WO2017005766A1

WO2017005766A1 - A process to make tricycic alcohol intermediates of crth2 antagonists

Info

Publication number: WO2017005766A1
Application number: PCT/EP2016/065909
Authority: WO
Inventors: Christophe Pierre Alain Chassaing
Original assignee: Intervet International B.V.; Intervet Inc.
Priority date: 2015-07-07
Filing date: 2016-07-06
Publication date: 2017-01-12

Abstract

This invention is directed to an improved process for the preparation of tricyclic alcohol compounds which are useful in the preparation of compounds of Formula (I) or a solvate or salt thereof.

Description

A PROCESS TO MAKE TRICYCIC ALCOHOL INTERMEDIATES OF CRTH2 ANTAGONISTS

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 a synthetic pathway where the chiral center was installed by reaction of the azaindole core with a chiral aziridine intermediate. This resulted in a lengthy synthesis with a poor overall yield.

SUMMARY OF THE INVENTION

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

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

with (4-methyl-N-((l 5',25 -2-((2-((4-methylbenzyl)oxy)ethyl)amino)- 1 ,2- diphenylethyl)phenylsulfonamido)ruthenium(II) chloride or (N-((15',25 -2-((2-((4- methylbenzyl)oxy)ethyl)amino)-l ,2-diphenylethyl)methylsulfonamido)ruthenium(II) chloride to give a compound of Formula (XIa)

wherein: Z is N or C;

X¹ and X² are independently hydrogen, halogen or are not present;

R⁴ is Ci-Ce alkyl or forms a heterocyclic ring with Q; and

Q is S0₂, C(O) or forms a heterocyclic ring with R⁴; and J is a bond or Ci-C₆ alkyl where in the Ci-C₆ alkyl is un-substituted or substituted with one or more groups selected from halogen or Ci-C₆ alkyl.

In another embodiment, the process further comprises reacting the compound of Formula (XIa) with an acid and an alkyl alcohol to give the compound of Formula (XI)

wherein R⁷ is alkyl.

DETAILED DESCRIPTION

This invention is directed to an improved process for the preparation of tricyclic

compounds which are useful in the preparation of compounds of Formula (I)

wherein Z is N or C;

X 1¹ and X 2" are independently hydrogen, halogen or are not present;

R⁴ is Ci-C₆ alkyl or forms a heterocyclic ring with Q; and

Q is S0₂, C(O) or forms a heterocyclic ring with R⁴; and J is a bond or Ci-C₆ alkyl where in the Ci-C₆ alkyl is unsubstituted or substituted with one or more groups selected from halogen or Ci-C₆ alkyl.

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 the total synthesis of the compounds of Formula lb.

Scheme 1

In an embodiment, the invention is a process for preparing a compound of Formula (I)

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

wherein: Z is N or C;

X 1¹ and X 2" are independently hydrogen, halogen or are not present; R⁴ is Ci-C₆ alkyl or forms a heterocyclic ring with Q; and Q is S0₂, C(O) or forms a heterocyclic ring with R⁴; and

J is a bond or Ci-C₆ alkyl where in the Ci-C₆ alkyl is un-substituted or substituted with one or more groups selected from halogen or Ci-C₆ alkyl.

wherein R⁷ is alkyl.

In another embodiment of the process, R 4 is methyl, Z is N, X 1 is not present, X2 is F, Q is C(O) and J is CH(CH₃).

4 1 2

In another embodiment of the process, R is methyl, Z is C, X is hydrogen, X is F, Q is S0₂ and J is a bond.

1 * 2 · · 4

In another embodiment of the process, Z is C, X¹ is F, X^z is F, J is CH₂ and Q and R are taken together to form a 1 ,2,3-triazole as shown below

Another embodiment of the invention is a compound of Formula (XIa) wherein the compound is

OH or OH

Another embodiment of the invention is a compound of Formula (XI) wherein the compound is

OH

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.

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 H₂0.

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 1A - Synthesis of ethyl 2-[(85)-8-hydroxy-6,7,8,9-tetrahydropyrido[3,2- b]indolizin-5-yl]acetate

Triethylamine (1.4 mL) is slowly added to formic acid (3.5 mL) and (4-methyl-N-((15',25 -2-((2- ((4-methylbenzyl)oxy)ethyl)amino)-l ,2-diphenylethyl)phenylsulfonamido)ruthenium(II) chloride (0.026 g; 0.04 mmol) in a dried round bottom flask under argon atmosphere. Under ice bath cooling, a slurry of 2-(8-oxo-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl)acetic acid (1.97 g; 8.07 mmol) in dimethylformamide (7.00 mL) is added and the mixture stirred at 60 °C for 80 min to ensure complete conversion of the starting material (Protocol B - Retention time: 1.17 min (m/z 247). The reaction mixture is cooled to room temperature, is diluted with ethanol (28.3 mL; 484 mmol) and concentrated sulfuric acid (1.179 mL; 22.1 1 mmol) is added carefully under stirring. The resulting mixture is heated to 80 °C and is reacted at this temperature for 1 h. The volatiles are then removed under reduced pressure, the obtained residue is taken up with ethyl acetate (100 mL) and is extracted with saturated aqueous sodium hydrogen carbonate (50 mL). The aqueous phase is extracted with ethyl acetate (2 x 50 mL) and the combined organic layers are dried over magnesium sulphate. After filtration and evaporation under reduced pressure, the residue is dried under high vacuum to afford the crude desired product (1.64 g; 5.92 mmol) which is engaged into the next step without further purification. The desired product is obtained in 95.4 % e.e. as determined by chiral HPLC using a Chiralpak AD-H column.

Protocol C - Retention time: 1.03 min (m/z 275)

Example IB - Synthesis of ethyl 2-[(75)-7-hydroxy-6,7,8,9-tetrahydropyrido[l,2-a]indol-10- yl] acetate

Triethylamine (3.5 mL) is slowly added to formic acid (9 mL) and (4-methyl-N-((15',25 -2-((2- ((4-methylbenzyl)oxy)ethyl)amino)-l ,2-diphenylethyl)phenylsulfonamido)ruthenium(II) chloride (0.067 g; 0.103 mmol) in a dried round bottom flask under argon atmosphere. A solution of 2-(7-oxo-8,9-dihydro-6H-pyrido[l ,2-a]indol-10-yl)acetic acid (5.0 g; 20.55 mmol) in dimethylformamide (15 mL) is added and the mixture stirred at

60 °C for 3.5 h min to ensure complete conversion of the starting material. The reaction mixture is cooled to room temperature, is diluted with ethanol (100 mL; 1758 mmol) and concentrated sulfuric acid (3 mL; 56.3 mmol) is added carefully under stirring. The resulting mixture is heated to 80 °C and is reacted at this temperature for 1 h. The volatiles are then removed under reduced pressure, the obtained residue is taken up in ethyl acetate (100 mL) and is extracted with saturated aqueous sodium hydrogen carbonate (50 mL). The aqueous phase is extracted with ethyl acetate (50 mL) and the combined organic layers are dried over magnesium sulphate. After filtration and evaporation under reduced pressure, the residue is dried under high vacuum to afford the crude desired product as an oil (5.5 g; 20.12 mmol) which is engaged into the next step without further purification. The desired product is obtained in 87.4 % e.e. as determined by chiral HPLC using a Chiralpak AD-H column.

Protocol A - Retention time: 0.74 min (m/z 246).

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 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: 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 98 2

0.2 98 2

2.0 2 98

2.5 2 98

3.0 98 2

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 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 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:

Claims

1. A process for preparing a compound of Formula (I)

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

with (4-methyl-N-((l 5',25 -2-((2-((4-methylbenzyl)oxy)ethyl)amino)- 1 ,2- diphenylethyl)phenylsulfonamido)ruthenium(II) chloride or (N-((15',25 -2-((2-((4- methylbenzyl)oxy)ethyl)amino)-l ,

2-diphenylethyl)methylsulfonamido)ruthenium(II) chloride to give a compound of Formula (XIa)

wherein: Z is N or C;

X¹ and X² are independently hydrogen, halogen or are not present; R⁴ is Ci-Ce alkyl or forms a heterocyclic ring with Q; and Q is S0₂, C(O) or forms a heterocyclic ring with R⁴; and

J is a bond or Ci-C₆ alkyl where in the Ci-C₆ alkyl is un-substituted or substituted with more groups selected from halogen or Ci-C₆ alkyl.

The process of claim 1 , further comprising reacting the compound of Formula (XIa) with acid and an alkyl alcohol to give the compound of Formula (XI)

wherein R⁷ is alkyl.

3. The process of any one of claims 1 -2, wherein R is methyl, Z is N, X¹ is not present, X is F, Q is C(O) and J is CH(CH₃).

4. The process of any one of claims 1 -2, wherein R⁴ is methyl, Z is C, X¹ is hydrogen, X² is F, Q is SO₂ and J is a bond.

1 2

5. The process of any one of claims 1 -2, wherein Z is C, X is F, X is F, J is CH₂ and Q and R⁴ are taken together to form a 1 ,2,3-triazole as shown below

A compound of Formula (XIa) wherein the compound is

OH