universidad de alcalá doctorado química médica · junio de 2011 1 universidad de alcalá...

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


ACICLOVIR

N

N N

N

OH

NH2

O

OH

1

2 4

56 7

8

93


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


ACICLOVIR

N

N N

N

OH

NH2

O

OH

1

2 4

56 7

8

93


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


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


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


O B

ROH

OH


Modificación de la base

OOH

OH

N

N N

N

Cl

NH2

CladribinaN

NH

O

O

OOH

OH

Br

BVDU

junio de 2011 11


O B

ROH

OH


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


O B

ROH

OH


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


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


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


“ 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


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


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


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


N

N N

NCl

Cl

1

2

6


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%)


(84%)semihydrate

diacetylguanine

NO2

expensive

Overal yield low

No desingned for large scale

Only enough material for preclinicalpreclinical studiesstudies


synthesissynthesis

Drawbacks

N

N N

NCl

Cl

1

2

6


2,6-dichloropurine

junio de 2011 23

Barrio´s SynthesisN

N N

NI

Cl

1

2

6



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


Barrio´s Synthesis


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


Farmhispania´s patents

Barrio´s Synthesis


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


synthesissynthesis


2,6-dichloropurine

Producto clave

N

N NH

N

11

Productos de partida

junio de 2011 26



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


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%)


(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


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


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


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


Persistent protective groups onC2 (NH2) and C6 (OH) - positions

N,N-diacethyl guanine route


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


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


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


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


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


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


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


Temporary protective groups onC2 (NH2) and C6 (OH) - positions


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


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


Temporary protective groups onC2 (NH2) and C6 (OH) - positions Syntex´s Process

Palo Alto

Variation of the sylylation process

US5565565, 1994



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




US5567816, 1995One year later

Industrial process, Oxalane is cheap Overall yield 60%


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


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


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


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


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


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

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