WO2019180634A1 - Synthesis of oxazinone-containing bicyclic aromatic and heteroaromatic aldehydes - Google Patents

Synthesis of oxazinone-containing bicyclic aromatic and heteroaromatic aldehydes Download PDF

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WO2019180634A1
WO2019180634A1 PCT/IB2019/052255 IB2019052255W WO2019180634A1 WO 2019180634 A1 WO2019180634 A1 WO 2019180634A1 IB 2019052255 W IB2019052255 W IB 2019052255W WO 2019180634 A1 WO2019180634 A1 WO 2019180634A1
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formula
compound
base
organic solvent
reacting
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PCT/IB2019/052255
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French (fr)
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Catherine Mary Alder
Lee J EDWARDS
Jerome Hayes
Rhodri Llŷr EVANS
Blandine Suzanne Jeanne MCKAY
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Glaxosmithkline Intellectual Property Development Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the invention is directed to novel syntheses for preparing intermediates useful in making antibiotic compounds.
  • a synthesis of 3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]oxazine-6-carbaldehyde is proposed in PCT Application No.WO2017/029602, along with novel antibiotic compounds.
  • routes are five or seven steps long to make this compound, many steps suffering low yields of 14 to a maximum of 80 percent yield with some only obtaining around 50 percent.
  • one route is seven steps, and consists of a number of steps, adding complexity to the route and a large volume of solvent use for isolation due to the number of step.
  • the seven steps route includes a dibromoination, which may simplify isolation but only one of the bromides is required for subsequent transformation and the additional one has to be removed by hydrogenation.
  • ester methyl 3-oxo-3,4-dihydro-2/-/-pyrazino[2,3-b][1 ,4]oxazine-6- carboxylate
  • alcohol 6-(hydroxymethyl)-2/-/-pyrazino[2,3- b][1 ,4]oxazin-3(4/-/)-one
  • aldehyde 3-oxo- 3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]oxazine-6-carbaldehyde
  • the invention provides a process for making a compound of formula (III):
  • Ri and R 2 are individually selected from the group consisting of CH and N, and R 3 is NH;
  • Y 1 is OCH3 or Cl and Y 2 is OH or Cl, with the proviso that when X 2 is H, Y 1 and Y 2 are each Cl and X 1 is OH;
  • the invention provides a process for making a compound of formula
  • Ri and R are individually selected from the group consisting of CH and N, and R 3 is NH;
  • Y 1 is OCH 3 or Cl and Y 2 is OH or Cl, with the proviso that when X 2 is H, Y 1 and Y 2 are each Cl and X 1 is OH;
  • X 1 is Cl
  • X 2 is Br
  • R 1 is N
  • R 2 is N
  • R 3 is NH
  • step (II) may be carried out under various conditions.
  • the step (i) is carried out in a single organic phase, e.g., in the absence of water.
  • suitable first organic solvents include, without limitation,
  • first bases can be used.
  • bases include, without limitation, potassium t- butoxide, sodium bicarbonate, potassium carbonate and N,N-diisopropylethylamine (i.e. , Hunig’s Base)
  • a preferred first base is potassium t-butoxide.
  • the base may be present e.g., as a solution or from solid. Most preferably, the base is potassium t- butoxide present at a molality of 1 M in THF.
  • Step (i) may be carried out under various temperature conditions.
  • the temperature may range from room temperature (e.g., 20°C to 1 10°C), preferably, from 50°C to 1 10°C . A more preferred temperature is 50°C.
  • Step (i) may, as an example, take place from 18 to 24 hours, other times are also encompassed.
  • the compound of formula (I) may be obtained commercially e.g., from D-L Chiral Chemicals of Princeton, New Jersey or Fluorochem via Sigma-Aldrich of Hadfield, United Kingdom.
  • the reactant of the formula may be obtained commercially e.g., from Apollo Scientific Ltd. of Manchester United Kingdom.
  • Step (ii) of the process of the invention is a reductive carbonylation reaction.
  • Such reactions are generally described e.g., in Angew. Chem. Int. Ed. 2006, 45, 154 -158, Organic Process Research & Development , 2007, 11,39-43, and Organometallics 2008, 27, 5402-5422
  • the step of reacting a compound of formula (II) with CO and H2 gas in the presence of a second organic solvent and a palladium complex catalyst to form a compound of the formula (III) may use various organic solvents.
  • second organic solvents are, without limitation, toluene, dimethylformamide, anisole and para-xylene. Such reaction occurs most preferably occurs e.g., in the absence of water.
  • various second bases can be used in step (ii).
  • such bases include, without limitation, N,N-diisopropylethylamine (i.e. , Hunig’s Base), and tetramethylethylenediamine.
  • the second base may be present e.g., in equivalents ranging from 1 .3 to 1 7eq. More preferably, the base is present at 1 .5 eq.
  • the reaction step (ii) may be carried out, e.g., at a temperature ranging from 80°C to 100°C
  • the CO/H2 gas (e.g., syngas or synthesis Gas) is employed preferably, in one embodiment, at a pressure ranging of from 4 to 6 bar.
  • Such gas is sold as a Lecture bottle -Special Gas Mixture : 50% CO in Hydrogen and may be commercially obtained from CK Special Gases LTD of West Bromwich, United Kingdom.
  • the palladium complex catalyst is selected from the group consisting of:
  • catalysts are cataCXium® catalysts which may be obtained commercially from Sigma Aldrich of Dorset, United Kingdom.
  • the invention provides a process for making a compound of formula (VI):
  • the first organic solvent is tetrahydrofuran and the first base is potassium t-butoxide in the process described above.
  • the second organic solvent is selected from the group consisting of
  • toluene and dimethylformamide and the second base is selected from the group consisting of N,N-diisopropylethylamine and tetramethylethylenediamine
  • the process is carried out as a two-step process.
  • the first step is a cyclization reaction with the reactant (of formula I) being suspended in the first organic solvent under an inert (e.g., N2) atmosphere, preferably stirred.
  • the first base is thereafter added.
  • Products are confirmed by LCMS and 1 H NMR.
  • the reaction typically takes place in a three (3) necked flask (e.g., a glass Pyrex® quickfit flask) typically from 18 to 24 hours at a temperature from 50°C.
  • an organic solvent eg., toluene, anisole, para-xylene, dimethylformamide
  • TDEMA may be added to the above mixture.
  • the reaction mixture is then transferred into a pressure vessel or sealed and pressurized to a pressure ranging from 4 to 6 bar of Syngas (e.g., CO:H 2 present e.g., in a 1 :1 ratio)
  • Syngas e.g., CO:H 2 present e.g., in a 1 :1 ratio
  • the mixture is cooled to room temperature and the vessel vented and mixture filtered using conventional means (e.g., cellite).
  • the filtered mixture is then wash with solvent (e.g., ethyl acetate), washed (e.g., with ammonium chloride) and dried (e.g, under vacuum) to provide the resulting product containing the compound of formula (III).
  • Solvent A 10 mM Ammonium Bicarbonate in water adjusted to pH 10 with Ammonia solution.
  • Solvent B Acetonitrile
  • HPLC High Performance Liquid chromatography
  • 6-bromo-3-chloropyrazin-2-amine (2g, 9.59 mmol) and methyl 2-hydroxyacetate (2.222 ml, 28.8 mmol) were suspended in Tetrahydrofuran (THF) (88 ml) under N 2 at ambient temperature in a multi necked flask.
  • THF Tetrahydrofuran
  • Potassium tert-butoxide 1 M in THF 23.99 ml, 23.99 mmol
  • the reaction was monitored by 2mins liquid chromatography-mass spectrometry (LCMS) (high pH). After 18hrs, starting material still present by LCMS.
  • LCMS liquid chromatography-mass spectrometry

Abstract

The invention provides a novel synthesis of 3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazine-6-carbaldehyde.

Description

SYNTHESIS OF OXAZINONE-CONTAINING BICYCLIC AROMATIC AND
HETEROAROMATIC ALDEHYDES
Cross-Reference to Related Applications
The present application claims priority to Serial No. 62/646,942 filed March 23, 2018, the disclosure of which is incorporated herein by reference in its entirety.
Field of the Invention
The invention is directed to novel syntheses for preparing intermediates useful in making antibiotic compounds.
Background of the Invention
A synthesis of 3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]oxazine-6-carbaldehyde is proposed in PCT Application No.WO2017/029602, along with novel antibiotic compounds. Examples of routes are five or seven steps long to make this compound, many steps suffering low yields of 14 to a maximum of 80 percent yield with some only obtaining around 50 percent. As an example, one route is seven steps, and consists of a number of steps, adding complexity to the route and a large volume of solvent use for isolation due to the number of step. The seven steps route includes a dibromoination, which may simplify isolation but only one of the bromides is required for subsequent transformation and the additional one has to be removed by hydrogenation. Also an over reduction of the ester (methyl 3-oxo-3,4-dihydro-2/-/-pyrazino[2,3-b][1 ,4]oxazine-6- carboxylate) is preferred to give the alcohol (6-(hydroxymethyl)-2/-/-pyrazino[2,3- b][1 ,4]oxazin-3(4/-/)-one) which is then oxidized back up to the desired aldehyde (3-oxo- 3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]oxazine-6-carbaldehyde) with a large excess of manganase dioxide in DCE'.
There is a perceived need in the art to shorten and improve the synthetic route to 3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]oxazine-6-carbaldehyde. Summary of the Invention
In one aspect, the invention provides a process for making a compound of formula (III):
Figure imgf000003_0004
wherein Ri and R2 are individually selected from the group consisting of CH and N, and R3 is NH;
comprising the steps of:
i) reacting a compound of formula (I):
Figure imgf000003_0001
wherein X1 is Br or Cl, and X2 is Br or H, with:
Figure imgf000003_0002
wherein Y1 is OCH3 or Cl and Y2 is OH or Cl, with the proviso that when X2 is H, Y1 and Y2 are each Cl and X1 is OH;
in the presence of a first base and first organic solvent to form a compound of formula (II):
Figure imgf000003_0003
wherein Ri, R2 , R3, and X2 are defined above; and
ii) reacting a compound of formula (II) with CO and H2 gas in the presence of a second organic solvent, a second base and a palladium complex catalyst to form a compound of the formula (III). This and other aspects are provided by the present invention.
Detailed Description of Representative Embodiments
Throughout this application, references are made to various embodiments relating to compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings.
In one aspect, the invention provides a process for making a compound of formula
(III):
Figure imgf000004_0002
wherein Ri and R are individually selected from the group consisting of CH and N, and R3 is NH;
comprising the steps of:
i) reacting a compound of formula (I):
Figure imgf000004_0001
wherein X is Br or Cl, and X2 is Br or H, with:
Figure imgf000005_0001
wherein Y1 is OCH3 or Cl and Y2 is OH or Cl, with the proviso that when X2 is H, Y1 and Y2 are each Cl and X1 is OH;
in the presence of a first base and first organic solvent to form a compound of formula (II):
Figure imgf000005_0002
wherein Ri , R2, R3 and X2 are defined above; and
ii) reacting a compound of formula (II) with CO and H2 gas in the presence of a second organic solvent, a second base and a palladium complex catalyst to form a compound of the formula (III).
In preferred embodiments, X1 is Cl, X2 is Br, R1 is N, R2 is N and R3 is NH.
With respect to the reaction of compound (I) to form compound (II), such a reaction is a cyclization reaction. Cyclization reactions are generally described in paper Synthetic Communications, 43: pp. 3315-3321 , 2013
The formation of compound (II) may be carried out under various conditions. As an example, the step (i) is carried out in a single organic phase, e.g., in the absence of water. Examples of suitable first organic solvents include, without limitation,
tetrahydrofuran, toluene, and dimethylformamide.
As an example, in various embodiments, a number of first bases can be used. Examples of such bases include, without limitation, potassium t- butoxide, sodium bicarbonate, potassium carbonate and N,N-diisopropylethylamine (i.e. , Hunig’s Base) A preferred first base is potassium t-butoxide. The base may be present e.g., as a solution or from solid. Most preferably, the base is potassium t- butoxide present at a molality of 1 M in THF.
Step (i) may be carried out under various temperature conditions. As an example, the temperature may range from room temperature (e.g., 20°C to 1 10°C), preferably, from 50°C to 1 10°C . A more preferred temperature is 50°C. Step (i) may, as an example, take place from 18 to 24 hours, other times are also encompassed.
The compound of formula (I) may be obtained commercially e.g., from D-L Chiral Chemicals of Princeton, New Jersey or Fluorochem via Sigma-Aldrich of Hadfield, United Kingdom. The reactant of the formula:
Figure imgf000006_0001
may be obtained commercially e.g., from Apollo Scientific Ltd. of Manchester United Kingdom.
Step (ii) of the process of the invention is a reductive carbonylation reaction. Such reactions are generally described e.g., in Angew. Chem. Int. Ed. 2006, 45, 154 -158, Organic Process Research & Development , 2007, 11,39-43, and Organometallics 2008, 27, 5402-5422
In various embodiments, the step of reacting a compound of formula (II) with CO and H2 gas in the presence of a second organic solvent and a palladium complex catalyst to form a compound of the formula (III) may use various organic solvents. Examples of such second organic solvents are, without limitation, toluene, dimethylformamide, anisole and para-xylene. Such reaction occurs most preferably occurs e.g., in the absence of water. Additionally, various second bases can be used in step (ii). In various embodiments, such bases include, without limitation, N,N-diisopropylethylamine (i.e. , Hunig’s Base), and tetramethylethylenediamine.
The second base may be present e.g., in equivalents ranging from 1 .3 to 1 7eq. More preferably, the base is present at 1 .5 eq. The reaction step (ii) may be carried out, e.g., at a temperature ranging from 80°C to 100°C
The CO/H2 gas (e.g., syngas or synthesis Gas) is employed preferably, in one embodiment, at a pressure ranging of from 4 to 6 bar. Such gas is sold as a Lecture bottle -Special Gas Mixture : 50% CO in Hydrogen and may be commercially obtained from CK Special Gases LTD of West Bromwich, United Kingdom. In preferred embodiments, the palladium complex catalyst is selected from the group consisting of:
Figure imgf000007_0001
and
Figure imgf000007_0002
Wherein L is:
Figure imgf000008_0001
Such examples of catalysts are cataCXium® catalysts which may be obtained commercially from Sigma Aldrich of Dorset, United Kingdom.
In another aspect, the invention provides a process for making a compound of formula (VI):
Figure imgf000008_0002
comprising the steps of:
i) reacting a compound of formula (IV):
Figure imgf000008_0003
with:
Figure imgf000009_0001
in the presence of a first base and a first organic solvent to form a compound of formula (V):
Figure imgf000009_0002
; and
ii) reacting a compound of formula (V) with CO and H2 gas in the presence of an second organic solvent, a second base and a palladium complex catalyst to form a compound of the formula (VI), wherein the palladium complex catalyst is:
Figure imgf000009_0003
Wherein L is:
Figure imgf000010_0001
In one embodiment, the first organic solvent is tetrahydrofuran and the first base is potassium t-butoxide in the process described above.
In one embodiment, the second organic solvent is selected from the group consisting of
toluene and dimethylformamide and the second base is selected from the group consisting of N,N-diisopropylethylamine and tetramethylethylenediamine
An example of a process of the present invention can be described according to the following description. It should be appreciated that this represents one embodiment and is for illustrative purposes only. As alluded to herein, the process is carried out as a two-step process. The first step is a cyclization reaction with the reactant (of formula I) being suspended in the first organic solvent under an inert (e.g., N2) atmosphere, preferably stirred. The first base is thereafter added. Products are confirmed by LCMS and 1 H NMR. The reaction typically takes place in a three (3) necked flask (e.g., a glass Pyrex® quickfit flask) typically from 18 to 24 hours at a temperature from 50°C. Base is thereafter added, and the mixture thereafter allowed to cool to ambient temperature, partitioned between aqueous and organic phases. This organic phase is discarded, and the aqueous phase acidified with aqueous HCI (e.g., 2M HCI), and extracted twice with organic solvent (eg. ethyl acetate). These combined extractions are washed with water and then dried by passing through a hydrophobic frit (Biotage, ISOLUTE® Phase separator) and concentrated under reduced pressure to give resulting material containing product confirmed by LCMS and 1 H NMR. This obtained product (of formula (II)), along with palladium-containing catalyst (preferably in an amount ranging from 5 mol % to 7.5 mol %), is dissolved in an organic solvent (eg., toluene, anisole, para-xylene, dimethylformamide) TDEMA may be added to the above mixture. The reaction mixture is then transferred into a pressure vessel or sealed and pressurized to a pressure ranging from 4 to 6 bar of Syngas ( e.g., CO:H2 present e.g., in a 1 :1 ratio) This reaction is preferably carried out at a temperature ranging from 80 °C to 100 °C for a period ranging from 18 to 24 hours. Afterwards, the mixture is cooled to room temperature and the vessel vented and mixture filtered using conventional means (e.g., cellite). The filtered mixture is then wash with solvent (e.g., ethyl acetate), washed (e.g., with ammonium chloride) and dried (e.g, under vacuum) to provide the resulting product containing the compound of formula (III).
Examples
The following examples are set forth to illustrate the invention and are not intended to limit the scope of the invention as defined by the claims. In the foregoing, the 1H NMR spectra were recorded on a Bruker 400MHz or 600MHz spectrometer. Chemical shifts are expressed in parts per million (ppm, 5 units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).
LC Conditions for cvclization are
The analytical resloution were recorded by UPLC (ultraperformance Liquid
chromatograph Mass spec) analysis was conducted on an Acquity UPLC using a CSH C18 column (50mm x 2.1 mm i.d. 1.7pm packing diameter) at 40 degrees centigrade using a gradient elution method.
The solvents employed were:
Solvent A = 10 mM Ammonium Bicarbonate in water adjusted to pH 10 with Ammonia solution.
Solvent B = Acetonitrile.
Constant A for 0.05mins followed by 3-97% B, then held at 97% B for 0.4mins to 100% B at 2mins(total run time 2mins) LC Conditions for reductive carbonylation
The HPLC(High Performance Liquid chromatography) analysis was conducted on an Phenomenex Luna C18 column (50mm x 2.1 mm i.d. 3pm packing diameter) at 40 degrees centigrade using a gradient elution method
The solvents employed were:
A = 0.1 % v/v solution of Trifluoroacetic Acid in Water.
B = 0.1 % v/v solution of Trifluoroacetic Acid in Acetonitrile
Starting with Constant A followed by 5-95% B over 8mins, then 95-100% B over 1 min and held at 100% B for 1 minute (total run time 10mins)
Example 1
Preparation of 6-bromo-2H-pyrazino[2,3-b][1 ,4]oxazin-3(4H)-one (3)
Cyclization
Figure imgf000012_0001
1 2
3
6-bromo-3-chloropyrazin-2-amine (2g, 9.59 mmol) and methyl 2-hydroxyacetate (2.222 ml, 28.8 mmol) were suspended in Tetrahydrofuran (THF) (88 ml) under N2 at ambient temperature in a multi necked flask. Potassium tert-butoxide 1 M in THF (23.99 ml, 23.99 mmol) was added and the mixture was stirred under N2 and heated to 50°C for 18hrs. The reaction was monitored by 2mins liquid chromatography-mass spectrometry (LCMS) (high pH). After 18hrs, starting material still present by LCMS. Potassium tert- butoxide 1 M in THF (9.59 ml, 9.59 mmol) was added and left to stir for an additional 1 hr.
After a total of 19hrs, starting material consumed by LCMS. The mixture was allowed to cool to ambient temperature then partitioned between water (60ml) and ethyl acetate (60ml) (organic layer discarded). The aqueous layer was acidified to pH=4 with aq 2M HCI then extracted twice with ethyl acetate (60ml). The combined organic layers were washed with water (75ml) then dried by passing through a hydrophobic frit and evaporated under vacuum to give the crude material 6-bromo-2H-pyrazino[2,3- b][1 ,4]oxazin-3(4H)-one (1 .9618g, 7.93 mmol, 83 % yield, with a purity of 93 % by NMR) as a red/brown solid. Sample carried through to next step without further purification LCMS (2mins, high pH): V4100473-3 rt = 0.44 mins, MH- = 230
IH NMR (400 MHz, DMSO-de) d ppm 4.90 (s, 2 H) 7.92 (s, 1 H) 11.81 (s, 1 H)
Example 2
Preparation of 3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]oxazine-6-carbaldehyde
Figure imgf000013_0001
6-bromo-2H-pyrazino[2,3-b][1 ,4]oxazin-3(4H)-one (100 mg, 0.435 mmol) and cataCXium® A Pd G3 (15.83 mg, 0.022 mmol) were added to a vial and dissolved in anhydrous Toluene (2 ml_). TMEDA (0.098 ml_, 0.652 mmol) was added and the vial was placed in the Biotage® Endeavor™ under 4bar of Syngas (1 :1 Carbon monoxide :
Hydrogen (lecture bottle supplier - CK Special Gases LTD) at 80° for 18hrs.
After 18hrs, the mixture was cooled to ambient temperature and the vessel vented. The reaction was monitored by 8mins LCMS (low pH TFA). The mixture was filtered through cellite and the filter pad was washed with ethyl acetate. The filtrate was washed with saturated aqeuous ammonium chloride (30ml). The organic layer was dried using a hydrophobic frit and evaporated under vacuum to give the crude product. The sample was loaded in dichloromethane and purified on Combi Flash RF + silica (Si) 12g using a 0-50% 3:1 Ethyl Acetate-EtOH : cyclohexane, over 10 mins. The appropriate fractions were combined and evaporated in vacuo to give the required product, 3-oxo-3,4- dihydro-2H-pyrazino[2,3-b][1 ,4]oxazine-6-carbaldehyde (14.7 mg, 0.082 mmol, 18.88 % yield) with a purity of a minimum of 70 % by NMR as a off-white solid.
LCMS: (8min. Low pH - TFA) VSW10665-1 rt = 0.56 mins, MH+ = 179.9
1 H NMR (400 MHz, DMSO-c/6) d ppm 5.01 (s, 2 H) 8.38 (s, 1 H) 9.89 (s, 1 H) 1 1 .90 (s, 1
H)
The embodiments and examples set forth hereinabove have served to illustrate the scope of the invention. It should be appreciated, however, that the scope of the invention is defined by the claim as set forth below.

Claims

THAT WHICH IS CLAIMED:
1. A process for making a compound of formula (III):
Figure imgf000014_0004
wherein Ri and R2 are individually selected from the group consisting of CH and N, and R3 is NH
comprising the steps of:
i) reacting a compound of formula (I):
Figure imgf000014_0001
wherein X1 is Br or Cl, and X2 is Br or H, with:
Figure imgf000014_0002
Wherein Y1 is OCH3 or Cl and Y2 is OH or Cl, with the proviso that when X2 is H, Yi and Y2 are each Cl and X1 is OH;
in the presence of a first base and first organic solvent to form a compound of formula (II):
Figure imgf000014_0003
wherein R1, R2, R3 and X2 are defined above; and
ii) reacting a compound of formula (II) with CO and H2 gas in the presence of a second organic solvent, a second base and a palladium complex catalyst to form a compound of the formula (III).
2. The process according to Claim 1 , wherein the first organic solvent is
tetrahydrofuran.
3. The process according to Claims 1-2, wherein the first base used in the step of reacting a compound of formula (I) with formula (II) is potassium t-butoxide.
4. The process according to Claims 1-3, wherein the step of reacting a compound of formula (I) with a compound of formula (II) occurs at a temperature ranging from 20 °C to 110°C.
5. The process according to Claims 1-4, wherein Xi is Cl, X is Br, R is N, and R is N.
6. The process according to Claims 1-5, wherein the step of reacting a compound of formula (II) with CO and H2 gas in the presence of a second organic solvent a second base and a palladium complex catalyst to form a compound of the formula (III) uses a second organic solvent which is selected from toluene and dimethylformamide.
7. The process according to Claims 1-6, wherein the palladium complex catalyst is selected from the group consisting of:
Figure imgf000015_0001
and
Figure imgf000016_0001
8. The process according to Claims 1-7, wherein the step of reacting a compound of formula (II) with CO and H2 gas in the presence of a second organic solvent, a second base and a palladium complex catalyst to form a compound of the formula (III) is carried out at a temperature ranging from 80 °C to 100°C.
9. A process for making a compound of formula (VI):
Figure imgf000017_0003
comprising the steps of:
iii) reacting a compound of formula (IV):
Figure imgf000017_0001
in the presence of a first base and a first organic solvent to form a compound of formula (V):
Figure imgf000017_0002
; and
iv) reacting a compound of formula (V) with CO and H2 gas in the presence of a second organic solvent, a second base and a palladium complex catalyst to form a compound of the formula (VI), wherein the palladium complex catalyst is:
Figure imgf000018_0001
10. The process according to Claim 9, wherein the first organic solvent is
tetrahydrofuran and the first base is potassium t-butoxide.
1 1 . The process according to Claims 9-10, wherein the second organic solvent is selected from the group consisting of toluene and dimethylformamide and the second base is selected from the group consisting of N,N-diisopropylethylamine and tetramethylethylenediamine
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