WO2007108006A1

WO2007108006A1 - Process for the preparation of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2, 3-dihydro-1h-pyrrolizin-5-yl acetic acid and its intermediates

Info

Publication number: WO2007108006A1
Application number: PCT/IN2006/000363
Authority: WO
Inventors: Arul Ramakrishnan; C. Khandekar Amit; Kale Y. Bhima
Original assignee: Unichem Laboratories Limited
Priority date: 2006-03-23
Filing date: 2006-09-12
Publication date: 2007-09-27

Abstract

The present invention relates to a process for the preparation of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2, 3-dihydro-1H-pyrrolizin-5-yl acetic acid, in which the key intermediate, 5-Benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole is obtained by the hydrogenation of 2,2-dimethyl-4-oxo-5-phenyl-nitropentane. The invention also relates to the preparation of the intermediates occurring in the above process.

Description

Title- Process for the preparation of 6-(4-chlorophenyl)-2,2-dimethyl-7~ phenyl-2, 3-dihydro-lH-pyrrolizin-5-yl acetic acid and its intermediates.

DESCRIPTION OF THE INVENTION:

The present invention relates to a process for the preparation of 6-(4- chlorophenyl)-2,2-dimethyl-7-phenyl-2, 3-dihydro-lH-pyrrolizin-5-yl acetic acid (ML 3000) and its key intermediate 5-Benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole which is prepared by the hydrogenation of 2,2-dimethyl-4-oxo-5-phenyl-nitropentane.

ML 3000 is described as a promising inhibitor of cyclooxygenase and 5- lipooxygenase and thus found suitable for the treatment of rheumatic type disorders and for the preventive treatment of allergically induced diseases. For this see for example Drugs of Future 1995, 20 (10), 1007-1009. The preparation possibilities of this drug substance are described in EP-A-397175, WO95/32970, WO95/32971, WO95/32972, Arch Pharm. Med. Chem. 330, 307-312 (1997)

In all these publications, the parent structure is synthesized according to scheme-A as shown below, i

(IV) (V)

Scheme-A

The pyrrolizine (V) is then converted to ML-3000 by reaction with diazoacetic ester, an oxalic ester chloride or oxalyl chloride and subsequent hydrolysis or hydrolysis and reduction of the Tceto group using hydrazine. These preparation procedures for ML- 3000 and analogously similar compounds are described for example in WO95/32971, example 5C, PCT/EP 01/00852, J. Med. Chem. 1994 (37), 1894 - 1897; Archiv der Pharmazie 321, 159- 162 (1988). An essentially solvent free crystal modification using similar process has also been described in WO 01/55149.

In all the above processes the key intermediate being 5-Benzyl-3,3-dimethyl-3,4- dihydro-2H-pyrrole, the synthesis of which takes place over the stages indicated by the following reaction scheme: B as shown below. _{s /}— OH SOCi \ /-O_{N NaCN} \ /-CN SOCI _s /— CN λ_, _*- V s S==cO

OH Stage- /W Stage i-- IIll / \_, OH Stage ^{^} /Vc,

Scheme: B

EP 0172371 Al describes stages I and II (scheme: B) wherein the reaction of 2,2- dimethyl- 1,3 -propanediol with thionyl chloride is carried out in an inert organic solvent eg a halogenated hydrocarbon or an ether at preferably 0-60 ⁰C. The further reaction of the resulting 5,5-dimethyl-l,3,2-dioxathiane-2-oxide with sodium cyanide to give 4- i n hydroxy-3, 3 -dimethyl butyronitrile is carried out in dimethyl sulphoxide (DMSO) at about 80 to 120 ⁰C. In stage III the reaction with thionyl chloride gives 4-chloro-3,3- dimethyl butyronitrile. Subsequent addition of benzyl magnesium chloride in stage IV leads to the desired pyrrole (IV).

PCT/EP 02/09356 discusses another process for the preparation of (IV) illustrated in

I S scheme: C as shown below.

HBr - HCN - MeNPh

Scheme: C

In both the processes mentioned above, metal cyanides such as sodium cyanide (scheme: B, stage II) and potassium cyanide (scheme: C) have been used. These potentially dangerous reagents pose a high risk to the operators at plant. Further more the acidic workup procedures leads to the evolution of hydrogen cyanide.

J. Org. Chem. 1997, 62, 7900-7901, discusses yet another method for the preparation of ML-3000. The method encompasses a Suzuki cross coupling reaction in presence of Pd(PPh₃).,. The production of ML-3000 using this protocol on a commercial scale may not be feasible.

It is therefore i an object of the present invention to make available an economical, environmentally benign and commercially viable process for the preparation of 5-Benzyl- 3;3-dimethyl-3,4-dihydro-2H-pyrrole and hence for the preparation of 6-(4- chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-ρyrrolizin-5-yl acetic acid (ML- 3000) in which the above mentioned disadvantages and the hazardous reactions are circumvented.

The object is achieved by the process for the preparation of the compound of formula (VI).

where, a) the compound of formula (III)

is converted into the compound of formula (IV)

by reduction of the compound of formula (III), followed by cyclization to (IV) b) reacting the compound of formula (IV) with ω-bromo-4 chloroacetophenone to give a compound of the formula (V)

and, c) introducing acetic acid radical into the compound of formula (V)

The present invention also relates to a process for the preparation of the compound of formula (IV) by hydrogenation of the compound of formula (III) and subsequent ring closure and to the corresponding processes for the preparation of the intermediates of formula (III).

The synthesis of the compound of formula (III) is carried out according to the invention preferably via the following stages: 1) Oxidation of the readily available mesityl oxide to 3, 3 -dimethyl acrylic acid.

Conversion of 3, 3 -dimethyl acrylic acid to its corresponding Weinreb amide (I) in presence of suitable acid activators.

(Ia) (I)

2) Grignard reaction of benzyl magnesium chloride to the Weinreb amide (I) to give the compound of formula (II).

3) Michael addition of nitromethane to the above intermediate (II) to give a compound of formula (III).

The preparation of 3,3-dimethyl acrylic acid from mesityl oxide is described in VOGEL' S Textbook of Practical Organic Chemistry. 0 The Weinreb amide (N-methoxy-N-methyl amide) of the formula I can be prepared using the general methodology described in the prior art eg; J. Org. Chem. 2001, 66, 2534- 2537; and/or references cited therein, or a modification thereof as exemplified herein. The preferred process conditions are indicated below.

Suitable acid activators used are ethyl chloroformate, methyl chloroformate, ^ isobutyl chloroformate, pivaloyl chloride etc, preferably ethyl chloroformate and pivaloyl chloride. These acid activators can be used in excess, however equimolar amounts are particularly preferred. Suitable bases used for the reaction are tertiary amines preferably N-methyl morpholine. Thus 3,3-dimethyl acrylic acid, N-methyl morpholine and pivaloyl chloride are employed in the molar ratio of 1:2: 1. The addition of pivaloyl chloride is carried out preferably below 5 ⁰C. When the acid is almost completely consumed, N₃O- dimethyl hydroxyl amine salt is added at a temperature preferably below 5 ⁰C. After the addition the reaction is continued at 5° to 30 ⁰C, preferably between 15° and 30 ⁰C, most preferably between 25° and 30 ⁰C, On completion of the reaction, the reaction mixture is quenched with water. Solvent layer separated and after usual work up gave the corresponding Weinreb amide (I). Addition of an ethereal solution of the amide (I), to an ethereal solution of benzyl magnesium chloride gives after workup the compound of formula (II). The addition is preferably carried out between 5° and 10 ⁰C. The crude product obtained in this step can be optionally purified tay column chromatography over silica.

As the next reaction stage the compound of formula (II) so obtained is reacted with nitromethane optionally in a polar solvent like DMSO in the presence of a base such as potassium carbonate. Nitromethane is usually employed in 1 to 6-fold excess compared to (II). The afore mentioned Michael addition reaction is preferably carried out between 20° and 80 ⁰C. Quenching in dilute acid solution followed by extractive workup then gives the Michael addition product (III). In the next stage the Michael addition compound (III) is then converted to the

5-Benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole by hydrogenation. In the hydrogenation of the nitro ketone (III) to the pyrroline of formula (IV) the primary nitro group is reduced to the amino ,group, which condenses spontaneously with the keto group with the elimination water to give cyclic imino compound. This hydrogenation is carried out in the presence of a metal catalyst such as raney nickel preferably in an anhydrous form.

Solvents such as Methanol, Isopropanol and mixtures of toluene and methanol can be used. The hydrogenation is carried out at 20° to 55 ⁰C.

On completion of the reaction the catalyst is allowed to sediment and the supernatant solution is filtered through celite. The catalyst can optionally be used for further hydrogenation. The solvent is distilled off from the reaction solution. The product can be purified by salt formation, eg, by hydrochloride formation and release of the compound of formula (I) using a base eg. ammonia, followed by re-extraction and evaporation.

The 2-benzyl-4,4-dimethyl-l-pyrroline of formula (I) is then cyclized with ω- bromo-4 chloroacetophenone to give 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-

5 dihydro-lH-pyrrolizine of the formula (V). ω-bromo-4 chloroacetophenone can be obtained as described in Bull. Soc. Chim. Fr. 21,69, (1899).

The reaction of the compound of formula (IV) with ω-bromo-4 chloroacetophenone is in general carried out in a polar organic solvent preferably methanol. The reaction is carried out in the presence of a base in order to trap the „ hydrogen bromide liberated. The most preferred bases used were alkali metal carbonates and alkali metal hydrogen carbonates of which the sodium and potassium compounds being particularly preferred. Satisfactory results were also observed with the use of other bases such as ammonium bicarbonate. These bases can be employed in the form of an aqueous solution. However it has proven to be particularly preferred to use these bases in

] S solid form. This helps removal of inorganic reaction products and facilitates easy isolation of the product. The base can be employed in equimolar amounts based on the amount of hydrogen bromide liberated. However it has been usually used in excess, for example in an excess of 1.2 to 1.8 equivalents. The reaction is carried out in the absence of light. Although the reaction temperature can be varied over a wide range, it is however

²⁰ preferably carried out in the range of 17° to24 ⁰C. The crude product from this reaction is t slurried in water at 40 to 45 ⁰C and treated for. an hour, before being filtered and dried.

Finally the compound of formula (V) is treated with oxalyl chloride and the resulting product is quenched in ice to obtain the keto acid (VII). Treatment of the optionally isolated keto acid (VII) with hydrazine hydrate followed by reduction of the so 25 formed intermediate using a base like sodium or potassium hydroxide and subsequent acidification of the salt gives the compound 6-(4-chlorophenyl)-2,2-dimethyl-7-ρhenyl- 2,3-dihydro-lH-pyrrolizin-5-yl acetic acid (VI).

The compound of the formula (V) can also be converted to the compound of formula (VI) by the reduction of the hydrazone derivative using sodium cyanoborohydride, followed by basic hydrolysis of the ester. These protocols are shown in the scheme D beloψ.

(VH)

Scheme: D

The invention is illustrated by the following examples. The examples are not intended to limit the scope of the invention as defined herein above and as claimed herein below.

Examples:

1. N-Methoxy-N.3-dimethyl-2-butenamide (I)

To a solution of 3, 3 -dimethyl acrylic acid (100.12g, IM) in methylene dichloride (Hit) was added N-methyl morpholine (202g, 2M) and the solution was cooled to 0-5 ⁰C. Pivaloyl chloride (120 g, IM) was added dropwise over a period of 20-30 mins, maintaining the temperature below 5 ⁰C. After complete addition the reaction mixture was stirred till completion of reaction. After about 3-4 hrs, N,O-dimethyl hydroxyl amine Ω hydrochloride was added and the reaction continued overnight below 20 ⁰C. After completion of the reaction, the reaction mixture was quenched with water (1 lit) and stirred for 30 mins. The MDC layer separated and washed thoroughly with 10 % NaHCO₃ solution. The organic phase separated and the solvent evaporated under reduced pressure to give the product as oil. S 1H NMR (CDCl₃): 6.05 (s, IH), 3.62 (s, 3H)₅ 3.15 (s, 3H)₃ 2.03 (s, 3H), 1.85 (s, 3H)

2. 4-methyl- 1 -phenyl-3 -pentene-2-one OT) To a solution of benzyl magnesium chloride in diethyl ether (from 287 g 2.27 M benzyl chloride and 54.5 g, 2.27 M magnesium) was added the weinreb amide (I) (130 g, 0.91M), maintaining ,the temperature below 5 ⁰C. The reaction mixture was stirred for further 3 to 4 hr at 20-25 ⁰C. The reaction mixture was quenched in ice-cold solution of 5 HCl and stirred for 30 mins. The layers were separated and the organic phase washed with water. Solvent ether was distilled to give oil, which was purified by column chromatography on silica to give the desired product as oil.

1H NMR (CDCl₃): 1.56 (s, 3H, -CH₃), 1.86 (s, 3H, -CH₃), 3.40 (s, 2H, -CH₂), 5.82 (s, IH, -CH), 6.92-7.05 (m, 5H, aromatic)

I _Q 3. 2.2-dimethyl-4-oxo-5-phenyl-nitropentane

To the ketone (10Og, 0.57 M) from example 2 taken in DMSQ (1 lit) was added K₂CO₃ (126.8g, 0.92 M) and nitromethane (175 g, 2.87M). The temperature of the reaction mixture was^ gradually increased to 60-65 ⁰C and the reaction maintained at this temperature till completion. The reaction mixture was then cooled to 20-25 ⁰C and

1 5 quenched in HCl diluted with water. The separated oil is extracted with ethyl acetate. The ethyl acetate extract is then washed thoroughly with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure to give the said product as oil. ¹H NMR (CDCl₃): 1.12 (s, 6H, -CH₃), 2.64 (s, 2H, -CH₂), 3.73 (s, 2H, -CH₂), 4.59 (s, 2H, -CH₂), 7.22-7.40 (m, 5H, aromatic)

20 4. 5-Benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole

Raney nickel, which has been freed before hand of the aqueous supernatant by decantation, is covered with a layer of nitrogen gas in a steel autoclave and then suspended in methanol for 10-15 min. After switching of the stirring the catalyst is allowed to settle and the supernatant solution is decanted. The catalyst is covered with a

2_<5 solution of the nitroketone from example 3 in methanol. The vessel is then flushed three times with nitrogen filled upto a pressure of 3 bar. It is then flushed with hydrogen at 1 bar and finally the hydrogen pressure is increased upto 3-4 bar. The hydrogenation is started by switching on the stirring and gradually increasing the temperature to 50-60 ⁰C. After completion of the reaction the excess hydrogen pressure is released and apparatus is flushed 3 times witH nitrogen. The catalyst is allowed to settle and the supernatant solution is filtered through a bed of celite. The bed is then washed with methanol. The filtrate along with the washings are collected and the solvent methanol is distilled off under reduced pressure. The residue of the distillation is diluted with toluene and washed

5 with water. The toluene layer is then treated with a solution of HCl at 15-20 ⁰C. and the two phase mixture is stirred at 40-45 ⁰C for 15-20 min. The aqueous layer is separated and cooled to 5-10 ⁰C. The pH of the aqueous phase containing the pyrroline extract is then adjusted to 10-11, maintaining the temperature below 10 ⁰C. The separated pyrroline is taken up in ether and the solvent ether is evaporated in vacuo to yield the desired

^{1 n} product.

¹H NMR (CDCl₃): 1.Θ3 (s, 6H, -CH₃), 2.22 (s, 2H, -CH₂), 3.56 (s, 2H, -CH₂), 3.64 (s, 2H, CH₂), 7.22-7.33 (m, 5H, aromatic).

5. 6-(4-chlorophenyl)-2.2-dimethyl-7-phenyl-2.3-dihydro-l-H-pyrrolizine.

The pyrroline (50 g) obtained from the example 4 above is dissolved in methanol

I ^ (500 mL). The solution is cooled to 15-20 ⁰C and ω-bromo-4-chloroacetophenone is added with stirring and in small lots over a period of 15 to 30 min. Ammonium bicarbonate (32 g) is added and the reaction is continued at 20-25 ⁰C with the exclusion of light. After around 24 hr, the yellowish suspension is then filtered under suction and the solid so obtained is washed with a small amount of cold methanol. The product is

20 suck dried and suspended in water at 40-45 ⁰C. Stirring continued for 30-35 min and the product purified from the inorganic impurities is then filtered under suction and dried in vacuo at 35-40 ⁰C.

6. 6-(4-chlorophenyl)-2.2-dimethyl-7-phenyl-2.3-dihydro-l-H-pyrrolizin-5-yl-acetic acid (ML-3000).

2^ 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-l-H-pyrrolizine (50 g,

0.156 M) is dissolved with stirring in dry tetrahydrofuran. The assembly is blanketed with nitrogen atmosphere. The yellow colored solution is cooled to 10-15 ⁰C and oxalyl chloride (31.6g, 0.24 M) is slowly added over a period of 10-15 min, such that the internal temperature is below 15 ⁰C. After complete addition the green colored solution is stirred at 18-25 ⁰C for 20-30 min. The reaction mixture is then quenched carefully in Ice (80 g) such that the internal temperature does not exceed above 20 ⁰C. The reaction mixture is then stirred at 20-30 ⁰C for 5-10 min. The solution is diluted with diethylene glycol (27Og) and hydrazine (65g, 1.28 mol). The internal temperature is then raised gradually and solvent THF is distilled off during the process until the temperature reaches

75-80 ⁰C. The suspension is then cooled to 50-55 ⁰C and KOH (113 g, 2.02 M) is added portion wise over a period of 30 min. The now yellowish liquid is then heated to 95-110 ⁰C gradually. During the process excessive frothing is observed. Nitrogen is blown through the reaction mixture by means of a dip tube at an increased stirring speed. The temperature is then raised slowly to 140-145 ⁰C and during the process aqueous distillate is collected. The batch is held at 130-145 ⁰C for 2-3 hr. The reaction temperature is then cooled to 35-40 ⁰C and water and diethyl ether are added. The mixture is stirred vigorously for 15-20 min and with the stirring switched off the layers are allowed to settle. The aqueous phase is separated cooled below 5 ⁰C and acidified to pH 1 using a solution of HCl maintaining temperature below 10 ⁰C. The separated solid is taken up in diethyl ether and ^"the ethereal extract is washed thoroughly with water. The ethereal extract is charcoalised before being evaporated under vacuo below 20 ⁰C. The solid is slurried in heptane and is filtered under suction and washed with heptane. The product is dried in vacuum at 45^-55 ⁰C.

Claims

Claims:

1. A process for the preparation of the compound of formula (VI)

where, a) the compound of formula (III)

is converted into the compound of formula (IV)

by reduction of the compound of formula (III), followed by cyclization to (IV) b) reacting the compound of formula (IV) with ω-bromo-4 chloroacetophenone to give a compound of the formula (V).

c) and introducing an acetic acid radical into the compound of the formula (V). 2. A process for the preparation of the compound of the formula (V)

(V) where, a) the compound of formula (III)

is converted into the compound of formula (IV)

A process for the preparation of the compound of the formula (IV)

where the compound of the formula (III)

is converted into the compound of the formula (IV)

by reduction of the compound of formula (III), followed by cyclization to (IV),

4. The process as claimed in one of the preceeding claims, wherein raney nickel is used as a catalyst in the reduction.

5. A compound of the formula (III)

6. A process for the preparation of the compound of the formula (III) where, a compound of the formula (II)

is reacted with nitromethane, in presence of a base and optionally in the presence of a polar solvent.

7. A process according to claim 6, wherein the said polar solvent is dimethyl sulphoxide (DMSO) and the said base is potassium carbonate.

8. A process for the preparation of the compound of formula (II) where, a compound o(f the formula (I)

^0Wle (I) is converted to the compound of the formula (II) by the grignard reaction of the appropriate benzyl magnesium halide.

9. A process for the preparation of the compound of the formula (I), where the substituted acid is treated with a suitable acid activator such as pivaloyl chloride in presence of a base to give an intermediate of the formula I-a.

10. A process as claimed in one of the preceeding claims, wherein the optionally isolated compound of formula I-a is reacted with N-O-dimethyl hydroxylamine salt in presence of a base to give the compound of the formula (I).

11. A process according to claims 9 and 10, wherein the said base is N-methyl morpholine.

12. The process according to the claim 8, wherein the grignard reagent is employed in excess of 1 to 3 mole equivalent of the compound of the formula (I).

13. The process according to the claim 6, wherein the nitromethane used is in excess of 1 to 6-mole equivalent of the compound of the formula (II).

14. The process according to the claim 2, wherein the base used in the reaction of the compound of the formula (III) with ω-bromo-4 chloroacetophenone is ammonium bicarbonate, ,