BACKGROUND

WO2010/099039, published September 2, 2010, discloses indole derivatives as CRTH2 receptor antagonists and process for making the same.

WO2010/031183, published March 25, 2010, also discloses indole derivatives as CRTH2 receptor antagonists and process for making the same.

Molinaro et al, The Journal of Organic Chemistry, 2012, 77, 2299-2309 discloses the CRTH2 Antagonist MK-7246 as well as process for making the same. U.S. Patent 8,546,422, issued October 1 , 2013 discloses azaindole derivatives as CRTH2 receptor antagonists.

WO2014/060596, published April 24, 2014, discloses process for preparing indole derivatives.

As documented in J. Org. Chem. 2012, 77, 2299-2309, a Dieckmann reaction performed on substrate 1 in the presence of potassium ieri-butoxide results in a mixture of the desired ketodiester 2 (64% yield) and of significant amounts of the side products 3 and 4 (at least 10% of each). As stated by the authors, the product distribution could not be improved despite extensive variation of the reaction parameters such as the base, the solvent or the reaction temperature. This does not only limit the yield of the reaction but renders necessary the removal of compound 4 from the reaction mixture by column chromatography. This mandatory purification step is a strong limitation for the preparation of large amount of compound.

SUMMARY OF THE INVENTION

The invention is a process for preparing intermediates of a compound of Formula (I)

or a solvate or salt thereof, comprising reacting a compound of Formula (VIII)

with Mg(EtO) ₂ to give a mixture of compounds of Formula (Bia) and (IXb)

In another embodiment, the process further comprising reacting the compounds of Formula (ΓΧ) with an acid preferably H ₂ SO ₄ or HCl to form the compound of Formula (X)

 DETAILED DESCRIPTION

This invention is directed to an improved process for the preparation of tricyclic ketone compounds which are useful intermediates in the preparation of compounds of Formula (I)

wherein Z is N or C;

X 1 ¹ and X 2" are independently hydrogen, halogen or are not present;

R ¹ , R ² , R ³ are independently Ci-C ₆ alkyl;

R ⁴ is Ci-C ₆ alkyl or forms a heterocyclic ring with Q; and Q is S0 ₂ , C(O) or forms a heterocyclic ring with R ⁴ ; and

J is a bond or Ci-C ₆ alkyl where in the Ci-C ₆ alkyl is unsubstituted or substituted with one or more groups selected from halogen or Ci-C ₆ alkyl.

In an embodiment, the process comprises the use of magnesium ethoxide for the formation of the tricyclic ketone intermediate. Compounds of Formula (I) are antagonists of the PGD2 receptor CRTH2 and are useful in the treatment and prevention of CRTH2 mediated diseases.

A subgenus of Formula (I) are the compounds of Formula (lb)

Scheme 1 demonstrates a synthetic access to intermediates (X) of compounds of Formula lb.

Scheme 1

Scheme 2 demonstrates another synthetic access to intermediates (X) of compounds of Formula lb.

Scheme 2

In an embodiment, the invention is a process for preparing intermediates of Formula (IXa) and (r b) of a compound of Formula (I)

or a solvate or salt thereof, comprising reacting a compound of Formula (VIII)

wherein: Z is N or C;

X ¹ and X ² are independently hydrogen, halogen or are not present;

1 2 3

R , R R ^J are independently Ci-C ₆ alkyl;

R ⁴ is Ci-C ₆ alkyl or forms a heterocyclic ring with Q; and

Q is S0 ₂ , C(O) or forms a heterocyclic ring with R ⁴ ; and

J is a bond or Ci-C ₆ alkyl where in the Ci-C ₆ alkyl is unsubstituted or substituted with one or more groups selected from halogen or Ci-C ₆ alkyl.

In another embodiment, the invention is a process for preparing intermediates of Formula (Bia) and (IXb) of a compound of Formula (I)

or a solvate or salt thereof, comprising reacting a compound of Formula (VII)

with a compound of Formula (VII) in the presence of Mg(EtO) ₂ to give a mixture of compounds of Formula (IXa) and (Bib)

wherein: Z is N or C;

X ¹ and X ² are independently hydrogen, halogen or are not present; 1 2 3

R , R R ^J are independently Ci-C ₆ alkyl;

R ⁴ is Ci-C ₆ alkyl or forms a heterocyclic ring with Q; and

Q is S0 ₂ , C(O) or forms a heterocyclic ring with R ⁴ ; and

J is a bond or Ci-C ₆ alkyl where in the Ci-C ₆ alkyl is unsubstituted or substituted with one or more groups selected from halogen or Ci-C ₆ alkyl.

In another embodiment, the process further comprising reacting the compounds of Formula (Bia) and (IXb) with an acid, preferably H ₂ SO ₄ or HC1, to form the compound of Formula (X)

In yet another embodiment of the process, R ⁴ is methyl, Z is N, X ¹ is not present, X ² is F, Q is C(O) and J is CH(CH ₃ ).

In yet another embodiment of the process, R ⁴ is methyl, Z is C, X ¹ is hydrogen, X ² is F, Q is S0 ₂ and J is a bond.

1 2 4

In yet another embodiment of the process, Z is C, X is F, X is F, J is CH2 and Q and R are taken together to form a 1 ,2,3-triazole as shown below

An embodiment of the invention is compound of Formula (IXa) wherein the compound is

An embodiment of the invention is compound of Formula (X) wherein the compound is

The following definitions are provided to more clearly describe the invention.

"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. In one embodiment alkyl groups contain about 1 to about 12 carbon atoms in the chain. In another embodiment alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, or decyl. "Alkoxy" means an -O-alkyl group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy. The bond to the parent moiety is through the ether oxygen.

"Trifiate" means trifluoromethane sulfonate.

With reference to the number of moieties (e.g., substituents, groups or rings) in a compound, unless otherwise defined, the phrases "one or more" and "at least one" mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is well within the knowledge of those skilled in the art.

When used herein, the term "independently", in reference to the substitution of a parent moiety with one or more substituents, means that the parent moiety may be substituted with any of the listed substituents, either individually or in combination, and any number of chemically possible substituents may be used.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

"Solvate" means a physical association of a compound of this invention with one or more solvent molecules. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H ₂ 0.

The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. EXAMPLES

Example 1 A - Synthesis of a mixture of ethyl 5-(2-ethoxy-2-oxo-ethyl)-8-oxo-7,9-dihydro- 6H-pyrido[3,2-b]indolizine-9-carboxylate and of ethyl 5-(2-ethoxy-2-oxo-ethyl)-8-oxo-7,9- dihydro-6H-pyrido[3,2-b]indolizine-7-carboxylate

Ethyl 3-[l ,3-bis(2-ethoxy-2-oxo-ethyl)pyrrolo[2,3-b]pyridin-2-yl]propa noate (16.09 g; 41.2 mmol) is dissolved in dimethylformamide (70 mL) and magnesium ethoxide (9.43 g; 82 mmol) is added. The resulting mixture is stirred overnight at 45 °C. After 16 h reaction time, the mixture is cooled to room temperature and is diluted with ethyl acetate (125 mL). Aqueous IN hydrochloric acid is added to the reaction mixture until acidic pH is reached. The aqueous phase is separated and the organic phase is extracted with IN hydrochloric acid (100 mL), is dried over magnesium sulphate, is filtered and is concentrated under reduced pressure. The obtained crude residue (12.9 g; 29.5 mmol) composed of ethyl 5-(2-ethoxy-2-oxo-ethyl)-8-oxo-7,9-dihydro-6H- pyrido[3,2-b]indolizine-9-carboxylate and of ethyl 5-(2-ethoxy-2-oxo-ethyl)-8-oxo-7,9-dihydro- 6H-pyrido[3,2-b]indolizine-7-carboxylate is engaged in the next step without further purification.

Protocol B - Retention times: 1.34, 1.58 and 1.80 min (m z 345)

Example IB - Synthesis of a mixture of ethyl 10-(2-ethoxy-2-oxo-ethyl)-7-oxo-8,9-dihydro- 6H-pyrido[l,2-a]indole-6-carboxylate and of ethyl 10-(2-ethoxy-2-oxo-ethyl)-7-oxo-8,9- dihydro-6H-pyrido [1,2-a] indole-8-carboxylate

Ethyl 3-[l ,3-bis(2-ethoxy-2-oxo-ethyl)indol-2-yl]propanoate (65 g; 167 mmol) (prepared according to the method described in J. Org. Chem. 2012, 77, 2299-2309) is dissolved in dimethylformamide (325 mL) and magnesium ethoxide (19.49 g, 167 mmol) is added. The resulting mixture is stirred for 18 h at 45 °C. The reaction mixture is cooled to room temperature and 1 M aqueous hydrochloric acid (500 mL) and tert-butylmethylether (500 mL) are added under stirring. The aqueous layer is extracted with tert-butylmethylether (250 mL). The combined organic layers are washed with half saturated aqueous sodium chloride (300 mL), are dried over sodium sulfate, filtered and concentrated under reduced pressure. The isolated brown oil (56.5 g; 164 mmol) composed of ethyl 10-(2-ethoxy-2-oxo-ethyl)-7-oxo-8,9-dihydro-6H- pyrido[l ,2-a]indole-6-carboxylate and of ethyl 10-(2-ethoxy-2-oxo-ethyl)-7-oxo-8,9-dihydro- 6H-pyrido[l,2-a]indole-8-carboxylate is engaged in the next step without further purification.

Protocol A - Retention times: 1.02 and 1.24 min (m/z 244)

Example 1C - Synthesis of a mixture of ethyl 10-(2-ethoxy-2-oxo-ethyl)-4-fluoro-7-oxo-8,9- dihydro-6H-pyrido[l,2-a]indole-6-carboxylate and of ethyl 10-(2-ethoxy-2-oxo-ethyl)-4- fluoro-7-oxo-8,9-dihydro-6H-pyrido[l,2-a]indole-8-carboxylat e

Dimethylformamide (96 mL) and ethyl bromoacetate (12.4 mL; 112 mmol) are added to ethyl 3- [3-(2-ethoxy-2-oxo-ethyl)-7-fiuoro-lH-indol-2-yl]propanoate (20.0 g; 62.2 mmol). Magnesium ethoxide (22.8 g; 199 mmol) is added in one portion to the reaction mixture maintained at room temperature. A mild exotherm is observed after this addition is complete. The resulting slurry is heated to 45 °C and is aged at this temperature until complete conversion is observed. The homogeneous reaction is inverse quenched into a stirring mixture of IN aqueous hydrochloric acid (250 mL) and toluene (200 mL). Cooling is applied such that the temperature does not exceed 20 °C. The phases are separated and the aqueous phase is extracted with toluene (50 mL). The combined organic phases are washed with 15% aqueous sodium chloride (50 mL) and the aqueous phase is discarded. The organic phase is assayed by double dilution assay to show 19.96 g desired products (89% AY).

Example 2A - Synthesis of 2-(8-oxo-7,9-dihydro-6H-pyrido[3,2-b]indolizin-5-yl)acetic acid

A mixture of ethyl 5-(2-ethoxy-2-oxo-ethyl)-8-oxo-7,9-dihydro-6H-pyrido[3,2-b]i ndolizine-9- carboxylate and of ethyl 5-(2-ethoxy-2-oxo-ethyl)-8-oxo-7,9-dihydro-6H-pyrido[3,2- b]indolizine-7-carboxylate (4.1 g; 9.41 mmol) is slurred in concentrated sulfuric acid (31.4 mL; 94 mmol), the mixture is degassed with argon and is heated at 81 °C inside temperature under an argon flow for 1 h. After cooling to room temperature, aqueous 4N sodium hydroxide is added under ice bath cooling until pH 4 is reached (about 50 mL). The precipitate formed is filtered and the filtrate is extracted with tetrahydroiuran (3 x 100 mL). The combined organic layers are dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford a solid which is combined with the precipitate. After drying under high vacuum the desired product is obtained (1.48 g; 6.08 mmol). Ή-NMR (DMSO- d ₆ ) δ ppm: 2.70 (2H, bt, J=6.7 Hz), 3.23 (2H, bt, J=6.7 Hz), 3.70 (2H, s), 4.79 (2H, s), 7.1 1 (IH, dd, J=4.7, 7.8 Hz), 7.91 (IH, dd, J=l .5, 7.8 Hz), 8.19 (IH, dd, J=l .5, 4.7 Hz).

Protocol C - Retention time: 1.21 min (m/z 245)

Example 2B - Synthesis of 2-(7-oxo-8,9-dihydro-6H-pyrido[l,2-a]indol-10-yl)acetic acid

A mixture of ethyl 10-(2-ethoxy-2-oxo-ethyl)-7-oxo-8,9-dihydro-6H-pyrido[l,2-a] indole-6- carboxylate and of ethyl 10-(2-ethoxy-2-oxo-ethyl)-7-oxo-8,9-dihydro-6H-pyrido[l,2-a] indole- 8-carboxylate (57.5 g; 167 mmol) is dissolved in N-methylpyrrolidone (375 mL) and nitrogen gas is bubbled through the resulting solution for 20 min. Concentrated sulfuric acid is added (558 mL; 1675 mmol) and the mixture is brought to 80 °C while the nitrogen flow maintained until this temperature is reached. The reaction is then stirred at this temperature for 21 h. Upon cooling to room temperature a precipitate forms. The reaction mixture is cooled to 5 °C and left at this temperature overnight. The precipitate is filtered off and is rinsed with water (3 x 100 mL). After drying in a vacuum oven at 40 °C and 3 mbar, the desired product is isolated as a beige solid (26.3 g; 105 mmol). ¾-NMR (DMSO- d ₆ ) δ ppm: 2.67 - 2.72 (2H, m), 3.20 (2H, bt, J=6.4 Hz), 3.66 (2H, s), 4.77 (2H, s), 7.02 - 7.13 (2H, m), 7.38 (IH, dd, J=l . l, 8.0 Hz), 7.48 - 7.51 (lH, m).

Protocol D - Retention time: 1.31 min (m/z 244)

Example 2C - Synthesis of 2-(4-fluoro-7-oxo-8,9-dihydro-6H-pyrido[l,2-a]indol-10-yl)ac etic acid

A mixture of ethyl 10-(2-ethoxy-2-oxo-ethyl)-4-fluoro-7-oxo-8,9-dihydro-6H-pyri do[l,2- a]indole-6-carboxylate and of ethyl 10-(2-ethoxy-2-oxo-ethyl)-4-fluoro-7-oxo-8,9-dihydro-6H- pyrido[l ,2-a]indole-8-carboxylate (14.7 g; 39.5 mmol) is dissolved in N-methylpyrrolidone (98 mL) and the resulting solution is degassed via subsurface nitrogen gas bubbline over 20 min. Aqueous 6Ν sulfuric acid (132 mL; 395 mmol) is added and the resulting biphasic solution is heated to 80 °C while degassing is continued until the desired temperature is reached. The reaction is aged at 80 °C for 24 h. After cooling to room temperature, toluene (74 mL) is added and the organic phase is separated. The aqueous phase is extracted with tert-butylmethylether (74 mL) and the combined organic phases are washed with 5 wt% aqueous sodium chloride (2 x 74 mL). The organic phase was assayed via wt/wt% for 9.16 g keto-acid (88.8% AY).

The compounds were named using the software Accelrys Draw 4.1 SP1 (Accelrys, Inc.).

ANALYTICS

HPLC-MS Methods System 1

In some instance, the compound analysis was performed using UHPLC/MS 1290 series (Agilent, Santa Clara, CA, USA) having a binary pump (G 4220A) including a degasser, a well plate sampler (G4226A), a column oven (G1316C), a diode array detector (G4212A), a mass detector (6130 Quadrupole LCMS) with ESI/APCI-source. Protocol A

The column used was this protocol was a Chromolith FastGradient RP-18 e 50-2mm (Merck,

Darmstadt, DE), having a 2.0 mm diameter and 50 mm length. The column was operated at 40 °C. The injection volume was 0.5 μί, the flow rate was 1.2 mL/min and the run time was 3.2 min (equilibration included). Two eluents were used with the following gradients:

System 2 In some instance, the compound analysis was performed using HPLC/MSD 1100 series (Agilent, Santa Clara, CA, USA) having a binary pump (G 1312A) with a degasser (G1379A), a well plate sampler (G1367A), a column oven (G1316A), a diode array detector (G1315B), a mass detector (G1946D SL) with ESI source and a NQ AD 500.

Protocol B The column used was this protocol was a Chromolith FastGradient RP-18 e 50-2mm (Merck, Darmstadt, DE), having a 2.0 mm diameter and 50 mm length. The column was operated at 35 °C. The injection volume was 1.2 μί, the flow rate was 1.2 mL/min and the run time was 3.5 min (equilibration included). Two eluents were used with the following gradients:

Time Solvent A (%) Solvent B (%)

(min) water/formic acid: 99.9/0.1 (v/v) acetonitrile/formic acid: 99.9/0.1 (v/v)

0.0 90 10

2.0 0 100

2.7 0 100

3.0 90 10 The samples were diluted in a 1 : 1 mixture of solvents A and B before analysis. The detection methods were UV at 210, 254 and 280 nm; ESI/MS (70-1000 m/z), positive ions and NQAD.

Protocol C

The column used was this protocol was a Chromolith FastGradient RP-18 e 50-2mm (Merck, Darmstadt, DE), having a 2.0 mm diameter and 50 mm length. The column was operated at 30 °C. The injection volume was 1.0 μί, the flow rate was 1.2 mL/min and the run time was 3.5 min (equilibration included). Two eluents were used with the following gradients:

The samples were diluted in a 1 : 1 mixture of solvents A and B before analysis. The detection methods were UV at 210 and 254 nm; ESI/MS (70-1000 m/z), positive ions and NQAD.

Protocol D

The column used was this protocol was a Chromolith FastGradient RP-18 e 50-2mm (Merck, Darmstadt, DE), having a 2.0 mm diameter and 50 mm length. The column was operated at 35 °C. The injection volume was 1.0 μί, the flow rate was 1.2 mL/min and the run time was 3.5 min (equilibration included). Two eluents were used with the following gradients:

Time Solvent A (%) Solvent B (%) (min) water/formic acid: 99.9/0.1 (v/v) acetonitrile/formic acid: 99.9/0.1 (v/v)

0.0 90 10

2.0 0 100

2.7 0 100

3.0 90 10

The samples were diluted in a 1 : 1 mixture of solvents A and B before analysis. The detection methods were UV at 210 and 254 nm; ESI/MS (70-1000 m/z), positive ions and NQAD.