Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-18
2002-08-27
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S475000, C549S023000, C549S051000, C549S057000, C549S058000, C549S462000, C549S470000, C549S471000, C546S146000, C546S174000, C548S468000
Reexamination Certificate
active
06441196
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compounds and processes useful in the synthesis of certain prostaglandin analogs. Specifically, the invention relates to intermediates and processes useful in the synthesis of certain 11-oxa prostaglandins.
BACKGROUND OF THE INVENTION
Substituted tetrahydrofuran analogs of D and F series prostaglandins for use in treating glaucoma and ocular hypertension are disclosed in commonly assigned U.S. Pat. No. 5,994,397, the entire contents of which are by this reference incorporated herein. 11-oxa PGF
2&agr;
analogs and/or synthetic schemes for their preparation are disclosed in Hanessian, et al., Carbohydrate Research, 141:221-238 (1985); Thiem et al., Liebigs Ann. Chem., 2151-2164 (1985); Arndt, et al., S. African J. Chem. 34:121-127 (1981); and U.S. Pat. No. 4,133,817. The entire contents of these references are hereby incorporated herein.
Previous routes to 11-oxa prostaglandins employ a C1-C2 olefination reaction of a tetrahydrofuran-2-carboxaldehyde for the introduction of the &ohgr;-chain. The &agr;-chain may be introduced before or after this step. The tetrahydrofuran-2-carboxaldehyde may be prepared from several readily available carbohydrates, which provide the four carbons of the tetrahydrofuran core and C1 of the &ohgr;-chain. The following carbohydrates have been used as starting materials in this approach: D-sorbitol (J. Thiem and H. Lüders, Liebigs Ann. Chem., 2151 (1985) and S. Hanessian, Y. Guindon, P. Lavallée and P. Dextraze, Carbohydrate Research, 141, 221 (1985)), D-xylose and D-glucose (G. J. Lourens and J. M. Koekemoer, Tetrahedron Letters, 43:3719 (1975) and R. R. Arndt, J. M. Koekemoer, G. J. Lourens and E. M. Venter, S.-Afri. Tydskr. Chem., 34:121 (1981)).
It is desirable, especially to improve therapeutic effect, to isolate the active isomer of the desired compound. In order for development of a pharmaceutical product comprising the enantiomerically enriched compound to be feasible, an economically viable synthetic route that will yield commercial quantities of the material is required.
Previously known syntheses of 11-oxa prostaglandins have suffered from various drawbacks that limit their usefulness for production of commercial quantities of the desired material. Such drawbacks include, without limitation, low yields, costly, time consuming, or inefficient synthetic sequences, and/or difficult or inadequate separation of the undesired enantiomer or epimer. A need exists, therefore, for an improved, commercially viable synthetic approach for 11-oxa prostaglandin analogs.
SUMMARY OF THE INVENTION
The present invention is directed to novel processes and intermediates useful in the preparation of preferred enantiomers of certain 11-oxa prostaglandins. The processes and intermediates of the present invention are particularly useful in the preparation of [2R(1E,3R),3S(4Z),4R]-7-[Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-furanyl]-4-heptenoic acid and its C1 esters.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to improved processes and intermediates for the preparation of certain 11-oxa prostaglandin analogs, including salt, ester, ether, alcohol, amine and amide derivatives thereof, and especially the 11-oxa prostaglandin analogs of formula I:
wherein:
R is H or a pharmaceutically acceptable cationic salt moiety, or CO
2
R forms a pharmaceutically acceptable ester moiety;
R
9
O and R
15
O are the same or different and constitute a free or functionally modified hydroxy group;
---
is a single or trans double bond;
X=(CH
2
)
q
or (CH
2
)
q
O; q=1-6; and
Y=a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, or a free or functionally modified hydroxy or amino group;
or X—Y=(CH
2
)
m
Y
1
, m=0-6,
wherein:
W=CH
2
, O, S(O)
m
, NR
10
, CH
2
CH
2
, CH═CH, CH
2
O, CH
2
S(O)
m
, CH═N, or CH
2
NR
10
;
m=0-2;
R
10
=H, alkyl, acyl;
Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, OH; and
----
=single or double bond.
The inventive processes and intermediates are preferably used to prepare the 11-oxa prostaglandin analogs of formula II:
wherein:
R=H or alkyl;
X=CH
2
CH
2
or CH
2
O; and
Y=phenyl, optionally substituted with halo or trihalomethyl.
The most preferred product of the presently claimed processes is isopropyl [2R(1E,3R),3S(4Z),4R]-7-[Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-furanyl]-4-heptenoate as provided by formula II, wherein R=isopropyl, X=CH
2
O, and Y=3-chlorophenyl.
It has now been discovered that by utilizing novel intermediates and by making certain modifications and additions to known synthetic processes, yields and purity of intermediates and ultimately the desired end product are significantly improved. The improved processes of the present invention thus provide a commercially viable route for the preparation of therapeutically useful 11-oxa prostaglandin analogs.
The novel process comprises conversion of D-sorbitol (1) to anhydro-D-glucitol (2) using acid and heat. Treatment of 2 with a trialkyl orthoalkanoate (preferred is trimethyl orthoacetate) affords ortho ester III (R
3
is alkyl or cycloalkyl, preferred is R
3
=CH
3
), which is silylated on the free hydroxy group using a silyl halide or triflate R
4
R
5
R
6
SiX (R
4
, R
5
, R
6
=same or different=alkyl, cycloalkyl, or aryl, preferred is R
4
and R
5
=Ph and R
6
=tert-butyl; X=Cl, Br, I, or OSO
2
CF
3
, preferred is X=Cl or OSO
2
CF
3
) in the presence of an amine base (e.g., NEt
3
or imidazole) to give silyl ether IV (R
4
, R
5
, R
6
=same or different=alkyl, cycloalkyl, or aryl, preferred is R
4
and R
5
=Ph and R
6
=tert-butyl).
Treatment of IV with acid and a hydroxylic solvent provides triol V, which is treated with dimethoxypropane in the presence of catalytic acid to yield acetonide VI. Oxidation of VI with, for example, DMSO/carbodiimide/acid affords ketone VII, which is condensed with Ph
3
P=CHCO
2
R
7
(R
7
=alkyl, aryl, or cycloalkyl; R
7
=alkyl is preferred) to give enoate VIII (R
7
=alkyl, aryl, or cycloalkyl, R
7
=alkyl is preferred).
Unsaturated ester VIII is reduced with hydrogen gas over a metal catalyst (e.g., Pd/C) to provide saturated ester IX, which is reduced with a metal hydride reagent (e.g., lithium aluminum hydride or lithium borohydride; preferred is lithium aluminum hydride) to give alcohol X. Treatment of alcohol X with R
8
SO
2
X (R
8
=alkyl, aryl, or trifluoromethyl, preferred is methyl, 4-methylphenyl, or trifluoromethyl; X=halide, preferably chloride, or OSO
2
R
8
(i.e., R
8
SO
2
X forms an anhydride)) in the presence of an amine base (such as pyridine, triethylamine, or DBU) yields sulfonate XI, which is reacted with a metal cyanide (preferably NaCN) in DMSO to afford nitrile XII. Oxidative deprotection of XII with H
5
IO
6
gives aldehyde XIII, which is condensed with (MeO)
2
P(O)CH
2
C(O)—X—Y (X and Y are as defined for formula I; preferred is X=O and Y=3-chlorophenyl) in the presence of an amine base (preferred are triethylamine and DBU) and LiCl or LiBr to provide trans-enone XIV. Alternatively, aldehyde XIII can be condensed with Ph
3
P═CHC(O)—X—Y (X and Y are as defined for formula I) to afford XIV.
Reduction of enone XIV to the corresponding allylic alcohol can be performed under several conditions. Reduction using NaBH
4
/CeCl
3
affords the alcohol XV as a nearly 1:1 mixture of diastereomers. More efficient production of the 15&agr; diastereomer can be achieved by using stoichiometric (−)-B-chlorodiisopinocampheylborane, or catalytic (3aR)-Tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]oxazaborole [(R)-2-methyl-CBS-oxazaborolidine, which is commercially available fr
Conrow Raymond E.
Dean William D.
Delgado Pete
Gaines Michael S.
Alcon Inc.
Copeland Barry L.
Dentz Bernard
LandOfFree
Processes and novel intermediates for 11-oxa prostaglandin... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Processes and novel intermediates for 11-oxa prostaglandin..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Processes and novel intermediates for 11-oxa prostaglandin... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2961875