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US 2017/0313643 A1Published application
Process for the preparation of treprostinil
AssigneeChinoin GyóGyszer éS VegyéSzeti TerméKek GyáRa Zrt.
InventorsImre JUHÁSZ, Irén HORTOBÁGYI, Tamás ALTSACH, István LÁSZLÓFI, Ágnes NAGYNÉ BORKÓ, Imre ROZSUMBERSZKI, Gábor HAVASI, Zsuzsanna KARDOS, Péter BUZDER-LANTOS
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Abstract
The invention provides a new process for the preparation of treprostinil of formula (I) and its salts using several new intermediates during the building of the ring system.
Claims65
Method for the preparation of treprostinil of formula I and its amorph salt forms, salt anhydrates, and monohydrates and polyhydrates of salts given with bases,
- characterized in that,
- a compound of the general formula XVII
- where in the formula
- R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-group,
- with the proviso that the R1 protective group must be selectively removable from R2 and R4,
- x represents 0 or 2—
- is reacted with a compound of the general formula XVI
- where in the formula
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group and n stands for 1,2,3,4—
- a1.) in the presence of Grignard reagent, and the resulting compound of the general formula XV
- where in the formula x, R1 and R2 have the meanings as defined above—is oxidized, the resulting compound of the general formula XIV
- where in the formula x, R1 and R2 have the meanings as defined above—is selectively reduced,
- or
- a2.) in the presence of chiral base and zinc salt, and
- the compound of the general formula XIII. obtained in step a1.) or a2.)
- where in the formula x, R1 and R2 have the meanings as defined above—
- is reacted with a compound suitable for the introduction of group R3—where R3 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group—,
- b.) the resulting compound of the general formula XII
- where in the formula x, R1, R2 and R3 have the meanings as defined above—is subjected to intramolecular cyclisation,
- c.) the resulting compound of the general formula XI
- where in the formula x, R1, R2 and R3 have the meanings as defined above—is catalytically hydrogenated, and in the case where x=0, isomerized,
- d.) the resulting compound of the general formula Xa. or Xb.
- where in the formula R1, R2 have the meanings as defined above, and in compound of formula Xa. x=0, in compound of formula Xb. x=2—, is reduced,
- e.) the resulting compound of the general formula IX
- where in the formula x, R1 and R2 have the meanings as defined above—
- is reacted with a compound suitable for the introduction of group R4—where R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p-methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group, with the proviso that the R4 protective group must be selectively removable from R2 and R1 must be selectively removable from R4,
- f.) from the resulting compound of the general formula VIII
- where in the formula x, R1, R2 and R4 have the meanings as defined above—the R1 protective group is cleaved in acidic medium,
- g.) the resulting compound of the general formula VII
- where in the formula x, R2 and R4 have the meanings as defined above—is oxidized,
- h.) the resulting compound of the general formula VI
- where in the formula x, R2 and R4 have the meanings as defined above—
- h1.) in the case where x means 0, is reacted in Wittig reaction with the compound of the general formula
- CH3—(CH2)4—CO—CH2—PO(OR6)2
- wherein R6 stands for C1-4 alkyl- or phenyl-group—, and the resulting compound of the general formula V
- where in the formula R2 and R4 have the meanings as defined above—is selectively reduced, and the R4 protective group of the resulting compound of the general formula IVa.
- where in the formula R2 and R4 have the meanings as defined above—, R4 is removed, and the resulting compound of the general formula III
- where in the formula R2 has the meaning as defined above—is hydrogenated, or
- h2.) in the case where x means 2, is reacted in the presence of chiral catalyst with an organic metal reagent, and the protective group R4 of the resulting compound of the general formula IVb.
- where in the formula R2 and R4 have the meanings as defined above—, R4 is removed,
- i) the compound of the general formula II obtained in steps h1.) or h2.)
- where in the formula R2 has the meaning as defined above is transformed by known method into treprostinil of formula I and if desired, into its salts given with bases.
41 more elements
Process for the preparation of the amorph, anhydrate salts of treprostinil of formula I given with bases, and the monohydrates and polyhydrates thereof
- characterized in that treprostinil is dissolved in polar solvent, the base is added to the solution, the reaction mixture is agitated, at the end of the salt formation the solution is filtered, concentrated, the solvent of the concentrate is exchanged for the organic solvent of the crystallisation and the treprostinil salt is crystallized.
The compounds of the general formula III
- where in the formula
- R2 represents —(CH2)n Y, where
- Y stands for hydrogen atom, halogen atom, phenyl-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group and n stands for 1, 2, 3, 4—, with the proviso that R5 in —COOR5 cannot stay for C1-4 alkyl.
1 more element
The compounds of the general formula IV
- where in the formula
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group, n stands for 1,2,3,4,
- R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p-methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group, with the proviso that the R4 protective group must be selectively removable from R2, and
- the dotted line represents single or double bond.
3 more elements
Compounds of the general formula V
- where in the formula
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group, n stands for 1,2,3,4 and
- R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p-methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group, with the proviso that the R4 protective group must be selectively removable from R2.
2 more elements
The compounds of the above general formula VI
- where in the formula
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group,
- n stands for 1,2,3,4,
- R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p-methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group, with the proviso that the R4 protective group must be selectively removable from R2, and
- x represents 0 or 2.
4 more elements
The compound of the general formula VII
- where in the formula
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group,
- n stands for 1,2,3,4,
- R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p-methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group, with the proviso that the R4 protective group must be selectively removable from R2, and
- x represents 0 or 2.
4 more elements
The compounds of the general formula VIII
- where in the formula
- R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-group, with the proviso that the R1 protective group must be selectively removable from R2 and R4,
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group,
- n stands for 1,2,3,4,
- R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p-methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group, with the proviso that the R4 protective group must be selectively removable from R2, and
- x represents 0 or 2.
5 more elements
The compounds of the general formula IX
- where in the formula
- R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-group, with the proviso that the R1 protective group must be selectively removable from R2 and R4,
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group,
- n stands for 1,2,3,4 and x represents 0 or 2.
3 more elements
The compounds of the general formula X
- where in the formula
- R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-group, with the proviso that the R1 protective group must be selectively removable from R2 and R4,
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group,
- n stands for 1,2,3,4 and x represents 0 or 2.
3 more elements
The compounds of the general formula XI
- where in the formula
- R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-group, with the proviso that the R1 protective group must be selectively removable from R2 and R4,
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group,
- n stands for 1,2,3,4,
- R3 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group,
- and x represents 0 or 2.
5 more elements
The compounds of the general formula XII
- where in the formula
- R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-group, with the proviso that the R′ protective group must be selectively removable from R2 and R4,
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group,
- n stands for 1,2,3,4,
- R3 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group, and x represents 0 or 2.
4 more elements
The compounds of the general formula XIII
- where in the formula
- R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-group, with the proviso that the R1 protective group must be selectively removable from R2 and R4,
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group,
- n stands for 1,2,3,4 and x represents 0 or 2.
3 more elements
The compounds of the general formula XIV
- where in the formula
- R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-group, with the proviso that the R1 protective group must be selectively removable from R2 and R4,
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group,
- n stands for 1,2,3,4 and x represents 0 or 2.
3 more elements
The compounds of the general formula XV
- where in the formula
- R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-group, with the proviso that the R1 protective group must be selectively removable from R2 and R4,
- R2 represents —(CH2)nY, wherein
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group,
- n stands for 1,2,3,4 and x represents 0 or 2.
3 more elements
Sodium salt monohydrate of treprostinil of formula I.
Amorph sodium salt of treprostinil of formula I.
Sodium salt anhydrate of treprostinil of formula I.
Sodium salt polyhydrate of treprostinil of formula I (3-5 mol water content).
Treprostinil intermediates of the general formulae III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV and XV
- where in the formula
- R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-group, with the proviso that the R1 protective group must be selectively removable from R2 and R4,
- R2 represents —(CH2)nY, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, —OR5 or —COOR5 group, wherein
- R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl-group,
- n stands for 1,2,3,4,
- R3 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group,
- R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p-methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group, with the proviso that the R4 protective group must be selectively removable from R2,
- x represents 0 or 2,
- and the dotted line represents single or double bond, with the proviso that in compound of the general formula III Y cannot stay for nitrile or —COOR5, where R5 stays for C1-4 alkyl.
7 more elements
Dependencies are inferred from the claim text.