Post on 08-Sep-2018
junio de 2011 1
Universidad de AlcalUniversidad de AlcalááDoctorado QuDoctorado Quíímica Mmica Méédicadica
ESTRATEGIAS EN SINTESIS DE FARMACOS ESTRATEGIAS EN SINTESIS DE FARMACOS ACICLOVIRACICLOVIR
Ana MarAna Maríía Cuadroa Cuadro-- Junio 2011Junio 2011
junio de 2011 2
Síntesis de Fármacos
ACICLOVIR
N
N N
N
OH
NH2
O
OH
1
2 4
56 7
8
93
9-[(2-hydroxyethoxy)methyl]guanine
Antiviral
(GlaxoSmithKline)
junio de 2011 3
Síntesis de Fármacos
ACICLOVIR
N
N N
N
OH
NH2
O
OH
1
2 4
56 7
8
93
9-[(2-hydroxyethoxy)methyl]guanine
Antiviral
Azucar R= OH: Ribosa (RNA)R= H, desoxirribosa (DNA)
O B
ROH
OP
O
OH
OH
3´
Los nucleósidos pueden combinarse con un grupofosfórico (ácido fosfórico:, produciendo nucleotidos,componentes moleculares básicos del ADN y RNA
junio de 2011 4
Síntesis de Fármacos
ACICLOVIR
N
N N
N
OH
NH2
O
OH
1
2 4
56 7
8
93
9-[(2-hydroxyethoxy)methyl]guanine
Antiviral
O B
ROH
OH
R= OH: Ribosa (RNA)R= H, desoxirribosa (DNA
NH
N
NH2
O NH
NH
O
OCH3
NH
NH
O
O
2
3
1 2
3
1 2
3
1
Cytosine Thymine Uracile
Pirimidínicas
RNA
N
N NH
N
NH2
NH
N NH
N
NH2
O
24
56 7
89
3
Adenine
1
2 4
56 7
8
93Guanine
(DNA, RNA)
Estructura general Estructura general nuclenucleóósidossidos
junio de 2011 5
Síntesis deSíntesis de Fármacos: Acyclovir
Purine Nucleosides Analogs
NucleNucleóósidossidos: : utilizacionutilizacion como dianas terapcomo dianas terapééuticas uticas para el disepara el diseñño de ano de anáálogos capaces de incorporarse a lalogos capaces de incorporarse a labiosbiosííntesis de los ntesis de los áácidos nucleicos (antimetabolitos)cidos nucleicos (antimetabolitos)
AnAnáálogos de logos de NucleNucleóósidossidosAnticancerosoAntiviricosantifungicos
N
N
NH2
O
S
OOH
2
3
1
3-TC (Lamivudine)
(hepatitis B, AIDS)
N
NH
O
OCH3
OOH
N3
2
3
1
AZT (Zidovudine)
(AIDS)
N
NH
O
OCH3
OOH
2
3
1
d4T(Stavudine)
((AIDS)
OOH N
NH
O
OI
OHIdoxuridine
junio de 2011 6
Síntesis deSíntesis de Fármacos: Acyclovir
OOH N
NH
O
OI
OH
Idoxuridine5-yododesoxiuridine
(herpes simplex y Varicela zoster)
OOH N
NH
O
O
OH
F3C
ONH2 N
NH
O
OI
OH
5-trifluorometildesoxiuridine
Trifluridina
5´-amino-5-yododesoxiuridine
junio de 2011 7
Síntesis de Fármacos: Acyclovir
N
N NH
N N
N N
NH
9H-purine
1
2 4
56 7
8
93
7-Hpurine
1
2 4
56 7
8
93
N
N NH
N
NH2
NH
N NH
N
NH2
O
24
56 7
89
3Adenine
1
2 4
56 7
8
93
Guanine(DNA, RNA)
OOH
OH
N
N N
N
NH2
OHO
OH
OH
OH
NH
N N
N
NH2
O
Adenosine Guanosine
Purines
AnAnáálogos de logos de NucleNucleóósidossidos
junio de 2011 8
Síntesis de Fármacos: Acyclovir
Purine Nucleosides Analogs
NH
N NH
N
NH2
O
N
N NH
N
Guanine
9H-purine
1
2 4
56 7
89
3
NH
N NH
N
S
(leukemia)
NH
N NH
N
O
Allopurinol(gote)
6-Mercatopurine
OOH
NH
N N
N
O
NH2
(AIDS)
NH
N N
N
O
NH2
O
OH
Acyclovir
N
N N
N
OH
NH2
O
OHOHGCV
Gancyclovir
OOH
OH
OH
NH
N N
N
NH2
O
Guanosine
N
N N
N
OH
NH2
OHOH
Penciclovir
N
N N
N
OH
NH2
O
OHOHGCV
Gancyclovir
junio de 2011 9
Síntesis de Fármacos: Acyclovir Introduction
O B
ROH
OH
AnAnáálogos de logos de NucleNucleóósidossidos
Modificación del azúcar--2,3-didesoxinucleósidos--otros sistemas heterociclícos-- análogos carbociclícos
Nucleósidos y desoxinucleósidos
Modificación de la base
Análogos aciclicos
OHO Base
DiseDiseññoo
-Similitud estructural-Aplicación Terapia antitumoral y antivir- Naturales y sintéticos
junio de 2011 10
Síntesis de Fármacos: Acyclovir Introduction
O B
ROH
OH
AnAnáálogos de logos de NucleNucleóósidossidos
Modificación de la base
OOH
OH
N
N N
N
Cl
NH2
CladribinaN
NH
O
O
OOH
OH
Br
BVDU
junio de 2011 11
Síntesis de Fármacos: Acyclovir Introduction
O B
ROH
OH
AnAnáálogos de logos de NucleNucleóósidossidos
Modificación del azúcar--2,3-didesoxinucleósidos--otros sistemas heterociclícos-- análogos carbociclícos
OOH
NH
N
N
NNH2
Aciclovir
Apertura de ciclo
Homologossuperiores o inferiores OH
NN
N
Br
O
OH
OH
OH
OH
NH
N N
N
NH2
O
CarvobirAnalogo carbociclico
N
NH
O
NH2
OOH
Eliminacion o sustitución C2 o C3
DDC
junio de 2011 12
Síntesis de Fármacos: Acyclovir Introduction
O B
ROH
OH
AnAnáálogos de logos de NucleNucleóósidossidos
Análogos aciclicos
OHO Base
DiseDiseññoo
-Similitud estructural-Aplicación Terapia antitumoral y antiviral- Naturales y sintéticos
NH
N N
N
O
NH2
O
OH
Acyclovir
N
N N
N
OH
NH2
OHOH
Penciclovir
N
N N
N
OH
NH2
O
OHOHGCV
Gancycloviradefovir
junio de 2011 13
Síntesis de Fármacos: Acyclovir
Human Herpesviruses
Herpes simplex type 1 (HSV-1)(labial herpes)
Herpes simplex type 2 (HSV-2)(Genital herpes)
Epstein Barr virus (EBV)Varicella-zoster virus (VZV)
Cytomegalovirus (CMV)
N
N N
N
OH
NH2
O
OH
1
2 4
56 7
8
93
ACV
junio de 2011 14
Síntesis de Fármacos: Acyclovir
The chemistry developed for the synthesis ofantiviral ACV, is an example of competitionamong industrial research groups
Quimica Shyntetica SALachema ASRecordatiChemical Ind. Co., etc....more than 20...
Burrroughs-Wellcome (Glaxo-Wellcome)(DMF) USA.
Acyclovir (ACV)
N
N N
N
OH
NH2
O
OH
1
2 4
56 7
8
931
HISTORIA
Acyclovir (ACV)
N
N N
N
OH
NH2
O
OH
1
2 4
56 7
8
931
HISTORIA
(GlaxoSmithKline)
junio de 2011 15
Síntesis de Fármacos: Acyclovir
“ a wrong or a missed word in the claim can create opportunities for the competitors “
To identify paten-free synthetic routes
The last 15 years a process-patent warbetween generic companies and the originatorGlaxo-Wellcome
Strategies adopted by the companies
Introduction
HISTORIA
junio de 2011 16
Síntesis de Fármacos: Acyclovir
N
NH
O
OCH3
OOH
N3
2
3
1
N
N N
N
OH
NH2
O
OHAZT
1
2 4
56 7
8
93
ACV
Basic research programme of Burrroughs-Wellcome(Glaxo-Wellcome) 1940s
Treatment of viral deseases
Introduction
HISTORIA
GlaxoSmithKline)
junio de 2011 17
Sir James W. Black (U.K☺
London University, King's CollegeHospital Medical SchoolLondon, United Kingdom
b. 1924-2010
The Nobel Prize in Physiology or Medicine 1988
"for their discoveries of important principles for drug treatment"
Gertrude B. Elion(USA)
b. 1918 d. 1999
Wellcome Research LaboratoriesResearch Triangle Park, NC, USA
George H. Hitchings(USA)
b. 1905 d. 1998
Wellcome Research LaboratoriesResearch Triangle Park, NC, USA
Síntesis de Fármacos: Acyclovir Introduction
junio de 2011 18
Síntesis de Fármacos: Acyclovir Mode of action
Activation by phosphorylation
N
NH
N
N
NH2O
OH H
OH
POO
O
OO
NH
N
N
NNH2
POO
O
O
guanilate kinase
POO
O
POO
O
OO
NH
N
N
NNH2
POO
O
O
phosphoglicerate kinase
DNA - Polimerasa
DNA - VIRAL
_
termination of the elongation in the virus DNA replication
OOH
NH
N
N
NNH2
O
N
NH
N
N
NH2O
OH H
O
POO
O
POO
O
POO
O
-
thymidine kinase1st activation
viral OO
NH
N
N
NNH2
POO
O
O
Aciclovir-MP
Aciclovir-DPTP
Acyclovir
2´desoxiguanosina
junio de 2011 19
ChemistrySíntesis de Fármacos: Acyclovir
Burrroughs-Wellcome (Glaxo-Wellcome)
Howard J. Schaeffer1974
N
N N
N
OH
NH2
O
OH
1
2 4
56 7
8
93
Acyclovir1978
N
N N
N1
2 4
56 7
8
3C2
C6
O
OH
coupling of the side chain
Explored nearly all thepossible synthetic approach
Modificacion C2 y C6
junio de 2011 20
Chemistry
N
N N
N
O
OH
C2
C6
9
N
N N
NCl
Cl
29
N
N N
NI
Cl
2
Síntesis de Fármacos: Acyclovir
Strategies
N
N N
N
OH
NH2
O
OH
1
2 4
56 7
8
93
Acyclovir
Equivalent functional groups on theC2 and C6 positions of purine
Persistent or temporary protection of theC2 amino and C6 hydroxyl of the guanine
AcTMS
junio de 2011 21
Síntesis de Fármacos: Acyclovir synthesissynthesis
N
N N
NCl
Cl
1
2
6
Schaeffer´s Synthesis
2,6-dichloropurine
O
OBz
N
N N
NNH2
NH2
OCl OBzN
N NH
NCl
Cl
O
OBz
N
N N
NCl
ClO
OH
N
N N
NNH2
Cl
O
OH
NH
N N
N
Cl
O
O
OH
NH
N N
N
NH2
O
6
4
120ºC, 18hNH3/MeOH
(12%)
Adenosine-deaminase pH 7- 8.5, 37ºC, 18 h
(84%)
recrystalization (MeOH) yield not given
9 Et3N, DMF, r.t. 24 h
(41%)2
3
NH3/MeOH
(94%)
NaNO2, AcOH
r.t. 5,5. h(50%)
595ºC, 18h
NH3/MeOH 125ºC, 5h
(75%)
semihydrate
67
1
Regioselective alkilation N9Different reactivity of C2/C6
Equivalent functional groups
Enzimatic aproach
FirstFirst synthesissynthesis ACVACV
junio de 2011 22
Síntesis de Fármacos: Acyclovir
N
N N
NCl
Cl
1
2
6
Schaeffer´s Synthesis
2,6-dichloropurine
OCl OBzN
N NH
NCl
Cl
NH
N NH
N
NH2
O
NH
N NH
N
NH
O
Ac
O
OBz
N
N N
NCl
Cl O
OH
N
N N
NNH2
Cl
O
OH
NH
N N
N
Cl
O
O
OH
NH
N N
N
NH2
O
O
OBz
N
N N
NNH2
NH2
Ac
9 Et3N, DMF, r.t. 24 h
(41%)2
Guanine
6
3 4
NH3/MeOH
120ºC, 18h
(94%)
NaNO2, AcOHr.t. 5,5. h
(50%)
5
NH3/MeOH
95ºC, 18h
(12%)
NH3/MeOH
125ºC, 5h (75%)
Adenosine-deaminase pH 7- 8.5, 37ºC, 18 h
(84%)semihydrate
diacetylguanine
NO2
expensive
Overal yield low
No desingned for large scale
Only enough material for preclinicalpreclinical studiesstudies
Equivalent functional groups
synthesissynthesis
Drawbacks
N
N N
NCl
Cl
1
2
6
Schaeffer´s Synthesis
2,6-dichloropurine
junio de 2011 23
Barrio´s SynthesisN
N N
NI
Cl
1
2
6
Síntesis de Fármacos: Acyclovir
Equivalent functional groups
synthesissynthesis
2-chloro, 6-iodide variation
-Yodo derivado mas reactivo-No se utiliza NaNO2/AcOH
Rto global 48-54%
OI
OSiMe3N
N NH
NI
ClO
OSiMe3
N
N N
NI
Cl
O
OH
N
N N
NI
Cl
O
OH
NH
N N
N
Cl
ONH
N N
NO
NH2O
OH
6
HNa, DMF, r.t.8
NH3/MeOH
- 63ªC
9 /cyclohexener.t. 3h,
KF, 0.5 h
75%
K2CO3, r.t.dioxane/H2O
80%
10
110ºC, 18 h(80-90%)
9
6
junio de 2011 24
Síntesis de Fármacos: Acyclovir
Barrio´s Synthesis
2-chloro, 6-iodide variation
N
N N
NI
Cl
1
2
6Equivalent functional groups
synthesissynthesis
Drawbacks
OI
OSiMe3
N
N N
NI
Cl O
OSiMe3
N
N N
NI
Cl
n
O
OH
N
N N
NI
Cl
O
OH
NH
N N
N
Cl
ON
N N
NO
NH2O
OH
6
9 HNa, DMF, r.t.
8
NH3/MeOH
-63ªC
9 /cyclohexener.t. 3h,
KF, 0.5 h
75%
K2CO3, r.t.dioxane/H2O
80%
10
110ºC, 18 h(80-90%)
cryogenic technologies
(liquid nitrogen)
junio de 2011 25
Síntesis de Fármacos: Acyclovir
Farmhispania´s patents
Barrio´s Synthesis
2-chloro, 6-iodide variation
N
N N
NI
Cl
1
2
6
N
N N
N
O
OCF3
O
Cl
Cl
O
OH
N
N N
NI
Cl
1410
N
N NH
NCl
Cl 92
Equivalent functional groups
synthesissynthesis
Schaeffer´s Synthesis
2,6-dichloropurine
Producto clave
N
N NH
N
11
Productos de partida
junio de 2011 26
Síntesis de Fármacos: Acyclovir
Equivalent functional groups
ACV
Farmhispania´s patents
synthesissynthesis
- never extended to other countries
- no industrial value
Drawbacks:
N
N NH
NCl
Cl
N
N NH
NO Cl
OF3C
O
N
N N
N
O
OCF3
O
N
N N
N
O
OCF3
O
Cl
ClO Cl
OCF3
O
O
OH
N
N N
NI
Cl
N
N N
NOH
NH2O
OH
2
NaOH, n-Bu4NBr60-70 ºC, 2.5 h. 13
11 85%
POCl3
14 10
HI, -2º 1 ha)
b) KHCO3/MeOH
1
CHCl3, NH3
150ªC, 5h
85%
75%
85%
85%
Purine
junio de 2011 27
Síntesis de Fármacos: Acyclovir
Equivalent functional groups Hatfield´s syntesis
O
OBz
N
N N
NNH2
NH2
OCl OBz
N
N NH
NCl
Cl
O
OBz
N
N N
NCl
Cl
O
OH
NH
N N
N
NH2
O
N
N N
NCl
Cl Si(Me)3
OBr OAc
O
OAc
N
N N
NCl
Cl
O
OAc
N
N N
NNH2
NH2
4
120ºC, 18hNH3/MeOH
(12%)
Adenosine-deaminase pH 7- 8.5, 37ºC, 18 h
(84%)
9
Et3N, DMF, r.t. 24 h(41%)
2
3
7
1
HMDS, (NH4)2SO4, 3h
Hg(CN)2
17
15
16bencene (80%)
150ºC, 3 d
93%
Adenosine-deaminase pH 7.5, r.t.
89%
reflux, 2h
Overal yield > 68%Schaeffer´s Synthesis
Academic
synthesissynthesis
1982, univ. Alberta , Canada
Drawbacks:
TOXIC PRODUCTS
EXPENSIVE STARTING MATERIAL
junio de 2011 28
Síntesis de Fármacos: Acyclovir
Equivalent functional groups Hatfield´s syntesis
synthesissynthesis
N
N NH
N N
N N
NH
N
N N
NCl
Cl Si(Me)3
N
N NH
NCl
Cl
(Me)3-Si-NH-Si (Me)3 N
N N
NCl
Cl
Si(Me)3
OBr OAc
N
N NH
NCl
Cl
Si(Me)3
O
OAc
N
N N
NCl
Cl
Si(Me)3
O
OAc
N
N N
NCl
Cl
9H-purine
1
2 4
56 7
8
93
7-Hpurine
1
2 4
56 7
8
93
15
+-H+
Br -
junio de 2011 29
Síntesis de Fármacos: Acyclovir synthesissynthesis
Equivalent functional groups Krenitsky´s prodrug approach
1982, Glaxo-Wellcome
Alternative ezimatic synthesis approach
N
N NH
NCl
NH2O
OH
N
N N
N
NH2
O
OH
NH
N N
N
NH2
O
Et3N, DMF, r.t.18 h
(44%)
EtOH, Et3N, Pd/C, H2 r.t. 20h
CH3NH2, CH3OH
62%
Xanthineoxidase phosphate buffer
% yield ???
Prodrug Drug
The conversion is relatedto enzime cocentration in the body
Oxidation at C6
junio de 2011 30
Síntesis de Fármacos: Acyclovir
Persistent protective groups onC2 (NH2) and C6 (OH) - positions
Temporary protective groups onC2 (NH2) and C6 (OH) - positions
Regioselectivity
Zovirax® (Glaxo-Wellcome) impurities
synthesissynthesis
NH
N N
N
O
NH
Ac Ac
N
N NH
N N
N N
NH
NH
N NH
N
NH2
O
24
56 7
89
3 N
N N
NO
NH
SiMe3
siMe3
SiMe3
20guanine
24
9H-purine
1
2 4
56 7
8
937-Hpurine
1
2 4
56 7
8
93
33
junio de 2011 31
Síntesis de Fármacos: Acyclovir
Persistent protective groups onC2 (NH2) and C6 (OH) - positions
N,N-diacethyl guanine route
Schaeffer´s Synthesis
Drawbacks:
Selectivity alkilationis not report
The patent no describe the parameters forPharmaceutical grade-ACV
1976
synthesissynthesis
NH
N N
NO
NH
Ac Ac
OAcO OAc
O
OAc
NH
N N
NO
NH
Ac
O
N
N N
NO
NH
Ac
OAc
O
NH
N N
NO
NH2
OAc
O
OH
NH
N N
NO
NH2
N
N NH
NO
NH2
21
20
PTSA, toluene, reflux, 16h
+
75%
1 ACV
CH3NH2
reflux, o.7 h.
crystalization (EtOH)
guanine
23
25
24
junio de 2011 32
Síntesis de Fármacos: Acyclovir
Matsumoto´s ProcessPersistent protective groups onC2 (NH2) and C6 (OH) - positions
EP806425
Matsumoto et al. Chem. Pharm. Bull. 1988, 36, 1153Kumar, A. et al, J. Org. Chem. 1999, 664, 4665
(Minophagen Pharmaceutical , Japan)
synthesissynthesis
NH
N N
NO
NH
Ac Ac
OAcO OAc
O
OAc
NH
N N
NO
NH
Ac
O
NH
N N
NO
NH
Ac
OAc
O
OH
NH
N N
NO
NH2
21
20
DMSO, PTSA, reflux
+
1 ACV
23
22/23
22
purified by chromatography
85% (72:28)
junio de 2011 33
Síntesis de Fármacos: Acyclovir
Chu´s PatentPersistent protective groups onC2 (NH2) and C6 (OH) - positions
Chu and Du, Univ. Georgia Research Fundation
US5583225, 1994
Dudycz, L.W.; Wright, G.E.; Nucleosudes nucleotides 1984, 3, 33
See also, J. Org. Chem. 1988, 53, 1294J. Org. Chem. 61, 9207
C.CC.T
< 1-1,5 %
Drawbacks:
synthesissynthesis
Patent granted in 1996
Lack of novelty
NH
N N
NO
NH
Ac Ac
OAcO OAc
O
OAc
NH
N N
NO
NH
AcO
NH
N N
NO
NH
Ac
OAc
O
OH
NH
N N
NO
NH2
NH
N NH
NO
NH2
O
NH
N N
NO
NH2
OAc
21
20H3PO4,85% H2O(cat.) toluene, reflux, 16h
+
1 ACV
30% NH4OH in H2O
crystalization (H2O)
guanine
23
24
Ac2O (16 equiv.), ACOH
reflux, 52 h
2 equiv.
22
r.t. 24 h
+
25
junio de 2011 34
Síntesis de Fármacos: Acyclovir
Ajimoto´S ProcessPersistent protective groups onC2 (NH2) and C6 (OH) - positions
Schaeffer patent( USA 4146715)Izawa, K. Koguchi, Y.; Shiragami, H. Uchida , Y.; Takamatsu, S. US 5688948
Studies on crystalization
22/23 b (%)Yield a (%)Solvent
98.2/1.892IPA
99.9/0.174EtOH
98.2/1.886AcOEt
99.9/0.178H2O
99.9/0.176MeOH
100/065H2O/MeoH
a)isolated yield fron 26;b) determinated by HPLC.
synthesissynthesis
No industrial value(expensive)
OOH
OH
OH
NH
N N
N
NH2
O
O
OAc
NH
N N
NO
NH
Ac
O
NH
N N
NO
NH
Ac
OAc
OAcO OAc
O
OAc
NH
N N
NO
NH
Ac O
OH
NH
N N
NO
NH2
Guanosine2322
21
2 equiv.
Ac2O (1O equiv.), DMF, PTSA (2.5 mol%), 100ºC, 18h
+
22/23 (71:29)
cristalyzation
100 ºC, 18 h 22/23 (89:11)
H2O/ MeOH 22/23 (100: 00)
global yield 60%
NaOH 5% 24 h
22
26
92%
Ac2O (5 equiv.), DMF, H3PO485% (2.5 mol%), 100ºC, 1.2 h
22/23 (95:5)
cristalyzationAcOEt
65%70%
(<5% )
junio de 2011 35
Síntesis de Fármacos: Acyclovir
Recordati´s ProcessPersistent protective groups onC2 (NH2) and C6 (OH) - positions
7 (claim) a compound with formula
O
N
N N
N
NH
X2
O
OX1
O
R1 R1= OH, NR2
X1
O
X2 = X1 or X1= X2represents Alkyl or phenyl
English /italiam version
Recordati´s research observed that the italian/english versionof Glaxo patent does not claim N-formyl derivative
X= H
synthesissynthesis
N,N-diacethyl guanine route
Schaeffer´s SynthesisSchaeffer patent (USA 4146715)
O
N
N N
NOH
NH
R
O
OR1
O
R, R1= H, Alkil C1-C4, Ph
1 (claim) a compound with formula
N-formyl derivative
junio de 2011 36
Síntesis de Fármacos: Acyclovir
Recordati´s ProcessPersistent protective groups onC2 (NH2) and C6 (OH) - positions
OAcO OAc
N
N NH
N
NH2
O
O
OAc
N N
NO
NH
NH
OH
N NH
NO
N
N
OH
OH
HN N
H
NO
NH
NH
OH
O
OH
N N
NO
NH
NH2
N NH
NO
N
N
OH
OH
H
OH
OH H
O
1
NaOH, in water
(98%)
9
2427
90%
HCOCOH 5% in H2O (2 equiv.)
80ºC, 4h
H2OH3PO4
pH= 1.8-2.2NaIO4 30ºC, 2h
28
(2.5 equiv.)PTSA118-120ºC, 9h
(98%)
29
r.t. 12 h.90%
70% overall yield
+
NH
N NH
N
NH
O
Ac Ac
diacetylguanine
N 7/N 9 isom ers
Drawbacks:
N-formyl prevent N7-isomer????
Long synthesis/purification process
synthesissynthesis
junio de 2011 37
Síntesis de Fármacos: Acyclovir
KRKA´S ProcessPersistent protective groups onC2 (NH2) and C6 (OH) - positions
N NH
NO
N
N
AcO
AcO
Ac
OAcO OAc
O
OAc
N N
NO
N
N
AcO
AcO
Ac
N
N N
NO
NH
Ac Ac
20
PTSA
Drawbacks:
many chemical stepsOverall yield lower
synthesissynthesis
NH
N N
NO
NH
Ac Ac
OAcO OAc
N NH
NO
N
N
OH
OH
Ac
O
OH
N N
NO
NH
NH2
N NH
NO
N
N
AcO
AcO
Ac
O
OAc
N N
NO
N
N
AcO
AcO
Ac
20
1 (81%)
30 70%
HCOCOH (0.37 equiv.)
r.t. overnight44%
Py, r.t., 1.5 h H20, 5ºC overnight
90%
Ac2O (3 equiv.)Py, 50ºC, 1h
(1.5 equiv.)
toluene, reflux, 7h
31
32
PTSA,
+
N7-isomer
50% CH3NH2
cristallyzation: EtOH, MeOH,H2O/ MeOH
23 % overall yield
junio de 2011 38
Síntesis de Fármacos: Acyclovir synthesissynthesis
Temporary protective groups onC2 (NH2) and C6 (OH) - positions
Schaeffer´s Synthesis
Aditional approach for industrial processBased on silanes as temporary protecting grou
silylation
Alkilation
deprotection
N
N N
NO
NH
SiMe3
siMe3
SiMe3
33
Overal yield 24%
OCl OBz
N
N NH
NO
NH2
H
O
OAc
N
N N
NO
NH2
H
N
N N
NO
NH
SiMe3
siMe3
SiMe3
O
OH
NH
N N
NO
NH2
9
Et3N, reflux 15 h.
(34%)
24
HMDS (50 equiv.), (NH4)2SO4 (0.86 mol
bencene reflux
33
EtOH, reflux 0.5 h
33 crystalization (H2OH)
NH3, CH3OH
80ºC, 16 h
75%
junio de 2011 39
Síntesis de Fármacos: Acyclovir
Temporary protective groups onC2 (NH2) and C6 (OH) - positions Solar´s Process
Improvement of the Glaxo route
50-100ºC0.5- 5 h
Overall yield 70-76%
Solar´s research also claimed a method for purification of ACVand the residual guanine (1%)
Bruzzese, T.; Guazzi, G.; Rognoni, M.; Marcon, G. EP 628558, 1994
O OAcBr
N
N NH
NO
NH2
H
O
OAc
N
N N
NO
NH2
H
N
N N
NO
NH
SiMe3
siMe3
SiMe3
O
OH
N
N N
NO
NH2
OOAc
N
N N
NO
NH2
HOOH
N
N N
NO
NH2
H
960ºC, 3h
24
xylene reflux,overnight 16 h 33
35
99/1
18
(1.1 equiv.)
+
36
70% yield
HMDS (2.8 equiv.), (NH4)2SO4 ( 8 mol %)
NaOH
extraction
organic phase
+
N9/N7
35% HCl
Slow reaction Toxic product
Elimination not described
synthesissynthesis
junio de 2011 40
Síntesis de Fármacos: Acyclovir
Temporary protective groups onC2 (NH2) and C6 (OH) - positions Syntex´s Process
Palo Alto
Variation of the sylylation process
US5565565, 1994
Temporary protective groups onC2 (NH2) and C6 (OH) - positions Syntex´s Process
Variation of the sylylation process
US5565565, 1994
synthesissynthesis
O OAcAcO
N
N NH
NO
NH2
H
O
OAc
N
N N
NO
NH2
HN
N N
NO
NH
SiMe3
siMe3
SiMe3
O
OAc
N
N N
NO
NH
Ac
O
N
N N
NO
NH2
H
O
OH
N
N N
NO
NH2
CF3
O
OSiMe3
9 120-125ºC, 8h 24
(TfOH (1 mol %)
reflux, 16 h33 35
75%
HMDS (66 equiv.)
35/36 95-98.5 /5-1,5%
21
(1.27 equiv.)
H2O, CH3COCH3
+
36
60% yield
(AcO)2O (1.6 equiv.)
4-DMAP, 100ºC, 1 h
CH3OH, NH4OH (28%)
53ºC 16h 22MeOH, reflux, 1 hH2O, carcoal 90-95ºCcrystallyzation 0ºC
ACV
90%
junio de 2011 41
Síntesis de Fármacos: Acyclovir
Temporary protective groups onC2 (NH2) and C6 (OH) - positions Syntex´s Process
Variation of the sylylation process
US5567816, 1995One year later
Industrial process, Oxalane is cheap Overall yield 60%
Temporary protective groups onC2 (NH2) and C6 (OH) - positions Syntex´s Process
synthesissynthesis
1,3-dioxolano
N
N NH
NO
NH2
H
O
OSiMe3
N
N N
NO
NH2
HN
N N
NO
NH
SiMe3
siMe3
SiMe3
OOSiMe3N
N N
NO
NH2
H
O
OH
NH
N N
NO
NH2
OO
CF3
O
OSiMe3
OOH
N
N N
NO
NH2
H
9reflux, 15 h
24
(TfOH (1 mol %)
reflux, 16 h33 38
69%
HMDS (66 equiv.)
38/39 95-98.5 /3.8--1,9%
H2O, CH3COCH3
+
39
87% yield
MeOH, reflux, 1 hH2O, carcoal 90-95ºCcrystallyzation 0ºC ACV
H2O, AcOH
reflux
+
125 1 / 25 99.9 / 0.1 %
junio de 2011 42
Síntesis de Fármacos: Acyclovir
Temporary protective groups onC2 (NH2) and C6 (OH) - positions Secifarma´s Process
N
N NH
NO
NH2
H N
N N
NO
NH
SiMe3
siMe3
SiMe3
9 xylene reflux,overnight 16 h
33
HMDS (2.8 equiv.), (NH4)2SO4 ( 8 mol %)
Slow reaction
Poor solubility of guanine in xylene
Cabri et al. IT MI97A 000931
synthesissynthesis
N
N N
N
O
NH
SiMe3
siMe3
SiMe3
OOAcAcO
O
OAc
N
N N
N
O
NH2
HO
OHN
N N
N
O
NH2
H
O
OH
N
N N
NO
NH2
H
N
N NH
N
O
NH2
H nBu4NI
21
(1.27 equiv.)
35 36
35/36 99: 1 %
95% yield80%
MeOH
NaOH 30%
9 xylene reflux,8-12 h
33
HMDS (2.8 equiv.)
junio de 2011 43
Síntesis de Fármacos: Acyclovir
9
N
N NH
NO
NH2
H
xylene reflux,8-12 h
N
N N
NO
NH
SiMe3
siMe3
SiMe3
33
nBu4NIHMDS (2.8 equiv.)
SiMe3
NH
SiMe3
(2 mol%)
I- I
SiMe3
Temporary protective groups onC2 (NH2) and C6 (OH) - positions Secifarma´s Process
N
N N
NO
NH
SiMe3
siMe3
SiMe3
O OAcAcO
(1.27 equiv.)
MeOH O
OAc
N
N N
NO
NH2
H
35
OOH
N
N N
NO
NH2
H
36
95% yield
ISiMe3 O OAcAcO
+
+ OAcSiMe3 + O OAcI
synthesissynthesis
junio de 2011 44
Síntesis de Fármacos: Acyclovir
CONCLUSIONES
-Synthesis (industrial)
- Two strategies
HMDS (3equiv)
(Solar, Synthrsis, Scifarma)
NH
N N
N
O
NH
Ac
N
N N
NO
NH
SiMe3
siMe3
SiMe3
20 33
N
N N
N
O
NH
Ac
H
Ac
NH
N NH
N
NH2
O
24
56 7
89
320
guanine24
junio de 2011 45
Síntesis de Fármacos: Acyclovir
CONCLUSIONES
genericEcological impact Starting material
Price competitionDesing of plant
Best approach ????
- Regioselectivity N
N N
N
O
NH
Ac
20 33
N
N N
NO
NH
SiMe3
siMe3
SiMe3
98.2-99: 1 95:5
Acetylation/SylylationAlkylation
deprotection
(One pot )
junio de 2011 46
Síntesis de Fármacos: Acyclovir
References
W. Cabri and R. Di Fabio. From bench to Market. The Evolution of the Chemical Synthdesis. Chapter 8.Oxford University Press.2000, J. Saundres. Top Drugs, Top Synthetic Routes. Oxford Sciece Publications. 2000A. Delgado, C. Minguillón y J. Jogler. Introducción a la Sintesis de Fármacos. Ed. Síntesis, Madrid (2002)Avendaño, C.y cols. Introducción a la Quimica Farmaceútica (2ª ed). Cap. 8. McGraw-Hill/Interamericana.2001Silverman, R.B. The Organic Chemistry of Drug Desing and Drug Action. (2ª Ed) Ed. Academic Press, N.Y. 2002