Pyrophosphoryl Chloride: A Green, Reductive Chlorination Reagent Utilized in the One-Pot Synthesis of Quetiapine

Article abstract of DOI:10.1080/10426507.2014.965813

A one-pot synthesis of quetiapine from dibenzo[b,f][1,4]thiazepin-11(10H)-one and 4-hydroxyethoxy ethyl piperazine (HEEP) in toluene using N,N-dimethylaniline (DMA) and pyrophosphoryl chloride (P₂O₃Cl₄) as a green reductive chlorination agent is described. A significant shortening of reaction times, a nearly quantitative yield, and high atom economy in the product were observed. The simplicity of the reaction, ease of execution, simple workup, and good yields, together with the use of easily accessible starting materials and an environmentally friendly procedure, are hallmarks of this process.

Full text of DOI:10.1080/10426507.2014.965813

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Phosphorus, Sulfur, and Silicon and the Related
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Pyrophosphoryl Chloride: A Green, Reductive
Chlorination Reagent Utilized in the One-Pot Synthesis
of Quetiapine
N. O. Mahmoodia, M. Pourhossein Parizada & K. Hosseinia
a Department of Chemistry, Faculty of Science, University of Guilan, Rasht, Iran, or
Accepted author version posted online: 21 Jan 2015.
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To cite this article: N. O. Mahmoodi, M. Pourhossein Parizad & K. Hosseini (2015): Pyrophosphoryl Chloride: A Green,
Reductive Chlorination Reagent Utilized in the One-Pot Synthesis of Quetiapine, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2014.965813
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Pyrophosphoryl Chloride: A Green, Reductive Chlorination
Reagent Utilized in the One-Pot Synthesis of Quetiapine
N. O. Mahmoodi, M. Pourhossein Parizad, K. Hosseini
Department of Chemistry, Faculty of Science, University of Guilan, Rasht, Iran
Email: mahmoodi@guilan.ac.ir or nosmahmoodi@gmail,com
Abstract A one-pot synthesis of quetiapine from dibenzo[b,f][1,4]thiazepin-11(10H)-one and 4-
hydroxyethoxy ethyl piperazine (HEEP) in toluene using N,N-dimethylaniline (DMA) and
pyrophosphoryl chloride (P2O3Cl4) as a green reductive chlorination agent is described . A
significant shortening of reaction times, a nearly quantitative yield, and high atom economy in
the product were observed. The simplicity of the reaction, ease of execution, simple workup, and
good yields, together with the use of easily accessible starting materials and an environmentally
friendly procedure, are hallmarks of this process.
O
H
N
O
P
O
P
O
OH
N
Cl
O
Cl
Cl
S
Cl
N
N
PhCH3
DMA
+
26 h, reflux
O
S
N
OH
HN
Yield = 99%
Keywords One-pot synthesis; Quetiapine, Pyrophosphoryl chloride; Antipsychotic; 4-
Hydroxyethoxy ethyl piperazine (HEEP)
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INTRODUCTION
Quetiapinefumarate,
a
2:1
salt
of
2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-
piperazinyl)ethoxy]ethanol with fumaric acid is one of the most widely used antipsychotic drugs.
The salt is a white crystalline powder that is moderately soluble in water. Quetiapine in tablet
form contains either 50,100, 200, or 300 mg of the active substance.
Quetiapine acts as an antagonist for multiple neurotransmitter receptor sites, including serotonin
(5HT1A; 5HT2A), dopamine (D1; D2), histamine (H1), and adrenaline (Alpha1; Alpha2) in the
brain, as an antipsychotic agent and as an antischizophrenic. Quetiapine has a lower affinity for
D2 receptors than dopamine, leading to an alternating D2 blockade, and could contribute to the
impressive tolerability profile of the substance. Quetiapine may act on depression through its
antagonism of 5-HT2A receptors, and on mania through its antagonism of D2 receptors. The
compound was also found to be useful in the treatment of acute bipolar mania, either as a
monotherapy or in combination with other mood stabilizers, and was useful as a monotherapy in
acute bipolar depression.1-14The initial synthesis of quetiapine was disclosed by Warawa and
Migler in a patent issued to ICI (now AstraZeneca) in 1987.15
Several other synthetic routes to quetiapine have been reported. Recently a company in Budapest
reported an alternative synthesis of quetiapine designed to provide a more economical process.15-
17
As part of our studies towards the development of new routes to the synthesis of medicinal
compounds 18–25, we wish to report a facile and efficient route for the one-pot synthesis of
quetiapine.
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RESULTS AND DISCUSSION
As far as we can tell, the one-pot synthesis of quetiapine in the presence of N,N-dimethylaniline
(DMA) 3 and pyrophosphoryl chloride (P2O3Cl4) 4 as a reductive chlorination reagent has not
been reported.26 Pyrophosphoryl chloride 4 previously was used in Vilsmeier formylation and
glycolation reactions of nucleophilic aromatic compounds. According to Figure 2, one equivalent
of pyrophosphorylchloride 4 can convert two equivalents of 2 in to two equivalents of the
chlorinated compound 5 via the in-situ formed active chlorinating agent 6. Thus, in comparison
to the use of other commercially available chlorinating reagents (e.g. POCl3), the reduced
amounts of 4 needed will result in a smaller volume of HCl gas being generated.27 The reaction
of phosphoric oxide with phosphorus pentachloride, the latter formed in situ from phosphorus
and chlorine, provides an excellent route to pyrophosphoryl chloride.
Initially, we examined different bases and solvents to optimize the reaction conditions for
preparation of 1 (Figure 3). The results are listed in Table 1. The reaction required more time in
the absence of catalyst, generating a low yield of product. Without a catalyst the reaction was
incomplete even after 48h (Table 1, entry 1).
In comparison to other bases such as pyridine, piperidine and triethylamine (TEA), N,N-
dimethylaniline (DMA) gave a good yield of product (Table 1, entry 5). Generally, the reaction
was incomplete in the presence of inorganic bases such as NaOH, K2CO3 and t-BuOK. After
optimization, intermediate 5 could be prepared in 72% yield from commercially available
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starting materials 2 and 4 by refluxing in toluene for 4.5 h in the presence of DMA . The same
reaction run in xylene required 7 h reaction time and gave a lower yield (68%) of 5.
Optimizing this reaction played a keyrole in the design of a one-pot synthesis of quetiapine 1 via
a multicomponent reaction of compounds 2, 3 and 4 in toluene in the presence of DMA (Fig. 2
& Fig. 3) which proceeds in 99% yield. Other attempts to prepare 1 using the isolated
intermediate 3 in a two-step process gave only a72% yield of 1. Thus the one-pot conversion
gave a 27% improvement in the yield of 1 when compared to the two-step process.
A nearly quantitative yield, a one-step process with a simple workup, ease of execution (e.g., no
isolation of unstable iminochloride 5), together with the use of the environmentally friendly
reagent pyrophosphoryl chloride (P2O3Cl4) 4, are hallmarks of this process.
Previously a two-step synthesis of 1 using NaOH and POCl3 in xylene has been reported to give
a 68% yield.15 The one-pot process described in this work could be easily scaled up for the
synthesis of 16.6 g (43.3 mmol) of 1: 2 (10 g, 44 mmol, 1 equivalent), 4 (7 g, 4.1 mL, 27 mmol,
0.63 equivalent), and DMA (6g, 49 mmol, 1.11 equivalent ) were combined in toluene (60 mL),
o
and the mixture was allowed to reflux for 4.5 h at 110 C. To the resulting solution containing
intermediate 5 was added 3 (29.2 mL, 31 g, 178 mmol, 4 equivalent), and the mixture was
o
allowed to reflux for an additional 21 h at 105 C. Conversion to 1 resulted via the nucleophilic
aromatic iminochloride substitution reaction of 3 and 5 in the presence of DMA, as shown in Fig.
2 & Fig. 3. The resulting quetiapine free base was isolated and reacted with fumaric acid in a
mixture of MeOH and water (pH of 4.5 to 5) to form the corresponding hemifumarate salt. IR,
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1H NMR, 13C NMR and mass spectroscopy confirmed the proposed structure for the synthesized
quetiapine salt.
EXPERIMENTAL
Products were characterized by comparison of their physical data with those of standard samples.
IR spectra were obtained using a Shimadzo 8400-s instrument. NMR data were recorded in
DMSO and CDCl3 with a Bruker DRX500 spectrometer. 1H and 13C chemical shifts are reported
in ppm (δ) using TMS as an internal reference. Mass spectra were recorded using an ESI method
with a Termo-LCQ Deca mass spectrometer. Sample 1H and 13C NMR spectra for quetiapine
base and quetiapine hemifumarate are presented in the Supplemental Materials (Figures S 1 – S
4)
Preparation of 11-chloro-dibenzo[b,f][1,4]thiazepine(5)
To a 500 mL three-neck round-bottom flask equipped with a reflux condenser were added
dibenzo[b,f][1,4]thiazepin-11(10H)-one 2 (10 g, 44 mmol), dry toluene 60 mL, pyrophosphoryl
chloride 4 (4.1 mL, 7g, 27 mmol) and N,N-dimethylaniline (6g, 49 mmol, 1.11 eq). The resulting
white suspension was mixed at 20-25°C for 30 minutes. The reaction mixture was then refluxed
at 110-112°C for 4.5 h. At that point the reaction was complete and all starting material had been
consumed (yield 72%). The flask temperature was reduced to 25°C slowly.
Preparation of 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol (1)
To the same flask containing the iminochloride intermediate 5 was added 4-hydroxyethoxy ethyl
piperazine 3 (29.2 mL,31 g, 178 mmol, 4 equivalent) at 25°C. The reaction mixture was refluxed
°
for 21 hours at 105-107 C. After completion of the reaction the mixture was allowed to cool to
room temperature. 100 mL of 5% NaOH solution was added to the reaction mixture over 15
5
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minutes. After 30 min stirring, the organic and aqueous phases were separated. The organic
phase was washed with 200 mL of water, the layers separated, and 70 mL of water was added to
the organic phase. The product was converted to its water-soluble HCl salt by adding 32% HCl
until the pH was between 2 and 3. The aqueous phase was separated and stirred, 80 mL of
CH2Cl2 added, followed by 25% aqueous NaOH solution until the pH was adjusted to 10-11. The
CH2Cl2 phase was separated, dried with 5 g of Na2SO4, and the CH2Cl2 distilled at atmospheric
pressure. Quetiapine free base was obtained (16.6 g, 43 mmol, 99% yield).
Preparation of Quetiapine hemifumarate salt
To a 250 mL round-bottom flask containing quetiapine free base (16.6 g, 43 mmol) were added
MeOH (70 mL) and activated carbon (1g) for decolorization. The resulting suspension was
heated at reflux for 30 min, then was filtered and allowed to cool to 40°C. Once at this
temperature solid fumaric acid was added slowly to the solution until the pH was adjusted to 4-5.
Quetiapine hemifumarate precipitated after cooling the reaction mixture to 0-5°C. The resulting
solid was filtered and dried to yield (16.5 g, 98%) of quetiapine hemifumarat eas a white
powder, mp = 173oC.
Acknowledgments
The partial support of this research by the Research Committee of the University of Guilan is
gratefully acknowledged. We also acknowledge the useful suggestions made by Douglas Fry of
SAFC, USA
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Table 1 Optimization of the catalyst
Entry
Catalyst
Time
(h)
48
36
28
36
25.5
48
Yield (%)b
1
2
3
4
5
6
None
Pyridine
Piperidine
TEA
21
54
70
65
99
DMA
Inorganic basea
Incomplete
a) NaOH, K2CO3 or t-BuOK; b) isolated yield
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Figure 1: Structure formula proposed for quetiapinehemifumarate
COOH
N
S
OH
N
N
O
COOH
2
Figure 2 Synthesis of advanced intermediate 5
O
P
O
P
H
N
Cl
O
H
N
O
P
N
Cl
O
4
Cl
Cl
Cl
O
6
Cl
+
Cl
DMA
S
5
S
4.5h , reflux
PhCH3
2
6
2
5
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Figure 3 One-Pot Synthesis of Quetiapine 1
O
H
N
O
P
O
P
O
OH
N
Cl
O
Cl
Cl
S
Cl
N
N
PhCH3
DMA
4
2
+
26 h, reflux
O
S
N
OH
HN
1
3
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