US2010029942A1PendingUtilityA1
Process for the preparation of benzoimidazol-2-yl pyrimidine derivatives
Est. expiryJun 30, 2028(~2 yrs left)· nominal 20-yr term from priority
Inventors:Sergio Cesco-CancianJeffrey S. GrimmNeelakandha S. ManiChristopher M. MapesDavid C. PalmerDaniel J. PippelTong XiaoDiego BrogginiSusanne Lochner
A61P 37/06A61P 9/10A61P 37/00A61P 7/06A61P 37/08A61P 27/02A61P 29/00A61P 25/00A61P 1/16A61P 11/02A61P 17/06A61P 1/04A61P 11/06A61P 11/00A61P 15/00A61P 19/02A61P 19/08A61P 17/04A61P 17/00A61P 21/04C07D 403/04A61K 31/506C07D 401/12C07D 401/14
61
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention is directed to benzoimidazol-2-yl pyrimidine derivatives useful as histamine H 4 receptor modulators and processes for the preparation of such compounds.
Claims
exact text as granted — not AI-modified1 . A process for the preparation of a compound of formula (I)
wherein
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, —CF 3 , —OCF 3 , —CN, halo, —NO 2 , —OC 1-4 alkyl, —SC 1-4 alkyl, —S(O)C 1-4 alkyl, —SO 2 C 1-4 alkyl, —C(O)C 1-4 alkyl, —C(O)phenyl, —C(O)NR a R b , —CO 2 C 1-4 alkyl, —CO 2 H, —C(O)NR a R b , and —NR a R b ; wherein R a and R b are each independently selected from the group consisting of H, C 1-4 alkyl, and C 3-7 cycloalkyl;
X 1 is C—R c ; wherein R c is selected from the group consisting of H, methyl, hydroxymethyl, dimethylaminomethyl, ethyl, propyl, isopropyl, —CF 3 , cyclopropyl, and cyclobutyl;
X 2 is N;
n is 1 or 2;
Z is selected from the group consisting of N, CH, and C(C 1-4 alkyl);
R 6 is selected from the group consisting of H, C 1-6 alkyl, and a monocyclic cycloalkyl;
R 8 is selected from the group consisting of H and C 1-4 alkyl;
R 9 , R 10 and R 11 are each independently selected from the group consisting of H and C 1-4 alkyl;
or pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; comprising
reacting a compound of formula (V) with a reducing agent system; in a solvent; at a temperature in the range of from about 0° C. to about 25° C., to yield compound of formula (VI); and
reacting compound of formula (VI) with a compound of formula (VII) in the presence of an oxidizing agent system, in a solvent, at a temperature in the range of from about 25° C. to about 100° C.
2 . A process for the preparation of a compound of formula (I-A)
or pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; comprising
reacting a compound of formula (V-S) with a reducing agent system; in a solvent; at a temperature in the range of from about 0° C. to about 25° C., to yield compound of formula (VI-S);
reacting compound of formula (VI-S) with a compound of formula (VII-A) in the presence of an oxidizing agent system, in a solvent, at a temperature in the range of from about 25° C. to about 100° C., to yield compound of formula (I-A).
3 . A process as in claim 2 wherein the reducing agent system is selected from the group consisting of Diabl-H, and RANEY® nickel and a source of hydrogen.
4 . A process as in claim 2 , wherein the reducing agent system is DIBAL-H; wherein the DIBAL-His present in an amount in the range of from about 1.0 to about 5.0 molar equivalents; and wherein the solvent in said reacting a compound of formula (V-S) is selected from the group consisting of anhydrous toluene and anhydrous THF.
5 . A process as in claim 4 , wherein DIBAL-His present in an amount of about 2.5 molar equivalents.
6 . A process as in claim 2 , wherein the reducing agent system is RANEY® nickel and a source of hydrogen; wherein the source of hydrogen is formic acid; and wherein the solvent in said reacting a compound of formula (V-S) is water.
7 . A process as in claim 6 , wherein the RANEY® nickel is present in an amount in of about 200% by weight and wherein the formic acid is present in an excess amount.
8 . A process as in claim 2 , wherein compound of formula (V-S) is reacted with the reducing agent system at a temperature of about 5 to about 25° C.
9 . A process as in claim 2 , wherein compound of formula (VII-A) is present as its corresponding free base.
10 . A process as in claim 2 , wherein the compound of formula (VII-A) is present in an amount in the range of from about 1.0 to about 1.25 molar equivalents.
11 . A process as in claim 10 , wherein the compound of formula (VII-A) is present in an amount in the range of from about 1.0 to about 1.1 molar equivalents.
12 . A process as in claim 2 , wherein the oxidizing agent system is selected from the group consisting of Na 2 S 2 O 5 /air and Na 2 SO 3 /air.
13 . A process as in claim 2 , wherein the oxidizing agent or oxidizing agent system is present in an amount in the range of from about 0.90 to about 1.5 molar equivalents.
14 . A process as in claim 13 , wherein the oxidizing agent system is present in an amount of about 1.0 molar equivalents.
15 . A process as in claim 2 , wherein the compound of formula (VI-S) is reacted with compound of formula (VII-A) in water.
16 . A process as in claim 2 , wherein the compound of formula (VI-S) is reacted with compound of formula (VII-A) at a temperature in the range of from about 55° C. to about 65° C.
17 . A process for the preparation of a compound of formula (I-B)
or pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; comprising
reacting a compound of formula (V-S) with a reducing agent system; in a solvent; at a temperature in the range of from about 0° C. to about 25° C.; to yield compound of formula (VI-S); and
reacting the compound of formula (VI-S) with a compound of formula (VII-B) in the presence of an oxidizing agent system, in a solvent at a temperature in the range of from about 25° C. to about 100° C., to yield compound of formula (I-B).
18 . A process as in claim 17 , wherein the reducing agent system is selected from the group consisting of DIBAL-H, and RANEY® nickel and a source of hydrogen.
19 . A process as in claim 17 , wherein the reducing agent system is DIBAL-H; wherein the DIBAL-His present in an amount in the range of from about 1.0 to about 5.0 molar equivalents; and wherein the solvent in said reacting a compound of formula (V-S) is selected from the group consisting of anhydrous THF and anhydrous toluene.
20 . A process as in claim 19 , wherein the DIBAL-His present in an amount of about 2.5 molar equivalents.
21 . A process as in claim 17 , wherein the reducing agent system is RANEY® nickel and a source of hydrogen; wherein the source of hydrogen is formic acid; and wherein the solvent in said reacting a compound of formula (V-S) is water.
22 . A process as in claim 21 , wherein the RANEY® nickel is present in an amount of about 20% by weight and wherein the formic acid is present in an excess amount.
23 . A process as in claim 17 , wherein the compound of formula (V-S) is reacted with the reducing agent system at a temperature of from about 5° C. to about 25° C.
24 . A process as in claim 17 , wherein the compound of formula (VII-B) is present as its corresponding free base.
25 . A process as in claim 17 , wherein the compound of formula (VII-B) is present in an amount in the range of from about 1.0 to about 1.25 molar equivalents.
26 . A process as in claim 25 , wherein the compound of formula (VII-B) is present in an amount in the range of from about 1.0 to about 1.1 molar equivalents.
27 . A process as in claim 17 , wherein the oxidizing agent system is selected from the group consisting of Na 2 S 2 O 5 /air and Na 2 SO 3 /air.
28 . A process as in claim 17 , wherein the oxidizing agent system is present in an amount in the range of from about 0.90 to about 1.5 molar equivalents.
29 . A process as in claim 28 , wherein the oxidizing agent system is present in an amount of about 1.0 molar equivalents.
30 . A process as in claim 17 , wherein the compound of formula (VI-S) is reacted with the compound of formula (VII-B) in water.
31 . A process as in claim 17 , wherein the compound of formula (VI-S) is reacted with the compound of formula (VII-B) at a temperature in the range of from about 55° C. to about 65° C.
32 . A crystalline hemi-tartrate of compound of formula (I-A)
33 . A crystalline hemi-tartrate of compound of formula (I-A)
whose powder X-ray diffraction spectrum comprises the following powder X-ray diffraction peaks:
Pos. [°2θ]
d-spacing [Å]
6.49
13.62
8.58
10.30
9.17
9.64
10.35
8.55
10.75
8.23
16.72
5.30
17.46
5.08
18.89
4.70
23.60
3.77
34 . A process for the preparation of a hemi-tartrate of compound of formula (I-A)
comprising:
dissolving the compound of formula (I-A) in an organic solvent forming a solution;
heating said solution to a first temperature in the range of from about 35° C. to about reflux;
adding L-tartaric acid to form a tartrate solution; and
heating said tartrate solution to a second temperature in the range of from about 50° C. to about reflux to form a heated mixture.
35 . A process as in claim 34 , wherein said heating said first temperature is about 50° C.
36 . A process as in claim 34 , wherein the L-tartaric acid is added in an amount of about 0.5 molar equivalents.
37 . A process as in claim 34 , wherein said second temperature is a temperature of about 70° C. to about 75° C.
38 . A process as in claim 34 , further comprising cooling said heated mixture to a temperature in the range of from about 0° C. to about −5° C.
39 . A process for the recrystallization of a hemi-tartrate of compound of formula (I-A)
comprising:
dissolving the hemi-tartrate of compound of formula (I-A) in a mixture of water and an organic solvent, or in a mixture of organic solvents; and
removing a sufficient amount of water to yield a mixture with boiling point of between about 78° C. and about 80° C.
40 . A process as in claim 39 , wherein the hemi-tartrate of compound of formula (I-A) is dissolved in one of the following mixtures: a mixture of water and denatured ethanol, and a mixture of methanol and denatured ethanol.
41 . A process as in claim 40 , wherein the hemi-tartrate of compound of formula (I-A) is dissolved in a mixture of water and denatured ethanol; and wherein the water in the mixture is present in an amount of from about 1% to about 1.5% by weight.
42 . A process as in claim 41 , wherein said water is present in an amount of about 1.4% by weight.
43 . A process as in claim 39 , wherein said dissolving is made in a mixture of water and an organic solvent, and further comprising heating said hemi-tartrate of the compound of formula (I-A) in said mixture of water and an organic solvent to azeotropically remove the water.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.