Patent Description:
Compound (I) is disclosed in Example <NUM> of the PCT Application No. <CIT>. Provided are processes that are conducive to preparing large scale synthesis of Compound (I).

<CIT> describes other compounds which are FGFR inhibitors and which are therefore useful for the treatment of diseases treatable by inhibition of FGFR, as well as pharmaceutical compositions containing said compounds and processes for preparing said compounds.

According to one aspect of the present invention, a process is provided for preparing a Compound (I):
<CHM>
including:.

According to another aspect of the present invention, a process is provided for preparing a compound of formula (<NUM>):
<CHM>
comprising:.

According to yet another aspect of the present invention, an intermediate of formula (<NUM>) is provided:
<CHM>
or a salt thereof, wherein:.

In a first aspect, the present invention provides a process of preparing a Compound (I):
<CHM>
comprising:.

The present invention provides the process of the first aspect, wherein the process comprises preparing compound (I) via Step (A).

The present invention provides the process of the first aspect, wherein the process comprises preparing compound (I) via Step (B).

The present invention provides the process of the first aspect, wherein the process comprises preparing compound (I) via Step (C).

The present invention provides the process of the first aspect, wherein the process comprises preparing compound (I) via Step (D).

In a first embodiment, of the first aspect, the process comprises the process of Step A where X is halo, phosphate, mesylate (methylsulfonate), tosylate (p-methylphenylsulfonate, or <NUM>, <NUM>,<NUM>-trifluoro-N-[(trifluoromethyl)sulfonate. In a first subembodiment of the first embodiment X is halo such as chloro, bromo, or iodo or phosphate. In a second subembodiment of the first embodiment X is chloro, bromo, or iodo.

In a second embodiment of the first aspect, and the first and second subembodiments contained therein, the process comprises the process of Step A where the reaction is carried out in an aprotic, polar organic solvent, preferably an ether, halogenated organic solvent, or dimethylformamide; more prefereable the reaction is carried out in dichloromethane, DMF, acetonitrile, or THF and a like.

In a third embodiment, the first and second embodiments and subembodiments contained therein, the process comprises the process of Step A where the base is either organic or inorganic bases, preferably organic amines, carbonates, bicarbonates, hydrides, hydroxides, e.g., triethylamino, DBU, Na(K)HCO<NUM>, Na(K, Cs)<NUM>CO<NUM>, lithium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, tert-butoxide, and the like.

In a fourth embodiment of the first aspect, the process comprises the process of Step A is carried under following conditions:.

In a fifth embodiment of the first aspect, the process comprises the process of Step B where the reducing agent is Lindlar catalyst.

In a sixth embodiment of the first aspect, the process comprises the process of Step C where the reducing agent is sodium borohydride or i-PrMgCl/THF and a source of proton such as an organic and/or inorganic acid.

In a seventh embodiment of the first apect, the process comprises the process of Step (D) where the chlorinating agent is N-chlorosuccinimide, sulfonyl chloride, sulfuryl chloride. Suitable organic solvents include halogenated hydrocarbon such as dichloromethane when the chlorinating agent is sulfonyl or sulfuryl chloride and organic acid such as acetic acid or halogenated hydrocarbon such as dichloromethane when the chlorinating agent is N-chlorosuccinimide. The reaction may be, preferably the reaction is, carried out in the presence of of a base such as diethylamine, pyridine, and the like.

In a second aspect, the present invention provides a process of preparing a compound (<NUM>):
<CHM>
where PG is a amino protecting group (preferably tert-butoxycarbonyl or benzyloxycarbonyl, more preferably tert-butoxycarbonyl); comprising:.

In a first embodiment of the second aspect, the process of Step G is where the reaction is carried out in the presence of a base, preferably an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate, NaH, potassium tert-butoxide, sodium or potassium amylate. In a second embodiment of the second aspect and in the first embodiment contained therein, the reaction is carried out in a polar organic solvent such as dimethylsulfoxide, dimethformamide, dioxane, N-N-methyl-<NUM>-pyrrolidone (NMP) or dimethyl-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrimidinone (DMPU), and the like, preferably dimethylsulfoxide. Preferably, the reaction is carried out in the presence of potassium carbonate and cesium carbonate in dimethylsulfoxide at about <NUM>.

In a third embodiment of the second aspect and the first embodiment and second embodiments contained therein, the process of Step H is where the reaction is carried out in the presence of a base, preferably inorganic bases such as Na(K)HCO<NUM>, Na(K, Cs)<NUM>CO<NUM>, lithium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, tert-butoxide, and the like. Preferably the reaction is carried out in a polar organic solvent, preferably in DMSO at about <NUM>° C.

(J) The process of the second aspect, further comprising reacting a compound of formula (<NUM>):
<CHM>
where PG is a amino protecting group (preferably tert-butoxycarbonyl or benzyloxycarbonyl, more preferably tert-butoxycarbonyl) with a chlorinating agent to provide a compound of formula (<NUM>) and/or (<NUM>):
<CHM>.

In a first embodiment of Step (J), the process of Step (J) is performed as described in Step (D) above.

(K) The process of the Step (J), further comprising treating a compound of formula (<NUM>) and/or (<NUM>):
<CHM>
with methylamine to give a compound of
<CHM>
(L) The process of the Step (K), further comprising removing the amino protecting group (PG) in a compound of formula (<NUM>):
<CHM>
to give a compound of formula (<NUM>):
<CHM>
(<NUM>) or a salt thereof.

In a first embodiment of Step (L), where PG is tert-butoxycarbonyl, it is removed under acidic hydrolysis reaction condition, preferably it is removed with strong acid such as hydrochloric acid, trifluoroacetic acid, and the like, and in a polar organic solvent such as a ketone, an ether, and the like. Where PG is benzyoxycarbonyl or substituted benzyloxycarbonyl, the deprotection of amine is carried out under hydrogenolysis reaction conditions in presence and absence of acids.

(M) The process of the Step (L), further comprising reacting a compound of formula (<NUM>)
<CHM>
with a compound of formula (i) where X is a leaving group under elimination reaction conditions and LG is a leaving group under acylation reaction conditions or hydroxyl to give a compound of formula (a).

In a first embodiment of Step (M), the process of Step M the reaction is carried under following conditions:.

(N) The process of the Step (L), further comprising reacting a compound of Formula (<NUM>) with an alkyne of formula (ii) where LG<NUM> is a leaving group under acylation conditions or hydroxy:
<CHM>
to give a compound of formula (b).

In a first embodiment of Step N, LG<NUM> is halogen or hydroxyl. In a second embodiment of Step (N):.

In a fourth aspect, the present invention provides an intermediate of formula (<NUM>):
<CHM>
or a salt thereof, wherein:.

Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning. All undefined technical and scientific terms used in this Application have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

"About" as used herein, unless otherwise specified, means + or - <NUM>%, preferably <NUM>% deviation from the listed value. For example, a composition containing about <NUM> by weight of a component may contain <NUM> to <NUM>.

The following examples are provided to further illustrate the compounds, compositions and methods of the present disclosure. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

<NUM>-(<NUM>,<NUM>-Dimethoxyphenyl)acetic acid (<NUM>) was charged into appropriately sized three-neck RBF equipped with a condenser and dissolved with methanol (<NUM>). Concentrated sulfuric acid (<NUM>) was added and a solution was brought to gentle boiling. Reaction progress was monitored by HPLC. The reaction mixture was transferred to appropriately sized RBF and concentrated to ca. and then co-evaporated with DMSO (<NUM>) to about <NUM> and the residue containing methyl <NUM>-(<NUM>,<NUM>-dimethoxyphenyl)acetate (<NUM>) was telescoped to Step <NUM>.

To an appropriate reactor equipped with mechanical stirrer methyl <NUM>-(<NUM>,<NUM>-dimethoxyphenyl)acetate (<NUM>) in DMSO (<NUM>), <NUM>-amino-<NUM>-(methylthio)-pyrimidine-<NUM>-carbaldehyde (<NUM>, <NUM> eq. ), potassium carbonate (<NUM>, <NUM> eq. ) and cesium carbonate (<NUM>, <NUM> eq. ) was charged and the mixture was stirred at <NUM>. After <NUM>, the mixture containing <NUM>-(<NUM>,<NUM>-dimethoxyphenyl)-<NUM>-(methylthio)pyrido[<NUM>,<NUM>-d]pyrimidin-<NUM>(<NUM>)-one was cooled to RT. Potassium carbonate (<NUM>, <NUM> eq. ) and tert-butyl <NUM>-(<NUM>-((methylsulfonyl)oxy)propyl)piperazine-<NUM>-carboxylate HCl (<NUM>, <NUM> eq. ) was charged. Upon completion of ther eaction, ethyl acetate and water were added.

Organic layer was separated and aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with <NUM>% aqueous solution of sodium chloride Organic phase was dried over anhydrous magnesium sulfate. Drying agent was filtered off and washed with ethyl acetate. The filtrate was concentrated to ca. and cooled to <NUM>-<NUM>. A solution of p-toluenesulfonic acid (<NUM>, <NUM> eq. ) in ethyl acetate (<NUM>) was added dropwise. The resulted suspension was slowly warmed to RT and stirred for <NUM>. Solids were filtered off, washed with ethyl acetate and dried give tert-butyl-<NUM>-(<NUM>-(<NUM>-(<NUM>,<NUM>-dimethoxyphenyl)-<NUM>-(methylthio)-<NUM>-oxopyrido[<NUM>,<NUM>-d]pyrimidin-<NUM>(<NUM>)-yl)propyl)piperazine-<NUM>-carboxylate <NUM>-methylbenzenesulfonate.

To an appropriate reactor equipped with mechanical stirrer was charged acetic acid (<NUM>), <NUM>-(<NUM>,<NUM>-dimethoxyphenyl)-<NUM>-(methylthio)pyrido[<NUM>,<NUM>-d]pyrimidin-<NUM>(<NUM>)-one (<NUM>) and triethylamine (<NUM>, <NUM> eq. Internal temperature was adjusted to approximately <NUM> and N-chlorosuccinimide (<NUM>, <NUM> eq. ) was added at <NUM>-<NUM>. Reaction was stirred for <NUM> hours. Ethyl acetate (<NUM>) was added. <NUM>% aqueous NaCl solution (<NUM>) was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with <NUM> % aqueous potassium carbonate solution (<NUM>). The organic layer was concentrated to ~ <NUM> and used for next step directly.

To tert-butyl-<NUM>-(<NUM>-(<NUM>-(<NUM>,<NUM>-dichloro-<NUM>,<NUM>-dimethoxyphenyl)-<NUM>-(methylsulfonyl)-<NUM>-oxopyrido[<NUM>,<NUM>-d]pyrimidin-<NUM>(<NUM>)-yl)propyl)piperazine-<NUM>-carboxylate (<NUM>) in ethyl acetate extract (<NUM>)from Step <NUM>, was added <NUM> methylamine solution in THF (<NUM>) was slowly added maintaining temperature below <NUM>. After reaction was complete, the suspension concentrated to <NUM> and ethyl acetate (<NUM>) was added. The mixture was heated at <NUM> for <NUM>, and then cooled to RT. Solids were filtered off and washed with ethyl acetate, water and dried to give tert-butyl-<NUM>-(<NUM>-(<NUM>-(<NUM>,<NUM>-dichloro-<NUM>,<NUM>-dimethoxyphenyl)-<NUM>-(methylamino)-<NUM>-oxopyrido[<NUM>,<NUM>-d]pyrimidin-<NUM>(<NUM>)-yl)propyl)piperazine-<NUM>-carboxylate (<NUM>).

tert-Butyl-<NUM>-(<NUM>-(<NUM>-(<NUM>,<NUM>-dichloro-<NUM>,<NUM>-dimethoxyphenyl)-<NUM>-(methylamino)-<NUM>-oxopyrido[<NUM>,<NUM>-d]pyrimidin-<NUM>(<NUM>)-yl)propyl)piperazine-<NUM>-carboxylate (<NUM>) was charged into appropriately sized three-neck RBF equipped with a condenser and suspended in acetone (<NUM>). Concentrated (<NUM>%) aqueous hydrochloric acid (<NUM>) was slowly added and the mixture was heated to <NUM> for <NUM>. the reaction mixture was gradually cooled to RT over <NUM> and filtered, washed with acetone and dried to give tert-butyl-<NUM>-(<NUM>-(<NUM>-(<NUM>,<NUM>-dichloro-<NUM>,<NUM>-dimethoxyphenyl)-<NUM>-(methylamino)-<NUM>-oxopyrido[<NUM>,<NUM>-d]pyrimidin-<NUM>(<NUM>)-yl)propyl)piperazine-<NUM>-carboxylate•3HCl (<NUM>) in <NUM>% yield.

To an appropriate reactor tert-butyl-<NUM>-(<NUM>-(<NUM>-(<NUM>,<NUM>-dichloro-<NUM>,<NUM>-dimethoxyphenyl)-<NUM>-(methylamino)-<NUM>-oxopyrido[<NUM>,<NUM>-d]pyrimidin-<NUM>(<NUM>)-yl)propyl)piperazine-<NUM>-carboxylate (<NUM>) and DMF (<NUM>) was charged while stirring at RT. The suspension was cooled to <NUM>-<NUM> and saturated aqueous sodium bicarbonate solution (<NUM>) was slowly added maintaining temperature below <NUM> with emission of CO<NUM>. The mixture was cooled again to <NUM>-<NUM> and acryloyl chloride (<NUM>, <NUM> eq. ) was slowly added at temperature below <NUM>. Once acryloyl chloride addition was finished the reaction mixture was gradually warmed to RT over <NUM>. Saturated aqueous sodium bicarbonate solution (<NUM>) was slowly added and the resulted mixture was heated at <NUM>-<NUM> for <NUM>-<NUM>. It was then gradually cooled to RT and stirred for another <NUM>-<NUM>. Solids were filtered off, washed with water and dried.

Claim 1:
A process of preparing a compound of formula (I):
<CHM>
comprising:
(A) treating a compound of formula (a), where X is a leaving group under elimination reaction conditions, with a base
<CHM>
to provide the compound of formula (I); or
(B) reducing the acetylene bond in compound (b)
<CHM>
to provide the compound of formula (I); or
(C) treating a compound of formula (c) with a reducing agent
<CHM>
to provide the compound of formula (I); or
(D) chlorinating a compound of formula (d)
<CHM>
to provide the compound of formula (I).