WO2003000658A1

WO2003000658A1 - PROCESS FOR THE PREPARATION OF A HIGHLY PURE PHARMACEUTICAL INTERMEDIATE, 4-(CYCLOPROPYLCARBONYL)-α,α-DIMETHYLPHENYLACETIC ACID

Info

Publication number: WO2003000658A1
Application number: PCT/IN2002/000135
Authority: WO
Inventors: Dandala Ramesh; Das Umashankar; Venkata Naga Srinivasa Rao Divvela; Sunderam Sivakumaran Meenakshi
Original assignee: Aurobindo Pharma Ltd
Current assignee: Aurobindo Pharma Ltd
Priority date: 2001-06-25
Filing date: 2002-06-19
Publication date: 2003-01-03
Anticipated expiration: 2003-12-25
Also published as: BG107476A; SI21232A; US20040077900A1; US6903232B2; JP2004521942A; EP1401815A1; SK712003A3

Abstract

This invention relates to a novel process to obtain hoghly pure 4-(cyclopropylcarbonyl)-α,α-dimethylphenylacetic acid of Formula I through crystallization from a mixture of para and meta regioisomers of Formula I and II in cyclohexane, whereby the amount of undesired meta isomer, 3-(cyclopropylcarbonyl)-α,$g)a)-dimethylphenylacetic acid of Formula II is decreased to below 0.5%. The compound of Formula I is a key intermediate for the preparation of high purity terfenadine carboxylate, which is a known antihistaminic.

Description

PROCESS FOR THE PREPARATION OF A HIGHLY PURE

PHARMACEUTICAL INTERMEDIATE, 4-(CYCLOPROPYLCARBONYLH ~ DIMETHYLPHENYLACETIC ACID.

FIELD FOR THE INVENTION

This invention relates to a novel process to obtain highly pure 4-(cyc!opropylcarbonyl)-c..α- dimethylphenylacetic acid of Formula I through crystaiϊϊzation from a mixture of para and meta regioisomers of Formula I and II in cyclohexane. whereby the amount of undesired meta isomer. 3-(cyclopropyIcarbonyl)-α,α-dimethylpheny!aceιic acid of Formula II

Formula I Formula H is decreased to below 0.5%. The compound of Formula 1 is a key intermediate for the preparation of high purity terfenadine carboxylate, which is a known antihistaminic.

BACKGROUND OF THE INVENTfOX

This invention relates to a process for the preparation of highly pure 4-(cycIopropylcarbonyl)-α,α- dimethylphenyiacetic acid of Formula I. a key intermediate useful in the preparation of highly pure Terfenadine carboxylate.

Formula

Terfenadine carboxylate is a non-sedative antihistaminic compound. It is reported to be a specific ! l;-receptor antagonist that is also devoid of any anticholinergic, antiserotonincrgic, and antiadrenereic effects.

Piperidine derivatives related to terfenadine carbox ate are disclosed in US Patent 4.254,129 and US Patent 4.254.130. In these patents, cx.α-dimethyl-4-[l-hydroxy-4-[4-(hydroxydiρhenyl methyl)-! -piperidiπyljbutyljbenzeneacetic acid of Formula til

Formula ill

is prepared by a Ik > kit ion of a substituted piperidine derivative of Formula IV

Formula IV

with an ω-haloalkyl substituted phenyl ketone of Formula V

Formula V

wherein halo is a halogen atom, such as. chlorine, bromine or iodine, and afkyl moiety has from 1 to 6 carbon atoms and is straight or branched, followed by reduction of the ketoπe group and subsequent base hydrolysis. Preparation of compounds of Formula V is achieved by reacting α,α-dimethyiphenylacetic acid alkyl esters with 4-halobutyryl halide under general conditions of Friεdel-Crafts acyiation. US Patent 4,254, 130 describes the preparation of ethyl 4-(4-chloro-l-oxobutyi)-α,o dimethylphenylacetate by reaction of 4-chlorobutyr l chloride, aluminum chloride and ethyl α.α-dimethylphenylacetate in carbon disulfide. However, the described reaction results in virtually inseparable mixture of monosubslituted aromatic para and meta regioisomers of the Formula VI where unwanted meta isomer predominates to about 65%.

Formula VI

₍ n _)j_cι Mixture of para and meta regioisomers.

CΛ Patent 2.1 IS.188 discloses a process, which has proved to be more selective in the formation of para isomer. In this process, Friedei-C rafts acyiation has been carried out on the derivative of Formula VII w ith 4-chlorobutyry! chloride as the acylating agent in carbon disulfide Hj

Formula VII

in the presence of aluminum chloride and the corresponding para acylated product has been obtained that contains no more than 10% of meta isomer. The presence of meta isomer at this stage results in an unacceptable level of meta isomer in terfenadine carboxylate and once again it is difficult to achieve pharmaceutically pure product from such a mixture. This requires time consuming purification processes which are wasteful of material and costly.

US Patent 5,578,610 provides a procedure wherein the mixture of regioisomers of Formula VI has been transformed to another mixture of para and meta regioisomers of Formula VIII and

Formula Vtll Mixture of para and meta regioisomers

subsequently the substantially pure para regiosiomer is obtained by fractional crystallization of the corresponding cinchonidine salt. This process exhibits several disadvantages such as use of expensive cinchonidine. its toxicity. low yield and in addition to that, two isolation steps are neccssan to obtain the desired product of Formula I.

US Patent 6.147.216 provides an alternate technique to obtain enriched para regioisomer by high vacmtm fracf mai disTrtlatrorr of mcthyi or ctfayl ester of the mixture of isomeric acids of Formula V1H followed by repeated fractional crys tUization at low temperatures. This process is operationally tedious, inefficient yields are tow and therefore, is not amenable to industrial scale.

The aim of the present invention is to provide an efficient method to obtain highly pure 4-(c\clopropylcarbonyl)-α. -dimethyiphenylacelic acid of Formula I. which is an useful intermediate for the preparation of pharmaceutically highly pure antihistaminic piperidine derivatives. DETAILED DESCRIPTION OF THE INVENTION

The instant invention relates to a novel process to produce highly pure para regioisomer, 4-(cyclopropylcarbonyl)-α,α-dimethylphenylacetic acid, of Formula I whereby the amount of meta isomer, 3-(cyclopropylcarbonyl)-α.α-dimethylphenylacefιc acid, of Formula II is decreased to below 0.5%.

Specifically the present invention involves treating I~acetoxy-2-methyl~2-phenylpropane, of Formula VII in methylene chloride with 4-chlorobutyryJ chloride and anhydrous aluminium chloride to obtain a mixture of regioisomers. of Formula IX that contains greater than 80% of para isomer.

Formula IX Mixture of para and meta regioisomers

This mixture of regioisomers is hydrolyzed under conditions effective to produce a mixture of regioisomers of Formula X. Typically this reaction is carried out by a base hydrolysis procedure which is well known in the art. The intermediate hydroxy compound is then oxidized

Formula X

Mixture of para and meta regioisomers

to give the corresponding carboxyiic acid regioisomers. of Formula VIII using, for example, potassium permanganate. The potassium permanganate oxidation is carried out m a

Formula V1U Mixture of para and meta regioisomers

suitable acidic medium such as acetic acid / acetone at a temperature ranging from room temperature to 60°C. Other suitable reagents for the oxidation are, chromium (IV) oxide, sodium periodate, M-chloroperbenzoic acid and nitric acid.

According to the present invention, the above mixture of para and meta regioisomers of formula VIII is subjected to crystallization process to recover higMy pure para cegtoisomer of Formula I. Such recovery is carried out by selective crystallization from a suitable solvent that inc ude hexanes, heptane, cyclohexane, diethyl ether, diϊsopropyl «Jκr and a mixture thereof. However, one may proceed preferably by using cyclohexane for crystallization.

Selective crystallization is achieved by dissolving a mixture of regioisomers of Formula VIII containing up to 20% of meta regioisomer in a solvent at a temperature ranging from 20°C to reflux temperature of the solvent. The amount of solvent is at least 5 parts by volume per part of the mixture of regioisomers. Higher amounts of solvent and generally upto 20 parts by volume may be used. The aforesaid solution is then slowly cooled to 20-25°C and the desired para regioisomer is obtained in highly pure form as a free flowing crystalline material which is isolated by filtration.

Major advantages realized in the present invention compared to the prior art are increased process productivity and product purity. The level of meta regioisomer under present crystallization conditions is reduced to less than 0.5% that enables the control of isomer purity in terfenadine carboxylate .product. The process of the present invention is feasible commercially and simple on industrial scale.

The aforesaid highly pure para regioisomer of Formula I can be reacted with

COOH

Formula I

piperidine compound of Formula IV

Formula IV

under the conditions effective to form the piperidine derivative compound of Formula XI

Formula XI

having a kcto group which is converted to hydroxvl group by reduction to produce pharmaceutically highly pure terfenadine carboxylate of Formula Hi coon

Formula III

that contains less than 0.1% of meta regioisomer. Further details of the present invention are to be found in the following examples without limiting if.

Example 1

PREPARA TION OF I-ACETOXY-2-METHYL-2~/4-(4-CHL ROBLTYR YL) P ENYLj PROPANE ami l-ACETOXY-2-METHYL-2-J3-(4-CHLOROBUTYRYL) PHENYLJ PROPANE

was slowh added to a mixture of crushed ice (720 g) and cone, hydrochloric acid ( 100 ml) at a temperature below 25°C. Methylene chloride layer was separated and aqueous layer was extracted with methylene chloride ( 100 ml). The combined methylene chloride extract was washed with 5% aqueous sodium bicarbonate solution ( 100 ml). Methylene chloride was removed under reduced pressure to obtain an oily residue containing a mixture of para- and meta- isomers (approximately 80:20 ratio, by Η NMR). Yield: 152 g.

'I I NMR (300 MHz) in CDC1₃ : δ(ppm) 7.93 (d. 2H. J = 9.0 Hz. Ar-H). 7.46 (J. 2H. J = 9.0 Hz. Λr-H). 4.15 (Λ. 211, CH₂-OCOCH₃). 3.69 (/. 2H. J = 7.5 Hz. CJLCI). 3.17 (/. 211. 7.5 I Iz. COCH-). 2.24 <#». 211, CQCHJCH;). 2.0 (,v, 311, COCΗ₃), 1.38 (.v. 6H. 2 x^'CHj). The meta isomer is recognized by its signals at δ(ppm) 7.95 (/«. I H, Ar-H). 7.92 (w. I II. Λr-H), 7.48 (/». I H. Ar-H). 7.26 (;w, I H, Ar-H), 4.14 (.v. 2H, CH-OCOCHj). 3.62 (/, 2H. CHjCi), 2.57 (/, 2H, COCH 2.21 (/», 2H, COO CH?).

Example 2

PREPARA TION Of 2-I4-CYCL PROPYLCARBONYLIPHESYL-2-M ETHYL PROPANOL and 2-P-CYCLOPROPYLCARBONY /PHENYL-2-ME7tiYI. PROPA.\Ot.

Sodium hydroxide (61.2 g, 1.53 mol) was dissolved in methanoi (600 ml) at 25-30°C and product obtained in I-xample 1 (152 g. 0.51 mol) was added slo ly at 25-30°C. Reaction mass was stirred for 2 hours and thereafter, methanoi was removed at 40-60 C under reduced pressure. The residue was cooled to 25-30 and DM water (300 ml) was added. Product was extracted w ith toluene (2x200 ml). The toluene extract was washed with DM water and toluene was removed at 5-70°C under reduced pressure to obtain the title product as an oily residue Yield: 1 0 g.

Example 3

PREPARA TION OF 4-(CYCLOPROPYLCARBOSYLha,a-DIMETHYLPHESYI_^4CETlCAClD and 3-(CYCLOPROPYLCARBOSY a,a-DlMETmLPHENY ΛCETICACID '

Substrate from the previous example ( 100 g. 0.45 mol) was dissolved in acetone (300 ml) at 25-30°C. DM water (450 ml) and acetic acid (60 ml) were added. Potassium permanganate ( 153 g. 0.96 mol) was added in small lots in 2 hours maintaining the temperature at 25-3ϋ^rC. Stirring was continued for 1 hour at 30-35°C and thereafter, temperature was raised to 40-45°. After stirring for 2 hours the reaction mass was filtered through hyflo and the residue was washed with acetone ( 100 ml). The filtrate was concentrated at 40-45°C under reduced pressure to remove acelonc. To the concentrated mass, hydrochloric acid (90 ml) was added followed by sodium metabisulfite (21.37 g) and stirring continued at 20-25°C for 30 minutes.^" The product was extracted with methylene chloride (2x200 ml). The combined methylene chloride extract was stirred with 800 ml of 5% w/w sodium hydroxide solution and aqueous layer was separated which was acidified to pH 1.8-2.0 at 10-I2°C by adding cone, hydrochloric acid. The title product was extracted with methylene chloride (2x150 ml). The methylene chloride extract was washed with DM water (80 ml) and methylene chloride was distilled at 40-45°C under reduced pressure to obtain an oily residue (72 g) that contained para- and meta- isomers approximately in the ratio of 80:20 (^SH NMR).

Η NMR (300 MHz) in CDC1₃: δ (ppm) 12.6 ( I H, COOH), 8.0 (d, 2H, Ar-H), 7.5 {d, 2H, Ar-H), 2.66 (w, I H. -COCH-). 1.66 (s. 6H, 2 x CH₃), i .25 (w. 2H. CH₂), 1.0 (m. 2H, Cfch). The meta isomer is recognized by its signals at δ (pp ) 8.1 (/?/. I H. Ar-H). 7.92 (/«. I H. Ar-H), 7.63 (ni. I H. Ar-H)! 7.46 (m. IH. Ar-H).

The regioisomers mixture thus obtained was subjected to crystallization to obtain highly pure 4-(cyc!opropy!carbonyl)-α,α-dimelhyIphenyiacetic acid as described in the follo ing examples:

Example 4

The mixture of regioisomers ( 100 g. 0.43 mol) obtained in accordance with F.xamplc 3 was dissolved in cyclohexane ( 1500 ml) at 60-65°C. The solution was seeded with 0.5 g of pure para regioisomer at 50-55°C and was cooled to 15- I ^C'C slow h in 2 hours and during this period, the product crystallizes out. Stirring was continued at 15- I 8°C for 1 hour to complete crystallization. The product was filtered, washed with cyclohexane (2x25 ml) and dried under reduced pressure at 35-40°C to yield 72 g of highly pure crystalline para regioisomer. 4-(cyclopropylcarbonyl)- ,α-dimethylphenylacetic acid, mp: 84-88°C. Η NMR (300 MHz) CDCI₃: δ (ppm) 12.6 ( I H. COOH). 8.0 (./. 211. Ar-H). 7.5 (</, 2H. Ar-H). 2.66 (/«. I H. -COCH-). 1.66 ( v. 611. 2 x CU._t), 1.25 (/;/. 211. CU;l 1.0 (in. 211. O N). The product contained 0.48% of meta isomer by I IP .

I/PLC CONDITIONS:

Column: 25 cm long, 4.0 mm internal diameter packed ith fi-cyclodextrin bonded to silica through amide linkage; particle size: 5 μm: column temperature: ambient

Dejection wavelength: 254 nm

Mobile Phase: Mixture of acetate buffer pH 4.0 and acctonitrile in the ratio of 50:50 v/v.

Acetate buffer pH 4.0 was prepared by adding 1.2 ml of acetic acid to 1000 ml water and pH adjusted to 4.0 with dilute aqueous ammonia.

Example 5

The mixture of regioisomers approximately para meta 80:20 (70 g, 0.30 mol) obtained from Example 3 was dissolved in cyclohexane (350 ml) at 60-65°C. Solution was cooled to 28-30°C slowly in 2 hours. The product was collected by filtration and was suspended in cyclohexane (280 ml) and heated to 65-68°C to obtain a clear solution. The solution was cooled to 25-28°C to crystallize out the product which was filtered and washed with cyclohexane (2x20 ml) and dried under reduced pressure at 35-40°C. The product contained 0.27% meta isomer by HPLC. Yield: 51.1 g. Example 6

Substrate of Example 3 (50 g, 0.21 mol) was dissolved in diisopropyl ether (60 ml) and diluted with cyclohexane (280 ml) at 15-20°C. The crystallized material was filtered and washed with cyclohexane (2x20 ml) to obtain para regioisomer. Yield: 30.7 g.

Example 7

PREPRA TION OF a.a-DIMETHYL-4-(4-(4-(HYDROXYDlPHENYLMETflYL)-l-PIPERIDINYLJ-!- OXOBL TYL/PIIENYLACETICACID, METHYL ESTER

!)-α.α-dimethylphenylacctic acid ( 100 g. 0.43 mol) prepared in accordance with the Example 4 was added to 25% methanolic hydrochloric acid (325 ml) at

20-25^'iC. The solution was stirred at 4()-45°C for 4 hours and methanoi was removed under reduced pressure. The concentrated mass was diluted ith water (320 ml) and product was extracted w ith toluene (2x150 ml). Toluene extract was washed with sodium bicarbonate solution and solvent was removed in vacuo to obtain 120 g of methyl 4-(4-chloro-l-oxobuty))-α,α- dimethylpheny lacetate which was dissolved in methyl isobutyl ketone (480 ml) and treated with 4- ( .α-diphenyl)piperidinemethanof (81 g. 0.30 mol). potassium bicarbonate (196 g. ! .96 mol) and potassium iodide (3.56 g. 0.02 mol) at 96-98°C for 30 hours. Thereafter, reaction mass was filtered to remove inorganics and the filtrate was concentrated under reduced pressure at 65-, 70°C. The concentrated mass was dissolved in ethyl acetate (400 ml) and treated with dry hydrochloric acid at I 0-15°C to precipitate the title product as a hydrochloridc salt which was. isolated by filtration, washed with ethyl acetate (2x80 ml) and dried at 40-45°C under reduced pressure. Yield: I 54 g. mp: 175- 181 °c^'

Example 8

PR EPA RA TION OF a. a-DIMETH YL-4-/4-/4-(H YDROXYDIPIIEN YI.M TH YL)- I-PIPERIDINYL /- I-IIYDROXYBVTYLIPUENY 4CETIC ACID HYDROCIILORIDE (TERFENA DINE CA RBOXYLA TE H YDROCHLORIDE)

To a solution of 1 4 g of methyl α.α-dimethyl-4-|4-|4-(hydroxydiphcnylmethyl)-l -piperidinyl]- l -oxobutyljphenylacetate hydrochloridc prepared in accordance with Example 7 in methanoi (460. ml) was added sodium hydroxide ( I /.2I g, 0.28 mol) at 25-30°C followed by sodium borohydride ( 1 .8 g. 0.42 moi) in small lots and stirring was continued for 3 hours. The reaction mass was cooled to 10- ! 5^C'C and water (390 ml) was added slowly followed by acetic acid (3 ml ).

Contents were heated to 40-45°(' for 30 min. Thereafter, the product slurry was cooled to 18- 20°C. filtered and washed with water (2x100 ml). The product thus obtained was suspended in ethanol (630 ml) and sodium hydroxide (28.8 g, 0.72 mol) dissolved in 120 ml of water was added. Reaction mass was heated at 75-80°C for 5 hours and thereafter cooled to 15-20°C and was diluted with water ( 1260 ml). Concentrated hydrochloric acid was-added slowly to lower the pH to 1.8-2.0 to afford the title product which was filtered and washed with water (2x125 ml). It was dried and crystallized from acetone to provide white crystalline terfenadine carboxylate hydrochloridc. Yield: 1 13.67 g. p: I96-197°C. The product was 99.93% pure and contained 0^03% of meta isomer bv HPLC. HPLC CONDITIONS:

Column: 25 cm long, 4.6 mm internal diameter comprising particles of silica, the surface of which has been modified by chemically bonded octadecylsilyl groups; particle size: 5 μm: column temperature: ambient

Detection wavelength: 215 nm

Mobile Phase: Mixture of buffer pH 2.5 and methanoi in the ratio of 40:60 v/v.

Buffer of pH 2.5 was prepared by dissolving 1.17 g of 1 -octanesulphonic acid sodium salt and 1 ml of tricthylamine in 1000 ml water and pH adjusted to 2.5 with orthophosphoric acid.

Claims

We claim:

( I ) A Process to obtain highly pure 4-(cyc!opropylcarbonyI)-α,α~dimethy!phenylacetic acid of Formula I

Formula 1

which comprises heating a mixture of para and meta regioisomers of Formula V11I

j j_{xture 0} p_{ara anc}| _{me .}a regioisomers of Formula VI 11

in a suitable solvent such as a hydrocarbon or an ether lo obtain a clear solution, and cooling such that compound of Formula 1 selectively crystallizes out whereby the amount of the by-product

I)-( .( -dimethy Iphenylacetic acid of Formula II

Formula II

is reduced to below 0.5%.

(2) The process according to claim 1 w herein a suitable solvent for crystallization is selected from the group consisting of hexane. heptane, cyclohexane, diethyl ether, diisopropyl ether and mixtures thereof.

(3) ITie process according to claim 1 wherein the said crystallization solvent is cyclohexane.

(4) A process to obtain highly pure para regioisomer of Formula I and reacting the said highly pure regioisomer with piperidine compound of Formula IV

II Formula IV

Formula XI

having a kcto group which is converted to hydroxy i group by reduction to produce pharmaceutically highly pure terfenadine carboxy late of Formula HI

Formula 111

that contains less than 0.1 % of meta reuioisomer.

Dated this the 2 , _c5ι"lι dav of June 20 1

Aurobindo Pharma Limited

. Nanda haskara

I. IX.ΛI. OFFIC ER

FOR THE APPLICANTS