IE55651B1 - Process for producing and separating diastereomeric urea derivatives - Google Patents

Description

& b ο 1 The present application has been divided out of our Patent Application Ho. 5 5 6 5 0 in which we have described and claimed a process permitting the 5 resolution of optical isomers of certain beta-adrenergic aryl- or hetaryl-oxypropanolamines, As explained in Patent Specification No. »δ 5 G ^ it is well established that many beta-adrenergic agents elicit more than a single biological 10 effect following administration. Resolution of the optical isomers of these agents which contain asymmetric centers has, in many instances, demonstrated marked differences in potency between these isomers. In addition to increasing knowledge of receptor site 15 topography, the pharmacologic profiles of the individual isomers may provide new and/or more desirable drug entities.

Previously, the optical isomers of ^-adrenergic agents have most generally been obtained by one of three 20 basic methods: 1) the fractional recrystallization of chiral acid salt derivatives; 2) synthesis of the single optical isomer using chiral epoxide 3 intermediates; and, more recently, 3) column chromatography utilizing chiral stationary phases. The difficulties associated with application of these methods are well known to practitioners in the art: specifically, the tedious and time-consuming fractional recrystallizations and repeated chromatography, requisite chiral syntheses of epoxide intermediates with the attendant complications associated with stereospecific synthesis, and size limitation of quantities obtained via chromatography. Generally, preparation of a single enantiomer by these methods is quite expensive.

Another resolving method, derivatization with a chiral organic reagent, has been used for resolution of compounds which can form derivatives. β-Adrenergic agents in general have two functional moieties amenable to derivatization, i.e. secondary amino and alcohol functionalities. The resolution of amines and alcohols by derivatization with chiral acyl halides or isocyanates is" well known in the chemical literature. The success of such a resolution strategy depends upon several factors, notably 1) formation of the diastereomeric derivatives in reasonably high yield, 2) facile separation of these diastereomers by chromatographic or crystallization techniques, and 3) the regeneration of the parent compound from the separated diastereomeric derivatives.

To our knowledge, this technique has never been utilized for the resolution of β-adrenergic propanolamines.

The following references disclose β-adrenergic propanolamines having a urea moiety incorporated into their structure. 1. O'Donnell, et al. Clin. Exp. Pharmacol.. 8/6, 614-615 (1981) disclose a β-adrenergic agent (ICI 89963) with a urea moiety in the terminal alkyl portion of the structure. 4 NHCH2CH2KHCNH ICX 89963 ο ft 2. Eckardt, et al., Die Pharmazie, 30, 633-637 (1975) disclose 6-blocking propanolamines with urea substituents on the aryl portion of the molecule: 5 OH Eckardt, et al.

These urea compounds differ structurally from the urea intermediates of the present process as the propanolamine nitrogen of the reference compounds is not a component of the urea grouping.

The next grouping of references relate to methods of 10 resolution of optical isomers which are deemed most relevant to the present process described herein. 3. J. Jacques, A. Collet, S. H. Wilen, in "Enantiomers, Racemates, and Resolutions", John Wiley & Sons, New fork, N.Y. (1981), pp. 330-335. This reference describes, among other things, formation 15 and separation of diastereomers comprising covalent derivatives of amines and alcohols. Specifically, amines may be resolved through conversion into diastereomeric ureas by reaction with optically active isocyanates; and, following separation of the diastereomeric ureas by crystallization or by chromatography, the resolved amine is recovered 20 through pyrrolysis. 4. F. C. Hhitmore in "Organic Chemistry", D. Van Nostrand Co., New York, N.Y. (1937), p. 551. This reference reports that dl-β-amino-lactic aldehyde dimethyl acetal, H^CH^CHOHCHtOCH^) 3 < .gave diastereomeric ureas when treated with JL-menthyl ieocyanate, as part of a scheme to prepare optically active glyceraldehydes.

. Kolomietes, et al, Zh. Org. Khim., English Edition, 16/5, pp. 854-857 (1980). This reference describes kinetic resolution of secondary alcohols.and amines using S-(-)-a-phenylethylisocyanate.

It is appreciated by the practitioner in the art, that derivatization of β-adrenergic aryloxypropanolamines might be expected to present difficulties by virtue of the molecule containing two reactive functionalities, e.g. both an amine and an alcohol moiety.

Reference 4., supra, is the only example of which we are aware that reports diastereomeric urea derivatization by isocyanate treatment of a molecule containing both amino and hydroxy moieties.

The compound being derivatized in the work mentioned by Whitmore is not related to the β-adrenergic propanolamine structure. The terminal primary amino group as opposed to the secondary hydroxyl in HjNCHjCHOH (0013)2 would be expected to be more accessible sterically to electrophilic attack by an isocyanate. Any steric advantage of the amino group is negated in β-adrenergic structures in which the amino nitrogen is further substituted with an alkyl group, which is usually branched, thereby giving a more hindered secondary amine. It would reasonably be expected prior to the present invention that reaction of an optically active isocyanate and a β-adrenergic aryloxypropanolamine would result in a complex product mixture containing both diastereomeric ureas and carbamates. In practice, it is discovered that the reaction 6 6 5 takes place preferentially at the site of the amine moiety, even v/hen sterically hindered, giving pre-dominently as novel intermediates the diastereomeric derivatives. This reaction selectivity forms the basis for the first step of the process of the present invention, as also for the first step of the process of Patent Specification No. 5 5 6 3.0 7 The process of Patent Specification No. Λ tiSy/ii’5 comprises treatment of the racemic mixture of ^-adrenergic propanolamines with a chiral isocyanate to give diastereomeric urea intermediates, separation of these 5 into the individual diastereomers, and facile generation of each optical isomer of the starting amine by cleavage of the intermediate urea compound with hydrazine hydrate.

In the present Application, however, we are 10 concerned only with the first two of the three steps just mentioned.

According to the present invention, in fact, we provide a process for producing and separating intermediate urea derivatives of Formula III δ Z-0-CH_CH-CH_-N-Y c, <£ , .

OX c=o NH Ar-CH '1 (III) wherein Z is substituted or unsubstituted aryl group for example'phenyl, tetralyl, indanyl, 5 indenyl or naphthyl; or a substituted or unsubstituted hetaryl group for example pyridine, benzopyridine, pyrrole, benzo-pyrrole, furan, benzofuran, thiophene, benzothiophene, pyrimidine, or thiadizole, 10 with the substituent or substituents bonded " to Z being a member or members selected from lower alkyl, lower alkoxy, lower alkenyl, lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower alkylthio, lower 15 alkanoyl, hydroxy-lower alkyl, cyano, lower cycloalkyl, lower cycloalkenyl, carbamoyl, lower alkylcarbamoyl, carbamoyl-lower alkyl, lower alkyl carbamoyl-lower alkoxy, lower alkyl-lower alkoxy, 9 lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy, lower alkenylthio, lower alkylthio-lower alkyl, lower alkoxy-lower alkylthio, halogen, halogen-lower alkyl, hydroxyl, carboxyl, Ν,Ν-dilower alkyl carbamoyl, N-lower alkyl 5 carbamoyl-lower alkyl, N,N-di-lower alkyl carbamoyl-lower alkyl, lower alkanoylamino-lower alkenyl, N-lower alkylamino, N,N-di-lower alkylamino, lower alkoxycarbonyl, lower alkoxy-carbonylamino, lower alkoxy-carbonylamino-lower alkyl, lower alkoxycarbonyl-10 amino-lower alkenyl, lower alkoxycarbonylamino-lower alkoxy, lower alkylcarbonylamino-lower alkyl, Ν'-lower alkyl-ureido, Ν,Ν'-di-lower alkyl-ureido, lower alkyl-sulfonylamino, nitro, lower alkenoyl, and N-morpholino; the word "lower" having the signification "up to Cg"r 15 Y is to alkyl or AB wherein A is an alkyl chain from 1 to 10 carbons, branched or unbranched, and B is a substituted or unsubstituted aryl or hetaryl group; X is hydrogen or R-CO- wherein R is C^-C^0 alkyl, phenyl, substituted phenyl, or alkylphenyl; Ar represents an aryl group, for example phenyl, substituted phenyl or naphthyl; and R1 is C^-Cg alkyl; said process comprising reacting a compound of Formula I Z-0-CH„CH-CH„NHY ^ | £ OX wherein Z, Y and X are as previously defined with a compound of Formula IX R1 * Ar-C-N=C=0 H wherein Ar and R^ are as previously defined so as to produce a pair of diastereomeric urea derivatives of Formula III and then separating said pair of diastereomeric urea derivatives of Formula III; said separating step being achieved by the use in the said reacting step of a reaction liquid In which one of said pair of diastereomeric urea derivatives of Formula III is soluble and the other of said pair of derivatives is insoluble. 11 The present improved process is convenient, and amenable to large-scale manufacture.

The following are optional or preferred features of the process of the present invention:- (a) Z is an ortho substituted phenyl ring; (b) Z is an ortho substituted pyridine ring; (c) A is a C2-C4 alkyl chain, branched or unbranched and B is an indole ring system; (d) X is hydrogen; 10 (e) R1 is methyl and Ar is 1-naphthyl.

It is preferred that X have ortho-substitution.

Where B is aryl, it may for example be phenyl, and, where B is hetaryl, it may additionally be a radical derived from, for example, 12 pyridine, benzopyridine, pyrrole, benzopyrrole, furan, benzofuran, thiophene, benzothiophene, pyrrolidine, or piperidine. Substituent groups attached to A comprise lower alkyl, alkoxy, alkenyl, nitro, hydroxy, amino, cyano, or halogen.

The substituent groups of the radicals Z and Y, listed above, may be more specifically defined. The term lower alkyl as used hereinabove denotes cyclic, straight and branched chain alkyl groups of 1-6 carbon atoms inclusive, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, or cyclohexyl 1 0 radicals bonded in any desired position.

The term lower alkenyl denotes straight and branched chain alkenyl groups of 2-6 carbon atoms, especially allyl or methallyl radicals.

The term lower alkynyl includes the straight or branched 15 chain alkynyl groups of 2-6 carbons, with the propargyl radical being especially suited.

The term lower alkyloxy or lower alkoxy denotes straight or branched chain alkoxy groups of 1-6 carbon atoms, for example, methoxy, ethoxy, propoxy and butoxy. 13 The term lower alkenyloxy denotes straight and branched chain lower alkenyloxy groups and the positional isomers thereof, having 2-6 carbons, for example, ethenoxy, propenoxy and butenoxy.

The term lower alkynyloxy embraces straight and branched 5 chain alkynyloxy groups of 2-6 carbon atoms, such as, for exaitple, ethynyloxy, 2-propynyloxy and 3-butynyloxy.

The term lower alkoxy-lower alkyl embraces» for exaitple, methoxymethyl, ethosynethyl and isoprqpoxyethyl. The term lower alkoxy-lower alkoxy embraces for example methoxymethoxy, methoxyethoxy, 10 ethoxyethoxy and etho>yisopropoxy. The term hydroxy-lcwer alkyl is, for example, hydroxymethyl and 1- or 2- hydroxyethyl.

The term lower alkylthio is, for example, methylthio, ethylthio, isopropylthio and n-butylthio. The term lower 15 alkenylthio is illustrated by, for exanple, 1-propenylthio, 1-butenyl- thio and 3-pentenylthio. Lower alkylthio-lower alkyl is illustrated by, for exanple, nethylthiomethyl, nethylthioethyl and 2-ethylthioethyl, Lower alkoxy-lower alkylthio is illustrated by, for exanple, methoxy-methylthio and ethoxymethylthio.

The term halogen is depicted by fluorine, chlorine, bromine, and iodine, especially fluorine or chlorine. The term halogen-lower alkyl is exemplified by, for exanple, trifluoromethyl and trichloronethyl.

It should also be understood that certain substituents as in the group set forth hereinabove may be attached to the Z ring at two sites,. usually adjoining ring atoms, to give, for example: tetralins, tetralones, indanes, indanones and indenes.

Adrenergic propanolamines embraced by structure I for the purpose of this invention are exemplified by the following beneficial 14 drugs which contain centers of asymmetry. Exemplary drugs are acehutolol or N-[3-acetyl-4-[2-hydroxy-3-[(l-methylethyl)amino]propoxy]-phenyl]butanamide; alprenolol or l-[(l-methylethyl)amino]-3-[2-(2-propenyl)-phenoxy]-2-propanol; atenolol or l-£-carbamoylmethyl-5 phenoxy-3-isopropylamino-2-propanol; bevantolol or l-[(3,4-dimethoxy-phenethyl)amino]-3-(m-tolyloxy)-2-propanol; buprenolol or l-(tert.-butylamino)-3-[(6-chloro-m-tolyl)oxy]-2-propanol; bunitrolol or 2-[3-[l,l-dimethylethyl)amino]-2-hydroxypropoxy]benzonitrile; bunolol or 5-[ 3-(1,1-dimethylethyl) amino]-2-hydroxypropoxy]-3,4-dihydro-l (211) -10 naphthalenone; exaprolol or 1-(o-cyclohexylphenoxy)-3-(isopropylamino)-2-propanol; indanolol or l-[indan-4-yloxy)-3-[l-methylethylamino]-2-propanol; metoprolol or 1-(isopropylamino)-3-[£-(2-methoxyethy1)phenoxy]-2-propanol; moprolol or l-(2-methoxyphenoxy)-3-I(1-methylethyl)amino]- 2- propanol; oxprenolol or l-(isopropylamino)-2-hydroxy-3-[£-(allyloxy)-15 phenoxy]propane; pamatolol or methyl-[£-[2-hydroxy-3-(isopropylamino)- propoxy]phenethyl]carbamate; pehbutolol or l-(2-cyclopentylphenoxy)- 3- [(l1l-dimethylethyl)amino]-2-propanol; pargolol or l-(tert.-butylamino)-3-[o-(2-propynyloxy)phenoxy]-2-propanol; procinolol or l-(o-cyclo-propylphenoxy)-3-(isopropylamino)-2-propanol; practolol or 1-(4- 20 acetamidophenoxy)-3-isopropylamino-2-propanol; tiprenolol or l-[(1-methylethyl)amino]-3-[2-(methylthio)-phenoxy]-2-propanol; tolamolol or 4-[2-[[2-hydroxy-3-(2-methylphenoxy)propyl] amino]ethoxy]benzaffiide; toliprolol or l-(isopropyIamino)-3-(m-tolyloxy)-2-propanol; nadolol or l-(tert.-butylamino)-3-[(5,6,7,8-tetrahydro-cis-6,7-dihydroxy-l-25 naphthyl)oxy]-2-propanol; pindolol or l-(indol-4-yloxy)-3-(isopropyl- amino)-2-propanol; and timolol or 1-(tert.-butylamino)-3-Γ(4-mornholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol. These beta-adrenergic propanol-amines are known to the art, appearing in the Merck Index, Unlisted 15 Drugs, USAN and USF Dictionary of Drug Names, and Annual Reports in Medicinal Chemistry, Vol. 10, pages 51-60 (1975), and ibid., Vol, 14, pages 81-90 (1979).

Certain conventions are used by those skilled in the art to 5 designate optical rotation and spatial configuration of optical isomers. Individual enantiomers are commonly designated according to the optical rotation they effect, by (+) and (-), (1) and (d), or Combinations of these symbols. The symbols (L) and (D) and the symbols (S) and (R), which stand for sinister and rectus, respectively, designate an absolute 10 spatial configuration of the enantiomer. A complete resolution utilizing the present process is detailed below.

Assignment of absolute configuration to the enantio mers separated therein is tentative and is based on the usual assignment of ^-configuration to the β-adrenergic aryloxypropanol-15 amine enantiomer with negative rotation. ' The following flow chart, Scheme 1, illustrates the resolution of a racemic mixture of β-adrenergic propanolamines utilizing the processes of parent Patent Specification No.3. /;'.>,·£' (the entire Scheme) and of the present Application (all but the final cleavages with hydrazine hydrate). 16 Scheme 1 [Step 1] R. s -* Z-0-CH.-CR-CH,-N-Y * I OX oo m Z-0-CH_-CH-CH,NH-Y + Ar- C-N=O0 £. I i , H (chiral) or (S),(R)-III OX (racemic X mixture) or (5),(8)-111 nh2m2 [Step 3] HH2NH2 00- or (S)-I (S)- or (R)-X In Scheme 1, X, Y, and Z are as defined above; Ar represents an aryl group such as phenyl, substituted phenyl or naphthyl, preferably 5 1-naphthyl; R^" can be a C^-Cg alkyl group, preferably methyl; and an asterisk denotes centers of asymmetry in the molecule. It is to be understood that other optically active isocyanates, e.g. menthyl isocyanate, may also be used in the present process.

Step 1 of the Scheme outlined above involves the reaction 10 of the adrenergic propanolamine with a chiral isocyanate of structure II to give a pair of novel diastereomeric ureas of Formula III. The reaction of step 1 is accomplished simply by stirring together equimolar quantities of the adrenergic amine, in its free base form, 17 and the chiral isocyanate in an inert organic liquid medium for several hours at approximately 25° C. The temperature can range from ambient room temperature up to the reflux temperature of the particular organic liquid used as reaction medium. This reaction is usually 5 complete within four to eight hours. Suitable reaction liquids include but are not limited to benzene, tetrahydrofuran, dibutyl-ether and dimethoxyethane. A preferred reaction liquid is benzene.

In the process of the present invention, as already indicated, an appropriate reaction liquid is chosen which 10 permits the separation of the diastereomeric ureas by virtue of one of the diastereomers being soluble in the liquid and the other being insoluble. 18 The subject process, as mentioned, is particularly adaptable to large-scale resolution and in that respect is both economical and convenient. The process may, for example, comprise: (1) treating an appropriate β-adrenergic aryl- or 5 hetaryl-oxypropanolamine, in the form of a racemic mixture, with a chiral isocyanate such as resolved l-(l-naphthyl) ethyl isocyanate, by stirring for six to 12 hours in an inert organic liquid medium such as benzene at a temperature of from about ambient room 10 temperature up to the reflux temperature of the organic liquid, thereby giving a pair of dlastereomeric ureas (in); (2) separation of the diastereomeric pair into individual diasteromers by virtue of one of them being 15 soluble, and the other insoluble, in the benzene or other inert organic liquid medium employed. 19 The process of this invention is further illustrated by the following examples, but these examples should not be construed as limiting the scope of the present invention. Melting points were determined using a Thomas-5 Hoover capillary melting point apparatus and are uncorrected. All temperatures are expressed in degrees Celsius. Optical rotation measurements were obtained on a Bendix-NPL 1169 automatic polarimeter with digital readout. The (R) - (-) -(1-naphthyl) ethyl isocyanate 10 can be prepared as reported in the literature (Pirkle et al, J. Org. Chem., 39 (1974) pages 3904-3906) or is available commercially (Aldrich Chemical Company).

Scheme 2 illustrates a specific procedure carried out with bucindolol (IA), which is an antihypertensive 15 agent currently under clinical investigation. Like Scheme 1, Scheme 2 illustrates the utilization of both Patent Specification 140.2./-1^0 (the entire Scheme) and the present Application (all but the final cleavages with hydrazine hydrate). 2.0 Scheme 2 νη2νη2·η2ο EtOH ΝΗ2ΝΗ2·Η20 EtOH 78¾ (R)-C±)-IA In examples which follow, the nuclear magnetic resonance (HMR) spectral characteristics refer to chemical shifts (6) expressed 5 as parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the ¾ NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs), singlet (s), 10 multiples (m), or doublet (d). Abbreviations employed are DMSO-dg (deuterodimethylsulfoxide), CDCl^ (deuterochloroform) and are otherwise 21 conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm having functional group identification value. The IR determinations were employed using potassium bromide (KBr) as diluent. The elemental analyses are reported as percent by 5 weight.

EXAMPLE 1 Diastereomeric Prea Derivatives of Bucindolol A hot solution of bucindolol hydrochloride salt (100 g, 0.28 mole) and 2.5 L of HjO was made basic with a 10% solution of 10 NaOH. Bucindolol is 2-[2-hydroxy-3-[[2-(lH-indol-3-yl)-l,1-dimethyl-ethyl ) amino ]propoxy]benzonitrilej cf: Kreighbaum, et al, U.S. Patent No. 4,234,595 patented November 18, 1980, and Journal of Medicinal Chemistry, 23:3, 285-289 (1980). After being allowed to cool, the aqueous layer of the basic mixture was decanted.and the residual gum 15 rinsed with HjO and crystallized from isoptopyl alcohol (500 ml) to provide 81 g of bucindolol free base, m.p. 126-128°C. The aqueous layer was allowed to stand overnight at 15°C, and a precipitate was collected by filtration, washed with HjO, and dried in air overnight to give a further 3.5 g of bucindolol free base. This material, a 20 mixture of (R,_S)-bucindolol base, was then derivatized.

A mixture of (R,S)-bucindolol base (1.8 g, 0.005 mole), (R)-(-)-l-(l-naphthyl)-ethylisocyanate (1.0 g, 0.005 mole), and benzene (100 mL) was stirred at 25¾ for 6 hrs. A white solid was removed by ' filtration and dried in air to give 1.24 g of (S), (R)-N-[3-(2-25 cyanophenoxy)-2-hydroxypropyl]-N-[1,1-dimethyl-2-(lH-indol-3-yl )- ethyl]-N'-[l-(l-naphthyl)ethyl]urea. This urea derivative melted at 167-168°C and gave a single spot on TLC (silica gel; CHjCl^Ethylacetate 9:1) and rotation of [a]*5 -14? (C 0.5%, CH30H). ° 2 Anal. Calcd. for C, 74.98; H, 6.48; N, 10.00.

Found: C, 74.89; H, 6.46; H, 9.74.

NMR (DMSO-dg): 1.38 (6,s); 1.52 (3,d [6.7 Ha]); 3.35 (4,m); 3.94 (3,m); 5.70 (l,m); 6.23 (1,6s); 7.01 (5,m); 7.59 (11,m); 8.27 (l,d 5 [9.5 Hz]); 10.72 (l,bs).

IR (KBr): 745, 1110, 1260, 1490, 1530, 1600, 1630, 2230, 2930, 2970, 3050, 3350, and 3410 cm"1.

The benzene filtrate from above was concentrated to dryness and the residual material chromatographed on silica gel eluting with 10 CHjClj-Ethylaostate (9:1) to give 0.70 g of (R), (R)-N-[3- (2-cyanqjhemoxy)·-2-hydroxypropyl]-N^[l,l-dimethyl-2-(lH-indol-3-yl)ethyl]-Nl-[1-(1-naphthyl)ethyl]urea as a foam. This material which did not crystallize had a rotation of [o]^ -119° (C 0.5%, CH^OH).

Anal. Calcd. for C^H^iyyliEtOAc: C, 73.49; H, 6.67; 15 N, 9.27. Found: C, 73.29; H, 6.60; N, 9.18.

HMR (DMSO-dg): 1.36 (3,s); 1.52 (6,m); 3.36 (4,m); 3.92 (3,m); 5.76 (l,m); 6.30 (l,bs); 7.00 (5,m); 7.55 (11,m); 8.26 (l,d [9.0 Hz]); 10.78 (l,bs).

IR (KBr): 745, 1115, 1260, 1495, 1540, 1600, 1635, 2220, 2930, 20 2980, 3060, 3350, and 3420 cm"1.

Treating racemic mixtures of other Formula I adrenergic amines with chiral isocyanates (II) using reaction procedures similar to those outlined above gives diastereomeric urea intermediates. Some additional examples of these are listed in Table 1. 23 Table 1 Adrenergic Propanolamine Urea Derivatives Z0CH2CHCH2NHY + ox ArCHN=C=0 + ZOCH,CHCH,NHCNHCHAr — 1 — It OX 0 (I) (ID (III) I - II Example X Y z R Ar 2 H H 2-cyanopyridyl Me phenyl 3 H i-Pr 2-(2-propenyl)phenyl Me 1-naphthyl 4 H i-Pr 1-naphthyl Me 1-naphthyl 5 H t-Bu "B= Me phenyl 6 H i-Pr 2-(2-propenyloxy)-phenyl Me phenyl 7 H i-Pr 4-(lH-indolyl) Et phenyl 8 H i-Pr 4-acetanilide Me 1-naphthyl 9 H i-Pr 2-(methylthio)phenyl Me 1-naphthyl 10 H i-Pr 2-cyanopyridyl Et 1-naphthyl 11 H t-Bu ' 2-cyanopyridyl Me 4-nitrophenyl 12 acetyl 2- (benzothiophen- 2-cyanopyridyl 3- yl)-1,1-dimethyl ethyl Me 1-naphthyl 13 H 2-(lH-indol-3-yl)- 2-cyanopyridyl Me 1-naphthyl 1,1-dimethylethyl Please note that in Table 1 and throughout this document i-Pr means isopropyl, t-Bu means tertiary butyl, Me means methyl, and Et means ethyl. Also degrees are given in degrees Centrigrade.

Claims (13)

1. 24. CLAIMS : 1A process for producing urea derivatives of Formula z-o-ch2ch-ch2-n-y OX C=0 1 NH * and separating intermediate III (III) wherein Z is a substituted or unsubstituted aryl group or a substituted or unsubstituted hetaryl group with the substituent or substituents bonded to Z being a member or members selected from lower alkyl, lower alkoxy, lower alkenyl, lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower alkylthio, lower alkanoyl, hydroxy-lower alkyl, cyano, lower cycloalkyl, lower cycloalkenyl, carbamoyl, lower alkylcarbamoyl, carbamoyl-lower alkyl, lower alkyl carbamoyl-lower alkoxy, lower alkyl-lower alkoxy, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy, lower alkenylthio, lower alkyl-thio-lower alkyl, lower alkoxy-lower alkylthio, halogen, halogen-lower alkyl, hydroxyl, carboxyl, N,N-dilower alkyl carbamoyl, N-lower alkyl carbamoyl-lower alkyl, N,N-di-lower alkyl carbamoyl-lower alkyl, lower alkanoylamino-lower alkenyl, N-lower alkylamino, N,N-di-lower alkylamino, lower alkoxy-carbonyl, lower alkoxy-carbonylamino, lower alkoxy-carbonylamino-lower alkyl, lower alkoxycarbonylamino-lower alkenyl, lower alkoxycarbonylamino-lower alkoxy, lower alkylcarbonylamino-lower alkyl, Ν'-lower alkyl-ureido, N,N'-di-lower alkyl ureido, lower alkylsulfon-ylamino, nitro, lower alkenoyl, and N-morpholino; the word "lower" having the signification "up to Cg"; Y is to C1Q alkyl or AB, wherein A is an alkyl chain from 1 to 10 carbons, branched or unbranched, and B is a substituted or unsubstituted aryl or hetaryl group; X is hydrogen or R—CO— wherein R is C1~C10 alkyl, phenyl, substituted phenyl, or alkylphenyl; Ar represents an aryl group ; R1 is C^-Cg alkyl; said process comprising reacting a compound of Formula X z-o-ch2ch-ch2nhy OX wherein Z, Y and X are as previously defined with a compound of Formula II Ar-C-N=C=0 H wherein Ar and R1 are as previously defined so as to produce a pair of diastereomeric urea derivatives of Formula III and then separating said pair of diastereomeric urea derivatives of Formula III; said separating step being achieved by the use in the said reacting step of a reaction liquid in which one of said pair of diastereomeric urea derivatives of Formula III is soluble and the other of said pair of derivatives is insoluble.

2. A process according to claim 1, wherein Z in Formula III is a substituted or unsubstituted aryl group selected from phenyl, tetralyl, indanyl, indenyl and naphthyl.

3. A process according to claim 1, wherein Z in Formula III is a substituted or unsubstituted hetaryl group selected from pyridine, benzopyridine, pyrrole, benzopyrrole, furan, benzofuran, thiophene, benzo-thiophene, pyrimidine and thiadiazole.

4. A process according to any one of claims 1 to 3, wherein Ar represents an aryl group selected from phenyl,. substituted phenyl and naphthyl. 26

5. A process according to claim 1, wherein Z is an ortho substituted phenyl ring.

6. A process according to claim 1, wherein Z is an ortho substituted pyridine ring. 5

7. A process according to any one of claims 1 to 6, wherein A is a C2~C^ alkyl chain, branched or unbranched, and B is an indole ring system.

8. A process according to any one of claims 1 to 7, wherein X is hydrogen. 10

9. A process according to any one of claims 1 to 8, wherein R1 is methyl and Ar is 1-naphthyl.

10. A process according to claim 1, wherein N-[3-(2-cyanophenoxy)-2-hydroxypropyl]-N-[1,l-dimethyl-2-(1H-indol-3-yl)ethyl]-Ν'-[1-(1-naphthyl)ethyl]urea diaster- 15 eomers are produced and separated.

11. A process according to any one of claims 1 to 10, wherein the said reaction liquid is benzene.

12. A process according to claim 1, substantially as described in respect of any of the foregoing Examples. 20

13. A urea derivative of the Formula III specified in claim 1, whenever prepared by a process claimed in any of claims 1 to 12. Dated this the 28th day of August , 1987. F. R. KELLY & CO. BY: 27, Clyde Road , BalQ/sbric EXECUTIVE 'sbridge, Dublin 4. AGENTS FOR THE APPLICANTS.