Synthesis of HIV-1 Protease Inhibitor DMP 323
J . Org. Chem., Vol. 61, No. 2, 1996 449
(complex, 10H), 5.0 (brs, 2H), 4.68 (d, 2H, J ) 8 Hz), 3.64 (t,
2H, J ) 8 Hz), 3.25 (d, 2H, J ) 7 Hz), 2.78 (m, 4H); 13C NMR
(75 MHz, DMSO-d6) δ 163.8, 139.4, 129.8, 128.8, 126.5, 70.5,
52.7, 38.0; HRMS calcd for C19H23N2O3 (M + H) 327.1709,
found 327.1715. Anal. Calcd for C19H22N2O3: C, 69.97; H,
6.80; N, 8.59. Found: C, 69.97; H, 6.76; N, 8.53.
to rt and the resulting slurry diluted with 12 mL of heptane.
After cooling in an ice bath, the product was filtered and dried
in vacuo at 40 °C to give 6.27 g crude product. The crude
product was recrystallized from 20 mL of acetonitrile to give
5.46 g (70%) of 15a . HPLC: 97.8 area %. Physical properties
were identical with product produced by method A.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-O-isop r op ylid en e-4,7-bis-
(p h en ylm eth yl)-2H-1,3-d ia za p in -2-on e (17). A slurry of 3
(14.5 kg, 39.8 mol) and TsOH‚H2O (0.30 kg, 1.6 mol) in DMF
(30.6 kg) and 2,2-dimethoxypropane (25.5 kg, 245 mol) was
heated at 65 °C for 2 h. Cyclohexane (24.1 kg) was added,
and the reaction mass was distilled to 95 °C pot temperature.
The reaction was cooled to 65 °C, fresh 2,2-dimethoxypropane
(12.7 kg, 122 mol) was added, and the reaction was maintained
at 65 °C for 1 h. Cyclohexane (11.8 kg) was added, and the
reaction mass was distilled to 95 °C pot temperature. After
repeating the addition/distillation procedure, the mixture was
cooled to 60 °C. NaOH (10 N) (0.095 kg, 2.4 mol) was added,
and the reaction mass was concentrated at 75 mmHg to
remove residual cyclohexane and 2,2-dimethoxypropane. Wa-
ter (60 L) and EtOAc (88 kg) were added, the reaction mass
was heated to 65 °C, and then the aqueous phase was removed.
The organic phase was concentrated to half of the original
volume at 70-80 °C. Fresh EtOAc was added, and the
distillation was continued to a final volume of approximately
45 L. The reaction mass was cooled to 0-5 °C and filtered.
The solids were washed with a cold mixture of heptane (62.6
kg) and EtOAc (27.7 kg). The product was dried in vacuo to
provide 11.2 kg (76.0%) of 17: mp 236-238 °C; [R]25D +161.46°
(c 0.410, MeOH); 1H NMR (300 MHz, CDCl3) δ 7.35-7.15
(complex, 10H), 6.3 (d, 2H, J ) 8 Hz), 4.14 (brs, 2H), 3.47 (brt,
2H), 3.30, 2.82 (2d, 1H, J ) 8 Hz), 2.95-2.75 (m, 3H), 1.43 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 161.0, 139.9, 129.9, 129.0,
109.7, 76.0, 53.9, 34.5, 27.2; HRMS calcd for C22H27N2O3 (M
+ H) 367.2022, found 367.2016. Anal. Calcd for C22H26N2O3:
C, 72.16; H, 7.16; N, 7.65. Found: C, 72.12; H, 7.11; N, 7.62.
4-(Hyd r oxym eth yl)ben zyl Ch lor id e (14). 1,4-Benzene-
dimethanol (13.8 g, 0.10 mol) was dispersed in chloroform (100
mL) and the mixture cooled to 0 °C in an ice bath. Thionyl
chloride (13.1g, 0.11 mol) dissolved in chloroform (10 mL) was
added over 10 min with rapid stirring to the cooled mixture.
As the addition proceeded, the mixture largely cleared. During
the addition step, and for 1 h thereafter, the reaction flask
was swept with N2 which was then passed through the
scrubber. The mixture was allowed to come to rt and stirred
for 20 h. NaHCO3 was added to neutralize any residual HCl.
The mixture was filtered and the solvent removed under
reduced pressure at 35 °C. The residue was chromatographed
on silica gel (200 g) with EtOAc:hexane (2:3) to give 11.64 g
Meth od C. To a slurry of 1,4-benzenedimethanol (69 g, 500
mmol) in CH2Cl2 (550 mL) was added SOCl2 (59.5 g, 500 mmol)
over 2 h, keeping the temperature below 10 °C. The mixture
was allowed to warm to rt and stir 4 h. Approximately half
the CH2Cl2 was then removed by atmospheric distillation.
Cyclohexane (250 mL) followed by trityl alcohol (100.3 g, 385
mmol) was added, and 250 mL solvent was distilled followed
by the addition of 250 mL cyclohexane. This distillation
procedure was repeated four times. The final pot temperature
was 74 °C. Cyclohexane (350 mL) was added and the mixture
cooled to 15-18 °C and held for 3 h. The product was filtered,
washed with cold cyclohexane (50 mL), and dried in vacuo at
50 °C to give 130 g crude product. HPLC: 86.7 area %.
A
100 g portion of the crude product was recrystallized from 200
mL of CH3CN to give 85 g (55%) of 15a . HPLC: 99.0 area %.
Physical properties were identical with product produced by
method A.
4-[(Tet r a h yd r op yr a n yloxy)m et h yl]b en zyl Ch lor id e
(15b). 3,4-Dihydro-2H-pyran (925 g, 1.1 mol) and p-(hy-
droxymethyl)benzyl chloride (1.33 kg, 1 mol) were dissolved
in CH2Cl2 (6 L) and cooled to 5 °C. Pyridinium p-toluene-
sulfonate (1.25 g, 5 mmol) was added as a catalyst. The
contents were allowed to warm to rt and stirred 24 h. The
solution was washed with water followed by a NaHCO3
solution and then dried over MgSO4. The residue, after
removal of solvent, was kept under high vacuum (1-2 mmHg)
for 24 h to give 2.28 kg (95%) of 15b as an oil. 1H NMR (300
MHz, CDCl3) δ 7.4 (s, 4H), 4.75 (t, 1H), 4.65 (AB quartet, 2H,
J ) 13 Hz), 4.6 (s, 2H), 3.85 (m, 1H), 3.55 (m, 1H), 1.5-1.95
(m, 6H).
4-(ter t-Bu tyloxym eth yl)ben zyl Ch lor id e (15c). A 5-gal
stirred pressure reactor was charged with p-(hydroxymethyl)-
benzyl chloride (600 g, 3.83 mol) in 6 L CH2Cl2 and H2SO4 (60
mL). Isobutylene gas was charged to the stirred solution for
2 h at 10 psi. At the end of 24 h the reaction was about 85%
complete. The reaction mixture was diluted with water and
neutralized to pH 7 with 25% aqueous NaOH. The CH2Cl2
extract was dried over Na2SO4, filtered, and concentrated in
vacuo and then fractionally distilled through a 24 cm Vigreux
column to provide 312 g (45%) of 15c as an oil: bp 115-125
°C (2-3 mmHg); 1H NMR (300 MHz, CDCl3) δ 7.4 (s, 4H), 4.58
(s, 2H), 4.45 (s, 2H), 1.3 (s, 9H).
4-[[(Meth oxyeth oxy)m eth oxy]m eth yl]ben zyl Ch lor id e
(15d ). To a slurry of p-(hydroxymethyl)benzyl chloride (255
g, 1.91 mol) in 2 L of CH2Cl2 was charged (2-methoxyethoxy)-
methyl chloride (300 g, 2.41 mol) followed by N,N-diisopropyl-
ethylamine (500 mL, 2.86 mol) at 20-25 °C. The resulting
exotherm caused the solvent to reflux vigorously for 20 min.
After stirring at rt for 24 h, the solution was washed with
water and brine. The organic phase was dried over MgSO4
and concentrated in vacuo, and then the residue was passed
through a plug of silica gel to provide 310 g (67%) of 15d as
an oil: 1H NMR (300 MHz, CDCl3) δ 7.35 (m, 4H), 4.80 (s,
2H), 4.62 (s, 2H), 4.58 (s, 2H), 3.72 (m, 2H), 3.58 (m, 2H), 3.4
(s, 3H).
4-(Ch lor om eth yl)ben za ld eh yd e (16). Benzyl chloride
15a (3.2 g, 8.0 mmol) and TsOH‚H2O (0.1 g, 0.5 mmol) were
dissolved in cyclohexane (20 mL) at reflux for 5 h. The solution
was cooled to rt, and the solids were isolated, washed with
cyclohexane (5 mL), and dried in vacuo to give 0.53 g (43%) as
a white crystalline solid: mp 70-72 °C (lit.33 mp 70-71 °C);
1H NMR (300 MHz, CDCl3) δ 10.0 (s, 1H), 7.86 (d, 2H, J ) 8
Hz), 7.56 (d, 2H, J ) 8 Hz), 4.63 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 191.8, 143.4, 136.4, 130.2, 129.0, 45.2.
1
(75%) of 14. mp: 58-60 °C; H NMR (CDCl3) δ 7.3 (m, 4H),
4.70 (s, 2H), 4.59 (s, 2H), 1.67 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 141.37, 135.10, 128.88, 127.37, 64.93, 46.12.
4-[(Tr ip h en ylm eth oxy)m eth yl]ben zyl Ch lor id e (15a ).
Meth od A. Trityl chloride (578 g, 2.07 mol) and 4-(chlorom-
ethyl)benzyl alcohol (300 g, 1.92 mol) were slurried in DMAc
(900 mL) and heated to 30 °C. To the mixture was added
DMAP (15.6 g, 128 mmol) followed by N,N-diisopropylethyl-
amine (270 g, 2.09 mol) over 1 h. The solution was heated at
40 °C for 24 h, cooled to rt and diluted with water (165 mL).
The resulting slurry was stirred for 12 h and then filtered.
The solids were washed with cold 70/30 water/DMAc (100 mL)
followed by 200 mL of water. The product was dried in vacuo
at 50 °C to give 774 g of crude product. The crude product
was recrystallized from 1.0 L of acetonitrile and dried in vacuo
at 45 °C to give 563 g (73%) of 15a : HPLC 99.3 area %; mp
1
127-128 °C; H NMR (300 MHz, CDCl3) δ 7.2-7.6 (complex,
19H), 4.60 (s, 2H), 4.18 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
144.1, 139.5, 136.2, 129.0, 128.8, 128.0, 127.3, 127.1, 65.4, 46.2;
HRMS calcd for C27H23ClO 398.1437, found 398.1421. Anal.
Calcd for C27H23ClO: C, 81.29; H, 5.81. Found: C, 80.94; H,
5.85.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-O-isop r op ylid en e-4,7-bis-
(p h en ylm eth yl)-1,3-bis[[4-[[(tr ip h en ylm eth yl)oxy]m eth -
yl]ph en yl]m eth yl]-2H-1,3-diazapin -2-on e (18a). Cyclic urea
Meth od B. Triphenylmethyl methyl ether (2.74 g, 10
mmol), trityl chloride (2.79 g, 10 mmol), 4-(chloromethyl)benzyl
alcohol (3.13 g, 20 mmol), toluene (12 mL), heptane (12 mL),
and 32% HCl (2 drops) were combined and refluxed while 12
mL of solvent was distilled over 2 h. The solution was cooled
(33) Arcus, C. L.; Salomons, N. S. J . Chem. Soc. 1962, 117, 1515.