Process for diastereoselective synthesis of vicinal diamines

Abstract

The present invention relates to an improved process for diastereoselective synthesis of vicinal diamines (1). The process involves highly regio- and diastereoselective addition of 2-azaallyl anions (4) to N-tert-butanesulfinylimines (5) to produce vicinal diamines (1).

Claims

1. A process for the preparation of diastereoselective synthesis of vicinal diamines of compound of formula (1), ##STR00025## the process comprising: (a) reacting a compound of formula (2) or a compound of formula (3) with a base in an organic solvent to produce 2-azaallyl anion of formula (4), which is optionally isolated; and ##STR00026## (b) condensing 2-azaallyl anion of formula (4) with a compound of formula (5) in a solvent to produce vicinal diamines of formula (1), ##STR00027## wherein, R and R.sub.1 is independently selected from H, C.sub.1-C.sub.10 linear or branched or cyclic alkyl, substituted or unsubstituted aryl, ester, ether, hetero aryl, halo, haloalkyl.

2. The process according to claim 1, wherein solvent(s) used in step (a) and (b) is selected from an ether; alcohol; halogenated; ketone solvent; aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethylsulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent; water or a mixture thereof.

3. The process according to claim 1, wherein in step (a) and step (b), the solvent is an ether solvent selected from the group consisting of tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran and diethyl ether.

4. The process according to claim 1, wherein in step (a) the base is selected from potassium hydride (KH), potassium tert-butoxide (tert-BuOK), sodium amide (NaNH.sub.2), sodium hexamethyldisilazide (NaHMDS) or a lithium amide base.

5. The process according to claim 1, wherein in step (a) the base is a lithium amide base selected from the group consisting of lithium diethylamide, lithium diisopropylamide (LDA), lithium pyrrolidinamide, lithium piperidinamide, lithium isopropylcyclohexylamide, lithium tetramethylpiperidide (LiTMP) and lithium hexamethyl disilazide (LiHMDS).

6. The process according to claim 1, wherein step (a) is carried out at temperature in the range of −70° C. to −90° C.

Description

EXAMPLES

(1) General Procedure:

(2) To a solution of Ketimine (2.0 mmol) in anhydrous THF (4.0 ml) was added LiHMDS (1.0 M in THF, 1.8 mmol) at −78° C. under a N.sub.2 atmosphere. After 15 min stirring, the sulfinamide (1.0 mmol) was added dropwise in dry THF (2.0 ml) solution for 15 min. The reaction mixture was stirred for 3.0 h at −78° C. Reaction was monitored by TLC then quenched with water (5.0 V) slowly at −78° C. and warmed to room temperature, extracted with EtOAc (3×5 V). The combined organic extracts were dried (Na.sub.2SO.sub.4) and the solvent concentrated in vacuo. The crude product was purified by column chromatography (1:3, EtOAc/hexane) to obtain the title product (vicinal diamines).

Example 1

(R)-N-((1R,2S)-2-((diphenylmethylene)amino)-1,2-diphenylethyl)-2-methylpropane-2-sulfinamide (1a)

(3) ##STR00018##

(4) Obtained 1a as a white solid (350 mg, 76%) according to the general experimental procedure as described above using N-tert-butanesulfinyl aldimine (R.sub.S) 5a (200 mg, 0.95 mmol), Ketimine 2a (1.91 mmol) and LiHMDS (1.0 M in THF, 1.72 mmol).

(5) Melting point=120-122° C., [α].sub.D.sup.25=108.57 (c. 0.25, CHCl.sub.3),

(6) .sup.1H-NMR: (400 MHz, DMSO-d.sub.6) δ 7.62 (d, J=7.2 Hz, 2H), 7.47-7.17 (m, 18H), 6.35 (d, J=7.2 Hz, 2H), 5.34 (d, J=10.0 Hz, 1H), 4.76 (dd, J=9.6, 4.0 Hz, 1H), 4.57 (d, J=4.0 Hz, 1H), 0.90 (s. 9H). .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ ppm: 168.6, 142.3, 139.2, 136.0, 130.8, 128.8, 128.6, 128.4, 128.2, 128.0, 127.6, 127.3, 127.2, 127.0, 71.3, 66.9, 56.2, 22.5.

Example 2

(R)-N-((1R,2S)-2-((diphenylmethylene)amino)-1-(4-methoxyphenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (1b)

(7) ##STR00019##

(8) Obtained 1b as an off-white solid (320 mg, 75%) according to the general experimental procedure as described above using N-tert-butanesulfinyl aldimine (R.sub.S) 5b (200 mg, 0.83 mmol), Ketimine 2a (1.67 mmol) and LiHMDS (1.0 M in THF, 1.5 mmol).

(9) Melting Point=56-58° C., [α].sub.D.sup.25=59.53 (c. 0.25, CHCl.sub.3)

(10) .sup.1H-NMR: (400 MHz, DMSO-d.sub.6) δ 7.62-7.15 (m, 15H), 6.77 (d, J=8.4 Hz, 2H), 6.45 (d, J=7.2 Hz, 2H), 5.23 (d, J=9.6 HZ, 1H), 4.70 (dd, J=9.2, 4.4 HZ, 1H), 4.54 (d, J=4.4 Hz, 1H) 3.70 (s, 3H), 0.9 (s, 9H).

(11) .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ ppm: 168.4, 158.6, 142.4, 139.3, 136.1, 134.3, 130.8, 130.1, 129.3, 128.9, 128.7, 128.6, 128.3, 127.7, 127.2, 113.4, 71.5, 66.5, 56.1, 55.5, 22.5.

Example 3

(R)-N-((1S,2S)-2-(4-chlorophenyl)-2-((diphenylmethylene)amino)-1-(furan-2-yl)ethyl)-2-methylpropane-2-sulfinamide (1g)

(12) ##STR00020##

(13) Obtained 1g as an off-white solid (450 mg, 90%) according to the general experimental procedure as described above using N-tert-butanesulfinyl aldimine (R.sub.S) 5c (200 mg, 0.99 mmol), Ketimine 1b (1.98 mmol) and LiHMDS (1.0 M in THF, 1.78 mmol).

(14) Melting Point=110-112° C., [α].sub.D.sup.25=66.49 (c. 0.25, CHCl.sub.3),

(15) .sup.1H-NMR: (400 MHz, DMSO-d.sub.6) δ 7.64 (d, J=7.2 Hz, 2H), 7.50-7.40 (m, 8H), 7.33 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 6.74 (d, J=5.6 Hz, 2H), 6.33 (s, 1H), 5.12 (d, J=9.6 Hz, 1H), 4.58 (d, J=5.2 Hz, 1H), 0.93 (s, 9H).

(16) .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ ppm: 168.7, 143.1, 141.3, 140.7, 139.3, 136.1, 131.7, 130.9, 129.7, 129.1, 128.9, 128.7, 128.7, 128.4, 127.3, 126.8, 110.7, 70.1, 59.5, 56.1, 40.6, 40.4, 40.2, 39.9, 39.7, 39.5, 39.3, 22.6.

Example 4

(R)-N-((1R,2S)-2-(2-chlorophenyl)-1-cyclohexyl-2-((diphenylmethylene) amino)ethyl)-2-methylpropane-2-sulfinamide (1p)

(17) ##STR00021##

(18) Obtained 1p as pale yellow solid (350 mg, 72%) according to the general experimental procedure as described above using N-tert-butanesulfinyl aldimine (R.sub.S) 5e (200 mg, 0.93 mmol), Ketimine 2c (1.86 mmol) and LiHMDS (1.0 M in THF, 1.67 mmol).

(19) Melting Point=142-144° C.,

(20) [α].sub.D.sup.25=−84.41 (c. 0.25, CHCl.sub.3),

(21) .sup.1H-NMR: (400 MHz, DMSO-d.sub.6) δ 7.69 (d, J=7.2 Hz, 2H), 7.52-7.22 (m, 10H), 6.82 (d, J=6.4 Hz, 2H), 4.93 (d, J=2.0 Hz, 1H), 4.81 (d, J=10.0 Hz, 1H), 3.32 (m, 1H), 2.00-1.00 (m, 11H), 0.95 (s, 9H).

(22) .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ ppm: 168.6, 142.3, 139.2, 136.0, 130.8, 128.9, 128.6, 128.4, 128.2, 128.0, 127.6, 127.3, 127.2, 127.0, 71.3, 66.9, 56.2, 22.5

Example 5

(R)-N-((1S,2R)-1-(4-bromophenyl)-1-((diphenylmethylene)amino)-3-methylbutan-2-yl)-2-methylpropane-2-sulfinamide (1s)

(23) ##STR00022##

(24) Obtained 1s as an off-white solid (410 mg, 68%) according to the general experimental procedure as described above using N-tert-butanesulfinyl aldimine (R.sub.S) 5d (200 mg, 1.14 mmol), Ketimine 2d (2.28 mmol) and LiHMDS (1.0 M in THF, 2.05 mmol).

(25) Melting Point=100-102° C., [α].sub.D.sup.25=67.93 (c. 0.25, CHCl.sub.3),

(26) .sup.1H-NMR: (400 MHz, DMSO-d.sub.6) δ 7.4 (d, J=6.8 Hz, 2H), 7.49-7.41 (m, 8H), 7.10 (d, J=8.4 Hz, 2H), 6.94 (d, J=4.0 Hz, 2H), 4.58 (d, J=9.2 Hz, 1H), 4.50 (d, J=4.0 Hz, 1H), 3.41-3.38 (m, 1H), 1.68-1.63 (m, 1H), 0.91 (s, 9H), 0.86 (d, J=6.8 Hz, 6H).

(27) .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ ppm: 168.3, 143.2, 139.4, 136.1, 131.5, 130.9, 129.8, 129.3, 128.9, 128.7, 128.7, 127.5, 120.1, 68.8, 67.3, 56.0, 31.3, 22.8, 20.3, 18.8.

Example 6

(1S,2S)-1-(4-chlorophenyl)-2-(furan-2-yl)ethane-1,2-diamine (7)

(28) ##STR00023##

(29) A starting material 1g (500 mg, 0.99 mmol) was dissolved 4 M HCl in 1,4-dioxane (10.0 V) and stirred at room temperature for 16 h. Upon completion of reaction, solvent was removed completely under reduced pressure and washed with ethyl acetate (5.0 V), dried to obtain 7 as a white solid (300 mg, 98%). Melting Point=less than 250° C.

(30) [α].sub.D.sup.25=10.40 (c. 0.25, H.sub.2O),

(31) .sup.1H-NMR: (400 MHz, D.sub.2O) δ 7.51 (s, 1H), 7.42 (s, 1H), 7.39 (d, 8.4 Hz, 2H), 7.19 (d, 8.4 Hz, 2H), 6.14 (s, 1H), 4.98 (d, J=7.2 Hz, 1H), 4.85 (d, J=6.8 Hz, 1H). .sup.13C NMR (100 MHz, D.sub.2O) δ ppm: 145.0, 143.3, 136.0, 129.7, 129.4, 128.7, 114.9, 108.5, 55.2, 48.8.

Example 7

(R)-N-((1S,2S)-2-amino-2-(4-chlorophenyl)-1-(furan-2-yl)ethyl)-2-methylpropane-2-sulfinamide (6)

(32) ##STR00024##

(33) To a solution of starting material (7) (200 mg, 0.39 mmol) in 1,4-dioxane (10.0 V) was added H.sub.2SO.sub.4 (1.0 M, 10.0 V) at room temperature and stirred for 6.0 h. Upon completion of reaction, diluted with water (5.0 V) and basified till pH 10 using NaOH solution and extracted with ethyl acetate (10.0 V×3). Organic solvent was dried on Na.sub.2SO.sub.4 and removed completely under reduced pressure to obtain 6 as an off-white solid (124 mg, 92%). Melting Point=114-116° C.,

(34) [α].sub.D.sup.25=11.20 (c. 0.25, CHCl.sub.3),

(35) .sup.1H-NMR: (400 MHz, DMSO-d.sub.6) δ 7.53 (s, 1H), 7.46 (s, 1H), 7.36-7.30 (m, 4H), 6.50 (s, 1H), 5.34 (d, 9.2 Hz, 1H), 4.27 (d, J=6.8 Hz, 1H), 4.20 (d, J=6.4 Hz, 1H), 1.00 (s, 9H).

(36) .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ ppm: 143.3, 142.8, 141.1, 131.5, 129.8, 128.1, 126.6, 110.8, 59.9, 59.3, 56.2, 22.9.