Chng 33

HP CHT D VNG 5 CNH NHIU D T

Mc tiu

1. Nu c cch phn loi v c c tn d vng 5 cnh nhiu d t. 2. Nu c mt s ng dng ca d vng 5 cnh nhiu d t trong ngnh Dc.

Phn loi. Cc d vng 5 cnh nhiu d t thng gp

D vng thm 2 d t khc nhau v ging nhau: 3

112

N

NH

NNH

1,3-Diazol1,2-Diazol

3

211

N

SN

S

1,3-Thiazol1,2-Thiazol1

N

ON

O

1,3-oxazol1,2-oxazol

12

3

D vng 3 v 4 d t khc nhau v ging nhau:

21

N NO 2

5

1,2,5-Oxadiazol 1,2,3-Oxadiazol

NN

O1

2

3

1,2,5-Thiadiazol

N NS1

5

1,2,3-Triazol

N NNH

21

5

4

1,2,4-Triazol

NN

NH

12

Tetrazol

NNN

NH

1. Nhm oxazol

1.1. Tng hp nhn oxazol

C nhiu phng php tng hp nhn oxazol

1.1.1. Ngng t -bromoceton vi amid

4-Phenyl-1,3-oxazolFormamidBromoacetophenon

+CC6H5 OH

CH Br

HN

CHHO

CC6H5 O

CH2 Br

N

O

C6H5

120

1.1.2. Ngng t hp cht nitrilmandelic vi aldehyd thm

Nitrilmandelic

CHO

C6H5CH

C N

H5C6OH

+

Aldehyd benzoic 2,5-Diphenyl-1,3-oxazol

N

OC6H5H5C6

Tnh thm ca oxazol thp hn thiazol. Oxazol th hin tnh cht ca mt dien lin hp c phn ng cng Diels -Alder.

+

N

CN

NO

CN

CH2 CH CNN

O

Et3N , 180oC

ng dng phn ng ny tng hp cc dn cht ca pyridin.

V du: Vitamin B6 c cha d vng pyridin c tng hp nh sau:

Pyridoxol (Vitamin B6)

+ LiAlH 4

N

CH2OHHOCH2 OH

Me N

COOEtEtOOC OH

Me HNO

COOEtEtOOC OEt

Me

+

+ H+

C CCOOEtEtOOC

H H 110oC

N

OEtO

Me

+NO

COOEtEtOOC OEt

Me

Mt vi hp cht cha vng oxazol nh 2,5-diaryloxazol c tnh hunh quang c s dng nh mt tc nhn pht quang. 5 (4H)-oxazolon cn gi l azalacton nh l mt anhydrid ca N-acylaminoacid.

Azalacton

CN

OR'

R

O

N

OArAr'

2,5-Diaryl-1,3-oxazol

1.2. Benzoxazol

Benzoxazol c iu ch bng cch un o-aminophenol vi acid carboxylic hoc anhydrid acid 160C.

NH2

OH

N

O

+ HCOOH

- H2O- H2O ,

NH

OH

CHO-H+

121

2. Nhm thiazol

2.1. Tng hp nhn thiazol

2.1.1. Cho cloracetaldehyd tc dng vi thioformamid

3

1

N

S- HCl- H2O ,+H2N

CHS

1,3-Thiazol

HC OCH2 Cl

2.1.2. Cho cloracetaldehyd tc dng vi thioure to 2-amino-1,3-thiazol

1

N

S NH2- HCl- H2O ,+

CH2

HC O

Cl

H2N

CS NH2

2-Amino -1,3-Thiazol

3

Thioure Cloacetaldehyd

Thiazol l cht lng khng mu c ts = 117C. 2-Aminothiazol l tinh th khng mu c t nc = 90C. Sulfathiazol l mt loi sulfamid c vng thiazol.

N

SNH SO2 NH2

Nhn thiazol c trong hp cht t nhin nh penicillin, vitamin B1 (thiamin), khng sinh bleomycin l phc hp c cu trc aminoglycosid cha vng thiazol. Mt s hp cht tng hp vng -lactam, vng 2-aminothiazol c tc dng tr liu nh cefotaxim.

+N

S

Me

HOCH2CH2

NH2

MeH

N

N+ 2 Cl-

Vitamin B1 ( thiamin)

N

SH2N

C NNOMe H

ON

S

CH2OACOOHCefotaxim

2.2. Penicillin

Trong phn t cc penicillin thng c vng thiazol ngng t vi vng -lactam. Ph thuc vo gc R ta c cc penicillin khc nhau.

122

R

C6H5CH2-

C6H5-O-CH2-

C6H5-CH=CH-CH2-

CH3CH2-CH2-CH2-CH2-

Tn

Penicillin G

Penicillin V

Penicillin F

Penicillin K Vong Lactam

Vong Thiazol

Penicillin

N

S

C=O

NHCORH3C

H3C

HOOC

2.3. Benzothiazol

+ CHO

HONH2

SH

N

S

Benzothiazol c tnh base yu. Tc dng vi alkylhalogenid to mui amoni bc 4

I-N

S+ CH3I

Benzothiazol

+N

S

CH3 I-

2-Methylbenzothiazol

N

S CH3+ CH3I

+N

S

CH3

CH3

Trong mi trng kim mui b mt mt phn t HI v chuyn v theo phn ng:

N

SCH3

C s chuyn v nhm methyl

toc - HI

NaOHN

S

CH3

HI-+

NC

SCH2

CH3toc

- HI

NaOHN

S

CH3

CH3

I-+

Mui 3-alkyl-2-methylbenzothiazol d tham gia phn ng kiu aldol ha.

2-Mercaptobenzothiazol uc s dng lm cht tng nhanh qu trnh lu ha trong cng nghip ch bin cao su.

2-Mercaptobenzothiazol 2-Aminothiophenol

NH2

SH+ CS2

- H2O

NC

SSH

123

3. Nhm Imidazol: 1,3-Diazol

Imidazol l mt d vng phng c nng lng cng hng cao hn mt t so vi pyrrol.

3

21

N

NH

3

21

N

NH

..

Vng imidazol c vai tr quan trng v n c trong thnh phn ca acid amin cn thit l histidin. Sn phm decarboxyl ha histidin l histamin.

N

NH

CHHOOC

H2N

N

NH

CHH

H2N

Histidin Histamin

Thnh phn histidin l trung tm hot ng ca ribonuclease v ca mt s enzym (men). Chc nng ca imidazol trong cc enzym ng vai tr xc tc trao i proton.

H thng imidazol c tc dng nh mt base hoc mt acid. Imidazol t do l mt base "cng" (pKa = 7.0) v n cng tc dng nh mt acid "mm" (pKa= 14,5). Cation v anion ca n l nhng cu trc i xng khng n nh. C th minh ha cc cu trc nh sau:

N

NH

N

NH

HN

NH

HN

N

N

N -

- +

+- H+

+ H+

- H++ H+

pKa = 14,5 pKa = 7,0 Dung dch sinh l c pH khong 7, 4 nng ca cc n v imidazol t

do cng nh imidazol proton ha c gi tr gn nhau, do trung tm ny ca enzym tc dng nh mt base th trung tm kia tc dng nh mt acid.

3.1. Tng hp nhn imidazol

3.1.1. un nng glyoxal vi amoniac v aldehyd

- 3H2O++ O = CH2NH3

NH3 N

NH

C OH

C OH

3.1.2. C th thay th glyoxal bng hp cht dicarbonyl khc

6

O = CH-C H5

Benzaldehyd 2,4,5-TriphenylimidazolBenzil

C OC6H5C OC6H5

N

NH

H5C6

H5C6 H5C6

NH3NH3

+ +- 3H2O

124

3.1.3. Cho -aminonitril tc dng vi aldehyd thm

N

NH

H5C6 H5C6CH C6H5OCH

C

NH5C6H

H

N

+ + H2O

Aminonitril Benzaldehyd 2,5-Diphenylimidazol

3.2. Tnh cht

Bng 33.1: Nhit nng chy v nhit si ca mt vi hp cht azol

Pyrol Imidazol 1,3,4-Triazol Tetrazol

ts 130 256 260 Thng hoa tnc Cht lng 90 121 156

Imidazol c nhit si cao l do gia cc phn t imidazol c lin kt hydro:

NNH NNH NNH: : : : ::. . . . . .2,0 A

Mt s dc phm c vng imidazol nh 2-nitroimidazol (azomycin), metronidazol, bifonazol, clotrimazol.

2-Nitroimidazol

N

NH

NO2

N

NCH2CH2OH

O2N CH3

N

N

PhPh

N

N

Cl

Ph

Ph

Metronidazol Bifonazol Clotrimazol

3.3. Benzimidazol

N

NH

Tng hp nhn benzimidazol:

Ngng t o -phenylendiamin vi formaldehyd NH2

NH2

N

NH

C HHO

O+

125

Ngng t o-phenylendiamin vi ester phenylcyanat

+ NH2

NH2

N

NH

NH2C6H5O C N + C6H5OH

4. Pyrazol: 1,2-Diazol

21N

NH

4.1. Tng hp nhn pyrazol

Ngng t hydrazin, alkyl hoc arylhydrazin vi hp cht 1,3-dicarbonyl

NNR

R

RNH2NR

H

C

CR

RO

O ++ 2H2O

Cng hp diazoalkan hoc diazoceton vi alkyn

NN

RR

R

H NN

RR

R

H

R C C R

R CH N NR CH N N :..

+

....:

++

4.2. Tnh cht

Pyrazol to lin kt hydro gia 2 phn t vi nhau. Pyrazol to mui vi kim loi.

Pyrazol l mt base yu v c kh nng to ta picrat.

Pyrazol c kh nng phn ng km hn pyrrol. Kh b kh v oxy ho. Metylpyrazol b oxy ha to acid pyrazolcarboxylic.

Pyrazol tham gia phn ng halogen ho, nitro ha v sulfon ha. S th i in t xy ra v tr 4.

4-Aminopyrazol c th diazo ha.

Vng pyrazol c hin tng h bin. V d: 3-metylpyrazol v 5-metylpyrazol l 2 ng phn h bin.

126

V vy t 3-metylpyrazol c th metyl ha v thu c hn hp gm 1, 3 v 1,5-dimetylpyrazol.

1,3-Dimethylpyrazol

5

4 3

2

4 54

3

211

54

3 1

2

5

3

21

3- Methylpyrazol 1,5-Di methylpyrazol5- Methylpyrazol

NN

CH3

CH3

NN

CH3

H

NN

CH3

CH3

NN

H

CH3

Khung pyrazol c chc ceton v tr 5 gi l 5-pyrazolon. 5-Pyrazolon l khung c bn ca cc thuc h nhit nh antipyrin v pyramidon.

5

4 3

21

4 4

5

3

215

3

21

PyramidonAntipyrin

1-Phenyl-2,3-dimethyl-4-dimethylamino-5-Pyrazolon1-Phenyl-2,3-dimethyl-5-Pyrazolon

5-Pyrazolon

C NN

O

CH3CH3

C6H5

(CH3)2N

C NN

O

CH3CH3

C6H5

C NNH

O

Khung pyrazolon c dng h bin.

Dang Metylenic

C NN

CH3

C6H5

OH

H1

C NN

CH3

C6H5

O H

Dng Imin

1 C NN

CH3

C6H5

HO

Dng Phenolic

1

127