GB2197650A - Process for preparing 2,5-diphenyl tetrahydrofurans and analogs thereof - Google Patents

Abstract

A process for preparing (-)-trans-2-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-5-(3, 4, 5-trimethoxyphenyl) tetrahydrofuran and other 2,5-diphenyl tetrahydrofurans has been developed. The process involves the cyclization of an appropriate stereoisomeric 1,4-butane-diol by dehydration in acidic medium. The 2, 5-diphenyl tetrahydrofurans are useful as PAF (platelet-activating factor) antagonists.

Description

PROCESS FOR PREPARING 2,5-DIPHENYL TETRAHYDROFURANS AND ANALOGS THEREOF BACKGROUND OF THE INVENTION 2,5-Diaryl tetrahydrofurans have been disclosed in copending application Sr. No. 852,07 as PAF (platelet-activating factor) antagonists. The compounds are of formula (I)

wherein Ar, R4, Y and R6 are as defined below.

Certain procedures for the preparation of these 2,5-diaryl tetrahydrofurans have been described in Serial No. 852,607. However, the yields from those procedures are generally low. For example, according to the procedures described in the specification of Serial No. 852,607, the total synthesis of trans-2-(3-methoxy-5-methylsulfonyl-4-propoxy phenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (Compound A) required extensive chromatography and the overall yield of the racemic mixture is only 19%.

On the other hand, the overall yield of compound A is 30% according to the procedures of the present invention and minimum chromatography is required.

Accordingly, it is the objective of this invention to provide a new process with improved yields for preparing 2,5-diaryl tetrahydrofurans, and the resolution of the racemates into optically active enantiomers useful as PAF-antagonists.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a process for the preparation of 2,5-diaryl tetrahydrofurans of formula

wherein Ar is (a) phenyl or substituted phenyl of formula

where R4-R8independently represent R2, wherein R2 represents H, C1-8 alkyl e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, pentyl and hexyl, C3-8 cycloalkyl, e.g., cyclopropyl, cyclopentyl and cyclohexyl, loweralkenyl especially C1-6 alkenyl e.g., vinyl, allyl, CH3CH=CHCH2-CH2, and CH3(CH2)3CH=CH-; YO-wherein Y is R, loweralkenyl such as -CH2-CH=CH2, loweralkynyl such as -CH-C-CH,

-CH2-C(O)OR, -CH2-OR, CH2AR -CH2C3-8- cycloalkyl such as

wherein Ar is phenyl or substituted phenyl; -CH2-CH(OH)-CH2OH; RS-; RSO; RSO2; CR3O-; CF3S-; CF3SO; 2 3 3 CF3S02;CH3OCH2-O-; R2R3N-, wherein R3 2 3 independently is R ; -OCH2CO2R; -SO2NR R -CO2R; -CONRR ; -NRCOR ; -OCONH2; -CRR R9; -CH2OR; -CH2CO2R; -CH2OCOR ; -CH2O-CO-OR; -NHCH2COOR; halo such as F, Cl, Br and I; N+RR R9X- wherein X is an anion and R9is the same as or different from R2; NRSO2R ; COR; NO3;CN; or R4-R5, R5-R6, R6-R7 and R7-R8 are joined together and form a bridge such as -OCH20-, -OCH2CH2-O- and -OCH2CH2N-; (b) monoheteroaryl, di- or polyheteroaryl, or fused heteroaryl containing from 1 to 3 of any one or more of the heteroatoms N, S or O in each heteroaryl ring thereof and each ring may either be unsubstituted or substituted appropriately with a radical selected from a group consisting of R4-R8, for example, pyridyl, pyrryl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbozolyl, and isoxazolyl and the like.

The following are the preferred heteroaryl groups: (1) pyrryl or pyrryl substituted with R4 -R6; (2) furyl or furyl substituted with R4-R6; (3) pyridyl or pyridyl substituted with R -R ; (4) thiophene or thiophene substituted with R -R ; (5) thiazolyl or thiazolyl substituted with R4~R5; or (6) pyrimidyl or pyrimidyl substituted with R4 -R 6 (c) heteroarylalkyl such as 2-pyridylmethyl, 2-thienylmethyl and 3-isothiazolylethyl; (d) heterocycloalkyl e.g., 1,3-dioxacyclohex-4-yl, piperidino, morpholino, oxacyclopropyl, pyrrolidino, tetrazolo, benzothiazolo, imidazolidino, pyrazolidino, and piperazino; or (e) heterocycloalkenyl such as pyrrolino, 2-imidazolidino, 3-pyrazolino or isoindolino.

In a preferred embodiment, the process of this invention is used for making a compound of formula:

or an enantiomer thereof wherein Ar, R4, R6 and Y are as previously defined.

The process of the present invention is illustrated by the following scheme: Part I: Preparation of 2,5-diaryl tetrahydrofuran derivatives according to the process of the present invention.

Ste I-A:

wherein Y and R6 are as previously defined and Y is iodo or bromo.

Step I-B:

ArCOCH3 + (HCHO)x/(CH3)2NH-HC1 1. C2H5OH/HCl 2. 2. NaOH/H2O Ar (CO) CH2CH2N (CH3)2 ArCOCH=CH2 L. /PI Heat III IIIa wherein Ar is as previously defined, and X is an integer.

Step I-C:

NaCN or II + (III or IIIa) thiazolium salts DMF 1 Ar(CO)CH2CH2(CO)Ar IV Ar is

Step I-D:

Step I-E:

In Step I-A, the conversion of the phenol group OH to OY can be effected by a base such as K2CO3, Na2CO3, and the like in a polar aprotic solvent, for example, DMF, DMSO, HMPA, or acetone, methyl ethyl ketone, etc., at about 60 -100 C, preferably at 750-850C.

In Step I-B, the condensation can be catalyzed first by a strong acid including HC1, HBr, and H2SO4 followed by neutralization with a strong base such as NaOH and KOH. The reaction is normally carried out at reflexing temperatures which can range from 40 - 1200C. The solvents that can be used for the condensation are 1-6 alkanols including methanol, ethanol, propanol and butanol or other polar solvents.

In Step I-C, reagents other than NaCN such as KCN, LiCN and other metallic cyanides or thiazolium salts may also be employed. The reaction is normally performed in solvents including DMF, DMSO, alkanols such as methanol, ethanol and the like at about 250 50"C preferably at 350C.

In Step I-D, the reduction is by sodium borohydride, lithium aluminum hydride or other reducing agents. Other loweralkanols such as methanol may be used to replace ethanol for reductions using NaBH4. In the case when lithium aluminum hydride is used as the reducing agent, the preferred solvents are those aprotic solvents such as ether and THF under anhydrous conditions.

In Step I-E, the ring closure may also be effected by acids other than CF3COOH. For example, p-toluenesulfonic acid, methane sulfonic acid or a Lewis acid such as borontrifluoride etherate may also be used. Solvents including CHC13, CH2C12, CCl4, THF, benzene, toluene, and xylene, preferably CHCl31 are normally used for the reaction.

In the isomerization of VII to VI, acids other than trifluoroacetic acid such as hydrochloric acid, sulfuric acid, P-Toluenesulfonic acid, methane sulfonic acid, trimethylsilyl chloride and sodium iodide are also effective. Most organic solvents including cholorform, dichloromethane, benzene, toluene, xylenes and lower alkanols such as methanol and ethanol can be used for the isomerization.

Part II: Resolution of racemates of asymmetric 2,5 diaryl tetrahydrofurans Step II-A:

SteII-B:

IX wherein base is 4-dimethylaminopyridine or other organic bases; and M is

Step II-C:

Step II-D:

Step II-E:

In Step II-A, controlled reduction was required, generally 0.3 equivalent of NaHBH4 per equivalent of IV was used and the reaction was conducted at 450C for 1-3 hours. Other lower alkanols such as methanol can also be used.

In Step II-B, acidic resolving agents such as (-)-R-Q-methyl-mandelic acid, its (+)-(S)-isomer, mandelic acid, a-methoxy-a-trifluoromethylphenyl- acetic acid, or menthonyl acetic acid and the like can also be used.

The diastereoisomers can be separated by column chromatography on silica gel or by HPLC.

In step Il-C, saponification can be accomplished with an inorganic base such as KOH, NaOH, Ba (OH)2 and Li (OH) in an alcoholic solvent, for example, ethanol, methanol and other C14 alkanols. Steps II-D to II-E are the specific applications of previously described steps I-D-E.

An important application of the process is the preparation of (-)-trans-2-(3-methoxy-5-methyl- sulfonyl-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (Compound A) according to the following scheme: Chemical Synthesis of Compound A (as Illustrated by @xample 1)

Resolution of Racemic Compound A (as illustrated by Example 2)

The detailed procedures according to the scheme are described below in Examples 1 and 2.

EXAMPLE 1 (-)-Trans-2-(3-methoxy-5-methylsulfonyl-4-propoxy- phenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran Step (a): Preparation of 5-Iodo-3-methoxy-4-propoxy benzaldehvde (1) n-Propyl bromide (29.2 mL, 0.32 mol) was added to a solution of 5-iodovanillin (50.0 g, 0.18 mol) in DMF (200 mL) containing potassium carbonate (48 g, 0.35 mol) at 80"C. The mixture was stirred at this temperature for 1 hour, cooled and the solvent was decanted into a separatory funnel containing ethyl ether and water. The ethereal layer was washed with cold 2.5 N sodium hydroxide and water, dried, and evaporated in vacuo to give (1) as an oil (52 g, 90%), which was used directly without further purification.

Anal. Calc. for C11H13IO3: C, 41.27; H, 4.09; Found: C, 41.59; H, 4.15.

Step (b): Preparation of N,N-Dimethylethyl 3,4,5 trimethoxynhenyl ketone (2) Conc. hydrocloric acid (1 mL) was added to a stirred mixture of 3,4,5-trimethoxyacetophenone (210 g, 1 mol), dimethylamine hydrochloride (81 g, 1 mol) and paraformaldehyde (45 g, 1.5 mol) in ethanol (300 mL). The reaction mixture was heated under reflux for 1 hour. Another batch of paraformaldehyde (30 g, 1 mol) was added, and the heating was continued for another 2 hours. The warm reaction mixture was poured with vigorous stirring into acetone (2.4 L).

The slurry was heated at 600C for 15 minutes, cooled, and filtered. The solid was washed with acetone and dried to give the hydrochloride salt of a (196 g, 65%), mp 175"C.

A mixture of the above hydrochloride (147.5 g, 0.48 mol) in 1 N NaOH (750 mL) was shaken with ethyl acetate (4 x 100 mL). The combined organic extracts were washed with aqueous sodium chloride, dried, and evaporated in vacua to give 2 (126 g, 97%), mp 45-470C.

Step (c): Preparation of 1-(5-iodo-3-methosy-4- propoxyphenyl)-4-(3,4,5-trimethoxyphenyl 1.4-butanedione (3) A solution of 1 (26 g, 0.08 mol), 2 (18 g, 0.07 mol) and sodium cyanide (2.6 g, 0.053 mol) in DMF (250 mL) was stirred at 35 C for 1.5 hours. It was poured into ice-cold 10% hydrochloric acid (2 L), and the solid was filtered, dried by suction, and taken up in dichloromethane. The organic layer was washed with aq. sodium bicarbonate, water, dried, filtered, and the filtrate was evaporated to dryness to give a crude product which by crystallization from Et2O-hexane gave purified 3 (24 g, 61%), mp 111-112 C.

Step (d): Preparation of 1-(3-methosy-5-methylthio-4- propoxyphenyl)-4-(3,4, 5-trimethoxyphenyl- 1.4-butanedione (4) A mixture of copper (10 g, 0.16 mol), methyl disulfide (10 mL, 0.11 mol) in 2,4-lutidine (100 mL) was heated with stirring at 1250C for 2 hours.

Compound 3 (14 g, 0.03 mol) was added to the mixture, and the contents were heated at 1600C for 16 hours.

The reaction mixture was filtered, and the filtrate was concentrated to a residue, which was taken up in dichloromethane. The organic phase was filtered through silica gel (100 g), and the solid was washed with dichloromethane and ethyl acetate. The combined filtrates were evaporated to afford the crude product.

Ethyl ether was added to the crude product to induce crystallization and the crystals were collected (8.85 g, 73%), mp 113-1140C.

Anal. Calc. for C24H30SO7: C, 62.32; H, 6.54; S, 6.93; Found: C, 62.69; H, 6.69; S, 7.02.

Step (e); Preparation of 1-(3-methoxy-5-methylsulfonyl 4-propoxyphenyl)-4-(3,4,5-trimethoxythenyl)- 1,4-butanedione (5) 3-Chloroperbenzoic acid (23 g, 0.13 mol) was added to a stirred solution of 4 (26 g, 0.056 mol) in dichloromethane (250 mL). After 2 hours at room temperature, the mixture was cooled, filtered, and the filtrate was evaporated to a small volume. Ethyl ether was added and the resultant crystals were filtered and washed with ethyl etherhexane to give ffi (24 g, 86%), mp 138-140"C. An analytical sample was recrystallized from methanol, mp 145-146"C.

Anal. Calc. for C24H30SOg: C, 58.29; H, 6.11; S, 6.48; Found: C, 58.23; H, 6.17; S, 6.46.

Step (f): Preparation of 1-(3-methoxy-5-methylsulfonyl 4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl) 1.4-butanediol (6) Sodium borohydride (2.3 g, 0.06 mol) was added to a suspension of 5 (23 g, 0.046 mol) in ethanol (300 mL), and the mixture was heated with stirring at 70 C for 1 hour. The solution was cooled and partioned between dichloromethane and 2.5 N hydrochloric acid. The organic layer was separated, washed with water, dried, and evaporated to a syrup (23.5 g, quantitative yield) containing (E) which was used directly in the next experiment without further purification.

Step (g): Preparation of trans-and cis-2-(3-methoxy-5- methylsulfonyl-4-propoxyphenyl)-5-(3,4,5 trimethoxyphenyl)tetrahydrofuran (7 & 8) Trifluroacetic acid (10% in chloroform, 150 mL) was added to a solution of 6 (22.5 g, 45 mmol) in chloroform (150 mL) at room temperature. After 35 minutes, anhydrous sodium carbonate (25 g) was added and the mixture was stirred for 10 minutes.The solid was filtered off and the filtrate was evaporated to a residue, which was purified by preparative HPLC (hexane-ethyl acetate, 2:1; v/v) to give a mixture of the cis isomer (8; 5.0 g,), mp 150-1510C and the more mobile trans isomer (7; 9.6 g, mp 99-1000C (Et2O-pet.Et2O); NMR (CDCI3): 6 1.05 (t, J = 7.5 Hz, CH3), 1.89 (m, CH2CH2CH3), 1.89 and 2.49 (2 m, H-3 & H-4), 3.26 (s, SO2CH3), 3.85, 3.89 and 3.93 (3 s, 4 OCH3), 4.12 (t, CH2CH2CH3), 5.16-5.28 (H-2 b H-5), 6.62 (s, C5ArH), 7.27 and 7.51 (2 d, J = 1.5 Hz, C2ArH).

The combined yield of cis and trans-isomers (7) and (8) was 73%.

Anal. Calc. for C24H32SO8 (2): C, 59.98; H, 6.71; ,6.67; Found: C, 59.97; H, 6.67; 6,6.90.

Anal. Calc. for C24H32SO8 (8): C, 59.98; H, 6.71; S, 6.67; Found: C, 60.09; H, 6.80; , 6.58.

Isomerization of 8 to 7 Trifluroacetic acid (10% in chloroform, 20 mL) was added to a solution of ss (5 g) in chloroform (20 mL) at room temperature. After 1 hour, anhydrous sodium carbonate (10 g) was added and the mixture was stirred for 15 minutes. The solid was filtered off and the filtrate was evaporated to dryness. Warm ethyl ether was added and the cis isomer (8) crystallized out (2 g). Hexane was added and the solution was cooled, and the trans isomer (2) crystallized (1.76 g) out. The above process can be repeated with more 8.

In the preparation of 4, 2,4-lutidine may be replaced by 2,6-lutidine, B-collidine or any other tertiary base such as triethylamine in a solvent such as DMF.

Compound 4 can be prepared from X and metallic thiomethyls such as copper thiomethyl and silver thiomethyl etc., in E-methyl-2-pyrrolidinone.

Alternatively, A may be prepared from 3 and metallic thioacylates such as copper thiobenzoate and copper thioacetate followed by methylation of the mercaptan intermediate with methyl iodide.

In the preparation of , other perbenzoic acids and peralkanoic acids may also be used. Common oxidants such as hydrogen peroxide, chromic acid and potassium dichromate can also be used in place of 3-chloroperbenzoic acid. Other halogenated solvents such as chloroform and carbon tetrachloride; aromatic solvents such as benzene, toluene and xylenes; and lower alkanols such as methanol and ethanol may also be used to replace dichloromethane.

In the preparation of 6, other reducing agents including borohydrides and lithium aluminum hydride may also be used. Solvents such as methanol and other lower alkanols may replace ethanol. In the case of LiACH4, preferable solvents are tetrahydrofuran and ethyl ether.

In the isomerization of ss to 7, mineral acids such as hydrochloric acids and sulfuric acid may also be used. P-Toluenesulfonic acid, methanesulfonic acid and trimethylsilyl chloride and sodium iodide are also effective. Most organic solvents such as dichloromethane, benzene, toluene, zylenes and lower alkanols such as methanol and ethanol may also be used.

EXAMPLE 2 Resolution of (+)-trans-2-(3-methoxy-5-methylsulfonyl- 4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran (9) Step (a): Preparation of 1-(3-methosy-5-methylsulfonyl- 4-propoxyphenyl)-4-oxo-4-(3,4,5-trimethoxy- phenol)-l-butanol (9) Sodium borohydride (122 mg, 3.2 mmol) was added to a suspension of 5 (5.3 g, 10.7 mmol) in ethanol (50 mL), and the mixture was heated with stirring at 450C (bath temperature) for 2 hours.

Another portion of sodium borohydride was added (50 mg, 1.3 mmol), and the heating was continued overnight. The solution was evaporated to dryness and the residue was partitioned between dichloromethane and water. The organic layer was washed with 2.5 N hydrochloric acid, water, dried, and evaporated to a syrup, which contained 9 and substantial amounts of 5 and as indicated by TLC.Compound 9 (1.6 g, 30%) was isolated by flash column chromatography with hexane-ethyl acetate (2:1, v/v) as the eluant; NMR (CDC13): & 1.05 (t, J = 7.5 Hz, CH2CH2CH3), 1.84 (m, CH2CH2CH3), 2.20 (m, CH2CHOH), 2.91 (d, J = 3.5 Hz, OH), 3.14 (t, J = 6.5 Hz, CO2), 3.25 (s, SO2CH3), 4.12 (t, J = 7.0 Hz, CH2CH2CH3), 4.85 (m, CH2CHOH), 7.22 (S, C4ArH), 7.27 (d, J = 1.5 Hz, C1ArH-2), 7.49 (d, J = 1.5 Hz, C1ArH-6).

Step (b): Preparation of 1-(3-methoxy-5-methylsulfonyl 4-propoxyphenyl)-4-oxo-4-(3,45-trimethoxy phenyl)-1-butanol Mandelate (10 & 11) A mixture of 9 (1.52 g, 3.1 mmol), (1)-R-O- methylmandelic acid (608 mg, 3.7 mmol), DCC (760 mg, 3.7 mmol) and 4-dimethylaminopyridine (47.7 mg, 0.39 mmol) in dichloromethane (50 mL) was stirred at room temperature for 2 hours, filtered and put on a flash column of silica gel and eluted with hexane-ethyl acetate (1:1, v/v). The two diastereomeric mandelate esters (10 & 11) were partially separated by HPLC.

Each enriched diastereoisomer was then re-separated carefully by flash column chromatography to give 10 (top spot; 320 mg), 11 (bottom spot; 210 mg) and varying amounts of mixture (950 mg; a total yield of 75%). The purity of each compound was checked by NMR. Compound 10 (top spot) had [α]D -25.8 ( 2.03, CHC13); NMR (CDCl3): 6 1.04 (t, J 7.5 Hz, CH2CH23), 1.87 (m, CH2CH2CH3), 2.17 (m, CH2CHOM), 2.65 (t, j = 7.0 Hz, COCH2), 3.25 (s, SO2CH3), 3.37 (s, PhCHOCH3), 3.86, 3.90 (6 H) and 3.93 (3 s, 4 OCH3), 4.11 (t, J = 7.0 Hz, CH2CH2CH3), 4.80 (s, PhCHOCH3), 5.84 (broad t, J = 6.5 Hz, CH2CHOM), 7.00 (s, C4ArH), 7.07 (d, J = 1.5 Hz, C1ArH-2), 7.21-7.48 (m, PhCHOCH3), 7.53 (d, J = 1.5 Hz, C1ArH-6).

Compound 11 (bottom spot) had [α]D -98 ; ( 2.1, CHC13), NMR (CDCl3): 6 1.03 (t, J = 7.5Hz, CH2CH2CH3), 1.84 (m, CH2CH2CH3), 2.27 (m, CH2CHOM), 2.93 (t, J = 7.0 Hz, COCH2), 3.17 (s, SO2CH3), 3.37 (s, PhCHOCH3), 3.65, 3.91 (6 H) and 3.93 (3 s, 4 OCH3), 4.06 (t, J = 7.0 Hz, CH2CH2CH3), 4.76 (s, PhCHOCH3), 5.86 (broad t, J = 6.5 Hz, CH2CHOM), 6.79 (d, J = 1.5 Hz, C1ArH-2), 7.13 (s, C4ArH), 7.24-7.36 (m, PhCHOCH3), 7.37 (d, J = 1.5 Hz, C1ArH-6).

Step (c): Preparation of (-)-l-(3-methoxy-5-methyl sulfonyl-4-propoxyphenyl)-4-oxo-4-(3,4,5 trimethoxyphenvl)-l-butanol (12) A solution of 10 t320 mg, 0.5 mmol) and KOH (41.5 mg, 0.74 mmol) in ethanol (5 mL) was heated with stirring at 550C for 15 minutes. The solution was partitioned between chloroform and water. The organic layer was washed with water, dried, and evaporated to dryness. The residue was purified by flash column chromatography (hexane-ethyl acetate; 1:1, v/v) to give 12 (172 mg, 70%); [α]D -14.3 (c 1.77, chloroform).

Step (d): Preparation of (+)-1-(3-methoxy-5-methyl- sulfonyl-4-propoxyphenyl)-4-oxo-4-(3,4,5 trimethotyphenyl)-l-butanol (13) The hydrolysis of li (210 mg, 0.33 mmol) with KOH (27.2 mg, 0.49 mmol) in ethanol (3 mL) was carried out in essentially the same way as for 1Q.

Compound 13 was isolated in 71% yield (115 mg); +13.3 (c, 1.15, CHCl3) Step (e): Preparation of (-)-Trans-2-(3-methoxy-5 methylsulfonyl-4-propoxyphenyl)-5-(3,4,5 trimethoxyphenyl)tetrahydrofuran (14) A solution of 12 (40 mg) in ethanol (3 mL) was treated with sodium borohydride (2 mg) at 700C for 0.5 hour. The reaction mixture was worked-up as usual to give diol intermediate, which was used directly without further purification.

A solution of 10% trifluoroacetic acid in CHC13 (0.5 mL) was added to a solution of the above diol in CHC13 (0.5 mL) 0-50C. After 5 minutes, anhydrous sodium carbonate (250 mg) was added and the mixture was stirred for 3 minutes at the same temperature. TLC indicated the presence of 1A, a minor amount of the cis isomer and a substantial amount of the starting material 1a. The solid was filtered off and the filtrate was evaporated to a syrup, which was purified by flash column chromatography (hexane-EtOAc; 2:1, v/v) to give 14 (15 mg); [α]D-67.3 ( 1.0, CHC13).

Step (f): Preparation of (+)-Trans-2-(3-methoxy-5 methylsulfonyl-4-propoxyphenyl)-5-(3,4,5 trimethoxyphenyl)tetrahydrofuran (15) The title compound was prepared from 12 similarly as for li. Compound 15 had [α]D+68 ( 1.06, CHC13).

EXAMPLE 3 Following substantially the same procedures as described in Example 1, the following compounds of formula Ia are prepared:

R4 Y CN CH2CH=CH2 I CH2CH=CH2 OCH3 C 2 CH2 OCH3 CH2CH=CH2 SCH3 CH2CH=CH2 SOCH3 CH2CH=CH2 SO2CH3 CH2CH=CH2 N02 CH2CH=CH2 NO2 CH2 < 0 NH2 CH2CH=CH2 NHCH2CO2 EtCH2CH=CH2 N(CH3)2 CH2CH = CH2 N(CH3)3 I~ CH2CH=CH2 NHSO2CH3 CH2CH=CH2 N(CH3)SO2CH3 CH2CH=CH2 NHCOCH3 CH2CH2CH3 CONH2 CH2CH2CH3 EXAMPLE 4 Following substantially the same procedures as described in Example 1, the following compounds of formula Ia are prepared: : R4 Y CN CH2CH2CH3 SCH3 CH2CH2CH3 SO2CH3 CH2CH2CH3 NO2 CH3 NO2 CH2CH2CH3 NO2 CH2CH2CH2CH3 NO2 CH2CH2CH2CH2CH3 NO2 CH2CH2CH2CH3 NH2 CH2CH2CH3 NHSO2CH3 CH2CH2CH3

Claims (10)

1. A process for preparing a resolved compound of formula or wherein Ar is (2) phenyl 1 of formula where R4-R8 independently represent R@ where R@ represents H; C1-8 alkyl; C3-8 cycloalkyl; or C2-6 alkenyl; YO- wherein Y is loweralkenyl, loweralkynyl, 2 -CH2-C(O)OR -CH2-OR@, -CH2C3-8 cycloalkyl, -CH2Ar wherein Ar2 is phenyl or substituted phenyl, or -CH2-CH(OH)-CH2OH; RS-; R2SO; R2SO2; CF3O-; CF3S-; CF3SO; CF3SO2; CONRR wherein R3 independently is R; -NRCOR ; -OCONH2; CH3OCH2-O-; -OCH2CO2R9; -SO2NRR ; -CO2R;RR N-; -CRR R9 wherein R9 is the same as or different from R; -CH2OR; -CH2CO2R; -CH2OCOR ; -CH2O-CO-OR; -NHCH2COOR; halo; N+RR R9X- wherein X- is an anion; NRSO2R ; COR; NO2; CN; or R4-R5, R5-R6, R6-R7 and R7-R8 are joined together and forr a bridge of formule -OCH2O-, -OCH2CH2O-or -OCH2CH2N-; comprising (a) Treating the racemic mixture of a compound of formula

1. wherein Ar is

with a resolving agent selected from a group consisting of (-)-(R)-methylmandelic acid, its (+)-(S)-isomer, mandelic acid, l-methoxy-2-trifluoro methylphenylacetic acid and menthonylacetic acid in the presence of DCC and a base to form a compound of formula * 1 Ar(CO)-CH2CH2-CH(O;;)Ar wherein N is C6H5CH(OCH3)(CO)- (b) Separating from the product f step (a) an enantiomer of formula

followed by hydrolysis: (c) Reducing the product of step (b) to form a compound of formula

(d) Treating the product of step (c) with an acid to form an enantiomer of formula

2.The process of Claim 1 wherein the resolve compound is of formula

3. The process of Claim 1 wherein the resolved compound is (-)-trans-2-(3-methoxy-5- methylSulfonyl-4-propoxyphenyl)-5-(3,4,5-trimethOxy- phenyl)tetrahydrofuran.

4. The process of Claim 1 wherein the resolved compound is defined as follows:

R4 Y CN CH2CH=CH2 I CH2CH=CH2 OCH3 CH2 OCH3 CH2CH=CH2 SCH3 CH2CH=CH2 SOCH3 CH2CH=CH2 SO2CH3 CH2CH=CH2 NO2 CH2CH=CH2 NO2 CH2 NH2 CH2CH=CH2 NHCH2CO2 EtCH2CH=CH2 N(CH3)2 CH2CH = CH2 +N(CH3)3I CH2CH=CH2 NHSO2CH3 CH2CH=CH2 N(CH3)SO2CH3 CH2CH=CH2 NHCOCH3 CH2CH2CH3 CONH2 CH2CH2CH3

5.The process of Claim 1 wherein the resolved compound is defined as follows:

R4 Y CN CH2CH2CH3 SCH3 CH2CH2CH3 SO2CH3 CH2CH2CH3 NO2 CH3 NO2 CH3 N02 CH2CH2CH3 N02 CH2CH2CH2CH3 02 CH2CH2CH2CH2CH3 NO2 CH2CO2CH2CH3 NH2 CH2CH2CH3 NHSO2C 3 CH2CH2CH3

6. Tre process for preparing a compound of formul

according to claim 1 comprising treating a compound of formula

with an reagent selected from a group consisting of trifluorcetic acid, hydrochloric acid, sulfuric acid, p-toloenesulfonic acid, methane sulfonic acid, trimethylphenylchloride, and sodium iodine.

7. The process of claim 6 wherein the reagent is trifluroacetic acid.

8. The process of claim 6 wherein the compound to be prepared is trans-2-(3-methoxy-5methylsulfonyl-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran.

9. The process of claim 6 wherein the compound to be prepared is of formu

10. The process of claim 6 wherein the compound to be prepared is defined as follows:

P - Y CN CH2CH=CH2 I CH2CH=CH2 OCH3 CH2CH-CH2 SCH3 CH2CH=CH2 SOCH3 CH2CH=CH2 SO2CH3 CH2CH=CH3 NO2 CH2CH=CH2 NO2 CH2 NH2 CH2CH=CH2 NHCH2C02 EtCH2CH=CH2 N(CH3)2 ~ CH2CH=CH2 +N(CH3)3I CH2CH=2 NHSO2CH3 CH2CH=2 N(CH3)SO2CH3 CH2CH=CH2 NHCOCH CH2CH2 CH3 CONH2 CH2CH2CH3 CN CH2CH2CH3 SCH3 CH2CH2CH3 SO2CH3 CH2CH2CH3 NO2 CH3 NO2 CH3 N02 CH2CH2CH3 N02 CH2CH2CH2CH3 N02 CH2CH2CH2CH2CH3 NO2 CH2CO2CH2CH3 NH2 CH2CH2CH3 NHSO2CH3 CH2CH2CH3