ANKALOIT V MT S PHNG PHP TNG HP

A/GII THIU CHUNG V ANKALOIT

I/Khi nim: Ankaloit l nhng hp cht hu c c cha d vng nit, c tnh baz, thng gp trong nhiu loi thc vt v i khi cn tm thy trong mt vi loi ng vt.

II/Thnh phn nguyn t v cu to ca ankaloit

1/Thnh phn nguyn t:

C 3 loi ankaloit: *Loi cha 3 nguyn t: C, H, N *Loi cha 4 nguyn t: C, H, N, O hoc C, H, N, S *Loi cha 5 nguyn t : C, H, N, O, S. Loi ny c c tnh rt cao trong cc loi nm c

2/Cu to: Ankaloit cha mt trong cc d vng sau:

Pirol
NH

Piridine
N

Pirolidine
NH

Piperidine
N

Mt vi v d v ankaloit:

Nicotine

Quinine

Heroine

Morphine

3/Tnh cht:

3.1/Trng thi:
-Ankaloit tn ti 2 dng: lng v rn. -Ankaloit cha oxi thng trng thi rn, cn ankaloit khng

cha oxi thng trng thi lng.

3.2/Tnh tan: Cc ankaloit khng tan trong nc (tr nicotin v cin), hu ht tan trong dung mi hu c: nh benzen, ete, clorofom 3.3/ Tc dng ca nh sng: Mt s ankaloit thng khng bn nh sng mt tri, tia t ngoi, c mt s b thoi ha khi chiu tia nh sng c bc sng nht nh

3.4/Tnh baz mnh:

- Cc ankaloit thng c tnh baz mnh c th lm xanh qu tm.

- Cc ankaoit trong cy kt hp vi cc axit nh axit oxalic

(C2H2O4), axit tatric (C4H6O6), axit lactic (C3H5O3), axit malic (C4H7O5) to thnh mui.

- Mt s ankaloit lm kt ta Fe(OH)3, Al(OH)3, trong dung

dch. - Mt s cc ankaloit c tnh baz mnh y c cc baz trung bnh ra khi mui ca chng.

3.5/Hot tnh sinh l cao:

Cc ankaloit tc dng vo h thn kinh rt mnh,

c tc dng l ha i vi c th ngi v ng vt. Ankaloit vi liu lng nh cha bnh hay gii kht nh cacao, c ph, Nhiu ankaloit l cht gy nghin cc k nguy him i vi con ngi nh thuc phin,

heroin,
Cc ankaloit c cha S thng c c tnh rt mnh, c mt trong cc loi nm c

B/ MT S ANKALOIT TIU BIU, CC HP CHT GY NGHIN

I/Nicotin:
1/Ngun gc: Nicotin c nh ha hc ngi c, Posselt v Reimann chit xut ra khi cy thuc l vo nm 1828 Nicotin c tng hp ln u tin bi nh bc

hc A.pictet v Crepieux vo nm 1839

2/Thnh phn v cu to:

-Cng thc phn t ca Nicotin:

-Tn khoa hc: -(N-metyl--pirolidil) piridin -Trong cu to c 1 nhn piridin kt hp vi nhn N-metyl-pirolidin.

3/Tnh cht: - L mt cht lng nh du, ht m v c th trn ln vi nc trong dng baz ca n.

- Khng mu, t0s=247 0C

- B nu li nhanh chng trong khng kh do b oxi ha - D tan trong nc, dung dch c tnh baz mnh - L mt baz gc Nit, nicotin to ra cc mui vi cc axit, thng thng c dng rn v ha tan c

trong nc.
- Nicotin d dng thm thu qua da.

4/Phng php tng hp Nicotin: 4.1/ Tng hp ng phn quang hc (S)-Nicotine: (S)-Nicotine mt hp cht thin nhin c trong cy thuc l. Bn bc tng hp (S)- Nicotine, c phn tch ngc nh sau :

1. Hydroxyxetone (3) c to thnh bi s trao i lithi-halogen ca 3- bromopyridine (1) vi N-BuLi ri tc dng vi lacton (2). 2. xi ha (3) ti andehyt c thc hin bng phng php Swern: (COCl)2, DMSO ((CH3)2SO), NEt3. 3. Sn phm (4) c to thnh bi phn ng ca (pyridin-3'-yl)-4-oxobutanone (4) vi 2,3,4,6- tetra-O-pivaloyl--D-Galactopyranosylamine . 4. Thy phn (4) trong mi trng acid cho ta cht quang hot (S)-nornicotine: 1M HCl/ MeOH.

4.2/ S tng hp ng phn quang hc (R)- Nicotine:

Tng hp ng phn quang hc nhn to cn thit

cho s nghin cu. V d v s tng hp (R)- Nicotine gm bn bc c m t y. Trong , cha kho ca phn ng l s Hydrobo ho v vng ho ni phn t. Phn tch qu trnh tng hp:

1. Allyl ho pyridinecarboxaldehyde (1) vi 2 (2:B-allyl diiso pinocampheylborane) trong Et2O 100oC. (S)Homoallylicalcool (2) c to ra (hiu sut 86%) 2. Azide bt i (3) c to ra t ru (2) bng phng php Thompson v khng c s tiu trin ho. Vi tc nhn DBU, (PhO)2P(O)- N3, Toluen. 3. S Hydrobore ho v vng ho ni phn t azidoolefin 3 (tc nhn B(C6H11)2H trong THF). Bc ny xut pht t s hydroboron ho lin kt i ca 3, tip theo l s hnh thnh lin kt boron-nitrogen gia azide v trialkylborane. S ng vng xut hin bi s chuyn v ca nhm methylene borane to ra nitrogen-1 ng thi l s mt Nitrogen. 4. S Ankyl ho (R)-Nornicotin 4 cho ta (R)- Nicotine.

3-Nhng s bin i ha hc ca nicotine:

Nicotine ch yu thay i trong c th sng,

c bit l phi. Nhng cht chuyn ha s cp ca Nicotine l cotinine v Nicotine N Oxide bi s oxi ho ca t bo P-450 Cytochrome.

Nicotine gy nguy him cho c th nh th no?

Nictin v nhng cht chuyn ha ca n c th gy nguy him

cho c th. Nictin l mt cht c kh nng gy bnh ung th rt mnh. Trong thc t, Nicotine c th tri qua vi loi bin i nh s m vng pyrole. Nhm methyl trn vng ny c th tr thnh mt tc nhn ankyl rt mnh khi b loi b t vng. Nhm amin ca nicotine phn ng vi Nitrogen monoxide hay vi Nitro axit to thnh "nitrosonium" dng phn t. Hn hp ny c th c thay i bi c th, bng s oxi ho v m vng. S m vng ny cho ra hai cht ng phn, hai "nitrosamino" dng phn t (R2N-N=O) ni m mt trong s hai nhm R l nhm methyl. Phn ng ny xy ra nh sau:

A= 4 (N-methyl-N-nitrosamino)-1-(3-pyridyl)-butan-1-one B = 4 (N-methyl-N-nitrosamino)-4-(3-pyridyl)-butanal

Trong

mi

trng

axit,

oxy

ca

nhm

"nitrosamino" nhn mt proton v lin kt i chuyn ti nitrogen trung tm, v n tr nn tch in dng. Phn t mi ny " nitrosamino" c th phn ng vi cc amine khc, vi s loi b

in tch dng ca nitrogen. Nu amin phn

ng li l mt phn ca cu trc DNA, mt s ankyl ha khng thun nghch DNA xut hin:

S ankyl ha ny tht s c hi v c th gy
nn s pht trin ca ung th khi n ngn cn s pht trin bnh thng ca t bo.

II/Quinin:
1/Tnh cht v mt s tc dng: Quinin l cht rn mu trng,

t0nc=1770C, t tan trong nc, d tan

trong ru v eter. V ng L mt ng phn lp phn ca quinidine. Tn ti di dng mui ca: hydroclorua, ihydrochloride, sulphate, gluconate
Quinin

c s dng trong quang ha hc nh mt

hunh quang chung tiu chun. Quinin gy ra chng ban xut huyt, gy ra chng lit nu tim thuc vo trong mt dy thn kinh

Tr st rt, chng bnh u ma, lm thuc

gim au. Quinin khng c s dng i vi nhng bnh nhn vi hemoglobin-niu, bnh nhc c nng hay vim dy thn kinh th gic

2/Tng hp Quinine:

S tng hp quinine (1) v quinidine (2). Vi mi

s tng hp, phn ng cha kha thit lp s khng i xng ca phn t ch l s cng lin hp i hnh c la chn v c pht trin bi nhm Jacobsen.

 S tng hp bt u vi amit alkenyl (3). Salen-Al xc tc cho s cng lin hp c tin hnh nh mt s

pha trn ca hn hp cho ta cht ng phn lp th

(5). S kh v s to vng theo sau bi s loi proton to thnh sn phm cis-dialkyl piperidine (6). S tha nhn hai chui phn ng cho ta este alkenyl boronic (8).

 Phn quinolin ca nhng ankaloit ch c iu ch bng vic ngng t p -Anisidine (9) vi etyl propiolate, theo sau l s Brom ho. Phn ng gia (10) vi este boronic (8) cho hp cht (11), trung gian cho s tng hp ca c (1) ln (2). Diol c th c chuyn i hon ton ti epoxide (11). S loi nhm bo v, theo sau l s to vng cho ta hp cht nh mong i l quinine (1). iu ch epoxide ng phn lp th, s dng AD-mix- theo sau bi s to vng cho quinidine (2). S ngn gn ca vic iu ch hai ankaloit c in ny l mt bng chng cho thy kh nng tng hp c kim sot cht phn ng.

III/Morphine:

1/Tnh cht:
Morphine c trong thuc phin,

iu kin thng morphine l tinh th

khng mu. L thuc ng mnh, gim au, dng gy m hi sc trong cc cuc phu thut, ngoi ra, morphine cn
Morphine

dng iu tr bnh ung th.

Tuy nhin, morphine l mt cht rt c

2/Tng hp:

Mt cch tng hp ()- Morphine ( 3), da vo

phn ng t ng vng lp th ni phn t Mannich t (1) thnh (2).

 S iu chnh lp th phn ca (1) c bt u

vi s epoxi ho diene (4) cho ra (6). Cht trit quang (6) c s dng tng hp Morphine, hiu sut (6) cao c th c quyt nh bi hp cht trung gian bromohydrin (5). t (6) cho ta (7),

ri c cho tc dng vi (8), theo c ch SN2.

Ru bc hai c o ngc, nhm t H syn ti k cn vi Pd kh H trong qu trnh s to vng Heck trong phn t ca (10) to thnh (2).

 S to vng Mannich trong phn t ca (1) ti

(2), trung gian trong s to vng r rng l cht

c mong i (11), m ta c th c c lp. Ch rng, di nhng iu kin cn bng ca s to vng, vng cis to thnh nh mong mun (2) l cht duy nht c quan st c.

 xy ha xeton (2) ti enone 12 (bng phng php Ito- Saegusa). N cn thit chuyn i enone thnh lin kt o ngc ca ru (14). Vi b khung Morphine c lp rp, vng thm ngn chn mt y ca enone, v vy c H2O2 ln cht Hyrua u tn cng t nh ca enone, cho ta (13). S chuyn i ca dn xut thiocarbamat to thnh gc t do ri to thnh epoxide, chuyn thnh (14). xi ha, cng Hyrua trn nh ca xeton, ng thi kh ur to thnh nhm N - Metyl, v s loi metyl nhm O-metyl to alcol ()-Morphine (3)

Morphine

Heroine

Ta thy heroine v morphine c cu trc tng t nhau, ngi ta iu ch heroine bng cch este ho morphine.

III/Atropine v cocaine:

Atropine v cocaine c tng hp bng cch kh

Tropinone (2) thnh tropine ri cho tc dng vi cc axt tng ng.

Atropine

Tropinone

Cocaine

S tng hp Tropinone:

S ngng t ca succinaldehyde vi axit dicarboxylic axeton v methylamine. Sn phm ban u l mui ca axit tropinone dicarboxylic, v mui ny mt hai phn t CO2 vi s hnh thnh tropinone khi axit ha un nng

S tng hp Atropine: u tin ta tng hp axit Tropic, sau cho axit ny phn ng vi tropine, ta thu c atropine.

Cocain cng c tng hp mt cch tng t, ta ch thay axit tropic bng axit benzoic.

CHN THNH
CM N THY V

CC BN CH
THEO DI.

CHC MI NGI MT NM MI HNH PHC

Ti liu tham kho:

1. Chuyn mt s hp cht thin nhin

Thy L Vn ng
2. http://www.chem.qmul.ac.uk/iupac/

3.http://www.chm.bris.ac.uk/motm/atropine/synth esis