Exo- and diastereo-selective syntheses of himbacine analogs
View Patent ↗This application discloses a novel process for the preparation of himbacine analogs useful as thrombin receptor antagonists. The process is based in part on the use of a base-promoted dynamic epimerization of a chiral nitro center. The chemistry taught herein can be exemplified by the following:
1. A process for preparing Compound 2:
wherein R 5 and R 6 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, heterocyclic and heteroaryl groups, or R 5 and R 6 , together with the nitrogen to which they are attached, form a 3- to 6-membered heterocyclic compound containing 1-4 heteroatoms, said process comprising:
(a) amidating (R)-butynol to form Compound 3:
(b) reducing Compound 3 to yield Compound 4:
(c) reacting Compound 4 with Compound 6:
to produce Compound 2;
wherein:
said heterocyclic group is a monocyclic ring containing three to eight ring atoms or a polycyclic ring system consisting of 2 rings containing six to sixteen atoms, where each heterocyclic ring contains carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen; and
said heteroaryl group is a monocyclic or multicyclic aromatic ring system containing 4 to 14 ring atoms, wherein the atoms in the ring system are carbon and at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen.
2. The process of claim 1 , wherein Compound 3 is prepared by a process selected from the group consisting of:
and,
wherein:
P is a protecting group;
X is a leaving group selected from the group consisting of Cl, Br, I, and heterocyclic rings;
L is selected from the group consisting of PR′ 3 and NR″,
wherein R′ is selected from the group consisting of alkyl, aryl, alkylaryl, and R″ is selected from the group consisting of alkyl, aryl, and alkylaryl;
Y is selected from the group consisting of Cl, Br, I, and R′″COO, wherein R′″ is selected from the group consisting of alkyl, aryl, alkylaryl, and arylalkyl; and
n is between 0 and 4.
3. The process of claim 1 , wherein Compound 6 is prepared by a process comprising:
(a) reacting acrolein with CH 3 NO 2 in the presence of an inorganic base in a C 1 -C 8 alcohol to produce crude Compound 8:
(b) reacting crude Compound 8 with a metal bisulfite to produce Compound 9:
(c) treating Compound 9 with a lower alkyl carbonyl compound and a carbonate base in a biphasic solvent system to produce purified Compound 8;
(d) reacting said purified Compound 8 with a secondary amine and a carboxylic acid in a first solvent to produce Compound 10:
(e) converting Compound 10 to Compound 6.
4. The process of claim 3 , wherein said inorganic base is selected from the group consisting of LiOH, KOH, NaOH, Ca(OH) 2 , Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 .
5. The process of claim 3 , wherein said alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol, pentanol, octanol, and mixtures of 2 or more thereof.
6. The process of claim 3 , wherein said lower alkyl carbonyl compound is selected from the group consisting of acetaldehyde, acetone, glyoxylic acid, and gyloxylate.
7. The process of claim 3 , wherein said metal bisulfite is selected from the group consisting of NaHSO 3 , KHSO 3 , Na 2 S 2 O 5 , and K 2 S 2 O 5 .
8. The process of claim 3 , wherein said carbonate base is selected from the group consisting of LiHCO 3 , NaHCO 3 , KHCO 3 , Li 2 CO 3 , Na 2 CO 3 , and K 2 CO 3 .
9. The process of claim 3 , wherein said biphasic solvent system comprises water and a water-immiscible solvent.
10. The process of claim 3 , wherein said secondary amine is selected from the group consisting of piperidine, pyrrolidine, piperazine, dialkylamines, and diarylalkylamines.
11. The process of claim 3 , wherein said secondary amine is pyrrolidine.
12. The process of claim 3 , wherein said carboxylic acid is selected from the group consisting of aliphatic and aromatic carboxylic acids.
13. The process of claim 3 , wherein said carboxylic acid is benzoic acid.
14. The process of claim 3 , wherein said first solvent is selected from the group consisting of CH 2 Cl 2 , chlorobenzene, t-butylmethylether, and toluene.
15. The process of claim 3 , wherein said step of converting Compound 10 to Compound 6 comprises the steps of:
reacting Compound 10 with Ph 3 P=CHCOOR 8 to produce Compound 6A:
hydrolyzing Compound 6A to Compound 6 by treating Compound 6A with a base catalyst or an acid catalyst:
wherein R 8 is C 1 to C 10 alkyl or arylalkyl.
16. The process of claim 15 , wherein said base catalyst is selected from the group consisting of alkaline hydroxide, carbonate, and phosphate bases.
17. The process of claim 15 , wherein said acid catalyst is selected from the group consisting of mineral and organic acids.
18. The process of claim 3 , wherein said step of converting Compound 10 to Compound 6 comprises reacting Compound 10 with malonic acid in a second solvent.
19. The process of claim 18 , wherein said second solvent is selected the group consisting of halogenated solvents, aromatic solvents and nitrogen-containing solvents.
20. The process of claim 18 , wherein said second solvent is selected from the group consisting of pyridine and toluene.)
21. The process of claim 18 , further comprising the use of a nitrogen-based catalyst to accelerate the reaction, wherein said nitrogen-based catalyst is selected from the group consisting of piperidine, pyrrolidine, piperazine, pyridine, and triethylamine.