Patent Application
20220340532
The present invention provides new procedure and intermediates for the preparation of Roxadustat.
Roxadustat which has the chemical name N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl) carbonyl]-glycine is a potent inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase, as described in U.S. Pat. No. 7,323,475. Roxadustat has the following chemical structure:
HIF prolyl hydroxylase inhibitors are useful for increasing the stability and/or activity of HIF, and useful for, inter alia, treating and preventing disorders associated with HIF, including anemia, ischemia, and hypoxia.
Roxadustat preparation and intermediates thereof is disclosed in U.S. Pat. No. 7,323,475 (example D81), as demonstrated in the following scheme A:
The process described above in U.S. Pat. No. 7,323,475 has significant disadvantages, since this process shows low isomeric selectivity and low yield.
Another U.S. Pat. Nos. 9,340,511 and 9,708,269 describe different process for the preparation of Roxadustat, as demonstrated by scheme B.
The process described above in U.S. Pat. Nos. 9,340,511 and 9,708,269 is not preferable since it includes many stages of synthesis that affects the complexity and the high cost of this procedure in production scale. Furthermore, the conversion of compound 17 to 18 (as defined above) involves special equipment such as pressure reactor and costly palladium catalyst under hydrogen gas which is not preferable procedure that can be used in high quantity production scale.
Another U.S. Pat. No. 9,206,134 describes also preparation of Roxadustat, as demonstrated by scheme C below.
The main disadvantage of the above described process (U.S. Pat. No. 9,206,134) is its low regioselectivity which resulted with low yield of Roxadustat.
Recently new International Publication No. WO 2019/106621 described another process for Roxadustat, as demonstrated by scheme D below.
The methylation of the 4-phenoxyphthalic acid generates two regio isomers, which are purified to get B1 therefore the theoretical yield of this process is only 50%. Furthermore, the conversion of B1 to C involves the highly flammable ethyl isocyanate which evolves the acute toxic gases which is not safe and must be controlled. In addition, the methylation reaction was performed by Suzuki coupling reaction from intermediate E to F with tetrakis triphenyl phosphine palladium and Trimethyl boroxin in dioxane which is genotoxic solvent and should be avoided.
Thus, it is the object of the present invention to devise other improved methods of synthesizing Roxadustat that lack the disadvantages of the procedures described in the prior art. Hence, there is a need for procedure which involves only few synthetic steps, and provides Roxadustat in high yield and quality, that can be utilized in industrial scale.
The present disclosure provides new procedure and intermediates for the preparation of Roxadustat.
In another aspect, the present disclosure provides novel intermediates, their preparation and their use in the preparation of Roxadustat.
According yet to another aspect the present invention relates to novel process by using the intermediate of formula (7′), preferably intermediate of formula (7) for the preparation of intermediate formula (6′), preferably intermediate of formula (6)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
Wherein Pg is H or —OH protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (6′), preferably intermediate of formula (6) for the preparation of intermediate formula (5′), preferably intermediate of formula (5)
wherein Pg is H or —OH protecting group.
According to another aspect the present invention relates to novel process by using the intermediate of formula (7′), preferably formula (7) for the preparation of formula (5′), preferably formula (5).
According to another aspect the present invention relates to novel process by combining the intermediate of formula (8) and formula (9) for the preparation of intermediate of formula (5′), preferably intermediate of formula (5).
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (5′), preferably intermediate of formula (5) for the preparation of intermediate formula (4′), preferably intermediate of formula (4)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (4′), preferably intermediate of formula (4) for the preparation of intermediate formula (3′), preferably for the preparation of intermediate of formula (3)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group or one R1 is alkyl and other R1 is oxygen attached to alkyl group or hydrogen or two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic.
wherein Pg is H or —OH protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (3′), preferably formula (3) for the preparation of intermediate formula (2′) and formula (2) respectively.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group. wherein Pg is H or —OH protecting group.
wherein X− is anion of corresponding amine preferably Iodo or methanesulfate.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (2′), preferably using intermediate of formula (2) for the preparation Roxadustat.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group
wherein Pg is H or —OH protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (5′), preferably formula (5), more preferably intermediate of formula (5-methyl) and formula (5-acid) for the preparation of intermediate formula (4a′), preferably intermediate of formula (4a) and formula (4b).
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, preferably H or methyl.
wherein Pg is H or —OH protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (4a′), preferably intermediate of formula (4a) and formula (4b) for the preparation of intermediate formula (2′), preferably for the preparation of intermediate of formula (2) or for the preparation of Roxadustat.
wherein Pg is H or —OH protecting group.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (5′) preferably formula (5) and more preferably intermediate of formula (5-methyl) and formula (5-acid) for the preparation of intermediate formula (4c′) preferably intermediate of formula (4c) and formula (4d).
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group. Preferably methyl and H.
wherein Pg is H or —OH protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (4c′) preferably intermediate of formula (4c) and formula (4d) for the preparation of intermediate formula (2′), preferably for the preparation of intermediate of formula (2) and for the preparation of Roxadustat.
wherein Pg is H or —OH protecting group.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (5′), preferably formula (5), more preferably intermediate of formula (5-methyl) and formula (5-acid) for the preparation of intermediate formula (4e′), preferably intermediate of formula (4e) and formula (4f).
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group. Preferably methyl and H.
wherein Pg is H or —OH protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (4e′) preferably intermediate of formula (4e) and formula (4f) for the preparation of intermediate formula (2′), preferably for the preparation of intermediate of formula (2) and for the preparation of Roxadustat.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group. Preferably methyl and H.
wherein Pg is H or —OH protecting group.
In yet further aspect the present disclosure provides novel intermediate of formula (5′), preferably formula (5) that can be used in the preparation of formula (4′), preferably formula (4)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group
wherein Pg is H or —OH protecting group.
In yet further aspect the present disclosure provides novel intermediate of formula (4′), preferably formula (4) that can be used in the preparation of formula (3′), preferably formula (3).
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group, or one R1 is alkyl and other R1 is oxygen attached to alkyl group or hydrogen or two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic.
wherein Pg is H or —OH protecting group.
In yet further aspect the present disclosure provides novel intermediate of formula (3′) and formula (3) that can be used in the preparation of Roxadustat.
wherein R is selected from the list consisting of substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group. Preferably R is selected from the group consisting of methyl, ethyl, t-butyl and benzyl, most preferably R is methyl.
wherein X− is anion of corresponding amine preferably Iodo or methanesulfate.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group or one R1 is alkyl and other R1 is oxygen attached to alkyl group or hydrogen or two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic.
wherein Pg is H or —OH protecting group.
In yet further aspect the present disclosure provides novel intermediate of formula (4a′), preferably formula (4a) and formula (4b) that can be used in the preparation of formula (2′) preferably formula (2) and in the preparation of Roxadustat.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group. wherein Pg is H or —OH protecting group.
In yet further aspect the present disclosure provides novel intermediate of formula (4c′), preferably formula (4c) and formula (4d) that can be used in the preparation of formula (2′), preferably formula (2) and in the preparation of Roxadustat.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, wherein Pg is H or —OH protecting group.
In yet further aspect the present disclosure provides novel intermediate of formula (4e′), preferably formula (4e) and formula (4f) that can be used in the preparation of formula (2′) preferably formula (2) and in the preparation of Roxadustat.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, wherein Pg is H or —OH protecting group.
According yet to another aspect, the present disclosure provides the novel compounds (3′), (4′) and (5′) preferably (3), (4) and (5).
According yet to another aspect, the present disclosure provides the novel compounds (4a′), (4c′) and (4e′), preferably (4a), (4b), (4c), (4d), (4e) and (4f).
In another aspect the present disclosure provides the use of any one of the compounds of formula (3′), (4′) and (5′) preferably (3), (4) and (5) in the preparation of Roxadustat.
In another aspect the present disclosure provides the use of any one of the compounds of formula (4a′), (4c′) and (4e′), preferably (4a), (4b), (4c). (4d), (4e) and (4f) in the preparation of Roxadustat.
In another aspect the present disclosure provides any one of compounds of formula (3′), (4′) and (5′) preferably (3), (4) and (5) for use in the preparation of Roxadustat.
In another aspect the present disclosure provides any one of compounds of formula (4a′), (4c′) and (4e′), preferably (4a), (4b), (4c), (4d), (4e) and (4f) for use in the preparation of Roxadustat
The present disclosure provides for novel processes for preparation of any one of compounds (3′), (4′) and (5′) preferably (3), (4) and (5) and for the preparation of Roxadustat.
The present disclosure provides for novel processes for preparation of any one of compounds (4a′), (4c′) and (4e′), preferably (4a), (4b), (4c). (4d), (4e) and (4f) for the preparation of Roxadustat.
The present disclosure provides for novel processes for preparation of compound (2′) from compound (3′) preferably compound (2) from compound (3).
In yet further aspect the present disclosure provides novel intermediate of formula (5′), preferably formula (5) that can be used in the preparation of formula (4′), preferably formula (4)
In yet further aspect the present disclosure provides novel intermediate of formula (5′), preferably formula (5) that can be used in the preparation of formula (4a′), (4c′) and (4e′), preferably (4a), (4b), (4c), (4d), (4e) and (4f).
In another embodiment the compound of formula (5′) preferably formula (5) is prepared by combining formula (8) and formula (10).
In yet another embodiment the compound of formula (5′) preferably formula (5) used above can be prepared by combining the intermediate of formula (8) and formula (9) to afford formula (10) followed by isoquinoline ring cyclisation
wherein R is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, preferably H or methyl.
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising
a) converting formula (7′), preferably formula (7)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
to afford the compound of formula (6′), preferably formula (6)
wherein Pg is H or —OH protecting group; and
b) converting the compound of formula (6′) preferably formula (6) to afford the compound of formula (5′) preferably formula (5)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group. alternatively,
c) converting Formula (7′) preferably formula (7) to obtain formula (5′) preferably, formula (5)
alternatively,
d) combining the intermediate of formula (8) and formula (9) to afford formula (10) followed by isoquinoline ring cyclisation to obtain formula (5′) preferably formula (5)
wherein R is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, preferably H or methyl; and
e) converting the compound of formula (5′), preferably formula (5) to afford compound of formula (4′), preferably formula (4)
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group, or one R1 is alkyl and other R1 is oxygen attached to alkyl group or hydrogen or two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
f) converting compound of formula (4′), preferably formula (4) to afford compound of formula (3′), preferably formula (3)
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group.
wherein Pg is H or —OH protecting group.
wherein X− is anion of corresponding amine.
g) converting compound of formula (3′), preferably formula (3) to afford compound of formula (2′), preferably formula (2)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
and optionally
h) converting compound of formula (2′) preferably formula (2) to Roxadustat.
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising:
a) converting compound of formula (7′) preferably formula (7) to compound of formula (5′) preferably formula (5) using formula (6′) preferably formula (6) according to steps a and b described above, or alternatively, converting compound of formula (7′) preferably formula (7) to compound of formula (5′) preferably formula (5)
alternatively,
b) combining the intermediate of formula (8) and formula (9) followed by isoquinoline ring cyclisation to obtain formula (5′) preferably formula (5); and
c) converting compound of formula (5′) preferably formula (5) to afford compound of formula (4a′) preferably formula (4a) and formula (4b)
wherein Pg is H or —OH protecting group.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
and
d) converting compound of formula (4a′) preferably formula (4a) and formula (4b) to afford compound of formula (2′) preferably formula (2)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, preferably methyl or H.
and;
e) converting compound of formula (2′) preferably formula (2) to Roxadustat
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising:
a. converting compound of formula (7′) preferably formula (7) to compound of formula (5′) preferably formula (5) using formula (6) preferably formula (6′), or converting compound of formula (7′) preferably formula (7) to compound of formula (5′) preferably formula (5) alternatively,
b. combining the intermediate of formula (8) and formula (9) to obtain formula (5′) preferably formula (5).
and;
c. converting compound of formula (5′) preferably formula (5) to afford compound of formula (4c′) preferably formula (4c) and formula (4d)
wherein Pg is H or —OH protecting group.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
and;
d. converting compound of formula (4c′) preferably formula (4c) and formula (4d) to afford compound of formula (2′) preferably formula (2)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, preferably methyl or H.
wherein Pg is H or —OH protecting group.
and;
e. converting compound of formula (2′) preferably compound of formula (2) to Roxadustat.
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising:
a. converting compound of formula (7′) preferably formula (7) to compound of formula (5′) preferably formula (5) using formula (6′) preferably formula (6), or converting compound of formula (7′) preferably formula (7) directly to compound of formula (5′) preferably formula (5) alternatively,
b. combining the intermediate of formula (8) and formula (9) to afford formula (5′) preferably formula (5).
and;
c. converting compound of formula (5′) preferably formula (5) to afford compound of formula (4e′) preferably formula (4e) and formula (4f)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group. Preferably methyl and H.
wherein Pg is H or —OH protecting group.
and
d. converting compound of formula (4e′) preferably formula (4e) and formula (4f) to afford compound of formula (2′) preferably formula (2)
and;
e. converting compound of formula (2′) preferably formula (2) to Roxadustat
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising—
a) converting formula (7′), preferably formula (7) under basic conditions, preferably with sodium hydroxide
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
to afford formula (6′), preferably formula (6)
wherein Pg is H or —OH protecting group.
and
b) reacting the compound of formula (6′) preferably formula (6), with Glycine ethyl ester or salt thereof to afford the compound of formula (5′), preferably formula (5)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
c) reacting the compound of formula (7′) preferably formula (7) with Glycine ethyl ester or salt thereof to afford formula (5′) preferably formula (5)
and
d) reacting the compound of formula (5′) preferably formula (5) with N,N,N′,N′-Tetra alkylmethanediamine reagent such as N,N,N′,N′-Tetramethylmethanediamine to afford compound of formula (4′), preferably formula (4)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group or one R1 is alkyl and other R1 is oxygen attached to alkyl group or hydrogen or two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic.
wherein Pg is H or —OH protecting group.
e) alkylation of compound (4′), preferably compound (4) to afford compound of formula (3′), preferably formula (3)
wherein alkylation reagent can be selected from methyl iodide, Di methyl sulfate (DMS), dimethyl carbonate (DMC), methyl bromide. Preferably methyl iodide, Di methyl sulfate (DMS).
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group.
Wherein two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic.
wherein Pg is H or —OH protecting group.
and
f) reduction compound of formula (3′) preferably formula (3) to afford formula (2′), preferably formula (2)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
and
g) converting formula (2′), preferably formula (2) to Roxadustat.
In another embodiment intermediate formula (5′) preferably formula (5) used above can alternatively be prepared by reacting the intermediate of formula (8) and formula (9) with halide of alkali and alkaline earth metals selected from sodium iodide, potassium iodide, potassium bromide and preferably sodium iodide under basic conditions to afford formula (10), followed by isoquinoline ring cyclisation with alkoxide of alkali and alkaline earth metals, preferably sodium methoxide, potassium tertiary butoxide, sodium tertiary butoxide, sodium amylate, potassium amylate, preferably sodium methoxide
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, preferably H or methyl.
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising—
a. coupling formula (7′), preferably formula (7) with Glycine to afford compound of formula (5′) preferably formula (5) more preferably compound of formula (5-acid)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, preferably H or methyl
wherein Pg is H or —OH protecting group.
alternatively,
b. reacting the intermediate of formula (8) and formula (9) with halide of alkali and alkaline earth metals, preferably sodium iodide, potassium iodide, potassium bromide and sodium iodide, more preferably sodium iodide, under basic environment to afford formula (10), followed by isoquinoline ring cyclisation with alkoxide of alkali and alkaline earth metals, preferably sodium methoxide, potassium tertiary butoxide, sodium tertiary butoxide, sodium amylate, potassium amylate, preferably sodium methoxide to obtain formula (5′) preferably formula (5)
and;
c. reacting the compound of formula (5′) preferably (5) more preferably formula (5-methyl) and formula (5-acid) with morpholine and Paraformaldehyde under acid conditions, preferably glacial acetic acid to afford compound of formula (4a′) preferably formula (4a) and formula (4b).
and;
d. reduction compound of formula (4a′) preferably formula (4a) and formula (4b) with reduction reagent selected from Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2. Sodium/liquid ammonia and zinc, preferably with zinc under acid conditions, preferably with hydrochloric acid to afford formula (2′) preferably formula (2-methyl) and Roxadustat respectively.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
and
e. converting compound of formula (2′) preferably formula (2-methyl) to Roxadustat under basic conditions, preferably using sodium hydroxide.
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising—
a) coupling formula 7′, preferably formula 7 with Glycine to afford compound of formula (5′) preferably formula (5) more preferably compound of formula (5-acid)
alternatively,
b) reacting the intermediate of formula (8) and formula (9) with halide of alkali and alkaline earth metals, preferably sodium iodide, potassium iodide, potassium bromide and more preferably sodium iodide under basic environment to afford formula (10), followed by isoquinoline ring cyclisation with alkoxide of alkali and alkaline earth metals, preferably sodium methoxide, potassium tertiary butoxide, sodium tertiary butoxide, sodium amylate, potassium amylate, more preferably sodium methoxide to obtain formula (5′) preferably formula (5)
and;
c) reacting the compound of formula (5′) preferably formula (5) more preferably formula (5-methy) and formula (5-acid) with N,O-Dimethylhydroxylamine and paraformaldehyde under acid conditions, preferably glacial acetic acid to afford compound of formula (4c′) and preferably formula (4c) and formula (4d)
and
d) reduction compound of formula (4c′) preferably formula (4c) and formula (4d) with reduction reagent selected from Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2. Sodium/liquid ammonia and zinc preferably with zinc under acid conditions, preferably with hydrochloric acid to afford formula afford formula (2′) preferably formula (2-methyl) and Roxadustat respectively.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
and;
e) converting compound of formula (2′) preferably formula (2-methyl) to Roxadustat under basic conditions, preferably using sodium hydroxide.
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising—
a) coupling formula (7′), preferably formula (7) with Glycine to afford compound of formula (5′) preferably formula (5) and more preferably formula (5-acid)
b) reacting the intermediate of formula (8) and formula (9) with halide of alkali and alkaline earth metals selected from sodium iodide, preferably sodium iodide, potassium iodide, potassium bromide and more preferably sodium iodide under basic environment to afford formula (10), followed by isoquinoline ring cyclisation with alkoxide of alkali and alkaline earth metals, preferably sodium methoxide, potassium tertiary butoxide, sodium tertiary butoxide, sodium amylate, potassium amylate, and more preferably sodium methoxide to obtain formula (5′) preferably formula (5).
and;
c) reacting the compound of formula (5′) preferably formula (5) more preferably formula (5-methyl) and formula (5-acid) with piperidine and paraformaldehyde under acid conditions, preferably glacial acetic acid to afford compound of formula (4e′) preferably formula (4e) and formula (4f)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, preferably H or methyl.
and;
d) reduction compound of formula (4e′) preferably formula (4e) and formula (4f) with reduction reagent selected from Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2. Sodium/liquid ammonia and zinc preferably with zinc under acid conditions, preferably with hydrochloric acid to afford formula (2′) preferably formula (2-methyl) and Roxadustat.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (7′), preferably formula (7) for the preparation of intermediate formula (5′) preferably formula (5).
wherein R is selected from the list consisting of substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, preferably R is selected from the group consisting of methyl, ethyl, t-butyl and benzyl, most preferably R is methyl.
wherein Pg is H or —OH protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (5′) preferably formula (5) for the preparation of intermediate formula (14)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (14) for the preparation of intermediate formula (4′) preferably formula (4) which can be later used for the preparation of Roxadustat.
In yet another embodiment the disclosure relates to a another process for preparation of Roxadustat comprising reacting the compound of formula (7′) preferably formula (7) with glycine to afford compound of formula (5′) preferably formula (5)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
Compound (5′) preferably compound of formula (5) can be used as intermediate for the preparation of Roxadustat.
In yet another embodiment the disclosure relates to a another process for preparation of Roxadustat comprising formula (14); and conversion of formula (14) to compound (4) which can be later used for the preparation of Roxadustat.
In a preferred aspect, the present disclosure provides a process for preparation of Roxadustat comprising:
a) adding basic condition to the compound of formula (7′) preferably formula (7) to afford the compound of formula (6′) preferably formula (6).
b) coupling glycine ethyl ester with compound of formula (6′) preferably formula (6) to afford the compound of formula (5′) preferably formula (5).
c) alternatively, coupling glycine ester with compound of formula (7′) preferably formula (7) using acid conditions to afford the compound of formula (5′) preferably formula (5).
d) alternatively, combining the intermediate of formula (8) and formula (9) with halide of alkali and alakaline earth metals, preferably sodium iodide, potassium iodide, potassium bromide, preferably sodium iodide to afford the compound of formula (10), and conversion to formula (5′) preferably formula (5).
and;
e) coupling N,N,N′,N′-Tetramethylmethanediamine with the compound of formula (5) to afford the compound of formula (4).
f) alkylation of compound of formula (4) with methyl iodide, DMS or DMC to afford the compound of formula (3).
g) reduction of compound of formula (3) to afford the compound of formula (2), optionally with zinc or in the present of catalyst.
h) converting compound (2) to Roxadustat.
Optionally,
i) coupling compound (7) with glycine ethyl ester to afford compound (5′) preferably formula (5).
j) Coupling tetramethyldiaminomethane with compound (5′) preferably formula (5) to afford compound (14).
k) Coupling compound (14) with to obtain compound (4)
d) using compound (4) for the preparation of Roxadustat
compound of formula (5′) preferably formula (5) can be used following to the above process for the preparation of Roxadustat.
In another aspect Roxadustat is prepared according to the process describes herein
In further aspect Roxadustat prepared according to present disclosure is substantially pure.
The present disclosure also encompasses the use of the Roxadustat prepared by the processes of the present disclosure for the preparation of pharmaceutical compositions of Roxadustat.
The present disclosure comprises processes for preparing the above mentioned pharmaceutical compositions. The processes comprise combining the Roxadustat prepared by the processes of the present disclosure with at least one pharmaceutically acceptable excipient.
Roxadustat prepared by the processes of the present disclosure and the pharmaceutical compositions of Roxadustat prepared by the processes of the present disclosure can be used as medicaments, particularly for the treatment of anemia.
The present disclosure also provides methods for the treatment of anemia, comprising administering a therapeutically effective amount of Roxadustat prepared by the processes of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject in need of the treatment.
The following process described herein can be summarized by the following scheme (Scheme E):
The present disclosure provides new procedure and intermediates for the preparation of Roxadustat.
The present invention describes new process for providing Roxadustat in high yield and high purity that can be adapted to production in an industrial scale, i.e., greater than 1 kilogram scale.
Furthermore, this novel process uses a starting material that can lead only to one possible regioisomer, which confirms lack of regioselectivity problems. Moreover, the process of the present disclosure involves also inexpensive and safe reagents used for the synthesis. More specifically this novel process does not involve any acute hazardous material as well as explosive or genotoxic solvents or materials.
As defined herein, “high purity” refers to chemical purity wherein at least about more than 99%, more than about 99.5% or more than about 99.8% Roxadustat, measured by any technique described in the literature. e.g. by HPLC.
As used herein, and unless indicated otherwise, the term “isolated” in reference to the intermediates of the present disclosure, their solid state forms thereof corresponds to compounds that are physically separated from the reaction mixture in which they are formed.
A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature”, often abbreviated “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20° C. to about 30° C., or about 22° C. to about 27° C., or about 25° C.
The processes or steps may be referred to herein as being carried out “overnight.” This refers to time intervals, e.g., for the processes or steps, that span the time during the night, when the processes or steps may not be actively observed. The time intervals are from about 8 to about 20 hours, or about 10 to about 18 hours, or about 16 hours.
As used herein, and unless indicated otherwise, the term “reduced pressure” refers to a pressure of about 10 mbar to about 500 mbar, or about 50 mbar.
The amount of solvent employed in chemical processes, e.g., reactions or crystallizations, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term “v/v” may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding MTBE (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.
As used herein, “halogen” or “halide” refers to fluoride, chloride, bromide or iodide. In certain embodiments, the halogen is bromide or iodide.
“Alkyl” refers to a monoradical of a branched or unbranched saturated hydrocarbon chain and can be substituted or unsubstituted. Lower alkyl groups may contain 1-6 carbon atoms or 1-4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc.
“Alkoxy” refers to the O-(alkyl) group where the alkyl group is defined above.
“Aryl” refers to phenyl and 7-15 membered monoradical bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic. Aryl groups can be substituted or unsubstituted. Examples include, but are not limited to, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl. An aryl group may contain 6 (i.e., phenyl) or 9 to 15 ring atoms, such as 6 (i.e., phenyl) or 9-11 ring atoms, e.g., 6 (i.e., phenyl), 9 or 10 ring atoms.
As defined herein, the intermediate/formula/compound described in this application have the following chemical names:
In another aspect, the present disclosure provides novel intermediates, their preparation and their use in the preparation of Roxadustat.
In another aspect, the present disclosure provides the novel compounds (3′), (4′) and (5′) preferably (3), (4) and (5).
In another aspect, the present disclosure provides the novel compounds (4a′), (4c′) and (4e′), preferably (4a), (4b), (4c), (4d), (4e) and (4f).
The present disclosure provides novel intermediates of formula (3′), (4′) and (5′) preferably (3), (4) and (5) and intermediates of formula (4a′), (4c′) and (4e′), preferably (4a), (4b), (4c), (4d), (4e) and (4f) that may advantageously be used for the preparation of Roxadustat
wherein R is selected from the list consisting of substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group. Preferably, R is selected from the group consisting of methyl, ethyl, t-butyl and benzyl, most preferably R is methyl.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group or one R1 is alkyl and other R1 is oxygen attached to alkyl group or hydrogen or two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic.
wherein X− is anion of corresponding amine preferably Iodo or methanesulfate.
wherein Pg is H or —OH protecting group.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group or one R1 is alkyl and other R1 is oxygen attached to alkyl group or hydrogen or two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic.
wherein Pg is H or —OH protecting group.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
wherein R is selected from the list consisting of substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group preferably R is selected from the group consisting of methyl, ethyl, t-butyl and benzyl, most preferably R is ethyl or methyl.
wherein Pg is H or —OH protecting group.
In another aspect the present disclosure provides the use of any one of the compounds of formulae (3′), (4′) and (5′) preferably formula (3), (4), (5) and compound of formula (4a′), (4c′) and (4e′), preferably formula (4a), (4b), (4c), (4d), (4e) and (4f) in the preparation of Roxadustat.
In another aspect the present disclosure provides any one of compounds of formula (3′), (4′) and (5′) preferably formula (3), (4), (5) and compound of formula (4a′), (4c′) and (4e′), preferably formula (4a), (4b), (4c), (4d), (4e) and (4f) for use in the preparation of Roxadustat.
The present disclosure provides for novel processes for preparation of any one of compounds (3′), (4′) and (5′) preferably formula (3), (4), (5) and compound of formula (4a′), (4c′) and (4e′), preferably formula (4a), (4b), (4c), (4d), (4e) and (4f) for the preparation of Roxadustat.
In another aspect Roxadustat is prepared according to the process describes herein.
According yet to another aspect the present invention relates to novel process by using the intermediate of formula (7′) preferably formula (7) for the preparation of compound of formula (6′) preferably formula (6)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
Wherein Pg is H or —OH protecting group.
According to one aspect the disclosure related to a process for preparation of compound of formula (6′) formula (6) by conversion of compound (7) via basic conditions to compound (6).
Wherein Pg is H or —OH protecting group.
The reaction may be performed in the presence of basic reagent such as sodium hydroxide.
According to one aspect the disclosure related to a process for preparation of compound of formula (5′) preferably formula (5) by condensation of formula (7′) preferably formula (7).
Preferably the condensation may be performed in the presence of an coupling reagent for example such as glycine ethyl ester
According yet to another aspect the present invention relates to novel process by using the intermediate of formula (7′) preferably formula (7) for the preparation of intermediate formula (5′) preferably formula (5) more preferably formula (5-acid) and formula (5-methyl)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group
According to one aspect the disclosure related to a process for preparation of compound of formula (5′) preferably formula (5) more preferably formula (5-ethyl) by coupling formula (7′) preferably compound (7) with Glycine ethyl ester.
The reaction may be performed in the presence of sodium methoxide.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (5-acid) for the preparation of intermediate formula (5-methyl).
In another embodiment the disclosure relates to a process for preparation of compound (5-methyl) comprising condensation of compound of formula (5-acid).
Preferably the condensation may be performed in the presence of a coupling reagent for example such as methanol under acid conditions, preferably sulfuric acid.
In another aspect the present disclosure provides novel intermediate of formula (5′) preferably formula (5) that can be used in the preparation of Roxadustat.
wherein R is selected from the list consisting of substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group preferably R is selected from the group consisting of methyl, ethyl, t-butyl and benzyl, most preferably R is methyl and ethyl.
wherein Pg is H or —OH protecting group.
In another aspect the present disclosure provides novel intermediate of formula (5′) preferably formula (5), and more preferably formula (5-methyl) and formula (5-acid) that can be used in the preparation of Roxadustat.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (6′) preferably formula (6) for the preparation of intermediate formula (5′) preferably formula (5).
In another embodiment the disclosure relates to a process for preparation of compound (5′) preferably compound (5) comprising condensation of compound of formula (6′) preferably formula (6).
Preferably the condensation may be performed in the presence of an coupling reagent for example such as glycine ethyl ester.
In another aspect the present disclosure provides another novel intermediate of formula (4′) preferably formula (4) that can be used in the preparation of Roxadustat.
wherein R is selected from the list consisting of substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group preferably R is selected from the group consisting of methyl, ethyl, t-butyl and benzyl, most preferably R is methyl and ethyl.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group or one R1 is alkyl and other R1 is oxygen attached to alkyl group or hydrogen or two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic.
wherein Pg is H or —OH protecting group
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (5′) preferably formula (5) for the preparation of intermediate formula (4′) preferably formula (4)
wherein R is selected from the list consisting of substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, preferably R is selected from the group consisting of methyl, ethyl, t-butyl and benzyl, most preferably R is ethyl or methyl.
wherein Pg is H or —OH protecting group.
In yet another embodiment the disclosure relates to a process for preparation of compound of compound (4′) preferably formula (4) comprising coupling N,N,N′,N′-Tetramethylmethanediamine with compound (5).
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
In another aspect the present disclosure provides another novel intermediate of formula (3′) preferably formula (3) that can be used in the preparation of Roxadustat.
wherein R is selected from the list consisting of substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group preferably R is selected from the group consisting of methyl, ethyl, t-butyl and benzyl, most preferably R is methyl and ethyl.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group or one R1 is alkyl and other R1 is oxygen attached to alkyl group or hydrogen or two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic.
wherein X− is anion of corresponding amine preferably Iodo or methanesulfate.
wherein Pg is H or —OH protecting group
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (4′) preferably formula (4) for the preparation of intermediate formula (3′) preferably formula (3).
In yet another embodiment the disclosure relates to a process for preparation of compound of formula (3′) preferably formula (3) comprising reduction the compound of formula (4′) preferably formula (4) using reduction reagent, preferably methyl iodide and DMS. According to yet another aspect the present invention relates to novel process by using the intermediate of formula (3′) preferably formula (3) for the preparation of intermediate formula (2′) preferably formula (2)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
In yet another embodiment the disclosure relates to a process for preparation of compound of formula (2′) preferably formula (2) comprising reduction compound of formula (3′) preferably formula (3).
Preferably the reduction agent can be selected from zinc dust and palladium on carbon.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (2′) preferably formula (2) for the preparation Roxadustat.
In yet another aspect the present invention relates to novel process for Roxadustat by converting the intermediate of compound (2′) preferably compound (2) under basic conditions. Preferably with sodium hydroxide.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (2′) preferably formula (2) and more preferably formula (2-methyl) for the preparation of Roxadustat.
In yet another aspect the present invention relates to novel process for Roxadustat by converting the intermediate of formula (2′) preferably formula (2) and more preferably formula (2-methyl) under basic conditions, preferably with sodium hydroxide.
In yet further aspect the present disclosure provides novel intermediate of formula (5) preferably formula (5) that can be used in the preparation of formula (4′) preferably formula (4)
wherein R is selected from the list consisting of substituted or unsubstituted alkyl, substituted or unsubstituted aryl alkyl, or acid protecting group preferably R is selected from the group consisting of methyl, ethyl, t-butyl and benzyl, most preferably R is methyl or ethyl.
wherein Pg is H or —OH protecting group.
In yet further aspect the present disclosure provides novel intermediate of formula (4′) preferably formula (4) that can be used in the preparation of formula (3′) preferably formula (3)
wherein R is selected from the list consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl or acid protecting group, preferably R is selected from the group consisting of H, methyl, ethyl, t-butyl and benzyl, most preferably R is methyl.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group or one R1 is alkyl and other R1 is oxygen attached to alkyl group or hydrogen or two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic.
wherein Pg is H or —OH protecting group
In yet further aspect the present disclosure provides novel intermediate of formula (3′) preferably formula (3) that can be used in the preparation of Roxadustat.
wherein R is selected from the list consisting of substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group. Preferably R is selected from the group consisting of methyl, ethyl, t-butyl and benzyl, most preferably R is methyl.
wherein R1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or amine protecting group or one R1 is alkyl and other R1 is oxygen attached to alkyl group or hydrogen or two R1 together with the nitrogen atom to which they are attached to form 4-8 membered heterocyclic like 1-Methylpiperazine, piperidine, pyrrolidine, morpholine or hetetroaromatic. wherein X− is anion of corresponding amine preferably Iodo or methanesulfate.
wherein Pg is H or —OH protecting group
In another aspect the present disclosure provides another novel intermediate of formula (4a′), (4c′) and formula (4e′) preferably formula (4a), (4b), (4c), (4d), (4e) and (4f) that can be used in the preparation of Roxadustat.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group. Preferably methyl and H.
wherein Pg is H or —OH protecting group.
In yet further aspect the present disclosure provides novel intermediate of formula (5′) preferably formula (5) and more preferably (5-methyl) and preferably (5-acid) that can be used in the preparation of formula (4a′) preferably formula (4a) and (4b).
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (5′) preferably formula (5) and more preferably formula (5-methyl) and formula (5-acid) for the preparation of intermediate of formula (4a′), (4c′) and formula (4e′) preferably formula (4a), (4b), (4c), (4d), (4e) and 4(f).
In yet another embodiment the disclosure relates to a process for preparation of compound of compound (4a′) preferably formula (4a) and (4b) comprising coupling morpholine with paraformaldehyde to form mannich base which reacts with formula (5′) preferably formula (5) and more preferably formula (5-methyl) and formula (5-acid) under acid conditions.
In yet further aspect the present disclosure provides novel intermediate of formula (4a′) preferably formula (4a) and (4b) that can be used in the preparation of formula (2′) preferably formula (2) and more preferably formula (2-methyl).
In yet further aspect the present disclosure provides novel intermediate of formula (4a′) preferably formula (4a) and (4b) that can be used in the preparation of Roxadustat.
Preferably, Roxadustat is obtained by reduction of formula (4a′) preferably formula (4a) and formula (4b) using reduction reagent selected from zinc, Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2 and sodium/liquid ammonia, preferably with zinc under acid conditions.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (4a′) preferably formula (4a) and (4b) for the preparation of intermediate formula (2′) preferably formula (2) and more preferably formula (2-methyl).
In yet another embodiment the disclosure relates to a process for preparation of compound of formula (2′) preferably formula (2) and more preferably formula (2-methyl) comprising reduction the compound of formula (4a′) preferably formula (4a) and (4b) using reduction reagent selected from Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2. Sodium/liquid ammonia and zinc, more preferably zinc under acid conditions.
Preferably reduction in the presence of Ethereal solvent, chlorinated solvent and dichloromethane, more preferably dichloromethane.
In yet further aspect the present disclosure provides novel intermediate of formula (4a′) preferably formula (4a) and (4b) that can be used in the preparation of formula (2′) preferably formula (2) and more preferably formula (2-methyl).
In yet further aspect the present disclosure provides novel intermediate of formula (4a′) preferably formula (4a) and (4b) that can be used in the preparation of Roxadustat.
Preferably, Roxadustat is obtained by reduction of formula (4a′) preferably formula (4a) and formula (4b) using reduction reagent selected from zinc, Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2 and sodium/liquid ammonia, preferably with zinc under acid conditions. In yet another embodiment the disclosure relates to a process for preparation of compound of compound (4c′) preferably formula (4c) and (4d) comprising coupling N,O-Dimethylhydroxylamine with paraformaldehyde to form mannich base to react with compound (5-methyl) under acid conditions.
Preferably the coupling may be performed with paraformaldehyde, preferably using glacial acetic acid.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (4c′) preferably formula (4c) and (4d) for the preparation of intermediate formula (2′) preferably formula (2) and more preferably (2-methyl).
In yet another embodiment the disclosure relates to a process for preparation of compound of formula (2′) preferably formula (2) and more preferably formula (2-methyl) comprising reduction the compound of formula (4c′) preferably formula (4c) and (4d) using reduction reagent.
Preferably reduction with reduction reagents selected from zinc, Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2. and Sodium/liquid ammonia. Preferably with zinc under acid conditions.
Preferably reduction in the presence of dichloromethane, Ethereal solvent, chlorinated alkane, acetic acid and water. More preferably, dichloromethane.
In yet further aspect the present disclosure provides novel intermediate of formula (2′) preferably formula (2) and more preferably formula (2-methyl) that can be used in the preparation of formula (4c′) preferably formula (4c) and (4d).
In yet further aspect the present disclosure provides novel intermediate of formula (4c′) preferably formula (4c) and (4d) that can be used in the preparation of formula (2′) preferably formula (2) and more preferably formula (2-methyl).
In yet further aspect the present disclosure provides novel intermediate of formula (4c′) preferably formula (4c) and (4d) that can be used in the preparation of Roxadustat.
Preferably Roxadustat is obtained by reduction of formula (4c′), preferably formula (4c) and (4d) with reduction reagents selected from zinc, Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2 and Sodium/liquid ammonia, preferably with zinc under acid conditions. In yet another embodiment the disclosure relates to a process for preparation of compound of compound (4e′) preferably formula (4e) and (4f) comprising coupling piperidine with paraformaldehyde to form mannich base which reacts with formula (5′) preferably formula (5) and more preferably formula (5-methyl) and formula (5-acid) under acid conditions.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (4e′) preferably formula (4e) and (4f) for the preparation of intermediate formula (2′) preferably formula (2) and more preferably formula (2-methyl).
In yet another embodiment the disclosure relates to a process for preparation of compound of formula (2′) preferably formula (2) and more preferably formula (2-methyl) comprising reduction the compound of formula (4e′) preferably formula (4e) and (4f) using reduction reagent selected from Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2. Sodium/liquid ammonia and zinc, more preferably zinc under acid conditions.
Preferably reduction in the presence of Ethereal solvent, chlorinated solvent and dichloromethane, more preferably dichloromethane.
In yet further aspect the present disclosure provides novel intermediate of formula (5′) preferably formula (5) and more preferably (5-methyl) and (5-acid) that can be used in the preparation of formula (4e′) preferably formula (4e) and (4f).
In yet further aspect the present disclosure provides novel intermediate of formula (4e′) preferably formula (4e) and (4f) that can be used in the preparation of formula (2′) preferably formula (2) and more preferably formula (2-methyl).
In yet further aspect the present disclosure provides novel intermediate of formula (4e′) preferably formula (4e) and (4f) that can be used in the preparation of Roxadustat.
Preferably, Roxadustat is obtained by reduction of formula (4e′) preferably formula (4e) and formula (4f) using reduction reagent selected from zinc, Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2 and sodium/liquid ammonia, preferably with zinc under acid conditions.
According yet to another aspect, the present disclosure provides the novel compounds (3′), (4′), (5′), (4a′), (4c′) and (4e′), preferably (3), (4), (5), (4a), (4b), (4c), (4d), (4e) and (4f).
In another aspect the present disclosure provides the use of any one of the compounds of formula (3′), (4′), (5′), (4a′), (4c′) and (4e′), preferably (3), (4), (5), (4a), (4b), (4c), (4d), (4e) and (4f) in the preparation of Roxadustat.
In another aspect the present disclosure provides any one of compounds of formula (3′), (4′), (5′), (4a′), (4c′) and (4e′), preferably (3), (4), (5), (4a), (4b), (4c), (4d), (4e) and (4f) for use in the preparation of Roxadustat.
The present disclosure provides for novel processes for preparation of any one of compounds (3′), (4′), (5′), (4a′), (4c′) and (4e′), preferably (3), (4), (5), (4a), (4b), (4c), (4d), (4e) and (4f) for the preparation of Roxadustat.
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising—
a. converting formula (7′) preferably formula (7)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
Wherein Pg is H or —OH protecting group.
To afford formula (6′) preferably formula (6)
Wherein Pg is H or —OH protecting group;
and
b. condensation of formula (6′) preferably formula (6) to obtain the compound of formula (5′) preferably formula (5)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group
c. Condensation of formula (7′) preferably formula (7) to obtain the compound of formula (′5) preferably formula (5)
or
d. combining the intermediate of formula (8) and formula (9) to afford formula (10) followed by isoquinoline ring cyclisation to obtain the compound of formula (5′) preferably formula (5)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, preferably H or methyl.
and
e. reacting the compound of formula (5′) preferably formula (5) with N,N,N′,N′-Tetramethylmethanediamine to afford compound of formula 4
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
f. alkylation of compound 4 to afford compound of formula 3
and
a. reduction the compound of formula 3, to afford formula 2
and
b. converting formula 2 to Roxadustat.
Preferably in step a) basic solution is used, more preferably sodium hydroxide
Step a) is typically carried out in the presence of one or more suitable protic or aprotic solvents or mixture thereof. Protic solvents selected from methanol, ethanol, propanol, isopropanol, water and aprotic solvent selected from THF, 2-methyl THF, acetone, ethyl acetate.
Preferably in steps b) and c) glycine ethyl ester or its salts such as hydrochloride is used.
Coupling in step b) and c) is typically with alkylamines selected from Tri ethyl amine, diisopropylethylamine, diisopropylamine, morpholine and propanephosphonic acid anhydride, or EDC, HOBt, DCC.
coupling formula (8) and formula (9) in step d) using halide of alkali and alkaline earth metals like sodium iodide, potassium iodide and potassium bromide more preferably sodium iodide to obtain formula (10)
preferably the solvent in the coupling step d) is dimethyl acetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and preferably dimethylformamide.
preferably step d) using basic condition selected from carbonate, bicarbonate of alkali and alkaline earth metals, sodium carbonate, sodium bicarbonate, cesium carbonate, preferably sodium carbonate.
preferably in step d) isoquinoline ring cyclisation by alkoxide of alkali and alkaline earth metals, preferably sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide, sodium amylate, potassium amylate preferably sodium methoxide.
Preferably isoquinoline ring cyclisation in step d) in alcoholic solvent, preferably methanol, ethanol, 2-propanol, butanol and preferably methanol.
Preferably in step e) acid solution is used preferably acetic acid.
Preferably in step f) the alkylating reagent can be selected from methyl iodide, Di methyl sulfate (DMS), Dimethyl carbonate (DMC). Preferably methyl iodide, Di methyl sulfate (DMS).
Preferably step f) is typically carried out in the presence of one or more suitable protic or aprotic solvents or mixture thereof Protic solvents selected from methanol, ethanol, propanol, isopropanol, water and aprotic solvent selected from THF, 2-methyl THF, acetone, ethyl acetate, preferably acetone.
Preferably in step g) zinc dust or palladium on carbon is used.
Preferably in step g) basic solution is used, more preferably sodium hydroxide.
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising—a. coupling formula 7′, preferably formula 7 with Glycine to afford compound of formula (5′) preferably formula (5) more preferably formula (5-acid)
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, preferably H or methyl
wherein Pg is H or —OH protecting group.
b. intermediate formula (5′) preferably formula (5) can alternatively be prepared by coupling the intermediate of formula (8) and formula (9) with halide of alkali and alkaline earth metals selected from sodium iodide, potassium iodide, potassium bromide, preferably sodium iodide under basic conditions to afford formula (10), followed by isoquinoline ring cyclisation with alkoxide of alkali and alkaline earth metals, preferably sodium methoxide, potassium tertiary butoxide, sodium tertiary butoxide, sodium amylate, potassium amylate, preferably sodium methoxide and;
c. reacting the compound of formula (5′) preferably (5) more preferably formula (5-methyl) and formula (5-acid) with morpholine and Paraformaldehyde under acid conditions, preferably glacial acetic acid to afford compound of formula (4a′) preferably formula (4a) and formula (4b).
and;
d. reduction compound of formula (4a′) preferably formula (4a) and formula (4b) with reduction reagent selected from Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2. Sodium/liquid ammonia and zinc, preferably with zinc under acid conditions, preferably with hydrochloric acid to afford formula (2′) preferably formula (2-methyl) and Roxadustat respectively.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
and
e. converting compound of formula (2′) preferably formula (2-methyl) to Roxadustat under basic conditions, preferably using sodium hydroxide.
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising—
a. coupling formula 7′, preferably formula 7 with Glycine to afford compound of formula (5′) preferably formula (5) more preferably compound formula (5-acid)
alternatively,
b. Intermediate formula (5′) preferably formula (5) can alternatively be prepared by intermediate formula (5′) preferably formula (5) can alternatively be prepared by coupling the intermediate of formula (8) and formula (9) with halide of alkali and alkaline earth metals selected from sodium iodide, potassium iodide, potassium bromide, preferably sodium iodide under basic conditions to afford formula (10), followed by isoquinoline ring cyclisation with alkoxide of alkali and alkaline earth metals, preferably sodium methoxide, potassium tertiary butoxide, sodium tertiary butoxide, sodium amylate, potassium amylate, preferably sodium methoxide;
and
c. reacting the compound of formula (5′) preferably formula (5) more preferably formula (5-methy) and formula (5-acid) with N,O-Dimethylhydroxylamine and paraformaldehyde under acid conditions, preferably glacial acetic acid to afford compound of formula (4c′) and preferably formula (4c) and formula (4d)
and;
d. reduction compound of formula (4c′) preferably formula (4c) and formula (4d) with reduction reagent selected from Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2. Sodium/liquid ammonia and zinc preferably with zinc under acid conditions, preferably with hydrochloric acid to afford formula afford formula (2′) preferably formula (2-methyl) and Roxadustat respectively.
wherein R is H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group.
wherein Pg is H or —OH protecting group.
and;
e. converting compound of formula (2′) preferably formula (2-methyl) to Roxadustat under basic conditions, preferably using sodium hydroxide.
In yet another embodiment the disclosure relates to novel process for preparation of Roxadustat comprising—
a. coupling formula (7′), preferably formula (7) with Glycine to afford compound of formula (5′) preferably formula (5) and more preferably formula (5-acid)
b. Intermediate formula (5′) preferably formula (5) can alternatively be prepared by coupling the intermediate of formula (8) and formula (9) with halide of alkali and alkaline earth metals selected from sodium iodide, potassium iodide, potassium bromide, preferably sodium iodide under basic conditions to afford formula (10), followed by isoquinoline ring cyclisation with alkoxide of alkali and alkaline earth metals, preferably sodium methoxide, potassium tertiary butoxide, sodium tertiary butoxide, sodium amylate, potassium amylate, preferably sodium methoxide and;
c. reacting the compound of formula (5′) preferably formula (5) more preferably formula (5-methyl) and formula (5-acid) with piperidine and paraformaldehyde under acid conditions, preferably glacial acetic acid to afford compound of formula (4e′) preferably formula (4e) and formula (4f)
and;
d. reduction compound of formula (4e′) preferably formula (4e) and formula (4f) with reduction reagent selected from Sn, SnCl2, Fe, Ni, and salt of this metal, Pd/C, Pt, Pd(OH)2. Sodium/liquid ammonia and zinc preferably with zinc under acid conditions, preferably with hydrochloric acid to afford formula (2′) preferably formula (2-methyl) and Roxadustat respectively.
In another embodiment intermediate formula (5′) preferably formula (5) can be prepared by coupling the intermediate of formula (8) and formula (9) with halide of alkali and alkaline earth metals selected from sodium iodide, potassium iodide, potassium bromide, preferably sodium iodide under basic environment to afford formula (10), followed by isoquinoline ring cyclisation with alkoxide of alkali and alkaline earth metals, preferably sodium methoxide, potassium tertiary butoxide, sodium tertiary butoxide, sodium amylate, potassium amylate, preferably sodium methoxide
wherein R is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, or acid protecting group, preferably H or methyl
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (5′) preferably formula (5) for the preparation of formula (14)
According yet to another aspect the present invention relates to novel process for compound (14) by coupling formula (5′) preferably formula (5) with tetramethyldiaminomethane.
According to yet another aspect the present invention relates to novel process by using the intermediate of formula (14) for the preparation of intermediate formula (4) which can be later used for the preparation of Roxadustat.
According yet to another aspect the present invention relates to novel process for compound (4) using alcoholic solvent with acid. Preferably alcoholic solvent selected from methanol, ethanol. Acid is selected from sulfuric acid, paratoluenesulphonic acid and hydrochloric acid, preferable sulfuric acid.
In yet another embodiment the disclosure relates to a another process for preparation of Roxadustat comprising
a) reacting the compound of formula (7′) preferably formula (7) with glycine to afford compound of formula (5′) preferably formula (5)
and;
b) adding tetramethyldiaminomethane and acetic acid to formula (5′) preferably formula (5) to afford compound of formula (14)
and;
c) conversion of formula (14) to compound (4) with ethanol and sulfuric acid which can be later used for the preparation of Roxadustat.
Preferably in step a) sodium methoxide is used.
The disclosure may be further understood by the below reaction schemes (Schemes F, G and H), which are described in more detail below. These schemes form further aspect of the disclosure. Accordingly a further aspect of the disclosure provides processes for the preparation of Roxadustat or a salt thereof according to Scheme F:
In Scheme F, AM1 in Option C1 for the preparation of compound 4′, 4″ or mixture thereof, may have R2, R3, R4 and R5 each independently being alkyl, arylalkyl or alkenyl, R2 and R3 and/or R4 and R5, taken together with the nitrogen atom to which they are bonded, each independently form a heterocyclic ring selected from:
wherein R6 is H or C1-6 alkyl. In the above Scheme F, it will be appreciated that where AM1 is a symmetrical amine (i.e. R4═R2 and R5═R3), the resulting product is a compound of formula 4′, and likewise the product in the N-substitution/N-substitution/esterification step is a compound of formula 3. When AM1 is a non-symmetrical amine, the resulting product is a mixture of 4′ and 4″, and likewise the product in the N-substitution/N-substitution/esterification step is a mixture of 3′ and 3″. In any embodiment of the disclosed processes, AM1 is a symmetrical amine, such that the resulting compounds of formula 4′ and 3′ are not prepared as a mixture.
In the amine AM2 in option C2 for the preparation of compound 4′, R2 is C1-4 alkyl and R3 is C1-4 alkoxy; or R2 and R3 taken together with the nitrogen atom to which they are bonded, form a heterocyclic ring selected from:
wherein R6 is H or C1-6 alkyl.
Also disclosed herein is a process for preparing Roxadustat or a salt thereof, wherein the compound of formula 4′ (see Scheme F) is prepared by Mannich reaction of the compound of formula 5′ wherein R1 is H (i.e. 5 ACID) using an amine of formula AM2, formaldehyde or par4aformaldehyde, in the presence of an acid. Thus a further aspect of the disclosure provides a process preparing Roxadustat or salt thereof according to Scheme G:
In Scheme G, the amine AM2 used in the preparation of compound 4′ from compound 5′ wherein R1 is H (i.e. 5 ACID), has R2 is C1-4 alkyl and R3 is C1-4 alkoxy; or R2 and R3 taken together with the nitrogen atom to which they are bonded, form a heterocyclic ring selected from:
wherein R6 is H or C1-6 alkyl.
The resulting compound 4′ may be converted either by direct reduction (after any ester hydrolysis/Pg removal) to form Roxadustat, or may be converted to the compound 3′ before reduction (and removal of Pg/ester hydrolysis) to form Roxadustat. The direct reduction route for compound 4′ to Roxadustat is shown below in Scheme H. Scheme H therefore represent a further aspect of the present disclosure:
The Roxadustat may be converted to a salt by well-known procedures.
In any of the processes and compounds disclosed herein, including in the processes set out in Schemes F, G and H, unless otherwise indicated, the substituents may be defined as follows:
wherein R6 is H or C1-6 alkyl; R7 is C1 to C6 alkyl; and/or
The disclosure further provides the following processes set out in the numbered paragraphs below. These paragraphs represent further aspects and embodiments of the present disclosure:
comprising:
(A) reducing a compound of formula 3′, 3″ or a mixture thereof:
Optionally, the compound 3′ is not present as a mixture with 3″.
Optionally, the compound of formula 4′ is not present in a mixture with 4″.
The compound of formula 5′ may be prepared by the following processes:
Option A
Option B
A further aspect of the disclosure provides the use of these compounds, especially the compounds of any of paragraphs 177, 178 and 179, for preparing Roxadustat or a salt thereof.
In further aspect Roxadustat prepared according to any process of the present disclosure is substantially pure.
In further aspect Roxadustat prepared according to any process of the present disclosure is substantially pure wherein at least about more than 99%, more than about 99.5% or more than about 99.8% Roxadustat is measured by any technique described in the literature. e.g. by HPLC.
The present disclosure also encompasses the use of the Roxadustat prepared by the any of the processes of the present disclosure for the preparation of pharmaceutical compositions of Roxadustat.
The present disclosure comprises processes for preparing the above mentioned pharmaceutical compositions. The processes comprise combining the Roxadustat prepared by any of the processes of the present disclosure with at least one pharmaceutically acceptable excipient.
Roxadustat prepared by any of the processes of the present disclosure and the pharmaceutical compositions of Roxadustat prepared by any processes of the present disclosure can be used as medicaments, particularly for the treatment of anemia.
The present disclosure also provides methods for the treatment of anemia, comprising administering a therapeutically effective amount of Roxadustat prepared by any of the processes of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject in need of the treatment.
Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (Compound 7, 50 gm, 0.169 moles) was added to the reactor followed by addition of the THF (150 ml) and Ethanol (250 ml). Reaction mass was stirred at 20-30° C. for 20-30 min and added Aq. Sodium Hydroxide solution (28 gm, 0.7 moles in 150 ml water) in drop wise to the reaction mass at 25-55° C. Reaction mass was maintained under stirring for 4-7 hrs. The reaction was monitored by HPLC. Reaction mass was acidified using conc. HCl up to pH 1-2, water (1500 ml) was added to the reaction mass and stirred for 20-30 min and filtered the reaction mass. The compound was dried under vacuum at 55° C. and material was forwarded to next stage without further purification. The yield obtained was 85-90% and HPLC purity >95%.
4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid (Compound 6, 45.0 gm, 0.159 moles) was added to the reactor at 20-30° C. MDC (360 ml) was added to the reaction mass followed by Glycine ethyl ester hydrochloride (44.51 gm, 0.31 mole). Tri ethyl amine (113 ml) and propanephosphonic acid anhydride (152.77 gm, 0.480 moles) was added subsequently. The reaction mass was heated up to 50-60° C. for 4-8 hrs. The reaction mass was monitored by HPLC. After completion of reaction, D.I. water (225 ml) was added to the reaction mass, the layers were separated and organic layer was washed with D. I. Water (90 ml). The organic layer was evaporated under reduced pressure to get crude compound, which was purified by mixture of ethyl acetate (45 ml) and cyclohexane (450 ml), the reaction mass was filtered and washed by cyclohexane (50 ml). The compound was dried under vacuum at 45° C. The yield obtained was 92-98% and HPLC purity >93%.
Ethyl (4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycinate (compound 5 55.0 gm, 0.150 moles) was charged in acetic acid (165 ml) into reactor. Added N,N,N′,N′-Tetramethylmethanediamine (28 ml) into the reaction mass at 20-30° C. in 10-20 min. Heated the reaction mass to 60-70° C. and stirred it for 6-10 hrs. The reaction mass was monitored by HPLC. After completion of reaction, reaction mass was cooled to 20-30° C. and charged ethyl acetate (300 ml) and water (200 ml) in to it. Stirred the mass and separated the organic layer. Organic layer was washed with aq. sodium carbonate solution. Organic layer was collected and was evaporated under reduced pressure to get crude compound. The yield obtained was 85-90% and HPLC purity >96%
Ethyl-(1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)-glycinate (compound 4.8 gm, 0.0189 moles) was charged in acetone (100 ml) in to the reactor. Reaction mass stirred at 20-30° C. for 30 min and added methyl iodide (3.20 gm, 0.022 moles) drop wise in to the reaction mass at 20-30° C. The reaction mass was maintained under stirring at 20-30° C. for 6-12 hour. The reaction was monitored by HPLC. After completion of reaction, reaction mass was filtered and washed the solid by acetone (24 ml). Wet solid was dried under vacuum at 45-55° C. for 5-15 hours. The yield obtained is 90-95% and HPLC Purity is >95%.
Ethyl-(1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)-glycinate (compound 4, 15 gm, 0.035 moles) was charged in acetone (120 ml) in to the reactor. Reaction mass stirred at 20-30° C. for 30 min and added DMS (5.36 gm, 0.042 moles) drop wise in to the reaction mass at 20-30° C. The reaction mass was maintained under stirring at 20-30° C. for 6-12 hour. The reaction was monitored by HPLC. After completion of reaction, reaction mass was filtered and washed the solid by acetone (30 ml). Wet solid was dried under vacuum at 45-55° C. for 5-15 hours. The yield obtained is 90-95% and HPLC Purity is >93%.
Charged 1-(3-((2-ethoxy-2-oxoethyl)carbamoyl)-4-hydroxy-7-phenoxyisoquinolin-1-yl)-N,N,N-trimethylmethanaminium iodide (3-Iodid 5 gm, 0.0088 moles) in to mixture of acetic acid (125 ml) and water (50 ml). Charged the acetone (50 ml) in to the reaction mass and heated to 50-60° C. Maintained the reaction mass for 30-60 min. zinc dust (2.88 gm, 0.044 moles) was charged in to the reaction mass and stirred reaction mass at 50-60° C. for 3-8 hours. The reaction was monitored by HPLC. After completion of reaction, reaction mass was cooled to 20-30° C. and charged reaction mass in mixture of dichloromethane (200 ml) and water (200 ml) in another reactor. Reaction mass was stirred for 1-2 hour at 20-30° C. Layers were separated at 20-30° C. Organic layer was collected and washed the organic layer with 4% aq. sodium carbonate solution (200 ml) and distilled the organic layer under vacuum at 45-55° C. Acetone (25 ml) was charged in to the residue at 20-30° C. Reaction mass was heated to 50-56° C. and stirred for 30-120 min. The reaction mass was cooled slowly to 20-30° C. and stirred for 1-3 hour at 20-30° C. Water (25 ml) was added (25 ml) in to the reaction mass at 20-30° C. in 20-30 min. Stirred the reaction mass for 2-4 hour and filtered. Wet cake washed with 20 ml (1:1) mixture of acetone and water. The wet compound dried under vacuum at 45-55° C. The yield obtained is 80-90% and HPLC Purity is >99%
1-(3-((2-ethoxy-2-oxoethyl)carbamoyl)-4-hydroxy-7-phenoxyisoquinolin-1-yl)-N,N,N-trimethylmethanaminium iodide (3-Iodid 1 gm, 0.0017 moles) charged in to mixture of acetone (40 ml) and water (10 ml). Stirred the mass at 30-40° C. for 30-60 min. Charged clear reaction mass in to autoclave at 20-30° C. followed by charging of 5% Pd/C (0.6 gm). Heated reaction mass to 50-70° C. and stirred the reaction mass at 50-70° C. and under 5-15 Kg/cm2 of hydrogen gas pressure for 8-16 hours. Reaction mass was cooled to 20-30° C. and released the hydrogen pressure. Reaction mass was filtered through the hyflo bed followed by washing of 30 ml (1:1) mixture of acetone and water. Solvent distilled out form the filtrate at 45-55° C. under vacuum. Charged ethyl acetate (25 ml) and water (15 ml) to the residue and stirred the reaction mass for 20-30 min at 20-30° C. Layers were separated and organic layer was distilled out under vacuum at 40-50° C. The yield obtained was 60% and HPLC Purity >91%.
Ethyl (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycinate (compound 2 2.8 gm, 0.0073 moles) was charged in to the reactor followed by the addition of THF (30 ml). Reaction mass was stirred for 10-15 min at 20-30° C. The solution of Sodium hydroxide (0.74 gm, 0.0185 moles) in water (20 ml) and Ethanol (20 ml) was charged in to the reaction mass at 20-30° C. The reaction mass was heated to 55-65° C. and stirred the mass for 2-8 hours. The reaction was monitored by HPLC. After completion of reaction, solvent was distilled out form the reaction mass under vacuum at temperature 45-55° C. Charged water (40 ml) and Ethyl acetate (30 ml) in to the residue at 20-30° C. and stirred it for 30-40 min at 20-30° C. Layers were separated and aqueous layer was collected and added conc. HCl (3.5 ml) in to the aqueous layer at 20-30° C. reaction mass was stirred the at 20-30° C. for 2-5 hours. Filtered the reaction mass at 20-30° C. followed by the water (30 ml) wash. Wet solid was charged in to the reactor followed by charging of Ethanol (50 ml) at 20-30° C. Heated the mass to 70-80° C. and stirred the mass at 70-80° C. for 1-3 hour. Cooled the mass to 20-30° C. and stirred the mass for 2-3 hour. Filtered the reaction mass followed by the ethanol (20 ml) wash. Wet solid was charged in to the reactor followed by charging of methanol (30 ml). Heated the reaction mass to 60-65° C. and stirred for 2-3 hour. Cooled the reaction mass to 20-30° C. and stirred the mass for 2-3 hour. Filtered the mass at 20-30° C. followed by the methanol (20 ml) wash. The wet compound dried under vacuum at 50° C. The yield obtained is 73.8% Roxadustat and HPLC Purity is >99%.
Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (Compound 7, 25.0 gm, 0.08 moles) was added to the reactor at 20-30° C. Methanol (350 ml) was added to the reaction mass followed by Glycine (31.72 gm, 0.31 mole) and Sodium methoxide (13.71 gm 0.58 mole). The reaction mass was heated to 80-90° C. for 8-10 hrs. The reaction mass was monitored by HPLC. After completion of reaction, reaction mass was filtered and dried over suction, the wet cake was dissolved in water (225 ml) & Ethyl acetate (125 ml). The layers were separated and acidify the aqueous layer with conc HCl up to pH 1-2. The Ethyl acetate (125 ml) was added to the aq. Layer and layers were separated, organic layer was collected and was evaporated under reduced pressure to get crude (4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine. The yield obtained was 92-98% and HPLC purity >98%.
(4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine (Compound 5-acid 5 gm, 0.0147 moles) was charged in to acetic acid (15 ml) in reactor. Added tetramethyldiaminomethane (1.88 gm, 0.0183 moles) in to reaction mass at 20-30° C. in 10-20 min. Reaction mass was heated to 55-65° C. and stirred for 5-15 hrs at 55-65° C. After completion of reaction, reaction mass was cooled to 20-30° C. and charged ethyl acetate (125 ml) and water (75 ml) in to the reaction mass. Reaction mass was stirred at 20-30° C. for 30-40 min. Layers were separated and charged ethyl acetate (100 ml) in to the organic layer at 20-30° C. and stirred reaction mass at 20-30° C. for 2-4 hour. Filtered the reaction mass followed by washing of ethyl acetate (20 ml). The wet compound was dried under vacuum at 50° C. The yield obtained is 48% and HPLC Purity is >99%.
(1-((dimethylamino)-methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine (compound 14, 2 gm, 0.005 moles) was charged in to Ethanol (40 ml) at 20-30° C. Sulfuric acid (0.5 gm) was charged at 20-30° C. The reaction mass was heated to 75-80° C. and stirred for 4-12 hour at 75-80° C. The reaction was monitored by HPLC. After completion of reaction, the solvent was distilled out from reaction mass at 50° C. Charged ethyl acetate (40 ml) and 10% sodium carbonate solution (30 ml) in to residue and stirred the reaction mass for 20-30 min. Layers were separated and organic layer was collected. Evaporate the organic layer under vacuum at 45-55° C. Charged cyclohexane (40 ml) in to residue and stirred it for 2-4 hour. Reaction mass was filtered and washed using cyclohexane (10 ml). The wet compound was dried under vacuum at 50° C. The yield obtained is 86.9% and HPLC Purity is 93%.
(4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine (compound5-acid, 5.5 gm, 0.160 moles) was added to the reactor at 20-30° C. Methanol (100 ml) and Sulfuric acid (1.0 ml) was added to the reaction mass at 20-30° C. Temperature of Reaction mass was raised 50-65° C. and maintained at 50-65° C. for 7-8 hrs. The reaction mass was monitored by HPLC. After completion of reaction, charged D.M. water (50 ml) and Ethyl acetate (300 ml) to the reaction mass. The reaction mass was monitored by HPLC. The yield obtained was 95-98% and HPLC purity >97%
Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (25.0 g, 0.08 moles, formula 7) was added to the reactor at 20-30° C. Methanol (350 ml) was added to the reaction mass followed by Glycine (31.72 gm, 0.31 mole) and Sodium methoxide (13.71 g, 0.58 mole). The reaction mass was heated to 60-65° C. for 8-10 hrs. The reaction mass was monitored by HPLC. After completion of reaction, reaction mass was filtered and dried over suction, the wet cake was dissolved in water (225 ml) & Ethyl acetate (125 ml). The layers were separated and acidify the aqueous layer with conc. HCl up to pH 1-2. The Ethyl acetate (125 ml) was added to the aq. Layer and layers were separated, organic layer was collected and was evaporated under reduced pressure to get (4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine. The yield obtained was 92-98% and HPLC purity >98%.
(4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine (5.5 g, 0.160 moles, obtained in example 11) was added to the reactor at 20-30° C. Methanol (100 ml) and Sulfuric acid (1.0 ml) was added to the reaction mass at 20-30° C. Temperature of Reaction mass was raised 50-65° C. and maintained at 50-65° C. for 7-8 hrs. The reaction mass was monitored by HPLC. After completion of reaction, charged D.M. water (50 ml) and Ethyl acetate (300 ml) to the reaction mass. The reaction mass was monitored by HPLC. The yield obtained was 95-98% and HPLC purity >97%.
Methyl (4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycinate (5.0 g, 0.0141 moles, formula 5-methyl), paraformaldehyde (1.7 g, 0.056 moles) and glacial acetic acid (25 ml) was added to reactor. To the mixture was added drop wise morpholine (4.94 g, 0.056 moles). Heated the reaction mass to 80-85° C. and stirred it for 3-5 hrs. The reaction mass was monitored by HPLC. After completion of reaction, reaction mass was cooled to 20-30° C. and charged ethyl acetate (50 ml) and water (75 ml) in to it. Stirred the mass and separated the organic layer. Organic layer was washed with water (30 ml). Organic layer was collected and was evaporated under reduced pressure to get formula (4a). The yield obtained was 85-90% and HPLC purity >96%.
Charged methyl (4-hydroxy-1-(morpholinomethyl)-7-phenoxyisoquinoline-3-carbonyl) glycinate (1.7 g, 0.0022, formula 4a) and dichloromethane followed by zinc (powder, 1.27 g, 0.19 moles). Charged conc. HCl (8.00 ml) drop wise. Stirred for one hour at 15-30° C. The reaction was monitored by HPLC. After completion of reaction water (10 ml) was added. Organic layer was collected and washed with water. Layer was separated and distilled the solvent under reduce pressure to yield 90-95% Methyl(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) glycinate and HPLC Purity is >99%.
Methyl (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycinate (5 g, 0.0136 moles, formula 2-methyl) was added with 7.5 ml methanol and 3.75 ml water. To the mixture was added 1.09 g sodium hydroxide. The mixture was stirred at 20-25° C. till completion. Reaction mixture was added with water (20 ml) and 10 ml ethyl acetate and stirred. The Layers were separated and aqueous layer was collected and added conc. HCl (3.5 ml) in to the aqueous solution at 20-30° C. Reaction mass was stirred the at 20-30° C. for 2-5 hours. Filtered the reaction mass at 20-30° C. followed by the water (5 ml) wash. Wet solid was charged in to the reactor followed by charging of Ethanol (5 ml) at 20-30° C. Heated the mass to 70-75° C. and stirred the mass at 70-75° C. for 1-3 hour. Cooled the mass to 20-30° C. and stirred the mass for 2-3 hour. Filtered the reaction mass followed by the ethanol (2 ml) wash. Wet solid was charged in to the reactor followed by charging of methanol (3 ml). Heated the reaction mass to 60-65° C. and stirred for 2-3 hour. Cooled the reaction mass to 20-30° C. and stirred the mass for 2-3 hour. Filtered the mass at 20-30° C. followed by the methanol (20 ml) wash. The wet compound dried under vacuum at 50° C. The yield obtained is 74% and HPLC Purity is >99%.
4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine (10.0 g, 0.0295 moles, formula 5-acid), paraformaldehyde (3.54 g, 0.118 moles) and glacial acetic acid (50 ml) was added to reactor. To the mixture was added drop wise morpholine (10.39 g, 0.118 moles). Heated the reaction mass to 80-85° C. and stirred it for 3-5 hrs. The reaction mass was monitored by HPLC. After completion of reaction, reaction mass was cooled to 25-30° C. and was added 100 ml water. Solid was precipitated. Filtered the solid and washed the solid with 30 ml water. Dried wet cake at 40-45° C. to get 85-90% yield and HPLC purity >98%.
Charged (4-hydroxy-1-(morpholinomethyl)-7-phenoxyisoquinoline-3-carbonyl) glycine (6 g, 0.0137, formula 4b) and dichloromethane followed by zinc (powder) (2.7 g, 0.042 moles). Charged conc. HCl (11 ml) drop wise. Stirred for one hour at 15-30° C. The reaction was monitored by HPLC. After completion of reaction 2-methyltetrahydrofuran (35 ml) was added. Organic layer was collected and washed with water. Layer was separated and distilled the solvent under reduce pressure to yield 80% 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) glycine and more than 90% HPLC purity.
Methyl (4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycinate (1.0 gm, 0.0028 moles, formula (5-methyl)), paraformaldehyde (0.34 g, 0.011 moles) and glacial acetic acid (5 ml) was added to reactor. To the mixture was added drop wise N,O-Dimethylhydroxylamine (0.69 g, 0.011 moles). Heated the reaction mass to 80-85° C. and stirred it for 3-5 hrs. The reaction mass was monitored by HPLC. After completion of reaction, reaction mass was cooled to 20-30° C. and charged ethyl acetate (5 ml) and water (10 ml) in to it. Stirred the mass and separated the organic layer. Organic layer was washed with water (5 ml). Organic layer was collected and was evaporated under reduced pressure to get crude compound (82-85% yield).
By following procedure of example 14, methyl (4-hydroxy-1-((methoxy(methyl)amino)methyl)-7-phenoxyisoquinoline-3-carbonyl)glycinate (formula 4C) can be converted to Methyl(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycinate, (Formula 2-methyl). Formula (2-methyl) can be converted to Roxadustat following example 15.
(4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycinate (1.0 g, 0.00295 moles), paraformaldehyde (0.354 g, 0.0118 moles) and glacial acetic acid (5.0 ml) were added to reactor. To the mixture was added N,O-Dimethylhydroxylamine (0.72 g, 0.0118 moles). Heated the reaction mass to 80-85° C. and stirred it for 3-5 hrs. The reaction mass was monitored by HPLC and continued for next step.
To the reactions mixture of example 20 was added MDC (Dichloromethane, 5 ml) and zinc (0.95 g, 0.0147) and heated the reaction mixture to 38° C. After completion of reaction, conc. HCl 10 ml was added and stirred for 1 hour. Methyl tetrahydrofuran was added and layers were separated. The organic layer was concentrated to obtain Roxadustat (compound 1).
To the mixture of (4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)glycine (Formula 5 acid) (10 g, 29.55 mmole), paraformaldehyde (4.43 g, 147.78 mmole) and acetic acid (40 ml) was slowly added piperidine (12.58 g, 147.78 mmole) and heated to 80° C. After completion of reaction the reaction mixture was cooled to 30-35° C. and 160 ml water was added and stirred for one hour. The solid was filtered and dried under reduce pressure to obtain (4-hydroxy-7-phenoxy-1-(piperidin-1-ylmethyl)isoquinoline-3-carbonyl)glycine (4f) (95% yield).
To the mixture of zinc (0.59 g, 9.18 mmole) and 4f (1 g, 2.29 mmole) in MDC (dichloromethane) was added drop wise concentrated hydrochloric acid at 25 to 30° C. The reaction completed in 30 minutes. After completion of reaction was added tetrahydrofuran 10 ml and 5 ml ethylacetate. Layers were separated and washed with 5 ml dilute hydrochloric acid. The solvent was distilled out. The residue was crystalized in 5 ml methanol and 10 ml concentrated hydrochloric acid to obtain Roxadustat (0.72 g).
To the slurry of (4-hydroxy-7-phenoxy-1-(piperidin-1-ylmethyl)isoquinoline-3-carbonyl)glycine (4e) (1 g) in methanol was added sulphuric acid 0.01 ml. The reaction mixture was heated the 65° C. After three hour reaction completed. Solvent was distilled out and added 10 ml dichloromethane and 10 ml 5 percent aqueous sodium carbonate solution. The layers were separated. The organic solution was washed with 10 ml water and without isolation taken for next step.
To the dichloromethane solution of example no. 24 was added zinc followed by drop wise concentrated hydrochloric acid (5 ml). After completion of reaction in one hour layer was separated. Organic solution was distilled out under reduce pressure to obtain methyl (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycinate (0.71 g with more than 99% purity).
To the mixture of formula 8-methyl (1.3 g, 4.14 mmol) and formula 9 (1.0 g, 0.0036) in 10 ml dimethylformamide was added sodium iodide (0.05 g, 0.33 mmol) and potassium carbonate (1.00 g, 3.6 mmol). The resulting reaction mixture was heated to 50-55° C. After four hour reaction completion was confirmed by HPLC. 0.5 ml of reaction mixture was extracted in ethyl acetate and solvent was distilled out to yield 0.12 g of compound 10. The reaction mixture was taken as such for next step in example 27.
To the reaction mixture of example no. 26 was added 5 ml 20% sodium methoxide in methanol. The reaction mixture was heated to 60 to 65° C. for 6 hours. The reaction was monitored by HPLC. The reaction mixture was cooled and 50 ml 10% methanolic hydrochloride was added and heated to 60° C. for two hours. The solvent was distilled out. To the reaction mixture was added 20 ml of water and 10 ml ethyl acetate and stir for 15 minutes. Layers were separated. The solvent was distilled out to yield 0.5 g compound 5-Methyl.
To the mixture of compound 8 (3.75 g, 12.5 mmol) and compound 9 (3.0 g, 10.8) in 30 ml dimethylformamide, was added sodium iodide (0.16 g, 1.08 mmol) and potassium carbonate (1.00 g, 21.6 mmol). The resulting reaction mixture was heated to 60 to 65° C. After 8 hour reaction completion was confirmed by HPLC to obtain compound (10 acid). To the reaction mixture was added with 15 ml methanol and 8 g sodium methoxide (25%) and heated to 65° C. for 8 hours. After completion of reaction the reaction mixture was cooled to 25° C. and 50 ml water was added and stirred for one hour. Thereafter reaction mixture was diluted with 50 ml ethyl acetate and stirred for 30 minutes. Aqueous layer was separated and 35 ml concentrated hydrochloric acid was added to adjust pH 2-3. The solid was precipitated out, filtered and dried under vacuum to yield 2.5 g compound (5 acid) (purity >90%).
To the mixture of compound 8-methyl (methyl tosylglycylglycinate, 227 g, 643 mmol) and compound 9 (methyl 2-(chloromethyl)-4-phenoxybenzoate, 165 g, 560 mmole) in 775 ml dimethylformamide, was added sodium iodide (12.4 g, 82 mmol) and potassium carbonate (155 g, 1120 mmol). The resulting reaction mixture was heated to 55 to 60° C. After 7 hour reaction completion was confirmed by HPLC to obtain compound (10 methyl). To the reaction mixture was added 325 ml sodium methoxide (25%) and heated to 55° C.-60° C. for 8 hours. After completion of reaction the reaction mixture was cooled to 25° C. and 500 ml water was added and stirred till 5-acid formed. Thereafter reaction mixture was diluted with 1Lt ethyl acetate and stirred for 30 minutes. Aqueous layer was separated and added with 250 ml concentrated hydrochloric acid (pH 2-3). The solid was precipitated out. The slurry was filtered and dried under vacuum to yield 145 g compound (5 acid) (purity >90%).
| Number | Date | Country | Kind |
|---|---|---|---|
| 201911032049 | Aug 2019 | IN | national |
| 201911046891 | Nov 2019 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US20/45128 | 8/6/2020 | WO |
