HK1063795B - Process for the production of the piperidine derivative fexofenadine - Google Patents

Description

Process for preparing piperidine derivative fexofenadine

Background

The present invention relates to a process for preparing certain piperidine derivatives, including fexofenadine (F), which is an active ingredient of a non-sedating antihistamine sold in the United states under the trade designation "Allegra". The invention also relates to novel synthetic intermediates useful in the process of the invention.

Summary of The Invention

The present invention relates to a process for the preparation of piperidine derivatives of formulae I, II, VI and VII:

wherein

n is 0 or 1;

r1 is hydrogen or hydroxy;

r2 is hydrogen;

r1 and R2 taken together form a double bond between the carbon atoms bearing R1 and R2;

r3 is COOH, CO₂Alkyl radical, CH₂OH, hydroxy, protected hydroxy, cyano, CONH₂CONH alkyl or CON (alkyl)₂Wherein any of them contains an alkyl group having 1 to 6 carbon atoms;

A. b and D may be substituents of the respective rings in meta, para or ortho position, which may be different or identical and may be hydrogen, halogen, alkyl, hydroxy or alkoxy;

with the proviso that when R1 and R2 taken together form a double bond between the carbon atoms bearing R1 and R2 or when R1 is hydroxy, n is 0.

The invention also relates to novel synthetic intermediates of formulae III, IIIa and VI for the preparation of piperidine derivatives of formulae I, II, VI and VII:

wherein A, B, D, R1, R2, R3 and n are as previously defined and X⁺Is a lewis acid.

Although a variety of piperidine derivatives may be prepared by the process of the present invention, the process is particularly useful for preparing fexofenadine (F), which is the active ingredient of a non-sedating antihistamine sold in the United states under the trade designation "Allegra":

thus, particularly preferred novel synthetic intermediates for use in the process of the invention, which are useful in the preparation of fexofenadine (F), are compounds of formulae VIII, VIIIa and IX:

wherein the alkyl group contains 1 to 6 carbon atoms and X⁺Is a lewis acid.

For the preparation of piperidine derivatives of formulae I, II, VI and VII, the process of the invention comprises:

a) reacting a starting compound of formula 19:

with a compound of formula 18:

the acylation is carried out under conditions effective to produce a mixture of regioisomers (regiooisomers) of formula XI:

b) recovering the compound of formula III from the mixture of regioisomers:

c) with a piperidine compound of formula 17:

converting the compound of step b) to a piperidine derivative of formula VI:

d) optionally reducing the piperidine derivative of step c) to provide a compound of formula I:

e) optionally reducing the piperidine derivative of step c) to provide a piperidine derivative of formula VII;

and the number of the first and second groups,

f) optionally oxidizing the piperidine derivative of step d to provide a piperidine derivative of formula II:

wherein all substituents are as previously defined.

Included in this process is a process for preparing fexofenadine (F), which is the active ingredient of a non-sedating antihistamine sold in the United states under the trade designation "Allegra", which comprises:

a) reacting a starting compound of formula 21:

with a compound of formula 20:

the acylation is carried out under conditions effective to produce a mixture of regioisomers of formula 25:

b) recovering the compound of formula VIII from the mixture of regioisomers:

c) with a piperidine compound of formula 23:

converting the compound of step b) into a piperidine derivative of formula IX:

d) reducing the piperidine derivative of step c) to provide a piperidine derivative of formula 24;

and the number of the first and second groups,

e) CO of piperidine derivatives of formula 24₂Partial conversion of alkyl groups to CO₂H moiety to yield fexofenadine (F)

Wherein the alkyl group contains 1 to 6 carbon atoms.

Detailed Description

The present invention relates to a process for the preparation of piperidine derivatives of formulae I, II, VI and VII:

wherein

n is 0 or 1;

r1 is hydrogen or hydroxy;

r2 is hydrogen;

r1 and R2 taken together form a double bond between the carbon atoms bearing R1 and R2;

r3 is COOH, CO₂Alkyl radical, CH₂OH, hydroxy, protected hydroxy, cyano, CONH₂CONH alkyl or CON (alkyl)₂Wherein any of them contains an alkyl group having 1 to 6 carbon atoms;

A. b and D may be substituents of the respective rings in meta, para or ortho position, which may be different or identical and may be hydrogen, halogen, alkyl, hydroxy or alkoxy;

with the proviso that when R1 and R2 taken together form a double bond between the carbon atoms bearing R1 and R2 or when R1 is hydroxy, n is 0.

The invention also relates to novel intermediates of formulae III, IIIa and VI:

wherein A, B, D, R1, R2, R3 and n are as previously defined and X⁺Is a lewis acid.

Although a variety of piperidine derivatives may be prepared by the process of the present invention, the process is particularly useful for preparing fexofenadine (F), which is the active ingredient of a non-sedating antihistamine sold in the United states under the trade designation "Allegra":

thus, particularly preferred novel synthetic intermediates for use in the process of the invention, which are useful in the preparation of fexofenadine (F), are compounds of formulae VIII, VIIIa and IX:

wherein the alkyl group contains 1 to 6 carbon atoms and X⁺Is a lewis acid.

For the preparation of piperidine derivatives of formulae I, II, VI and VII, the process of the invention comprises:

a) reacting a starting compound of formula 19:

with a compound of formula 18:

the acylation is carried out under conditions effective to produce a mixture of regioisomers of formula XI:

b) recovering the compound of formula III from the mixture of regioisomers:

c) with a piperidine compound of formula 17:

converting the compound of step b) to a piperidine derivative of formula VI:

d) optionally reducing the piperidine derivative of step c) to provide a compound of formula I:

e) optionally reducing the piperidine derivative of step c) to provide a piperidine derivative of formula VII;

and the number of the first and second groups,

f) optionally oxidizing the piperidine derivative of step d to provide a piperidine derivative of formula II:

wherein all substituents are as previously defined.

Included in this process is a process for preparing fexofenadine (F), which is the active ingredient of a non-sedating antihistamine sold in the United states under the trade designation "Allegra", which comprises:

a) reacting a starting compound of formula 21:

with a compound of formula 20:

the acylation is carried out under conditions effective to produce a mixture of regioisomers of formula 25:

b) recovering the compound of formula VIII from the mixture of regioisomers:

c) with a piperidine compound of formula 23:

converting the compound of step b) into a piperidine derivative of formula IX:

d) reducing the piperidine derivative of step c) to provide a piperidine derivative of formula 24;

and the number of the first and second groups,

e) CO of piperidine derivatives of formula 24₂Partial conversion of alkyl groups to CO₂H moiety to yield fexofenadine (F)

Wherein the alkyl group contains 1 to 6 carbon atoms.

The novel processes for the preparation of piperidine derivatives of formula I, II, VI and VII and the novel intermediates III, IIIa and VI for the preparation of piperidine derivatives of formula I, II, VI and VII are summarized in scheme a. In scheme a, all substituents are as previously defined unless otherwise indicated.

Flow chart A

Scheme a provides a general synthetic method for the preparation of piperidine derivatives of formula I, II, VI and VII as well as novel intermediates III, IIIa and VI for the preparation of piperidine derivatives of formula I, II, VI and VII.

In step a, the starting compound of formula (19) is acylated with a dibasic acid anhydride of formula (18) under standard Friedel-Crafts conditions known in the art to produce a first mixture of regioisomers of formula XI, typically in the form of about 60% para, 40% meta isomers. The acylation conditions of step a are those typically used for Friedel-Crafts acylation. Examples of compounds of formula (18) are substituted succinic anhydride, glutaric anhydride, substituted glutaric anhydride, polymeric anhydrides of higher dibasic acids, maleic anhydride or substituted maleic anhydride.

For example, the acylation reaction of step a is performed with a Lewis acid such as AlCl₃In a mixture of anhydrous aprotic solvents such as carbon disulfide, tetrachloroethane, dichloromethane, nitrobenzene or anhydrous aprotic solvents. The reaction is generally carried out at about 0 ℃ to the reflux temperature of the solvent used, preferably about 0 ℃ to about 25 ℃ for about 1 to about 18 hours, preferably about 12 to about 18 hours.

In step b1, step b2 and step b3, the compound of formula III is recovered from the first mixture of regioisomers of formula XI. The recovery is performed as follows: first, in step b1, a second mixture of salts of the regioisomers of formula XIa is formed:

wherein X⁺Is a lewis acid and R3 and a are as previously defined; next, in step b2, the salt of formula IIIa is crystallized from the second mixture of salts of regioisomers of formula XIa:

wherein X⁺Is a lewis acid and a and R3 are as previously defined. The crystallization is carried out by fractional crystallization techniques known in the art. Suitable solvents for fractional crystallization include: alcohol solvents such as methanol, ethanol, isopropanol; ketone solvents such as acetone or methyl ethyl ketone; ester-containing solvents such as ethyl acetate or isopropyl acetate; ether solvents such as tetrahydrofuran; and acetonitrile. The preferred solvent is isopropanol. Suitable salts for fractional crystallization include alkali metal salts or preferably of the formula NR₁₀R₁₁R₁₂Of ammonium salt of (1), whereinR₁₀、R₁₁And R₁₂Is hydrogen or a linear or branched alkyl group containing 1 to 6 carbon atoms, which alkyl group may be substituted at any position by a phenyl ring or a substituted phenyl ring. Among the salts of this form, phenylethylamine is preferred. The pure regioisomer is isolated by filtration and then converted to the free acid in step b3 by methods known in the art to give the compound of formula III. This conversion is usually accomplished by treatment with an acid.

In step c, a compound of formula III is coupled to a piperidine derivative of formula 17 under conditions effective to form a piperidine derivative of formula VI. Such couplings are known in the art. The process generally involves activating the free carboxyl group with a reagent such as 1, 3-Dicyclohexylcarbodiimide (DCC), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), p-nitrophenol, or forming an acid chloride or mixed anhydride, followed by the addition of a primary or secondary amine. These reactions are carried out in an anhydrous aprotic solvent such as ethyl acetate, dichloromethane, tetrahydrofuran or dimethylformamide, with tetrahydrofuran being the preferred solvent. The reaction is generally carried out at about 0 ℃ to reflux temperature of the solvent used, preferably about 0 ℃ to about 25 ℃ for about 0.5 to about 12 hours, preferably about 2 to about 12 hours.

In optional step d, the amido and keto moieties of the piperidine derivative of formula VI are reduced to provide the piperidine derivative of formula I. The reduction may be carried out with borane complexes such as borane-dimethylsulfide, borane-tetrahydrofuran in suitable solvents. Alternatively, if an optically active derivative is desired, asymmetric reduction can be carried out by adding a suitable catalyst such as a borazaoxazolidine (oxabolodine) based catalyst. The reduction is carried out in an anhydrous aprotic solvent such as tetrahydrofuran or dioxane. The preferred solvent is tetrahydrofuran. The reduction is typically carried out at a temperature of about 25 ℃ to the reflux temperature of the solvent. Typical reaction times are from about 0.5 hours to about 48 hours, preferably from about 12 to about 48 hours. Amino-borane complexes formed from borane complexes during reduction are known in the art and cleavage is typically carried out by reaction of the complex with an acid or by addition of TMEDA (N, N' -tetramethylethylenediamine) to an ether solution of the complex or by heating in a protic medium. The reaction is carried out in an alcoholic solvent such as methanol, ethanol, isopropanol. The preferred solvent is ethanol. The reaction is carried out at 25 ℃ to the reflux temperature of the solvent for a reaction time of about 0.5 to about 24 hours, preferably about 12 to about 24 hours.

In an optional step e, the ketone moiety of the piperidine derivative of formula VI is selectively reduced without affecting the amide moiety, thereby producing the piperidine derivative of formula VII. Selective reduction is typically accomplished with sodium borohydride in a lower alcohol solvent such as methanol, ethanol or isopropanol. The reaction is carried out at a temperature of about 25 ℃ to the reflux temperature of the solvent. The reaction time is generally about 0.5 hours to about 12 hours.

In an optional step f, the hydroxy moiety of the piperidine derivative of formula I is oxidized to produce the piperidine derivative of formula II.

The novel process for the preparation of fexofenadine (F), which is the active ingredient of a non-sedating antihistamine sold in the United states under the trade designation "Allegra _", and the novel intermediates VIII, VIIIa and IX are summarized in scheme B. In scheme B, all substituents are as previously defined unless otherwise indicated.

Flow chart B

Scheme B provides a general synthetic method for preparing fexofenadine (F), which is the active ingredient of the non-sedating antihistamine sold in the united states under the trade designation "Allegra _", and novel intermediates VIII, VIIIa, and IX.

In step a, the starting compound of formula (21) is acylated with succinic anhydride of formula (18) under standard Friedel-Crafts conditions known in the art to produce a first mixture of regioisomers of formula 25, typically in the form of about 60% para, 40% meta isomers. The acylation conditions of step a are those typically used for Friedel-Crafts acylation.

For example, the acylation reaction of step a is performed with a Lewis acid such as AlCl₃In a mixture of anhydrous aprotic solvents such as carbon disulfide, tetrachloroethane, dichloromethane, nitrobenzene or anhydrous aprotic solvents. The reaction is generally carried out at about 0 ℃ to the reflux temperature of the solvent used, preferably about 0 ℃ to about 25 ℃ for about 1 to about 18 hours, preferably about 2 to about 18 hours.

In step b1, step b2 and step b3, the compound of formula VIII is recovered from the first mixture of regioisomers of formula 25. The recovery is performed as follows: first, in step b1, a second mixture of salts of the regioisomers of formula 25 is formed:

wherein X⁺Is a lewis acid and alkyl is as previously defined; next, in step b2, a salt of formula VIIIa is crystallized from the second mixture of salts of regioisomers of formula 25 a:

wherein X⁺Is a lewis acid and alkyl is as previously defined. The crystallization is carried out by fractional crystallization techniques known in the art. Suitable solvents for fractional crystallization include: alcohol solvents such as methanol, ethanol, isopropanol; ketone solvents such as acetone or methyl ethyl ketone; ester-containing solvents such as ethyl acetate or isopropyl acetate; ether solvents such as tetrahydrofuran; and acetonitrile. The preferred solvent is isopropanol. Suitable salts for fractional crystallization include alkali metal salts or preferably of the formula NR₁₀R₁₁R₁₂Wherein R is₁₀、R₁₁And R₁₂Is hydrogen or a linear or branched alkyl radical containing from 1 to 6 carbon atoms, said alkaneThe groups may be substituted at any position by a phenyl ring or substituted phenyl ring. Among the salts of this form, phenylethylamine,

providing a compound of formula 25a 'after step b1 and a compound of formula VIIIa' after step b 2:

the pure regioisomer is isolated by filtration and then converted to the free acid in step b3 by methods known in the art to give the compound of formula VIII. This conversion is usually accomplished by treatment with an acid.

In step c, a compound of formula VIII is coupled to a piperidine derivative of formula 23 under conditions effective to form a piperidine derivative of formula IX. Such couplings are known in the art. The process generally involves activating the free carboxyl group with a reagent such as 1, 3-Dicyclohexylcarbodiimide (DCC), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), p-nitrophenol, or forming an acid chloride or mixed anhydride, followed by the addition of a primary or secondary amine. These reactions are carried out in an anhydrous aprotic solvent such as ethyl acetate, dichloromethane, tetrahydrofuran or dimethylformamide, with tetrahydrofuran being the preferred solvent. The reaction is generally carried out at about 0 ℃ to reflux temperature of the solvent used, preferably about 0 ℃ to about 25 ℃ for about 0.5 to about 12 hours, preferably about 2 to about 12 hours.

In step d, the amido and keto moieties of the piperidine derivative of formula IX are reduced to provide the piperidine derivative of formula 24. The reduction may be carried out with borane complexes such as borane-dimethylsulfide, borane-tetrahydrofuran in suitable solvents. Alternatively, if an optically active derivative is desired, asymmetric reduction can be carried out by adding a suitable catalyst, such as a borazaoxazolidine based catalyst. The reduction is carried out in an anhydrous aprotic solvent such as tetrahydrofuran or dioxane. The preferred solvent is tetrahydrofuran. The reduction is typically carried out at a temperature of about 25 ℃ to the reflux temperature of the solvent. Typical reaction times are from about 0.5 hours to about 48 hours, preferably from about 12 to about 48 hours. Amino-borane complexes formed from borane complexes during reduction are known in the art and cleavage is typically carried out by reaction of the complex with an acid or by addition of TMEDA (N, N' -tetramethylethylenediamine) to an ether solution of the complex or by heating in a protic medium. The reaction is carried out in an alcoholic solvent such as methanol, ethanol, isopropanol. The preferred solvent is ethanol. The reaction is carried out at 25 ℃ to the reflux temperature of the solvent for a reaction time of about 0.5 to about 24 hours, preferably about 12 to about 24 hours.

In step e, the ester moiety of the piperidine derivative of formula 24 is converted to the carboxylic acid by techniques and methods known to those skilled in the art to give fexofenadine (F). For example, the ester moiety is hydrolyzed with a suitable non-nucleophilic base such as sodium methoxide in methanol as is known in the art. Other methods known in the art for ester decomposition include methanolic potassium carbonate, methanolic ammonia, potassium carbonate, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, methanolic sodium hydroxide/pyridine, ethanolic potassium cyanide solution, and aqueous alcoholic sodium hydroxide solution, preferably potassium hydroxide. The reaction is typically carried out in an aqueous lower alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, 2-ethoxyethanol, or ethylene glycol or pyridine at about room temperature to about the reflux temperature of the solvent for a reaction time of about _ hour to about 100 hours.

The following examples set forth typical synthetic methods shown in schemes a and B. These examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. The following terms used herein have the indicated meanings: "g" means grams; "mmol" means millimole; "mL" refers to milliliters; "bp" refers to boiling point; "mp" means melting point; "° c" means degrees celsius; "mmHg" refers to millimeter of mercury; "μ L" means microliter; "μ g" refers to micrograms and "μ M" refers to micromolar.

Example 1

Flow chart B, step a: preparation of 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid and 4- [3- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid (25)

The method comprises the following steps: aluminum chloride (144g, 1.08 mol) was added to 200mL of carbon disulfide in a 1L reaction tank under a stirring and nitrogen atmosphere. After cooling the mixture to 0 ℃ to 5 ℃ and then adding succinic anhydride (20) (26.0g, 0.260 mol) in one portion. Methyl α, α -dimethylphenylacetate (21) (40.0g, 0.224 mol) was added dropwise to the reaction mixture over 20 minutes. After addition, the ice bath was removed and the mixture was warmed to room temperature. After 2.75 hours, the carbon disulfide was decanted and discarded. The hard reaction product was placed in portions in concentrated hydrochloric acid (150mL) and crushed ice (1000 g). The product was extracted with ethyl acetate (2X 400mL) and washed with water (2X 300mL), brine (1X 300 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and the ethyl acetate was removed in vacuo to give the title compound (25) as a pale yellow oil as a 60: 40 (p: m) mixture.

The method 2 comprises the following steps: succinic anhydride (20) (2g, 0.050 moles) was added to a stirred solution of anhydrous dichloromethane (25mL) and nitrobenzene (5mL) under a nitrogen atmosphere. The reaction mixture was cooled to 0-5 ℃ and aluminum chloride (20g, 0.150 moles) was added in 5g increments over 30 minutes. Methyl α, α -dimethylphenylacetate (21) (5.6g, 0.031 moles) was added dropwise to the reaction mixture over 20 minutes. After 4 hours, the ice bath was removed and the reaction was allowed to proceed at room temperature for 16 hours. The reaction was stopped by pouring slowly into concentrated hydrochloric acid (50mL) and crushed ice (300 g). Ethyl acetate (400mL) was added with stirring. The organic phase was separated and washed with dilute brine (3X 300 mL). The product was removed from the organic phase by extraction with saturated aqueous sodium bicarbonate (2X 100mL) containing brine (50 mL). The aqueous layer was acidified by pouring slowly into concentrated hydrochloric acid (50ml) and ice (300 g). The product was recovered from the acidified reaction solution using ethyl acetate (200 mL). The organic phase was washed with water (400mL), brine (100mL) and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give the title compound (25) (4.5g, 0.016 mol) as a yellow oil in 80.4% yield.

The method 3 comprises the following steps: succinic anhydride (16g, 0.0160 mol) was added to anhydrous carbon disulfide (110mL) with stirring and under a nitrogen atmosphere. The reaction mixture was cooled to 0-5 ℃ and then aluminum chloride (72g, 0.540 moles) was added in 18g increments over 30 minutes. Methyl α, α -dimethylphenylacetate (21) (19.7g, 0.111 mol) was added dropwise to the reaction mixture over 30 minutes. After 4 hours, the carbon disulfide was decanted from the insoluble reaction product, which was removed and carefully decomposed with concentrated hydrochloric acid (100mL) and crushed ice (500 g). Ethyl acetate (600mL) was added with stirring. The organic phase was separated and washed with dilute brine (3X 400 mL). The product was removed from the organic phase as its sodium salt by extraction with saturated aqueous sodium bicarbonate (2X 200mL) containing brine (50 mL). The aqueous layer was acidified by pouring slowly into concentrated hydrochloric acid (100mL) and ice (600 g). The product was recovered from the acidified reaction solution using ethyl acetate (300 mL). The organic phase was washed with water (2X 300mL), brine (200mL) and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to afford the title compound (25) (22g, 0.079 mol) as a clear oil in 71.2% yield.

Example 2

Flow chart B, step B1: preparation of 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid phenethylamine salt and 4- [3- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid phenethylamine salt (25 a') (see section, et al in the text for examples of the invention)

The method comprises the following steps: a mixture of 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid and 4- [3- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid obtained in example 1, method 1 (25) was dissolved in 150mL of diethyl ether and cooled to 5 ℃. To this solution (62.5 g, 0.224 mole assuming 100% yield) was added phenethylamine (28.5g, 29.5mL, 0.235 mole, 1.05 eq) dropwise over 10 minutes. The suspension was placed in a refrigerator overnight. The insoluble phenethylamine salt was collected by vacuum filtration and washed with 75mL of fresh cold diethyl ether to give 72.0g (over two steps-example 1, method 1 and example 2, method 1 gave a yield of 80.5% with a purity of 94.7% by HPLC) of the title compound (25 a') as a white solid.

The method 2 comprises the following steps: to a solution of 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid and 4- [3- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid (25) (22.0g, 0.079 mol, 1.0 eq) obtained in example 1, method 2 in 100mL of diethyl ether was added phenethylamine (10.5g, 10.9mL, 0.087 mol, 1.1 eq). The insoluble phenethylamine salt was collected by vacuum filtration and rinsed with 25mL of fresh diethyl ether to give 30.0g (95% yield) of the combined isomer phenethylamine salt (25 a').

Example 3

Flow chart B, step B2: preparation of 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid phenethylamine salt (VIIIa')

The method comprises the following steps: a mixture of 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid phenethylamine salt and 4- [3- (1-methoxycarbonyl-1-methyl-ethyl) phenyl ] -4-oxo-butyric acid phenethylamine salt (25 a') (71.0g) obtained in example 2, method 1 was crystallized from 2.1L of hot isopropanol and collected by vacuum filtration to give 36.9g (52% yield) of a 91: 9 (p: m) isomer mixture. The collected solid (36.9g) was recrystallized from 1100mL of hot isopropanol and then collected by vacuum filtration to give 30.0g (81.3% yield, 42.3% overall yield, 70.4% overall recovery of para isomer based on the original mixture) of 4- [4- (methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid phenethylamine salt (VIIIa'). (Note: taking into account the maximum yield and crystallization rate, it is recommended to inoculate the solution with the pure substance after cooling to room temperature, and then to leave it at-10 ℃).

The method 2 comprises the following steps: the mixture of 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid phenethylamine salt and 4- [3- (1-methoxycarbonyl-1-methyl-ethyl) phenyl ] -4-oxo-butyric acid phenethylamine salt (25 a') (30.0g) obtained in example 2, method 2 was crystallized with 1 liter of hot isopropanol and then collected by vacuum filtration to give 12.8g (43% yield) of 85: 15 (p: m) isomer mixture. The collected solid (12.8g) was recrystallized from 375mL of hot isopropanol and then collected by vacuum filtration to yield 10.2g (80% yield, 34% overall yield based on the original mixture) of the title compound (VIIIa').

Example 4

Flow chart B, step B3: preparation of 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] -4-oxo-butyric acid (VIII)

The method comprises the following steps: 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] obtained in example 3, method 1]4-oxo-butyric acid phenethylamine salt (VIIIa') (30.0g) was dissolved in 800mL of warm water and acidified to pH2 with concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2X 300 mL). The organic phase was washed with water (1X 100mL), brine (1X 100mL), and MgSO₄Drying, filtration and concentration in vacuo afforded 20.5g (98.1% yield converted to the free acid) of the title compound (VIII) as a white crystalline solid (99.8% purity by HPLC). (Note: salt isolation not required as in example 1. crude oil from example 1 was dissolved directly in isopropanol and phenethylamine was added and crystallization was carried out at-10 ℃ with a slight decrease in the overall yield.) MH⁺ 279.2。

The method 2 comprises the following steps: 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] obtained in example 3, method 2]4-oxo-butyric acid phenethylamine salt (VIIIa') (10.2g) was dissolved in 200mL of warm water and acidified to pH2 with concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2X 150 mL). The organic phase was washed with water (1X 50mL), brine (1X 50mL), and MgSO₄Drying, filtration and concentration in vacuo gave 6.8g (96% yield) of the title compound (VIII) as a clear oil which solidified on standing.

Example 5

Flow chart B, step c: preparation of 2- (4- {4- [4- (hydroxy-diphenyl-methyl) -piperidin-1-yl ] -4-oxo-butyryl } -phenyl) -2-methyl-propionic acid methyl ester (IX)

The method comprises the following steps: 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] obtained in example 4, method 1]-4-oxo-butyric acid (VIII) (20.0g, 0.0719 moles) was dissolved in 250mL of anhydrous tetrahydrofuran, to which triethylamine (7.28g, 10.02mL, 0.0719 moles) was added in one portion. The flask containing the solution was placed in a room temperature water bath. To this solution was added dropwise over 1 minute a solution of ethyl chloroformate (7.02g, 6.19mL, 0.0647 moles) in THF (60 mL). After the addition, the mixture was stirred at room temperature for 15 minutes. To this mixture was added a solution of α, α -diphenyl-4-piperidinylmethanol (23) (19.2g, 0.0719 moles) in THF (120mL) over 2 minutes. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo and the residue was added to 600mL of ethyl acetate. The organic phase was washed with water (1X 200mL), dilute acid (1X 200mL), saturated potassium carbonate (2X 200mL), water (1X 200mL), brine (1X 200mL), MgSO₄Treatment, filtration, concentration and then drying under high vacuum afforded the title compound (IX) as a white solid (29.2g, 85.6% yield, 98.2% purity by HPLC). MH⁺ 528.4。

The method 2 comprises the following steps: 4- [4- (1-methoxycarbonyl-1-methyl-ethyl) -phenyl ] obtained in example 4, method 2]-4-oxo-butyric acid (VIII) (6.8g, 0.024 mol) and p-nitrophenol (6.7g, 0.048 mol) were dissolved in ethyl acetate (300mL) and cooled to 0 ℃ in an ice bath. 1, 3-dicyclohexylcarbodiimide (9.9g, 0.048 mol) was added to the ice-cold solution in one portion. The mixture was stirred at 0 ℃ for 1 hour, then warmed to room temperature and the mixture was stirred for 7 hours. Azacyclo-alcohol (23) (7.1g, 0.026 mol) was then added to the mixture in one portion. The mixture was stirred overnight for 15 hours. The reaction mixture was filtered through Whatman 541 filter paper to remove precipitated 1, 3-dicyclohexylurea. The filtrate is taken up with a saturated K₂CO₃(3X 100mL), water (2X 100mL)Diluted acid (1X 100mL), water (1X 75mL), brine (1X 100mL) and MgSO₄Work-up, filtration and concentration gave a yellow oil (10.9g, 86% yield). The product was pure enough for the next reaction or, if desired, a purer sample could be obtained by crystallization from acetonitrile (6ml/g, 80% recovery).

Example 6

Flow chart B, step d: preparation of methyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] -1-hydroxybutyl ] -a, a-dimethylphenylacetate (24)

The method comprises the following steps: methyl 2- (4- {4- [4- (hydroxy-diphenyl-methyl) -piperidin-1-yl [ -4-oxo-butyryl } -phenyl) -2-methyl-propanoate (IX) (28.0g, 0.0531 mol) from example 5, method 1 was dissolved in 300mL of dry THF. To the stirring solution was added borane-dimethyl sulfide complex (0.136 mol, 12.92mL) dropwise over 5 minutes. The mixture was heated to reflux for 60 minutes and then cooled to room temperature over 15 minutes. Methanol (200mL) was added (initially 50mL was added dropwise) and the mixture was stirred for 30 minutes. The mixture was concentrated in vacuo to give a white solid. The residue was dissolved in 300mL of denatured ethanol and heated to reflux for 26 hours. The ethanol was evaporated in vacuo and the reaction product was added to ethyl acetate (1X 500 mL). The organic phase was washed with water (3X 200mL), brine (1X 200mL), and MgSO₄Work-up, filtration and concentration in vacuo afforded 26.4g (96.6%, 91.0% purity by HPLC) of the title compound (24) as a white solid. MH₊ 516.6。

The method 2 comprises the following steps: the 2- (4- {4- [4- (hydroxy-diphenyl-methyl) -piperidin-1-yl radical obtained in example 5, method 2]-4-oxo-butyryl } -phenyl) -2-methyl-propionic acid methyl ester (IX) (5.28g, 0.01 mol) was dissolved in 75mL dry THF. To the stirring solution was added borane-dimethyl sulfide complex (0.027 mol, 2.65mL) dropwise over 5 minutes. The mixture was heated to reflux for 45 minutes and then cooled to room temperature. Methanol (40mL) was added (initially slowly) and the mixture was stirred for 30 minutes. The solvent was evaporated in vacuo to give a solid, which was dissolved in ethyl acetate (500mL) and washed with water(1X 200mL) and (saturated K)₂CO₃(1X 200mL), water (1X 200mL), brine (1X 200mL), washed with MgSO 4₄Work up, filter and concentrate in vacuo to give a white solid. The white solid was dissolved in 60mL of methanol, to which was added 30mL of 37% formaldehyde. The mixture was refluxed for 18 hours. Methanol was distilled off in vacuo (alternatively, the reaction solution was diluted 5-fold with water instead of removing methanol) and the reaction product was extracted with ethyl acetate (2X 150 mL). The organic phase was washed with water (2X 100mL), brine (1X 100mL), and MgSO₄Work-up, filtration and concentration in vacuo afforded 4.7g (91%) of the title compound (24) as a white solid, pure enough for the next reaction.

Example 7

Flow chart B, step e: preparation of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] -1-hydroxybutyl ] -a, a-dimethylphenylacetic acid (F)

The method comprises the following steps: 4- [4- [4- (Hydroxydiphenylmethyl) -1-piperidinyl radical from example 6, method 1]-1-hydroxybutyl radical]Methyl- α, α -dimethylphenylacetate (24) (20.0g, 0.0388 mol) was dissolved in 200mL of methanol. To this solution was added sodium hydroxide solution (8.5g in 85mL water). The reaction mixture (initially cloudy and then clarified) was heated to reflux for 3 hours and then cooled to room temperature. The solution was acidified to pH 4-5 with acetic acid (13.8 mL). The mixture was stirred at room temperature for 1.5 hours. The precipitate was collected by vacuum filtration and dried in vacuo to give 3.30g (85% yield) of the title compound fexofenadine (F) as a white solid. The purity was assessed by HPLC to be 99.9%. The retention time and spectrum were determined by HPLC to be consistent with the non-solifenadine standard. MH⁺ 502.4。

The method 2 comprises the following steps: 4- [4- [4- (Hydroxydiphenylmethyl) -1-piperidinyl radical from example 6, method 2]-1-hydroxybutyl radical]Methyl- α, α -dimethylphenylacetate (4.0g, 0.0078 mol) was dissolved in 80mL of methanol. To this solution was added sodium hydroxide solution (2.8g in 24mL water). The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The solution is treated with acetic acidTo pH 4-5, 40mL of methanol was added. The mixture was stirred at room temperature for 1.5 hours. The precipitate was collected by vacuum filtration. The precipitate was dried in vacuo to yield 3.3g (85%) of the title compound fexofenadine (F) as a white solid. The purity was assessed by HPLC to be 99.9%. The retention time and spectrum were determined by HPLC to be consistent with the non-solifenadine standard. MH⁺ 502.4。

Example 8

Scheme a, optional step f: preparation of methyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] -1-oxobutyl ] -alpha, alpha-dimethylphenylacetate

4- [4- [4- (hydroxydiphenylmethyl) -1-piperidyl]-1-hydroxybutyl radical]Methyl- α, α -dimethylphenylacetate (2.05g, 0.00398mol) was dissolved in 100mL of acetone and cooled in an ice bath. To this solution was added dropwise Jones reagent (prepared by the method of Feiser and Feiser) until a persistent red color appeared. The reaction was warmed to room temperature and then stirred at room temperature for 18 hours. The mixture was concentrated in vacuo to give a green solid. The residue was partitioned between ethyl acetate (150mL) and water (150 mL). The organic layer was separated, washed with water (3X 100mL), brine (1X 100mL), and MgSO₄Work up, filter and concentrate in vacuo to give a pale green solid. Purification by column chromatography gave 1.25g (61% yield) of the title compound as a white solid. MH⁺ 514.6。

Claims (36)

1. A compound of the formula

Wherein the alkyl group contains 1 to 6 carbon atoms.

2. The compound of claim 1, wherein alkyl is methyl.

3. The compound of claim 1, wherein alkyl is ethyl.

4. A compound of the formula

Wherein X⁺Is a Lewis acid and the alkyl group is 1 to 6 carbon atoms.

5. The compound of claim 4, wherein X⁺Is that

6. The compound of claim 5, wherein alkyl is methyl.

7. The compound of claim 5, wherein alkyl is ethyl.

8. A compound of the formula

Wherein the alkyl group contains 1 to 6 carbon atoms.

9. The compound of claim 8, wherein alkyl is methyl.

10. The compound of claim 8, wherein alkyl is ethyl.

11. A process for the preparation of piperidine derivatives of the formula

Wherein the alkyl group contains 1 to 6 carbon atoms, which process comprises providing a compound of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms, and then converting the compound to a piperidine derivative using a piperidine compound of the formula:

12. the method of claim 11, wherein providing the compound comprises:

a) starting compounds of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms, with a compound of the formula:

the acylation is carried out under conditions effective to produce a mixture of regioisomers of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms; then the

b) Recovering from the mixture of regioisomers a compound of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms.

13. The method of claim 12, wherein said recovering comprises crystallizing a regioisomeric salt of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms and X⁺Is a lewis acid.

14. The method of claim 13, wherein said recovering comprises crystallizing a regioisomeric salt of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms.

15. The method of claim 12, wherein alkyl is methyl.

16. The method of claim 12, wherein alkyl is ethyl.

17. A process for the preparation of a compound of the formula

Wherein R is COOH or COO alkyl and the alkyl group contains 1 to 6 carbon atoms, which comprises reducing a compound of the formula:

18. the method of claim 17, wherein said reducing is performed with borane-dimethyl sulfide.

19. A process for the preparation of piperidine derivatives of the formula

The method includes providing a compound of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms, followed by a piperidine compound of the formula

Converting the compound into a piperidine derivative of formula (IX)

Wherein the alkyl group contains 1 to 6 carbon atoms, and then,

reducing the compound to provide a piperidine derivative of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms; then the

Introducing CO₂Partial conversion of alkyl groups to CO₂And (4) a H part.

20. The method of claim 19, wherein providing the compound comprises:

a) starting compounds of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms, with a compound of the formula:

the acylation is carried out under conditions effective to produce a mixture of regioisomers of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms; then the

b) Recovering from the mixture of regioisomers a compound of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms.

21. The method of claim 20, wherein said recovering comprises crystallizing a regioisomeric salt of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms and X⁺Is a lewis acid.

22. The method of claim 21, wherein said recovering comprises crystallizing a regioisomeric salt of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms.

23. The method of claim 19, wherein alkyl is methyl.

24. The method of claim 19, wherein alkyl is ethyl.

25. A process for preparing a compound of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms, which process comprises:

a) starting compounds of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms, with a compound of the formula:

the acylation is carried out under conditions effective to produce a mixture of regioisomers of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms; then the

b) Recovering from the mixture of regioisomers a compound of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms;

c) with a piperidine compound of the formula:

converting the compound of step b) into a piperidine derivative of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms, and then,

d) reducing the piperidine derivative prepared in step c).

26. The method of claim 25, wherein the reduction in step d) is performed using borane-dimethyl sulfide.

27. The process of claim 25, wherein said recovering in step b) comprises crystallizing a regioisomeric salt of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms and X⁺Is a lewis acid.

28. The process of claim 27, wherein said recovering in step b) comprises crystallizing a regioisomeric salt of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms.

29. The method of claim 25, wherein alkyl is methyl.

30. The method of claim 25, wherein alkyl is ethyl.

31. A process for preparing a compound of the formula:

the method comprises the following steps:

a) starting compounds of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms, with a compound of the formula:

the acylation is carried out under conditions effective to produce a mixture of regioisomers of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms;

b) recovering from the mixture of regioisomers a compound of the formula:

c) with a piperidine compound of the formula:

converting the compound of step b) into a piperidine derivative of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms, and then,

d) reducing the piperidine derivative of step c) to provide a piperidine derivative of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms; then the

e) Introducing CO₂Partial conversion of alkyl groups to CO₂And (4) a H part.

32. The method of claim 31, wherein the reduction in step d) is performed using borane-dimethyl sulfide.

33. The process of claim 32, wherein said recovering in step b) comprises crystallizing a regioisomeric salt of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms and X⁺Is a lewis acid.

34. The process of claim 33, wherein said recovering in step b) comprises crystallizing a regioisomeric salt of the formula:

wherein the alkyl group contains 1 to 6 carbon atoms.

35. The method of claim 30, wherein alkyl is methyl.

36. The method of claim 29, wherein alkyl is ethyl.