WO1999025689A1 - Process for the preparation of acetal derivatives of 1,4-dihydropyridines - Google Patents

Process for the preparation of acetal derivatives of 1,4-dihydropyridines Download PDF

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Publication number
WO1999025689A1
WO1999025689A1 PCT/DK1998/000493 DK9800493W WO9925689A1 WO 1999025689 A1 WO1999025689 A1 WO 1999025689A1 DK 9800493 W DK9800493 W DK 9800493W WO 9925689 A1 WO9925689 A1 WO 9925689A1
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alkyl
general formula
aralkyl
cycloalkyl
represent
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PCT/DK1998/000493
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French (fr)
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Gunnar Leo Karup
Herbert Fritz Preikschat
Søren Bols Pedersen
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A/S Gea Farmaceutisk Fabrik
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Publication of WO1999025689A1 publication Critical patent/WO1999025689A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to a process for the preparation of acetal derivatives of 1 , 4-dihydropyridines of the general formula II indicated below, which are useful as intermediates for the preparation of
  • a particularly preferred compound of this class of 1 , 4-dihydropyridines is the compound, 2-(2-amino- ethoxymethyl) -4- (2-chlorophenyl) -6-methyl-1 , 4-dihydro- pyridine-3 , 5-dicarboxylic acid 3 -ethyl ester 5-methyl
  • the present invention provides a process, whereby 35 the 1, 4-dihydropyridine acetal derivatives can be obtained in high yield by the Hantzsch synthesis.
  • the amlodipine acetal intermediate has been obtained in a yield of 42 % starting with the reaction of 2-di- ethoxyethanol with ethyl 4-chloroacetoacetate .
  • the acetal derivatives of formula II can be converted into the 1 , 4-dihydropyridines of formula I in high yield, whereby the latter can be obtained in a high overall yield.
  • amlodipine maleate has been obtained from the acetal derivative in a yield of 62 % corresponding to an overall yield of 29 % starting with the reaction of 2 , 2-diethoxyethanol with ethyl 4-chloroacetoacetate.
  • EP 0 089 167 B discloses amlodipine and other 1,4- dihydropyridines having an amino-containing group attached to the 2 -position and their preparation.
  • the 1 , 4-dihydropyridines are prepared by removal of the amino-protecting group from the corresponding amino-protected 1 , 4-dihydropyridine or by reduction of the corresponding azido com- pound into the amine.
  • the amino-protected 1,4- dihydropyridines as the azido compounds are prepared by Hantzsch synthesis, which is carried out in a C ] _-C 4 alkanol solvent, particularly methanol , ethanol or isopropanol .
  • Example 11 in the patent an overall yield of 1 %, only, is stated for the production of amlodipine maleate starting with the reaction of 2-azido ethanol with ethyl 4-chloroacetoacetate, whereas an overall yield of 8.8 % is disclosed in a later publication by the inventors of EP 0 089 167 B, J. Med. Chem. , (1986), 29, 1696 - 1702, see particularly pp. 1700 - 1701.
  • the acetal derivatives of formula II can e.g. be converted into the 1 , 4-dihydropyridines of formula I by reaction with hydroxylamine or a derivative thereof to produce an oxime intermediate which is reduced to provide the desired 1 , 4-dihydropyridine, optionally as a pharmaceutically acceptable acid addition salt thereof, as described in more detail in the following.
  • CA 2,188,071 A discloses a process for the prep- aration of 1 , 4-dihydropyridine derivatives, i.a. amlodipine, by reductive amination of the corresponding aldehyde under specific conditions, or by reaction of the aldehyde with hydroxylamine hydrochloride and base to give the corresponding oxime followed by conversion of the oxime into the final product under specific conditions .
  • CA 2,188,071 A discloses an acetal, viz. the compound 4 - (2-chlorophenyl) -2 - (2 , 2-dimethoxy- ethoxymethyl) -1, 4-dihydro-6-methyl-3 , 5-pyridinedicar- boxylic acid 3-ethyl 5-methyl ester, as well as its preparation from 2 , 2-dimethoxyethanol and 2-(2-chloro- methyl) -4 - (2-chlorophenyl) -1 , 4 -dihydro-6-methyl-3 , 5- pyridinedicarboxylic acid 3-ethyl 5-methyl ester and its conversion into a bicyclic structure forming an oxazine ring with the pyridine nitrogen atom (cf.
  • CA 2,188,071 A also includes a general formula XX for an acetal, but the formula includes two undefined substituents, R 10 and R n , and accordingly it cannot be considered an anticipating disclosure of any specific acetal.
  • EP 225 175 A2 discloses a substantive number of 1 , 4-dihydropyridine derivatives and different processes for their preparation.
  • Amlodipine is not among the disclosed derivatives.
  • One of the disclosed processes is a process for the preparation of a 1 , 4-dihydropyridine derivative, i.a. having a (2 -aminoethoxy) methyl substituent in the 2 -position, but a fluoromethyl substituent in the 6 -position.
  • the 1 , 4-dihydropyridine derivative is prepared by reduction of the corresponding oxime which in turn is prepared by reaction of the corresponding acetal with hydroxylamine.
  • EP 225 175 A2 does not mention anything about the acetal being obtained directly by the Hantz- sch synthesis and even less by a Hantzsch synthesis carried out under azeotropic removal of water of reaction as specified herein and the particular advantages obtainable thereby.
  • the acetal is prepared from the corresponding bromomethyl substituted 1 , 4-dihydropyridine derivative obtained by reaction of the corresponding methyl substituted 1 , 4-dihydropyridine derivative with pyridinium perbromide, a process which would be unsuitable for the preparation of the acetal deriva- tives prepared by the process according to the present invention due to side reactions.
  • the invention provides a process for the preparation of 1 , 4-dihydropyridine acetal derivatives of the general formula II
  • R 1 each, independently, represents H, Cl or CF 3
  • R 2 represents H, C x -C 5 alkyl, C 3 -C 6 cycloalkyl or aralkyl ,
  • R 3 and R which may be the same or different, represent C ⁇ C ⁇ alkyl, C 3 -C 6 cycloalkyl, aralkyl or together represent -(CH 2 ) m -, wherein m is 2 or 3, and n is 1 or 2, in which process the 1 , 4-dihydropyridine ring structure is formed by a Hantzsch synthesis carried out in one or more steps using a compound containing a group of the formula 0R-
  • R 3 and R 4 have the same meanings as defined above, as one of the reactants in the Hantzsch condensation, the Hantzsch synthesis, or at least one step thereof, being carried out in a solvent, which is capable of forming an azeotrope with water, under azeotropic removal of water of reaction.
  • the Hantzsch synthesis as such is well-known in the art . In principle it is carried out by reacting an aldehyde with a /3-keto ester and an aminocrotonic acid ester as shown in the following Scheme 1, illustrating the preparation of compounds of formula II:
  • the reaction with the ketoester can be assisted by addition of an amine, particularly a secondary amine such as piperidine or morpholine.
  • the Hantzsch synthesis or at least one step thereof, is carried out in a solvent, which is capable of forming an azeotrope with water, under removal of water of reaction as an azeotrope with the solvent . If the Hantzsch synthesis is carried out in more than one step, such as in two steps, all steps will normally be carried out in a solvent, which is capable of forming an azeotrope with water, under azeotropic removal of water of reaction although benefits may be obtained already by carrying out a single step of the synthesis under such conditions. Steps carried out in a solvent not being capable of forming an azeotrope with water may e.g. be carried out in a lower alkanol such as methanol , ethanol or isopropanol as is known in the art.
  • solvents being capable of forming an azeotrope with water
  • toluene, benzene and xylene can be mentioned with toluene as a presently preferred solvent.
  • the azeotropic removal of water of reaction is preferably carried out by heating of the reaction mixture to reflux for a sufficient period to allow the reaction to take place, using a water separator such as a Dean-Stark separator to catch the water of reaction.
  • the process according to the invention comprises the step of reacting a compound of the general formula IV
  • the process according to the invention comprises the step of reacting a compound of the general formula VI
  • the starting materials used in the process according to the invention are either known compounds or may be prepared by processes known in the art for the preparation of similar compounds.
  • R 1 each, independently, represents H, Cl or CF 3 ,
  • R 2 represents H, C ⁇ - ⁇ alkyl, C 3 -C 6 cycloalkyl or aralkyl ,
  • R 3 and R 4 which may be the same or different, represent C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, aralkyl or together represent -(CH 2 ) m -, wherein m is 2 or 3, and n is 1 or 2, with the proviso that when R 2 is H, and no R 1 is CF 3 , then R 3 and R 4 are other than methyl.
  • a preferred group of novel acetales of the general formula II is represented by the compounds wherein n is
  • R 1 is chloro in the 2 -position of the phenyl ring
  • R 2 is H, and R 3 and R 4 , which may be the same or dif- ferent, represent C 2 -C 5 alkyl.
  • Particularly preferred is the compound 4- (2- chlorophenyl) -2- (2 , 2-diethoxy-ethoxymethyl) - 6 -methyl - 1 , 4-dihydro-pyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester.
  • the acetal derivatives of the general formula II are useful for the preparation of pharmaceutically active 1 , 4-dihydropyridines and other intermediates of use for such purpose.
  • a particular aspect of the invention relates to the use of acetal derivatives of the general formula II as an intermediate for the preparation of a 1, 4-dihydropyridine of the general formula I
  • R .1 1 each, independently, represents H, Cl or CF 3 ,
  • R 2 represents H, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl or aralkyl , and n is 1 or 2, or an acid addition salt thereof, particularly amlodi- pine or an acid addition salt thereof.
  • a specific embodiment relates to the use of an acetal derivative of the general formula II wherein n is 1, R 1 is chloro in the 2 -position of the phenyl ring, R 2 is H, and R 3 and R 4 , which may be the same or different, represent C 1 -C 5 alkyl, for the preparation of amlodipine or an acid addition salt thereof.
  • the 1 , 4-dihydropyridines of the general formula I and acid addition salts thereof can be obtained by reacting an acetal derivative of the formula II with a compound of the formula
  • R 5 represents H, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl or aralkyl , so as to provide an oxime of the general formula III wherein
  • R 1 , R 2 , R 5 and n have the same meanings as defined above , and reducing the formed oxime of formula III so as to provide a 1 , 4-dihydropyridine of formula I, and, if desired, converting a compound of formula I obtained as the free base into a pharmaceutically acceptable acid addition salt thereof or vice versa.
  • the reaction of the acetal of formula II with R 5 ONH 2 or an acid addition salt thereof to give the oxime of formula III may be carried out in an appropriate solvent, such as an alcoholic solvent comprising a lower alkanol, such as methanol , ethanol or isopropa- nol, e.g. in admixture with water.
  • an appropriate solvent such as an alcoholic solvent comprising a lower alkanol, such as methanol , ethanol or isopropa- nol, e.g. in admixture with water.
  • an aqueous solution of R 5 ONH 2 , hydrochloride may be combined with a solution of the acetal in methanol, and the mixture heated to reflux for a suitable period, such as 2 - 8 hours, normally around 4 hours.
  • the reduction of the oxime of formula III into the desired 1 , 4-dihydropyridine of formula I may be carried out using a suitable reduction agent selected from the numerous reduction agents being known for the reduction of oximes into amines, see e.g. the surveys given in R. C. arock, "Comprehensive Organic Transformations", VCH
  • the reduction may be carried out by cataly- tical hydrogenation, preferably using a nobel metal catalyst, such as platinum or palladium, or a Raney nickel catalyst.
  • the reduction is preferably carried out under acidic conditions.
  • the reduction may be carried out by catalytical hydrogenation in acetic acid using palladium-on-carbon as a catalyst.
  • the reduction may also be carried out using sodium borohydride/nickel chloride hydrate as reduction agent.
  • catalysts which may be of use for the present purpose, the following can be mentioned: sodium borohydride in combination with other compounds, such as titanium tetrachloride or molybdenum trichloride; lithium aluminum hydride or zinc powder.
  • a compound of formula I obtained as the free base may, if desired, be converted into a pharmaceutically acceptable acid addition salt thereof or vice versa.
  • the hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, besylate, lactate, tartrate, citrate and gluconate salts are examples of such pharmaceutically acceptable acid addition salts.
  • the maleate and the besylate salts are particularly preferred.
  • Another aspect of the invention relates to the use of the acetal derivatives of the general formula II as intermediates for the preparation of oximes of the general formula III
  • R 1 each, independently, represents H, Cl or CF 3
  • R 2 represents H, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl or aralkyl
  • R 5 represents H, C- ⁇ alkyl, C 3 -C 6 cycloalkyl or aralkyl, and n is 1 or 2, particularly the compound, 4- (2-chlorophenyl) -2- (2- hydroxyimino-ethoxymethyl ) - 6 -methyl -1,4 - dihydro - pyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester.
  • a specific embodiment relates to the use of an acetal derivative of the general formula II wherein n is 1, R 1 is chloro in the 2 -position of the phenyl ring, R 2 is H, and R 3 and R 4 , which may be the same or different, represent C 1 -C 5 alkyl, for the preparation of 4- (2-chlorophenyl) -2- (2-hydroxyimino-ethoxymethyl) - 6 -methyl -1 , 4-dihydropyridine-3 , 5-dicarboxylic acid 3- ethyl ester 5-methyl ester.
  • C 1 -C 5 alkyl includes linear and branched alkyl groups like methyl, ethyl, propyl, incl. n-propyl and i-propyl, butyl, incl. n-butyl, sec . -butyl and tert. -butyl, and pentyl , incl. n-pentyl and tert . - pentyl .
  • the definition C 3 -C 6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl
  • the definition aralkyl includes groups having a phenyl or naphthyl group, particularly a phenyl group, as the aryl moiety and a C- ⁇ Cg alkyl group as defined above as the alkyl moiety, the benzyl group being a particularly preferred aralkyl group.
  • Examples 1 - 2 illustrates the preparation of starting materials
  • examples 3 - 5 illustrates the process according to the invention
  • examples 6 - 8 illustrates the use of the acetal derivatives for the preparation of other valuable 1 , 4-dihydropyridines .
  • Example 1. 2 2-Diethoxy-ethanol .
  • the mixture was cooled on an icebath and 600 g of potassium carbonate was dissolved therein while stirring.
  • the mixture was extracted with 2 1 of diethyl ether and dried with MgS0 4 .
  • the diethyl ether was evaporated off and the crude product was distilled in vacuo at 75-76 'C (15 mm Hg) .
  • Example 3 4- (2-chloro-phenyl) -2- (2 , 2 -diethoxy- ethoxymethyl) -6 -methyl -1 , 4-dihydro-pyridine-3 , 5-dicar- boxylic acid 3-ethyl ester 5-methyl ester (4) .
  • Example 6 2 - (2-aminoethoxymethyl ) -4 - (2 -chloro- phenyl) -6-methyl-l , 4 -dihydropyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester, maleate; Amlodipine maleate .
  • Example 7 2 - (2 -aminoethoxymethyl) -4- (2-chloro- phenyl) -6-methyl-l , 4-dihydropyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester, maleate; Amlodipine maleate .
  • the mixture was filtered and then made alkaline with cone, ammonium hydroxide (pH > 8.5) .
  • the filtrate was extracted twice with dichloro- methane, and then dried with MgS0 4 .
  • the organic phase was evaporated to give 0.274 g (56.7 %) of the crude base.
  • the product was dissolved in a small amount of ethanol.
  • 0.08 g (0.7 mmol) maleic acid was added with cooling. After a while the maleate salt precipitated and was then filtered off and washed with diethyl ether and dried in vacuo, giving the product as a fine white powder.
  • Example 8 4- (2-chloro-phenyl) -2- (2 -benzyloxy- imino-ethoxymethyl) -6-methyl-l , 4 -dihydro-pyridine-3 , 5- -dicarboxylic acid 3-ethyl ester 5-methyl ester (8) .

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Abstract

A process for the preparation of 1,4-dihydropyridine acetal derivatives of formula (II) wherein R1 each, independently, represents H, Cl or CF¿3; R?2 represents H, C¿1?-C5 alkyl, C3-C6 cycloalkyl or aralkyl; R?3 and R4¿ which may be the same or different, represent C¿1?-C5 alkyl, C3-C6 cycloalkyl, aralkyl or together represent -(CH2)m-, wherein m is 2 or 3, and n is 1 or 2, wherein the 1,4-dihydropyridine ring structure is formed by a Hantzsch synthesis carried out in one or more steps using a compound containing a group of formula (a); wherein R?3 and R4¿ have the same meanings as defined above, as one of the reactants in the Hantzsch condensation, is described. The Hantzsch synthesis, or at least one step thereof, is carried out in a solvent, which is capable of forming an azeotrope with water, under azeotropic removal of water of reaction. The compounds of formula (II) are useful as intermediates for the preparation of pharmaceutically active 1,4-dihydropyridines and other intermediates of use for such purpose.

Description

PROCESS FOR THE PREPARATION OF ACETAL DERIVATIVES OF 1 , 4-DIHYDROPYRIDINES
5
The present invention relates to a process for the preparation of acetal derivatives of 1 , 4-dihydropyridines of the general formula II indicated below, which are useful as intermediates for the preparation of
10 pharmaceutically active 1 , 4-dihydropyridines as well as for the preparation of other intermediates of use for such purpose. Furthermore, the invention relates to the use of the acetal derivatives for such purpose.
In particular, the acetal derivatives are useful
15 for the preparation of 1 , 4-dihydropyridines of the general formula I indicated below, which have an amino group attached to a substituent in the 2 -position of the 1, 4-dihydropyridinium ring and pharmaceutically acceptable acid addition salts thereof.
20 Compounds belonging to this class of 1, 4-dihydropyridines have shown activity as calcium-channel biockers and have found utility as anti-ischaemic and antihypertensive agents. Furthermore, compounds of this class have been used in the treatment of Raynaud' s
25 syndrome.
A particularly preferred compound of this class of 1 , 4-dihydropyridines is the compound, 2-(2-amino- ethoxymethyl) -4- (2-chlorophenyl) -6-methyl-1 , 4-dihydro- pyridine-3 , 5-dicarboxylic acid 3 -ethyl ester 5-methyl
30 ester, known under the generic name, amlodipine.
With a single exception, the 1 , 4-dihydropyridine acetal derivatives of formula II appear to be novel compounds .
The present invention provides a process, whereby 35 the 1, 4-dihydropyridine acetal derivatives can be obtained in high yield by the Hantzsch synthesis. Thus the amlodipine acetal intermediate has been obtained in a yield of 42 % starting with the reaction of 2-di- ethoxyethanol with ethyl 4-chloroacetoacetate . As a further point, the acetal derivatives of formula II can be converted into the 1 , 4-dihydropyridines of formula I in high yield, whereby the latter can be obtained in a high overall yield. Thus amlodipine maleate has been obtained from the acetal derivative in a yield of 62 % corresponding to an overall yield of 29 % starting with the reaction of 2 , 2-diethoxyethanol with ethyl 4-chloroacetoacetate.
EP 0 089 167 B discloses amlodipine and other 1,4- dihydropyridines having an amino-containing group attached to the 2 -position and their preparation.
According to said patent, the 1 , 4-dihydropyridines are prepared by removal of the amino-protecting group from the corresponding amino-protected 1 , 4-dihydropyridine or by reduction of the corresponding azido com- pound into the amine. As well the amino-protected 1,4- dihydropyridines as the azido compounds are prepared by Hantzsch synthesis, which is carried out in a C]_-C4 alkanol solvent, particularly methanol , ethanol or isopropanol . In Example 11 in the patent an overall yield of 1 %, only, is stated for the production of amlodipine maleate starting with the reaction of 2-azido ethanol with ethyl 4-chloroacetoacetate, whereas an overall yield of 8.8 % is disclosed in a later publication by the inventors of EP 0 089 167 B, J. Med. Chem. , (1986), 29, 1696 - 1702, see particularly pp. 1700 - 1701.
The overall yield for the alternative process has not been given in the patent and cannot be calculated on the basis of the information given therein. However, in part calculated on the basis of yields reported by others having reproduced the process, the overall yield seems to be in the order of 12 - 20 %, starting with the reaction of 2-phthalimido ethanol with ethyl 4- chloroacetoacetate and ending with removal of the protecting group and preparation of the maleate salt. Using the process according to the invention and the acetal derivatives obtainable thereby, the 1,4- dihydropyridines of formula I can be obtained in higher overall yield. Furthermore, the use of potentially explosive azide starting materials (see e.g. Chem. Ind., (1986), 10, 337) is avoided.
The acetal derivatives of formula II can e.g. be converted into the 1 , 4-dihydropyridines of formula I by reaction with hydroxylamine or a derivative thereof to produce an oxime intermediate which is reduced to provide the desired 1 , 4-dihydropyridine, optionally as a pharmaceutically acceptable acid addition salt thereof, as described in more detail in the following.
CA 2,188,071 A discloses a process for the prep- aration of 1 , 4-dihydropyridine derivatives, i.a. amlodipine, by reductive amination of the corresponding aldehyde under specific conditions, or by reaction of the aldehyde with hydroxylamine hydrochloride and base to give the corresponding oxime followed by conversion of the oxime into the final product under specific conditions .
In CA 2,188,071 A it is stated that the dihy- dropyridine derivatives are formed in good yields employing easily available precursors, and that the overall yield is far greater than the prior art, i.e. 46 % for amlodipine. This yield, however, seems to be calculated on the compound, 4- (2-chlorophenyl) -2- (2 , 3- dihydroxypropoxymethyl ) - 1 , 4 -dihydro- 6 -methyl -3,5- pyridinedicarboxylic acid 3 -ethyl 5-methyl ester, in CA 2,188,071 A designated IC. But as this compound already includes the 1 , 4-dihydropyridine ring, an "overall" yield calculated on this basis cannot be compared to the overall yields indicated above.
A calculation on a comparable basis, i.e. based on the compound being reacted with ethyl 4-chloroacetoacetate, viz. the compound 2 , 2-dimethyl- [1 , 3] dioxolane- 4 , 5-dimethanol , gives a yield of the aldehyde intermediate of about 15 % resulting in an overall yield of amlodipine of about 7 %, i.e. several times smaller than the overall yield of about 29 % which has been obtained via the acetal derivative obtainable by the process according to the invention.
Also the yields, which have been obtained by conversion of the aldehyd intermediate into amlodipine by the process according to CA 2,188,071 A (about 48 % by the reductive amination and about 43 % by conversion via the oxime) , are far below the yield of about 62 %, which has been obtained using the acetal intermediate according to the invention as starting material, the latter yield even including the preparation of the maleate salt.
Incidentally, CA 2,188,071 A discloses an acetal, viz. the compound 4 - (2-chlorophenyl) -2 - (2 , 2-dimethoxy- ethoxymethyl) -1, 4-dihydro-6-methyl-3 , 5-pyridinedicar- boxylic acid 3-ethyl 5-methyl ester, as well as its preparation from 2 , 2-dimethoxyethanol and 2-(2-chloro- methyl) -4 - (2-chlorophenyl) -1 , 4 -dihydro-6-methyl-3 , 5- pyridinedicarboxylic acid 3-ethyl 5-methyl ester and its conversion into a bicyclic structure forming an oxazine ring with the pyridine nitrogen atom (cf. Examples 11 and 12) . However, neither the preparation of the acetal by Hantzsch synthesis nor any possible use of the acetal as intermediate in the preparation of amlodipine or its conversion into the corresponding oxime has been disclosed. CA 2,188,071 A also includes a general formula XX for an acetal, but the formula includes two undefined substituents, R10 and Rn, and accordingly it cannot be considered an anticipating disclosure of any specific acetal. Furthermore, neither the preparation of the acetal by Hantzsch synthesis nor any possible use of the acetal as intermediate in the preparation of amlodipine or any other 1 , 4-dihydropyridine having a substituent with an amino group in the 2 -position of the 1 , 4-dihydropyridinium ring or its conversion to the corresponding oxime has been disclosed.
EP 225 175 A2 discloses a substantive number of 1 , 4-dihydropyridine derivatives and different processes for their preparation. Amlodipine is not among the disclosed derivatives. One of the disclosed processes is a process for the preparation of a 1 , 4-dihydropyridine derivative, i.a. having a (2 -aminoethoxy) methyl substituent in the 2 -position, but a fluoromethyl substituent in the 6 -position. The 1 , 4-dihydropyridine derivative is prepared by reduction of the corresponding oxime which in turn is prepared by reaction of the corresponding acetal with hydroxylamine.
However, EP 225 175 A2 does not mention anything about the acetal being obtained directly by the Hantz- sch synthesis and even less by a Hantzsch synthesis carried out under azeotropic removal of water of reaction as specified herein and the particular advantages obtainable thereby.
On the contrary, the acetal is prepared from the corresponding bromomethyl substituted 1 , 4-dihydropyridine derivative obtained by reaction of the corresponding methyl substituted 1 , 4-dihydropyridine derivative with pyridinium perbromide, a process which would be unsuitable for the preparation of the acetal deriva- tives prepared by the process according to the present invention due to side reactions.
Thus, it can be concluded, that the process according to the invention and the use of the acetal derivatives obtainable thereby for the preparation of 1 , 4-dihydropyridines having a substituent with an amino group in the 2 -position of the 1 , 4-dihydropyridinium ring and a methyl group in the 6 -position, particularly amlodipine, presents substantive advantages over the prior art and cannot be considered obvious in view thereof.
Accordingly, the invention provides a process for the preparation of 1 , 4-dihydropyridine acetal derivatives of the general formula II
Figure imgf000008_0001
wherein
R1 each, independently, represents H, Cl or CF3 , R2 represents H, Cx-C5 alkyl, C3-C6 cycloalkyl or aralkyl ,
R3 and R , which may be the same or different, represent C^C^ alkyl, C3-C6 cycloalkyl, aralkyl or together represent -(CH2)m-, wherein m is 2 or 3, and n is 1 or 2, in which process the 1 , 4-dihydropyridine ring structure is formed by a Hantzsch synthesis carried out in one or more steps using a compound containing a group of the formula 0R-
/
-CH20CH2CH H
\
OR4
wherein
R3 and R4 have the same meanings as defined above, as one of the reactants in the Hantzsch condensation, the Hantzsch synthesis, or at least one step thereof, being carried out in a solvent, which is capable of forming an azeotrope with water, under azeotropic removal of water of reaction. The Hantzsch synthesis as such is well-known in the art . In principle it is carried out by reacting an aldehyde with a /3-keto ester and an aminocrotonic acid ester as shown in the following Scheme 1, illustrating the preparation of compounds of formula II:
Figure imgf000010_0001
Figure imgf000010_0002
Scheme 1
However, as is known in the art, various modifications of the Hantzsch synthesis are possible.
Instead of performing the reaction in one step as illustrated above, the synthesis can be carried out using preformed intermediates, e.g. as illustrated in the following Schemes 2, 3 and 4:
Figure imgf000010_0003
Scheme 2
Figure imgf000011_0001
Scheme 3
Figure imgf000011_0002
Scheme 4
As will be appreciated by a person skilled in the art the above schemes are only examples and other modifications of the Hantzsch synthesis can be made without deviating from the scope and spirit of the invention.
The reaction with the ketoester can be assisted by addition of an amine, particularly a secondary amine such as piperidine or morpholine. According to the invention the Hantzsch synthesis, or at least one step thereof, is carried out in a solvent, which is capable of forming an azeotrope with water, under removal of water of reaction as an azeotrope with the solvent . If the Hantzsch synthesis is carried out in more than one step, such as in two steps, all steps will normally be carried out in a solvent, which is capable of forming an azeotrope with water, under azeotropic removal of water of reaction although benefits may be obtained already by carrying out a single step of the synthesis under such conditions. Steps carried out in a solvent not being capable of forming an azeotrope with water may e.g. be carried out in a lower alkanol such as methanol , ethanol or isopropanol as is known in the art.
As specific examples of solvents being capable of forming an azeotrope with water, toluene, benzene and xylene can be mentioned with toluene as a presently preferred solvent. The azeotropic removal of water of reaction is preferably carried out by heating of the reaction mixture to reflux for a sufficient period to allow the reaction to take place, using a water separator such as a Dean-Stark separator to catch the water of reaction. In a preferred embodiment, the process according to the invention comprises the step of reacting a compound of the general formula IV
Figure imgf000012_0001
with a compound of the general formula V
Figure imgf000013_0001
In another preferred embodiment, the process according to the invention comprises the step of reacting a compound of the general formula VI
Figure imgf000013_0002
with a compound of the general formula VII
Figure imgf000013_0003
Generally, the starting materials used in the process according to the invention are either known compounds or may be prepared by processes known in the art for the preparation of similar compounds.
With the exception of the compound 4- (2-chlorophenyl ) - 2 - (2,2 -dimethoxy-ethoxymethyl ) - 1 , 4 -dihydro- 6 - methyl-3 , 5-pyridine-dicarboxylic acid 3-ethyl 5-methyl ester, the acetales of formula II appear to be novel compounds and as such represent a particular aspect of the invention.
A specific group of acetales according to the invention are the compounds of the general formula II
Figure imgf000014_0001
wherein
R1 each, independently, represents H, Cl or CF3 ,
R2 represents H, C^-^ alkyl, C3-C6 cycloalkyl or aralkyl ,
R3 and R4 , which may be the same or different, represent C1-C5 alkyl, C3-C6 cycloalkyl, aralkyl or together represent -(CH2)m-, wherein m is 2 or 3, and n is 1 or 2, with the proviso that when R2 is H, and no R1 is CF3 , then R3 and R4 are other than methyl.
A preferred group of novel acetales of the general formula II is represented by the compounds wherein n is
1, R1 is chloro in the 2 -position of the phenyl ring,
R2 is H, and R3 and R4 , which may be the same or dif- ferent, represent C2-C5 alkyl.
Particularly preferred is the compound 4- (2- chlorophenyl) -2- (2 , 2-diethoxy-ethoxymethyl) - 6 -methyl - 1 , 4-dihydro-pyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester. The acetal derivatives of the general formula II are useful for the preparation of pharmaceutically active 1 , 4-dihydropyridines and other intermediates of use for such purpose.
A particular aspect of the invention relates to the use of acetal derivatives of the general formula II as an intermediate for the preparation of a 1, 4-dihydropyridine of the general formula I
Figure imgf000015_0001
wherein R .11 each, independently, represents H, Cl or CF3 ,
R2 represents H, C1-C5 alkyl, C3-C6 cycloalkyl or aralkyl , and n is 1 or 2, or an acid addition salt thereof, particularly amlodi- pine or an acid addition salt thereof.
A specific embodiment relates to the use of an acetal derivative of the general formula II wherein n is 1, R1 is chloro in the 2 -position of the phenyl ring, R2 is H, and R3 and R4 , which may be the same or different, represent C1-C5 alkyl, for the preparation of amlodipine or an acid addition salt thereof.
The 1 , 4-dihydropyridines of the general formula I and acid addition salts thereof can be obtained by reacting an acetal derivative of the formula II with a compound of the formula
R5ONH2
or an acid addition salt thereof, wherein R5 represents H, C1-C5 alkyl, C3-C6 cycloalkyl or aralkyl , so as to provide an oxime of the general formula III
Figure imgf000016_0001
wherein
R1, R2 , R5 and n have the same meanings as defined above , and reducing the formed oxime of formula III so as to provide a 1 , 4-dihydropyridine of formula I, and, if desired, converting a compound of formula I obtained as the free base into a pharmaceutically acceptable acid addition salt thereof or vice versa. The reaction of the acetal of formula II with R5ONH2 or an acid addition salt thereof to give the oxime of formula III may be carried out in an appropriate solvent, such as an alcoholic solvent comprising a lower alkanol, such as methanol , ethanol or isopropa- nol, e.g. in admixture with water. E.g. an aqueous solution of R5ONH2 , hydrochloride may be combined with a solution of the acetal in methanol, and the mixture heated to reflux for a suitable period, such as 2 - 8 hours, normally around 4 hours. The reduction of the oxime of formula III into the desired 1 , 4-dihydropyridine of formula I may be carried out using a suitable reduction agent selected from the numerous reduction agents being known for the reduction of oximes into amines, see e.g. the surveys given in R. C. arock, "Comprehensive Organic Transformations", VCH
Publishers, (1989). p. 424, Houben-Weyl : "Methoden der
Organischen Chemie", Vol. E16d, Part 2, (1992), pp. 884
893, and Houben-Weyl: "Methoden der Organischen
Chemie", Vol. Xl/1, (1957), pp. 495 -504. E.g., the reduction may be carried out by cataly- tical hydrogenation, preferably using a nobel metal catalyst, such as platinum or palladium, or a Raney nickel catalyst. The reduction is preferably carried out under acidic conditions. In a specific embodiment, the reduction may be carried out by catalytical hydrogenation in acetic acid using palladium-on-carbon as a catalyst.
The reduction may also be carried out using sodium borohydride/nickel chloride hydrate as reduction agent. As other examples of catalysts, which may be of use for the present purpose, the following can be mentioned: sodium borohydride in combination with other compounds, such as titanium tetrachloride or molybdenum trichloride; lithium aluminum hydride or zinc powder. A compound of formula I obtained as the free base may, if desired, be converted into a pharmaceutically acceptable acid addition salt thereof or vice versa. The hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, besylate, lactate, tartrate, citrate and gluconate salts are examples of such pharmaceutically acceptable acid addition salts. The maleate and the besylate salts are particularly preferred.
Another aspect of the invention relates to the use of the acetal derivatives of the general formula II as intermediates for the preparation of oximes of the general formula III
Figure imgf000017_0001
wherein R1 each, independently, represents H, Cl or CF3 , R2 represents H, C1-C5 alkyl, C3-C6 cycloalkyl or aralkyl,
R5 represents H, C-^^ alkyl, C3-C6 cycloalkyl or aralkyl, and n is 1 or 2, particularly the compound, 4- (2-chlorophenyl) -2- (2- hydroxyimino-ethoxymethyl ) - 6 -methyl -1,4 - dihydro - pyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester. A specific embodiment relates to the use of an acetal derivative of the general formula II wherein n is 1, R1 is chloro in the 2 -position of the phenyl ring, R2 is H, and R3 and R4 , which may be the same or different, represent C1-C5 alkyl, for the preparation of 4- (2-chlorophenyl) -2- (2-hydroxyimino-ethoxymethyl) - 6 -methyl -1 , 4-dihydropyridine-3 , 5-dicarboxylic acid 3- ethyl ester 5-methyl ester.
In the present specification and claims, the definition C1-C5 alkyl includes linear and branched alkyl groups like methyl, ethyl, propyl, incl. n-propyl and i-propyl, butyl, incl. n-butyl, sec . -butyl and tert. -butyl, and pentyl , incl. n-pentyl and tert . - pentyl . The definition C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the definition aralkyl includes groups having a phenyl or naphthyl group, particularly a phenyl group, as the aryl moiety and a C-^Cg alkyl group as defined above as the alkyl moiety, the benzyl group being a particularly preferred aralkyl group. The invention will now be further illustrated by specific examples which, however, should not be regarded as any limitation of the scope of the invention.
Examples 1 - 2 illustrates the preparation of starting materials, examples 3 - 5 illustrates the process according to the invention, and examples 6 - 8 illustrates the use of the acetal derivatives for the preparation of other valuable 1 , 4-dihydropyridines .
EXAMPLES .
Example 1. 2 , 2-Diethoxy-ethanol .
302,6 g (8 mol) of sodium borohydride was added to 2 1 of 1 , 2-dimethoxyethane (monoglyme) with stirring, after which 704,8 g (4 mol) ethyl diethoxyacetate dissolved in 4 1 of ethanol was added dropwise within 4 hours so that the temperature was kept below 50 "C. The mixture was then heated to reflux for 3 hours. Then 2 1 of ethanol was distilled off, and 4 1 of water was added dropwise while the remaining ethanol and then the 1 , 2-dimethoxyethane was removed by distillation. During the water addition an abundant precipitate was formed which dissolved towards the end of the addition. The mixture was cooled on an icebath and 600 g of potassium carbonate was dissolved therein while stirring. The mixture was extracted with 2 1 of diethyl ether and dried with MgS04. The diethyl ether was evaporated off and the crude product was distilled in vacuo at 75-76 'C (15 mm Hg) .
Yield = 475.8 g = 88.7 %
Elemental analysis: Calculated: C 53.7% H 10.5%
Found: C 53.11% H 10.57%
IR: 3441 cm"1; 2976 cm"1; 2931 cm"1; 2883 cm"1; 1445 cm"1 1374 cm"1; 1345 cm"1; 1235 cm"1; 1134 cm"1; 1073 cm"1 (Between KBr plates) Example 2. 4- (2 , 2-Diethoxy-ethoxy) -3-oxo-butyric acid ethyl ester (1) .
To a stirred suspension of 58,8 g 60 % (1.47 mol) sodium hydride in 600 ml anhydrous tetrahydrofuran, a solution of 94 g (0.7 mol) 2 , 2-diethoxy-ethanol in 160 ml tetrahydrofuran was added dropwise, so that the temperature was kept below 40 °C. After completion of the addition, the reaction mixture was stirred for further 30 minutes. Then 115 g (0.7 mol) ethyl 4- chloroacetoacetate in 500 ml anhydrous tetrahydrofuran was added dropwise within 3 hours, so that the temperature was kept between 10 °C and 40 *C, preferentially at about 20 'C. The mixture was stirred overnight at room temperature. Then 90 ml ethanol was added drop- wise, and the mixture was poured into 900 g of ice after which pH was adjusted to 6 with hydrochloric acid. The organic phase was separated and dried over MgS04. The tetrahydrofuran was evaporated off and the product was separated from the oily layer in a separation funnel. Then the product was dissolved in toluene and purified by filtration through a short column of silica. The toluene was evaporated off, leaving the product as a light yellow oil. The product was purified by distillation in vacuo .
yield: 130.9 g = 71.4 %
bp. = 112-114 °C at 0.2 mm Hg
Elemental analysis: Calculated: C 54.9% H 8.5% Found: C 54.48% H 8.7%
IR: 2986 cm" 1726 cm -1 1748 cm" 1119 cm" 1067 cm -1 (Between KBr plates)
NMR: 250 MHz 1H-NMR (CDC13) (δ ppm) :
4.646 (t, H, CH) ; 4.286 (s, 2H, CH2 ) ; 4.224 (s, 2H, CH2) ; 3,708 (q, 2H, CH2 ) ; 3.568 (q, 2H, CH2 ) ; 3.556 (d, 2H, CH2) ; 1.30 (t, 3H, CH3 ) ; 1.21 (m, 6H, CH3 ) .
Example 3. 4- (2-chloro-phenyl) -2- (2 , 2 -diethoxy- ethoxymethyl) -6 -methyl -1 , 4-dihydro-pyridine-3 , 5-dicar- boxylic acid 3-ethyl ester 5-methyl ester (4) .
A. 3- (2-chloro-phenyl) -2- [2- (2 , 2 -diethoxy-eth- oxy) -acetyll -acrylic acid ethyl ester (cis and trans isomer) (2) .
A solution of 53 g (0.38 mol) 2-chlorobenzalde- hyde, 98 g (0.38 mol) 4- (2 , 2-diethoxy-ethoxy) -3-oxo- butyric acid ethyl ester (1) and 6 ml piperidine in 1600 ml toluene was refluxed in a Dean-Stark water separator for four hours until 6.2 ml of water had been separated (theoretical amount = 6.5 ml) . The reaction mixture was cooled to room temperature and washed twice with 200 ml of water, then with 500 ml of a saturated solution of sodium bisulphite and finally with 200 ml of water. The mixture was dried over MgS04 and the toluene was evaporated off to give the product as a dark red oil .
yield: 99.3 g = 67.9 %
Elemental analysis:
Calculated: C 59.3% H 6.5% Cl 9.2%
Found: C 59.41% H 7.11% Cl 9.2%
IR: 2977 cm"1; 2931 cm"1; 1725 cm"1; 1617 cm"1; 1443 cm"1; 1375 cm"1; 1253 cm"1; 1121 cm"1; 1057 cm"1; 760 cm"1; (Between KBr plates)
NMR: 500 MHz 1H-NMR (CDC13) (δ ppm) : Mixture of geometric isomers
8.07, 7.97 (2 s cis, trans, 1H, CH) ; 7.48-7.12 (m, 4H,
ArH) ; 4.656, 4.576 (2 t cis, trans, 2H, CH) ; 4.3 (d.d.,
2H, CH2) ; 4.154 (m, 2H, CH2 ) ; 3.682 (m, 2H, CH2 ) ; 3.53
(m, 4H, CH2) ; 1.324 (t, 3H, CH3 ) ; 1.184 (t, 6H, CH3 ) .
B . 4- (2-chloro-phenyl) -2- (2 , 2-diethoxyethoxyme- thyl) -6 -methyl -1 , 4-dihydro-pyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester (4) .
A mixture of 83 g (0.218 mol) 3- (2-chloro-phenyl) - 2- [2- (2 , 2-diethoxy-ethoxy) -acetyl] -acrylic acid ethyl ester (cis and trans isomer) (2) and 25 g (0.218 mol) of methyl-3 -aminocrotonate in 800 ml toluene was refluxed in a Dean-Stark water separator for 30 hours. Toluene was evaporated off to give 104 g of the crude product (70 % purity, HPLC) as a dark red oil. The crude product was chromatographed on silica with toluene/ethylacetate 20:1 as eluent . Appropriate fractions were combined to give the product (95-98 % purity, HPLC) as a light yellow glass, which crystallized after several days of standing.
yield: 56.6 g = 53.9 %
mp. 64-67 °C
Elemental analysis:
Calculated: C 59.8% H 6.7% N 2.9% Cl 7.4%
Found: C 59.59% H 7.14% N 2.76% Cl 7.5% IR: 3349 cm"1; 2977 cm"1; 2931 cm"1; 1692 cm"1; 1646 cm" 1611 cm-1; 1482 cm"1; 1208 cm"1; 1163 cm"1; 1100 cm"
Figure imgf000023_0001
(KBr)
NMR: 500 MHz 1H-NMR (CDCl3) (δ ppm) :
7.41 (br. s, 1H, NH) ; 7.08-7.39 (m, 4H, ArH) ; 5.42 (s, 1H, CH) ; 4.774 (d.d., 2H, CH2 ) ; 4.684 (t, 1H, CH) ; 4.04 (q, 2H, CH2); 3.74 (m, 2H, CH2 ) ; 3.61 (s, 3H, CH3 ) ; 3.58 (s, 4H, CH2) ; 2.35 (s, 3H , CH3 ) ; 1.26 (d. t, 6H, CH3) ; 1.176 (d. t, 3H, CH3 ) .
FAB-MS: 482 [MH+],481 [M+],370 [M+-C6H4Cl]
Example 4. 4 - (2 -chloro-phenyl) -2- (2 , 2-diethoxy- ethoxymethyl) -6 -methyl -1 , 4-dihydro-pyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester (4) .
A. 3 -amino-4- (2 , 2-diethoxy-ethoxy) but-2-enoic acid ethyl ester (3) .
A mixture of 26.2 g (0.1 mol) 4- (2 , 2-diethoxy- ethoxy) -3 -oxo-butyric acid ethyl ester (1) and 8.47 g (0.11 mol) of ammonium acetate in 75 ml of ethanol was refluxed for 60 minutes. The ethanol was evaporated off and the resulting crude 3 -amino-4- (2 , 2-diethoxy-ethoxy) but-2-enoic acid ethyl ester was dissolved in 100 ml of toluene and washed twice with 75 ml of water. The organic phase was evaporated off and the crude product was distilled in vacuo giving the pure compound as a colourless liquid.
bp. = 130-131 'C at 0.3 mm Hg yield : 23 . 0 g = 88 %
Elemental analysis:
Calculated: C 55.2% H 8.9% Cl 5.4% Found: C 55.91% H 8.9% Cl 5.4%
IR: 3445 cm"1; 3336 cm"1; 2976 cm"1; 2930 cm"1;1669 cm"1; 1622 cm"1; 1564 cm"1; 1445 cm"1; 1367 cm"1; 1286 cm"1; 1162 cm"1; 1116 cm"1; 1065 cm"1; 788 cm"1.
NMR: 250 MHz 1H-NMR (CDC13) (δ ppm) : (Imine tautomer) 4.632 (t, H, CH) ; 4,512 (s br . , H, NH) ; 4,112 (q, 2H, CH2) ; 4,102 (s, 2H, CH2 ) ; 3,705 (q, 2H, CH2 ) ; 3,576 (q, 2H, CH2) ; 3,508 (d, 2H, CH2 ) ; 1,266 (m, 9H, CH3 )
FAB-MS: 261 [MH+] , 216, 170
B . 4- (2-chloro-phenyl) -2- (2 , 2 -diethoxyethoxy- methyl) -6-methyl-l , 4-dihydro-pyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester (4) .
26,13 g (0,1 mol) 3 -amino-4- (2 , 2-diethoxy-ethoxy) -but -2 -enoic acid ethyl ester (3) and 23.90 g (0.1 mol) 2-acetyl-3- (2-chloro-phenyl) -acrylic acid methyl ester was dissolved in 200 ml toluene and refluxed in a Dean-Stark water separator for 26 hours. Toluene was evaporated off to give the crude product (88% purity, HPLC) as a yellow oil, which became semicrystalline overnight. The semicrystalline product was stirred vigorously with hexane for a few hours. The resulting crystalline product was filtered off and dried to give 28 g of the pure product. The hexane was evaporated off and the residue was chromatographed on silica with toluene/ethylacetate 20:1 as eluent . Appropriate fractions were combined to give the product (95-98% purity, HPLC) as a light yellow glass, which was stirred with hexane for a few hours. This gave further 8,30 g of pure product after filtering and drying.
Combined yield: 36.3 g = 75.3 %
mp. 64-67 °C
Elemental analysis:
Calculated: C 59.8% H 6.7% N 2.9% Cl 7.4%
Found: C 59.59% H 7.14% N 2.76% Cl 7.5%
IR: 3349 cm"1; 2977 cm"1; 2931 cm"1; 1692 cm"1;1646 cm"1; 1611 cm"1; 1482 cm"1; 1208 cm"1; 1163 cm"1; 1100 cm"1; 1060 cm"1; 757 cm"1; (KBr)
NMR: 500 MHz 1H-NMR (CDC13) (δ ppm) : 7.41 (br. s, 1H, NH) ; 7.08-7.39 (m, 4H, ArH) 5.42 (s, 1H, CH) ; 4.774 (d.d., 2H, CH2 ) ; 4.684 (t, 1H, CH) ; 4.04 (q, 2H, CH2) ; 3.74 (m, 2H, CH2 ) ; 3.61 (s, 3H, CH3 ) ; 3.58 (s, 4H, CH2) ; 2.35 (s, 3H, CH3 ) ; 1.26 (d. t, 6H, CH3) ; 1.176 (d. t, 3H, CH3).
FAB-MS: 482 [MH+] ,481 [M+] ,370 [M+- CfiH4Cl]
Example 5.1 -Benzyl - -4- (2-chloro-phenyl) -2-(2,2-di- ethoxy-ethoxymethyl) -6- - methyl- 1 , 4 - di hydro -pyr i dine -
-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester
(7)
A mixture of 9.6 g (0.025 mol) 3- (2-chloro-phenyl) -2- [2- (2 , 2-diethoxy-ethoxy) -acetyl] -acrylic acid ethyl ester (cis and trans isomer) (2) and 5.12 g (0.025 mol) of methyl -3 -benzylaminocrotonate in 250 ml toluene was refluxed in a Dean-Stark water separator for 48 hours. The toluene was evaporated off to give 14 g of the crude product (68 % purity) as a dark red oil. The crude product was chromatographed on silica with chloroform as eluent.
Appropriate fractions were combined to give the product (95-98% purity) as a light brown oil.
yield: 7.8 g = 55 %
Elemental analysis:
Calculated: C 65.1% H 6.7% N 2.4% Cl 6.2%
Found: C 64.38% H 7.06% N 2.34% Cl 6.4%
FAB-MS: 572 [MH+] , 571 [M+]
Example 6. 2 - (2-aminoethoxymethyl ) -4 - (2 -chloro- phenyl) -6-methyl-l , 4 -dihydropyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester, maleate; Amlodipine maleate .
A. 4- (2-chloro-phenyl) -2- (2-hvdroxyimino-ethoxy- methyl) -6-methyl-l, 4-dihydro-pyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester (5) .
2,4 g (5 mmol) 4- (2-chloro-phenyl) -2- (2 , 2-di- ethoxy-ethoxymethyl) -6-methyl-l, 4-dihydro-pyridine-3 , 5- -dicarboxylic acid 3-ethyl ester 5-methyl ester (4) was dissolved in 75 ml methanol. 20 ml of 0,5 M hydroxylamine hydrochloride in water was added, and the mixture was refluxed for four hours. The methanol was evaporated off, and 75 ml of chloroform was added. The organic phase was washed twice with 75 ml of water and then dried with magnesium sulphate. The chloroform was evaporated off leaving the crude product which was stirred for a few hours with 40 ml of petroleum ether bp. 60-80 °C and 10 - 15 ml of toluene. The precipitate was filtered off and then washed with petroleum ether, giving the product as a white powder.
yield: 1.40 g = 66.2 %
mp. 159-160 °C
Elemental analysis:
Calculated: C 56.8% H 5.5% N 6.6% Cl 8.4
Found: C 56.8% H 5.67% N 6.4% Cl 8.5%
IR: 3405 cm"1; 2982 cm"1; 2947 cm"1; 1694 cm"1;1607 cm"1; 1481 cm"1; 1310 cm"1; 1284 cm"1; 1211 cm"1; 1101 cm"1; 758 cm"1; (KBr)
FAB-MS: 423 [MH+],422 [M+],311 [M+-C6H4C1]
NMR: 500 MHz 1H-NMR (CDCl3) (δ ppm) :
6.96-7.57 (m, 6H, ArH, CH, NH) 5.414 (s, 1H, CH) ; 4.774 (d.d., 2H, CH2) ; 4.462 (d, 1H, OH); 4.232 (d. d, 2H, CH2) ; 4.048 (m, 2H, CH2 ) ; 3.618 (s, 3H, CH3 ) ; 2.34 (s, 3H, CH3) ; 1.18 (t, 3H, CH3 ) .
B. 2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -6- methyl-1 , 4-dihydropyridine-3 , 5-dicarboxylic acid 3- ethyl ester 5-methyl ester, maleate; Amlodipine maleate .
1.00 g (2.4 mmol) 4- (2-chloro-phenyl) -2- (2-hydroxyimino-ethoxymethyl ) -6-methyl-l , 4 -dihydro-pyri- dine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester (5) was dissolved in 20 ml glacial acetic acid and hydrogenated for four hours at atmospheric pressure and room temperature using 0.062 g palladium 10% on carbon as catalyst. The catalyst was filtered off after which the acetic acid was evaporated off. The residue was dissolved in ether and washed successively with 10% sodium bicarbonate solution and water. After drying with MgS04 the ether was evaporated off and the residue was dissolved in a small volume of ethanol. To the resulting solution 0.28 g (2.4 mmol) of maleic acid was added with cooling. The maleate salt precipitated after a while and was then filtered off and washed with diethyl ether and dried in vacuo, giving 0.9 g of the product as a fine white powder. By addition of a small amount of ether to the mother liquor further 270 mg of product was obtained.
Combined yield: 1.17 g = 92.9 %
mp. 170-172 "C
Elemental analysis:
Calculated: C 54.9% H 5.6% N 5.3% Cl 6.8% Found: C 53.86% H 5.6% N 5.11% Cl 6.9%
IR: 3392 cm"1; 2946 cm"1; 1688 cm"1; 1648 cm"1; 1603 cm"1; 1479 cm"1; 1283 cm"1; 1206 cm"1; 1100 cm"1; 759 cm"1; (KBr)
FAB-MS: 409 [MH+],408 [M+],297 [M+-C6H4Cl]
NMR: 500 MHz 1H-NMR (D6-DMS0) (δ ppm) :
8.37 (s, 1H, NH) ; 7.87 (br. s, 3H, NH) ; 7.10-7.35 (m,
4H, ArH) ; 6.06 (s, 2H, CH) ; 5.31 (s, 1H, CH) ; 4.66 (d. d., 2H, CH2) ; 3.97 (q, 2H, CH2 ) ; 3.66 (t, 2H, CH2 ) ; 3 . 50 ( s , 3H , CH3 ) ; 3 . 09 ( t , 2H , CH3 ) ; 2 . 3 ( t , 3H , CH3 ) ; 1 . 12 ( t , 3H , CH3 ) .
Example 7. 2 - (2 -aminoethoxymethyl) -4- (2-chloro- phenyl) -6-methyl-l , 4-dihydropyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester, maleate; Amlodipine maleate .
0.5 g (1.2 mmol) 4- (2 -chloro-phenyl) -2- (2-hy- droxyimino-ethoxymethyl) -6-methyl-l, 4-dihydro-pyridine- -3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester (5) and 0.56 g (2.4 mmol) nickel chloride hydrate was dissolved in 35 ml methanol and cooled to -30 °C. 0.454 g (0.012 mol) sodium borohydride was added in small portions over 30 minutes whereafter the mixture was stirred for 1 hour at room temperature. The mixture was evaporated to dryness and 20 ml of 6N hydrochloric acid was added with stirring. The mixture was filtered and then made alkaline with cone, ammonium hydroxide (pH > 8.5) . The filtrate was extracted twice with dichloro- methane, and then dried with MgS04. The organic phase was evaporated to give 0.274 g (56.7 %) of the crude base. The product was dissolved in a small amount of ethanol. To the resulting solution 0.08 g (0.7 mmol) maleic acid was added with cooling. After a while the maleate salt precipitated and was then filtered off and washed with diethyl ether and dried in vacuo, giving the product as a fine white powder.
yield: 0.21 g = 33.4 %
mp. 170-172 °C Elemental analysis:
Calculated: C 54.9% H 5.6% N 5.3% Cl 6.8%
Found: C 54.94% H 5.65% N 5.23% Cl 7.05%
IR: 3392 cm"1; 2946 cm"1; 1688 cm"1; 1648 cm"1; 1603 cm" 1479 cm"1; 1283 cm"1; 1206 cm"1; 1100 cm"1; 759 cm"1; (KBr)
FAB-MS: 409 [MH+],408 [M+],297 [M+-C6H4C1]
Example 8. 4- (2-chloro-phenyl) -2- (2 -benzyloxy- imino-ethoxymethyl) -6-methyl-l , 4 -dihydro-pyridine-3 , 5- -dicarboxylic acid 3-ethyl ester 5-methyl ester (8) .
2,4 g (5 mmol) 4- (2-chloro-phenyl) -2- (2 , 2-diethoxy-eth- oxymethyl) -methyl-1, 4-dihydro-pyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester (4) was dissolved in 75 ml methanol. 20 ml of 0,5 M O-benzylhydroxylamine hydrochloride in water was added, and the mixture was refluxed for four hours. The methanol was evaporated off, and 75 ml of dichloromethane was added. The organic phase was washed twice with 75 ml of water and then dried with magnesium sulphate. Dichloromethane was evaporated off leaving the product as an oil . The crude product was chromatographed on silica with chloroform as eluent. Appropriate fractions were combined to give the product as a brown oil.
yield: 2.3 g = 90 %
Elemental analysis:
Calculated: C 63.2% H 5.7% N 5.5% Cl 6.9%
Found : C 62.5% H 5.8; N 5.2 Cl 6.6=i FAB-MS: 513 [MH+] , 512 [M+],401 [M+-C6H4Cl]
In the preceding the invention has been described by means of specific examples of preferred embodiments. However, it will be appreciated by a person skilled in the art that various modifications can be made without deviating from the spirit and scope of the invention.

Claims

P A T E N T C L A I M S 1. A process for the preparation of 1 , 4-dihydropyridine acetal derivatives of the general formula II
Figure imgf000032_0001
wherein
R1 each, independently, represents H, Cl or CF3 , R2 represents H, C^Cg alkyl, C3-C6 cycloalkyl or aralkyl ,
R3 and R4 , which may be the same or different, represent C-L-Cς alkyl, C3-C6 cycloalkyl, aralkyl or together represent -(CH2)m-, wherein m is 2 or 3, and n is 1 or 2, c h a r a c t e r i z e d in that the 1,4-dihy- dropyridine ring structure is formed by a Hantzsch synthesis carried out in one or more steps using a compound containing a group of the formula
OR-
/ -CH2OCH2CH
\
OR4
wherein
R3 and R4 have the same meanings as defined above, as one of the reactants in the Hantzsch condensation, the Hantzsch synthesis, or at least one step thereof, being carried out in a solvent, which is capable of forming an azeotrope with water, under azeotropic removal of water of reaction.
2. A process according to claim 1, c h a r a c t e r i z e d in comprising the step of reacting a compound of the general formula IV
Figure imgf000033_0001
with a compound of the general formula V
Figure imgf000033_0002
3. A process according to claim 1, c h a r a c t e r i z e d in comprising the step of reacting a compound of the general formula VI
Figure imgf000033_0003
with a compound of the general formula VII
Figure imgf000034_0001
4. A process according to any of claims 1 - 3, c h a r a c t e r i z e d in using toluene, benzene or xylene as solvent which is capable of forming an azeotrope with water.
5. A process according to any of claims 1 - 4, c h a r a c t e r i z e d in using toluene as solvent which is capable of forming an azeotrope with water.
6. An acetal derivative of the general formula II
Figure imgf000034_0002
wherein
R1 each, independently, represents H, Cl or CF3 , R2 represents H, C^Cg alkyl, C3-C6 cycloalkyl or aralkyl , R3 and R4 , which may be the same or different, represent C1-C5 alkyl, C3-C6 cycloalkyl, aralkyl or together represent -(CH2)m-, wherein m is 2 or 3, and n is 1 or 2, with the exception of the compound 4- (2-chlorophenyl) - 2 - (2,2 -dimethoxy-ethoxymethyl) -1 , 4-dihydro-6-methyl- 3 , 5-pyridine-dicarboxylic acid 3-ethyl 5-methyl ester.
7. An acetal derivative of the general formula II
Figure imgf000035_0001
wherein
R1 each, independently, represents H, Cl or CF3 ,
R2 represents H, C-^^ alkyl, C3-C6 cycloalkyl or aralkyl , R3 and R4 , which may be the same or different, represent C-j^^ alkyl, C3-C6 cycloalkyl, aralkyl or together represent -(CH2)m-, wherein m is 2 or 3 , and n is 1 or 2, with the proviso that when R2 is H, and no R1 is CF3 , then R3 and R4 are other than methyl .
8. An acetal derivative of the general formula II
Figure imgf000035_0002
wherein n is i,
R1 is chloro in the 2 -position of the phenyl ring,
R2 is H, and
R3 and R4 , which may be the same or different, represent C2-C5 alkyl.
9. The compound 4- (2-chlorophenyl) -2- (2 , 2 -diethoxy-ethoxymethyl) -6-methyl-l, 4-dihydro-pyridine-3 , 5- dicarboxylic acid 3-ethyl ester 5-methyl ester.
10. The use of an acetal derivative of the general formula II
Figure imgf000036_0001
wherein
R1 each, independently, represents H, Cl or CF3 , R2 represents H, C^Cg alkyl, C3-C6 cycloalkyl or aralkyl ,
R3 and R4 , which may be the same or different, represent C-^Cg alkyl, C3-C6 cycloalkyl, aralkyl or together represent -(CH2)m-, wherein m is 2 or 3, and n is 1 or 2, as an intermediate for the preparation of a 1, 4-dihydropyridine of the general formula I
Figure imgf000036_0002
wherein
R1, R2 and n are as defined above, or an acid addition salt thereof.
11. The use according to claim 10 for the prepara- tion of amlodipine or an acid addition salt thereof.
12. The use according to claim 11 of an acetal derivative of the general formula II
Figure imgf000037_0001
wherein n is 1 ,
R1 is chloro in the 2 -position of the phenyl ring, R2 is H, and
R3 and R4 , which may be the same or different, represent C1-C5 alkyl.
13. The use of an acetal derivative of the general formula II
Figure imgf000037_0002
wherein R1 each, independently, represents H, Cl or CF3 ,
R2 represents H, C1-C5 alkyl, C3-C6 cycloalkyl or aralkyl ,
R3 and R4 , which may be the same or different, represent C-L-Cg alkyl, C3-C6 cycloalkyl, aralkyl or together represent -(CH2)m-, wherein m is 2 or 3, and n is 1 or 2, as an intermediate for the preparation of an oxime of the general formula III
Figure imgf000038_0001
wherein
R1 , R2 and n are as def ined above , and
R5 represents H, Cx-C5 alkyl , C -33 ~-cC66 cycloalkyl or aralkyl .
14. The use according to claim 13 for the preparation of 4- (2-chlorophenyl) -2- (2-hydroxyimino-ethoxymethyl) -6-methyl-l , 4-dihydro-pyridine-3 , 5-dicarboxylic acid 3-ethyl ester 5-methyl ester.
15. The use according to claim 14 of an acetal derivative of the general formula II
Figure imgf000038_0002
wherein n is i ,
R1 is chloro in the 2 -position of the phenyl ring,
R2 is H, and
R3 and R4 , which may be the same or different, represent C1-C5 alkyl.
PCT/DK1998/000493 1997-11-14 1998-11-13 Process for the preparation of acetal derivatives of 1,4-dihydropyridines WO1999025689A1 (en)

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AT7110U3 (en) * 2000-12-29 2005-05-25 Pfizer Ltd PROCESS FOR THE PRODUCTION OF AMLODIPINMALEAT

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AT7110U3 (en) * 2000-12-29 2005-05-25 Pfizer Ltd PROCESS FOR THE PRODUCTION OF AMLODIPINMALEAT
AT7109U3 (en) * 2000-12-29 2005-05-25 Pfizer Ltd PROCESS FOR THE PRODUCTION OF AMLODIPINMALEAT
US6680334B2 (en) 2001-08-28 2004-01-20 Pfizer Inc Crystalline material

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