New synthetic route to (1s)-4,5-dimethoxy-1-[(methylamino)methyl] benzocyclobutane, a key intermediate of ivabradine

Article abstract of DOI:10.1080/00397911.2012.686081

An efficient process for the preparation of (1S)-4,5-dimethoxy-1- [(methylamino)methyl] benzocyclobutane (S)-3 as ivabradine intermediate, which was obtained in 56% yield, is described. The salient feature of this process is the racemization of the undesired (1R)-4,5-dimethoxy-1,2- dihydrocyclobutabenzene-1-carboxylic acid (R)-12, and the overall yield of (S)-12 was improved to 70% by three resolutions of the racemized acid with R-(α)-phenylethanamine. The reduction of amide (S)-13 was achieved with NaBH4-I2 in refluxing tetrahydrofuran, giving the corresponding amine (S)-3 in 90% yield. The improved synthetic route described herein is cost-efficient, environmentally friendly and feasibile for scale-up production.

Full text of DOI:10.1080/00397911.2012.686081

This article was downloaded by: [Moskow State Univ Bibliote]
On: 29 December 2013, At: 08:08
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
New Synthetic Route to (1S)-4,5-
Dimethoxy-1-[(methylamino)methyl]
Benzocyclobutane, a Key Intermediate
of Ivabradine
Xin Liu a , Yu Liu a b , Huili He a , Zhan Cai a & Yushe Yang a
a State Key Laboratory of Drug Research , Shanghai Institute of
Materia Medica, Chinese Academy of Sciences , Shanghai , P. R.
China
b Novel Technology Center of Pharmaceutical Chemistry , Shanghai
Institute of Pharmaceutical Industry, Shanghai Engineering, Research
Center of Pharmaceutical Process , Shanghai , P. R. China
Published online: 27 Dec 2013.
To cite this article: Xin Liu , Yu Liu , Huili He , Zhan Cai & Yushe Yang (2014) New Synthetic Route to
(1S)-4,5-Dimethoxy-1-[(methylamino)methyl] Benzocyclobutane, a Key Intermediate of Ivabradine,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:4, 451-456, DOI: 10.1080/00397911.2012.686081
To link to this article: http://dx.doi.org/10.1080/00397911.2012.686081
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 44: 451–456, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.686081
NEW SYNTHETIC ROUTE TO (1S)-4,5-DIMETHOXY-1-
[(METHYLAMINO)METHYL] BENZOCYCLOBUTANE,
A KEY INTERMEDIATE OF IVABRADINE
Xin Liu,1 Yu Liu,1,2 Huili He,1 Zhan Cai,1 and Yushe Yang1
1State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, Shanghai, P. R. China
2Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute
of Pharmaceutical Industry, Shanghai Engineering, Research Center of
Pharmaceutical Process, Shanghai, P. R. China
GRAPHICAL ABSTRACT
Abstract An efficient process for the preparation of (1S)-4,5-dimethoxy-1-[(methylamino)
methyl] benzocyclobutane (S)-3 as ivabradine intermediate, which was obtained in 56%
yield, is described. The salient feature of this process is the racemization of the undesired
(1R)-4,5–dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (R)-12, and the
overall yield of (S)-12 was improved to 70% by three resolutions of the racemized acid with
R-(a)-phenylethanamine. The reduction of amide (S)-13 was achieved with NaBH4-I2 in
refluxing tetrahydrofuran, giving the corresponding amine (S)-3 in 90% yield. The
improved synthetic route described herein is cost-efficient, environmentally friendly and
feasibile for scale-up production.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Benzocyclobutane; ivabradine; reduction; resolution
Received October 9, 2011.
Xin Liu and Yu Liu contributed equally to this work.
Address correspondence to Yushe Yang, State Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. E-mail: ysyang@
simm.ac.cn
451

452
X. LIU ET AL.
INTRODUCTION
Ivabradine (3) is the first selective sinus node If channel inhibitor for the treatment
of stable angina pectoris, which was approved by the European Medicines Agency in
2005. It is specific for the If current, lowering heart rate at concentrations that do not
affect other cardiac ionic currents.[1–3] A commonly employed synthetic route to 3
(Scheme 1) involves the condensation of (1S)-N-[(4,5-dimethoxybenzocyclobut-1-
=
yl)methyl]-N-(methyl)amine (2) with compound 1 (R CHO, Cl or I) to afford the desired
product,[4–8] thus making amine 2 an important intermediate for the preparation of
ivabradine.
Two methods have been described for the preparation of 2. The first one,
reported in a patent,[9] started from (R,S)-1-cyano-4,5-dimethoxybenzocyclobutane
4 followed by three steps, namely reduction of the cyano group to 5, acylation of
5 to 6, and reduction of 6 with LiAlH4.
In the second method (Scheme 3),[10,11] amine 5 prepared by reduction of 4, was
resolved with N-acetyl-L-glutamic acid to produce the optical isomer 8, followed by
acylation of 8 with ethyl chloroformate to get 9 and reduction of 9 with LiAlH4 to
afford 2. Although the yield of the resolution step was improved to 40%, the mother
liquor from the resolution could not be racemized and recycled for use. Furthermore,
an excess of LiAlH4 (2–4 equiv) was required in reduction of 9, which would leads to
a large amount of waste in industrial production.
Scheme 1. Commonly employed synthetic route to ivabridine 3 to afford the racemate methylamine 7. The
resolution of 7 with d-camphorsulfonic acid gave 2 in only 5% yield (Scheme 2).
Scheme 2. (a) BH3 complexed with THF, 90%; (b) ethyl chloroformate, Et3N, DCM, room temperature,
80%; (c) LiAlH4, THF, reflux, 92%; and (d) d-camphorsulfonic acid, 5%.

ROUTE TO IVABRADINE INTERMEDIATE
453
Scheme 3. (a) H2=Raney Ni, THF, 60 ꢂC, 30 bar; (b) (i) N-acetyl-L-glutamic acid, EtOH; (ii) NaOH aq.,
40%; (c) ethyl chloroformate, Et3N, CH2Cl2, 80%; and (d) LiAlH4, THF, reflux, 93%.
To solve the problems mentioned and improve the resolution yield of amine 5,
we tried to racemize and recycle the ‘‘waste’’ isomer after resolution. Several bases,
such as sodium ethoxide, potassium tert-butoxide, and n-butyllithium, were screened
for racemization; however, no racemized amine 5 was obtained. Considering the fact
that the commercially available cyano compound 4[12] can be easily hydrolyzed to the
carboxylic acid 10, which can be treated with chiral resolution reagents to afford (ꢀ)
isomer 11, we decided to develop a new route based on carboxylic acid 10. To opti-
mize the racemization condition, sodium ethoxide, potassium tert-butoxide, and
n-butyllithium were attempted.[13–15] To our delight, racemization of (þ) isomer of
12 occurred smoothly by heating the mother liquor in the presence of sodium ethox-
ide, so the overall resolution yield of 11 is thus improved to 73%.
Thus our new procedure, illustrated in Scheme 4, proceeds via the facile
hydrolysis of 4 with KOH in ethanol to give the carboxylic acid 10. Dissolution of
racemic 10 and R-(a)-phenyl ethylamine in hot i-PrOH followed by crystallization
Scheme 4. (a) KOH, EtOH, reflux, 95%; (b) (i) R-(a)-phenylethanamine, i-PrOH; (ii) 10% HCl, overall
yield 70%; (c) ethyl chloroformate, CH3NH2 ꢁ HCl, EtOH, THF, 93%; and (d) NaBH4=I2, THF, 90%.

454
X. LIU ET AL.
at room temperature gave the salt of (ꢀ) isomer. The mother liquor thus formed was
treated with sodium ethoxide for racemizatiom. The optical isomer 11 could be
obtained in 73% overall yield through two resolutions. Compounds 11 reacted with
ethyl chlorformate and methyl amine hydrochloride to afford 13 in 93% yield.
NaBH4-I2 was used to replace LiAlH4 in the reduction of 13 to give 2 in 90% yield.[16]
In conclusion, we have developed an efficient process to key intermediate 2.
The most excited step of this route is the racemization of 12, which leads a good
overall yield with simple workup and is cost efficient, environmentally friendly,
and suitable for scale-up production.
EXPERIMENTAL
All reagents and solvents were commercially available and used without further
purification unless otherwise stated. 1H NMR spectra were recorded on a Bruker 300
NMR spectrometer in CDCl3 with tetramethylsilane (TMS) as an internal standard.
Electron impact–mass spectrometry (EI-MS) spectra were obtained on a Finnigan
MAT 95 mass spectrometer. Elemental analyses were obtained using a Vario EL
spectrometer. High-performance liquid chromatographic (HPLC) analysis and reac-
tion monitoring were performed on Shimadzu SPD10AV liquid chromatograph
equipped with a Chiralcel OD-H 250 mm ꢃ 4.6 mm 5-mM column; flow rate
0.5 mL=min, wavelength 230 nm, temperature 25 ꢂC. The mobile phase for the HPLC
analysis of 2 was done with hexane = isopropanol = trifluoroacetic acid (85:15:0.1).
(R,S)-4,5-Dimethoxy-1,2-dihydrocyclobutabenzene-1-
carboxylic Acid (10)
A mixture of 4 (50.0 g, 0.26 mol) and KOH (250.0 g, 4.5 mol) in ethanol
(1000 mL) was refluxed in a round-bottomed flask for 5 h. The reaction mixture
was cooled to room temperature and then water (2500 mL) was added slowly into
reaction flask until it became clear. Ethanol was evaporated off in vacuo, and the
residue was acidified to pH 3 with concentrated HCl and extracted with ethyl acetate
(500 mL ꢃ 3). The combined extract was dried over anhydrous Na2SO4 and then
concentrated in vacuo. The residue was washed with ethyl acetate (200 mL) to yield
1
a white solid of 10 (52.0 g, 95%), mp 137–138 ꢂC. H NMR (300 MHz, CDCl3): d
3.40 (m, 2H), 3.85 (s, 6H), 4.25 (t, 1H, J ¼ 3.8 Hz), 6.71 (s, 1H), 6.77 (s, 1H). 13C
NMR (100 MHz, CDCl3): 32.4, 46.2, 58.3, 114.5, 115.6, 127.7, 139.8, 148.5, 149.6,
178.6. EI-MS m=z 208 (M). Anal. calcd. for C11H12O4: C, 63.45; H, 5.81. Found:
C, 63.65; H, 6.01.
(S)-4,5-Dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic
Acid (11)
R-(a)-Phenylethanamine (28.8 g, 0.24 mol) was added dropwise in 30 min into
solution of 10 (50.0 g, 0.24 mol) in isopropanol (500 mL). The mixture was refluxed
for 1 h and allowed to crystallize at room temperature overnight. The white solid was
collected and recrystallized from isopropanol three times, dissolved in water
(125 mL), and acidified with 10% aqueous HCl to pH 2–3. The aqueous solution

ROUTE TO IVABRADINE INTERMEDIATE
455
was extracted with ethyl acetate (125 mL ꢃ 3). The ethyl acetate extracts were com-
bined, dried over anhydrous Na2SO4, and concentrated to afford 11 of 19.5 g (40%
20
yield) as a colorless solid, mp 136–137 ꢂC, [a]D ¼ ꢀ61 (c 0.5, MeOH), ee ¼ 99.4%.
The mother liquor from the crystallization was collected and concentrated. The
residue was dissolved in water (125 mL) and acidified with 10% aqueous HCl to pH
2–3. The aqueous solution was extracted with ethyl acetate (125 mL ꢃ 3). The ethyl
acetate layers were combined, dried over anhydrous Na2SO4, and concentrated to
afford a solid (32.5 g). Sodium ethoxide (32.6 g, 0.48 mol) was added to an ethanol
solution (250 mL) of the solid, and the mixture was stirred under refluxing for 8 h.
After the reaction mixture was cooled to room temperature, water (250 mL) was
added. The solvent was adjusted to pH 1–2 with 10% aqueous HCl. The aqueous sol-
ution was extracted with ethyl acetate (250 mL ꢃ 3), and the ethyl acetate layers were
combined, dried over anhydrous Na2SO4, and concentrated to afford 32.5 g of the
racemic acid 10. The racemic acid 10 obtained from stage II was resolved following
the workup described previously to give 11.4 g of 11 as a colorless solid (yield 22.8%,
20
mp 135–137 ꢂC, [a]D ¼ ꢀ60 (c 0.5, MeOH), ee ¼ 98.9%). Then the the mother
liquor was also recycled as the procedure described previously and was resolved to
give another 7.5 g of 11 as a colorless solid (yield 15.4%, mp 136–138 ꢂC,
20
[a]D ¼ ꢀ62 (c 0.5, MeOH), ee ¼ 98.8%). Finally an overall 38.4 g (76.8% yield) of
20
11 was obtained (ee ¼ 98.9%). Mp 136–138 ꢂC, retention time: 9.28 min, [a]D
¼
1
ꢀ60 (c 0.5, MeOH). H NMR (300 MHz, CDCl3): d 3.40 (m, 2H), 3.85 (s, 6H),
4.25 (t, 1H, J ¼ 3.8 Hz), 6.71 (s, 1H), 6.77 (s, 1H). EI-MS m=z 208 (M). Anal. calcd.
for C11H12O4: C, 63.45; H, 5.81. Found: C, 63.50; H, 6.08.
(S)-(4,5-Dimethoxybenzocyclobut-1-yl)-N-(methyl)formamide (13)
Et3N (9.6 g, 0.10 mol) was added to the solution of compound (S)-11 (20.0 g,
0.10 mol) in THF (200 mL) in flask I, ethyl chloroformate (10.4 g, 0.10 mol) was
added dropwise, and the resulting mixture was stirred for 20 min at room tempera-
ture. Another portion of Et3N (29.3 g, 0.29 mol) was added to a solution of methyl
amine hydrochloride (20.0 g, 0.29 mol) in THF (120 mL)=H2O (80 mL) in flask II and
stirred for 10 min. The mixture in flask II was dropped into the solution in flask I and
reacted for another 20 min. Water (300 mL) was added to the residue after THF was
removed in vacuo, and the aqueous solution was extracted with ethyl acetate
(200 mL ꢃ 3). The extract was washed with 1 N aqueous HCl, aqueous NaHCO3,
and brine successively, dried over Na2SO4, and then concentrated to afford (S)-13
20
(20.0 g, 93%, ee ¼ 98.0%). Mp 144–146 ꢂC, retention time: 16.67 min, [a]D ¼ ꢀ
1
31.2 (c 0.5, MeOH). H NMR (300 MHz, CDCl3): d 2.82 (d, 3H, J ¼ 4.8 Hz), 3.15
(d, 1H, J ¼ 13.6 Hz), 3.50 (dd, 1H, J ¼ 13.6 Hz, 5.5 Hz), 3.87 (d, 6H, J ¼ 3.3 Hz),
4.10 (m, 1H), 6.75 (d, 2H, J ¼ 2.9 Hz). EI-MS m=z 221 (M). Anal. calcd. for
C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 64.95; H, 6.71; N, 6.25.
(1S)-4,5-Dimethoxy-1-[(methylamino)methyl]benzocyclobutane (2)
A solution of iodine (46.0 g, 0.18 mol) in THF (200 mL) was added dropwise to
a stirred suspension of NaBH4 (15.0 g, 0.40 mol) and 13 (30.0 g, 0.14 mol) in THF
(300 mL) at 0–5 ꢂC. The resulting mixture was stirred under reflux for 24 h before

456
X. LIU ET AL.
it was cooled to 0 ꢂC, and then carefully quenched by addition of 1 N aqueous HCl
500 mL. After neutralization with 1 N NaOH, the mixture was concentrated. H2O
(300 mL) was added to the residue, and the aqueous solution was extracted with
ethyl acetate (200 mL ꢃ 3). The organic layer was combined and dried over Na2SO4,
and the product 2 was obtained as a white solid by removal of the solvent without
20
further purification (25.6 g, 90%, ee ¼ 99.1%). Retention time: 18.14 min, [a]D
¼
1
ꢀ27.2 (c 0.5, CHCl3). H NMR (300 MHz, CDCl3): d 2.50 (s, 3H), 2.76 (d, 1H,
J ¼ 13.4 Hz), 2.88 (m, 2H), 3.25 (dd, 1H, J ¼ 13.4 Hz, 4.9 Hz), 3.58 (m, 1H), 3.85
(s, 6H), 6.71 (d, 2H, J ¼ 5.6 Hz). EI-MS m=z 207 (M). Anal. calcd. for
C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.45; H, 8.25; N, 6.65.
ACKNOWLEDGMENT
We are grateful to Nanjing C&O Pharmaceutical Technology (Holdings)
Limited for the support of this research.
REFERENCES
1. Thollon, C.; Cambarrat, C.; Vian, J.; Prost, J. F.; Peglion, J. L.; Vilaine, J. P. Br. J. Pharmacol.
1994, 112, 37.
2. Sulfi, S.; Timmis, A. D. Int. J. Clin. Pract. 2006, 60, 222.
3. Le Grand, B.; Pignier, C.; Letienne, R.; Cuisiat, F.; Rolland, F.; Nlas, A.;
Vacher, B. J. Med. Chem. 2008, 51, 3856.
4. Lerestif, J. M.; Lecouve, J. P.; Souvie, J. C.; Brigot, D. US Patent 2005228178, 2005;
Chem. Abstr. 2005, 143, 367292.
5. Dwivedi, S. D.; Kumar, R.; Patel, S. T.; Shah, A. P. C. WO Patent 2008065681, 2008;
Chem. Abstr. 2008, 49, 32210.
6. Luo, J. Z.; Yan, Y. M.; Tu, Y. R. WO Patent 2008125006, 2008; Chem. Abstr. 2008, 149,
471352.
7. Singh, S. P.; Singh, G.; Wadhwa, L. WO Patent 2008146308, 2008; Chem. Abstr. 2008,
150, 5614.
8. Lerestif, J. M.; Gonzalez-Blanco, I.; Lecouve, J. P.; Brigot, D. EP Patent 1598333, 2005;
Chem. Abstr. 2005, 144, 6568.
9. Peglion, J. L.; Vian, J.; Vilaine, J. P.; Villeneuve, N.; Janiak, P.; Bidouard, J. P. EP Patent
534859, 1993; Chem. Abstr. 1993, 119, 117147.
10. Bose, P.; Siripalli, U. B. R.; Kandadai, A. S. WO Patent 2010072409, 2010; Chem. Abstr.
2010, 153, 116027.
11. Sun, P. Y.; Chen, Y. J.; Yu, G. L. WO Patent 2009062377, 2009; Chem. Abstr. 2009, 150,
539428.
12. Zhao, S. Y.; Liang, H. Y.; Shao, Z. Y.; Chen, R. J. Chem. Res. 2009, 7, 420.
13. Jahangir Fisher, L. E.; Clark, R. D.; Muchowski, J. M. J. Org. Chem. 1989, 54, 2992.
14. Matsuya, Y.; Imamura, Y.; Miyahara, T.; Ochiai, H., Nemoto, H. Eur. J. Org. Chem.
2008, 8, 1426.
15. Chavan, A. B.; Gundecha, S. S.; Kadam, P. N.; Maikap, G. C.; Gurjar, M. K. Org.
Process Res. Dev. 2010, 14, 1481.
16. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993, 58, 3568.