t vn

Hin nay, nhu cu thuc phng v iu tr bnh l rt ln, c bit l cc bnh nhim khun nn vic tm ra cc thuc mi cng cp thit hn. Gia cu trc ho hc v tc dng dc l thng c mi quan h mt thit, do ngi ta tm ti v la chn ra nhng khung v nhm chc c tc dng sinh hc tng hp, bn tng hp ra thuc mi. Cc base azometin, cc oxim v cc hydrazon c cc nh khoa hc trn th gii nghin cu t lu, khng ch c s dng nh mt cht trung gian tng hp mt s hp cht d vng cha N hay tng hp - aminoceton m chnh bn thn n cng c mt s tc dng sinh hc nh khng khun, khng nm, iu tr lao, hi, li tiu . . . Nhiu cht trong s c dng lm thuc. Tetracyclin l mt khng sinh trong h khng sinh Tetracyclin, l nhng dn cht ca octahydronaphtacen 4 vng c tc dng trn nhiu loi cu khun v trc khun Gram(+), Gram(-). Hin nay tetracyclin t c s dng cho tr em v d to phc chelat vi canxi do lm vng rng tr em, hn na n c v rt ng. V nhng l do trn, ngy cng c nhiu nghin cu vi nh hng kt hp cu trc azometin (- CH = N - ), oxim ( = N - OH ), hydrazon ( - HC = N - NH - ) vi tetracyclin nhm hy vng tng hp ra mt s hp cht mi c tc dng sinh hc v ng dng c vo thc t iu tr lm sng.

1. S lc v lch s nghin cu v ng dng cc hp cht Azometin, Oxim v Hydrazon 1.1. Azometin Cc azometin ( base Schiff ) l nhng hp cht hu c trong phn t c cha nhm imin ( - CH = N - ), chng c nghin cu t lu v l sn phm trung gian tng hp mt s hp cht c tc dng sinh hc bn thn chng cng c tc dng sinh hc. Vo khong nm 1850 khi trn mt hn hp ng phn t benzadehyd v anilin th Laurent v Gerhard thu c mt hp cht c cng thc C13H11N gi l benzoylanilid (Sau ny ngi ta tm ra cng thc cu to l C6H5 - CH = N - C6H5 v gi tn l benzylidenanilin hay benzalanilin ). y l cht u tin thuc dy anilin th. T nm 1864 n nay, nhiu tc gi trn th gii tip tc nghin cu mt cch c h thng phn ng ca cc aldehyd vi amin bc 1, bc 2 thuc dy bo, dy thm v d vng. V d: Amin bc 1 ( 1 mol ) R-CHO + H2N R R CH = N R + H2O (-aminoceton, cc hp cht d vng cha N nh quinolin, pyrazol, thiazol ...),

Ti Vit Nam cng c mt s cng trnh nghin cu v vn ny (GS-ng Nh Ti v cng s) Ti Trng i hc Dc H Ni cng c mt s lun n PTS nghin cu tng hp cc azometin t cc aldehyd thm v amin thm lm cht trung gian tng hp cc dn cht thuc dy -aminoceton. 1.2. Mt s azometin - oxim v hydrazon dng lm thuc

Bng 1. Mt s Azometin-Oxim-Hydrazon dng lm thuc ST T 1 Tn thuc Phtivazid ( 3 - methoxy - 4 hydroxy benzaldehy Isonicotinoylhydra zon Tibion (pacetamidobenzal dehyd thiosemicarbazon) Nitrofuran, furacin (5 - nitro 2 furfuraldehyd Semicarbazon Nifuroxim (Anti - 5 - nitro furaldoxim Cng thc cu to
CONH N CH OH OCH3 N

Tc dng Chng lao

CH3 C NH O

NH2 CH N NH C S

Chng lao

O2N

CH N NH C O

NH2

Khng khun Khng nm

O 2N

CH=N OH
O

5 Sulfacinamin 6 Ampecloral 7
Cl
CH=CH CH=N

S NH2 O

Khng khun iu tr chng bing n Thuc li tiu

CH2 CH CH3 N CH CCl3

OH N CH C CH3 S NH CH2 CH CH2 O O O

Ambuside
H2N S O

8 Terizidone
O N H

N CH O

HC N O N H O

Thuc chng lao

2. S lc v Tetracyclin Tetracyclin l mt trong nhng dn xut ca octahydronaphtacen 4 vng. y l mt khng sinh trong nhm khng sinh c tn l tetracyclin. Cc tetracyclin c chia thnh 2 nhm: + Cc tetracyclin thin nhin c ngun gc t Streptomyces + Cc tetracyclin bn tng hp. Cc khng sinh trong nhm ny c khung cu trc chung nh sau:

R 1R
7 8

3 6 11

R2 R4 H
5a 5 12 4a 4

CH3 CH3 OH 3
2

R6

10

OH O

OH OH O

COR 5

Cc tetracyclin u di dng bt kt tinh mu vng, v ng. Dng base rt t tan trong nc, tan trong ethanol v cc dung mi hu c t phn cc. Dng mui hydroclorid tan c trong nc. L nhng hp cht lng tnh c th to mui vi acid v kim. c bit cc tetracyclin to ra nhng chelat bn vng vi mt s kim loi nh Ca, Mg, Fe do rng tr em b nhum vng khi dng tetracylin lu ngy ( 2 3 tun ). Theo mt s tc gi cc tetracyclin ng li trong rng trong nhng giai on u ca s calci ho, c i lc vi Ca ca xng, do tr em di 8 tui c th b hng men rng, ph n c mang dng tetracyclin th c th gim s pht trin ca xng di v cc n rng ca thai ngi. Ni chung cc

tetracylin c hot ph tc dng rng, bao gm nhiu loi cu khun v trc khun Gram(+) v Gram(-), xon khun, Rickettsia, Trichomonas, Amip, giun kim, Chlamydia, Mycoplasma, khng c tc dng trn trc khun m xanh, trc khun lao, Proteus, Candida albicans. Tuy vy cc tetracyclin c tc dng mnh yu khc nhau trn mt s vi khun .V d nh vi t cu, lu cu, mng no cu th clotetracyclin c tc dng tt hn tetracylin, oxytetracyclin nhng i vi trc khun l th nguc li. Cc tetracyclin khc nhau cng c thi hn bn hu khc nhau, c mc lin kt vi protein ca huyt thanh khc nhau do c liu dng v mc ch iu tr cng khc nhau. V d nh doxycyclin hp th nhanh v gn nh trn vn, bi xut li rt chm nn duy tr nng trong mu khong 24 (h), trong khi tetracyclin li bi xut rt nhanh trong nc tiu, do khi dng doxycyclin ch nn dng ngy 1 ln vi liu lng thp v khng nn dng trong trng hp nhim khun ng niu v bnh nhn b thiu nng thn. Hai trng hp ny th nn dng tetracyclin c tc dng ngn hn do bi xut nhanh. 3. Tnh cht chung ca cc Oxim - Hydrazon Azometin. 3.1. Tnh cht vt l * Oxim c hnh thnh do s kt hp ca hydroxylamin vi aldehyd hoc ceton. Oxim thng l cc cht rn kt tinh, c im chy xc nh, t tan trong nc( Tr acetoxim ), tan -

trong alcolethylic, ether, DMF. Oxim ca cc aldehyd thm v cc ceton khng i xng RCOR tn ti di 2 dng ng phn syn v anti. Dng syn ( cu hnh cis ) l dng c nhm OH cng pha vi gc R hoc Ar lin kt vi Cacbon trong nhm
C= N

cn dng anti c cu hnh i lp. im nng

chy ca oxim dng anti cao hn dng syn. * Azometin L nhng cht c cu trc imin ( - CH = N - ) thng khng bn do khuynh hng polyme ho, ngng t hoc thu phn. Dng mch h thng khng bn, khng th tch ra thnh dng t do. Cc azometin c cu trc th th bn vng hn azometin c cu trc khng th. Vi cc azometin th N ( dy N - alkyl ho hoc N - aryl ho ) cu trc R - CH = N - R th gc R l mch h thng l cht lng v km bn, trong cu trc CH2 = N - R tn ti trng thi trimer ho song cu trc ca n l mt d vng, cc cht khc nhanh chng b trng hp ho. Vi gc R thm th azometin l nhng cht rn kt tinh, tn ti di dng n phn t, c tnh kim, t tan trong nc, tan trong alcol, cloroform, benzen, DMF ..., khng tan trong ether. *Hydrazon Phn ln hydrazon thm l cht kt tinh. Cc hydrazon va mi iu ch thng c mu vng nht hoc khng mu.

Xc nh im nng chy l mt trong nhng cch nh tnh cc hp cht carbonyl, tuy nhin vic xc nh im nng chy ca cc hydrazon c kh khn do n d b phn hu bi nhit. 3.2. Tnh cht ho hc * Oxim + Phn ng thu phn Khi un nng oxim vi dung dch acid v c trong nc n b thu phn tr thnh hp cht carbonyl ban u v hydroxylamin. R R
+ + H2O H C N OH

R R

C O + H2N OH

+ Phn ng kh ho oxim b kh ho to sn phm l amin bc 1 bi cc tc nhn kh thng dng nh LiAlH4, ZnCl2, Natri trong alcol, ..., khng nn dng cht kh acid trnh thu phn. R R C N OH + [H] R + CH NH2 H2O R

Oxim ca cyclohexanon khi hydro ho vi xc tc en platin trong dung dch alcol - nc v hydrocloric to ra cyclohexyl hydroxylamin N OH + H2 NH OH

Cc aldoxim khi b kh ho cng c th to thnh hydroxylamin v amoniac

2RCH = N-OH +

3 H2

RCH2 RCH2

+ NOH H2O + NH3

+ Cc phn ng alkyl ho v acyl ho Oxim tc dng vi methyl iodua trong mi trng trung tnh s to ra dn xut N-methyl
C C

R R'

C N OH +

CH3I

R'
C

C N

CH3 CH3
C

R -HI R'

C N

CH3 O

Trong mi trng kim phn ng methyl ho xy ra nguyn t Oxy R R R OHC N C N C N R' OCH3 R' O R' OH + Ngoi nhng phn ng trn oxim cn tham gia mt phn ng rt quan trng na, l chuyn v Beckmann Khi cho anhydrid acetic hoc acetylclorid tc dng vi cetoxim ng l thu c dn xut acetyl ca oxim th Beckmann(1886) li thu c amid th . Nhng amid l ng phn ca oxim ban u v c to thnh bng cch chuyn v ni phn t gi l chuyn v Beckmann

C 6H5

C N

C 6H5 OH

C HO C 6H5 C

C N

C C 6H5

C 6H5 C C

C N

C C6H5 H C

* Cc azometin

10

Tnh cht c bn ca azometin l do lin kt i (HC=N-) khng tng t nh cc lin kt i ethylenic(C=C) . Cc hp cht ny c phn bit bi 3 tnh cht c bn sau - Tnh base - Phn ng cng hp - S d dng ct mch m in hnh l phn ng thu phn a. Tnh base Do trn nguyn t N c cp in t khng chia s nn N l mt trung tm base Lewis. Lin hp (n,) c nh hng nht nh n tnh cht base ca hp cht azometin.Ngoi ra,cc nhm th trn nhn thm ca phn amin cng nh hng r rt n tnh base ny. Kt hp vi acid to mui R - CH = N - R + HCl b. Phn ng cng - Cng hp hydro
R-CH=N-R +H2 R - CH2 - NH - R

C (+) R CH N H C

(-)

Cl

- Cng hp halogen Sn phm cng hp halogen vo azometin lm bo ho dy ni i

R-CH=N-R + Br2 R - CHBr - NBr - R

- Cng hp cc acid sulfur v cc sulfit kim

11

C6H5 - CH = N - C6H5 + H2SO3 C6H5 - CH - N - C6H5 H SO3H - Cng hp vi acid cyanhydric : cho sn phm l nitril R - CH = N - R + HCN R - CH - NH - R CN - Cng hp vi cc hp cht c magie Theo Busch v cng s, cc hp cht c magie c th tham gia phn ng cng vi cc azometin l dn cht ca aldehyd thm vi cc amin thm Ar - CH = N - Ar + RMgX Ar - CH - N - Ar
+H O 2 Ar - CH - NHAr + MgX(OH)

MgX

R - Cng hp vi cc ceton Cc ceton c hydro linh ng v tr s cng hp c vi cc azometin to thnh hp cht -aminoceton, phn ng thng cn xc tc acid. R - CH = N - R + H3C - CO - C6H5 R - CH - NH - R CH2 CO C6H5 c.Phn ng ct mch - Phn ng thu phn cc azometin th Cc azometin N-alkyl b thu phn bi dung dch NaOH 30%, trong khi cc base azometin N-aryl th bn vng trong kim v b thu phn d dng nhit lnh vi s c mt ca acid v c to aldehyd v amin tng ng

12

R - CH = N - R + H2O RCHO + H2N - R d. bn vng ca cc azometin Cc azometin c to thnh t aldehyd thm v amin thm mi bn vng, cn to thnh t aldehyd mch h v amin mch h th thng khng bn, d b trng hp ( c bit nhiu cht d b trimer ho ) to hp cht d vng.

CH3 N 3H2C N CH3 CH3

* Hydrazon + Phn ng thu phn un nng vi acid v c long b thu phn thnh hydrazin v hp cht carbonyl. C6H5-CH2-NH = N = CH - R + H2O RCHO + C6H5 - CH2 - N = NH + Vi s c mt ca ZnCl 2, arylhydrazon ca mt s ln cc hp cht carbonyl b chuyn thnh indol v amoniac. Phn ng c tin hnh bng cch nung chy 180oC trn bnh cch du. C 6H5 NH N CH CH2 CH3 ( propanal hydrazon ) + Phn ng oxy ho Mt s hydrazon thm to hp cht azoic c mu khng bn NH3
+

CH3

CH3 NH

3 - metyl Indol ( Scatol )

13

R C N NH C6H5 R'CH

R' CH2

C NH NH C6H5

R R'CH

C N N C6H5

( azoic c mu ) + Phn ng kh ho Cc hydrazon b kh ho to amin bc nht.

R1 R2 C N NH R + 2H2 R1 CH NH2 R NH2 + R2

4. Tng hp cc dn cht Oxim - Azometin - Hydrazon 4.1. Phng php tng hp chung Tnh hot ng ca nhm carbonyl l do s phn ccC ca lin kt lun phn cc v pha oxy v oxy c m in ln hn ca carbon. carbon ca nhm carbonyl l trung tm tip nhn tc nhn i nhn. Do da trn tnh cht ca nhm carbonyl c th ngng t vi cc hp cht kiu B - NH2 to sn phm kt tinh c im nng chy xc nh. R R' C O+ H2N B H+ R R' C N B + H2O
O

4.2 C ch phn ng Thc cht y l phn ng cng hp i nhn vo nhm carbonyl to ra sn phm cng trung gian rt khng bn v b tch nc ngay thnh sn phm ngng t. C ch phn ng c m t nh sau:

14

R R'

.. C O + H2N B

C NH2 B R' O R R'

Nhanh

C NH B R' OH

-H O 2

C N B

y l phn ng thun nghch, cn bng v tc phn ng ph thuc vo pH ca mi trng. Bc cng hp trong mi trng trung tnh hoc base u xy ra nhanh v bc dehydrat ho l bc quyt nh tc phn ng. Bc dehydrat ho lun c xc tc bi acid nn thm acid s lm tng tc phn ng. Nu ch tnh n hp cht carbonyl, phn ng cng hp thun li khi [H+] cao, nhng tc nhn B NH2 trong mi trng [H+] ln s b proton ho to B - N+H3 lm mt i in t ca n. V vy iu kin mi trng phn ng tu thuc vo tnh base ca tc nhn B - NH2 v ho tnh ca hp cht carbonyl. 4.3. Cc yu t nh hng a. Yu t in t Xt phn ng cng hp i nhn: B + C O B C O
+ -

C 2 yu t nh hng n tc phn ng + Mt in t trn B cng ln ( cng c tnh base mnh ) th tc phn ng cng ln v ngc li.

15

+ in tch dng carbon ca nhm carbonyl cng ln th tc phn ng cng ln v ngc li. * Cc yu t nh hng n mt in t trn phn t amin + Gc B Nu gc B c kh nng y in t ( Hiu ng +I, +M ) s lm tng kh nng tham gia phn ng. Do vy kh nng tham gia phn ng cng i nhn ca phn t amin tng dn khi mt in t trn B cng ln. Nu gc B c kh nng ht in t s lm gim mt in t trn N nn kh nng phn ng ca hp cht gim. + S c mt v v tr ca cc nhm th trn nhn thm cng nh hng n kh nng phn ng. Nhm th loi I ( ankyl, -OH, -OCH 3 ...) gy hiu ng +I, +M lm tng mt in t trn N nn tham gia phn ng cng i nhn AN d hn anilin. Nhm th loi II ( -CHO, -NO 2, -COOH ) cn tr phn ng xy ra. V d: Cc amin thm sau c sp xp theo kh nng phn ng tng dn.
O ON

.. NH

< 2

O HO

.. NH2 <

.. NH2 < CH3

.. NH2

* Xt yu t nh hng ln in tch dng ca carbon trn nhm carbonyl

R C O H

16

Nu gc R c kh nng ht in t ( -I, -M ) s lm in tch dng trn C ca nhm carbonyl tng nn, lm tng kh nng phn ng cng hp i nhn ca hp cht. Nu gc R c kh nng y in t v kh nng ny tng ln theo s lng nguyn t C s lm in tch dng phn trn C ca carbonyl gim dn ti kh nng tham gia phn ng cng i nhn cng gim. Hiu ng lin hp ( +M ) lm phn t aldehyd thm kh tham gia phn ng cng i nhn hn formaldehyd. Mt khc s c mt v v tr ca cc nhm th trn nhn thm cng nh hng n kh nng phn ng ca hp cht. Cc nhm th loi I gy hiu ng +I, +M lm tng mt in t trong nhn thm v lm gim in tch trn C ca nhm carbonyl, lm kh nng phn ng km hn benzaldehyd. Cc nhm th loi II gy hiu ng -I, -M lm gim mt in t trn nhn thm v lm tng tnh phn cc ca lin kt carbonyl, phn ng cng i nhn d dng xy ra hn b. Yu t khng gian Hiu ng khng gian gy ra bi cc nhm th cng nh hng nhiu n kh nng phn ng. Trong phn ng cng i nhn ca nhm carbonyl, gc R cng cng knh th cng gy hin tng n ng khng gian, gim kh nng phn ng. Mt khc yu t khng gian ca phn t amin cng nh hng nhiu v bc cng hp t hp cht carbonyl c cu trc tam gic phng ( I ) khi cng hp s hnh thnh sn phm

17

cng hp t din ( II ) v cc nhm th phi thu li gn nhau hn, v vy s cng hp li cng kh khn C O
+

HB

C OH (II)

(I) c. Yu t xc tc

HB: Tc nhn i nhn ( amin bc 1 ) Phn ng tng hp c th dng xc tc acid, base hoc khng cn xc tc. iu ny ph thuc vo tnh i nhn ca tc nhn i nhn. Nu tnh i nhn yu ( tnh base yu ) th cn xc tc acid mnh ( HCl, H2SO4 ). Ngc li vi cc hp cht ca N c tnh base mnh hn th phn ng cng hp c th xy ra trong mi trng acid yu, trung tnh, thm ch base yu C ch: Xc tc base: B - NH2 + -OH B - -NH + H2O C O
+

HN- B

C OHN B

H2O

C OH HN B

-H O 2

C N B

Xc tc acid: C O + H+
+ .. C OH + H2N B

+ C O H
+ C NH2 B OH

+ C OH
- H2O

.. C NH B

- H+

C N B

Vy phn ng xy ra thun li nht ti mt pH nht nh ch khng phi trong mi trung acid hay base mnh. Ti v

18

tr pH ti u ny aldehyd c hot ha mnh ng thi vn cn phn ln thnh phn i nhn dng t do khng b proton ho. Ni chung thng trong vng tr s pK ca tc nhn i nhn. C th biu din s ph thuc ca tc phn ng vo pH theo s sau C% v a

b pH a : Nng aldehyd c proton ho theo pH b: Nng amin dng t do theo pH d. Cc yu t nh hng khc * T l cht tham gia phn ng: y l phn ng ng mol gia aldehyd v amin, do khi d: + Aldehyd: Aldehyd s b oxh to acid tng ng. c bit aldehyd thm rt d b oxy ha: Ar - CHO [o] Ar - COOH + Amin: S cho sn phm ph pH

B NH2 B NH2

O CH R

- H2O

BNH CH R BNH

19

Cc sn phm ph ny lm gim hiu sut tng hp v lm qu trnh tinh ch kh khn. * Thi gian phn ng: Nn chn sao cho phn ng xy ra gn nh hon ton m khng lm phn hu sn phm. * Nhit phn ng: Nhit tng lm tc phn ng tng, tuy nhin ch nn duy tr nhit ph hp v nhit cao gy phn hu sn phm. * Dung mi l rt quan trng i vi phn ng. Nu cc cht phn ng l cht rn phi ho tan trong dung mi ( Hoc hn hp dung mi ) ph hp chng c th trn
C u. NgoiO ra dung mi cn nh hng n tnh phn cc

ca lin kt

cng nh tnh i nhn ( Mt in t )

C O

trn N lm phn ng thun li hoc kh khn. Phn ng cng hp aldehyd vi amin bc I nu chn dung mi alcol s lm s phn cc ca lin kt li hn. tng gip phn ng c thun

20

21