Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-20
2001-10-02
Oswecki, Jane C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06297382
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to producing a process for making (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenylacetic acid.
BACKGROUND OF THE INVENTION
(4-(2-(2-(6-arinopyddin3-yl)-2(R)-ydroxyethylarino)ethoxy)phenylacebc acid (herein also referred to as “Compound I”) has the following structure:
A specific synthesis for compound I is disclosed in Example 1 of International Patent Application PCT/IB95/0344, published internationally as WO 96/356713 which designated, inter alia, the United States, which was filed in the U.S. as copending application Ser. No. 08/1945,551 on Nov. 4, 1997 and which is herein incorporated by reference.
The compound is a selective &bgr;-adrenergic receptor agonist which has utility for, inter alia, the treatment of hyperglycemia, obesity, intestinal motility disorders, depression, prostate disease, dyslipidemia, and airway inflammatory disorders such as asthma and obstructive lung disease. The compound is also useful for increasing lean meat deposition and/or improving the lean meat to fat ratio in edible animals such as ungulate animals and poultry. The majority of agonist activity resides in the R-enantiomer.
SUMMARY OF THE INVENTION
This invention provides a process for preparing a compound of the formula:
comprising deprotecting a compound of the formula
wherein R
2
and R
3
are independently C
1
-C
3
alkyl or phenyl. Deprotecting in this instance thus means converting the pynolidino group to free amino. As indicated, R
2
and R
3
can be different. It is preferred that R
2
and R
3
are the same.
The invention further provides a process for preparing a compound of formula III:
wherein R
1
is C
1
-C
8
alkyl, comprising converting the pyrrolidino group in a compound of formula
wherein R
2
and R
3
are as previously defined, to an amino (—NH
2
) group. It is noted that compound IlIl is useful as a penultimate intermediate which can be hydrolyzed by base in a reaction inert solvent to make compound (I).
In another aspect this invention provides a process for preparing a compound of formula I, comprising deprotecting a compound having the formula
wherein R
1
, R
2
, and R
3
are is as previously defined. Deprotecting in this instance means converting the western end of the molecule from pyrrolidino to amino, and converting the eastern (amide) portion, (e.g., by hydrolysis) to the free acid.
In further aspects, as further disclosed and described below, this invention provides certain intermediates useful in the processes described above.
DETAILED DESCRIPTION
The chemistry of the instant invention is disclosed as a flow chart in Scheme 1.
As illustrated, 2-amino-5-bromopyridine (5), available commercially from a number of suppliers including Aldrich Chemical Company, Inc., Milwaukee, Wis., is treated with a compound of the formula R
2
CO(CH
2
)
2
COR
3
, wherein R
2
and R
3
are as previously defined, under Dean-Stark conditions to make a 5-bromro-(2,5-dialkyl-pyrrol-1-yl)-pyridine (10), such as 5-bromo-(2,5-dimethylpyrrol-1-yl)-pyridine (10). The reaction conducted in any conventional reaction inert solvent, which allows water removal by distillation, such as toluene or ethylbenzene, or by contacting with a conventional drying agent Workup can be by isolation of the product under reduced pressure followed by cleanup with a waterfisopropyl ether extraction system, with product being isolated, if desired, by evaporation to yield an oil that solidifies.
Bromide (10) can be converted to 5-(2-haloacety)-2-(2,5-dimethylpyrrol-1-yl)pyndine (15), wherein X, the halo group, is chloro or bromo, by lithium-halogen exchange of the bromide using butyllithium followed by acylation. Bromide (10) can be treated with butyllithium at reduced temperature, for example −78° C., followed by acylation with the corresponding 2-halo-methoxy-N-methylacetamide or &agr;-halodimethylacetamide while maintaining reduced temperature, to yield &agr;-haloketone (15). The reaction is conducted In a suitable solvent, such as diisopropyl ether, diethyl ether, or preferably, methyl tert-butyl ether (MTBE). The &agr;-haloketone (15) product can be worked up conventionally, for example using aqueous (e.g, 1M) hydrochloric acid, followed by separation of the phases and isolation of (15) by evaporation.
&agr;-haloketone (15) can be used to introduce chirality into the molecule by asymmetrically reducing (15) to the corresponding chiral alcohol (35) [structure shown in left hand pathway] with a chiral pinene-derived boron reagent such as (−)-&bgr;-chlorodiisopinocampheylborane (DIP-CI) orwith alpine borane, with DIP-CI being preferred. The reaction can be run at reduced temperature in a solvent such as methyl tert-butyl ether or, preferably, THF. Oxidative workup of the intermediate chiral alcohol to afford epoxide (20), without isolating alcohol (35), can be effected by any of several oxidizing agents in the presence of base, including any of hydrogen peroxide, triethylamine Noxide, sodium percarbonate or sodium perborate in the presence of an alkali metal hydroxide such as sodium hydroxide. Sodium percarbonate and sodium perborate are preferred.
Epoxide (20) can be reacted with compound (25) [structure shown in left hand pathway], an alkyl 4-(2-aminoethoxy)phenylacetamide wherein R
1
is C
1 -
C
8
alkyl, to form the protected intermediate (IV). A crude solution of the epoxide, generated as described above, and the amide (25) can be combined in DMSO and heated to within the range of 60 to 100° C., typically for a timespan of several hours. The product can be worked up by any convenient liquid-liquid extraction procedure (e.g. EtOAc/water) and can be further purified by acid/base extraction. The product can be isolated conventionally by concentration of solvent, for example by evaporation.
A preferred alternative procedure for preparing protected intermediate (IV) involves making &agr;-haloketone (15) as described above and conducting the chemistry alternatively illustrated (left hand pathway) in Scheme 1. Chirality is introduced via an asymmetric reduction of (15), thereby producing chiral alcohol (35), by treating ketone (15) with a catalytic amount of oxazaborolidine as shown, made in situ by combining (1S,2R)-2-amino-1,2-diphenylethanol with BH
3
.
500 SMe
2
in a solvent such as THF or toluene. Alcohol (35) can then be epoxidized by adding base to the reaction medium to produce epoxide (20) (not shown), which can then be reacted directly with intermediate amide (25) to produce protected alcohol (IV). Epoxide (20), not shown in the left synthesis branch of Scheme 1, was not isolated. Generally a solvent such as DMSO or THF is employed and the reaction medium is heated to a temperature between 60 and 100° C., typically 80-90° C.
Those skilled in the art will appreciate that the asymmetric chiral reduction of &agr;-chloroketone (15) can be conducted using a number of additional chiral reductants, other than those specifically disclosed and illustrated, which are known and/or commercially available.
The preparation of amide (25) has been described in International Patent Publication Number WO 98/21184, herein incorporated by reference, and such compounds are disciosed therein as compounds of formula XVI. Such compounds may be prepared as set forth in the Examples below. For example, the amide of formula (25) wherein R
4
is methyl is prepared as set forth in Preparation I below. Other such C
1
-C
8
alkyl amides (25) may be prepared by methods analogous thereto.
The final product, compound I, is made as shown in Scheme 2, by deprotection of compound (IV).
The compound (IV) is treated with a base, preferably an alkali metal hydroxide, and with hydroxylamine hydrochloride to deprotect at both the eastern and western ends of the molecule. Thus alcohol (IV) can proceed through compound II or compound III enroute to forming the desired final product. The particular sequence of deprotecton is not considered critical. Alcohol (IV) can first be treated with base to hydrolyze the eastern (amide) portion of the molecu
Benson Gregg C.
Oswecki Jane C.
Pfizer Inc.
Richardson Peter C.
Sherwood Michelle A.
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