Isolation, synthesis and structure confirmation of the impurity in crude roflumilast product

Article abstract of DOI:10.1007/s11164-012-0823-3

An impurity was isolated from crude synthesized roflumilast and characterized by ¹H NMR, ¹³C NMR, and HR-MS, which confirmed the structure as N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-3- hydroxybenzamide. To further verify the str

Full text of DOI:10.1007/s11164-012-0823-3

Res Chem Intermed
DOI 10.1007/s11164-012-0823-3
Isolation, synthesis and structure confirmation
of the impurity in crude roflumilast product
•
•
•
•
Yan Lin Peijun Huang Haofei Qi Ligong Chen
Donghua Wang
Received: 6 August 2012 / Accepted: 14 September 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract An impurity was isolated from crude synthesized roflumilast and char-
acterized by 1H NMR, 13C NMR, and HR-MS, which confirmed the structure as N-
(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-3-hydroxybenzamide. To further verify
the structure, this compound was synthesized from 4-difluoromethoxy-3-hydro-
1
xybenzaldehyde. Comparison of the H NMR, 13C NMR, HR-MS, and the HPLC
spectrum of the impurity and the authentic sample indicated that this impurity was
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-3-hydroxybenzamide. This demon-
strated the significance of monitoring the reaction process of roflumilast.
Keywords Impurity Á PDE-4 inhibitor Á Roflumilast Á Structure confirmation Á
Synthesis
Introduction
Roflumilast, one of the second generation PDE-4 inhibitors, was developed by
Altana AG and first put into the market in Europe for the treatment of COPD in July,
Electronic supplementary material The online version of this article
(doi:10.1007/s11164-012-0823-3) contains supplementary material, which is available to authorized
users.
Y. Lin Á H. Qi Á L. Chen (&)
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072,
People’s Republic of China
e-mail: lgchen@tju.edu.cn
P. Huang
Tianjin Bohai Chemical Industry Group Co. Ltd, Tianjin 300040, People’s Republic of China
D. Wang
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072,
People’s Republic of China
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Y. Lin et al.
2010 [1]. It has displayed high efficacy and a good safety profile and is currently
widely used for the treatment of COPD, athsma, and other inflammatory diseases
[2–4].
The synthetic methods of roflumilast have been intensively studied [5–7], but
there are only a few reports related to impurities in roflumilast. Cook et al. [8]
described the process and impurities in the synthesis of 3-cyclopentyloxy-N-(3,5-
dichloropyrid-4-yl)-4-methoxybenzamide (INN: piclamilast). This paved the way
to the study of the impurities in roflumilast synthesis. It was reported that, when
the synthetic method of piclamilast is applied analogously to roflumilast, it leads
to the formation of more than 3 % N-(3,5-dichloropyrid-4-yl)-3-cyclopropyl-
methoxy-4-hydroxybenzamide [9]. In addition, this compound was also detected
when sodium hydroxide was employed in the synthesis of roflumilast [10]. In this
paper, we present another impurity in the synthesis of roflumilast, and the
characterization of its structure shows it to be N-(3,5-dichloropyrid-4-yl)-4-
difluoromethoxy-3-hydroxybenzamide. This compound was then synthesized to
make comparisons. The comparison of the impurity and the authentic compound
indicated that this compound was N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-3-
hydroxybenzamide.
Results and discussion
Generally, roflumilast is synthesized via O-alkylation, oxidation, chlorination of the
corresponding carboxylic acid and N-acylation reaction of 3,5-dichloropyridine-4-
amine. And it is obvious that the N-acylation reaction is the crucial step in the
synthesis due to the low nucleophilic ability of 3,5-dichloropyridine-4-amine.
Several alkalis have been employed to activate the amine group, including
potassium tert-butoxide, sodium hydride, and sodium hydroxide [9–11]. So ,we
followed the general procedure to synthesize roflumilast from 4-difluoromethoxy-3-
hydroxybenzaldehyde and bromomethyl cyclopropane and put effort into the study
of sodium hydride because of its cleanliness and high activity. In the process, a new
impurity was detected and successfully separated from the crude roflumilast
product. It was characterized by 1H NMR, 13C NMR, and HR-MS, which indicated
the chemical structure to be compound 1 in Fig. 1.
To further confirm the impurity structure, we synthesized compound 1 from
4-difluoromethoxy-3-hydroxybenzaldehyde (Fig. 1). The oxidation of aldehyde
has been widely reported to give the corresponding carboxylic acid [8, 12]. As
seen in Fig. 1, the oxidation of compound 2 was achieved by sulfamic acid and
sodium chlorite in acetonitrile and yielded compound 3. It was then chloridized by
SOCl2 to give compound 4. Just as in the synthesis of roflumilast, it is difficult to
carry out the obvious amidation reactions of compounds 4 and 5. This was
probably a consequence of the steric congestion around the amino group and the
electron attractive effect of the aromatic pyridine ring. Due to the high activity of
sodium hydride in the synthesis of roflumilast, it was still employed to make the
amine more nucleophilic in the reaction of synthesizing compound 1. An amount
of 1 M Eq of sodium hydride seemed to be enough. Considering the hydroxyl
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Impurity in crude roflumilast product
O
O
O
HO
HO
O
HO
O
H
NaClO2,H2NSO3H
Acetonitrile, H2O
OH
Cl
SOCl2,DMF
Toluene
O
F
F
F
F
F
F
2
4
4
3
Cl
O
O
N
NH2
HO
O
HO
O
NaH
Acetonitrile
Cl
N
H
Cl
Cl
+
Cl
N
F
F
F
F
5
1
Fig. 1 Synthesis of N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-3-hydroxybenzamide
group in compound 5, it consumed another mole of sodium hydride. Hence, it was
necessary to use more than 2 Eq of sodium hydride to achieve compound 1. Thus,
the amine 5 was added to the suspension of the sodium hydride, giving the amino
anion and unreacted sodium hydride. Then, the acid chloride 4 was added slowly
to the suspension to give product 1. Later, the purified compound 1 was
1
characterized by H NMR, 13C NMR, and HR-MS, which showed the identity of
the impurity isolated from crude roflumilast product. In addition, comparison of
the HPLC spectrum between them also confirmed that the impurity was N-(3,5-
dichloropyrid-4-yl)-4-difluoromethoxy-3-hydroxybenzamide. Considering the syn-
thetic method of roflumilast, it was probably that the alkylation reaction of
compound 2 was not processed completely, thus contributing to the formation of
compound 1 after multistep reactions. It can be reduced by the complete
alkylation reaction of the raw material, and showed the great importance of
monitoring the reaction process.
Conclusion
An impurity was separated from the synthesized roflumilast and characterized by 1H
NMR, 13C NMR, and HR-MS, which confirmed the structure as N-(3,5-dichloro-
pyrid-4-yl)-4-difluoromethoxy-3-hydroxybenzamide. To further verify the impurity
structure, N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-3-hydroxybenzamide was
synthesized from 4-difluoromethoxy-3-hydroxybenzaldehyde via oxidation, chlori-
nation, and amidation reaction. Comparisons between the impurity and the authentic
compound confirmed that the impurity was indeed N-(3,5-dichloropyrid-4-yl)-4-
difluoromethoxy-3-hydroxybenzamide. This could have significance for monitoring
the industrial production process of roflumilast.
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Y. Lin et al.
Experimental
Reagents and solvents were obtained from commercial suppliers. All reactions
were monitored by thin layer chromatography using commercial silica gel plates.
1
The purity of products was detected by HPLC on Agilent 1,100 series. H NMR
and 13C NMR spectra were recorded on Varian Inova-400, Bruker AV400 NMR,
and Bruker avance III 600. HR-MS was recorded on MicroOTOF-Q II.
Melting points were observed on a YRT-3 Melting Point Tester which was
uncorrected.
The crude synthesized roflumilast was recrystallized in methanol/water = 90/10
(v/v). The filtrates were combined and concentrated. The residue was separated by
silica gel column (petroleum ether/ethyl acetate = 3/1, V/V) to afford the impurity.
1H NMR (CD3OD, 400 MHz) d: 8.62 (d, J = 2.8 Hz, 2H of pyridine), 7.56 (s, 1H
of benzene), 7.50–7.48 (m, 1H of benzene), 7.25 (d, J = 8.4 Hz, 1H on benzene),
6.91 (t, J = 74.4 Hz, 1H on CF2H); 13C NMR (CD3OD, 100 MHz) d: 166.02
(C = O), 148.80, 147.92, 142.41 (3C on pyridine), 141.17, 131.28, 130.87, 120.72,
119.16, 116.73 (6C on benzene), 118.81, 116.27, 113.65 (CF2H). HR-MS (ESI),
calcd C13H8Cl2F2N2O3: [M ? H]? m/z: 348.9958, found: 348.9940.
Synthesis of 4-difluoromethoxy-3-hydroxybenzoic acid (3) [12]
Compound 2 (53.16 mmol) was dissolved in 50 mL acetonitrile and added to the
solution of sulfamic acid (74.42 mmol) in 50 mL water. Then, sodium chlorite
(74.42 mmol) in 50 mL water was added slowly at 0–10 °C and the reaction
mixture were stirred at 30 °C for 5 h. Then, the acetonitrile was evaporated and the
mixture was extracted with ethyl acetate. The organic phases were combined, dried,
and concentrated. The residue was purified by silica gel column (petroleum ether/
ethyl acetate = 6/1, V/V) to give a white solid compound 3 5.17 g, 90.4 %.
Mp.164–165 °C; 1H NMR (DMSO-d6, 400 MHz) d: 12.90 (s, 1H on COOH), 10.25
(s, 1H on OH), 7.53 (d, J = 1.2 Hz, 1H on benzene), 7.41–7.39 (m, 1H on benzne),
7.40 (dd, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H on beneze), 7.15 (t, J = 74.4 Hz, 1H on
CF2H); 13C NMR (DMSO-d6, 100 MHz) d: 166.71 (C = O), 148.45, 142.31,
128.78, 120.95, 120.77, 118.03 (6C of benzene), 119.05, 116.48, 113.91 (CF2H).
HR-MS (ESI), calcd C8H6F2O4: [M - H]- m/z: 203.0156, found: 203.0080.
Synthesis of 4-difluoromethoxy-3-hydroxybenzoyl chloride (4) [8, 10]
Compound 3 (4.9 mmol) in 50 mL toluene was heated to reflux until dissolving and
the water was removed by Dean-Stark apparatus. The solution was then cooled to
90 °C, and SOCl2 (7.4 mmol) and several drops of DMF were added. The solution
was heated at reflux for 3.0 h. Then, it was cooled to room temperature and
concentrated to give compound 4 as a yellow oil.
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Impurity in crude roflumilast product
Synthesis of N-(3,5-dichloropyridin-4-yl)-4-difluoromethoxy-3-
hydroxybenzamide (1)
Sodium hydride (12.3 mmol) was slowly added to the mixture of compound 5
(4.9 mmol) in 30 mL anhydrous acetonitrile at 0–5 °C. After 2 h, the chloride 4 in
anhydrous acetonitrile was added and the mixture was stirred at 0–15 °C for 1.5 h.
After the solvent was evaporated, the residue was dissolved in ethyl acetate and
washed successively by 1 mol/L hydrochloric acid and water. The organic phase
was dried over anhydrous magnesium sulfate and concentrated. The residue was
purified by silica gel column (petroleum ether/ethyl acetate = 3/1, V/V) to give a
white solid 0.43 g, 25.2 %. 1H NMR (DMSO-d6, 600 MHz) d: 10.61–10.58 (m, 2H,
OH), 8.75 (s, 2H on pyridine), 7.57 (d, J = 1.8 Hz, 1H on benzene), 7.51 (dd,
J1 = 1.8 Hz, J2 = 8.4 Hz, 1H on benzene), 7.29 (d, J = 8.4 Hz, 1H on benzene),
7.18 (t, J = 74.4 Hz, 1H on CF2H); 13C NMR (DMSO-d6, 150 MHz) d: 164.19
(C = O), 148.59, 148.23, 141.76 (3C on pyridine), 141.26, 130.77, 130.72, 120.83,
119.07, 116.92 (6C on benzene), 118.07, 116.35, 114.64 (CF2H). HR-MS (ESI),
calcd C13H8Cl2F2N2O3: [M - H]- m/z: 346.9802, found: 346.9728.
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