Available online www.jocpr.com
Journal of Chemical and Pharmaceutical Research, 2016, 8(8):518-538
ISSN : 0975-7384
CODEN(USA) : JCPRC5
Review Article
Synthesis of fesoterodine: An enantiopure active pharmaceutical ingredient (API)
Veerareddy Arava* and Sreenivasulareddy Bandatmakuru
R&D centre Suven Life Sciences Ltd, Jeedimetla, Hyderabad-500055. (AP) India
ABSTRACT
Fesoterodine is in a class of medicines called anti muscarinics. It is used to treat overactive bladder condition.
Several generic drug manufactures have reported alternate approaches to this drug molecule, through an
intermediate of 5-hydroxy methyl tolterodine. This compound was reacted with isobutyryl chloride to react with
phenolic group followed by fumaric acid salt formation to produce the drug. Very few deviated this route. Different
strategies followed by different groups are discussed in detail.
.
Keywords: Fesoterodine, 5-hydroxy methyl tolterodine, Cinnamic acid, Heck reaction, Oxidation, Resolution,
Friedel-Crafts alkylation, Reductive amination
INTRODUCTION
Fesoterodine (1) is used to treat overactive bladder (a common problem with old age, a condition in which the
bladder muscles contract unconcontrollably and cause frequent urination, urgent need to urinate, and inability to
control urination). Fesoterodine is in a class of medicines called antimuscarinics. It works by relaxing the bladder
muscles to prevent urgent, frequent or uncontrolled urination. Fesoterodine was developed by Schwarz pharma AG
to treat overactive bladder syndrome (OAB).It was approved by European Medicines agency in April 2007, then
USFDA in 2008, and Health Canada on Feb9, 2012. Fesoterodine is a prodrug. It is broken down into its active
metabolite, 5-hydroxy methyl tolterodine (2) by plasma esterages. Pfizer Inc. acquired the worldwide rights on
fesoterodine during April 2006.
O
OH
O
N
HOOC
N
COOH
HO
HO
Fesoterodine Fumarate 1
5-Hydroxy methyl Tolterodine 2
Figure 1: Structure of fesoterodine Fumarate (1) and 5-Hydroxy methyl Tolterodine (2)
By 2014 Toviaz (brand of fesoterodine) reached $236 million. Currently tablets are formulated in strengths of 4, 8
mg of fesoterodine as the freebase equivalent. Fesoterodine fumarate is a white crystalline solid and is soluble in
methanol, 95% ethanol and slightly soluble in water. It has one chiral center, having an (R)-absolute configuration.
Its chemical name is [2-[(1R)-3-(di(propan-2yl)amino)-1-phenyl propyl]-4-(hydroxyl methyl)phenyl]-2-methyl
propionate.
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Veerareddy Arava and Sreenivasulareddy Bandatmakuru
J. Chem. Pharm. Res., 2016, 8(8):518-538
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Given the importance of fesoterodine as a drug. several academic groups and generic drug manufactures have
searched for alternative synthetic processes. Almost all syntheses were used 5-hydroxy methyl tolterodine (2) as a
precursor. The synthesis of compound 2 was either from tolterodine direct oxidation or conversion of methyl to
methyl alcohol by different methods was used as strategy by different teams. In some cases it was started with
hydroxyl methyl compound. The various synthetic strategies are discussed in detail.
Synthetic approaches involving Friedel-Crafts alkylation.
Process scientists from Dipharma Mantegazza, S [1] reacted Methyl-4-Hydroxy benzoate with 3-diispropylamino1-phenyl propanol (3) in the presence of methane sulfonic acid at 50-55°C to give 3-(3-diisopropyl amino-1-phenylpropyl)-4-hydroxy benzoate (4) in 92% of yield. Further the product 4 on resolution with (+) 2,3-dibenzoyl
OH
OH
O
N
O
(+) DBTTA
COOMe
MeO
Methane sulfonc acid
3
N
or (+) CSA
OH
MeO
N
OH
4
5
LAH
THF
O
1)
HOOC
HO
Cl
N
O
HO
COOH
2)
O
HOOC
N
OH
COOH
2
1
Scheme 1:
Benzylation of phenol derivative from benzyl alcohols 3
–D-tartaric acid in ethanol gave (+)2,3-dibenzoyl –D-tartaric acid of 3-(3-diisopropyl amino-1-phenyl-propyl)-4hydroxy benzoate (5). Compound 5 was reduced with lithium aluminium hydride to give R-(+)-2-(3diisopropylamino-1-phenyl-propyl)-4-hydroxy methyl-phenol (2) in 95% of yield, compound 2 was reacted with
isobutyryl chloride followed by salt formation with fumaric acid to give 1.
Reaction with β, γ-unsaturated Amines.
Sterk. D [2] disclosed a method that involves the coupling of (R)-2-amino-2-(4-hydroxy phenyl)acetic acid [(R)para hydroxyl phenyl glycine] with N,N-Diisopropyl-3-phenyl prop-2-en-1-amine (DIPA) in the presence of
methanesulfonic acid/ sulfuric acid at 130°C to give 2-amino-2-(3-(3-diisopropyl amino)-1-phenyl propyl)-4hydroxy phenyl)acetic acid (6) in 96% yield. Further reaction of 6 with potassium or sodium per--oxodisulfate in
water gave 3-(3-(diisopropylamino)-1-phenylpropyl)-4-hydroxy benzaldehyde intermediate (7-dl) in 37 % yield.
The reaction of 7-dl with sodium borohydride gave 2-dl in 86 %yield. It was resolved with O-acetyl mandelic acid
to give 2 in 34.3% yield.
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Veerareddy Arava and Sreenivasulareddy Bandatmakuru
J. Chem. Pharm. Res., 2016, 8(8):518-538
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Cl
93%
NH2
NH2
COOH
COOH
HO
N
HO
MSA
HO
N
H2SO4,
Sodium
peroxodisulfate
N
DIPA
CHO
MSA,
Potassium
peroxodisulfate
6
7-dl
37%
86%
O
1)
NaBH4
MeOH
OH
Cl
1
OH
HO
O-Acetyl mandalic acid
N
2) Fumaric acid
HO
Resolution
34.4%
N
2
2-dl
Scheme 2: p-hydroxy phenyl glycine benzylation with DIPA
Similarly crystal pharma team [3] started from 4-hydroxy benzoic acid and reacted with N,N-Diisopropyl-3-phenyl
prop-2-en-1-amine in presence of AcOH and H2SO4 at 85°C to give 3-(3-diisopropyl amino-1-phenyl-propyl)4hydroxy benzoic acid (8-dl). Further 8-dl was reacted with isobutyryl chloride in presence of TEA to give 2-(3diisopropyl amino-1-phenyl-propyl)-4-carboxy phenol isobutyrate (9). Compound 9 was reacted with borane in THF
to give dl-Fesoterodine in 96% of yield. Which was resolved with O-acetyl mandelic acid to give drug 1.
HO
COOH
N
O
HO
N
40%
OH
8-dl
O
HO
N
Borane in THF
HO
N
O
O
1
O
O
1-dl
9
Scheme 3: 4-Hydroxy benzoic acid benzylation with DIPA
Fusher [4] from Lek group started with N,N-diisopropyl -3-phenyl prop-2-en-1-amine and reacted with 4-cyano
phenol in presence of ethane sulfonic acid at 130°C to give 3-(5-cyano-2-hydroxy phenyl)-N,N-diisopropyl-3phenyl propylamine (10),Which on resolution with tartaric acid in ethanol gave (R)- 3-(5-cyano-2-hydroxy phenyl)-
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Veerareddy Arava and Sreenivasulareddy Bandatmakuru
J. Chem. Pharm. Res., 2016, 8(8):518-538
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N,N-diisopropyl-3-phenyl propylamine. Further it was reacted with triisopropyl silyl chloride in presence of
imidazole to give (R)-N,N-diisopropyl-3-phenyl- (5-formyl- 2- triisopropyl silyloxy phenyl) -prop-2-en-1 amine
(11). Compound 11 on DIBAL reduction gave compound 12 which on hydrolysis gave 7, and 7 on further
transformations gave 2 in good yields.
In another methodology (R)-N,N-diisopropyl-3-phenyl- (5-cyano- 2- triisopropyl silyloxy phenyl) -prop-2-en-1
amine (11) was reacted with aq. HCl to give R-3-(3--(diisopropylamino)-1-phenyl propyl)-4-hydroxy benzoic acid
(8). Further it was reacted with LAH in THF to give 2-(3-diisopropylamino-1-phenyl)-4-hydroxy methyl phenol 2.
X
X
X
OH
N
OH
X=CH3, Br, Cl, CN, CHO, I
MSA
DIPA
N
N
OSiipr3
11
10=X=CN
X=CN
OHC
OHC
N
DIBHAL
N
HO
N
OH
OH
OSiipr3
12
7
2
Scheme 4: 4-substituted phenol benzylation with DIPA
X
N
X=CN
HCl
LAH
HOOC
N
OSiipr3
11
HO
N
OH
8
OH
2
1
Scheme 5: Conversion of Aromatic –CN group to –CH2OH
Reaction with unsatured acid derivatives
Meese and Sparf [5] from Schwarz pharma originally followed this process the 4-bromo phenol was reacted with
cinnamoyl chloride in presence of TEA to give 3-phenyl acrylic acid-4-bromo phenyl ester (13) in 99% of yield.
Which was reacted with AcOH and H2SO4 to give 6-bromo-4-phenyl,3,4-dihydro-coumarane -2-one (14), which
was further reacted with benzyl chloride in presence of K2CO3 to give methyl-3-(2-benzyloxy-5-bromo phenyl)-3phenyl propionate (15). Compound 15 was hydrolyzed with NaOH to give 3-(2-benzyloxy-5-bromo phenyl)-3phenyl propionic acid (16-dl). The dl acid 16 on resolution with 1S, 2R ephedrine hemi hydrate gave R-(-)3-(2benzyloxy-5-bromo phenyl)-3-phenyl propionic acid (16). Later 16 was converted to its acid chloride and was
reacted with diisopropylamine to give (R)-N,N-diisopropyl-3-(2-benzyloxy-5-bromo phenyl)-3-phenyl
propionamide (17). Amide 17 was reacted with LAH to give R-N, N-diisopropyl-3-(2-benzyloxy-5-bromo phenyl)3-phenyl propanamine (18). Further the bromo compound 18 was converted to acid 19 with ethyl magnesium
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Veerareddy Arava and Sreenivasulareddy Bandatmakuru
J. Chem. Pharm. Res., 2016, 8(8):518-538
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OH
O
O
TEA
DCM
100%
Cl
+
O
O
AcOH
Conc.H2SO4
Br
Br
44%
Br
14
13
K2CO3
NaI
MeOH
Acetone
O
O
Br
NaOH
OMe MeOH
Br
O
O
Acetone
Ethanol
15
16-dl
O
Br
1S, 2R ephedrine
hemi hydrate
OH
72%
Cl
100%
O
O
O
SOCl2
OH
Br
Cl DIPA, EtOAc
Br
DMF, EtOAc
O
N
O
O
16
17
LAH
Br
EtBr
Mg
THF
N
HOOC
N
O
CO2
O
MeOH
H2SO4
LAH
19
18
HO
N
HO
RaNi
N
O
1
OH
2
20
Scheme 6: Friedel-Craft alkylation of phenolic esters 13 to 14
bromide and CO2 , the acid 19 was converted to ester, (R)-[4-benzyloxy -3-(3-diisopropylamino-1-phenylpropyl)
benzoate and then it was reduced with LAH to give (R)-[4-benzyloxy -3-(3-diisopropylamino-1-phenylpropyl)phenyl]-methanol (20). Finally 20 was debenzylated with Raney Ni to give (R)-2-(3-diisopropylamino-1phenylpropyl)-4-hydroxy methyl phenol (2).
The same team [5] followed different strategy to prepare compound 2. The 5-bromo-2-hydroxy-benzaldehyde was
reacted with benzyl chloride to give 2-benzyloxy-5-bromo-benzaldehyde (21). Further 21 was converted to cinnamic
acid derivative 22 with malonic acid. The acid 24 was reacted with pivaloyl chloride and on condensation with ( R)2-phenyloxazolidin-2-one (chiral auxiliary) in presence of lithium chloride gave 3-[3-(2-benzyloxy-5-bromophenyl)acryloyl]-(4R)-4-phenyl-oxazolidin-2-one (23). Further 23 was reacted with phenyl magnesium bromide in presence
of dimethyl sulfide and copper(I) chloride gave 3-[-(2-benzyloxy-5-bromophenyl]-(3S)-3-phenyl propionyl]-(4R)-4phenyloxazolidin-2-one (24). Chiral auxiliary was cleaved with hydrogen peroxide and lithium hydroxide to give S(+)-3-(2-benzyloxy-5-bromophenyl)-3-phenyl propionic acid (16). Further it was converted to S-(+)-N,Ndiisopropyl-3-(2-benzyloxy-5-bromo phenyl)-3-phenyl propionamide. And final the amide on reduction with LAH
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Veerareddy Arava and Sreenivasulareddy Bandatmakuru
J. Chem. Pharm. Res., 2016, 8(8):518-538
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gave S-(+)-[3-(2-benzyloxy-5-bromo-phenyl)-3-phenyl]-diisopropyl amine (18). Compound 18 was converted 2 and
then 1.
O
O
OH
Br
Br
CHO
Br
O
Br
OH
CHO
N
OBn
21
OBn
22
Br
N
MgBr
OBn
18
2
O
O
Br
OH
O
Ph
23
O
Br
O
N
OBn
16
OBn
O
Ph
24
1
Scheme 7: Preparation of Chiral 16 via chiral auxiliary ( R)-2-phenyl oxazolidine-2-one
Synthesis approaches involving a reductive amination
Process chemists from Pfizer [6] reported a safe, practical and highly efficient approach to fesoterodine. The
procedure for dl-2 involves only three synthetic steps with an overall yield of 44.8 %. They first studied the reaction
of 4-(hydroxyl methyl) phenol with trans-Cinnamaldehyde in the presence of N-methylpiperrazine at 100-115°C.
The water formed was removed by azeotropic distillation to give (2-hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6yl)methanol (25) in 54% yield. Further it was reacted with diisopropyl amine and hydrogen in presence of 5% Pd/C
to give 2-[3-(diisopropylamino)-1-phenyl propyl]-4-(hydroxyl methyl) phenol (2-dl) in 83% of yield. 2-dl was
resolved with acetyl-d-mandelic acid to 2 and was converted to 1 in good yields.
OH
O
OH
O
HO
HO
N-Methyl piperazine
Toluene
54%
N
OH
Diisopropylamine
pd/c
83%
25
OH
2-dl
1
Scheme 8: Benzylation of 4-hydroxy methyl phenol with cinnamaldehyde
Cinambecchini [7] of Chemi group started with 4-trimethyl silyloxy methyl phenol and is reacted with
cinnamaldehyde in presence of morpholine at 110-115° during azeotropic distillation gave (2-hydroxy-4-phenyl-3,4dihydro-2H-chromen-6-yl) methanol (26) in 60%yield. Next it was reacted with diisopropylamine followed by
reduction with sodium borohydride gave 2-[3-(diisopropylamino)-1-phenyl propyl]-4-(hydroxyl methyl) phenol (2dl) in 80% yield.
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Veerareddy Arava and Sreenivasulareddy Bandatmakuru
J. Chem. Pharm. Res., 2016, 8(8):518-538
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O
O
OH
O
O
O
N
OH
OPG
Morpholine
N
GPO
60%
26
O
1
HO
OH
N
Diisopropylamine
NaBH4
OH
2-dl
OH
80%
25
Scheme 9 : Benzylation of protected 4-hydroxy methyl phenol with cinnamaldehyde
Meese.C [8] of Schwarz pharma started with 4-Hydroxy methyl benzoate and reacted with cinnamic acid in
presence of acetic acid and sulfuric acid at 100°C to give (R,S)-4-phenyl-2-chromanone-6-carboxylic acid (28-dl) in
78% yield. further it was resolved with cinchonidine in 2-butanone to give (R)-4-phenyl-2-chromanone-6carboxylic acid cinchonidine salt in 90% of yield. Salt was reacted with aq HCl to give free chiral acid 28, which
was reacted with thionyl chloride and methanol in presence of pyridine to give ( R)-2-oxo-4-phenyl chroman-6carboxylic acid methyl ester (29) in 65%of yield. The ester 29 was reacted with DIBAL to give R-(6)-hydroxy
methyl-4-phenyl chroman-2-(R,S)-ol (30) in 65% yield. Next 30 was reacted with diisopropylamine in presence of
Pd/C under hydrogenation conditions to give (R)-4-hydroxy methyl-2-(3-diisopropylamino-1-phenyl propyl)-phenol
2.
Rajesh [9] et al from panacea started with 4-Hydroxy methyl benzoate (27) and reacted with cinnamaldehyde in
presence of N-methyl piperazine in toluene at 110-115°C during which the water formed in reaction was removed
azeotropically to give methyl-2-hydroxy-4-phenyl chromane-6-carboxylic acid (31) in 75% yield. Further reaction
with DIPA and 10% Pd/C in methanol under hydrogenation gave 3-(3-diisopropylamino-1-phenyl propyl)4-hydroxy
benzoic acid methyl ester (4) in 72% of yield. Further 4 was reacted with vitride in toluene at 10°C to give 2-(3diisopropylamino-1-phenyl propyl)-4-hydroxy methyl phenol (2-dl). Compound 2-dl was resolved with L(-) malic
acid to giver R (+) 2-(3-diisopropylamino-1-phenyl propyl)-4-hydroxy methyl phenol 2.
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Veerareddy Arava and Sreenivasulareddy Bandatmakuru
J. Chem. Pharm. Res., 2016, 8(8):518-538
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O
OH
OH
O
O
OMe
H
O
O
N
H
HO
HOOC
AcOH
H2SO4
O
OOC
Cinchonidine
28-dl
Aq HCl
O
O
O
O
HO
O
SOCl2
MeOOC
O
HOOC
MeOH
DIBHAL
30
29
HO
28
1
OH
2
Scheme 10:
Resolution of 28-dl with cinchonidine to 28
OH
O
O NMP
Toluene
+
OH
DIPA
MeOH
Pd/c
MeO
O
O
27
OMe
O
MeO
N
OH
4
31
Vitride
Toluene
L(-) malic acid
HO
N
HO
OH
N
OH
2
2-dl
1
Scheme11: 4-hydroxy benzoic acid methyl ester alkylation with cinnamaldehyde
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Veerareddy Arava and Sreenivasulareddy Bandatmakuru
J. Chem. Pharm. Res., 2016, 8(8):518-538
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Reddy R.B.[10] et al started with 4-benzyloxy benzaldehyde (32) and protected the aldehyde and under alkyl lithium
conditions it was phenylated, deprotected, oxidized and etherified to give 33-dl and was resolved to get 33 chiral,
which was converted 2 in a regular way.
O
O
O
N
O
RLi
CHO
RO
N
Cl
OR
RO
OR
N
1
1) deprotection
2) oxidation
3)esterification
32
O
OR
33
Scheme 12: Phenylation of benzyl ethers
Synthetic approaches from tolterodine.
Kumar. Y [11] etal from ranbaxy (India) group started from dl-tolterodine (34) Phenolic group of tolterodine was
protected with benzyl chloride to give 3-(2-bezyloxy-5-methyl-phenyl)3-phenyl-propyl)-diisopropylamine (35-dl).
Further 35-dl was reacted with copper sulfate and sodium persulfate in acetonitrile to give 4-benzyloxy-3-(3diisopropylamino-1-phenyl-propyl)-benzaldehyde (36). Compound 36 on reduction with sodium borohydride gave
[4-benzyloxy-3-(3-diisopropylamino-1-phenyl-propyl)-phenyl] methanol (20-dl), compound 20-dl on debenzylation
with 10% Pd/C gave 2-(3-diisopropyl amino-1-phenyl-propyl)-4-hydroxy methyl –phenol (2-dl).
OHC
N
N
HBr
Aq. CH3CN
O
OH
34
O
36
35-dl
HO
N
CuSO4/Na2S2O4
N
O
HO
N
1
OH
20-dl
2-dl
Scheme 13: Oxidation of 35-dl with sodium persulfate and copper sulfate to 36
Raman J.V [12] et al started from p-cresol and was reacted with cinnamic acid in acidic conditions to give 3,4dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one (37). Further 37 was benzylated to give methyl-3-(2-benzyloxy5-methyl-phenyl)-3-phenyl-propionate (38). Compound 38 was hydrolyzed with KOH to give 3-(2-Benzyloxy-5methyl-phenyl)-3-phenyl-propionic acid, the acid was reacted with thionyl chloride and later with DIPA to give 3(2-Benzyloxy-5-methyl-phenyl)-N,N-diisopropyl-3-phenyl-propionamide (39). Compound 39 was reduced with
NaBH4 and BF3 etherate to give [3-(2-Benzyloxy-5-methyl-phenyl)-3-phenyl-propyl]-diisopropyl-amine (35-dl).
compound 35-dl on resolution with DPTTA gave R-[3-(2-Benzyloxy-5-methyl-phenyl)-3-phenyl-propyl]diisopropyl-amine (35). The aromatic methyl group of chiral 35 was converted with ceric ammonium nitrate(CAN)
to aldehyde (36), compound 36 was reduced with NaBH4 to give R-(+)-[4-benzyloxy-3-(3-diisopropylamino-1phenyl-propyl)-phenyl] methanol (20) and was debenzylated with raney Ni to give R-(+)-2-(3-diisopropylamino-1phenyl-propyl)-4-hydroxy methyl phenol(2).
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Veerareddy Arava and Sreenivasulareddy Bandatmakuru
J. Chem. Pharm. Res., 2016, 8(8):518-538
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O
OH
O
K2CO3
NaI
MeOH
Acetone
O
H2SO4
O
OMe
OH
+
O
Br
Toluene
38
37
O
O
O
KOH
MeOH
OH
O
SOCl2
N
Cl
O
O
DMF
39
NaBH4,
BF3 etherate
DPTTA
N
NaOH
Salt
O
O
35
35-dl
N
Na2CO3
N
CAN
OHC
N
35
HO
N
Fumaric acid
O
O
NaBH4
O
20
36
NaOH
RaNi
HO
N
OH
2
Scheme 14: Oxidation of 35 with ceric ammonium nitrate to 36
Raman, J. V [13] et al developed another oxidation method to convert the benzyl tolterodine 35 to 22 with copper
sulphate, copper acetate and sodium persulfate in presence of sulfuric acid. 20 was reduced with sodium
borohydride in 79% of yield, and was debenzylated with Raney Ni to give R-(+)-[4-hydroxy-3-(3-diisopropylamino1-phenyl-propyl)-phenyl]-methanol(2).
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Veerareddy Arava and Sreenivasulareddy Bandatmakuru
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1) Copper sulphate.5H2O
Copper acetate.H2O
Sodium persulfate
Sulfuric acid
ACN, H2O,DMSO HO
N
2) NaBH
O
Raney Ni/H
Methanol
N
2
1
O
4
20
35
Scheme 15: Oxidation of 35 with copper sulfate, copper acetate and sodium persulfate followed by reduction to 20
Reddy, M.S [14] et al converted tolterodine 34 to 2 via halogenation and nucleophilic substitution with acetate
followed by hydrolysis. Tolterodine (34) was brominated with N-bromo succinimide to give ( R)-4-(bromomethyl)2-(-(diisopropylamino)-1-phenyl propyl) phenol (40). Further 40 was acetylated with sodium acetate in DMF to give
( R)-3-(3-(diisopropylamino)-1-phenyl propyl)-4-hydroxy benzyl acetate (41). Compound 41 was hydrolyzed with
lithium hydroxide in aq methanol to give compound 2.
N
OH
NBS
NCS
X
N
NaOAc
KOAc AcO
N
OH
OH
41
X=Br,Cl
34
40
HO
N
OH
2
Scheme 16: Oxidation of 34 via halogenation of 34 and solvolysis of 40 to 41 and 2
Process involving Heck reaction
Oreste. P [15] et al has disclosed a new method that involves the coupling of ethyl-3-bromo-4-hydroxy benzoate
with N,N-Diisopropyl-cinnamide in presence of N,N-dicyclohexyl-methylamine and pd catalyst [Pd(pt-Bu3)2] to
give 3-(3-N,N-diisopropyl amino)-3-oxo-1-phenyl prop-1-en-1-yl)-4-hydroxy benzoate (42). Compound 42 was
hydrogenated in the presence of 5% pd/C and 2-Me-THF to give (R, S)-3-(3-N, N-diisopropylamino -3-oxo-1phenyl propyl)-4-hydroxy benzoate (43) in 94% yield. Further reduction with vitride in toluene at 25-30°C gave a
dl-2-(3-N, N-Diisopropyl amino-1-phenyl propyl)-4-hydroxy methyl-phenol.HCL (2-dl) in 76% yield. It was
resolved and converted 1.
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Veerareddy Arava and Sreenivasulareddy Bandatmakuru
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OH
Br
O
O
N
O
OEt
O
O
EtO
N
O
EtO
N
OH
OH
42
43
89%(E:Z93:7)
98%
[H]
Vitride
78% (E>99%)
MP:178-182°C
1) Resolution
1
HO
2) Ester & Salt formation
N
OH
2-dl
Scheme 17: Heck of cinnamic derivative with 2-bromo phenol derivative to 42
Mease. C and Sparf. B [5] described another heck reaction with N,N-Diisopropyl acrylamide and methyl-3-bromo4-methoxy benzoate in presence of bis-(benzonitrile)-palladium-II-chloride and sodium acetate in N-methyl-2pyrrolidinone to give N,N-diisopropyl-3-(2-methoxy-5-methoxycarboxyphenyl)acrylamide (44). Further 44 was
reacted with lithium diphenyl cuprate in presence of trimethylchlorosilane to give N,N-diisopropyl-3-(2-methoxy-5methoxy carboxy phenyl)-3-phenyl propionamide (45). Compound 45 was reduced with LAH and AlCl3 to give 2(3-diisopropylamino-1-phenyl)-4-hydroxy methyl phenol (2-dl), which is then resolved to give chiral 2.
1)Lithium diphenyl cuprate
N
OMe
MeOOC
Br
pd catalyst
NMP
OMe
OMe
O
N
MeOOC
44
N
MeOOC
O
O
45
70%(E)
MP:139-140°C
LAH/AlCl3
OH
HO
1
N
2-dl
Scheme 18: Heck reaction of Acrylamide to bromoanisole derivative to 44
5 Synthesis approaches via chromanone derivative
Charugundla.K [16] et al started the synthesis from p-bromo phenol and reacted with cinnamic acid in presence of
H2SO4 to give 6-bromo-4-phenyl chroman-2-one (14), which was reacted with benzyl chloride in presence of K2CO3
in acetone and methanol to give 3-(2-benzyloxy)-5-bromophenyl)-3-phenyl propionate (15). Compound 15 was
reduced with NaBH4 to give 3-(2-benzyloxy)-5-bromophenyl)-3-phenyl propan-1-ol, and the primary alcohol was
converted to diisopropyl amine via tosylate to give benzyloxy amine (18-dl). Further 18-dl was resolved with p-
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tolyl –L-tartaric acid to give chiral 20. and 20 was reacted with Mg and CO2 to give (R)-4-benzyloxy -3-(3diisopropylamino-1-phenylpropyl)-benzoic acid hydrochloride (19). Further 19 was converted to fesoterodine via a
similar route of Meese5 et al.
O
OH
OH
O
H2SO4
+
NaI
BnCl
Acetone
Methanol
K2CO3
O
O
Br
OMe
Br
O
Br
15
14
p-TSCl
TEA Br
OH DCM
Br
NaBH4
MeOH
OTs
O
DIPA
ACN Br
N
O
Di-ptoluoyl
tartrate
O
46
18-dl
Br
N
O
Mg
EtBr
THF HOOC
CO2
N
SOCl2
MeOH
MeOOC
N
O
O
18
NaBH4
19
pd/C
HO
HO
N
THF
Monoglyme
N
1
OH
O
2
20
Scheme 19 : Alkylation of 4-bromo phenol with cinnamic acid to 14
Dasai, S. J [17] et al described the reduction of acid 21 with BH3.DMS in THF to give N,N-diisopropyl-3-(2benzyloxy-5-hydroxy methyl phenyl)-3-phenyl propylamine (20-dl), which on debenzylation with raney Ni to give
N,N-Diisopropyl-3-(2-Hydroxy-5-hydroxy methyl phenyl)-3-phenyl propylamine 2-dl. It was resolved and
converted to drug.
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HOOC
N
THF
BH3.DMS
O
Raney Ni
HO
N
O
20-dl
19-dl
Resolution
HO
HO
N
1
N
Acetyl mandalic acid
OH
OH
2
2-dl
Scheme 20: Reduction of carboxyl derivative of 19-dl to 20-dl
Dwivedi, S. D. [18] et al reduced 19-dl with vitride in toluene to give (R)-[4-benzyloxy -3-(3-diisopropylamino-1phenylpropyl)-phenyl]-methanol(20-dl). 20-dl on debenzylation with pd/c in methanol gave (R)-2-(3diisopropylamino-1-phenylpropyl)-4-hydroxy methyl phenol (2).
Compound
HOOC
N
Vitride
Toluene
HO
N
O
19-dl
pd/c HO
N
OH
O
2
20-dl
1
Scheme 21 : Reduction of carboxyl group of 19-dl to give 20-dl with Vitride
Johansson [19] et al resolved compound 18-dl with L(+) tartaric acid to give (+)-N,N-diisopropyl-3(2-benzyloxy-5bromophenyl)-3-phenyl propylamine (18). The chiral compound 18 was reacted with Mg and CO2 in presence of
ether and I2 to give (-)N,N-Diisopropyl-3-(2-benzyloxy-5-carboxy phenyl)-3-phenyl propyl amine.HCl (19) in 77%
of yield. Compound 19 was reacted with MeoH in presence of H2SO4 to give ester of 19, which was reduced with
LAH to give (+)-N,N-diisopropyl-3-(2-benzyloxy-5-hydroxy methyl phenyl)-3-phenyl propylamine (20). Finally
debenzylation was done with Raney Ni to give compound 2.
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Br
N
L(+)-tartaric acid Br
N
O
O
Mg
I2
EtBr
Ether
CO2
HOOC
O
HCl
18
18-dl
N
19
O
MeOH
H2SO4
MeO
N
LAH
Ether
HO
N
Raney Ni
O
O
20
HO
N
1
OH
2
Scheme 22: Grignard reaction of 18-dl to give 19.
Synthetic approaches via Grignard reaction
Reddy, R.B [10] et al started from 3-(2-benzyloxy-5-bromo phenyl)-3-phenyl propane-1-ol and was converted it via
its tosylate and reacted with diisopropyl amine to N,N-diispropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenyl
propylamine (46). further bromo derivative was converted to acid 19-dl via Grignard reaction with solid CO2. The
acid was resolved with DBTA( dibenzoyl tartaric acid) to give (-)-N,N-diisopropyl-3-(2-benzyloxy-5-carboxy
phenyl )-3-phenyl propylamine. DBTA. Which was converted to ester and was reduced with vitride to give (+) N,Ndiispropyl-3-(2-benzyloxy-5-hydroxy-methyl phenyl)-3-phenyl propylamine, which was further debenzylated with
raney nickel to give (+)-N,N-diispropyl-3-(2-hydroxy-5-hydroxymethyl phenyl)-3-phenyl propylamine 2.
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Br
DMAP
Br
OTs
OH
p-TSCl
N
DIPA
KI
ACN
OBn
OBn
Br
46
OBn
18-dl
MeOOC
N
OBn
HOOC
H2SO4
N
HOOC
N
OBn
MeOH
OBn
19
Vitride
HO
DBTTA
Mg
I2
EtBr
CO2
19-dl
N
Raney Ni
HO
1
N
OBn
OH
2
Scheme 23 : Resolutioon of 19-dl to 19 with DBTA
Ennirs, C.S [20] et al from Schwarz converted R-(-)-[3-(2-benzyloxy-5-bromo phenyl)-3-phenyl propyl]-diispropyl
amine (18) with magnesium ethyl bromide and paraformaldehyde to R-(-)-4-benzyloxy-3-(3-diispropyl amio-1phenyl propyl)-phenol methanol (20). Compound 20 was debenzylated in presence of Pd/C to give (+)-N,Ndiispropyl-3-(2-hydroxy-5-hydroxymethyl phenyl)-3-phenyl propylamine (2)
Mg
Br
HO
N
OBn
18
N
(CH2O)n
O
O
OBn
HO
pd/c
20
O
N
OH
2
pd/c
1
Scheme 24: Formylation of 18 with para formaldehyde to 20
Browne.R and Kilkellt, M [21] reacted (+)-N,N-Diisopropyl-3-(2-benzyloxy-5- bromo phenyl)-3-phenyl propyl
amine (28) with Mg in presence of dimethyl carbonate in THF to give R-(-)-4-benzyloxy-3-(3-diisopropylamino-1phenyl propyl)-benzoic acid methyl ester. Further the ester was reduced with LAH to give (+)-N,N-diisopropyl-3(2-benzyloxy-5-hydroxy-methyl phenyl)-3-phenyl propylamine (20) in 99% of yield, which was debenzylated with
Raney Ni to give 2.
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O
Br
N
Mg
MeO
N
Dimethyl carbonate
O
LAH
O
Ether
THF
20
HO
HO
N
1
N
OH
O
2
22
Scheme 25 : Quenching of Grignard of 18 with dimethyl carbonate followed by reduction to 20
Manne, S.R [14] et al reacted the bromo compound 18-dl with DMF in presence of n-Butyl lithium to give 4(benzyloxy)-3-(3-(diisopropyl amino)-1-phenyl propyl) benzaldehyde 36-dl. Further it was resolved with D-(-)
tartaric acid in IPA to give R-4-(benzyloxy) - 3 - ( 3- ( diisopropyl amino)-1-phenyl propyl) benzaldehyde 36. The
Br
N
n-BuLi,THF OHC
DMF
OHC
N
O
O
Resolution
N
O
36
36-dl
18-dl
O
Cl
OHC
N
1
OHC
O
N
OH
O
7
47
Scheme 26: Formylation 18-dl with BuLi and DMF to 36-dl
debenzylation of 36 with 5% Pd/C to give (R)-N,N-diisopropyl-3-(5-formyl-2-hydroxy phenyl)-3-phentl
propanamine (7). Compound 7 was reacted with methacryloyl chloride to give R-2-(3-diisopropyl amino-1-phenyl
propyl)-4-formyl phenyl methacrylate (47). Compound 47 was converted to 1.
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Miscellaneous Synthetic approaches
Donsbach. M [22] et al reacted p-hydroxy methyl benzoate with phenyl acetylene in presence of SnCl4 and
tributylamine to give 4-hydroxy-3-(1-phenyl vinyl)-methyl benzoate (48). Further 48 was reacted with
benzylbromide in presence of K2CO3 to give 4-benzyloxy-3-(1-phenyl vinyl)-methyl benzoate (49). Compound 49
was reacted with diisopropyl amine in presence of Pd catalyst and BINAP and CO in dioxane to give 4-benzyloxy3-(3-diispropylamine-1-phenyl-propyl)-methyl benzoate. The ester was reduced with LAH in presence of ether to
give (+)-N,N-diisopropyl-3-(2-benzyloxy-5-hydroxy methyl phenyl)-3-phenyl propylamine (20). Finally
debenzylation with Raney Ni in presence of MeOH to give (+)N,N-Diisopropyl-3-(2-Hydroxy-5-hydroxy methyl
phenyl)-3-phenyl propylamine (2).
OH
Ph
OH BnBr, K2CO3
SnCl4, Bu3N,EDC
Acetone
MeOOC
48
COOMe
MeOOC
DIPA
Pd, CO, BINAP
MeOOC
49
Ph
HO
LAH
N
O
Resolution
Ph
HO
N
N
OH
Raney Ni, H2
O
O
2
20
1
Scheme 27: Methyl-4-hydroxy benzoate reaction with phenyl acetylene to 48
Crystal pharma [23] team resolved 3-(3-N,N-diisopropylamino-1-phenyl-propyl)-4-hydroxy benzoic acid with chiral
auxiliary D(+) menthol in presence of thionyl chloride to give D-(+)-methyl-3-(3-N,N-diisopropylamino-1(R)phenyl-propyl)-4-hydroxy benzoate.HCl (50), which was hydrolyzed with KOH to give R(+)3-(3-N,Ndiisopropylamino-1-phenyl-propyl)-4-hydroxy benzoic acid (8). Further it was reacted with isobutyryl chloride to
give R (+)3-(3-N,N-diisopropylamino-1-phenyl-propyl)-4-isobutyryloxy benzoic acid (51). Compound 51 was
reacted with B2H6/DMS in THF to give Fesoterodine (1).
O
O
HO
SOCl2
N
D (+) Menthol
OH
TEA
IBCl
O
O
Ment
HO
N
51
N
OH
8
COOH
HO
N
THF
O
O
OH
50
1) B2H6/DMS
HO
KOH
MeOH
N
O
2) Fumaric acid
HOOC
O
O
1
Scheme 28: Reduction with borane DMS of 51 to 1
Manne S.R [14] et al reacted compound 2 with methacryloyl chloride in chloroform to give ( R)-2-(3(diisopropylamino)-1-phenyl propyl)-4(hydroxyl methyl)- phenyl methacrylate (52). Further 52 was reacted with
Pd/C to give isobutyric acid-2(( R)-3-diisopropylammonium-1-phenyl propyl)-4-(hydroxyl methyl) phenyl ester (1).
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O
Cl
HO
HO
N
HO
N
N
O
O
OH
O
O
2
1
52
Salt
Scheme 29: Reduction 50 with Pd-C/hydrogenation to 1
The same team reported the synthesis of fesoterodine 1, from 2, by reacting 2 with 2-bromo-2-methyl propanoyl
chloride or 3-bromo-2-methyl propanoyl chloride in
O
Cl
HO
N
X
HO
N
HO
N
O
OH
2
O
X
O
O
53
O
Cl
X
HO
HO
N
N
O
O
O
O
1
54
X
1 Salt
Scheme 30: Dehydrohalogenation of 53/54 with Pd/C to 1
presence of sodium bicarbonate to give 2-(( R)-3-(diisopropylamino)-1-phenyl propyl)-4-(hydroxymethyl) phenyl-2
or 3 bromo-2-methyl propanoate (53/54). Further 53/54 was reacted with sodium acetate in presence 10% Pd/C
under hydrogenation conditions gave isobutyric acid-2(( R)-3-diisopropylammonium-1-phenyl propyl)-4-(hydroxyl
methyl) phenyl ester (1).
Hartwig and Chen [24] reported a novel method of fesoterodine via Iridium-catalysed enantio slective allylic
substitution of enolsilanes 55 on vinologous. ester/amides Compound 56 was converted to into diene 61 with
NaHMDS and TBSCl [25]. [4+2] cycloaddition of diene 61 and ethyl propiolate at 50°C in toluene provided 1,1
diarylalkene 58 in 77% yield. DIBAl reduction of the ethyl ester of 58 gave alcohol and on protection with TBSCl
gave bis-TBS ether 59 in 85% yield. Hydroboration and oxidation of 59, followed by Dess-martin oxidation of the
resulting primary alcohol afforded aldehyde 60 in 77% yield. Reductive amination of aldehyde 60 with
diisopropylamine and NaBH(OAc)3, followed by deprotection of the two TBS groups with TBAF provided
compound 2 in 76% yield.
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OTBS
O
Ph
O
OMe
+
NMe2
55
Me
NMe2
THF, RT
73%
56
2) Toluene, 50° C
COOEt
77%
93% ee
COOEt
O
P
O
N
57
1) NaHMDS -78 to -40° C
TBSCl -78°C
O
4 mol % 55
Ir
NMe2
61
Ph Ph
H
1) BBN/NaBO3
1) DIBAL
COOEt
2) TBSCl, Im
85%
TBSO
OTBS
TBSO
2) Dess-Martin
O
OTBS
TBSO
77%
60
59
58
1) NaBH(OAc)3
DIPA
2) TBAF
76%
1
2
Scheme 31: Enantioselective synthesis of fesoterodine
CONCLUSION
In this review, we have compiled an overview of the different approaches towards the synthesis of fesoterodine.
Except few syntheses, most of the syntheses pass through 5-hydroxy methyl tolterodine. Although significant
chemistry has been developed for fesoterodine, three main strategies have been tried by different groups. First one
being oxidative method from tolterodine, second one is grignard method of halocompounds for introduction of
hydroxyl methyl group(-CH2OH from Br), and the third and important one is starting from cinnamyl derivative.
Commercially the cinnamaldehyde route was reported to have good yields.
The other methods are more of academic interest for example Heck reaction and palladium/CO reaction. The present
review explains how generic manufacturers search for non-infringing, novel approaches to an API of interest.
Hopefully more novel and imaginative ideas will provide new approaches to this drug in the coming years.
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