 2005
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
San lng nha Opium ca Afghanistan
(1990-2006; ngan tn)
8000
6724

6000
5032
4630
3765 3611 3748
4000
3091
2568 2574
2183
2000

204
0
1994 2004
1990
1 2 3 4 5 6 7 8 10 11 2001
9 1999 12 13 14 15 16 2006
17

Ngun: United Nations Office on Drugs and Crime (UNODC)


* Taliban had almost shut off Afghan opium production by 2001.
* U.S. invasion restored flow in 2002.
* 1980s: CIA had funded Mujahedeen resistance:
warlords for Afghan opium production;
Richard Armitage, current Deputy Secretary of State worked
with CIA in Islamabad.
* Afghan opium worth at least $180 billion anually.
B phn dung
Nha thuc phin (Opium): Ly t qua gia cha chin.

Nha TP co th bao quan hang chc nm vn khng h

Qua (Fructus Papaveris)

- qua a ly nha (anh/cu tuc xac), vn con it alk.

- qua cha ly nha : Chit alkaloid.

Hat (Semen Papaveris) : Dung ly du bo.

L (Folium Papaveris) : Lam thuc dung ngoai

(thuc xoa bop, giam au).


Alkaloid:
Toan cy va qua: > 40 cht (tn tai ch yu: mui meconat).
Nha: alkaloid toan phn # 10-20%; gm 5 nhom chinh:

nhm alkaloid in hnh trong nha Opi


morphinan ** morphin*, codein*, thebain*
benzyl papaverin*, laudanin, laudanidin,
isoquinolin laudanosin
phtalid narcotin* (noscapin), narcein,
isoquinolin narcotilin
protopin protopin, cryptolin

aporphin apomorphin*, isothebain


a. Nhm morphinan
R1O

O
N Me

R2O

% trong
R1 R2
nha
morphin
H H 8 17%
*
codein* Me H 0,7 5%
thebain* Me Me 0,1 2.5%
-morphin, neopin rt thp
b. Nhm benzyl isoquinolin

Papaverin : 0,5-1,5% Laudanidin: rt it


Laudanin : 0,01% Laudanosin: rt it

MeO MeO

N N Me
MeO MeO
OMe OR1

OMe OR2

papaverin* R1 R2
(0.5 1.5%) laudanin H Me
laudanidin Me H
lausanosin Me Me
c. Nhm phtalid isoquinolin

- narcotin (= noscapin; 110%), narcotolin (0,1%);


- narcotin oxy hoa cotarnin, cm mau trong ph khoa.

O O
N Me N Me
O O O O
OMe OH

OMe OMe

OMe OMe

narcotin = noscapin narcotilin


(1 10%) (0.1%)
d. Nhm protopin e. Nhm aporphin

HO
O
Me
N HO
O
O Me
N
O

protopin apomorphin
(gy nn, RLC, Parkinson)
MeO
Me
N
MeO
O
O
ngoi ra cn vi nhm alkaloid
O
khac, ham lng rt thp.
cryptonin
Thanh phn khac
- khong 56%, ng, cht nhy, pectin (20%).
- protein, acid amin t do.
HOOC O COOH
- cac acid hu c:
acid lactic, fumaric, acetic, vanilic,
O

cc acid cetonic. acid meconic


acid meconic *** (3-5%),
FeCl3

mau
Anh tuc xac (qua a ly nha) : con rt it alkaloid.

Qua cha ly nha: 0,5% alkaloid tp. (ty loi),

Thanh phn # nha.

L : t alkaloid (0,020,04%).

Hat : glucid: 15%; protid: 20%, lipid: 4050%

Hat khng co alkaloid,

Du hat: Ch s iod 130145, co gia tri dinh dng cao.


Chit xut
morphin
1. Phng phap Thiboumery

- Ha nha vao nc nong (7080 C), vt / gan b tap.

- Thm nc vi nong loc b ta, thu dich loc.

- Dich loc + NH4Cl ta (morphin base th)

- Loc ly ta, ra ta bng nc morphin base.

- Kt tinh di dang mui morphin.HCl (HCl + C*)

- Kt tinh lai vai ln / cn thp morphin.HCl t.khit.


+ sa vi
bt nha Thuc phin dich kim
n pH 12
hoa nc nong
NH4Cl n pH 8-9

ta morphin base th

C* + HCl / H2SO4, loc thu dich

dich acid (morphin mui)

NH4OH n pH 8-9

HCl
tinh th morphin HCl ta morphin base TK
Chit xut
2. Phng phap Kabay morphin
- Chit bt qua bng nc nong, c thanh cao c.
- Chit cao c bng cn nong, c thu hi cn.
- ri + (NH4)2SO4 v NH4OH + benzen
- Loc thu ring dich benzen va ta morphin base th.
benzen codein, thebain, narcotin (HCl).
ta morphin base morphin.HCl.

3. Phng phap dung nha trao i ion (SAX)


Ra giai bng HCl loang.
inh tinh
1. inh tinh acid meconic
(1)
- chit nha thuc phin = nc,
- acid hoa dich loc + HCl + Et2O.
- dich Et2O + (nc + FeCl3) lp nc co mau .

2. Phan ng vi thuc th Marquis


- alkaloid base + TT Marquis mau / tim.

3. Phan ng vi thuc th Frhde


- alkaloid base + TT Frhde tim lc vng.
inh tinh (2)
4. Phan ng vi HNO3 .
- alkaloid base + HNO3 cam n vang.
- mau vang khng mt khi + SnCl2 (khc brucin).

5. Phan ng Huseman
- alkaloid base + H2SO4 / BM mau cam.
- ngui + NaNO2 (hay HNO3 ) xanh tm
mau mt mau (morphin apomorphin).
- nhay: 10 mg morphin.
inh tinh (3)
6. inh tinh bng SKLM
- Cht hp ph: silica gel
- Dung mi khai trin:
benzen MeOH (4 : 1),
xylen-MEK-MeOH-DEA (40:60:6:2).
- Phat hin: thuc th Dragendorff.
inh lng (1)
inh lng morphin trong nha thuc phin
Nguyn tc: mophin (va alkaloid co OH phenol)
tan it / nc, tan c / dung dich kim.
Tinh kt qua: nhn vi 1 h s bu tr

1. Phng phap cn (phng phap Pfeifer):


morphin + 3,5-dinitrofluorobenzen
morphin dinitrophenylether kt ta.
Loc ta, ra sach, sy kh. Cn ham lng morphin.
inh lng (2)
2. inh lng morphin bng phng phap th tich:

Phng phap 2.1. (nha opium)

- Chit morphin = nc vi trong ( morphinat Ca tan),

- ta morphin = NH4Cl (tao NH4OH, CaCl2 tan)

- Loc, ra = ether, nc bao hoa morphin sy kh.

- Hoa tan ta / methanol nng (ko tan mui Ca++)

- inh lng morphin bng HCl 0,1N, ch thi methyl .

- Tinh kt qua: (P morphin) x (h s hao ht).


inh lng (3)
Phng phap 2.2. (bt qua)
(bt qua) (n-prOH/HCl) cn alk mui.
cn alk mui + HCl, loai b tap tan / CHCl3
cn alk. mui + NaOH dd NaOH (morphinat Na tan)
loai alk base khac bng cach lc vi CHCl3 (gi dich NaOH).
+ HCl pH 7, chit = (CHCl3 iso-PrOH; 3:1) (dich 1)
+ NaHCO3 pH 9, chit = (CHCl3 iso-PrOH; 3:1) (dich 2)
Gp 2 dich PrOH lm khan c cn + HCl 0,1 N,
Chun = NaOH 0,1 N, ch thi methyl (pH 5.2 1)
1 ml HCl 0,1N # 28,53 mg morphin base.
= NaOH 0.1 N / methyl

bt qua Th. Phin * Dich inh lng *

HCl, nPrOH hi lu, C HCl 0.1 N d ch.xc

cn alk. mui cn morphin base

CHCl3 / HCl tap KPC C

alkaloid mui morphin base / C.P

CHCl3 / NaOH alk. khc Na2SO4 khan

MORPHINAT Na morphin base / C.P

+ HCl (pH 7), chit = Cf-iPrOH (3:1)


+ NaHCO3 (pH 9), chit = Cf-iPrOH (3:1)
inh lng (4)
3. inh lng morphin bng phng phap o quang
(PP. Kleischmidt va Mothes) : trong mi trng kim,
morphin nitroso morphin ( m)
o hp thu [morphin].

4. Cac phng phap inh lng khac


Ph UV : it dung
HPLC : hin nay thng dng.
Tac dung dc ly
Morphin co tac dng giam au manh nhng gy nghin.
Trn TKTW
- Liu nh : hng phn giam au manh.
- Liu cao : gy ng.
Trn h h hp
- gy th nhanh, nng th chm ngng th.
- c ch trung tm ho giam ho
Trn h tiu hoa
- Liu nh : kich thich co bop da day, gy nn
- Liu cao : chng nn, nhu ng rut tri tiu chay.
Codein
- tac dng giam au km morphin
- tac dng tri ho manh hn morphin.
- Lam dng cung co th gy nghin.
Papaverin
- Giam co tht c trn, c bit / h trang vi.
Narcotin
- iu ch cotarnin co tac dng cm mau.
Cng dung
Nha thuc phin, morphin: c bang A gy nghin.
Nha thuc phin (Opium)
- Thuc giam au, cha ho, tiu chay
- Chit morphin, codein, papaverin v.v
- Ban tng hp cac thuc (ethylmorphin, pholcodin)
Trc y: iu ch Bt thuc phin (10%),
iu ch cn thuc phin (1%)
Hin nay : Ch dung lam nguyn liu
Khng con cp phat trc tip hay k toa (BP 1993)
Cng dung
Qua: Chit morphin codein
Chit alk. toan phn thay nha thuc phin
Anh tc xc : Thuc ho, tiu chay, giam au.
Hat : p ly du dung trong thc phm,
lam thuc can quang lipiodol.
Mt s loai Papaver khng co morphin :
P. bracteatum (thebain),
P. orientale (oripavin hay mecambridin),
P. pseudo-orientale (isothebain, orientalidin).
Ht