Organocatalytic asymmetric synthesis of antidepressants

Abstract

The present invention relates to a short enantioselective synthesis of 1-amino aryl tetraline compounds of Formula 1 via nucleophilic enamine catalysis using organocatalyst such as proline. ##STR00001## wherein R.sub.1 and R.sub.2 represent independent of each other hydrogen, (un)substituted or substituted amine; R.sub.3 and R.sub.4 represent independent of each other hydrogen or halogen.

Claims

1. A process for the enantioselective synthesis of a 1-amino aryl tetralin compound of Formula (I): ##STR00031## wherein: one of R.sub.1 and R.sub.2 is hydrogen and the other is unsubstituted amine; and R.sub.3 is hydrogen or halogen; the process comprising the steps of; a. reacting N-Boc-benzaldimine with acetaldehyde in the presence of D or L-proline to obtain a compound 1: ##STR00032## b. reacting compound 1 with a triphenyl phosphonium salt in presence of n-butyl lithium or .sup.tBuOK in dry THF to obtain an olefinic carbamate compound 2: ##STR00033## c. alkylating the olefinic carbamate compound 2 in the presence of alkyl halide and NaH at 0 to 10 C. to obtain compound 3, wherein the unsubstituted amino group is alkylated; and ##STR00034## d. deprotecting the N-Boc group of compound 3, followed by an intramolecular FCC (Friedel-Crafts intramolecular cyclization) in the presence of acid to afford the compound of Formula (I).

2. The process as claimed in claim 1, wherein the compound of Formula (I) is (+) sertraline or (+) tametraline ##STR00035##

3. The process as claimed in claim 1, wherein (+)-sertraline is prepared with ee>95% ##STR00036## and the process comprises the steps of: a. reacting N-Boc-benzaldimine with acetaldehyde in the presence of L-proline to obtain ()--amino aldehyde (1a): ##STR00037## b. treating ()--amino aldehyde (1a) with semistabilized 3,4-dichlorobenzyl phosphorous ylide, obtained in-situ, in presence of a base to yield carbamate (2a): ##STR00038## c. methylating carbamate (2a) using methyl iodide and NaH at 0 to 10 C. to obtain N-methylated olefin (3a); ##STR00039## d. deprotecting the Boc group, followed by intramolecular FCC of the N-methylated olefin in the presence of polyphosphoric acid in a solvent under reflux conditions to obtain a mixture of (+)-sertraline and its C.sub.4-epimer ()-2 with a syn: anti ratio of 1:3 and e. separating the (+)-sertraline and the C.sub.4-epimer ()-2 using column chromatography, followed by converting to the respective hydrochloride salt.

4. The process as claimed in claim 1, wherein (+)-tametraline is prepared with ee>95% and comprises the steps of: a. reacting N-Boc-benzaldimine with acetaldehyde in the presence of D-proline to obtain (+)--amino aldehyde (1b): ##STR00040## b. treating (+)--amino aldehyde (1b) with semistabilized benzyl phosphorous ylide, obtained in-situ, in the presence of a base to yield olefin (2b) with an optical purity of 99% ee and a cis: trans isomeric ratio of 1:1.9: ##STR00041## c. methylating olefin (2b) with methyl iodide and NaH at 0 to 10 C. to obtain N-methylated olefin (3b): ##STR00042## d. deprotecting the N-Boc group, followed by intramolecular FCC of the N-methylated olefin in the presence of polyphosphoric acid in a solvent under reflux conditions to obtain a mixture of (+)-tametraline [(+)-3] and its C.sub.4 epimer with a syn:anti ratio of 1:1 and e. converting the (+)-tametraline [(+)-3] and its C.sub.4 epimer to the respective hydrochloride salt, followed by separating the crystals of (+)-tametraline-D-()-mandelate selectively using D-()-mandelic acid.

Description

BRIEF DESCRIPTION OF THE DRAWING

(1) FIG. 1 represents enantioselective synthesis of anti-depressants 1-amino aryl tetralin compound of Formula (I).

(2) FIG. 2 represents synthesis of (+) sertraline.

(3) FIG. 3 represents synthesis of (+)-tametraline.

SUMMARY OF THE INVENTION

(4) Accordingly, present invention provides a process for the enantioselective synthesis of 1-amino aryl tetralin compound of Formula (I)

(5) ##STR00003##
wherein
R.sub.1 and R.sub.2 represent independent of each other hydrogen, (un)substituted or substituted amine;
R.sub.3 and R.sub.4 represent independent of each other hydrogen or halogen;
comprising; a. reacting aryl N-Boc-imine with an aldehyde in presence of D or L-proline to obtain compound 1;

(6) ##STR00004## b. reacting compound 1 with triphenyl phosphonium salt in presence of n-butyl lithium or .sup.tBuOK in dry THF to obtain olefinic carbamate (2);

(7) ##STR00005## c. alkylating olefinic carbamate (2) in presence of alkyl halide and NaH at 0 to 10 C. to obtain compound (3); and

(8) ##STR00006## d. deprotecting the N-boc group followed by intramolecular FCC in presence of acid to afford desired compound of formula I.

(9) In an embodiment of the present invention, representative compound of formula I comprising (+) sertraline and (+) tametraline.

(10) ##STR00007##

(11) In yet another embodiment, present invention provides a process for the preparation of (+) sertraline with ee>95%

(12) ##STR00008## comprising the steps of: a. reacting N-Boc-benzaldiimine with acetaldehyde in presence of L-proline to obtain ()-amino aldehyde (1a);

(13) ##STR00009## b. treating () -amino aldehyde (1a) with semistabilized 3,4-dichlorobenzyl phosphorous ylide obtained in-situ in presence of base to yield carbamate (2a);

(14) ##STR00010## c. methylating carbamate (2a) using methyl iodide and NaH at 0 to 10 C. to obtain N-methylated olefin (3a); d. deprotecting the Boc group followed by intramolecular FCC of N-methylated olefin in presence of polyphosphoric acid in solvent under reflux condition to obtain mixture of (+) sertraline and its C4-epimer ()-2 with syn:anti ratio of 1:3; e. separating (+) sertraline and its C4-epimer ()-2 through coloumn chromatography followed by converting to their hydrochloride salts respectively.

(15) In yet another embodiment, present invention provides a process for the preparation of (+)-tametraline with ee>95% comprising the steps of: a. reacting N-Boc-benzaldiimine with acetaldehyde in presence of D-proline to obtain (+) -amino aldehyde (1b); b. treating (+) -amino aldehyde (1b) with semistabilized benzyl phosphorous ylide obtained in-situ in presence of base to yield olefin (2b) with optical purity 99% ee and cis:trans isomeric ratio of 1:1.9; c. methylating olefin (2b) with methyl iodide and NaH at 0 to 10 C. to obtain N-methylated olefin (3b); d. deprotecting the N-Boc group followed by intramolecular FCC of N-methylated olefin in presence of polyphosphoric acid in solvent under reflux condition to obtain a mixture of (+)-tametraline [(+)-3] and its C4 epimer with syn:anti ratio of 1:1; e. converting (+)-tametraline [(+)-3] and its C4 epimer to hydrochloride salt followed by separating the crystals of (+)-tametraline-D-()-mandelate selectively using D-()-mandelic acid.

(16) In yet another embodiment, present invention provides an intermediates comprising: a. (S)-tert-Butyl (3-oxo-1-phenylpropyl)carbamate;

(17) ##STR00011## b. tert-butyl (S)-(4-(3,4-dichlorophenyl)-1-phenylbut-3-en-1-yl)carbamate;

(18) ##STR00012## c. (S)-tert-butyl-(4-(3,4-dichlorophenyl)-1-phenylbut-3-en-1-yl(methyl) carbamate

(19) ##STR00013## d. (R)-tert-buty-(1,4-diphenylbut-3-en-1-yl)(methyl)carbamate;

(20) ##STR00014##

(21) In yet another embodiment of the present invention, compound of formula I as prepared along with pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION

(22) Present invention provides a highly enantioselective synthesis of 1-amino aryl tetralin compound of formula (I), with high therapeutic value as antidepressants, using proline catalyzed Mannich reaction of suitable aldehyde as chirality inducing step.

(23) The proline catalyzed Mannich reaction of aldehyde and acid catalyzed intramolecular Friedel-Crafts alkylation constitute the key steps in synthesis of 1-amino aryl tetralins, thus reducing the steps of synthesis and providing desired compounds with high enantioselectivity and provides the flexibility in arriving at desired diasteromers of biologically active amino-aryl tetralin compound of formula I.

(24) Present invention provides a short, cost effective proline catalysed process for enantioselective synthesis of anti-depressants 1-amino aryl tetralin compound of Formula (I)

(25) ##STR00015##

(26) wherein R.sub.1 and R.sub.2 independent of each other represent hydrogen, (un)substituted or substituted amine group; R.sub.3 and R.sub.4 independent of each other represent hydrogen or halogen; comprising the steps of: a. reacting aryl N-Boc-imine with an aldehyde in presence of D or L-proline to obtain compound (1); b. reacting compound (1) with triphenyl phosphonium salt in presence of n-butyl lithium or .sup.tBuOK in dry THF to obtain olefinic carbamate (2); c. alkylating carbamate (2) in presence of alkyl halide and NaH at 0 to 10 C. to obtain compound (3); d. deprotecting the N-boc group of compound (3) followed by intramolecular FCC in presence of acid to afford desired compound of formula I. (FIG. 1)

(27) The 1-amino aryl tetralines are obtained in diastereomeric ratio ranging between 1:1 to 1:3 (syn:anti).

(28) They are converted to their hydrochloride salts or further treated with D-()-mandelic acid to obtain both syn and anti-isomer in quantitative yields selectively.

(29) The process of the present invention affords synthesis of 1-amino-aryl tetralin compound of formula I selected from (+) sertraline and (+) tametraline with ee>95%.

(30) The present invention provides short, cost effective proline catalysed enantioselective synthesis of (+) sertraline with ee>95%

(31) ##STR00016## comprising the steps of: a. reacting N-Boc-benzaldimine with acetaldehyde in presence of L-proline to obtain ()-amino aldehyde (1a); b. treating () -amino aldehyde (1a) with semi stabilized 3,4-dichlorobenzyl phosphorous ylide obtained in-situ in presence of base to yield olefinic carbamate (2a) with optical purity 99% ee and cis: trans isomeric ratio of 1.3:1; c. methylating olefinic carbamate (2a) with methyl iodide and NaH at 0 to 10 C. to obtain N-methylated olefin (3a); d. deprotecting the Boc group of compound (3a) followed by intramolecular FCC of N-methylated olefin in presence of polyphosphoric acid in solvent under reflux condition to obtain mixture of (+) sertraline and its C.sub.4 epimer with syn:anti ratio of 1:3; e. converting (+) sertraline and its C.sub.4 epimer seperated through coloumn chromatography and converting them to their hydrochloride salts respectively.

(32) Accordingly, N-Boc-benzaldimine was subjected to L-proline catalyzed Mannich reaction with acetaldehyde to obtain -aminoaldehyde ()1a. Aldehyde ()-1a was then treated with semistabilized 3,4-dichlorobenzyl phosphorous ylide [in situ derived from the reaction between 3,4-Cl.sub.2C.sub.6H.sub.3CH.sub.2PPh.sub.3Br Wittig salt and n-BuLi or KO.sup.tBu] to obtain carbamate (2a) in 60% yield using n-BuLi as base or 71% yield using KO.sup.tBu as base. The optical purity of olefin 2a was found to be 99% ee with cis:trans isomeric ratio of 1.3:1 determined from chiral HPLC analysis. The olefin 2a was methylated using MeI and NaH at 0 to 10 C. to obtain N-methyl olefin (3a). The N-boc group was deprotected followed by intramolecular Friedel-Crafts alkylation of N-methylated olefin 1c in one pot by treatment with polyphosphoric acid in ethylene dichloride under reflux condition overnight to yield (+)-sertraline (+)1 (syn) and its C4 epimer ()2 (anti) with syn:anti ratio of 1:3 after column chromatographic separation.

(33) ##STR00017##

(34) Further, (+)-sertraline (+)1 and its C.sub.4-epimer ()2 were converted into their hydrochloride salts by treating with dry HCl gas in dry Et.sub.2O separately to obtain each of (+)-1. HCl and ()-2. HCl selectively.

(35) The olefin (2a) and its N-methyl olefin were characterized by NMR, IR and mass spectroscopy.

(36) The present invention provides short, cost effective proline catalysed enantioselective synthesis of (+)-tametraline with ee>95%

(37) ##STR00018## comprising the steps of: a. reacting N-Boc-benzaldimine with acetaldehyde in presence of D-proline to obtain (+) -amino aldehyde (1b); b. treating () -amino aldehyde (1b) with semistabilized 3,4-dichlorobenzyl phosphorous ylide obtained in-situ in presence of base to yield olefinic carbamate (2b) with optical purity 99% ee and cis: trans isomeric ratio of 1:1.9; c. methylating olefin of step (b) using methyl iodide and NaH at 0 to 10 C. to obtain N-methylated olefin (3b); d. deprotecting the N-Boc group of N-methylated olefin (3b) as obtained in step (c) followed by intramolecular FCC of N-methylated olefin in presence of polyphosphoric acid in solvent under reflux condition to obtain a mixture of (+)-tametraline [(+)-3] and its C4 epimer with syn:anti ratio of 1:1; e. converting (+)-tametraline [(+)-3] and its C.sub.4 epimer to hydrochloride salt and separating the crystals of (+)-tametraline-D-()-mandelate selectively using D-()-mandelic acid;

(38) Accordingly, -aminoaldehyde (+)-1b was derived from Mannich reaction of acetaldehyde and N-Boc-benzaldimine using D-proline. This was treated with semi-stabilized benzyl phosphorous ylide [derived from C.sub.6H.sub.5CH.sub.2PPh.sub.3Br and n-BuLi] to provide the olefin (2b). The optical purity of olefin 2c was found to be 99% ee with cis:trans isomeric ratio of 1:1.9 determined from chiral HPLC analysis. The olefin 2b was treated with methyl iodide and NaH at 0 to 10 C. to yield N-methylated olefin (3b). The N-boc group was deprotected followed by subjecting the N-methylated olefin to intramolecular FCC in one pot by treating with polyphosphoric acid in ethylene dichloride as solvent under reflux condition for 12 h to yield a mixture of (+)-tametraline [(+)-3] and its C4 epimer. (+)-tametraline [(+)-3] and its C4 epimer was treated with dry HCl gas in dry Et.sub.2O to obtain the hydrochloride salts respectively which were separated using D-()-mandelic acid to obtain the crystals of (+)-tametraline-D-()-mandelate selectively.

(39) The olefin (2c) and its N-methyl olefin were characterized by NMR, IR and mass spectroscopy.

(40) The present invention discloses novel intermediates comprising; a. (S)-tert-Butyl (3-oxo-1-phenylpropyl)carbamate;

(41) ##STR00019## b. tert-butyl (S)-(4-(3,4-dichlorophenyl)-1-phenylbut-3-en-1-yl)carbamate;

(42) ##STR00020## c. tert-butyl (S)-(4-(3,4-dichlorophenyl)-1-phenylbut-3-en-1-yl)(methyl)carbamate

(43) ##STR00021## d. tert-buty-(R)-(1,4-diphenylbut-3-en-1-yl)(methyl)carbamate;

(44) ##STR00022##

(45) The present invention provides pharmaceutical composition comprising 1-amino aryl sertraline viz. (+) sertraline and (+) tametraline prepared by the process of current invention along with pharmaceutically acceptable excipients.

EXAMPLES

(46) The following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

Example 1

(47) General Experimental Procedure for the Synthesis of (+)-Sertraline

(i) (S)-tert-Butyl (3-oxo-1-phenylpropyl)carbamate

(48) ##STR00023##

(49) To a stirred solution of aryl N-Boc-imine (1.4 mmol) and redistilled acetaldehyde (0.39 mL, 7 mmol) in CH.sub.3CN (15 mL) at 0 C. was added L-proline (0.032 g, 20 mol %) and the mixture stirred further at 0 C. for 3 h. After the completion of reaction (monitored by TLC), it was quenched with water and extracted with Et.sub.2O (350 mL). The combined organic layers were washed with brine, dried over anhyd. Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crude aldehyde. Flash column chromatographic purification [silica gel (230-400 mesh) and pet. ether:EtOAc as an eluent] gave -aminoaldehyde.

(50) Yield: 55%; pale yellow solid; mp: 91-94 C., (lit..sup.33 mp: 92-93.5 C.); [].sup.D.sub.25 30.10 (c, 1.15, CHCl.sub.3); lit..sup.33 [].sup.D.sub.25 +29.0 (c, 1.4, CHCl.sub.3) for its antipode; IR (CHCl.sub.3, cm.sup.1): .sub.max 700, 1021, 1049, 1169, 1250, 1369, 1391, 1498, 1513, 1692, 2977, 3341; .sup.1H NMR (200 MHz, CDCl.sub.3): 1.41 (s, 9H), 2.83-2.96 (m, 2H), 4.87 (br s, 1H), 5.17 (br s, 1H), 7.26-7.34 (m, 5H), 9.73 (t, J=1.7 Hz, 1H); .sup.13C NMR (50 MHz, CDCl.sub.3): 28.3, 39.9, 49.9, 79.9, 126.3, 127.7, 128.8, 135.2, 155.0, 193.3, 199.8; Analysis: C.sub.14H.sub.19NO.sub.3 requires C, 67.45; H, 7.68; N, 5.62. found: C, 67.32; H, 7.41; N, 5.46%.

(ii) (S)-tert-butyl-(4-(3,4-dichlorophenyl)-1-phenylbut-3-en-1-yl)carbamate

(51) ##STR00024##

(52) To a stirred solution of 3,4-dichlorobenzyl triphenylphosphonium bromide (1.3 equiv) in dry. THF kept at 0 C. added n-butyllithium (1.2 equiv, 1.6M solution in n-hexane) and allowed to stir for 30 min at the same temperature to generate the ylide. Then a solution of -aminoaldehyde (1 equiv.) in dry. THF was added to the ylide and the reaction mixture was stirred for 1 h. After completion of reaction of reaction, it was quenched with sat.NH.sub.4Cl solution. The combined organic layers were washed with brine, dried over anhyd. Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crude olefin. Flash column chromatographic purification [silica gel (230-400 mesh) and pet. ether:EtOAc as an eluent] gave the desired carbamate.

(53) Yield: 60%, yellow gum; [].sup.25.sub.D: 37.0 (c, 1.32, CHCl.sub.3); IR (CHCl3, cm.sup.1): 628, 700.25, 830.4, 874.8, 1059, 1142, 1335, 1365, 1394, 1447.26, 1475, 1656, 3357; .sup.1H NMR (CDCl.sub.3, 200 MHz): 1.39 (s, 9H), 2.64-2.7 (m, 2H), 4.81-4.88 (m, 2H), 5.65-6.13 (m, 1H), 6.29-6.37 (m, 1H), 7.06-7.17 (dd, J=2.02, 8.34 Hz, 1H), 7.2-7.41 (m, 7H); .sup.13C NMR (CDCl.sub.3, 125 MHz): 28.42, 40.51, 54.62, 79.64, 125.3, 126.3, 127.5, 127.9, 128.03, 128.71, 130.17, 130.4, 130.8, 131.01, 133, 137.34, 155.1; Anal. Calcd for C.sub.21H.sub.23Cl.sub.2NO.sub.2 requires C, 64.29; H, 5.91; Cl, 18.01; N, 3.57. found: C, 64.5; H, 5.74; Cl, 18.35; N, 3.4%.

(iii) (S)tert-butyl-(4-(3,4-dichlorophenyl)-1-phenylbut-3-en-1-yl)(methyl) carbamate

(54) ##STR00025##

(55) To a stirred solution of carbamate in anhydrous THF and DMF (4:1) was added NaH (1.5 equiv, 60% in mineral oil) at 0 C. After stirring for 30 min, CH.sub.3I (2.5 equiv) was added at 0 C. under N.sub.2. The reaction mixture was stirred at room temperature for 6 h under N.sub.2 and quenched with H.sub.2O (10 mL). The aqueous layer was extracted with EtOAc (225 mL). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc=97/3) to afford 3 in 95% yield: Yield: 95%, pale yellow viscous liquid; [].sup.25.sub.D: 37.0 (c, 1.32, CHCl.sub.3); IR (CHCl3, cm.sup.1): 565.3, 598.34, 627.4, 698.8, 737, 765.3, 826.3, 874, 950.9, 1028.8, 1138.8, 1255.8, 1324.77, 1365.5, 1389.5, 1447.33, 1473.4, 1682, 2928, 2975; .sup.1H NMR (CDCl.sub.3, 200 MHz): 1.43-1.49 (br s, 9H), 2.46-2.6 (br s, 3H), 2.75-2.9 (m, 2H), 5.39-5.51 (br s, 1H), 5.6-6.46 (m, 1H), 6.36-6.46 (m, 1H), 7.11-7.43 (m, 8H); .sup.13C NMR (CDCl.sub.3, 125 MHz): 28.25, 28.46, 29.41, 33.8, 57.48, 60.77, 79.66, 124.77, 125.17, 127.3, 127.38, 127.8, 127.86, 128.42, 128.63, 129.07, 129.8, 130.15, 130.26, 130.42, 131.15, 132.36, 132.55, 137.24, 137.45, 139.55, 139.69, 155.94; Anal. Calcd for C.sub.22H.sub.25C.sub.12NO.sub.2 requires C, 65.03; H, 6.2; Cl, 17.45; N, 3.45. found: C, 65.32; H, 6.46; Cl, 17.35; N, 3.57%.

(iv) (1S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride

(56) ##STR00026##

(57) A solution of 3 (1 equiv) dissolved in 1,2-dichloroethane was added to movable liquid of polyphosphoric acid (liquefied after heating the neat polyphosphoric acid at 80 C.). The above reaction mixture was stirred overnight at 90 C. Then 1,2-dichloroethane was removed under vacuo and quenched with sat.NaHCO.sub.3 solution. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography using neutralized silica gel with Et.sub.3N (n-hexane/EtOAc=97/10) to afford amine in 82% yield.

(58) Yield: 84% (dr=1:3, of syn:anti), yellow oil; For syn isomer: .sup.1H NMR (500 MHz, CDCl.sub.3) 1.25 (br s, 1H), 1.85-2.15 (m, 4H), 2.55 (s, 3H), 3.81 (m, 1H), 3.97-3.99 (dd, J=9.16, 6.1 Hz, 1H), 6.79-6.8 (d, J=7.6 Hz, 1H), 6.98-7.0 (dd, J=8.24, 1.83 Hz, 1H), 7.1-7.13 (m, 1H), 7.18-7.21 (m, 1H), 7.26-7.27 (m, 1H), 7.33-7.35 (d, J=8.24 Hz, 1H), 7.38-7.39 (d, J=7.6 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) 23.99, 28.78, 32.4, 44.19, 56.84, 127.05, 127.84, 128.02, 128.94, 129.67, 130.28, 130.3, 130.43, 130.57, 136.32, 138.58, 147.08;

(59) Anti isomer: .sup.1H NMR (500 MHz, CDCl.sub.3) 1.62 (br s, 1H), 1.74-1.78 (m, 2H), 1.93-2.38 (m, 2H), 2.51 (s, 3H), 3.78-3.8 (m, 1H), 4.12-4.14 (m, 1H), 6.82-6.85 (m, 2H), 7.11-7.14 (m, 2H), 7.21-7.26 (m, 1H), 7.31-7.32 (d, J=8.24 Hz, 1H), 7.44-7.46 (d, J=7.6 Hz, 1H); .sup.13C NMR (125 MHz, CDCl.sub.3) 24.53, 28.71, 33.85, 44.28, 57.05, 126.75, 127.12, 128.11, 128.59, 129.92, 130.07, 130.11, 130.56, 132.18, 138.02, 139.52, 147.51;

(v) (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride

(60) ##STR00027##

(61) Yield: 94%, white solid; 1H NMR (400 MHz, CDCl.sub.3) 2.04-2.39 (m, 4H), 2.57 (s, 3H), 3.97-4.00 (m, 1H), 4.3 (m, 1H), 6.85-6.87 (d, J=7.6 Hz, 1H), 7.16-7.25 (m, 3H), 7.34-7.4 (m, 2H), 7.75-7.76 (d, J=7.05 Hz, 1H), 9.87-9.99 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) 23.08, 27.63, 29.6, 44.99, 56.27, 127.5, 128.6, 129.6, 129.7, 130.4, 130.5, 130.7, 130.9, 131.3, 132.58, 139.9, 145.1;

Example 2

General Experimental Procedure for the Synthesis of Tametraline

(62) The same experimental procedure was followed for tametraline synthesis as shown for the above compounds.

(R)-tert-butyl-(1,4-diphenylbut-3-en-1-yl)carbamate

(63) ##STR00028##

(64) Yield: 58%, pale yellow gum; 1H NMR (CDCl.sub.3, 200 MHz): 1.39 (s, 9H), 2.67-2.78 (m, 2H), 4.78-4.87 (m, 2H), 5.55-6.13 (m, 1H), 6.3-6.55 (m, 1H), 7.15-7.4 (m, 10H); .sup.13C NMR (CDCl.sub.3, 125 MHz): 28.42, 35.78, 40.56, 54.81, 79.44, 125.5, 126.2, 126.3, 126.35, 126.85, 127.23, 127.75, 128.24, 128.55, 128.74, 128.94, 129.9, 131.61, 133.23, 137.14, 142.39, 155.1; Anal. Calcd for C.sub.21H.sub.25NO.sub.2 requires C, 77.98; H, 7.79; N, 4.33. found: C, 78.06; H, 7.9; N, 4.56%.

(R)-tert-butyl-(1,4-diphenylbut-3-en-1-yl)(methyl)carbamate

(65) ##STR00029##

(66) Yield: 94%, pale yellow viscous liquid; 1H NMR (CDCl.sub.3, 200 MHz): 1.42-1.49 (br s, 9H), 2.45-2.59 (br s, 3H), 2.8-2.95 (m, 2H), 5.38 (m, 1H), 5.6-6.23 (m, 1H), 6.45-6.55 (m, 1H), 7.14-7.34 (m, 10H); .sup.13C NMR (CDCl.sub.3, 125 MHz): 28.21, 28.39, 29.35, 33.6, 57.48, 60.77, 79.66, 125.42, 126.15, 126.28, 126.81, 127.32, 127.64, 128.38, 128.47, 128.74, 128, 129.89, 131.64, 133.18, 137.21, 142.35, 155.42; Anal. Calcd for C.sub.22H.sub.27NO.sub.2 requires C, 78.3; H, 8.06; N, 4.15. found: C, 78.71; H, 8.17; N, 4.45%.

(1R,4S)N-methyl-4-phenyl-1,2,3,4-tetrahydronaphthalen-1-amine

(67) ##STR00030##

(68) Yield: 83% (dr=1:1, of syn:anti), yellow oil; Anti isomer: .sup.1H NMR (200 MHz, CDCl.sub.3) 1.6 (br s, 1H), 1.78-2.16 (m, 4H), 2.52 (s, 3H), 4.03-4.08 (m, 1H), 4.15-4.2 (m, 1H), 6.85-7.61 (m, 9H); .sup.13C NMR (125 MHz, CDCl.sub.3) 28.4, 29.8, 34.93, 46.86, 59.74, 126.9, 127.84, 128.56, 129.23, 129.81, 130.37, 130.98, 132.26, 138.46, 139.38, 143.16;

ADVANTAGES OF INVENTION

(69) Commercially available D or L-Proline as cheap catalyst. Cheap and simple starting materials. High yielding process with excellent enantio-selectivity and diastereomeric ratio of syn:anti 1:3 (for sertraline), and 1:1 (for tametraline). The route comprises of only four steps as compared to already reported methods.