Convenient Synthesis of Memantine Hydrochloride

Full text of DOI:10.1080/00304948.2017.1291004

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: http://www.tandfonline.com/loi/uopp20
Convenient Synthesis of Memantine
Hydrochloride
Elena A. Ivleva & Yuri N. Klimochkin
To cite this article: Elena A. Ivleva & Yuri N. Klimochkin (2017) Convenient Synthesis of
Memantine Hydrochloride, Organic Preparations and Procedures International, 49:2, 155-162
To link to this article: http://dx.doi.org/10.1080/00304948.2017.1291004
Published online: 20 Apr 2017.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=uopp20
Download by: [The UC San Diego Library]
Date: 20 April 2017, At: 13:28

Organic Preparations and Procedures International, 49:155–162, 2017
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2017.1291004
Convenient Synthesis of Memantine Hydrochloride
Elena A. Ivleva and Yuri N. Klimochkin
Department of Organic Chemistry, Samara State Technical University, 244
Molodogvardeiskaya St., 443100 Samara, Russian Federation
Alzheimer’s disease is the most common cause of dementia, affecting more than
48 million people worldwide. It has been predicted that by 2050 this figure will be more
than 130 million.1 Alzheimer’s disease is a neurodegenerative disorder characterized by
a progressive and irreversible loss of neurons in specific brain regions. The disease gradu-
ally affects memory, causes behavior and personality changes, interferes with the individ-
ual’s ability to perform daily activities, followed by complete dementia, and ultimately
leads to death2–3. It is the most common type of dementia among people older than 65,
accounting for about 60–70% of cases, and is associated with various risks including
genetic, epigenetic and lifestyle factors. Among the means available for the treatment of
Alzheimer’s disease, two classes of drugs are most known4–9: acetylcholinesterase inhibi-
tors for mild-to-moderate disease that include rivastigmine, donepezil and galantamine,
and memantine for moderate and severe forms of disease. (Figure 1).
Figure 1 Drugs for the treatment of Alzheimer’s disease.
Received August 30, 2016; in final form November 29, 2016.
Address correspondence to Elena A. Ivleva, Department of Organic Chemistry, Samara State
Technical University, 244 Molodogvardeiskaya St., 443100 Samara, Russian Federation. E-mail:
orgchem@samgtu.ru
155

156
Ivleva and Klimochkin
Memantine is a moderate affinity non-competitive N-methyl-D-aspartate (NMDA)
receptor antagonist,10–15 which preferentially blocks excessive NMDA receptor activity
without disrupting normal activity. Memantine can also be used for the treatment of other
CNS disorders16–19: Parkinson’s disease, epilepsy, stroke, CNS trauma, amyotrophic lat-
eral sclerosis, drug dependence and chronic pain. In 2015, worldwide production of mem-
antine was more than 25 tons, and its sales exceeded $ 3 billion20. Thus, the development
of new and efficient methods for the synthesis of memantine hydrochloride remains an
area of current interest.
Today, there are several approaches to the synthesis of memantine hydrochloride (1)
(Scheme 1)21–37. Most of these methods include preparation and isolation of 1-acet-
amido21–29 or 1-formamido-3,5-dimethyladamantane30–37 via Ritter reaction or by ada-
mantylation of amides in acidic media. Further alkaline21–29 or acidic30–34,36 hydrolysis
of these compounds leads to memantine base. The memantine base is converted into its
hydrochloride salt by treating with anhydrous hydrogen chloride or hydrochloric
acid.21–29,32–35
Scheme 1 Typical pathways for the synthesis of memantine hydrochloride 1.
Compound 1 can be prepared from 1-bromo- (or chloro-) 3,5-dimethyladamantane and
urea in 80% formic acid at 80ꢀC38 or in the absence of solvent at 220ꢀC in a closed ves-
sel39. Hydrolysis then yields crude memantine that is converted to 1 in EtOH-concen-
trated hydrochloric acid38 or by action of dry HCl39.
Memantine hydrochloride can also be prepared by the one-pot amination of 1,3-
dimethyladamantane through the formation of N-(1-adamantyl)urea as the key intermedi-
ate40, which decomposes to the amine in the mixture of nitric acid and acetic acid.41,42
Some other syntheses43–49 of 1 are less suitable for large-scale processing. There are
a number of problems encountered with the conventional processes for preparing 1. The
yields of some steps are low, the reaction time is relatively high.
One-pot syntheses have attracted considerable attention in organic chemistry as they
can produce target products from available starting materials in a single operation avoid-
ing separation and purification of the intermediate chemical compounds to save time and
resources while increasing yields.50,51 Compared to stepwise reactions, one-pot processes
minimize waste since the amounts of solvents, reagents and energy are decreased.
There are not enough one-pot methods for the preparation of 1 from 1,3-dimethylada-
mantane as the starting material. The current methods for the preparation of 1 include the
isolation and purification of 1-formamido- and 1-acetamido-3,5-dimethyladamantane that
lead to low yields. The hydrolysis of 1-acetamido-3,5-dimethyladamantane can’t be car-
ried out under acidic conditions because of formation of 1-chloro- and 1-hydroxy-3,5-
dimethyladamantane derivatives as by-products.52

Convenient Synthesis of Memantine Hydrochloride
157
We now report a new one-pot method for preparation of memantine hydrochloride
(1) starting from 1,3-dimethyladamantane (2) directly. The process of preparing 1 can be
considered as several steps: an activation of the 1,3-dimethyladamantane (2) tertiary C-H
bond through nitroxylation reaction53–62, a Ritter reaction63 with HCN formed from ace-
tone cyanohydrin, hydrolysis of 1-formamido-3,5-dimethyladamantane (5) and conver-
sion of memantine base (6) into its hydrochloride salt (1) (Scheme 2).64 The conditions
highlighted in Scheme 2 are optimized and scaled at 1 kg of 2. The development and the
optimization of each synthesis step will described below.
Scheme 2 Preparation of Memantine Hydrochloride 1.
For nitroxylation of 2 we decided to use fuming nitric acid, because under these conditions
the key intermediate 4 is generated in situ. The nitroxylation of adamantane and other cage
compounds is a well-known reaction that has been described in many papers53–62
.
During the reaction 1-nitroxy-3,5-dimethyladamantane (intermediate 4) and by-products
1-hydroxy-3,5-dimethyladamantane, 1-nitro-3,5-dimethyladamantane and 3,5-dimethyl-1-
adamantylnitrite are formed together. There are further reactions with HCN generated from 3.
It is known that 1-nitro-3,5-dimethyladamantane is converted into 1-nitroxy-3,5-dimethylada-
mantane (intermediate 4) through the formation of the 3,5-dimethyl-1-adamantyl cation in
fuming nitric acid media65. Nitroxylation of 2 was carried out at 20ꢀC within 1 h with effective
cooling of the reaction mixture. Nitric acid was added dropwise over a period of one hour under
vigorous stirring. The addition of fuming nitric acid to 2 is exothermic. A temperature over 30
degrees leads to a decrease of reaction yield. The minimal quantity of fuming nitric acid, which
is necessary for nitroxylation of 2, is 13 eq 56. When using a smaller amount of fuming nitric
acid, the reaction mixture contains unreacted 1,3-dimethyladamantane (2).
Acetone cyanohydrin (3) gives hydrocyanic acid under the reaction conditions,
which reacted with the 3,5-dimethyl-1-adamantyl cation generated from nitroxy deriva-
tive 4 during the process. The reaction with HCN formed from acetone cyanohydrin and
subsequent hydrolysis of formamide derivative 5 were studied under different conditions.
The amount of acetone cyanohydrin and its addition time into the reaction mixture, tem-
perature, diluent and reaction time were varied.
The influence of the amount of 3 and addition conditions on the yield of 1 were stud-
ied. It should be noted that optimization of the method for the preparation of 1 was carried
with the use of 50 mL (45 g) 2 and 13 eq. fuming nitric acid as the model system. A com-
prehensive review of reaction conditions of the synthesis 1 is presented in Table 1. The fol-
lowing discussion takes place entry-by-entry in Table 1. The use of 2 eq. or 3 eq. of

158
Ivleva and Klimochkin
Table 1
Optimization of Reaction Conditions for the Synthesis of 1
3 / Quantity Addition time
(eq.)
Diluent:
HNO3 (vol.) t, (ꢀC) Yielda, (%)
Entryb
of 3 (min) Diluent
1c
2
3
4
6
4
4
6
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
< 1
< 1
< 1
< 1
30
H2O
H2O
3.33: 1
3.33: 1
3.33: 1
3.33: 1
3.33: 1
3.33: 1
3.33: 1
1.67: 1
6.67: 1
13.33: 1
13.33: 1
13.33: 1
13.33: 1
3.33: 1
1.07: 1
1.33: 1
2.67: 1
2.67: 1
2.67: 1
2.67: 1
2.67: 1
2.67: 1
75
75
11.2
18.6
22.3
35.8
36.7
51.2
52.6
26.3
62.6
68.7
64.5
73.1
79.4
38.3
79.7
81.4
83.6
86.7
84.3
86.5
85.8
87.4
2c
3c
4c
H2O
H2O
75
75
5d,e
6e
H2O
H2O
75
75
30
30
7e
H2O
H2O
75
75
8e
30
30
9e
H2O
H2O
75
75
10e
11e
12e
13e
14e
15e
16e
17e
18e,f
19e,g
20e,h
21e,i
22e,j
30
60
H2O
H2O
50
75
60
60
H2O
100
100
110
110
110
110
110
110
110
110
60
60
NaOH (40%)
aq. NH3 (25%)
aq. NH3 (25%)
aq. NH3 (25%)
aq. NH3 (25%)
aq. NH3 (25%)
aq. NH3 (25%)
aq. NH3 (25%)
aq. NH3 (25%)
60
60
180
180
180
180
180
aIsolated yield.
bReaction was carried out with 45 g of 2 (entries 1–17).
cThe hydrolysis was carried out immediately after the addition of 3 and without addition of urea.
dThe hydrolysis was carried out without addition of urea.
eThe reaction time after the addition of 3 is 30 min.
fReaction was carried out with 100 g of 2.
gReaction was carried out with 150 g of 2.
hReaction was carried out with 250 g of 2.
iReaction was carried out with 450 g of 2.
jReaction was carried out with 990 g of 2.
acetone cyanohydrin (3) leads to an extremely low yield (entries 1 and 2). Increasing the
acetone cyanohydrin (3) to 4 eq. and 6 eq. results in slight improvement of the reaction
yields (entries 3 and 4). The acetone cyanohydrin (3) was first added quickly (entries 1–4).
The addition of 3 dropwise during a period of 30 min and the further stirring of the reaction
mixture within 30 min increased the reaction yield (entry 5). When acetone cyanohydrin
(3) was added during a period of 1 h, the yield of 1 was increased (entries 11–13).
The following step involves the optimization of the hydrolysis procedure for interme-
diate 5. At first, the hydrolysis of formamide derivative 5 was carried out at 75ꢀC after
water dilution of nitric acid to 30%. The reaction completed within 1 h (entries 1–5). Dur-
ing the hydrolysis 1-hydroxy-3,5-dimethyladamantane is formed as a by-product because
of the reaction of intermediate 6 with HNO2 generated by the thermolysis of nitric acid.
Key to optimization of the hydrolysis step is the addition of urea. The addition of 1 eq. of

Convenient Synthesis of Memantine Hydrochloride
159
urea suppresses the formation of 1-hydroxy-3,5-dimethyladamantane due to the reaction
of urea with HNO2 to give N-nitrosourea, which decomposes to ammonia, CO2 and N2.
This leads to increasing the reaction yield (entry 6). The reaction completed within 2.5 h
at 75ꢀ in 30% nitric acid. When the hydrolysis was carried out in 60% nitric acid, the
yield of 1 was decreased significantly (entry 8).
The decrease of acidity is provided by water dilution. After several attempts, a high
dilution of the reaction mixture was found best to ensure high yields of 1 (entries 9–11).
Encouraged with these results we carried out the hydrolysis at various temperatures
(entries 11–13) and found that the optimal temperature is 100ꢀC (entry 13). In these con-
ditions the hydrolysis completed within 15 min.
The replacement of a solution of urea in water as a diluent with a solution of urea in
aq. 40% NaOH failed. The time of hydrolysis increased up to 9 h and the yield of 1 signif-
icantly reduced (entry 14).
The best results were obtained using a solution of urea in 25% aq. ammonia as the
diluent for decreasing of the amount of water and the acidity for the hydrolysis step
(entries 15–17). The isolated yield of 1 was 83%. The reaction completed within 7 h at
reflux (110ꢀC). It should be noted that addition of the first portions of the urea solution to
the reaction mixture was exothermic and therefore this stage of the reaction must be car-
ried out with careful temperature control.
Since at the hydrolysis step we used a solution of ammonia, we decided to use it in
the isolation step of the product. The memantine base (intermediate 6) was isolated by
neutralization of the reaction mixture with 25% aq. ammonia solution to pH 11 followed
by extraction with toluene. The memantine base was converted into its hydrochloride salt
1 by reacting the toluene extract with concentrated hydrochloric acid. The product 1 pre-
cipitated from the toluene solution and was isolated by filtration. The crude product was
purified by recrystallization from water. After recrystallization the memantine hydrochlo-
ride content is 99.9% according to GC.
The reaction was repeated on several different scales (up to 1 kg of 2), all with com-
parable yields (entries 18–22). In these cases, acetone cyanohydrin was added during a
period up to 3 h.
In summary, the process described in Scheme 2 has the advantage of an economically
competitive synthesis of 1. Other advantages of this approach include the use of available
reagents, simple experimental procedures and easy product isolation. This one-pot proce-
dure yielding 87% starting from 1,3-dimethyladamantane could be considered as a basis
for future development on industrial scale.
Experimental Section
GC-MS analyses was carried out with a ThermoFinnigan DSQ instrument (70 eV, 30 m £
0.32 mm ZB5MS column, stationary phase thickness 0.25 mm, 1.5 mL/min of helium as car-
rier gas, heating from 80ꢀC to 340ꢀC at 20ꢀC/min, injector temperature 300ꢀC). Melting points
1
were determined using OptiMelt automated melting point system and are uncorrected. H
NMR spectra were recorded with a Jeol JNM ECX-400 (400 MHz) instrument.
Preparation of Memantine Hydrochloride 1
Fuming nitric acid (3.2 L, 78 mol) was added at 20–25ꢀC to 1,3-dimethyladamantane 2 (1.1 L,
6 mol) during a period of 2 h under effective cooling, and the reaction mixture was stirred for
1 h. Reaction completion was monitored by GC.* Acetone cyanohydrin 3 (2.2 L, 24 mol) was

160
Ivleva and Klimochkin
added to reaction mixture during a period of 3 h at 20–25ꢀC. The resulting mixture was stirred
for 30 min at 20–25ꢀC. Reaction completion was monitored by GC.** The solution was
cooled to 10ꢀC, and a solution of urea (360 g, 6 mol) in aqueous ammonia (25%) (9 L) was
added. The resulting mixture was refluxed (110ꢀC) for 7 h (hydrolysis completion was moni-
tored by GC),*** then cooled to 50ꢀC and aqueous ammonia (25%) (8 L) was added to pH 11
with cooling. The product 6 was extracted with toluene (5 L) at 50–60ꢀC. Aqueous HCl (36%)
(700 mL) was added to the toluene layer. The suspension was cooled to room temperature and
the precipitate filtered off. The wet cake was washed with toluene and dried under vacuum
(yield 1184 g, 92%). The product was recrystallized from water (4.7 L). Yield of memantine
1
hydrochloride 1 after recrystallization 1131 g (87%), GC purity 99.90%. M.p. 317ꢀC. H
NMR (DMSO-d6): 0.80 (s, 6H), 1.04 (d, 1H, J D 12.84 Hz), 1.11 (d, 1H, J D 12.40 Hz), 1.25
(s, 4H), 1.38 (d, 2H, J D 11.44 Hz), 1.44 (d, 2H, J D 11.92 Hz), 1.61 (s, 2H),
2.08–2.11 (m, 1H), 8.19 (br. s, 3H). MS (EI) m/z (%): 180 [M-Cl] (4), 179 [M-HCl] (18), 164
(6), 122 (90), 108 (100).
* Sample preparation for GC
An aliquot (1 mL) was taken, mixed with water (1 mL) and ammonia (3 mL, 25%)
was added to pH 11. The solution was extracted with toluene (1 mL). The toluene layer
was dried with sodium sulfate, filtered and examined by GC. If the 1,3-dimethyladaman-
tane (2) content was more than 1%, the reaction mixture was stirred 30 min at 20–25ꢀC.
1,3-Dimethyladamantane MS (EI) m/z (%): 164 [M] (10), 163 [M-1] (100).
** If the 1-formamido-3,5-dimethyladamantane (5) content was less than 90%, the
reaction mixture was stirred 15 min at 20–25ꢀC. 1-Formamido-3,5-dimethyladamantane
MS (EI) m/z (%): 208 [MC1] (14), 207 [M] (100), 163 (70), 149 (28), 107 (60).
*** If the 1-formamido-3,5-dimethyladamantane (5) content was more than 3%, the
reaction mixture was heated at reflux 30 min.
Acknowledgments
This work was financially supported by the Russian Ministry of Education and Science
(4.1597.2014/K) and the Russian Foundation for Basic Research (14-03-97075).
References
1. World Alzheimer Report 2015. The Global Impact of Dementia. Alzheimer’s Disease Interna-
tional, https://www.alz.co.uk/research/WorldAlzheimer Report2015.pdf
2. C. M. Filley, Geriatrics., 50, 18 (1995).
3. B. Rive, S. Gauthier, S. Costello, C. Marre and C. Francois, CNS Drugs., 27, 573 (2013).
4. S. K. Sonkusare, C. L. Kaul and P. Ramarao, Pharm. Res, 51, 1 (2005).
5. L. S. Schneider, P. S. Insel and M. W. Weiner, ARCH Neurol, 68, 58 (2011).
6. L. E. Farrimond, E. Roberts and R. McShare, BMJ Open, 2, 1 (2012).
7. A. Witt, N. Macdonald and P. Kirkpatrick, Nat. Rev. Drug Discovery, 3, 109 (2004).
8. C-C. Tan, J-T. Yu, H-F. Wang, M-S. Tan, X-F. Meng, C. Wang, T. Jiang, X-C. Zhu and L. Tan,
Journal of Alzheimer’s Disease, 41, 615 (2014).
9. G.L. Plosker, Drugs, 75, 887 (2015).
10. C.G. Parsons, W. Danysz and G. Quack, Neuropharmacology, 6, 735 (1999).

Convenient Synthesis of Memantine Hydrochloride
11. S. A. Lipton, J. Alzheimer’s Dis, 6, 61 (2004).
161
12. P. Seeman, C. Caruso and M. Lasaga, Synapse, 62, 149 (2008).
13. G. C. Palmer, Curr. Drug Targets, 2, 241 (2001).
14. J. W. Johnson and S. E. Kotermanski, Curr. Opin. Pharmacol, 6, 61 (2006).
15. H. Martinez-Coria, K. N. Green, L. M. Billings, M. Kitazawa, M. Albrecht, G. Rammus, C. G.
Parsons, S. Gupta, P. Banerjee and F. M. LaFerla, Am. J. Pathology, 176, 870 (2010).
16. A. Nazem and G. Mansoori, Insciences J., 4, 169 (2011).
17. D. Olivares, V. K. Deshpande, J. Shi, D. K. Lahiri, N. H. Greig, J. T. Rogers and X. Huang,
Curr. Alzheimer Res, 9, 746 (2012).
18. A. Kurz and T. Grimmeer, Expert Opin. Pharmacother, 15, 1955 (2014).
19. G. Sani, G. Serra, G. D. Kotzalidis, S. Romano, S. M. Tamorri, G. Manfredi, M. Caloro, C. L.
Telesforo, S. S. Caltagirone, I. Panaccione, A. Simonetti, F. Demontis, G. Serra and P. Girardi,
CNS Drugs, 26, 663 (2012).
20. https://newport.thomson-pharma.com
21. K. Gerzon, E. V. Krumkalns, R. L. Brindle, E. J. Marshall and M. A. Root, J. Med. Chem, 6,
760 (1963).
22. M. K. Madhra, M. Sharma, and C. H. Khanduri, Org. Process. Res. Dev, 11, 922 (2007).
23. E. Vigano, E. Landonio, S. Lanfranconi and R. Molteni, US Pat. US 20060258885, 2006.
24. V. Merli, A. Vailati and P. Daverio, PCT Int. Appl. WO Patent 2007126886, 2007.
25. R. U. Roy, P. Chand, R. Kumar and D. S. Dhar, PCT Int. Appl. WO Patent 2008062472, 2008.
26. M. Satya-Narayana Reddy, S. Eswaraian, G. Venkat Reddy and C. Suresh, PCT Int. Appl. WO
Patent 2009057140, 2009.
27. B. Parthasaradhi Reddy, K. Rathnakar Reddy, R. Raji Reddy, M. Ramakrishna Reddy and B.
Vamsi Krishna, PCT Int. Appl. WO Patent 2011125062, 2011.
28. O. D. Tyagi, G. S. Ramanjaneyulu, B. Mohan, I. V. S. Kumar and K. N. Rao, PCT Int. Appl.
WO Patent 2007132476, 2007.
29. P. R. Schreiner and L. Wanka, PCT Int. Appl. WO Patent 2006010362, 2006.
30. I.K. Moiseev, E.I. Bagrii, Yu.N. Klimochkin, T.N. Dolgopolova, M.N. Zemtsova and P.L.
Trakhtenberg, Russ. Chem. Bull., 9, 1983 (1985).
31. M. R. Gold, A. Jirgensons and F. A. M. Huber, PCT Int. Appl. WO Patent 2010069555, 2010.
32. J. M. Reddy, G. Prasad, V. Raju, M. Ravikumar, V. Himabindi and G. M. Reddy, Org. Process.
Res. Dev, 11, 268 (2007).
33. G. Quack and M. R. Gold, US Pat. US 20110282100, 2011.
34. P. R. Schreiner, A. A. Fokin, L. Wanka and D. M. Wolfe, US Pat. US 20090299097, 2009.
35. Yu.N. Klimochkin, E.I. Bagrii, T.N. Dolgopolova and I.K. Moiseev, Russ. Chem. Bull., 4, 757 (1988).
36. F.A.M. Huber, G. Gallo and C. de Faveri, US Pat. US 20110082317, 2011.
37. L. Wanka, C. Cabrele, M. Vanejews, P.R. Schreiner, Eur. J. Org. Chem., 9, 1474 (2007).
38. F. Zhang, M. Hu, L. Zhao and M. Ge, EP 1674446, 2006.

162
Ivleva and Klimochkin
39. A. Scherm, B. Homburg, D. Peteri, US Pat. US 4122193, 1978.
40. Yu. N. Klimochkin and I.K. Moiseev, J. Org. Chem. USSR (Engl. Transl.), 9, 2025 (1987).
41. M. V. Leonova, M.Yu. Skomorokhov, I.K. Moiseev and Yu. N. Klimochkin, Russ. J. Org.
Chem., 12, 1703 (2015).
42. Yu. N. Klimochkin, M.V. Leonova and A.K. Timofeeva, Russia Pat. RU 2246482 CA 142,
240121, 2005.
43. T. Sasaki, S. Eguchi, T. Katada and O. Hiroaki, J. Org. Chem, 42, 3741 (1977).
44. K. Huard and H. Lebel, Chem. Eur. J., 14, 6222 (2008).
45. C. Schikaneder, EP 1820792, 2007.
46. F. Vreser, R. Zupet, J. Pucelj and M. Pelko, EP 1908748, 2008.
47. A. G. Kraus, US Pat. US 5599998, 1997.
48. J. Tihi, M. Meleh, F. Vreser, R. Zupet, J. Pucelj and M. Pelko, PCT Int. Appl. WO Patent
2008040560, 2008.
49. S. L. Pathi and R. N. Kankan, PCT Int. Appl. WO Patent 2010007351, 2010.
50. W. Zhao and F.-E. Chen, Curr. Org. Synth., 6, 873 (2012).
51. Y. Hayashi, Chem. Sci., 7, 866 (2016).
52. F. N. Stepanov and Yu. T. Srebrodol’skii, J. Org. Chem. USSR (Engl. Transl.), 2, 1612 (1966).
53. H.W. Geluk, Tetrahedron Lett., 47, 4473 (1971).
54. I. K. Moiseev, N.G. Belyaev, N.V. Barabanova, O.P. Bardyug, E.N. Vishnevsky, N.I. Novat-
skaya, E.L. Golod and V.B. Gidaspov, J. Org. Chem. USSR., 11, 1 (1975).
55. I. K. Moiseev, Yu. N. Klimochkin, M.N. Zemtsova and P.L. Trakhtenberg, J. Org. Chem. USSR
(Engl. Transl.), 7, 1435 (1984).
56. I. K. Moiseev, E.I. Bagrii, Yu.N. Klimochkin, T.N. Dolgopolova, M.N. Zemtsova and P.L.
Trakhtenberg, Russ. Chem. Bull., 9, 1980 (1985).
57. Yu. N. Klimochkin and I. K. Moiseev, J. Org. Chem. USSR (Engl. Transl.), 24, 497 (1988).
58. Yu. N. Klimochkin, E.O. Zhilkina, O.V. Abramov and I. K. Moiseev, Russ. J. Org. Chem., 29,
1126 (1993).
59. J. M. Bakke and B. Knudsen, Acta Chem. Scan., 47, 620 (1993).
60. N.V. Stulin, A.V. Yudashkin, A.K. Shiryaev, I.K. Moiseev and A.S. Petrov, Pharm. Chem. J.,
18, 337 (1984).
61. Yu. N. Klimochkin, M.V. Leonova and I.K. Moiseev, Russ. J. Org. Chem., 3, 381 (1997).
62. N.A. Fokina, B.A. Tkachenko, A. Merz, M. Serafin, J.E.P. Dahl, R.M.K. Carlson, A.A. Fokin
and P.R. Schreiner, Eur. J. Org. Chem., 28, 4738 (2007).
63. J. J. Ritter and J. Kalish, J. Am. Chem. Soc., 70, 1948 (4048).
64. E. A. Ivleva, K. A. Ovchinnikov, Yu. N. Klimochkin, Russia Pat. RU 2541545, CA
162,352884, 2015.
65. I. K. Moiseev, Yu. N. Klimochkin, M. N. Zemtsova and P. L. Trakhtenberg, J. Org. Chem.
USSR, 20, 1435 (1984).