"All water chemistry" for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine

Article abstract of DOI:10.1039/c3gc36997h

A novel strategy of 'all water chemistry' is reported for a concise total synthesis of the novel class anti-anginal drug ranolazine in its racemic (RS) and enantiopure [(R) and (S)] forms. The reactions at the crucial stages of the synthesis are promoted by water and led to the development of new water-assisted chemistries for (i) catalyst/base-free N-acylation of amine with acyl anhydride, (ii) base-free N-acylation of amine with acyl chloride, (iii) catalyst/base-free one-pot tandem N-alkylation and N-Boc deprotection, and (iv) base-free selective mono-alkylation of diamine (e.g., piperazine). The distinct advantages in performing the reactions in water have been demonstrated by performing the respective reactions in organic solvents that led to inferior results and the beneficial effect of water is attributed to the synergistic electrophile and nucleophile dual activation role of water. The new 'all water' strategy offers two green processes for the total synthesis of ranolazine in two and three steps with 77 and 69% overall yields, respectively, and which are devoid of the formation of the impurities that are generally associated with the preparation of ranolazine following the reported processes.

Full text of DOI:10.1039/c3gc36997h

Green Chemistry
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“All water chemistry” for a concise total synthesis of
the novel class anti-anginal drug (RS), (R), and (S)-
ranolazine†
Cite this: Green Chem., 2013, 15, 756
Damodara N. Kommi, Dinesh Kumar and Asit K. Chakraborti*
A novel strategy of ‘all water chemistry’ is reported for a concise total synthesis of the novel class anti-
anginal drug ranolazine in its racemic (RS) and enantiopure [(R) and (S)] forms. The reactions at the
crucial stages of the synthesis are promoted by water and led to the development of new water-assisted
chemistries for (i) catalyst/base-free N-acylation of amine with acyl anhydride, (ii) base-free N-acylation of
amine with acyl chloride, (iii) catalyst/base-free one-pot tandem N-alkylation and N-Boc deprotection,
and (iv) base-free selective mono-alkylation of diamine (e.g., piperazine). The distinct advantages in per-
forming the reactions in water have been demonstrated by performing the respective reactions in
organic solvents that led to inferior results and the beneficial effect of water is attributed to the synergis-
tic electrophile and nucleophile dual activation role of water. The new ‘all water’ strategy offers two
green processes for the total synthesis of ranolazine in two and three steps with 77 and 69% overall
yields, respectively, and which are devoid of the formation of the impurities that are generally associated
with the preparation of ranolazine following the reported processes.
Received 10th December 2012,
Accepted 17th January 2013
DOI: 10.1039/c3gc36997h
www.rsc.org/greenchem
system and have had widespread and generally safe use for
more than 25 years. These drugs reduce the oxygen demand by
Introduction
Cardiovascular diseases (CVDs) are the leading cause of death reducing the heart rate and lowering the blood pressure (BP)
worldwide, accounting for one-third (16.6 million) of global and the calcium channel blockers. They are also commonly
deaths in 20011 and 1 million deaths every year in the western used therapeutics for angina as they dilate the blood vessels
world. According to the Lancet report of 2005, hypertension and lower the BP.6 However, due to intolerability on BP or
(high blood pressure) is one of the five major CVDs affecting heart rate and adverse hemodynamic side effects such as hypo-
more than 330 million adults in Europe and North America tension, bradycardia, and sexual dysfunction, often it is not
and Vision gain predicted more than 1.5 billion people to possible to increase the doses of these drugs to the desired
suffer from this disease worldwide by 2025. Globally, the level. Moreover, at least 25% of the patients on medically opti-
hypertension therapeutics market is one of the largest and mized regimens still have the clinically relevant angina at
most profitable with total sales of $36 600 million in 2006. 5-year follow-up.7 Hence for full control of chronic stable
Stable angina pectoris affects more than 9 million US individ- angina, drugs with an alternative mode of action are needed.8
uals as part of the morbidity related to coronary artery disease.
Ranolazine,
N-(2,6-dimethylphenyl)-2-[4-{2-hydroxy-3-
The pharmacotherapy of angina involves the corrective (2-methoxyphenoxy)propyl}piperazin-1-yl]acetamide (1) (Fig. 1),
measure of imbalance of the myocardial oxygen demand and offers a new approach to treating chronic angina pectoris. It
supply.2 β-Adrenergic blocking agents are effective life-saving was approved by the US FDA in January 20069 and launched in
medicines in the management of cardiovascular disorders,3 the US in March 2006 for patients who do not show adequate
including hypertension,4 angina pectoris, cardiac arrhythmias response to other anti-anginals and is the first drug of a novel
and other disorders5 related to the sympathetic nervous class to be approved in the US in more than 20 years for treat-
ment of this disease condition.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India.
E-mail: akchakraborti@niper.ac.in, akchakraborti@rediffmail.com
†Electronic supplementary information (ESI) available: List of impurities for
reported procedure of synthesis, optimisation study and scanned spectra. See
DOI: 10.1039/c3gc36997h
Fig. 1 The anti-anginal drug ranolazine (1).
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Scheme 1 Route A for the synthesis of ranolazine (1).
Scheme 3 Route C for the synthesis of ranolazine (1).
Scheme 4 Route D for the synthesis of ranolazine (1).
Scheme 2 Route B for the synthesis of ranolazine (1).
These reported processes for the synthesis of 1 (Schemes
Various processes have been reported for the synthesis of 1–4)10 have several drawbacks such as the use of Et3N, pyri-
ranolazine.10 Route A (Scheme 1) involves the reaction of 2,6- dine, SOCl2 (harmful, carcinogenic), volatile organic solvents
dimethylaniline (2) with chloroacetyl chloride (3a) in the pres- (DCM, CHCl3, THF, dioxane, MeCN, DMF, etc.), auxiliary
ence of Et3N using DCM as solvent, to form the 2-chloro-N- agents, long reaction times and the involvement of a multiple
(2,6-dimethylphenyl)acetamide (4) which is subsequently (4–7) step sequence. The other noticeable and most critical
treated with piperizine (5a) to obtain the N-(2,6-dimethylphe- disadvantage is that various impurities are generated.† The
nyl)-2-(piperazin-1-yl)acetamide (6a). The treatment of 2-((2- removal/separation of these impurities is a difficult task and
methoxyphenoxy)methyl)oxirane (9) with 6a in DMF at 90 °C requires elaborative purification procedures. Identification,
for a prolonged period results in the formation of (RS)-1. The estimation, and minimisation of these impurities have been
intermediate 9 is synthesized by the reaction 2-methoxyphenol the major focus of pharmaceutical industries.11 These draw-
(7) with epichlorohydrine (8) in the presence of NaOH using backs press the need for a concise and more effective process
water–dioxane as the reaction medium under reflux.
for the synthesis of 1.
Route B (Scheme 2) involves the condensation of 1-amino-
Analysis of the reported processes (Schemes 1–4) reveals
3-(2-methoxyphenoxy)propan-2-ol (12), prepared from 9 by that these are based on the common synthetic strategy to use 9
opening of the epoxide ring with succinimide in the presence as the key intermediate and most of the impurities are gener-
of pyridine in EtOH under reflux for 20 h followed by hydro- ated during the preparation of 9 by reaction of 8 with 7 and
lysis of the intermediate 11, with 2-[bis(2-chloroethylamino)-N- non-selective reaction of 9 with other reactants such as
(2,6-dimethylphenyl)]acetamide (15) in the presence of Et3N 6a and 5a.† In some cases, the use of the intermediate 6a
using aq. acetone as solvent. The preparation of the intermedi- also adds up to the list of impurities as the preparation of 6a
ate 15 requires N-alkylation of diethanolamine with 4 in is associated with the formation of the corresponding N,N-
methyl isobutyl ketone (MIBK) in the presence of Et3N and NaI dialkylated by-product 6c during the reaction of 4 with 5a.
under reflux to form 14 followed by treatment with SOCl2 in The use of excess 5a also becomes a cause for generat-
chloroform in the presence of CaCl2.
ing further impurities in the subsequent stages of the
In Route C (Scheme 3), (R)-1 is prepared by N-alkylation of synthesis.†
6a with (S)-1-chloro-3-(2-methoxyphenoxy)propan-2-ol (16) in
It was realised that (i) as 8 is ambidently electrophilic and
the presence of Na2CO3 and KI in dry MeCN under reflux over- (ii) the reaction is performed under basic conditions (to gener-
night. The intermediate (S)-16 is obtained by enzymatic ate the phenolate anion due to the poor nucleophilicity of the
hydrolysis of (RS)-17, prepared by DMAP-catalysed acylation of phenolic oxygen in 7), the formation of these by-products is
(RS)-16 with isobutyric anhydride in DCM overnight. (RS)-16 is inevitable. Thus, a new synthetic strategy that would avoid the
obtained by copper-catalysed opening of the epoxide ring in 9 preparation and use of 9 is in dire necessity.
by LiCl in THF overnight.
To avoid the generation of the impurities associated with
Route D involves N-alkylation of 1-(2-methoxyphenoxy)- the formation and use of the intermediate 9, it was realized
3-(piperazin-1-yl)propan-2-ol (18) with 4 in the presence of that incorporation of the 2-hydroxypropane moiety, derived
K2CO3 and NaI in DMF (Scheme 4). The intermediate 18 is pre- from 8, by reaction of the amine component (as amine is a
pared by the reaction of 9 with 5a in MeOH.
better nucleophile than phenol and might not require base)
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Table 1 Water-assisted N-acylation of 2 with 3a and 3b to form 4 under
metal/base-free conditionsa
Yieldb (%)
Entry
Solvent
With 3a
With 3b
Fig. 2 New disconnection approaches for 1.
1
2
3
4
5
6
7
8
Tap water
Pure waterd
Ultra-pure watere
MeOH
45c
—
—
41f
—
—
—
65
58
60
63
36
55
70
73
38
94
93
94
21g
EtOH
20
17
15
iPrOH
tBuOH
1,4-Dioxane
THF
Trace
Trace
Trace
Trace
Trace
Trace
94h
9
10
11
12
13
14
15
16
MeCN
DMF
Hexane
DCE
TFE
HFIP
None
Scheme 5 New alternate strategy for synthesis of 1.
94i
Trace
and insertion of the 2-methoxyphenol moiety in the final step
would be advantageous (Fig. 2) and a new and alternate syn-
thetic strategy (Scheme 5) was devised.
a 2 (1 mmol) was treated with 3a (1.5 mmol, 1.5 equiv.) or 3b (1 mmol,
1 equiv.) in the indicated solvent (1 mL) at rt (∼35 °C) for 2 h.
b Isolated yield of 4. c 59% yield was obtained at 20 °C. d The pure water
was obtained by purification of normal/tap water through reverse
osmosis and ionic/organic removal and has a resistivity of 15 MΩ cm
at 25 °C. e The ultrapure water was obtained by further subjecting pure
water to UV treatment (185/254 nm), deionization and ultra membrane
filtration (0.01 μm) under pressure upto 145 psi (10 bar) and has
resistivity of 18.2 MΩ cm at 25 °C. f The remaining product was methyl
chloroacetate. g 4 was formed in 90% yield after 4 h. h The reaction was
completed in 30 min. i The reaction was completed in 20 min.
Results and discussion
The reported procedures for the synthesis of 4 involve acyl-
ation of 2 with chloroacetyl chloride (3a) in the presence of
stoichiometric amounts of bases in halogenated solvents that
do not comply with the demand for eco-friendly/green approaches
(sustainable chemistry development).12 The major drive for
sustainable development in the pharmaceutical industry is the
replacement of volatile organic solvents (VOSs) by green reac-
tion media.13 In this regard, water is considered as the most
preferred solvent.12,14 It was realised that the preparation of
the essential starting material 4 by acylation of 2 requires cata-
lytic assistance to avoid the use of stoichiometric quantities of
bases as the auxiliary substances. Although a green initiative is
in practice in the use of Lewis/Brönstead acid catalysts15 for
acylation, a metal-free procedure is desirable. Thus attention
was directed towards the ‘electrophile nucleophile dual acti-
vation’ role of water in promoting N-Boc formation and other
organic reactions.16 However, with the apprehension of the
potential of hydrolytic decomposition of 3a in aqueous
medium, the less water-sensitive acylating agent, chloroacetic
anhydride (3b), was chosen and reacted with 2 in water as well
as in a few common organic solvents (Table 1).
outcome is not influenced by any dissolved metallic or organic
impurities in the water. The limited reports on acylation of
amines or amine hydrochlorides with anhydrides in aqueous
medium require catalytic assistance or stoichiometric
amounts of base.17 Thus, the catalyst/base-free protocol deve-
loped under this study offers a novel water-assisted N-acylation
chemistry. The inefficiency of organic solvents (entries 4–13,
Table 1) or neat conditions (entry 16, Table 1) clearly indicates
specific rate acceleration by water. The role of water in promot-
ing the acylation may be depicted in Scheme 6.
The excellent yield in water is attributed to its hydrogen
bond donor (HBD) ability (to activate the electrophile) in pro-
moting the acylation. To support this proposal we used
Excellent yields (93–94%) were obtained in water (entries
1–3, col 4, Table 1). After addition of the reactants, the reaction
mixture took a cloudy appearance during the progress of the
reaction which was followed by the formation of a white solid
upon completion of the reaction. The comparable results
obtained in tap, pure, and ultra-pure water suggest that the Scheme 6 Plausible role of water in promoting N-acylation of amine.
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trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP) that
have better HBD values18 and were pleased to obtain compar-
able yields (entries 14 and 15, Table 1). As a matter of fact, the
reaction took place in shorter time periods (30 and 20 min,
respectively) in TFE and HFIP compared to that in water (2 h).
The poor results in alcohols could be rationalised due to their
inferior HBD values. The optimal amount of water required for
acylation with 3b was found to be 0.5 mL mmol−1 of 2 whereas
a 3 molar equiv. of TFE and 2 molar equiv. of HFIP afforded19
comparable yields (∼95%) after 30 and 20 min, respectively.†
However, water offered advantages in the isolation/purification
stage as the product (4) precipitated out in aqueous medium
and was isolated by filtration. Therefore, further execution of
the synthetic planning (Scheme 5) 4 was prepared following
the water-assisted N-acylation chemistry.
The feasibility of using 3a was considered for the water-
assisted N-acylation of 2 to synthesise 4 but poor yield was
obtained in water due to the competitive hydrolytic decompo-
sition (entry 1, col 3, Table 1). The use of alcohol (e.g., MeOH)
gave poor yield due to the competitive ester formation.
However, TFE and HFIP afforded 70 and 73% yields, respect-
ively, as the competitive interaction of TFE/HFIP with 3a is sig-
nificantly decreased due to the poor nucleophilicity of TFE
and HFIP. To suppress the hydrolysis and facilitate the N-acyl-
ation, it was planned to take advantage of the surfactants as
catalytic aids.20 Out of the various neutral, cationic, and
anionic surfactants used (Table 2), sodium dodecyl sulfate
(SDS) gave 80% yield during the treatment of 2 with 3a in
water (1 mL per mmol of 2) at 20 °C (entry 10, Table 2). The
reaction mixture became milky white when all of the reactants
were added in water and remained as such until completion.
Further studies on the optimisation of the reaction con-
ditions to minimize the competitive hydrolytic decomposition
of 3a revealed that the reaction temperature and the amount of
Table 3 The influence of the amount of water during the water-assisted
N-acylation of 2 with 3a to form 4 under base-free conditionsa
Entry
Amount of water
Yieldb (%)
1
2
3
4
5
1 mmol
3 mmol
5 mmol
10 mmol
1 mL
52
85
90
86
80
a Reaction of 2 (1 mmol) with 3a (1.5 mmol, 1.5 equiv.) in the
presenceof surfactant (5 mol%) in different amounts of water at 20 °C
for 30 min. b Isolated yield of 4.
water is crucial (Table 3). Use of 5 molar equiv. of water at
20 °C provided the best result (90% yield, entry 3, Table 3). A
decrease in the yield of 4 was observed either in decreasing or
increasing the amount of water and increasing the reaction
temperature above 20 °C.
To assess any advantage of using water over organic sol-
vents, the SDS-promoted acylation of 2 with 3a was performed
in a few commonly used organic solvents (Table 4) that
afforded inferior yields of 4 and demonstrated the distinct
advantage of the use of an aqueous medium.
The classical Schotten–Baumann procedure involves acyl-
ation of aromatic amines with acyl halides in large excess
aqueous alkali.21 The reported procedure for acylation of
aniline (a representative aromatic amine) with 3a in aqueous
medium used 3 equiv. of NaOH and afforded the correspond-
ing N-acylated compound in poor (58%) yield after prolonged
period (overnight).22 Hence, the base-free protocol developed
under the present study provides a novel water-assisted N-acyl-
ation chemistry. The poor yields obtained in using organic sol-
vents (entries 2–7, Table 4) clearly suggest the beneficial effect
of water and may be rationalized due to the synergistic electro-
phile nucleophile dual activation ability of water akin to that
depicted for the water-assisted N-acylation using acyl anhy-
dride (Scheme 6).
Table 2 Water-assisted N-acylation of 2 with 3a to form 4 under base-free
conditionsa
Therefore, two new water-assisted N-acylation procedures
have been developed for the preparation of 4, the essential
starting material for the synthesis of 1: (i) the catalyst-free reac-
tion of 2 with 3b in water (0.5 mL per mmol of 2) at room
temperature (25–30 °C) and (ii) the base-free reaction of 2 with
Entry
Surfactant
Yieldb (%)
Table 4 The SDS-catalysed reaction of 2 with 3a in organic solventsa
1
2
3
4
5
6
7
8
Span 80
Tween 80
Triton X-100
β-Cyclodextrin hydrate
Benzalkonium chloride
Tetrabutylammonium bromide
Tetrabutylammonium iodide
Cetyltrimethylammonium bromide
Hexadecyl pyridinium chloride
SDS
65
68
71
62
52
45
48
55
52
80
65
78
Entry
Solvent
Yieldb (%)
1
2
3
4
5
6
7
Water
90c
52c
42d
25d
35d
36d
55d
MeOH
1,4-Dioxane
Hexane
Toluene
DCE
9
10
11
12
Sodium deoxy cholate
Sodium dioctyl sulfosuccinate
TFE
a 2 (1 mmol) was treated with 3a (1.5 mmol, 1.5 equiv.) in the presence
a Reaction of 2 (1 mmol) with 3a (1.5 mmol, 1.5 equiv.) in the presence of SDS (5 mol%) in different solvents at 20 °C for 30 min. b The
of surfactant (5 mol%) in water (1 mL) at 20 °C for 30 min. b Isolated isolated yield of 4. c The reaction was performed using 5 mmol of the
yield of 4.
solvent. d The reaction was performed using 1 mL of the solvent.
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Comparable results were obtained in organic solvents.
However, it was observed that when the N-alkylation of 4 with
5b was carried out in water, an in situ N-t-Boc deprotection23
can be achieved by further treatment of the reaction mixture at
110 °C (oil bath) for 3 h to afford 6a in 94% yield. Treatment of
4 with 5b in EtOH under reflux for 4 h afforded 6b in 95%
yield, which remained unchanged on further treatment in
EtOH under reflux for 3 h and 6a could be obtained in poor
(12%) yield after a prolonged period (∼8 h).† This further high-
lighted the advantage of using water. Although N-alkylation of
an aromatic amine has been performed in water under micro-
wave heating at 150 °C,24 N-alkylation of 5b has been reported
in DMF containing Et3N and the N-Boc deprotection involved
treatment with aq. HCl to form the resultant N-mono-alkylated
piperazine.25 Thus, the water-assisted one-pot tandem N-alkyl-
ation-N-Boc-deprotection method represents a novel synthetic
process for the preparation of 6a from 4.
The synthesis of the final intermediate 2-[4-(3-chloro-
2-hydroxypropyl)piperazin-1-yl]-N-(2,6-dimethylphenyl)aceta-
mide (19) would involve opening of the epoxide ring of 8 with
6a. The aminolysis of epoxide remains the mainstay of the syn-
thesis of β-adrenergic blocking agents and various Lewis/Brön-
stead acid catalysts have been developed to promote the
reaction.26 A metal/catalyst-free condition was adopted for the
reaction of 6a with (RS)-8 in different solvents (Table 6). Excel-
lent yield (97%) of 19 was obtained in water (entry 1,
Table 6).27 The reaction mixture became cloudy after mixing
all of the reactants in water and remained as such until
Scheme 7 Formation of 6 by the reaction of 4 with 5.
3a in water (5 molar equiv. of 2) in the presence of SDS
(5 mol%) at 20 °C. The water-assisted acylation of 2 with 3a or
3b under the respective optimized reaction conditions
afforded comparable yields (∼90%) up to 30 mmol scale reac-
tion. However, for larger scale (e.g., 50 mmol) operation, the
use of 3b proved to be advantageous as a decrease in the
product yield was observed using 3a (80% yield) perhaps due
to the ineffectiveness in suppressing the hydrolytic cleavage
and accuracy in maintaining the reaction temperature at 20 °C
(due to local heating) in the presence of a larger volume of
water. Although the use of 3a would have the projected advan-
tage in terms of cost and atom efficiency, the use of 1 equiv. of
3b as compared to the requirement of the use of 1.5 equiv. of
3a would to some extent compensate for these aspects.
The preparation of 6a by the reaction of 4 with 5a has the
potential problem to form the corresponding N,N-dialkylated
derivative 6c as a side product (Scheme 7).
Thus, 4 was treated with the N-Boc piperazine (5b) in water
at 80 °C for 4 h to afford the N-(2,6-dimethylphenyl)-2-[(4-tert-
butoxycarbonyl)piperazin-1-yl]acetamide (6b) in 95% yield
(entry 1, Table 5). After addition of all of the reactants in water
the reaction mixture took a cloudy appearance and a white
solid precipitated after completion of the reaction. No signifi-
cant amount of 6b was formed in performing the reaction at rt
and 39% yield was obtained when carrying out the reaction at
60 °C (footnotes c and d, respectively; entry 1, Table 5).
Table 6 Influence of solvent on epoxide aminolysis during the reaction of 8
with 6a to form 19a
Table 5 The influence of the solvent on N-monoalkylation of 2-chloro-N-(2,6-
dimethylphenyl)acetamide (4) with N-Boc-piperazine (5b)a
Entry
Solvent
Yieldb (%)
1
2
3
4
Water
97
96
96
20
Pure waterc
Ultra-pure waterd
MeOH
5
6
7
EtOH
18
19
15
iPrOH
Entry
Solvent
Yield of 6bb (%)
tBuOH
8
9
1,4-Dioxane
THF
CH3CN
DMF
Toluene
MeNO2
TFE
Trace
Trace
Trace
Trace
Trace
Trace
25
1
2
3
4
5
6
7
8
Water
95 (Trace,c 36d)
10
11
12
13
14
13
Pure water
Ultrapure water
MeOH
94
95
94
95
92
90
92
88
89
92
0
EtOH
1,4-Dioxane
CH3CN
DMF
Toluene
DCE
TFE
None
HFIP
31
a 8 (1 mmol) was treated with 6a (1 mmol, 1 equiv.) in different
solvents (1 mL) at 15 °C for 1 h. b The isolated yield of 19. c Pure water
was obtained by purification of normal/tap water through reverse
osmosis and ionic/organic removal and has a resistivity of 15 MΩ cm
at 25 °C. d Ultra-pure water was obtained by further subjecting pure
water to UV treatment (185/254 nm), deionization and ultra membrane
filtration (0.01 μm under pressure upto 145 psi (10 bar) and has a
resistivity of 18.2 MΩ cm at 25 °C.
9
10
11
12
a Reaction of 4 (1 mmol) with N-Boc-piperazine (5b) (1 mmol, 1 equiv.)
in solvent (5 mL) at 80 °C (oil bath) for 4 h. b Isolated yield of 6b.
c Yield of 6b at rt. d Yield of 6b at 60 °C (oil bath).
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Scheme 9 The O-alkylation of 7 with 19 to form 1.
Scheme 8 The role of water in epoxide aminolysis.
completion. The use of organic solvents afforded poor yields
and highlighted the importance of using an aqueous medium.
Surprisingly, TFE and HFIP were ineffective.28
Scheme 10 Two step ‘all water’ process for the synthesis of (RS)-1.
The comparison of the results of entries 1–3 with those of
entries 4–13 (Table 6) clearly indicates the specific assistance
by water in promoting the epoxide aminolysis. The comparable
yields obtained in using the different types of water (entries
Having the chemistry at each step standardised, (RS)-1
1–3, Table 6) rule out any possible catalytic assistance by trace could be obtained in 82% yield from 4 by sequential treatment
with 5b, (RS)-8, and 7 in one-pot without isolation of the inter-
mediately formed products 6b, 6a, and 19. The reaction
amounts of inorganic/organic impurities in the water.
Although the rate acceleration during epoxide aminolysis in
water has been marked,27a there has been no specific mechan- mixture took a dull white appearance and remained as such
until completion. The overall synthesis of 1 from 2 was exe-
istic proposal to rationalise the water-assisted epoxide amino-
cuted by a two step sequence (Scheme 10) involving the
lysis. To account for the water-assisted aminolysis of 8 with 6a
we envisaged a synergistic electrophile nucleophile dual acti- tandem water-assisted N-alkylation and N-Boc deprotection
chemistry (to form 6a from 4 and 5b) to afford (RS)-1 in 77%
overall yield (starting from 2). This represents a new and
vation role by water (Scheme 8).
An initial activation of the epoxide ring of 8 takes place
through bifurcated HB formation involving the epoxide oxygen shorter (two step) synthesis of 1 from 2.
For a protecting group free synthesis,31 it was planned to
exploit the dual activation ability of water for the reaction of 4
and the water dimer to form the TS-I. This is followed by
nucleophilic attack by the secondary nitrogen (NH) of the
piperidine moiety of 6a at the terminal carbon of the epoxide with 5a. However, no significant amount of product formation
was observed either at rt or at 60 °C. The use of a phase trans-
ring to form TS-II in which the NH hydrogen forms HB
fer catalyst (PTC) proved to be beneficial and 6a was obtained
(nucleophilic activation) with the oxygen atom of the second
water molecule of the water dimer. Thus, in TS-II, a synergistic in 85, 88, and 81% yields in the presence (10 mol%) of TBAB,
TBAI, and CTAB, respectively (entries 11, 12, and 13; Table 7).
The use of other PTCs afforded lesser yields of 6a along with
electrophile nucleophile dual activation occurs through a relay
of HB formation via the water dimer.29 The inability of the
organic solvents such as dioxane, THF, MeCN, DMF, and the formation of increasing amounts of 6c.
The use of water proved to be beneficial as the TBAI-cata-
lysed reaction of 4 with 5a in various organic solvents (protic/
MeNO2 to form the relay of HB akin to TS-II justify the ineffi-
ciency of these solvents to promote the epoxide aminolysis.
The poor results with the alcoholic solvents may be due aprotic polar, ethereal, and hydrocarbon) afforded inferior
to their inferior HBD values compared to that of water.18
yields (35–68% as compared to 88% yield obtained in water) of
6a with concomitant formation of 6c in higher amounts
(HBA) properties of TFE and HFIP (the HBA values, β, of (10–18%) compared to that (6%) obtained in water (Table 8).
On the other hand the lack of hydrogen bond acceptor
Next, the tandem epoxide ring opening of (RS)-8 with 6a to
form (RS)-19 followed by O-alkylation with 7 was performed via
a one-pot reaction to form (RS)-1 in 85% yield (Scheme 11).
The reaction mixture took a dull white appearance and
remained as such until completion. The overall sequence pro-
TFE, HFIP and water are 0.00. 0.00, and 0.18, respectively)
might be the reason for the poor results obtained in these
solvents.
In the final step, the O-alkylation of 19 with 7 was tried
under various conditions to form (RS)-1 (Scheme 9).† The best
result was obtained in the presence of K2CO3 (1.3 equiv.) in vides a new three step synthesis of 1 from 2.
Ranolazine contains one stereocentre and exhibits chirality.
There has been a growing concensus against the marketing of
water affording 93% yield at 90 °C after 5 h. The reaction
mixture took a dull white appearance and remained as such
until completion of the reaction. In order to reduce the reac- racemates, and as per FDA guidelines,32 it is necessary to
evaluate the physicochemical differences of the racemic and
single enantiomer in terms of solubility, stability etc. in
tion time, the reaction was performed under microwave
irradiation to obtain a comparable yield in 30 min.30
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Table 7 Influence of surfactant on N-alkylation of 4 with 5a to form 6aa
Scheme 11 One-pot synthesis of (RS)-1.
Yieldb (%)
Entry
Surfactant
6a
6c
1
2
3
4
5
6
7
8
None
Span 80
Tween 80
Triton X-100
Triton X-114
Triton X-135
β-Cyclodextrin hydrate
Benzalkonium chloride
Tetrabutylammonium fluoride
Tetrabutylammonium chloride
Tetrabutyl ammonium bromide
Tetrabutylammonium iodide (TBAI)
Cetyltrimethylammonium bromide
Hexadecyl pyridinium chloride
Sodium dodecyl sulphate (SDS)
Sodium deoxycholate
Sodium dioctyl sulfosuccinate
Cetrimide
Trace
10
14
52
55
50
30
31
35
48
85
88
81
40
42
38
59
35
0
Trace
Trace
13
15
15
12
10
10
8
9
10
11
12
13
14
15
16
17
18
5
6
Scheme 12 Three step ‘all water’ process for the synthesis of (RS)-1.
12
10
13
12
20
15
efficacy of (R)-1 and (S)-1. Therefore 1 is prescribed as a
racemic mixture.10c
To prepare 1 in optically pure forms, the water-assisted
aminolysis of (R)-8 and (S)-8 was performed with 6a to afford
(R)-19 and (S)-19 in 97 and 96% yields with 98.7 and 98.5% ee,
respectively. The one-pot tandem epoxide ring opening of (R)-8
and (S)-8 with 6a followed by O-alkylation of the in situ formed
(R)-19 and (S)-19 with 7 afforded (R)-1 and (S)-1 in 86 and 85%
yields with 96.2 and 95.6% ee, respectively (Scheme 11).
The overall synthesis of 1 in (RS), (R), and (S) forms in the
second process was executed via a three step sequence
(Scheme 12) involving a protecting group-free strategy for the
preparation of 6a from 4 and 5b to obtain (RS)-1 in 69% overall
yield (starting from 2).
a Reaction of 4 (1 mmol) with 5a (1 mmol, 1.5 equiv.) in the presence
of catalyst (10 mol%) in water (1 mL) at 60 °C (oil bath) for 3 h.
b Isolated yield.
Table 8 The TBAI-catalysed reaction of 4 with 5a in organic solventsa
Yieldb (%)
Entry
Solvent
6a
6c
1
2
3
4
5
6
7
8
Water
MeOH
EtOH
88
65
68
66
62
45
38
40
35
42
46
62
60
0
6
12c,d
15
13
15
10
13
15
10
12
18
16
18
0
iPrOH
tBuOH
1,4-Dioxane
THF
Conclusions
A new strategy of ‘all water chemistry’ has been demonstrated
for concise (two and three steps) total synthesis of the novel
class anti-anginal drug ranolazine in racemic (RS) and enantio-
pure [(R) and (S)] forms in higher overall yields (69–77%). The
new synthetic designs avoided the generation of the side pro-
ducts normally associated with the reported processes for the
preparation of ranolazine. In the critical stages of the syn-
thesis, the reactions have been promoted by water and gener-
ated novel chemistries through the development of new water-
assisted synthetic methodologies such as, (i) catalyst/base-free
N-acylation of amine with acid anhydride, (ii) base-free N-acyl-
ation of amine with acid chloride, (iii) catalyst/base-free tandem
N-alkylation and N-Boc deprotection, and (iv) base-free selec-
tive mono N-alkylation of diamine (e.g., piperazine). In each
stage, the advantage of using water has been demonstrated by
CH3CN
DMF
Toluene
MeNO2
TFE
HFIP
None
9
10
11
12
13
14
a Reaction of 4 (1 mmol) with 5a (1 mmol, 1.5 equiv.) in the presence
of TBAI (10 mol%) in the respective solvent (1 mL, except for entry) at
60 °C (bath temp.) for 3 h. b Isolated yield. c 6a and 6c were formed in
70 and 25% yields, respectively, when performing the reaction under
reflux (bath temp 80 °C) for 4 h. d 6a and 6c were formed in 65 and
20% yields, respectively, when performing the reaction under reflux
(bath temp 80 °C) for 2 h.
addition to the data on pharmacology. Thus, efforts were performing the respective reactions in organic solvents that
made to prepare 1 in enantio form.10c However, the activities afforded inferior yields. The beneficial effect of water has been
of the racemic and single enantiomer of 1 have been tested for depicted according to its role for ‘synergistic dual activation of
clinical efficacy and showed only a slight difference in the the electrophile and the nucleophile.’ In view of the ongoing
762 | Green Chem., 2013, 15, 756–767
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concern over the environmental impact of chemical processes, was continued at the same temperature. After completion of
the present work provides cleaner and greener reaction con- reaction (30 min, TLC), the solvent was evaporated under
ditions. The use of water as the reaction medium, shorter reac- rotary vacuum evaporation. To the above crude reaction
tion times, excellent chemoselectivity, high overall yields, mixture, water (100 mL) was added and stirred for 0.5 h at rt.
prevention/minimisation of waste/by-products, avoidance of The white precipitate was filtered off, washed with cold water
auxiliary substances (e.g., organic solvents, additional (3 × 5 mL) and dried to get pure 2-chloro-N-(2,6-dimethylphe-
reagents, metal catalysts etc.), and ease of product isolation/ nyl)acetamide (4) (9.26 g, 94%).11a
purification comply with the ‘triple bottom-line philosophy of
Typical experimental procedure for N-acylation of
2,6-dimethylaniline (2) with chloroacetic anhydride (3b)
in HFIP (entry 15, Table 1)
green chemistry’33 and make the present process environmen-
tally benign.
To the magnetically stirred mixture of 2,6-dimethylaniline (2)
Experimental
(6.05 g, 50 mmol) in HFIP (20 mmol) at rt was added chloro-
acetic anhydride (3b) (8.45 g, 50 mmol, 1 equiv.) and stirring
was continued at the same temperature. After completion of
reaction (20 min, monitored by TLC), the solvent was evapo-
rated under rotary vacuum evaporation. To the above crude
reaction mixture, water (25 mL) was added and stirred for
0.5 h at rt. The white precipitate was filtered off, wash with
cold water (3 × 2 mL) and dried to get pure 2-chloro-N-(2,6-
dimethylphenyl)acetamide (4) (0.92 g, 94%).11a
Chemicals and all solvents were commercially available and
used without further purification. The 1H and 13C NMR
spectra were recorded on a 400 MHz NMR spectrometer in
CDCl3 with residual undeuterated solvent (CHCl3: 7.26/77.0)
using TMS as an internal standard. Chemical shifts (δ) are
given in ppm and J values are given in Hz. The 13C NMR
spectra were fully decoupled and were referenced to the
middle peak of the solvent CHCl3 at 77.00 ppm. Splitting pat-
terns were designated as s, singlet; bs, broad singlet; d, Representative experimental procedure for small scale
doublet; dd, doublet of doublet; t, triplet; m, multiplet. Mass synthesis of 2-chloro-N-(2,6-dimethylphenyl)acetamide by the
spectra were recorded under APCI mode of ionisation. Infra- reaction of 2,6-dimethylaniline (2) with chloroacetyl chloride
red (IR) spectra were recorded in the range 4000–600 cm−1 (3a) (entry 1, Table 3)
either as neat for liquid or KBr pellets for solid samples. Purity
compounds were checked on the silica gel GF-254 under UV at
254 nm. Melting points were measured using melting point
apparatus and were uncorrected. Evaporation of solvents was
To the magnetically stirred mixture of 2,6-dimethylaniline (2)
(0.60 g, 5 mmol) and SDS (5 mol%) in water (25 mmol) at
20 °C was added chloroacetyl chloride (3a) (0.84 g, 7.5 mmol,
1.5 equiv.) and stirring was continued at the same temperature
for 30 min (TLC). The reaction mixture was neutralized with
NaHCO3 (until the effervescence ceases), precipitate was fil-
tered off, washed with cold water (3 × 1 mL) and dried. The
crude product was recrystallized in toluene to get pure
2-chloro-N-(2,6-dimethylphenyl)acetamide (4) (0.88 g, 90%).
performed at reduced pressure, using
evaporator.
a rotary vacuum
Typical experimental procedure for N-acylation of 2,6-
dimethylaniline (2) with chloroacetic anhydride (3b) in water
(entry 1, Table 1)
Representative experimental procedure for large scale
synthesis of 2-chloro-N-(2,6-dimethylphenyl)acetamide by the
reaction of 2,6-dimethylaniline (2) with chloroacetyl chloride
(3a) (entry 1, Table 3)
To the magnetically stirred mixture of 2,6-dimethylaniline (2)
(6.05 g, 50 mmol) in water (50 mL) at rt was added chloroacetic
anhydride (3b) (8.45 g, 50 mmol, 1 equiv.) and stirring was
continued at the same temperature. After completion of the
reaction (2 h, TLC), the white precipitate was filtered off,
washed with cold water (3 × 5 mL) and dried to get pure
2-chloro-N-(2,6-dimethylphenyl)acetamide (4) (9.26 g, 94%);
White solid; mp = 147–148 °C; IR (Neat) ν: 3219, 3031, 2947,
To the magnetically stirred mixture of 2,6-dimethylaniline (2)
(6.05 g, 50 mmol), and SDS (5 mol%) in water (250 mmol) at
20 °C was added chloroacetyl chloride (3a) (8.39 g, 75 mmol,
1.5 equiv.) and stirring was continued at the same temperature
for 30 min (TLC). The reaction mixture was neutralized with
NaHCO3 (until the effervescence ceases), precipitate was fil-
tered off, washed with cold water (3 × 5 mL) and dried. The
crude product was recrystallized in toluene to get pure 2-
chloro-N-(2,6-dimethylphenyl)acetamide (4) (7.68 g, 78%).11a
1640, 1600, 1590, 1468, 1451, 1255, 1160 cm−1 1H NMR
;
(CDCl3, 400 MHz) δ: 7.84 (brs, 1H), 7.16–7.08 (m, 3H), 4.25 (s,
2H), 2.24 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 164.3, 135.3,
132.7, 128.4, 127.9, 42.8, 18.3; MS (APCI) m/z 198.1 (M +
H)+.11a
Typical experimental procedure for N-acylation of
2,6-dimethylaniline (2) with chloroacetic anhydride (3b)
in TFE (entry 14, Table 1)
Typical experimental procedure for the synthesis of tert-butyl
4-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperazine-
1-carboxylate (6b) using tert-butyl piperazine-1-carboxylate
(entry 1, Table 5)
To the magnetically stirred mixture of 2,6-dimethylaniline (2)
(6.05 g, 50 mmol) in TFE (150 mmol) at rt was added chloro- To the magnetically stirred mixture of 2-chloro-N-(2,6-
acetic anhydride (3b) (8.45 g, 50 mmol, 1 equiv.) and stirring dimethylphenyl)acetamide (4) (1.97 g, 10 mmol) in water
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(50 mL) at 80 °C was added tert-butyl piperazine-1-carboxylate Typical experimental procedure for the synthesis of
(5b) (1.86 g, 10 mmol, 1 equiv.) and stirring was continued for (R)-2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-yl)-
4 h (TLC). The reaction mixture was cooled to rt, the precipi- N-(2,6-dimethylphenyl)acetamide (R-19)
tate was filtered off, washed with cold water (3 × 2 mL) and
To the magnetically stirred mixture of N-(2,6-dimethylphenyl)-
dried to get analytically pure tert-butyl 4-(2-((2,6-dimethylphe-
2-(piperazin-1-yl)acetamide (6a) (0.494 g, 2 mmol) in water
nyl)amino)-2-oxoethyl)piperazine-1-carboxylate (6b) (3.29 g,
(1 mL) at 15 °C was added (R)-epichlorohydrine (R-8) (0.184 g,
2 mmol, 1 equiv.) and stirring was continued for 1 h (TLC).
The reaction mixture was extracted with EtOAc (3 × 2 mL) and
concentrated under rotary vacuum evaporation to get analyti-
95%); white solid; mp: 117–119 °C; IR (Neat) ν: 3326, 3015,
2985, 2866, 1746, 1679, 1595, 1470, 1255, 1158; 1H NMR
(CDCl3, 400 MHz) δ: 8.58 (brs, 1H), 7.11–7.08 (m, 3H), 3.51
(t, J = 4.72 Hz, 4H), 3.22 (s, 2H), 2.64 (t, J = 4.64 Hz, 4H), 2.23
cally pure (R)-2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-yl)-N-
(s, 6H), 1.47 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ: 168.1,
(2,6-dimethylphenyl)acetamide (R-19) (0.66 g, 97%). The
154.6, 134.9, 133.5, 128.3, 127.3, 80.1, 61.9, 53.6, 28.4, 18.6;
product was subjected to chiral HPLC analysis using a chiral
HRMS (ESI) m/z calcd for C19H30N3O3 [M + H+], 348.2282;
AD-H column and the two enantiomers were eluted at tS
=
Found 348.2280.11a
34.4 min and tR = 38.9 min (80 : 20 : 0.1, hexane : 2-propanol :
diethylamine) and the optical purity was found to be 98.7% ee.
Typical experimental procedure for the synthesis of
N-(2,6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (6a)
using tert-butyl piperazine-1-carboxylate (5b)
Typical experimental procedure for the synthesis of
(S)-2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-yl)-
N-(2,6-dimethylphenyl)acetamide (S-19)
To the magnetically stirred mixture of 2-chloro-N-(2,6-
dimethylphenyl)acetamide (4) (3.94 g, 20 mmol) in water
(100 mL) at 80 °C was added tert-butyl piperazine-1-carboxylate
(5b) (3.72 g, 20 mmol, 1 equiv.) and stirring was continued for
4 h. Thereafter the reaction temperature was increased to
110 °C and the stirring continued for further 3 h (TLC). The
reaction mixture was cooled to rt and neutralized with sodium
bicarbonate (until the effervescence ceases). The precipitate
was filtered off, washed with cold water (3 × 4 mL) and dried
to get analytically pure N-(2,6-dimethylphenyl)-2-(piperazin-
1-yl)acetamide (6a) (4.69 g, 95%); white solid; mp = 115–117 °C;
IR (Neat) ν: 3324, 3285, 3010, 2931, 1679, 1590, 1476, 1252,
To the magnetically stirred mixture of N-(2,6-dimethylphenyl)-
2-(piperazin-1-yl)acetamide (6a) (0.494 g, 2 mmol) in water
(1 mL) at 15 °C was added (S)-epichlorohydrine (S-9) (0.184 g,
2 mmol, 1 equiv.) and stirring was continued for 1 h (TLC).
The reaction mixture was extracted with EtOAc (3 × 2 mL) and
concentrated under rotary vacuum evaporation to get analyti-
cally pure (R)-2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-yl)-N-
(2,6-dimethylphenyl)acetamide (S-19) (0.65 g, 96%). The
product was subjected to chiral HPLC analysis using a chiral
AD-H column and the two enantiomers were eluted at tS
=
34.3 min and tR = 39.1 min (80 : 20 : 0.1, hexane : 2-propanol :
diethylamine) and the optical purity was found to be 98.5% ee.
1152 cm−1 1H NMR (CDCl3, 400 MHz) δ: 8.69 (brs, 1H),
;
7.10–7.06 (m, 3H), 3.18 (s, 2H), 2.96 (d, J = 9.64 Hz, 4H),
2.67–2.66 (m, 2H), 2.23 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ:
168.5, 134.9, 133.6, 128.3, 127.2, 62.4, 55.1, 46.3, 18.6; MS
(APCI) m/z 248.1 (M + H)+.11a
Typical experimental procedure for the synthesis of (RS)-
ranolazine (1) (Scheme 9)
To the magnetically stirred mixture of 2-methoxyphenol (7)
(0.124 g, 1 mmol, 1 equiv.) and K2CO3 (0.18 g) in water (1 mL)
at 90 °C was added (RS)-2-(4-(3-chloro-2-hydroxypropyl)pipera-
zin-1-yl)-N-(2,6-dimethylphenyl)acetamide (19) (0.339 g,
1 mmol) and stirring was continued for 5 h (TLC). The reaction
mixture was cooled to rt and neutralized with NaHCO3 (until
the effervescence ceases). The reaction mixture was cooled to
0–5 °C and diluted with 1 : 1 methanol and acetone (5 mL).
The solid that precipitated out (2–3 h) was filtered off, washed
with chilled methanol (2 mL), and dried to get analytically
pure ranolazine (1) (0.4 g, 93%).11a
Typical experimental procedure for the synthesis of (RS)-
2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-yl)-
N-(2,6-dimethylphenyl)acetamide (19) (entry 1, Table 6)
To the magnetically stirred mixture of N-(2,6-dimethylphenyl)-
2-(piperazin-1-yl)acetamide (6a) (4.94 g, 20 mmol) in water
(20 mL) at 15 °C was added epichlorohydrine (8) (1.84 g,
20 mmol, 1 equiv.) and stirring was continued for 1 h (TLC).
The reaction mixture was extracted with EtOAc (3 × 10 mL) and
concentrated under rotary vacuum evaporation to get analyti-
cally pure (RS)-2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-yl)-N-
(2,6-dimethylphenyl)acetamide (19) (6.57 g, 97%); colourless
viscous liquid; IR (Neat) ν: 3345, 3018, 2978, 1671, 1592, 1466,
Typical experimental procedure for a protecting group free
synthesis of N-(2,6-dimethylphenyl)-2-(piperazin-1-yl)-
acetamide (6a) using piperizine (5a) (entry 12, Table 7)
1
1245, 1139 cm−1; H NMR (CDCl3, 400 MHz) δ: 7.17 (brs, 3H),
4.85–4.75 (m, 1H), 4.62–4.58 (m, 2H), 4.26–4.15 (m, 2H), 3.75 To the magnetically stirred mixture of 2-chloro-N-(2,6-
(brs, 2H), 3.67 (brs, 2H), 2.95–2.71 (m, 4H), 2.26 (brs, 1H), 2.22 dimethylphenyl)acetamide (4) (9.85 g, 50 mmol) and pipera-
(s, 6H); 13C NMR (CDCl3, 100 MHz) δ: 170.9, 136.8, 135.0, zine (5a) (6.45 g, 75 mmol, 1.5 equiv.) in water (50 mL) at rt
129.2, 128.6, 73.1, 62.6, 61.1, 60.8, 59.8, 54.8, 18.6; HRMS (ESI) was added tetrabutylammoniumiodide (10 mol%) and the
m/z calcd for C17H27ClN3O2 [M
+
H+], 34.1786; Found reaction temperature raised to 60 °C and stirring was contin-
340.1784.
ued for 3 h. The reaction mixture was cooled to 5–10 °C and
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sodium bicarbonate was added (till the effervescence ceases). Typical experimental procedure for tandem ring opening of
The mixture was evaporated to dryness under rotary vacuum epichlorohydrine (7) with 6a and O-alkylation of 2-methoxy-
evaporation and the solid residue was triturated with methanol phenol (8) for the synthesis of (RS)-ranolazine (RS-1)
(3 × 10 mL). The combined methanolic extracts are concen- (Scheme 11)
trated under vacuum rotary evaporation and the solid residue
washed with cold water (2 × 5 mL) and dried to get analytically
To the magnetically stirred mixture of N-(2,6-dimethylphenyl)-
2-(piperazin-1-yl)acetamide (6a) (4.94 g, 20 mmol) in water
(20 mL) at 15 °C was epichlorohydrine (8) (1.84 g, 20 mmol,
1 equiv.) and stirring was continued for 1 h (TLC) followed by
pure N-(2,6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (6a)
(10.5 g, 85%).11a
addition of 2-methoxyphenol (7) (2.48 g, 20 mmol, 1 equiv.)
and the stirring continued at 90 °C for further 5 h (TLC). The
reaction mixture was cooled to rt and neutralized with
Typical experimental procedure for the synthesis of (RS)-
ranolazine (RS-1) under microwave condition (Scheme 9)
NaHCO3 (until the effervescence ceases). The mixture was
The mixture of (RS)-2-(4-(3-chloro-2-hydroxypropyl)piperazin-
cooled to 0–5 °C and diluted with 1 : 1 methanol and acetone
1-yl)-N-(2,6-dimethylphenyl)acetamide (19) (0.339 g, 1 mmol)
and 2-methoxyphenol (7) (0.124 g, 1 mmol, 1 equiv.) and
K2CO3 (0.18 g) in water (1 mL) was stirred magnetically at
100 °C under microwave for 30 min (TLC). The reaction
(20 mL). The solid that precipitated out (2–3 h) was filtered,
washed with chilled methanol (5 mL), and dried to get analyti-
cally pure ranolazine (1) (7.25 g, 85%).11a
mixture was cooled to rt and neutralized with NaHCO3 (till the
effervescence ceases). The mixture was cooled to 0–5 °C and
diluted with 1 : 1 methanol and acetone (5 mL). The precipi-
tated solid (2–3 h) was filtered, washed with chilled methanol
Typical experimental procedure for tandem ring opening of
epichlorohydrine (7) with 6a and O-alkylation of 2-methoxy-
phenol (8) for the synthesis of (R)-ranolazine (R-1)
(Scheme 11)
(2 mL), and dried to get analytically pure ranolazine (1) (0.38 g,
To the magnetically stirred mixture of N-(2,6-dimethylphenyl)-
2-(piperazin-1-yl)acetamide (6a) (0.497 g, 2 mmol) in water
(2 mL) at 15 °C was added (R)-epichlorohydrine (R-8) (0.18 g,
91%).11a
Typical experimental procedure for tandem N-alkylation and
deprotection and O-alkylation for the synthesis of (RS)-
ranolazine (RS-1) (Scheme 10)
2 mmol, 1 equiv.) and stirring was continued for 1 h (TLC) fol-
lowed by addition of 2-methoxyphenol (7) (0.25 g, 2 mmol,
1 equiv.) and the stirring continued at 90 °C for further 5 h
(TLC). The reaction mixture was cooled to rt and neutralized
with NaHCO3 (until the effervescence ceases). The reaction
mixture was cooled to 0–5 °C and diluted with 1 : 1 methanol
and acetone (5 mL). The solid that precipitated out (2–3 h) was
filtered, washed with chilled methanol (2 mL), and dried to get
analytically pure ranolazine (R-1) (0.73 g, 86%). The product
was subjected to chiral HPLC analysis using a chiral AD-H
column and the two enantiomers were eluted at tR = 27.1 min
To the magnetically stirred mixture of 2-chloro-N-(2,6-
dimethylphenyl)acetamide (4) (3.94 g, 20 mmol) in water
(100 mL) at 80 °C was added tert-butyl piperazine-1-carboxylate
(5b) (3.72 g, 20 mmol, 1 equiv.) and stirring was continued for
4 h. Thereafter, the reaction temperature was increased to
110 °C and the stirring was continued for a further 3 h (TLC).
The reaction mixture was cooled to rt and neutralized with
sodium bicarbonate (until the effervescence ceases). The reac-
tion mixture was further cooled to 10 to 15 °C, to which epi-
chlorohydrine (8) (1.84 g, 20 mmol, 1 equiv.) was added and
stirring continued for 1 h (TLC) followed by addition of
2-methoxyphenol (7) (2.48 g, 20 mmol, 1 equiv.) and K2CO3
(3.61 g, 26 mmol, 1.3 equiv.). The reaction temperature was
raised to 90 °C and the stirring continued for a further 5 h
and tS
=
46.2 min (70 : 30 : 0.1, hexane : 2-propanol :
diethylamine) and the optical purity was found to be 96.2% ee.
Typical experimental procedure for tandem ring opening of
epichlorohydrine and O-alkylation of 2-methoxyphenol for the
synthesis of (S)-ranolazine (S-1) (Scheme 11)
(TLC). The reaction mixture was cooled to rt and neutralized To the magnetically stirred mixture of N-(2,6-dimethylphenyl)-
with NaHCO3 (until the effervescence ceases). The mixture was 2-(piperazin-1-yl)acetamide (6a) (0.497 g, 2 mmol) in 1 mL
cooled to 0–5 °C and diluted with 1 : 1 methanol and acetone water at 15 °C was added (S)-epichlorohydrine (S-8) (0.18 g,
(20 mL). The precipitated solid (∼2–3 h) was filtered, washed 2 mmol, 1 equiv.) and stirring was continued for 1 h (TLC) fol-
with chilled methanol (3 × 5 mL), and dried to get analytically lowed by addition of 2-methoxyphenol (7) (0.25 g, 2 mmol,
pure ranolazine (1) (3.5 g, 82%); white solid; mp = 121–122 °C; 1 equiv.) and the stirring continued at 90 °C for a further 5 h
IR (Neat) ν: 3329, 3012, 2975, 2935, 1676, 1586, 1505, 1475, (TLC). The reaction mixture was cooled to rt and neutralized
1
1259, 1149 cm−1; H NMR (CDCl3, 400 MHz) δ: 6.98–6.96 (m, with NaHCO3 (until the effervescence ceases). The reaction
3H), 6.86–6.77 (m, 4H), 4.06–4.02 (m, 1H), 3.89–3.86 (m, 1H), mixture was then cooled to 0–5 °C and diluted with
3.82–3.78 (m, 1H), 3.71 (s, 3H), 2.58 (brs, 8H), 2.55–2.43 (m, 1 : 1 methanol and acetone (5 mL). The solid that precipitated
2H) 2.08 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ: 170.2, 149.4, out (2–3 h) was filtered, washed with chilled methanol (2 mL),
148.3, 135.3, 133.7, 127.7, 127.0, 121.4, 120.9, 113.7, 112.0, and dried to get analytically pure ranolazine (S-1) (0.72 g,
71.9, 67.0, 60.9, 60.5, 55.1, 53.1, 52.9, 17.3; MS (APCI) m/z 85%). The product was then subjected to chiral HPLC analysis
428.2 (M + H)+.11a
using a chiral AD-H column and the two enantiomers were
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eluted at tR = 27.9 min and tS = 46.5 min (70 : 30 : 0.1, hexane :
2-propanol : diethylamine) and the optical purity was found to
be 95.6% ee.
Biotransform., 2005, 23, 45; Route D: P. B. Deshpande and
A. D. Chauhan, PCT Int Pat, 008753 A1, 2006.
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Acknowledgements
DNK and DK thank CSIR, New Delhi, India for a Senior
Research fellowship and Research Associateship, respectively.
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