WO2006008635A1

WO2006008635A1 - Process for the preparation of a 3-phenoxy-pyridine derivative

Info

Publication number: WO2006008635A1
Application number: PCT/IB2005/002037
Authority: WO
Inventors: Robert Walton
Original assignee: Pfizer Corp Belgium; Pfizer Ltd Great Britain; Pfizer Corp SRL
Current assignee: Pfizer Corp Belgium; Pfizer Ltd Great Britain; Pfizer Corp SRL
Priority date: 2004-07-14
Filing date: 2005-07-01
Publication date: 2006-01-26
Anticipated expiration: 2007-01-14

Abstract

The present invention is concerned with an improved process for the preparation of the selective serotonin reuptake inhibitor N-Methyl{3-[3-methyl-4-(methylthio)phenoxy]-4-pyridyl}methylamine (L) or (D) tartrate (I) and with intermediate products therein. Formula (I)

Description

PROCESS FOR THE PREPARATION OF A 3 -PHENOXY- PYRID INE DERIVATIVE

The present invention is concerned with an improved process for the preparation of the selective serotonin reuptake inhibitor Λ/-Methyl{3-[3-methyl-4- (methylthio)phenoxy]-4-pyridyl}methylamine (L) or (D) tartrate and with intermediate products therein.

WO 02/083643 describes the preparation of Λ/-Methyl{3-[3-methyl-4- (methylthio)phenoxy]-4-pyridyl}methylamine (L) tartrate (I)₁ in which the compound is prepared by (a) reaction of 3-chloroisonicotinonitrile (II) with 3- methyl-4-(methylthio)phenol (III) in the presence of potassium carbonate in a suitable solvent such as Λ/,Λ/-dimethylformamide (DMF), at elevated temperature; (b) carrying out a hydrolysis of 3-[3-methyl-4-

(methylthio)phenoxy]isonicotinonitrile (IV) with 6M sodium hydroxide solution in a suitable solvent such as ethanol, at elevated temperature, followed by quenching with a suitable acid such as cone. HCI(_aq); (c) reaction of crude 3-[3-methyl-4- (methylthio)phenoxy]isonicotininc acid (V) (obtained from step (b)) with carbonyldiimidazole (CDI) in a suitable solvent such as tetrahydrofuran (THF), followed by treatment with a 2M solution of methylamine in a suitable solvent such as THF; (d) reduction of the amide (Vl) with BH₃THF, in a suitable solvent such as THF, to form /V-Methyl{3-[3-methyl-4-(methylthio)phenoxy]-4- pyridyljmethylamine (VII); (e) the corresponding L-tartrate salt was prepared by dissolving amine (VII) in isopropyl alcohol, adding L-tartaric acid, allowing the mixture to cool and then recrystallising the resulting solid twice from EtOH.

The complete sequence may be represented as follows:

(II) (III) (IV)

(VII) (I)

Scheme 1

There are a number of problems with this route, when applied to bulk scale synthesis, namely:

(i) Reaction times for process step (a) are slow when carried out on a large scale, typically 18 to 24 hours. Additionally, the work-up procedure for process step (a) requires large volumes of solvent. This is impractical on an industrial scale, as it is time consuming (a significant economic disadvantage), and most notably because a large amount of waste solvent must be disposed of after the product has been isolated. Also, the product obtained must be purified by column chromatography; again this is not desirable when preparing large amounts of product.

(ii) Again for process step (b) large volumes of solvent are required for the work-up, this leads to the same difficulties as outlined above. Furthermore the by-product, NH₄CI was difficult to remove when this step was carried out on scale. Additionally it was found that residual amounts of the NH₄CI by-product, when carried through to process step (c), unexpectedly led to the formation of a by-product, the primary carboxamide derivative of compound (V).

(iii) The product of process step (c) is obtained, after work-up and without further purification, as a foam. Such a product is not easily handled in bulk, and accordingly this work-up procedure is ill suited to an industrial process.

(iv) The reaction quench in process step (d) involves addition of methanol followed by 6M HCI(_aq). Such a two-step process involving large volumes of solvent is undesirable on a large scale.

(v) In process step (e), the formation of salt (I) is carried out using a large volume of isopropyl alcohol. The isolation of salt (I) is then achieved via two recrystallisations from ethanol. Such an inefficient process is economically costly on an industrial scale.

In summary, whilst this reaction sequence provides an adequate route for the production of the compound of formula (I) on a laboratory scale, there is a clear requirement for a robust process that would be more applicable to industrial scale generation of these compounds.

As a result the synthetic process depicted in scheme 1 has been improved according to the following embodiments of the invention:

1. In process step (a), compounds of formula (IV) are prepared by reaction of 3-chloroisonicotinonitrile (II) with 3-methyl-4-(methylthio)phenol (III) in a suitable solvent, at elevated temperature; followed by a work-up; characterised by performing the reaction in the presence of a base having particle size D_g0<900 microns and VMD <500 microns.

Preferably the base is potassium carbonate of particle size Dgo<9OO microns and VMD <500 microns. Following completion of the reaction, preferably the work-up consists of the slow addition of water to the stirred reaction mixture at 60⁰C, followed by collection of the crystallised product, compound (IV).

Other suitable bases include carbonate bases such as sodium carbonate, caesium carbonate; butoxide bases such as potassium t-butoxide, lithium t- butoxide, sodium t-butoxide; hydroxide bases such as sodium hydroxide; and organic bases such as pyridine and morpholine.

Suitable reaction solvents include polar aprotic solvents such as Λ/-methyl-2- pyrrolidinone (NMP), tetrahydrofuran, dimethylsulfoxide, dioxan, acetonitrile and ethers.

2. Compounds of formula (V) are prepared by process step (b), hydrolysis of a compound of formula (IV). The reaction is carried out using a suitable base in a suitable solvent, at elevated temperature, followed by quenching with a suitable acid; characterised by the purification of the crude product by slurrying in water, at 40-70⁰C, followed by filtration and drying.

Suitable bases include KOH_(aq), and LiOH_(aq).

Suitable solvents include methanol, isopropyl alcohol, n-butanol, t-butanol, 2- butanol, t-amyl alcohol and tetrahydrofuran.

Suitable acids include concentrated H₂SO₄ (_aq), HBr_(aq₎, and aqueous acetic acid.

The preferred base is 1 M-2.5M NaOH_(aq).

After the quench, the solid material is isolated prior to purification.

3. The amide (Vl) is generated by process step (c), reaction of acid (V) with carbonyldiimidazole (CDI) in a suitable solvent, followed by addition of a suitable methylamine source; characterised by the distillation and replacement of the reaction solvent with fe/f-butyl methyl ether (TBME), and the isolation of the product by crystallisation.

Suitable solvents include DCM, f-BuOMe, and ethyl acetate.

Suitable sources of methylamine include methylamine gas, and salts of methylamine in the presence of a base (a suitable salt would include hydrochloride, suitable bases would include triethylamine and DMAP).

The preferred solvent is DCM.

The product containing TBME solution may be washed with NaOH_(aq), NH₄CI_(aq) and water, prior to the isolation of the product by crystallisation.

4. Compound (VII) is prepared by process step (d), reduction of amide (Vl) using a suitable reducing agent in a suitable solvent; characterised by the direct quenching of the reaction by the addition of a solution of a suitable acid in a suitable solvent.

Upon completion of the quench, the THF is preferably distilled and replaced with water. This solution is adjusted to pH12 by the addition of 40% NaOH_(aq), and then extracted with f-BuOMe.

Suitable solutions of acids include HCI(_aq), H₂SO₄ (_aq), HBr(_aq), and aqueous acetic acid, in a suitable solvent such as THF.

The preferred acid solution is 6M HCI_(aq)/THF

Suitable reaction solvents include dioxan, and methyl THF ethers.

Suitable reducing agents include LiAIH₄, solutions of AIH₃, DIBAL-H, catalytic hydrogenation, NaBH₄/BF₃.THF, and BF₃-Et₂O.

The preferred reducing agent is NaBH₄/BF₃.THF. 5. Compound (I) is prepared by process step (e), addition of D or L tartaric acid to compound (VII), in a suitable solvent optionally at elevated temperature.

Suitable solvents include aqueous ethanol, methanol, methyl ethyl ketone, acetone, n-butanol, t-butanol, 2-butanol, t-amyl alcohol, and THF (all as aqueous mixtures).

The preferred solvent is aqueous ethanol.

Preferably the L form of tartaric acid is used.

Following salt formation, compound (I) is obtained by recrystallisation from a suitable solvent, such as aqueous ethanol, methanol, methyl ethyl ketone, acetone, n-butanol, t-butanol, 2-butanol, t-amyl alcohol, and THF (all as aqueous mixtures).

Preferably compound (I) is recrystallised from aqueous ethanol.

6. In a particularly preferred embodiment, process steps (d) and (e) are combined to avoid the isolation of compound (VII).

In this embodiment, preferred conditions for process step (d) are THF as solvent and NaBH₄/BF₃.THF as reducing agent.

Following completion of process step (d), including quench and work-up, compound (VII) is isolated as a solution in TBME, by extraction with TBME. This solvent is then preferably distilled and replaced with ethanol.

In this embodiment, preferred conditions for process step (e) are aqueous ethanol as solvent, and use of the L form of tartaric acid.

The advantages of the embodiments described above may be summarised as follows: (i) The use of potassium carbonate of particle size D₉₀<900 microns and VMD <500 microns, in process step (a), led to a surprising reduction in reaction time, from 24 hours to 12 hours. Furthermore, following completion of reaction, slow addition of water to the reaction mixture allows the isolation of compound (IV) by crystallisation. This procedure can be completed in two hours; whereas using the procedure described in WO 02/083643, it would take two days. Additionally, far less waste solvent is generated in the improved route. All these advantages bring significant environmental and economic benefits.

(ii) In process step (b), the development of a slurrying process for the work up, has the advantage of reducing the volume of solvent required. This process also facilitates the removal of the NH₄CI by-product, thus preventing the formation of the carboxamide by-product in process step (c).

(iii) For process step (c), the procedure described in WO 02/083643 does not provide compound (Vl) in physical from that is amenable to industrial scale processing. The high solubility of amide (Vl) renders it less susceptible to crystallisation techniques. In the improved process, the use of DCM as reaction solvent allows its replacement with TBME at the end of the reaction. This in turn allows the compound to be isolated by crystallisation, following washing with NH₄CI_(aq₎ to remove imidazole. This inventive choice of solvent would not be obvious to one skilled in the art.

(iv) The reaction quench in process step (d) involves addition of a 6M HCI_(aq)/THF mixture. This allows the resultant hydrogen evolution to be controlled, thus making it a safer procedure. This improved method is highly advantageous on a large scale as only one quench need be carried out, and as a result, far less solvent is used.

(v) The use of aqueous ethanol for both salt formation and recrystallisation in process step (e) is far more efficient than the process described in WO 02/083643, and further more gives a higher yield of compound (I). (vi) Compound (VII) is an oil, and as such is difficult to remove from large reaction vessels. The improved route allows the combination of process steps (d) and (e), thus avoiding the isolation of amine (VII). When process steps (d) and (e) are combined as described, the yield is 68%. When process steps (d) and (e) are carried out according to the procedure of WO 02/083643, the yield is only 48%.

(vii) This improved process is suitable for producing quantities of compound (I) on an industrial scale.

The invention also encompasses a further embodiment that provides an alternative synthesis of compound (VII). This embodiment is illustrated by the following reaction scheme:

Scheme 2

Aldehyde (IX) can be prepared by process step (a), reaction of 3- chloronicotinaldehyde (VIII; prepared by reaction of 3-chloropyridine with Lithium diisopropylamide in DMF at -78⁰C) with phenol (III), in the presence of potassium carbonate in a suitable solvent such as DMF. Compound (VII) is then prepared from aldehyde (IX) by process step (f), reductive amination. Methylamine is the amine source and NaBH₄ is the reducing agent. The reaction is carried out in a suitable solvent such as THF.

Alternatively, aldehyde (IX) can be prepared by process step (g), reduction of nitrile (IV) with DIBAL (diisobutylaluminium hydride) in a suitable solvent such as THF; as illustrated by scheme 3 below.

Scheme 3

The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used:

GDI carbonyldiimidazole

MEK methylethyl ketone

DMF Λ/,/V-dimethylformamide

TBME / 1- te/f/ary-butyl methyl ether

BuOMe

DMSO dimethylsulfoxide

DCM dichloromethane

DMSO dimethylsulfoxide m/z mass spectrum peak

HPLC High Pressure Liquid Chromatography

MS mass spectrum

NMR nuclear magnetic resonance q quartet S singlet t triplet br broad

THF tetrahydrofuran

Kg Kilograms

L Litre ml_ millilitre g grams

CDCI₃ deuterated chloroform

NMR spectra were obtained using a Varian Inova 300 MHz spectrometer by dissolving the sample in an appropriate solvent.

Mass spectra were obtained using a LC/MS system consisting of an 1100 series Hewlett Packard LC in combination with a Micromass ZMD mass spectrometer.

1) 3-[3-methyl-4-(methylthio)phenoxy]isonicotinonitrile

DMF (120ml) was charged to the vessel and stirred at 22°C under a nitrogen atmosphere. 3-Methyl-4-(methylthio)phenol (17.5g; commercially available) was charged to the vessel, a yellow solution was formed. K₂CO₃ (22.4g) was then charged to the vessel, a yellow suspension was produced. Finally, 3-chloro- isonicotinonitrile (15g; WO 02/083643, preparation 71) was charged to the vessel, and a yellow/orange suspension was formed. This suspension was heated to 100°C for 6 hours, and was then cooled to 6O⁰C. Water (300ml) was added over 1 hour. The suspension was cooled to 22°C over 2 hours and stirred for a minimum of 6 hours. The solid was collected by filtration and pulled dry. The solid cake was washed with water (15ml) and pulled dry. The product was dried under vacuum at 50°C for 12 hours. Yield = 85%

¹HNMR δ_H (CDCI₃, 300 MHz) 2.36 (3H, s), 2.48 (3H, s), 6.97(2H, m), 7.21 (1 H, d), 7.51 (1 H, d), 8.31(1 H, s), 8.45(1H, d); MS m/z (ES+) 257 (MH⁺).

2) 3-[3-methyl-4-(methylthio)phenoxy]isonicotinic acid

Ethanol (200ml) was charged to the vessel and stirred at 22°C under a nitrogen atmosphere. 3-[3-methyl-4-(methylthio)phenoxy]isonicotinonitrile (2Og) was charged to the vessel, a cream suspension was formed. Sodium hydroxide (9.36g), dissolved in 200 ml of water, was added to the vessel. The resulting suspension was heated to reflux 85°C, after 30mins a brown solution was formed. After 3 hours the solution was cooled to 22°C. The resulting solution was pH adjusted to 1-1.5 by the addition of c.HCI. A thick suspension was formed, which was stirred for 2 hours at 22°C. The solid was collected by filtration, washed with 2 x water (20ml) and pulled dry. The product was dried under vacuum at 70°C. Yield = 115%.

The product can be further purified by the following method:

Water (100ml) was charged to the vessel and stirred at 22°C under a nitrogen atmosphere. 3-[3-methyI-4-(methylthio)phenoxy]isonicotinic acid (1 Og) was charged to the vessel, a cream suspension was formed. The suspension was heated 70°C for 2 hours, and then the solid was collected by filtration and pulled dry. The solid cake was washed with 2x water (20ml) and pulled dry. The product was dried under vacuum at 7O⁰C for 12 hours. Yield = 7.5g

¹HNMR δ_H (DMSO-d_6l 300 MHz) 2.23 (3H, s), 2.42 (3H, s), 6.78 (1 H, d), 6.87 (1 H₁ m), 7.18 (1 H, d), 7.70 (1 H, d), 8.34 (1 H, s), 8.50 (1 H₁ d); MS m/z (ES^") 274 (MH^").

3) /V-methyl-3-[3-methyl-4-(methylthio)phenoxy]isonicotinamide

To a clean dry vessel DCM (500ml) was charged and stirred at 22°C under a nitrogen atmosphere. 3-[3-methyl-4-(methylthio)phenoxy]isonicotinic acid (5Og) was charged to the vessel, a cream suspension was formed. CDI (30.92g) was added portionwise over 10 minutes. The resulting suspension was stirred at 22⁰C for 2 hours. After 2 hours a clear solution was formed and methylamine (2M) in THF (108.7ml) was added slowly maintaining the temperature range of 20- 30°C. The resulting suspension was stirred at 22°C. After 3 hours the DCM was stripped to minimum stir volume and replaced with f-BuOMe to give a final volume of 1000ml (20ml/g f-BuOMe). The solution was cooled to 22⁰C. The organic phase was washed with 1 N NaOH (150ml) and the organic phase held. The aqueous NaOH was extracted with f-BuOMe (200ml) and the organic phases combined. The organic phase was washed with saturated ammonium chloride (2x 125ml), and then with water (100ml). The organic phase was collected and the solvent level was reduced to approx 3ml/g. The solution was cooled to 22⁰C and stirred for at least 4 hours. The resulting white suspension was cooled to 0 to -5⁰C and stirred for at least 2 hours. The product was collected by filtration, washed with the mother liquors and pulled dry. Yield = 71%. ¹HNMR δ_H (CDCI₃, 300 MHz) 2.35 (3H, s), 2.47 (3H, s), 3.01 (3H, d), 6.91 (2H₁ m), 7.20 (1 H₁ d), 7.61 (1 H, br, s), 8.07(1 H, s), 8.21 (1 H, s), 8.46(1 H, d); MS m/z (ES+) 289 (MH⁺)

4) Λ/-Methyl{3-[3-methyl-4-(methylthio)phenoxy]-4-pyridyl}methylamine

To a clean dry vessel was charged THF (340ml) and stirred at 22°C under a nitrogen atmosphere. Λ/-methyl-3-[3-methyi-4-

(methylthio)phenoxy]isonicotinamide (2Og) was charged to the vessel. The reaction was stirred for 30 minutes to give a clear solution. Sodium borohydride (7.87g) was added, resulting in a white suspension. This suspension was cooled to -10°C and stirred for 30minutes. Borontrifluoride.THF (30.61 ml) was added slowly to the suspension, maintaining the temperature in the range of -10 to 5⁰C. The reaction was heated to 60°C over 90 minutes. After 9 hours the reaction was cooled to 22⁰C and stirred. A 6N HCI_(aq)/THF mixture was prepared from 37% HCI (27.4g), de-ionised water (23.6ml) and THF (92ml). The reaction mixture was cooled to -1O⁰C and the 6N HCI solution was added slowly keeping the temperature <10°C. The suspension was heated at 50⁰C for 90 mins then cooled to 22°C. The solvent was reduced to minimum volume to remove THF and replaced with de-ionised water to leave a final water volume of 300ml. The reaction was cooled to 22⁰C, charged with TBME (120ml) and the mixture stirred for 10 mins.

The organic phase was removed and discarded.

The aqueous phase was recharged to the vessel along with TBME (200ml).

The 2-phase mixture was stirred and the pH adjusted to pH 11-12 with 32%

NaOH. The phases were separated and the aqueous extracted with TBME (1 x 120ml). The organic phases were combined and the solvent removed under vacuum to leave a pale pink oil (18.2g, 96%)

¹HNMR δ_H (DMSO-d₆, 300 MHz) 2.23(6H, d), 2.41 (3H, s), 3.63 (2H₁ s), 6.78 (1 H₁ d), 6.85 (1 H, m), 7.19 (1H, d), 7.52 (1H₁ d), 8.12 (1H₁ s), 8.35 (1 H, d); MS m/z (ES+) 275 (MH⁺)

5) /V-Methyl{3-[3-methyl-4-(methylthio)phenoxy]-4-pyridyl}methylamine - (L)-tartrate

A solution of Λ/-Methyl{3-[3-methyl-4-(methyIthio)phenoxy]-4-pyridyl}methylamine in TBME (450ml) was charged to a clean spec free vessel via an inline filter. The solution was stirred at 22⁰C under a nitrogen atmosphere. The f-BuOMe was stripped to minimum stir volume and replaced with ethanol to give a final volume of 187ml (6.5ml/g ethanol). The resulting solution was cooled to 22⁰C over 1 hour. L-tartaric acid (15.82g) was charged to a vessel containing purified water (15ml) and ethanol (56.6ml); this was stirred at 22⁰C until a clear solution was formed. This was added in one portion to the solution of the amine via an in-line filter. The vessel was rinsed with ethanol (14.4ml) and the contents were added to the amine solution via an in-line filter. After 1 hour a white suspension was formed. The suspension was cooled to O⁰C over 3 hours. The suspension was stirred for a least 1 hour. The product was collected by filtration, washed with ethanol (1 ml/g) and pulled dry. The product was dried under vacuum at 5O⁰C for 12 hours. Yield = 84% ¹HNMR δ_H (DMSO-d₆, 300 MHz) 2.25 (3H, s), 2.43 (3H, s), 2.48(3H, m), 3.98 (2H₁ s), 4.04 (2H, s), 6.83 (1H, d), 6.94 (1H, s), 7.23 (1H, d), 7.56 (1H, d), 8.13 (1H₁S)₁8.38(1 H, d); MS m/z (ES+) 275 (MH⁺)

Claims

1 A process for the preparation of a compound of formula (VII):

(VII) comprising the reaction of a compound of formula (Vl)

with a suitable reducing agent in a suitable solvent;

characterised by the direct quenching of the reaction by the addition of a solution of a suitable acid in a suitable solvent.

2 A process according to claim 1 wherein the reducing agent is NaBH₄/BF₃.THF and the acid solution is 6M HCI_(aq)/THF.

3 A process according to claims 1 and 2 which further comprises the preparation of a compound of formula (Vl) by the reaction of a compound of formula (V)

(V) with carbonyldiimidazole in a suitable solvent, followed by the addition of a suitable methylamine source;

characterised by the distillation and replacement of the reaction solvent with TBME upon completion of the reaction, and the isolation of the product by crystallisation. 4 A process according to claim 3 wherein the reaction solvent is DCM.

5 A process according to claims 3 and 4 which further comprises the preparation of a compound of formula (V) by the hydrolysis of a compound of formula (IV)

(IV) with a suitable base, in a suitable solvent followed by quenching with a suitable acid;

Charaterised by the purification of the crude product via a water slurry at elevated temperature.

6 A process according to claims 5 which further comprises the preparation of a compound of formula (IV) by the reaction of a compound of formula (II)

with a compound of formula (III)

(III) in a suitable solvent at elevated temperature;

charaterised by performing the reaction in the presence of a base having a particle size Dgo<9OO microns and VMD<500 microns.

7 A process according to claim 6 wherein the base is K₂CO₃ of particle size Dg₀<900 microns and VMD<500 microns. 8 A process for the preparation of a compound of formula (I),

(I)

.HO₂CCH(OH)CH(OH)CO₂H

comprising the consecutive steps of:

(a) the reaction of a compound of formula (Vl)

with a suitable reducing agent in a suitable solvent, followed by quenching and work-up, and subsequent extraction with TBME; to obtain the crude compound of formula (VII)

(VII) as a solution in TBME;

(b) distillation and replacement of the TBME with ethanol;

(c) treatment of the resulting ethanolic solution of compound (VII) with a solution of tartaric acid in aqueous ethanoi, to form the desired salt. ,. g

A process for the preparation of a compound of formula (I):

.HO₂CCH(OH)CH(OH)CO₂H comprising the reaction of a compound of formula (VII)

^(V"⁾ with tartaric acid;

characterised in that the reaction and purification are carried out in a suitable aqueous solvent.

10 A process according to claim 9 wherein the solvent is aqueous ethanol.