CA2349119A1 - Processes and intermediates in the synthesis of 5-(3-¬exo-bicyclo¬2.2.1|hept-2-yloxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1h)-one - Google Patents

Abstract

Disclosed are processes for producing compounds of the formulae:
(wherein X and Y are both -CN, -CONH2, -CO2alkyl or -CONHOH or together form a cyclic urea), by (1) reacting isovanillin with QCH2CO2H (in which Q is -CN, -CONH2, -CO2alkyl or -CONHOH) to yield (II) (in which X and Y are Q), (2) when required, converting (II) (in which X and Y are Q) to (II) (in which X
and Y together form a cyclic urea) and (3) when required, reacting (II) with norborneol. The compounds (II) and (III) are useful as intermediates for producing 5- (3-[(2S or 2R) -exo-bicyclo[2.2.1.]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one that is useful as a pharmaceutical agent, e.g. antidepressant.

Description

PROCESSES AND INTERMEDIATES IN THE SYNTHESIS OF 5-(3-[EXO-BICYCLO[2.2.1]HEPT-2-YLOXY]-4-METHOXYPHENYL)-3,4,5,6 TETRAHYDROPYRIMIDIN-2(1H)-ONE
This is a div_~sional application of Canadian Patent Application No. 2,196,309 filed May 4, 1995.
The subject matter of the parent application was restricted to a process for producing a compound of the formula (VI) or (VI') described hereinunder and intermediates of the formula (V) or (v' ) desc:ribed hereinunder formed during the process. The subject matter of this divisional application is restricted to a process for producing a compound of the formula (III), (III') and (II) described hereinunder as well as a compound of the formula (II) itself. Nevertheless, the expression "this invention" or the like throughout the specification should be understood to encompass the subject matter of both the parent and divisional applications.
Background of the Invention This invention relates to novel processes for preparing the pharmaceutically active compound 5-(3-[(2S)-exo-bicyclo [2 .2 . 1] hept-2-yloxy] -4-methoxyphenyl) -3, 4, 5, 6-tetrahydropyrimidin-2(1H)-one and its corresponding 2R
enantiomer and for preparing certain intermediates used in the synthesis of these compounds. It also relates to novel intermediates used in the synthesis of such pharmaceutically active compounds and to other novel compounds that are related to such intermediates.
International Patent Application WO 87/06576, which was published on November 5, 1987, refers to 5- [3- (2-exo-bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]-3,4,5,6-tetrahydropyrimidin-2(1H)-one, and states that it is useful as an antidepressant. International Patent Application WO
91/07178, which was pub7_ished on May 30, 1991, refers to the utility of this compound in the treatment of asthma, inflammatory airway diseases and skin diseases.
United States Patent 5,270,206, which issued on December 14, 1993, refers to a process for preparing (+)-(2R)-endo-norborneol (also referred to as (2R)-endo-bicyclo [2 .2 . 1] heptan-2-of or (1S, 2R, 4R) -bicyclo [2 .2 . 1] heptan-2-0l) and (-) - (2S) -endo--norborneol (also referred to as (2S) -endo-bicyclo [2 .2 . 1] heptan-2-of or (1R, 2S, 4S) -bicyclo[2.2.1]heptan-2-ol), and to their further conversion into the pharmaceutical7_y active agents 5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(iH)-one, depicted below, O-_~ \
VI
~1 IHN,\ /NH
~O
and 5- (3- [ (2R) -exo-bicyc;lo [2 .2 . 1] hept-2-yloxy] -4-methoxyphenyl)-3,4,5,6-t:etrahydropyrimidin-2(1H)-one, depicted below, -2a-y~0 V I' HN\ i,NH
~O
Summary of the Invention This invention relates to a compound having the formula:

OCH., H
CII) wherein X and Y are the same .and are selected from -CN, -C01(C,-Ce)alkyl, -and -CONHOH, ar X and Y, taken together, form a group of the formula NH NH
(a>
i This invention also relates to a compouna ha..ng cne rorm~,a \ CV) R~0 NH HN OR2 wherein R' and R2 are independently selected from (C,-C5)alkyl and hydrogen.
X Y

This invention also relates to compounds of the formulae OCH., .5 HN N OR2 ( V I I I ) and w HzN HN~ 0R2 (VII) wherein each R~ is independenl:ly selected from (C,-C6) alkyl.

This invention also relates to a process for preparing a compound of the formula H
(II) k wherein X and Y are the same and are selected from -CN, -COz(C,-Ce)alkyl, -CONH~
and -CONHOH, or X and Y, taken together, form a graup of the formula ",,t,.,~ _"
NH NH
w C a) comprising: (1 ) reacting 3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH~CO~H, wherein X is defined as above, in the presence of a base, preferably a tertiary amine, to yield a compound of the formula II wherein X
and Y are both -CN, -COz(C,-Ce)alkyl, -CONH~ or -CONHOH; or (2) (a) reacting a compound of the formula II wherein X and Y are both -CN with hydrogen peroxide, preferably basic aqueous hydrogen peroxide, to 1'orm the corresponding bis-amide in which both -CN
groups are replaced by -CONHz; (b) subjecting the bis-amide formed in step (a) to a Hoffman rearrangement using an oxidizing agent Leg.-, bis(acetoxy)iodobenzene, bis(trifluorocetoxy)iodobenzene, NaOCI, NaOBr or lead tetraacetate) to form the corresponding biscarbamate; and (c) reacting the biscarbamate formed in step (b) with a base '~, an alkali metal alkoxide containing from one to six carbon atoms or an alkali metal hydroxide), to form a. cyclic urea wherein X and Y, taken together, form a group of the formula 'a', as depi~~ted above.
This invention also relates to a process for preparing a compound of the formula nrH, (III>
or t5 (III~>
2 i7 X Y
wherein X and Y are defined as vfor formula II above, comprising reacting a compound 2.°~ of formula II, as defined above, with, respectively, R-(+)-endo-norborneol or S-(-)-endo-norborneol, a tria.ryt or trialkyl phosphine and an azo dicarboxylate.
This invention also relates to a process for preparing a compound of the formula X Y

_7.
NCH;
/ (III>
Or i ;~
CIII >
2() X Y
wherein X and Y are the same and are selected from -CN, -CONH~, CO~(C,-Ca)alkyl and -CONHOH, or X and Y, taken together, form a group of the formula 2;~
rdH NH
c Q~

3~~
comprising: (1) reacting 3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCHzCOzH, wherein X is -CN, -CO~(C,-C6)alkyl, -CONH~ or -CONHOH, in the presence of a base, preferably a tertiary amine, to fcrm a compound of the formula X Y

-g_ H
(II>
1 C~
wherein X and Y are the same and are selected from -CN, -CONH?, -CO(C,-Ca)alkyl and -CONHOH; or (2) (a) reacting a compound of the formula Il wherein X and Y are both -CN with hydrogen peroxide to 'form the corresponding bis-amide in which both -CN
groups are replaced by -CONH~,; (b) subjecting the bis-amide formed in step (a) to a 1;i Hoffman rearrangement using an oxidizing agent (e-q_, bis(acetoxy)iodobenzene, bis(trifiuorocetoxy)iodobenzene, NaOCI, NaOBr or lead tetraacetate) to form the corresponding biscarbamate; and (c) reacting the biscarbamate formed in step (b) with a base ~, an alkali metal alkoxide containing from one to six carbon atoms), to form a cyclic area wherein X and Y, taken together, form a group of the formula 2() -"?"' '",Y'' NH NH
( a>
a 2!5 and then (3) reacting said compound of formula II so formed in step 1 or 2 above with, respectively, R-(+)-endo-norborneol or S-(-)-endo-norborneol, a triaryl or trialkyl phosphine and an azo dicarbox;ylate.
This invention also relates to a process for preparing a compound of the formula ;~C Y

_g_ (V) R10, NH HN OR2 t0 or t i (V ) R10~ NH HN ORS

wherein R' and RZ are independently selected from hydrogen and (C,-C6)alkyl, comprising reacting, respectively, a compound of the formula OCH., or (IV) ( IV~>
CONH2 CONH~
with diacetoxyiodabenzene, NaOZ and Z'OH, wherein Z and Z' are independently selected from hydrogen and (C,-Ce)alkyl.
This invention also relates to a process for preparing a compound of the formula (VI>
HN /NH

or 1:~

2C) (VI >
HN N;~
25.

comprising reacting, respectively, a compound of the formula ;5 . \
(V) R'-0~ /NH HN OR
1 () or 20 \
i (V ) R 0.~ NH NN~ OR

wherein R' and R~ are independently selected from hydrogen and (C,-C6)alkyl with compounds of the formulae NaOZ and Z'OH, wherein Z and Z' are independently selected from hydrogen and (C,-Cfi)alkyl.
This invention also relates to a process for prepay ing a compound of the formula -~3-OC~3 C
(vI>
HN. NH

or (vI
HN n~H

comprising:
i reacting, respectively, a compound of the formula 0 i ~~
CONH, CONH~
t0 or CIv) J
c iv') i with diacetoxyiodobenzene, NaOZ and Z'OH, wherein Z and Z' are independently selected from hydrogen and (C~-~q)alkyl, to form an intermediate of the formula (V) R iC NH HN~ OR
1n or Z ;~

2C) (V~>
R10~ NH HN~ ORS
2:~ 0 0 wherein R' and R' are independently selected from hydrogen and (C,-C6)alkyl;
and then either (b1) isolating said intermediate of fcrmula V or V' and reacting it with 30 compounds of the formulae NaOZ and Z'OH, wherein Z and Z' are defined as above;
or (b2) reacting said intermediate of formula V or V' in situ with compounds of the formula NaOZ and Z'OH, wherein Z and Z' are defined as above.

-1 b-As used herein, the expression 'reaction inert solvent' refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects trre yield of the desired product or products.
The term 'alkyl', as used herein, unless otherwise indicated, includes saturated monovalent hydror_arbon radicals having straight, branched or cyclic moieties or combinations thereof.
Formulae II, and V and V' z.bove include.compounds identical to those depicted but for the fact that one or mare hydrogen, carbon, nitrogen or oxygen atoms are replaced by radioactive or stable isotopes thereof. Such radiolabelled compounds are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
Detailed Cescriotion of the Invention The processes of the this invention and methods of preparing the novel compounds of this invention are described in the following reaction schemes and discussion. Unless otherwise indicated, the substituents X, Y, R, R', R~, R', and R', group '(a)' and forrnulae II, III, 111', IV, IV', V, V', VI and VI' in the reaction schemes and discussion that follow are defined as above.

_17_ H 0~
CHO
! S c~ v a n : 1 r~ )'; Y
:ii) ,~ i ~~I
X Y
(iIi) _ 18_ OCH3 OCH~
CONH2 CONH_ CN CN
(IV) (::iH) 0CH3 ~~H3 P, 0' NH HN~OR' HN~NH
v~IfI011~I ~IIOII/
(V) (Vi>

_19_ nru_ L~
NH HN /Gr?' cv~
OWi3 G.~H~
I
W
HzN NH ~OR~
HN N G
r7 t G
~vI(~ I ; ;v::~

SCHEME 2A cont'd (VII) (VIII) 00N, (VI>
HN N

v'w. 0 '~ /
RO,C CC,R
CR=cCl-CG>a?~~y,t ~IIIB>
n~H, 0~~=~Oh I I I C >

SCHEME 3 cont'd (IIIC) 2~

HN NH

(VI) Scheme 1 illu:~trates the preparation of compounds of the formulae II and III.. Scheme 2 illustrates the preparation of compounds of the forrnula V and also the preparation of 5-(3-[ (2S) -exo-bicyclo [2 .2 . 1] kept-2-yloxy] -4-methoxyphenyl) -3, 4, 5, 6-tetrahydropyrimidin-2(1H)-one (compound VI) from the compound of formula III wherein X and Y are both -CN. (Such compound of formula III wherein X and Y are both -CN is referred to in scheme 2 and hereinafter: as the compound of formula IIIA.).
Scheme 3 illustrates thE: preparation of compound VI from compounds of the formula III wherein X and Y are both -COZ(C1-C6)alkyl or -CONHOH. (T'he compound of formula III wherein X and Y are both -COZ (C1-C6) al~:yl or -CONHOH are referred to in scheme 3 and hereinafter, respectively, as the compound of formula IIIB or IIIC).
Referring to scheme 1, isovanillin (compound I) is condensed with two molar: equivalents of a compound of the formula XCH2C02H, wherein X is -CN, -COZ (C1-C6) alkyl, -CONHZ or -CONHOH, in a sequential. Knoevenagel-Michael sense with accompanying decarboxylation, to yield a compound of the formula II, wherein X and Y are the same and are selected from the values given in the above definition of X, in a reaction inert solvent in the presence of a base, preferably a tertiary amine. This reaction may be conducted at a temperature ranging from about 10°C to about 130°C. It is preferably conducted at about the reflux temperature. Suitable solvents include but are not limited to N-met:hylmorpholine, triethylamine, pyridine, diisopropylamine, as we7.1 as non-basic reaction-inert solvents such as tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile and toluene:. Preferably, a secondary amine (e. g., piperidine or pyrrolidine) is also added as a catalyst. In one preferred embodiment of the reaction, N-methylmorpholine is used as the solvent/base and piperidine is also added to the -23a-reaction mixt:ure .
Compounds of 'the formula II wherein X and Y, taken together, form a group of the "a" (i.e., the cyclic urea) may be prepared by subjecting the compound of formula II wherein X
~~ and Y are both -CN to the series of reactions illustrated in scheme 2 and described :later in this application.
The compound of formula II formed in the above reaction can be converted into the corresponding compound of the formula 7:II by coupling it under Mitsunobu conditions with either R-(+)-~endo-norbo:rneol, depicted below, ,,,,,0 H
or S-endo-norbomeol, depicted below ,,,0 H
to yield, respectively, the corre~;ponding compound of formula III or III' having the opposite stereochemistry as determined by the endo-norborneol reactant. Thus, if R-endo-norborneol is used, the product will be a compound of the formula III
that has an 'S' configuration, and if S-enda-norborneol is used, the product v~ill be a compound of the formula III' that has an 'R" configuration.
1:.~ This reaction is typically carried out in the presence of a triaryl or trialkyl phosphine such ecs triphenylphosphine or tributylphosphine and an azo dicarboxylate oxidizing agent. It is also generally carried out in an aprotic soivent such as tetrahydrofuran (THF) acetonitrile, methylene chloride, DMF, toluene and benzene, preferably THF, at atemperature from about 10°C to about 150°C, preferably at about the reflux temperature. Suitable zzo compounds include diisopropylazodicarboxylate, azodicarbonyldipiperidine and diethylazodicarboxylate.
Diisopropylazodicarboxylate and azodicarbonyldipiperidine are preferred.
The stereochemistry of the compound of formula III or III' formed in the above step is retained in all subsequent steps shown in schemes 2 and 3.
2!~ As indicated above, scheme 2 illustrates the conversion of compounds of the formula IIIA into compounds of i.he formula VI. Referring to scheme 2, a compound of the formula IIIA is hydrolyzed with hydrogen peroxide, preferably basic aqueous hydrogen peroxide, to form the bis-amide of formula IV. This reaction is typically conducted in a polar solvent such as acetone, ethanol, isopropanol or methyl ethyl ketone, with acetone being prefEUred, at a temperature from about 0° C
to about 100° C, with about room temperature being preferred. Sodium carbonate or another inorganic salt of similar basicity may be added to the reaction mixture to accelerate the reaction.

The compound of formula IV so formed is then subjected to a Hoffma rearrangement reaction in which both carboxamide groups are converted, witf.
migration of nitrogen, into the carbamate groups of formula V. Suitable oxidizing reagents include bis(acetoxy)iodobenzene, bis(trifluoroacetoxy)iodobenzene, NaOCi, NaO8r and lead tetracetate may be used. Bis(acetoxy)iodobenzene is preferred.
This reaction is typically carried out in the presence of a base. When diacetoxyiodobenzenE
is used, acceptable bases include alkali metal hydroxides and (C,-Ce)alkoxides. ThE
reaction temperature may range from about -20°C to about 100°C, with from abou', 0°C to about 2~°C: being preferred. Examples of appropriate reaction-inert solvents are (C,-CQ)alkanols, THE, DMF arid acetonitrile.
The final step in the sequence is the base catalyzed closure of the biscarbamate of formula V to forrn the symmetrical pyrimi.din-2-one of formula VI. This reaction may be carried out frorn about 0°C to about 100°C, and is preferably carried out at the reflux temperature. Suitable solvents include but are not limited to lower alcohols, with 1 S methanol being preferred. Suitable bases include alkali metal alkoxides containing from one to six carbon atoms. The preferred base is sodium methoxide.
Altemativell~, the last tv~o steps of the sequence may be accomplished in a combined fashion without the isolation of the bis-carbamate V. This modification is essentially identical to the previous description of the Hoffman rearrangement. It is preferable to conduct the reaction at the reflux temperature of the solvent.
It is also preferable to add additional base to the reaction mixture. The range of acceptable oxidizing agents, bases and solvents is the same as described previously. The preferred reaction utilizes diacetoxyiodobenzene, sodium methoxide and methanol.
The reaction of compounds of the formula V to form compounds of the formula VI, as described above, may proceed through one or both of the intermediates of formulae VII and VIII shown in scheme 2A.
The compound of formula III wherein X and Y are both -CONHz is the same as the compound of formula IV, arid therefore it can be converted into compound (VI) using the methods illustrated in 'scheme 2.
Compounds of the formula III wherein X and Y are both -CONHOH or -CO~(C,-CB)alkyl may be converted into compound VI using the methods illustrated in scheme 3.

Referring to scheme 3, the diester of formula IIIB is reacted with hydroxylamine hydrochloride in tire presence of a base, ~, a tertiary amine base, to form the hydroxamic acid of formula IIIC. This reaction can be conducted in a variety of reaction-inert solvents that do not have a strong nucfeophi(ic character, including but not limited to lower aicohols, cy :lic and acyclic ethers (e q., ethyl ether or THF), neutral aromatic compounds such as bEznzene and toluene, DMF, dimethylacetamide, ethyl acetate, acetonitrile and water, at a temperature from about 0°C to about 100°C, preferably at about 20 ° C.
The hydroxamic acid of formula IIIC can then be converted into compound VI
via a Loessen rearrangement using conditions or a reagent having the ability to dehydrate an alcohol, at a temperature from about 0°C to about 100°C, preferably at about 20°C. The preferred reagent is p-toluenesulfonylchloride.
Alternatively, one can form a different ester of the hydroxamic acid, optionally in situ, and then convert that ester via heat and!or acid treatment into the compound of formula VI, using methods 1 S well known in the art.
The preparation of other compounds of the present invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
In each of the reactions discussed or illustrated in the scheme above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 3 atmospheres are generally acceptable, and ambient pressure, i.e., about 1 atmosphere, is preferred as a matter of convenience.
The processes and products of this invention are useful in the synthesis of the pharmaceutically active compounds VI and VI'. Compounds VI and VI', as well as racemic mixtures of these compounds (hereinafter referred to, collectively as 'the active compounds') are useful in the treatment of depression, asthma, inflammatory airway disorders and skin disorders (e.g., psoriasis and atopic dermatitis).
The active compounds are calcium independent c-AMP phosphodiesterase inhibitors. The ability of such compounds to inhibit c-AP~iP phosphodiesterase may be determined by the method of Davis, Biochimica nt BioDhvsica. Acta.. 797, 3~-(1980.

The antidepressant activity of the active compounds may be determined by the behavioral despair paradigm described by Porsult et al., Arch. Int.
Pharmacodvn., 227, 327-336 (1977) and by the procedure described by Roe et al., J. Phamiacol.
EXD.
ThBfap., 226, 68fi-700 (1983) for determining the ability of a test drug to counteract :i reserpine hypothermia in mice.
When used for the treatment of depression the active compounds are used as is or in the form of pharmaceutical compositions comprising an active compound and pharmaceutically-acceptable carriers or diluents. For oral administration, the preferred route for administering the active compounds, suitable pharmaceutical carriers include inert diluents or fillers, thereby forming dosage forms such as tablets, powders, capsules, and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
For example, tablets containing various excipiE=nts, such as sodium citrate, are employed, together with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules.
preferred materials therefor include lactose or milk sugar and high molecular weight polyethylene glycols.
For oral administration, the daily dose of active agent is from about 0.1 mg to about 10 mg, and for parenteral administration, preferably i.v. or i.m., from about 0.01 mg. to about b mg.. The prescribing physician, of course, will ultimately determine the appropriate dose for a given human subject dependent upon factors such as the severity of the patie'nt's symptoms and the patient's response to the particular drug.
26 In vitro and in vivo tests relevant to the utility of the active compounds in treating asthma and skin disorders are discussed in international Patent Application WO 97/07178, referred to above on pages 4 and S of the specification and in Examples 1-3.
(n the systemic treatment of asthma or inf;ammatory skin diseases with one of the active compounds, the dosage is generally from about 0.01 to 2 mg/kg/day (0.5-100 mg/day in a typical human weighing 50 kg) in single or divided doses, regardless of the route of administration. Of course, depending upon the exact compound and the exact nature of the individual illness, doses outside this range will be prescribed at the discretion of the attending physician. In the treatment of asthma, intranasal (drops or spray), inhalation of an aerosol through the mouth, and conventional oral administration are generally preferred. However, if the patient is unable to swallow, or oral absorption is otherwise impaired, the preferred systemic route of administration will be parenteral (i.m., i.v.). fn the treatment of inflammatory skin diseases, the preferred route of administration is oral or topical. In the treatment of inflammatory airlvay diseases, the preferred route of ~.dministration is intranasal or oral.
The active compounds are generally administered in the form of pharmaceutical compositions comprising one of said compounds together with a pharmaceutically acceptable vehicle or diluent. Such compositions are generally formulated in a conventional manner utilizing solid or liquid vehicles or diluents as appropriate to the mode of desired administration: for oral administration, in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders and the like; for parenteral administration, in the form of injectable solutions or suspensions, and the like; for topical administration, in the four of solutions, lotions, ointments, salves and the like, in general conta.ir~ing from about 0.1 to 1 ~ (w/v) of the active ingredient;
and for intranasal or inhaler administration, generally as 0.1 to 1 ~ (w/v) solution.
The present invention is illustrated by the following examples. It will be understood, however, that the invention is not limited to the specific details of these examples.

3-f 3-Hydroxv-4-methoxyohenyl)-pentane-1.5-dinitrile To a 500 mL flask containing isovanillin (30.4 gm, 200 mmol) and cyanoacetic acid (68.0 gm, 800 mmol) was char ged a solution consisting of 3.0 mL (30 mmol) piperidine and 151 mL N-methylmorpholine. The initially formed yellow slurry eras warmed to mild reflux for 21 hours and then cooled to room temperature and concentrated on a rotary evaporator. The resulting brown oil vas dissolved in 430 mL
ethyl acetate (EtOAc), washed sequentially with water (Hz0), five normal hydrochloric acid (5N HCI) and H20 and the combined aqueous washes back extracted with dichloroethane. Combination of ';he organic layers followed by solvent removal led to a thick orange oil which was crystallized frcm ethyl acetate/methylene ch!or;de (EtOAc/CHZCI~) to yield 38.3 gm of orange solids after filtration and drying.

Recrystallization from EtOAc/diiscprcpyl ether gave 35.3 gm (82°~) of light yellow solid, m.p. 90-92°C.

3-(3-((2S)-exo-Bicvclof2.2.11heot 2-yloxyl-~-methoxyphenyl)-1 5-oentanedinitrile To a tetrahydrofuran (T';-!F) solution (20 mL) containing R-(+)-endo-norbomeol (1.12 gm, 10.0 mmol), 3-(3-hydrox:y-4-methoxyphenyl)-pentane-1,5-dinitrile (4.33 gm, 20 mmol) and triphenylphosphine (TPP) (3.93 gm, 15 mmol) was added 1,1' (azodicarbonyl)-dipiperidine (ADDP) (3.78 gm, 15 mmol) at room temperature.
The resulting brown slurry was heated at reflux for 12 hours, and then diluted with 10 mL
THF and 30 mL toluene, cooled to room temperature and granulated for 30 minutes.
After filtration to remove the reduced ADDP, the filtrate was washed 2X with 20 ml 1 N
sodium hydroxide (NaOM) and the remaining organic phase stirred with 0.2 gm activated charcoal and 20 gm sodium sulfate (Na,SO,), filtered and concentrated to a thick, dark brown oil. Recrystallization from isopropanol/hexanes gave 2.34 gm (75°x) 1~~ of an off-white solid, m.p. 126-1:?~l°C.

3- 3- 2S ~xo-Bicvcfof2_.2._tlheot 2 vloxyl-~-methoxyflhenyl)-eentane-1.5-dinitrile To a reflu;King solution of THF (30 mL) containing norbomeol (2.243 gm, 20.00 mmol) and triphanylphosphine (5.272 gm, 20.10 mmol) was added a second THF
solution of 3-(3-h~~droxy-4-methoxyphenyl)-pentane-1,5-dinitrile (4.350 gm, 20.10 mmol) and diisopropyl ~gzodicarboxylate (D1AD) (4.044 gm, 21.00 mmol). The mixture was heated at reflux for 18 hours, cooled and concentrated on the rotary evaporator, and then redissolved in BO mL toluene. The resulting brown toluene solution was washed 2 times with 1 N t~laOH, dried over Na~SO" and filtered and concentrated to yield 18 gm of beige solid. Recrystallization from 1/1 isopropanol/hexanes gave 4.26 gm (69°o) of white solid, m.p. 127-128°C.

_3-f3-((2S'v-exo-Bicyclo f 2.2.11he~t-2-vloxy]-4-methoxyohenyllolutaramide To acooled (6°C) acetone solution (46 mL) of 3-(3-[(2S)-exo-bicycfo[2.2.1]hept 2-yfoxy]-4-methc>xyphenyl)-pentane-1,5-dinitrile (2.29 gm, 7.38 mmol) was added 24 mL
of 1096 aqueous sodium carbonate (NazC03) (23 mmol) followed by 5.2 mL of 30~
hydrogen pyroxide (HzO~). The resulting slurry was stirred at room temperature for 4 days, treated with an additional 1.7 mL 30°~ H~O~ and then stirred for two more days.

The excess peroxide was decomposed by the addition of 4 equivalents of sodium bisulfate (NaHSO,) and the volume was reduced to about 80 mL on the rotary evaporator. The thick slurry vras then acidified using 6.5 mL of concentrated HCI, neutralized with concentrated ammonium hydroxide (NH,OH) and condensed to about 50 mL of volume. Filtration and vacuum drying provided 2.20 gm {86%) of white solids, m.p. 161-163°C.

5- 3-( j(2S'~~exo-Bicycloj2 2 l~hept 2 VIoxVI-4-methoxVphenvll-3.4.5.6-t_etrahydrowrinidin-2(1 H~-one To a cooled (2°) methanol (MeOH) (40 mL) suspension of diacetoxyiodoben:zene (43.60 grn, 133 mmol) was added 152 mL of 25°o sodium methoxide (NaOMe) in MeOH solution over 10 minutes. After stirring.for 20 minutes at 3°C, 3-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxyJ~-methoxyphenyl)glutaramide (22.98 gm, 66.5 mmol) was added as a precooled slurry in 45 mL MeOH and the 1:i reaction was allowed to warm to room temperature over 3 hours followed by 45 minutes of heating at reflux. The slurry eras cooled to room temperature, treated with 152 mL
of 25'Y° NaOMe in MeOH solution and heated to reflux for 16 hours. The condenser was then replaced with a distillz.tion head and 350 mL of MeOH was removed.
The resulting slurry was cooled to 1 G'. .° C, diluted with 200 mL CH,CIz and 100 ml HBO and neutralized with concentrated HCI. Separation of the layers and extraction of the aqueous layer 2~: with CH~CIr provided 3 organic layers which were combined, dried over sodium sulfate (Na~SO,), filtered and then concentrated to yield 39 gm of pale orange solid. Reslurry in refluxing EtOAc gave 15.48 gm of white solid (77'~) m.p. 199-200 ° C.

N.N'-Dimethoxycarbonyl-2-(3-j(2S1-exo-bicvcto(2.2.11heot-2-vloxyl-4-methoxYOhenYl)-1.3-prooanedia_mine To a cooled (0°C) suspension of 3-(3-[{2S)-exo-bicyclo[2.2.1Jhept-2-yloxyJ-4 methoxyphenyl)-glutaramide (0..346 gm, 1.00 mmol) in 1.75 ml of MeOH was added ~~0 0.140 gm of potassium hydroxide (KOH) (2.50 mmol) followed by 0.657 gm {3.0 mmol) diacetoxyiodobenzene. The resulting hazy yellow solution was allowed to warm to room temperature, stir for 80 minutes and was then concentrated on the rotary evaporator to a paste. The material eras transferred to a separatory funnel with water and extracted two times with CHZC12. The combined organic layers dried over NazSO"
filtered and concentrated to pravide 0.506 gm (125 ro) of the desired bis-carbamate as an impure yellow foam. Thin layer chromatography (TLC): R, - 0.74 in 9:1 CHZCI~/MeOH. Gas chromatography - mass spectrometry showed the major peak with a molecular ion of 406 which is the molecular weight of the title compound.
cvn~~m c w 5-(3((2R)-exo-bicycfof2.2.11heot-2-yloxyl-4-methoxVphenyl)-3.4.5.6-tetrahydrooyrimidin-2(1 Hl-one The crude bis-carbamate foam from Example 6 (98 mg, 0.2 mmol) was dissolved in MeOH (0.5 mL), treated with 0.5 mL of 25% NaOMe in MeOH, and refluxed for hours. After removal of the solvent, the resulting solid was dissolved in water, extracted two times with CH~CIZ and the combined organic layers dried over magnesium sulfate (MgSO,). Filtration and concentration of the filtrate gave 48 mg (75°~) of the desired urea as a yellow solid. Thin layer chromatography (TLC): F~, - 0.57 in 9:1 CH~CI~/MeOH.

Claims (27)

1. A process for preparing a compound of the formula:
wherein X and Y are the same and are selected from the group consisting of -CN, -CONH2, -CO2(C1-C6)alkyl and -CONHOH, or X and Y, taken together, form a group of the formula:
which process comprises:
(1) reacting 3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH2CO2H, wherein X is -CN, -CO2(C1-C6)alkyl, -CONH2 or -CONHOH, in the presence of a base, to form a compound of the formula:

wherein X and Y are the same and are selected from -CN, -CONH2, -CO2(C1-C6) alkyl and -CONHOH; or (2) (a) reacting a compound of the formula (II) wherein X and Y are both -CN with hydrogen peroxide to form the corresponding bis-amide in which both -CN groups are replaced by -CONH2; (b) subjecting the bis-amide formed in step (a) to a Hoffman rearrangement using an oxidizing agent to form the corresponding biscarbamate; and (c) reacting the biscarbamate formed in step (b) with a base to form a cyclic area wherein X
and Y, taken together, form a group of the formula:
then (3) reacting the compound of formula (II) formed in step (1) or (2) above with a triaryl or trialkylphosphine, an azo dicarboxylate, and either R-(+)-endo-norborneol or S-(-)-endo-norborneol, respectively.

2. A process according to claim 1, wherein the base used in process step (1) is a tertiary amine.

3. A process according to claim 2, wherein both the tertiary amine and a secondary amine are employed in process step (1).

4. A process according to claim 3, wherein the tertiary amine is selected from N-methylmorpholine, triethylamine, pyridine and diisopropylamine and the secondary amine is selected from piperidine and pyrrolidine.

5. The process according to any one of claims 1 to 4, wherein only process step (1) is conducted using the compound of the formula XCH2CO2H wherein X is -CN, thereby producing the compound of the formula (III) or (III') in which X and Y are both -CN.

6. The process according to any one of claims 1 to 4, in which:
process step (1) is conducted using the compound of the formula XCH2CO2H wherein X is -CN, to obtain the compound of the formula (II) wherein X and Y are both CN;
process step (2) is next conducted using the compound of the formula (II) obtained in process step (1); and then process step (3) is conducted.

7. The process according to claim 6, wherein:
process step (1) is conducted by using the tertiary amine as a solvent at a temperature of from 10°C to 130°C;
process step (2)(a) is conducted using basic aqueous hydrogen peroxide in a polar solvent at a temperature of from 0°C to 100°C;

process step (2)(b) is conducted using bis(acetoxy)iodobenzene, bis(trifluoroacetoxy)iodobenzene, NaOCl, NaOBr or lead tetraacetate as the oxidizing agent in the presence of a base at a temperature of from -20°C to 100°C in a reaction-inert solvent; and process step (2)(c) is conducted by using an alkali metal alkoxide containing from one to six carbon atoms in a lower alcohol solvent at: a temperature of from 0°C to 100°C.

8. A process according to any one of claims 1 to 7, wherein the azo dicarboxylate is selected from diisopropylazadicarboxylate and azodicarbonyldipiperidine.

9. A process according to any one of claims 1 to 8, wherein the triarylphosphine is triphenylphosphine.

10. A compound having the formula:
wherein X and Y are the same and are selected from the group consisting of -CO2(C1-C6)alkyl, -CONH2 and -CONHOH, or X and Y, taken together, form a croup of the formula:

11. The compound according to claim 10, wherein X and Y
are both -CONH2.

12. The compound according to claim 10, wherein X and Y, taken together, form a croup of the formula (a).

13. The compound according to claim 10, wherein X and Y
are both -CO2 (C1-C6) alkyl.

14. The compound according to claim 10, wherein X and Y
are both -CONHOH.

15. A process for preparing a compound of the formula:
wherein X and Y are the same and are selected from the group consisting of -CO2(C1-C6)alkyl, -CONH2 and -CONHOH, or X and Y, taken together, form a croup of the formula:
which process comprises:
(1) reacting 3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH2CO2H, wherein X is selected from the group consisting of -CO2(C1-C6)alkyl, -CONH2 and -CONHOH, in the presence of a base, to yield a compound of the formula (II) wherein X and Y are both -CO2(C1-C6)alkyl, -CONH2 or -CONHOH; or (2)(a) reacting a compound of the formula (II) wherein X and Y are both -CN with hydrogen peroxide to form the corresponding bis-amide in which both -CN groups are replaced by -CONH2; (b) subjecting the bis-amide formed in step (a) to a Hoffman rearrangement using an oxidizing agent to form the corresponding biscarbamate; and (c) reacting the biscarbamate formed in step (b) with a base to form a cyclic urea wherein X
and Y, taken together, form a group of the formula:

16. The process according to claim 15, wherein 3-hydroxy-4-methoxybenzaldehyde is reacted with HOOCCH2CONHOH, thereby preparing the compound of the formula (II) in which X and Y are both -CONHOH.

17. The process according to claim 15, wherein 3-hydroxy-4-methoxybenzaldehyde is reacted with HOOCCH2CONH2, thereby preparing the compound of the formula (III) in which X and Y
are both -CONH2.

18. The process according to claim 15, wherein 3-hydroxy-4-methoxybenzaldehyde is reacted with HOOCCCH2CO2(C1-C6)alkyl, thereby preparing the compound of the formula (III) in which X
and Y are both -CO2(C1-C6)alkyl.

19. The process according to any one of claims 15 to 18, wherein the base used in process step (1) is a tertiary amine.

20. The process according to claim 19, wherein both the tertiary amine and a secondary amine are employed in process step (1).

21. The process according to claim 20, wherein the secondary amine is piperidine or pyrrolidine.

22. The process according to claim 15, wherein process variant (2) is chosen.

23. The process according to claim 22, wherein:
process step (2)(a) is conducted using basic aqueous hydrogen peroxide in a polar solvent at a temperature of from 0°C to 100°C;
process step (2)(b) is conducted using bis(acetoxy)iodobenzene, bis(trifluoroacetoxy)iodobenzene, NaOCl, NaOBr or lead tetraacetate as the oxidizing agent in the presence of a base at a temperature of from -20°C to 100°C in a reaction-inert solvent; and process step (2)(c) is conducted by using an alkali metal alkoxide containing from one to six carbon atoms in a lower alcohol solvent at a temperature of from 0°C to 100°C.

24. A process for preparing a compound of the formula:
wherein X and Y are the same and are selected from the group consisting of -CN, -CONH2, -CO2(C1-C6)alkyl and -CONHOH, or X and Y, taken together, form a group of the formula:
which process comprises:
reacting a compound of the formula:
wherein X and Y are the same and are defined as above, with a triaryl or trialkylphosphine, an azo dicarboxylate and either R-(+)-endo-norborneol or S-(-)-endo-norborneol, respectively.

25. The process according to claim 24, wherein the reaction is conducted in an aprotic reaction-inert solvent at a temperature of from 10°C to 150°C.

26. The process according to claim 24 or 25, wherein the azo dicarboxylate is diisopropylazodicarboxylate, azodicarbonyldipiperidine or diethylazodicarboxylate.

27. A process for preparing a compound of the formula:
(wherein X and Y are the same and are selected from the group consisting of -CN, -CONH2, -CO2(C1-C6) alkyl and -CONHOH, or X and Y, taken together, form a group of the formula:

provided that X and Y are other than -CN in the formula (II)), which process comprises:.
[A] when the compound of the formula (II) is required:
(1) reacting 3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH2CO2H, wherein X is selected from the group consisting of -CO2(C1-C6)alkyl, -CONH2 and -CONHOH, in the presence of a base, to yield a compound of the formula (II) wherein X and Y are both -CO2(C1-C6) alkyl, -CONH2 or -CONHOH; or (2)(a) reacting a compound of the formula (II) wherein X and Y are both -CN with hydrogen peroxide to form the corresponding bis-amide in which both -CN groups are replaced by -CONH2; (b) subjecting the bis-amide formed in step (a) to a Hoffman rearrangement using an oxidizing agent to form the corresponding biscarbamate; and (c) reacting the biscarbamate formed in step (b) with a base to form a cyclic urea wherein X
and Y, taken together, form a group of the formula:

[B] when the compound of the formula (III) or (III') is required:
(1) reacting 3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH2CO2H, wherein X is -CN, -CO2(C1-C6) alkyl, -CONH2 or -CONHOH, in the presence of a base, to form a compound of the formula:

wherein X and Y are the same and are selected from -CN, -CONH2, -CO2(C1-C6) alkyl and -CONHOH; or (2) (a) reacting a compound of the formula (II) wherein X and Y are both -CN with hydrogen peroxide to form the corresponding bis-amide in which both -CN groups are replaced by -CONH2; (b) subjecting the bis-amide formed in step (a) to a Hoffman rearrangement using an oxidizing agent to form the corresponding biscarbamate; and (c) reacting the biscarbamate formed in step (b) with a base to form a cyclic area wherein X
and Y, taken together, form a group of the formula:

then (3) reacting the compound of formula (II) formed in step (1) or (2) above: with a triaryl or trialkylphosphine, an azo dicarboxylate, and either R-(+)-endo-norborneol or S-(-)-endo-norborneol, respectively.