U.S. patent application number 09/795027 was filed with the patent office on 2002-02-07 for process for making 2, 5-substituted pyridine.
Invention is credited to O'Shea, Paul, Tillyer, Richard, Wang, Xin.
Application Number | 20020016470 09/795027 |
Document ID | / |
Family ID | 26881313 |
Filed Date | 2002-02-07 |
United States Patent
Application |
20020016470 |
Kind Code |
A1 |
O'Shea, Paul ; et
al. |
February 7, 2002 |
Process for making 2, 5-Substituted pyridine
Abstract
2-lithio-5-halopyridine is formed as a predominant component of
a reaction mixture by reacting BuLi with 2,5-dihalopyridine in a
non-coordinating solvent.
Inventors: |
O'Shea, Paul; (Kirkland,
CA) ; Wang, Xin; (Kirkland, CA) ; Tillyer,
Richard; (Cranford, NJ) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Family ID: |
26881313 |
Appl. No.: |
09/795027 |
Filed: |
February 27, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60185630 |
Feb 29, 2000 |
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Current U.S.
Class: |
546/345 |
Current CPC
Class: |
C07D 213/61
20130101 |
Class at
Publication: |
546/345 |
International
Class: |
C07D 213/08 |
Claims
What is claimed is:
1. A method of forming a reaction product mixture predominantly
containing 2-lithio-5-halopyridine, said method comprising the step
of: reacting a compound represented by (I) 6wherein X is
independently bromine or iodine, with an effective amount of BuLi
in an effective amount of a non-coordinating solvent at a
temperature from about -50.degree. C. to about -78.degree. C. to
form a compound represented by (II) 7
2. The method according to claim 1, wherein said compound
represented by (I) is 2,5-dibromopyridine.
3. The method according to claim 1, wherein said non-coordinating
solvent is CH.sub.2Cl.sub.2 or toluene.
4. A method of forming 2-electrophile-5-halopyridine, said method
comprising the steps of A) reacting a compound represented by (I)
8wherein X is independently bromine or iodine, with an effective
amount of BuLi in an effective amount of a non-coordinating solvent
at a temperature from about -50.degree. C. to about -78.degree. C.
to form a reaction product mixture predominantly containing a
compound represented by (II) 9and B) reacting (II) with an
effective amount of an electrophilic reactant represented by E+
effective to replace the Li with an electrophile represented by E
effective to form a compound represented by (III) 10
5. The method according to claim 4, wherein said compound
represented by (I) is 2,5-dibromopyridine.
6. The method according to claim 4, wherein said non-coordinating
solvent is CH.sub.2Cl.sub.2 or toluene.
7. The method according to claim 4, wherein said electrophilic
reactant is DMF, TMSCl, MeSSMe, PhCOMe, Me.sub.2CO, PhCHO,
DMF/NaBH.sub.4, or MeSSMe/Oxone.
8. The method according to claim 4, wherein said electrophile is
CHO, CH.sub.2OH, TMS, SMe, SO.sub.2Me, C(OH)MePh, C(OH)Me.sub.2, or
CH(OH)Ph.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is directed to a process for making
2,5-substituted pyridine compounds. In particular, this invention
is directed to a process for making 2,5-substituted pyridine
compounds utilizing butyllithium in order to produce a
2-electrophile 5-halo substituted pyridine.
[0003] 2. Related Background
[0004] Hormones are compounds that variously affect cellular
activity. In many respects, hormones act as messengers to trigger
specific cellular responses and activities. Many effects produced
by hormones, however, are not caused by the singular effect of just
the hormone. Instead, the hormone first binds to a receptor,
thereby triggering the release of a second compound that goes on to
affect the cellular activity. In this scenario, the hormone is
known as the first messenger while the second compound is called
the second messenger. Cyclic adenosine monophosphate (adenosine 3',
5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as a
second messenger for hormones including epinephrine, glucagon,
calcitonin, corticotrophin, lipotropin, luteinizing hormone,
norepinephrine, parathyroid hormone, thyroid-stimulating hormone,
and vasopressin. Thus, cAMP mediates cellular responses to
hormones. Cyclic AMP also mediates cellular responses to various
neurotransmitters.
[0005] Phosphodiesterases ("PDE") are a family of enzymes that
metabolize 3', 5' cyclic nucleotides to 5' nucleoside
monophosphates, thereby terminating cAMP second messenger activity.
A particular phosphodiesterase, phosphodiesterase-4 ("PDE4", also
known as "PDE-IV"), which is a high affinity, cAMP specific, type
IV PDE, has generated interest as potential targets for the
development of novel anti-asthmatic and anti-inflammatory
compounds. PDE4 is known to exist as at lease four isoenzymes, each
of which is encoded by a distinct gene. Each of the four known PDE4
gene products is believed to play varying roles in allergic and/or
inflammatory responses. Thus, it is believed that inhibition of
PDE4, particularly the specific PDE4 isoforms that produce
detrimental responses, can beneficially affect allergy and
inflammation symptoms.
[0006] Inhibition of PDE4 activity is believed effective for the
treatment of osteoporosis by reducing bone loss. For example,
Ken-ici Miyamoto et al., Biochem. Pharmacology, 54:613-617(1997)
describes the effect of a PDE4 on bone loss. Therefore, it would be
desirable to provide novel compounds and compositions that inhibit
PDE4 activity.
[0007] Novel compounds and compositions that inhibit PDE4 activity
remain desirable. Further, more efficient methods to produce known
PDE4 inhibiting compounds are a continuing need.
[0008] U.S. Pat. Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144,
5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034,
5,866,593, 5,891,896, and International Patent Publication WO
95/35283 describe PDE4 inhibitors that are tri-substituted aryl or
heteroaryl phenyl derivatives. U.S. Pat. No. 5,580,888 describes
PDE4 inhibitors that are styryl derivatives. U.S. Pat. No.
5,550,137 describes PDE4 inhibitors that are phenylaminocarbonyl
derivatives. U.S. Pat. No. 5,340,827 describes PDE4 inhibitors that
are phenylcarboxamide compounds. U.S. Pat. No. 5,780,478 describes
PDE4 inhibitors that are tetra-substituted phenyl derivatives.
International Patent Publication WO 96/00215 describes substituted
oxime derivatives useful as PDE4 inhibitors. U.S. Pat. No.
5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and
alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
[0009] In many of the processes to produce the compounds described
in the above patents and publications, various intermediate
compounds are utilized. In particular,
2-electrophile-5-halopyridine intermediate compounds derived from a
2-lithio -5-halopyridine have utility and novel processes to
produce such intermediate compounds are desirable.
[0010] C. Bolm, et al., Chem. Ber. 125:1169(1992); F. C.
Alderweireldt, et al., Nucleosides Nucleotides, 8:891(1989); J.
Wicha and M. Masnyl, Heterocycles, 16:521(1981); and F. J.
Romero-Salguero and J. M. Lehn, Tetrahedron Lett., 37:2357(1996),
describe reactions utilizing coordinating solvents such as ether,
MTBE, and THF to cause lithiation at the 5-position, or mixed
monolithiation at the 5- and 2-positions, with predominantly
lithiation at the 5-lithiated position. M. A. Peterson and J.
Mitchell, J.Org.Chem.,62:8237(1997) describes how solvents can
influence the formation, structure, and properties of
organolithiums. Nevertheless, 2-electrophile -5-halopyridine
intermediate compounds derived from a 2-lithio-5-halopyridine are
particularly desirable and novel processes to produce such
intermediate compounds efficiently are desirable.
SUMMARY OF THE INVENTION
[0011] The present invention is directed to a novel method to
produce a 2-electrophile -5-halopyridine compound which includes
the steps of i) selective monolithiation at the 2 position of
2,5-dihalopyridine with butyllithium to form a 2-lithio
-5-halopyridine and ii) replacing the lithio group with an
electrophilic group to form the 2-electrophile-5-halopyridine
compound.
DETAILED DESCRIPTION OF THE INVENTION
[0012] A method of this invention comprises the steps of
[0013] A) reacting a compound represented by (I) 1
[0014] wherein X is independently bromine or iodine, with an
effective amount of BuLi in an effective amount of a
non-coordinating solvent at a temperature from about -50.degree. C.
to about -78.degree. C. to form a compound represented by (II)
2
[0015] and
[0016] B) reacting (II) with an effective amount of an
electrophilic reactant represented by E+ effective to replace the
Li with an electrophile represented by E effective to form a
compound represented by (III) 3
[0017] The halogen, X, is independently iodine or bromine. It is
preferred that the halogen is bromine. It is preferred that the
compound (I) is 2,5-dibromopyridine.
[0018] As used herein, "coordinating solvents" are solvents with
oxygen or nitrogen atoms in the solvent molecule. Such solvents are
available for coordinating with BuLi or pyridinyl lithium. As used
herein, "non-coordinating solvents" are solvents that do not have
oxygen or nitrogen atoms for coordination with BuLi or pyridinyl
lithium.
[0019] As reported in C. Bolm, et al., Chem. Ber. 125:1169(1992);
F. C. Alderweireldt, et al., Nucleosides Nucleotides, 8:891(1989);
J. Wicha and M. Masnyl, Heterocycles, 16:521(1981); and F. J.
Romero-Salguero and J. M. Lehn, Tetrahedron Lett., 37:2357(1996),
coordinating solvents such as, for example, ether, MTBE, and THF
caused lithiation at the 5-position or a mixture of monolithiation
at the 5- and 2-positions with predominantly lithiation at the
5-lithiated position.
[0020] However, the method of this invention surprisingly found
that the use of noncoordinating solvents such as, for example,
toluene or methylene chloride produced monolithiation predominantly
at the 2-position. Accordingly, this invention forms a reaction
product mixture that contains predominantly
2-lithio-5-halopyridine. By predominantly, it is meant that the
2-lithio-5-halopyridine is the largest percent component by weight.
Unless specifically stated otherwise, the percentages stated herein
are by weight.
EXAMPLES
Comparative Example 1
[0021] In Comparative Example 1, following the procedures described
in Bolm and the other references above, BuLi (2.5 M in hexanes, 1.2
eq.) was added to 0.085 M 2,5-dibromopyridine in THF at -78.degree.
C. After 40 minutes, the reaction was quenched with 10 mL MeOH and
the products were quantified by HPLC. (Zorbax.RTM. SB C18, 5 .mu.M,
250.times.4.6, 0.1% H.sub.3PO.sub.4/CAN 5-96% 12 min hold, 5 min.,
2 mL/min., 35.degree. C., 235 nM) The product distribution was
found to be 12.3/11.5/66.5/9.8 by weight of
2,5-dilithiopyridine/2-lithio,5-bromopyridine/2-bromo,5-lithiop-
yridine/2,5-dibromopyridine.
[0022] Repeating but quenching after 2 hr, produced a product
distribution of 12.3/12.0/65.6/10.1.
[0023] Thus, the product was predominantly the 5-lithiated
compound.
Comparative Example 2
[0024] Comparative Example 2 followed the procedure set forth in
Comparative Example 1, except ether was utilized as the solvent.
The product distribution, quenching at 40 min., was
4.8/6.9/84.9/3.4. The product distribution, quenching at 2 hr., was
4.3/10.6/81.7/3.4. Finally, the product distribution, quenching
after 18 hr., was 8.6/11.3/78.0/2.2.
[0025] Thus, the product was predominantly the 5-lithiated
compound.
Comparative Example 3
[0026] Comparative Example 3 followed the procedure set forth in
Comparative Example 2 except that the concentration of the
2,5-dibromopyridine was 0.017 M. The product distribution,
quenching at 20 min., was 0.3/10.7/44.8/44.4. The product
distribution, quenching at 2 hr., was 2.7/27.2/65.7/4.4.
[0027] Thus, the product was predominantly the 5-lithiated
compound.
Comparative Example 4
[0028] Comparative Example 4 followed the procedure set forth in
Comparative Example 2 except that the concentration of the
2,5-dibromopyridine was 0.28 M. Although the 2,5-dibromopyridine
and its lithiated pyridines were not completely soluble at this
concentration, the product distribution, quenching at 40 min., was
9.6/6.7/81.6/2.1. The product distribution, quenching at 160 min.,
was 10.2/11.2/72.4/6.2. The product distribution, quenching at 4
hr., was 6.5/22.2/59.8/11.5.
[0029] Thus, the product was predominantly the 5-lithiated
compound.
Comparative Example 5
[0030] Comparative Example 5 followed the procedure set forth in
Comparative Example 1 except that the solvent used was MTBE (at
0.085 M). The product distribution, quenching at 40 min., was
9.6/6.7/81.6/2.1. The product distribution, quenching at 160 min.,
was 10.2/11.2/72.4/6.2. The product distribution, quenching at 4
hr., was 6.5/22.2/59.8/11.5.
[0031] Thus, the product was predominantly the 5-lithiated
compound.
Comparative Example 6
[0032] Comparative Example 6 followed the procedure set forth in
Comparative Example 2 except that the temperature was -50.degree.
C. The product distribution, quenching at 40 min., was
15.1/9.1/74.8/1.0. The product distribution, quenching at 2 hr.,
was 12.8/16.6/69.0/1.6. The product distribution, quenching at 22
hr., was 8.0/40.7/50.2/1.1.
[0033] Thus, the product was predominantly the 5-lithiated
compound.
Example 1
[0034] Example 1 followed the procedure set forth in Comparative
Example 1 except that CH.sub.2Cl.sub.2 at 0.085 M was used at
-78.degree. C. The product distribution, quenching at 40 min., was
0.4/83.1/7.9/8.6 while the product distribution, quenching at 2
hr., was 0.7/90.3/8.5/0.6.
[0035] Thus, the product was predominantly the 2-lithiated
compound.
Example 2
[0036] Example 2 followed the procedure set forth in Example 1
except that Toluene at 0.085 M was used at -78.degree. C. The
product distribution, quenching at 30 min., was 5.2/72.8/4.4/17.7.
The product distribution, quenching at 2 hr., was 5.5/83.5/4.2/6.3,
while the product distribution, quenching at 3 hr., was
5.0/86.8/4.2/4.0.
[0037] Thus, the product was predominantly the 2-lithiated
compound.
Example 3
[0038] Example 3 followed the procedure set forth in Example 2
except that Toluene at 0.017 M was used at -78.degree. C. The
product distribution, quenching at 1 hr., was 0.5/67.6/3.0/29.0
while the product distribution, quenching at 7 hr., was
0.6/94.2/2.7/2.5.
[0039] Thus, the product was predominantly the 2-lithiated
compound.
Example 4
[0040] Example 4 followed the procedure set forth in Example 2
except that Toluene at 0.28 M was used at -78.degree. C. The
product distribution, quenching at 50 min., was
6.7/71.8/11.7/9.8.
[0041] Thus, the product was predominantly the 2-lithiated
compound.
Example 5
[0042] Example 5 followed the procedure set forth in Example 2
except that Toluene at 0.085 M was used at -50.degree. C. The
product distribution, quenching at 40 min., was 1.5/90.4/7.5/0.5
while the product distribution, quenching at 2 hr., was
1.9/90.2/7.0/0.9.
[0043] Thus, the product was predominantly the 2-lithiated
compound.
[0044] In all cases, 1.2 eq. BuLi were necessary because lithiation
using less than 1.2eq. produced substantial amounts of
2,5-dibromopyridine remaining. The above results from the
Comparative Examples 1-6 show that the 2-bromo-5-lithiopyridine is
the dominant product for the known processes. The selectivity of
the reactions in ether, MTBE, and THF were approximately 12:1,
6.3:1 and 5.8:1 respectively for the 2-bromo-5-lithiopyridine over
the 2-lithio-5-bromopyridine. At lower concentration, the
selectivity for the 2-bromo-5-lithiopyridine decreased from 12:1 to
4:1. Nevertheless, the reactions would be very inefficient for the
production of a substitution by an electrophile at the 2-position
of a pyridine analogue.
[0045] In comparison, the Examples 1-5, show that the process of
this invention produces 2-lithio-5-bromopyridine as the predominant
product. For example, after 2 hours reaction time at -78.degree.
C., the selectivity of monolithiation in CH.sub.2Cl.sub.2 (0.085 M)
was 11:1 in favor of the 2-position, while in toluene (0.085 M) the
ratio was 20:1. Dilution also favored the 2-position. For, example,
the selectivity for 2-lithio-5-bromopyridine over
2-bromo-5-lithiopyridine reached equilibrium at 34:1 after 7 hours.
Furthermore, at this low concentration, only small amounts of
2,5-dilithiopyridine and 2,5-dibromopyridine were detected. Thus,
the reactions of this invention were more efficient for the
production of a substitution by an electrophile at the 2-position
of a pyridine analogue.
Examples 6-13
[0046] Following the procedure of Example 2, without quenching,
various electrophilic reactants were added to the reaction mixture
according to the following schematic formula:
1 4 The results are shown in the following table: % m.p. E+ E Yield
(.degree. C.) Lit. m.p. Example 6 DMF CHO 49 96.4-97.3 78-80
Example 7 DMF/NaBH.sub.4 CH.sub.2OH 78 60.1-60.7 52-54 Example 8
TMSCI TMS 51 Oil New Cmpd Example 9 MeSSMe SMe 80 39.0-39.6 38-39
Example MeSSMe/ SO.sub.2Me 77 94.7-96.6 95-96 10 Oxone Example
PhCOMe C(OH)MePh 81 69.3-70.8 New Cmpd 11 Example Me.sub.2CO
C(OH)Me.sub.2 79 Oil New Cmpd 12 Example PhCHO CH(OH)Ph 82 Oil n/a
13
[0047] The 2-lithio-5-bromopyridine was determined by NMR
(toluene-d8, -78.degree. C.): .delta.6.1-6.2 (m, 2H), 7.8 (s, 1H).
In Example 7, in situ treatment of NaBH.sub.4 (2eq.) gave the
alcohol directly. In Example 10, in situ treatment of
H.sub.2O/MeOH/Oxone (3eq.) gave the sulfone directly. The yields
were determined as isolated yields after flash column
chromatography. The reference for Examples 6 and 7 was G. Jones, et
al., Tetrahedron, 53:8257(1997). The reference for Examples 9 and
10 was L. Testaferri, et al., Tetrahedron, 41:1373(1996). The
reference for Example 13 was Y. Kondo, et al., J. Chem. Soc.
Perkins Trans., 1:1781(1996).
[0048] A typical procedure is as follows. To a solution of
2,5-dibromopyridine (1.0 g, 4.2 mmol) in toluene (50 mL) at
-78.degree. C. was slowly added BuLi (2.5 M in hexanes, 2.0 mL, 5.0
mmol). The reaction mixture was allowed to stand for 2 hr. The
electrophilic reactant was then added. The solution was stirred for
1 hr at -78.degree. C. and then warmed to -10.degree. C. NH.sub.4Cl
saturated aqueous solution (10 mL) was added and the mixture was
warmed to rt. Separation of the two phases gave the toluene
solution which was concentrated to dryness. Purification by flash
chromatography yielded the desired product.
[0049] The results show that the method of this invention can
easily and efficiently provide substitution by an electrophile at
the 2-position of pyridine while maintaining an accessible halogen
substituent at the 5-position of pyridine. Such 2-electrophile
-5-halopyridine are useful as intermediate compounds to form PDE4
inhibiting compounds such as 5
[0050] for example.
* * * * *