Convergent synthesis of renin inhibitors and intermediates useful therein

1. A method for the preparation of a compound satisfying formula (1), or a pharmaceutically acceptable salt thereof,

with R 1 being selected from the group consisting of F, Cl, Br, I, C 1-6 halogenalkyl, C 1-6 alkoxy-C 1-6 alkyloxy, and C 1-6 alkoxy-C 1-6 alkyl; R 2 being selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy; R 3 and R 4 each independently being branched C 3-6 alkyl; and R 5 being selected from the group consisting of C 1-12 cycloalkyl, C 1-12 alkyl, C 1-12 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkanoyloxy-C 1-6 alkyl, C 1-12 aminoalkyl, C 1-6 alkylamino-C 1-6 alkyl, C 1-6 dialkylamino-C 1-6 alkyl, C 1-6 alkanoylamino-C 1-6 alkyl, HO—(O)C—C 1-12 alkyl, C 1-6 alkyl-O—(O)C—C 1-6 alkyl, H 2 N—C(O)—C 1-12 alkyl, C 1-6 alkyl-HN—C(O)—C 1-6 alkyl, (C 1-6 alkyl) 2 -N—C(O)—C 1-6 alkyl; saturated, unsaturated, or partially saturated C 1-12 heterocyclyl bonded via a carbon atom, and which heterocyclyl is optionally substituted one or more times by C 1-6 alkyl, trifluoromethyl, nitro, amino, N-mono- or N,N-di-C 1-6 alkylated amino, C 1-6 alkanoyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxycarbonylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyloxy, C 1-12 aryl, N-mono or N,N-di-C 1-6 alkylated carbamoyl, optionally esterified carboxyl, cyano, halogen, halo-C 1-6 alkoxy, halo-C 1-6 alkyl, C 1-12 heteroaryl, saturated, unsaturated or partially saturated C 1-6 heterocyclyl, hydroxyl, nitro; comprising the following steps:

a) reacting a first compound according to formula (2),

wherein R 1 , R 2 , and R 3 have the aforementioned meaning and Re denotes:

a reactive moiety selected from F; Cl; Br; I; M(X) n , wherein X is F, Cl, Br, I, CN, C 1-12 alkyl, or C 1-6 alkoxy, M is a metal, and n is 0, 1, 2, 3, or 4; MM′(X) n (Y) n′ , wherein each of M and M′ is a metal, X and Y are each independently chosen from F, Cl, Br, I, or CN, C 1-12 alkyl, C 1-6 alkoxy, and n, n′ are each independently chosen from the values as described above for n;

or Re is OR 9 , wherein R 9 is a group capable of making OR 9 a leaving group,

with a second nitrogen containing compound satisfying either formula (7)

wherein R 4 , has the meaning given above, R 6 represents H, or optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl, or optionally substituted C 1-12 aryl; R 7 represents H, or is an O-protecting group; or R 6 forms with R 7 an, optionally substituted C 1-12 (hetero)cyclic compound, as such protecting both the acid and alcohol group; Nf is a group comprising a carbon atom directly bonded to a nitrogen atom,

with said compound according to formula (7) being selected from the group of compounds consisting of (7a), (7b), (7c), (7d), (7e), (7f), (7g) and (7h) and Z is a N-protecting group; R 11 is a O-protecting group; R 12 and R 13 are either the same or different fragments, chosen from the group of H, optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl and optionally substituted C 1-12 aryl, or R 12 and R 13 are joined together in a C 1-20 (hetero)cyclic structure; Ra + is a counter-cation; St is a group capable of stabilizing the imine,

or the lactonized form thereof according to formula (8)

with said compound according to formula (8) being selected from the group of compounds consisting of (8a), (8b), (8c), (8d), (8e), (8f), (8g) and (8h) and wherein R 4 , Z, R 11 , Ra + , St, R 12 , and R 13 have the meaning given above,

optionally in the presence of a suitable catalyst and/or an additive and/or a suitable base, also depending on the choice of Nf in the compounds according to formula (7) and/or (8),

which reaction results in the formation of a compound according to formula (9a), or its lactonized form (11a) or a mixture thereof,

or which reaction results in the formation of a compound according to formula (12) or its lactonized form (13) or a mixture thereof,

wherein the R 1 , R 2 , R 3 , R 4 and R 7 groups have the same meaning as described above, and wherein R 8 denotes H, or a group remaining after the reaction of the Nf group as it was present in the compound of formula (7) or (8);

b) depending on the choice of Nf in the compound(s) according to formula (7) or (8), performing one or more reactions to make the moiety attached via the N-atom to the C-5 stereogenic center of the compounds (9a) and/or (11a) inactive for the reaction step c); and

c) further reacting the compound according to formula (9a) and/or (11a), or a mixture thereof, or the compound according to formula (12) or (13), or mixture thereof, with an amine of the general formula H 2 N—R 5 , with R 5 having the meaning given above, under conditions suitable to form an amide bond.

2. A process according to claim 1 comprising the step of purifying the compound according to formula (9a), or (11a) or mixture thereof, or the compound according to formula (12) or (13), or mixture thereof, to obtain a desired diastereomeric purity for the C-5 stereogenic center.

3. A process according claim 1 , comprising the step of reducing the compound according to formula (12) or (13), or mixture thereof, to obtain a compound according to formula (9a), or (11a) or mixture thereof, and subsequently a protection step to make the moiety attached via the N-atom to the C-5 stereogenic center of the compounds (9a) and/or (11a) inactive for the reaction step c).

4. A process according claim 3 , comprising the step of deprotecting the moiety attached via the N-atom to the C-5 stereogenic center of the compounds (9a) and/or (11a), or a reducing step of the nitro moiety, if the reaction step c) is performed with the compound according to formula (12) or (13), or a mixture thereof.

5. A process according to claim 1 , comprising isolating the compound according to formula (1), in such a way that the desired diastereomeric purity in compound of formula (1) is obtained, or by isolating any suitable salt thereof.

6. A method according to claim 1 , wherein the reaction of building block of formula (2) with building block of formula (7) and/or (8), results in the formation of compound satisfying formula (9) or (11) or a mixture thereof,

wherein the R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 groups have the same meaning as described in claim 1 .

7. A method according to claim 1 , wherein R 1 is 3-methoxy-propoxy, R 2 is methoxy, and R 3 and R 4 are 2-propyl.

8. A method according to claim 1 , wherein the reaction of building block of formula (2) with a compound of formula (7) and/or (8), results in the formation of compound satisfying formula (9) and/or (11) or a mixture thereof

wherein the R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 groups have the same meaning as described in claim 1 , and wherein the desired configuration at the C-5 stereogenic center is obtained by dynamic kinetic resolution techniques of the compound satisfying formula (9a) or (11a) or a mixture thereof, or by dynamic kinetic resolution techniques of compound according to formula (12) or its lactonized form (13) or a mixture thereof.

9. A method for the preparation of a compound satisfying formula (1), or a pharmaceutically acceptable salt thereof,

with R 1 is 3-methoxy-propoxy, R 2 is methoxy, and R 3 and R 4 are 2-propyl, and R 5 is selected from the group consisting of C 1-12 cycloalkyl, C 1-12 alkyl, C 1-12 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkanoyloxy-C 1-6 alkyl, C 1-12 -aminoalkyl, C 1-6 alkylamino-C 1-6 alkyl, C 1-6 dialkylamino-C 1-6 alkyl, C 1-6 alkanoylamino-C 1-6 alkyl, HO—(O)C—C 1-12 alkyl, C 1-6 alkyl-O—(O)C—C 1-6 alkyl, H 2 N—C(O)—C 1-12 alkyl, C 1-6 alkyl-HN—C(O)—C 1-6 alkyl, (C 1-6 alkyl) 2 -N—C(O)—C 1-6 alkyl; saturated, unsaturated, or partially saturated C 1-12 heterocyclyl bonded via a carbon atom, and which heterocyclyl is optionally substituted one or more times by C 1-6 alkyl, trifluoromethyl, nitro, amino, N-mono- or N,N-di-C 1-6 alkylated amino, C 1-6 alkanoyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxycarbonylamino, C 0-6 alkylcarbonylamino, C 1-6 alkylcarbonyloxy, C 1-12 aryl, N-mono or N,N-di-C 1-6 alkylated carbamoyl, optionally esterified carboxyl, cyano, halogen, halo-C 1-6 alkoxy, halo-C 1-6 alkyl, C 1-12 heteroaryl, saturated, unsaturated or partially saturated C 1-6 heterocyclyl, hydroxyl, nitro; comprising the following steps:

a) reacting a first compound according to formula (2),

wherein R 1 , R 2 , and R 3 have the aforementioned meaning and Re denotes:

a reactive moiety selected from F; Cl; Br; I; M(X) n , wherein X is F, Cl, Br, I, CN, C 1-12 alkyl, or C 1-6 alkoxy, M is a metal, and n is 0, 1, 2, 3, or 4; MM′(X) n (Y) n′ , wherein each of M and M′ is a metal, X and Y are each independently chosen from F, Cl, Br, I, or CN, C 1-12 alkyl, C 1-6 alkoxy, and n, n′ are each independently chosen from the values as described above for n;

or Re is OR 9 , wherein R 9 is a group capable of making OR 9 a leaving group,

with a second nitrogen containing compound satisfying either formula (7)

wherein R 4 , has the meaning given above, R 6 represents H, or optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl, or optionally substituted C 1-12 aryl; R 7 represents H, or is an O-protecting group; or R 6 forms with R 7 an, optionally substituted C 1-12 (hetero)cyclic compound, as such protecting both the acid and alcohol group; Nf is a group comprising a carbon atom directly bonded to a nitrogen atom,

with said compound according to formula (7) being selected from the group of compounds consisting of (7a), (7b), (7c), (7d), (7e), (7f), (7g) and (7h) and Z is a N-protecting group; R 11 is a O-protecting group; R 12 and R 13 are either the same or different fragments, chosen from the group of H, optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl and optionally substituted C 1-12 aryl, or R 12 and R 13 are joined together in a C 1-20 (hetero)cyclic structure; Ra + is a counter-cation; St is a group capable of stabilizing the imine,

or the lactonized form thereof according to formula (8)

with said compound according to formula (8) being selected from the group of compounds consisting of (8a), (8b), (8c), (8d), (8e), (8f), (8g) and (8h) and wherein R 4 , Z, R 11 , Ra + , St, R 12 , and R 13 have the meaning given above,

optionally in the presence of a suitable catalyst and/or an additive and/or a suitable base, also depending on the choice of Nf in the compounds according to formula (7) and/or (8),

which reaction results in the formation of a compound according to formula (9a), or its lactonized form (11a) or a mixture thereof,

or which reaction results in the formation of a compound according to formula (12) or its lactonized form (13) or a mixture thereof,

wherein the R 1 , R 2 , R 3 , R 4 and R 7 groups have the same meaning as described above, and wherein R 8 denotes H, or a group remaining after the reaction of the Nf group as it was present in the compound of formula (7) or (8);

b) depending on the choice of Nf in the compound(s) according to formula (7) or (8), performing one or more reactions to make the moiety attached via the N-atom to the C-5 stereogenic center of the compounds (9a) and/or (11a) inactive for the reaction step c);

c) further reacting the compound according to formula (9a) and/or (11a), or a mixture thereof, or the compound according to formula (12) or (13), or mixture thereof, with an amine of the general formula H 2 N—R 5 , with R 5 having the meaning given above, under conditions suitable to form an amide bond;

d) purifying the compound according to formula (9a), or (11a) or mixture thereof, or the compound according to formula (12) or (13), or mixture thereof, to obtain a desired diastereomeric purity for the C-5 stereogenic center; and

e) isolating the compound according to formula (1), in such a way that the desired diastereomeric purity in compound of formula (1) is obtained, or by isolating any suitable salt thereof.

10. A method according to claim 1 or 9 , wherein M is selected from the group consisting of Mg, Ce, Li, Ba, Al, B, Cu, Zn, Mn, Ti, Zr, and In.

11. A method according to claim 1 or 9 , wherein each of M and M′ of the formula MM′(X) n (Y) n′ is independently selected from the group consisting of Mg, Ce, Li, Ba, Al, B, Cu, Zn, Mn, Ti, Zr, and In.

12. A method according to claim 1 or 9 , wherein R 9 is acetyl, trifluoroacetyl; CF 3 SO 2 , CH 3 SO 2 , CH 3 C 6 H 4 SO 2 , C(O)OCH 3 , or C(O)OC 4 H 9 .