US2011306794A1PendingUtilityA1
Process for preparing cinacalcet hydrochloride
Est. expiryFeb 19, 2029(~2.6 yrs left)· nominal 20-yr term from priority
Inventors:Nicola CatozziLivius CotarcaJohnny FolettoMassimiliano ForcatoRoberto GiovanettiGiorgio SoriatoMassimo Verzini
C07C 305/12C07C 221/00C07C 211/30C07C 209/70C07C 211/28C07C 303/28
44
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Claims
Abstract
A process for preparing N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)-phenyl]propan-1-amine hydrochloride salt of formula (I) i.e. Cinacalcet hydrochloride and its intermediates of formulae (VII) and (VIII) wherein Z is chloride or another pharmaceutically acceptable anionic counterion.
Claims
exact text as granted — not AI-modified1 . A method for preparing Cinacalcet hydrochloride of formula (I)
which comprises the steps of:
e) reducing a compound of formula (VII)
wherein Z is chloride or another pharmaceutically acceptable anionic counterion, to obtain a compound of formula (Ia)
wherein Z is as defined above and, when in a compound of formula (Ia) Z is a pharmaceutically acceptable anionic counterion different from chloride,
f) converting said compound of formula (Ia) to Cinacalcet hydrochloride of formula (I).
2 . A method according to claim 1 , wherein the pharmaceutically acceptable anionic counterion different from chloride is selected from bromide, bisulfate, methanesulfonate, p-toluenesulfonate, phosphate, hydrogenphosphate, oxalate, formate, acetate, citrate, tartrate, succinate, maleate and malonate.
3 . A method according to claim 1 , wherein when in the compound of formula (VII) Z is chloride, the compound has formula (VIIa)
4 . A method according to claim 3 , which further comprises obtaining the compound of formula (VIIa), with a process which comprises the step of:
g) converting a compound of formula (VII)
wherein Z is a pharmaceutically acceptable anionic counterion different from chloride.
5 . A method according to claim 1 , wherein in a compound of formula (VII), Z is different from chloride.
6 . A method according to claim 4 , wherein in the compound of formula (VII) Z is bisulfate, namely it is a compound of formula (VIIb)
7 . A method according to claim 4 , which further comprises obtaining a compound of formula (VII) wherein Z is a pharmaceutically acceptable anionic counterion different from chloride, with a process which comprises the step of:
j) eliminating sulfuric acid from the compound of formula (VIII)
wherein the wavy line represents a bond connected to carbon having R or S configuration, with a strong acid, neutralizing and acidifying with an acid HZ, wherein Z is a pharmaceutically acceptable anionic counterion different from chloride.
8 . A method according to claim 7 , wherein the strong acid is sulfuric or phosphoric acid.
9 . A method according to claim 7 , wherein the acid HZ is H 2 SO 4 .
10 . A method according to claim 7 , which further comprises obtaining the compound of formula (VIII), with a process which comprises the steps of
k) reducing the compound of formula (V)
to the corresponding benzylic alcohol of formula (Va)
wherein [ ] means that the compound of formula (Va) can be isolated or not from the reaction mixture, in the presence of a reducing agent or by mean of a catalytic hydrogenation process, and
l) converting the compound of formula (Va) into the sulfate ester of formula (VIII).
11 . A method according to claim 10 , which further comprises obtaining the compound of formula (V), with a process which comprises the steps of:
a) reacting 3-(trifluoromethyl)acetophenone of formula (II)
with (R)-(1-naphthyl)ethylamine of formula (III) optionally in the hydrochloride form,
in the presence of formaldehyde and hydrochloric acid.
12 . A method according to claim 10 , which further comprises obtaining the compound of formula (V), with a process which comprises the steps of:
b) reacting the compound of formula (II)
(i) with a compound of formula
HNR 1 R 2 ,
wherein R 1 and R 2 represent, independently, hydrogen or C 1 -C 5 alkyl, provided that when one of R 1 and R 2 is hydrogen, the other is not hydrogen; or
wherein R 1 and R 2 together form a C 4 -C 7 alkyl bridge, so that with the inclusion of the nitrogen atom to which they are linked a heterocycle is formed, wherein one —CH 2 — group of the C 4 -C 7 alkyl bridge, can be replaced by —O—, in the presence of formaldehyde; or
(ii) with a N-methyl-N-methylenemethanaminium halide of formula
wherein Hal is a halogen atom,
to obtain the compound of formula (IV)
wherein R 1 and R 2 are as defined above;
c) alkylating the compound of formula (IV) with an alkylating agent selected from the group of compounds of formula:
R 3 —X, CO(OR 3 ) 2 , SO 2 (OR 3 ) 2 , PO(OR 3 ) 3 , CH 3 PO(OR 3 ) 2 and (4-NO 2 C 6 H 4 O)PO(OR 3 ) 2 , wherein R 3 is C 1 -C 4 alkyl and X is I, Br, OSO 2 CF 3 or OSO 2 F, to obtain a compound of formula (IVa)
wherein Y═X as defined above, R 3 OCO 2 , R 3 OSO 3 , (R 3 O) 2 PO 2 , CH 3 PO 2 OR 3 , or (4-NO 2 —C 6 H 4 O)PO 2 OR 3 ; and
d) coupling a compound of formula (IVa) with (R)-(1-naphthyl)ethylamine of formula (III)
13 . A method for preparing Cinacalcet intermediate of formula (VIII)
wherein the wavy line represents a bond connected to carbon having R or S configuration, which comprises the steps of:
k) reducing the compound of formula (V)
to the corresponding benzylic alcohol of formula (Va)
wherein [ ] means that the compound of formula (Va) can be isolated or not from the reaction mixture, in the presence of a reducing agent or by mean of a catalytic hydrogenation process, and
l) converting the compound of formula (Va) in the sulfate ester of formula (VIII).
14 . A method for preparing Cinacalcet hydrochloride of formula (I)
which comprises the steps of
k) reducing the compound of formula (V)
to the corresponding benzylic alcohol of formula (Va)
wherein [ ] means that the compound of formula (Va) can be isolated or not from the reaction mixture, in the presence of a reducing agent or by mean of a catalytic hydrogenation process,
l) converting the compound of formula (Va) into the sulfate ester of formula (VIII)
wherein the wavy line represents a bond connected to carbon having R or S configuration,
j) eliminating sulfuric acid from the compound of formula (VIII) with a strong acid, neutralizing and acidifying with the H 2 SO 4 to give the compound of formula (VIIb)
g) converting the compound (VIIb) into the compound (VIIa) and
e) reducing the compound (VIIa) to Cinacalcet hydrochloride of formula (I).
15 . Cinacalcet intermediate having the following formula (VII)
wherein Z is chloride or another pharmaceutically acceptable anionic counterion.
16 . Cinacalcet intermediate according to claim 15 , wherein the pharmaceutically acceptable anionic counterion is selected from chloride, bromide, bisulfate, methanesulfonate, p-toluenesulfonate, phosphate, hydrogenphosphate, oxalate, formate, acetate, citrate, tartrate, succinate, maleate and malonate.
17 . Cinacalcet intermediate having the following formula (VIIa)
18 . Cinacalcet intermediate having the following formula (VIIb)
19 . Cinacalcet intermediate having the following formula (VIIc)
20 . Cinacalcet intermediate having the following formula (VIId)
21 . Cinacalcet intermediate having the following formula (VIIe)
22 . Cinacalcet intermediate having the following formula (VIII)
wherein the wavy line represents a bond connected to carbon having R or S configuration.Join the waitlist — get patent alerts
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