Convenient route to efavirenz analogues as potential non-nucleoside HIV-1 reverse transcriptase inhibitors

Article abstract of DOI:10.1515/znb-2004-0519

Treating 2-chloro-4-(4-chlorophenyl)-6-methylbenzo[d]-3,1-oxazinium hexachloroantimonate (1) with one equivalent of alcohol or mercaptane led, after hydrolysis with aq. NaOH, to the formation of 4,4-disubstituted-1,4-dihydro-2H- 6-methyl-3,1-benzoxazin-2-

Full text of DOI:10.1515/znb-2004-0519

Convenient Route to Efavirenz Analogues as Potential non-Nucleoside
HIV-1 Reverse Transcriptase Inhibitors
Atef A. Hamed
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El- Koam, Egypt
Reprint requests to Dr. Atef A. Hamed. Fax: +20-48-235689. E-mail: atef2000 99@yahoo.com
Z. Naturforsch. 59b, 589 – 596 (2004); received April 16, 2003
Dedicated to Prof. Dr. J. C. Jochims on the occasion of his 66th birthday
Treating 2-chloro-4-(4-chlorophenyl)-6-methylbenzo[d]-3,1-oxazinium hexachloroantimonate (1)
with one equivalent of alcohol or mercaptane led, after hydrolysis with aq. NaOH, to the formation of
4,4-disubstituted-1,4-dihydro-2H-6-methyl-3,1-benzoxazin-2-ones (3). Large excess addition of al-
cohol afforded either 4’-chloro-2-isocyanato-5-methylbenzophenone disubstitutedketal (4) or N-{2-
[(4-chlorophenyl)dialkoxymethyl]-4-methylphenyl} alkylcarbamate (5). Reaction of 4 with primary
amines furnished 1-{2-[(4-chlorophenyl)dialkoxymethyl]-4-methylphenyl}-3-substituted urea (6).
Key words: Efavirenz Analogues, 3,1-Benzoxazin-2-ones, Urea Derivatives, Ketals, Isocyanates,
Human Immunodeficiency Virus
Introduction
The acquired immunodeficiency syndrome (AIDS)
caused by the human immunodeficiency virus (HIV)
is a serious health problem throughout the world.
Effective therapies of this disease require combina-
tions of antiviral drugs: a) nucleoside reverse tran-
scriptase inhibitors (NRTI) such as AZT, DDC,
DDI and D4T, b) protease inhibitors such as ri-
tonavir, saquinavir, indinavir or nelfinavir, c) non-
nucleoside reverse transcriptase inhibitors (NNRTI).
The class of NNRTI’s is rapidly developing and
different type of compounds within this class have
been described, for example, derivatives of dipyridodi-
azepinone (nevirapine) [1, 2], of bis (heteroaryl) piper-
azine (BHAP) (delavirdine,ateviridine) [3, 4], of ben-
zoxazines (efavirenz) [5], of 1-[(2-hydroxyethoxy)-
methyl)]-6-phenylthio) thymine (HEPT) and of its
analogue MKC442 [6, 7], of dihydroalkoxy benzy-
loxopyrimidines and thio analogues (DABO’s, S-
DABO’s) [8, 9], of phenethylthiazolyl thiourea (PETT)
compounds (trovirdine) [10 – 12]. Other recent series
belong to NNRTI’s such as alkenyldiarylmethanes
(ADAM’s) [13, 16], anilinophenylacetamide ( APA)
(loviridine) [17], and thiocarboxanilide derivatives
(UC84, UC38) [18]. From these compounds only nevi-
Fig. 1. Efavirenz (Sustiva).
drugs by the Food and Drug Administration (FDA).
Efavirenz (Fig. 1) showing high potency against HIV-
1 is an essential component of an effective combina-
tion therapy when administered together with other
HIV drugs. However, as with all current HIV therapies,
the development of drug-resistant strains of the virus
is of major concern. Therefore, it is necessary to de-
velop improved efavirenz analogues to overcome or re-
duce this problem. Several approaches have been used
to improve the potency of efavirenz against resistant
mutants. Modifications were carried out by replacing
the cyclopropyl ring with small heterocycle, alkyl or
alkoxy group [19]. Other series was constructed by in-
corporating different atoms or groups on the aromatic
ring [20, 21]. Recent studies were performed in which
the heterocycle oxazine of efavirenz was transformed
to quinazoline [22], quinoxaline [23], or thiadiazine
[24]. Here we report on convenient and simple access
to a new series of efavirenz analogues.
R
R
rapine (Viramuneꢀ), delaviridine (Rescriptorꢀ), and
efavirenz (SustivaTM) have been approved as anti-HIV
c
0932–0776 / 04 / 0500–0589 $ 06.00 ꢀ 2004 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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A. A. Hamed · Convenient Route to Efavirenz Analogues
Scheme. 1. Reagents and Conditions:
◦
i: 1,2-Dichloroethane, −40 to 23 C, aq.
NaOH◦, 20 min. ii: large excess ROH, −10
to 23 C, aq. NaOH, 20 min., iii: as de-
scribed for ii except 3 – 4 h., iv: R1NH2,
Et2O, 35 ◦C, 10 min.
Results and Discussion
Under these conditions the isocyanate group of 4 is not
attacked by the alcohol. However, stirring the reaction
mixture at room temperature for a few hours and sub-
sequent hydrolysis with aqueous NaOH gave the cor-
responding carbamate 5 (Scheme 1).
In this communication, the synthesis of efavirenz
analogues is reported starting from the benzoxazinium
salt 1, which was prepared as described in literature
[25] by add◦ing a solution of SbCl5 in CH2Cl2 to a
cold (−30 C) mixture of p-tolylisocyanate and p-
chlorobenzotrichloride. This salt is extremely sensi-
tive toward nucleophiles. For instance, on dropwise
addition of one molar equivalent of an alcohol or
thioalcohol 2 to a cold suspension of 1 in abso-
lute dichloromethaneor 1,2-dichloroethane,the orange
suspension dissolved immediately. Subsequent hydro-
lysis with aqueous NaOH afforded the target com-
pound 3 in 50– 75% yield.
The structural assignments of the prepared com-
pounds are based on their spectral (IR, 1H and
13C NMR) and elemental analyses data. The IR spec-
trum of 3 showed an absorption bands in the range
of 1715– 1724 cm−1 (C=O), 3419– 3423 cm−1 (NH).
Besides, compounds 3d and 3g showed absorption
bands at 2254 cm−1 (CN) and 2105 cm−1 (C≡C)
respectively. In the 1H NMR spectrum of 3, di-
astereotopic CH2 protons are observed. Singlet signals
in the range of 2.10– 2.27 and 9.34– 10.20 ppm are at-
tributed to CH3 and NH groups respectively. Signals
in the ranges of 95.9– 107.8 and of 149.8– 152.4 ppm
in the 13C NMR spectrum (CD3Cl) are assigned to the
saturated ketal carbon atoms and carbonyl carbons, re-
spectively. Spectral data of the carbamates 5 were con-
Considering the scope and limitation of the reaction,
it should be mentioned that only electron rich aryliso-
cyanates and electron deficient chlorocarbenium salts
can be used to form benzoxazinium salts. Excess of al-
cohol or thioalcohol has to be avoided.
Addition of a large excess of alcohol to the cold sistent with the assigned structure. The IR spectrum
◦
(−10 C) suspension of 1 in CH2Cl2 led to the for- showed absorption bands at 1737 cm−1 characteristic
mation of the isocyanate 4 in almost quantitative yield. for the ester group (COOR) and 3388 cm−1 for (NH).
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A. A. Hamed · Convenient Route to Efavirenz Analogues
591
The saturated ketal carbon atom of 5 showed a signal points were determined with a Kofler block apparatus and
in 13C NMR at 101.5 ppm. The constitution of the iso-
are uncorrected. IR spectra were recorded with Perkin-Elmer
1
Model 1720 FTIR spectrometer. H and 13C NMR spectra
cyanates 4 were derived from the spectral data. Its IR
spectrum showed a strong NCO band at ∼ 2287 cm−1
were determined with Varian Gemini 2000 and Bruker AC-
(film) and the 13C NMR spectrum exhibit a signal at
250 FT spectrometers.The chemical shifts in ppm are ex-
pressed on the δ scale using tetramethylsilane as internal
∼ 122 ppm (CD3Cl) for NCO carbon. Further charac-
standard. Coupling constants are giving in Hz. TLC was per-
terization of 4 was achieved by reaction with primary
formed on Merck silica gel 60-F254 precoated plastic plates.
Microanalyses were performed in the unit of microanalyses
at the Universities of Cairo (Egypt) and Odense (Denmark).
The biological activity was determined in Retro-
virus Laboratory, State Serum Institute, Copenhagen
amines in warm diethylether affording the correspond-
ing urea derivatives 6. Spectral data and elemental
analyses of 6 were consistent with the assigned struc-
ture (see Experimental Section). Recently, some urea
derivatives such as urea - PETT compounds showed
(Denmark).
high potency against HIV strains [10– 12, 26 – 28].
While several steps are required for synthesis of
efavirenz [29] or its analogues [19 – 21], including re-
action with phosgene, we have developed a simple one
pot synthesis of a new series of efavirenz analogues.
General procedure for the preparation of 4,4-disubstituted-
1,4-dihydro-2H-3,1-benzoxazin-2-ones (3b−m)
A solution of alcohol or thioalcohol 2 (7 mmol) in abso-
lute dichloromethane or 1,2-dichloroethane (10 ml) is added
◦
to a cold (−40 C) suspension of 1 (3.13 g, 5 mmol) in
Antiviral activity
CH2Cl2 (50 ml). The orange suspension 1 is disappeared im-
mediately and the reaction mixture become clear yellow so-
lution. Subsequently, a solution of NaOH (2.00 g, 50 mmol)
in H2O is added. After warming to 23 ◦C, the reaction mix-
ture is stirred for 20 minutes. The organic layer is sep-
arated and the aqueous layer is repeatedly extracted with
CH2Cl2. The combined organic extracts is dried over anhy-
drous Na2SO4. Filtration and evaporation of the solvent af-
forded a solid product which recrystallized from appropriate
solvents.
Compounds 3b-m were examined for possible an-
tiviral activity against HIV-1 strain HTLV-IIIB [30].
This strain◦ of HIV-1 was propagated in H9 cells
[31] at 37 C, 5% CO2 using RPMI 1640 with 10%
heat-inactivated fetal calf serum (FCS) and antibiotics
(growth medium). The culture supernatant was filtered
◦
(0.45 nm), aliquoted, and stored at −80 C until use.
The MT-4 cells, which used as target cells, were in-
cubated with virus (0.005 MOI) for 2 h, washed, and
added in a proportion of 1:10 to uninfected cells which
had been preincubated in growth medium containing
the test compound for six days in parallel with virus-
infected control cultures without compoundadded. Ex-
pression of HIV in the culture medium was quantified
by HIV antigen detection assay ELISA [32]. Com-
pounds 3b-m did not show any significant activity at
non-toxic concentrations. The potent activity of the
lead compound efavirenz against HIV-1 can be re-
tained despite significant modification of its structure.
For example, the cyclopropylacetylene group in posi-
tion C-4 and the chlorine in position C-6 can be re-
placed by an alkoxy side chain [19] and methyl group
[20] respectively. This leading us to believe that incor-
porating aryl group in position C-4 of compounds 3
instead of trifluoromethyl group in efavirenz may not
be favorable for good activity.
4-(4-Chlorophenyl)-1,4-dihydro-6-methyl-4-propyloxy-2H-
1,3-benzoxazin-2-one (3c)
From n-propyl alcohol 2c (0.42 g, 7 mmol) and 1 as de-
scribed before. Recrystallization from CHCl3 / n-pentane af-
fords colourless powder; M.p. 198 – 200 ◦C; yield (73%). –
IR (KBr): ν = 1610 (C=C), 1718 (C=O), 3432 cm−1(NH). –
1H NMR (CDCl3): δ = 0.93 (t, 3H, J = 7.2 Hz, CH3), 1.67
(m, 2H, CH2), 2.26 (s, 3H, CH3), 3.54 (m, 2H, OCH2),
6.79 – 7.47 (m, 7H, Ar-H), 9.55 (NH). – 13C NMR (CDCl3):
δ = 10.9, 21.2 (CH3), 23.2, 66.4 (CH2), 107.1 (OCO),
115.0, 120.5, 127.1, 128.5, 128.9, 131.5, 132.9, 133.6, 135.4,
138.6 (Ar-C), 152.2 (C=O). -C18H18ClNO3 (331.8): calcd.
C 65.16, H 5.48, N 4.22; found C 64.8, H 5.1, N 3.8.
4-(4-Chlorophenyl)-1,4-dihydro-4-(2-cyanoethoxy)-6-me-
thyl-2H-1,3-benzoxazin-2-one (3d)
From 2-cyanoethanol 2d (0.50 g, 7 mmol) as described
for 3c. However, column chromatography on silica gel (25%
EtOAc / n-hexane) provides a pure titled compound as
Experimental Section
All solvents were dried by standard methods. All experi- pale yellow powder; M.p. 173 – 174 ◦C; yield (57%). –
ments were carried out with exclusion of moisture. Melting IR (KBr): ν = 1610 (C=C), 1723 (C=O), 2254 (CN),
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A. A. Hamed · Convenient Route to Efavirenz Analogues
3419 cm−1(NH). – 1H NMR (CDCl3): δ = 2.27 (s, 3H, 4-(4-Chlorophenyl)-1,4-dihydro-4-(2-chloroethoxy)-6-me-
CH3), 2.70 (m, 2H, CH2), 3.83 (m, 2H,OCH2), 6.88 – 7.51 thyl-2H-1,3-benzoxazin-2-one (3h)
(m,7H,Ar-H) 9.74(NH). – 13C NMR (CDCl3): δ = 21.1
From 2-chloroethanol 2h (0.56 g, 7 mmol) as described
(CH3), 19.2, 59.4(CH2), 106.8 (OCO),117.6 (CN), 115.2,
for 3c. However, column chromatography on silica gel (15%
119.4, 126.9, 128.3, 129.1, 132.0, 132.6, 134.1, 135.9,
EtOAc / n-hexane) affords colourless powder. M.p. 184 –
137.2 (Ar-C), 151.4 (C=O). -C18H15ClN2O3 (342.8): calcd.
186 ◦C; yield (58%). – IR(KBr): ν = 1610 (C=C), 1718
C 63.06, H 4.42, N 8.17; found C 63.0, H 4.4, N 8.0.
(C=O), 3431 cm−1(NH). – 1H NMR (CDCl3): δ = 2.26 (s,
3H, CH3), 3.69 (m, 2H, OCH2), 3.87 (t, 2H, J = 5.5 Hz,
4-Chlorophenyl)-1,4-dihydro-4-(2-methoxyethoxy)-6-me-
thyl-2H-1,3-benzoxazin-2-one (3e)
2’-H), 6.86 – 7.50 (m, 7H, Ar-H), 9.68(NH). 13C NMR
(CDCl3): δ = 21.2 (CH3), 42.9, 64.8 (CH2), 106.9 (OCO),
115.2, 119.9, 127.1, 128.5, 129.1, 131.9, 132.7, 134.0, 135.8,
137.6 (Ar-C), 151.8 (C=O). -C17H15Cl2NO3 (352.2): calcd.
C 57.97, H 4.30, N 3.98; found C 57.9, H 4.2, N 4.0.
From 2-methoxyethanol 2e (0.53 g, 7 mmol) as de-
scribed for 3c. Recrystallization from EtOAc / n-hexane
gives colourless powder. M.p. 187 – 189 ◦C; yield (75%). –
IR (KBr): ν = 1610 (C=C), 1718 (C=O), 3430 cm−1(NH). –
1H NMR (CDCl3): δ = 2.23 (s, 3H, CH3), 3.36 (s,
1H, OCH3), 3.60 (t, 2H, J = 4.1 Hz, OCH2), 3.77
(m, 2H, OCH2), 6.81 – 7.51 (m, 7H, Ar-H) 9.44(NH).
4-(4-Chlorophenyl)-1,4-dihydro-4-isopropyloxy-6-methyl-
2H-1,3-benzoxazin-2-one (3i)
From isopropyl alcohol 2i (0.42 g,7 mmol) as described
13C NMR (CDCl3): δ = 21.1 (CH3), 59.3(CH3), 46.1, for 3c. Recrystallization from CHCl3/n-pentane gives colour-
◦
71.7(CH2), 107.0 (OCO), 115.0, 120.0, 127.3, 128.7, 129.0, less powder. M.p. 189 – 191 C; yield (62%). – IR (KBr):
131.6, 132.7, 133.7, 135.5, 137.8 (Ar-C), 151.9 (C=O). ν = 1610 (C=C), 1715 (C=O), 3431 cm−1(NH). – 1H NMR
-C18H18ClNO4 (347.8): calcd. C 62.16, H 5.23, N 4.03; (CDCl3): δ = 1.06 (d, 3H, J = 5.9 Hz, CH3), 1.15 (d, 3H,
found C 62.0, H 5.3, N 4.0.
J = 6.2 Hz, CH3), 2.10 (s, 3H, CH3), 3.92 (m, 1H, OCH),
6.73 – 7.34 (m, 7H, Ar-H), 10.04 (NH). 13C NMR (CDCl3):
δ = 21.2 (CH3), 24.2, 24.3 (CH3), 69.3 (CH),107.8 (OCO),
115.2, 120.5, 127.1,128.4, 128.6, 131.4, 132.7, 133.2, 135.1,
139.3 (Ar-C), 152.3 (C=O). -C18H18ClNO3 (331.8): calcd.
C 65.15, H 5.48, N 4.22; found C 64.8, H 5.2, N 3.9.
4-(4-Chlorophenyl)-1,4-dihydro-4-allyloxy-6-methyl-2H-
1,3-benzoxazin-2-one (3f)
From allyl alcohol 2f (0.41 g, 7 mmol) as described for 3c.
Crystallization from EtOAc /◦n-hexane furnishes faint yel-
low powder. M.p. 192 – 194 C; yield (75%). – IR (KBr): 4-(4-Chlorophenyl)-1,4-dihydro-6-methyl-4-(2-phenyl-
ν = 1610 (C=C), 1718 (C=O), 3430 cm−1(NH). – 1H NMR ethoxy)-2H-1,3-benzoxazin-2-one (3j)
(CDCl3): δ = 2.24 (s, 3H, CH3), 4.14 (m, 2H, OCH2),
From 2-phenylethanol 2j (0.85 g, 7 mmol) as described
5.18 (dd, 1H, Jcis = 10.4 Hz, 3’-Ha), 5.30 (dd, 1H, J
=
trans
for 3c. Recrystallization from EtOAc / n-hexane affords
17.2 Hz, 3’-Hb), 5.93 (m, 1H, 2’-H), 6.80 – 7.50 (m, 7H, Ar-
H) 9.90 (NH). – 13C NMR (CDCl3): δ = 21.2 (CH3), 66.0
(CH2), 107.2 (OCO), 117.7, 133.7 (CH=CH2), 115.2, 120.3,
127.0, 128.5, 129.0, 131.6, 132.8, 133.7, 135.5, 138.1 (Ar-
C), 152.2 (C=O). -C18H16ClNO3 (329.8): calcd. C 65.55,
H 4.90, N 4.25; found C 65.7, H 5.0, N 4.3.
◦
pale yellow powder. M.p. 205 – 207 C; yield (58%). – IR
(KBr): ν = 1611 (C=C),1718 (C=O), 3422 cm−1(NH). –
1H NMR (CDCl3): 2.16 (s, 3H, CH3), 2.93 (t, 2H, J =
6.9 Hz, CH2), 3.76 (m, 2H, OCH2), 6.52 – 7.54 (m, 12H, Ar-
H), 10.20 (NH). 13C NMR (CDCl3): δ = 20.5 (CH3), 35.7,
64.5 (CH2), 105.6 (OCO), 114.3, 119.2, 126.1, 126.2, 127.6,
127.9, 128.0, 128.7, 130.6, 132.0, 133.1, 134.2, 138.1, 138.6
(Ar-C), 149.8 (C=O). C23H20ClNO3 (393.9): calcd. C 70.14,
H 5.13, N 3.56; found C 69.8, H 4.9, N 3.7.
4-(4-Chlorophenyl)-1,4-dihydro-6-methyl-4-propargyloxy-
2H-1,3-benzoxazin-2-one (3g)
From propargyl alcohol 2g (0.39 g, 7 mmol) as de-
scribed for 3c. Recrystallization from CHCl3/n-pentane gives
faint yellow powder. M.p. 196 – 198 ◦C; yield (67%). –
IR(KBr): ν = 1609 (C=C), 1722 (C=O), 2105 (C≡C),
4-(4-Chlorophenyl)-1,4-dihydro-4-isopropylthio-6-methyl-
2H-1,3-benzoxazin-2-one (3k)
From isopropyl mercaptan 2k (0.53 g, 7 mmol) as de-
3421 cm−1(NH). – 1H NMR (CDCl3): δ = 2.24 (s, 3H, scribed for 3c. Recrystallization from EtOAc / n-hexane pro-
CH3), 2.46 (s, 1H, 3’-H), 4.30 (m, 2H, OCH2), 6.81 – vides pale yellow powder. M.p. 148 – 150 ◦C; yield (60%). –
7.56 (m, 7H, Ar-H), 9.81(NH). – 13C NMR (CDCl3): δ = IR (KBr): ν = 1604 (C=C), 1724 (C=O), 3430 cm−1(NH). –
21.2 (CH3), 53.4 (CH2), 75.5, 79.0 (CCH), 107.1 (OCO), 1H NMR (CDCl3): δ = 1.21 (d, 3H, J = 6.8 Hz, CH3), 1.34
115.3, 119.7, 127.1, 128.6,129.1, 131.9, 132.7, 133.9, 135.8, (d, 3H, J = 7.1 Hz, CH3), 2.25 (s, 3H, CH3), 3.02 (m, 1H,
137.0 (Ar-C), 151.7 (C=O). – C18H14ClNO3 (327.8): calcd. SCH), 6.82-7.68 (m, 7H, Ar-H), 9.46 (NH). – 13C NMR
C 65.95, H 4.31, N 4.27; found C 66.3, H 4.6, N 4.2.
(CDCl3): δ = 21.3 (CH3), 24.4, 25.6 (CH3), 37.4 (CH),
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A. A. Hamed · Convenient Route to Efavirenz Analogues
593
96.5 (OCS),115.4, 122.3, 126.7, 128.9, 129.4, 131.2, 132.4, 6H, 2OCH3), 3.39, 3.58 (m, 8H, 4OCH2), 6.83 - 7.86 (m, 7H,
133.5, 135.1, 138.0 (Ar-C), 152.4 (C=O). -C18H18ClNO2S Ar-H). – 13C NMR (CDCl3): δ = 21.6 (CH3), 59.3 (2OCH3),
(347.9): calcd. C 62.14, H 5.23, N 4.03; found C 62.5, H 4.9, 61.4, 71.8 (4OCH2), 100.9 (OCO), 121.7 (NCO), 126.5,
N 3.7.
128.3, 128.8, 129.0, 129.6, 130.3, 134.2, 135.2, 135.5, 139.0
(Ar-C).- C21H24ClNO5 (405.9): calcd. C 62.14, H 5.96,
N 3.45; found C 62.5, H 5.7, N 3.2.
4-(4-Chlorophenyl)-1,4-dihydro-6-methyl-4-propylthio-2H-
1,3-benzoxazin-2-one (3l)
4’-Chloro-2-isocyanato-5-methylbenzophenone-diallylketal
(4f)
From n-propyl mercaptan 2l (0.53 g, 7 mmol) as described
for 3c. Recrystallization from EtOAc / n-hexane affords pale
yellow powder. M.p. 188 – 190 ◦C; yield (55%). – IR (KBr):
ν = 1604 (C=C), 1727 (C=O), 3431 cm−1(NH). – 1H NMR
(CDCl3): δ = 0.92 (t, 3H, J = 7.3 Hz, CH3), 1.59 (m, 2H,
CH2), 2.26 (s, 3H, CH3), 2.62 (m, 2H, SCH2), 6.83 – 7.65
(m, 7H, Ar-H), 9.52 (NH). 13C NMR (CDCl3): δ = 10.9,
21.3 (CH3), 24.4, 35.6 (CH2), 95.9 (OCS), 115.4, 122.2,
126.9, 129.0, 129.4, 131.2, 132.5, 133.6, 135.2, 137.9 (Ar-
C), 152.5 (C=O). -C18H18ClNO2S (347.9): calcd. C 62.14,
H 5.23, N 4.03; found C 61.9, H 5.2, N 3.9.
From allyl alcohol (3 ml) as described for 4b; yellow oil
(90%). – IR (film): ν = 1594 (C=C), 2287 cm−1 (NCO). –
1H NMR (CDCl3): δ = 2.40 (s, 3H, CH3), 3.78 (m, 4H,
2OCH2), 5.15 (dd, 2H, Jcis = 10.4 Hz, 3’-Ha), 5.33 (dd,
2H, Jtrans = 17.1 Hz, 3’-Hb), 5.93 (m, 2H, 2’-H), 6.84 –
7.90 (m, 7H, Ar-H). – 13C NMR (CDCl3): δ = 21.6 (CH3),
63.2 (2OCH2), 100.8 (OCO), 123.4 (NCO), 116.6, 130.3 (2
CH=CH2), 126.6, 128.3, 128.6, 129.0, 129.1, 129.5, 134.5,
135.3, 135.6, 139.1 (Ar-C). -C21H20ClNO3 (369.9): calcd.
C 68.19, H 5.45, N 3.79; found C 67.9, H 5.6, N 4.0.
4-(4-Chlorophenyl)-1,4-dihydro-6-methyl-4-allylthio-2H-
1,3-benzoxazin-2-one (3m)
General procedure for the preparation of (5a−c)
From allyl mercaptan 2m (0.52 g, 7 mmol) as described
for 3c. Recrystallization from EtOAc / n-hexane furnishes
From excess alcohol (3 ml) as described for 4b. However,
the reaction mixture was stirred at room temperature for 4 h
before the addition of aq. NaOH. Usual work-up, evaporation
of the solvent affords oily residue. Recrystallization from n-
hexane gives fine crystals.
◦
faint yellow powder. M. p. 175 – 176 C; yield (56%). – IR
(KBr): ν = 1619 (C=C), 1723 (C=O), 3426 cm−1(NH). –
1H NMR (CDCl3): 2.27 (s, 3H, CH3), 3.30 (m, 2H, SCH2),
5.05 (dd, 1H, Jcis = 9.8 Hz, 3’-Ha), 5.11 (dd, 1H, Jtrans
=
16.9 Hz, 3’-Hb), 5.82 (m, 1H, 2’-H), 6.83 – 7.76 (m, 7H, Ar-
H), 9.34 (NH). – 13C NMR (CDCl3): δ = 21.3 (CH3), 34.7
(CH2), 118.6, 131.3 (CH=CH2), 95.9 (OCS), 115.4, 121.8,
127.0, 128.9, 129.0, 129.4, 133.2, 133.7, 135.3, 137.6 (Ar-
C), 152.1 (C=O). -C18H16ClNO2S (345.9): calcd. C 62.50,
H 4.67, N 4.05; found C 62.2, H 4.5, N 3.8.
N-{2-[(4-Chlorophenyl)dimethoxymethyl]-4-methyl-
phenyl}methylcarbamate (5a)
From methanol (3 ml) as described before. Recrystalliza-
tion from n-hexane affords pale yellow fine crystals (78%). –
M.p. 80 – 81 ◦C. – IR (KBr): ν = 1595 (C=C), 1734 (C=O),
3384 cm−1 (NH). – 1H NMR (CDCl3): δ = 2.35 (s, 3H,
CH3), 3.10 (s, 6H, 2OCH3), 3.60 (s, 3H, OCH3), 7.11 – 8.00
(m, 7H, Ar-H), 8.28 (s, 1H, NH). – 13C NMR (CDCl3):
δ = 21.3 (CH3), 49.5 (2OCH3), 52.3 (OCH3), 101.3 (OCO),
120.5, 128.4, 128.7, 128.8, 128.9, 130.2, 131.6, 133.5, 135.5,
139.0 (Ar-C), 154.2 (C=O). -C18H20ClNO4 (349.8): calcd.
C 61.81, H 5.76, N 4.00; found C 62.0, H 6.0, N 4.1.
General procedure for the preparation of 4’-chloro-2-iso-
cyanato-5-methylbenzophenonedisubstituted ketal (4b,e,f)
A solution of large excess alcohol (3 ml) in CH2Cl2
(10 ml) is added in one portion to a cold (−10 ◦C) suspension
of 1 (3.13 g, 5 mmol) in CH2Cl2 (40 ml). After warming to
23 ◦C in the course of 20 min., a solution of NaOH (2 g) in
H2O (50 ml) is added. Usual work-up, drying over Na2SO4,
filtration and evaporation of the solvent give pure oily prod-
uct.
N-{2-[(4-Chlorophenyl)diethoxymethyl]-4-methyl-
phenyl}ethylcarbamate (5b)
From ethanol (3 ml) as described for 5a. Recrystalliza-
tion from n-hexane gives pale yellow fine crystals (73%). –
M.p. 52 – 53 ◦C. – IR (KBr): ν = 1595 (C=C), 1737 (C=O),
3386 cm−1 (NH). 1H NMR (CDCl3): δ = 2.34 (s, 3H,
CH3),1.24 (m, 9H, 3CH3), 3.32 (m, 4H, 2OCH2), 4.04 (q,
2H, J = 7.1 Hz, OCH2), 7.08 – 7.77 (m, 7H, Ar-H), 8.11
4’-Chloro-2-isocyanato-5-methylbenzophenone-diethylketal
(4b)
From ethanol (3ml) as described before [25].
4’-Chloro-2-isocyanato-5-methylbenzophenone-di-
(2-methoxyethyl)ketal (4e)
From 2-methoxyethanol (3 ml) as described for 4b; yel- (s, 1H, NH). – 13C NMR (CDCl3): δ = 14.9 (CH3), 15.3
low oil (92%). – IR (film): ν = 1594 (C=C), 2286 cm−1 (2CH3), 21.4 (CH3), 57.6 (2OCH2), 61.0 (OCH2), 101.7
(NCO). – 1H NMR (CDCl3): δ = 2.39 (s, 3H, CH3), 3.36 (s, (OCO), 120.6, 128.3, 128.5, 128.6, 128.9, 130.0, 131.6,
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A. A. Hamed · Convenient Route to Efavirenz Analogues
133.5, 134.0, 140.0 (Ar-C), 153.9 (C=O). -C21H26ClNO4 (Ar-C), 153.7 (C=O). -C26H29ClN2O3 (453): calcd. C 68.94,
(391.9): calcd. C 64.36, H 6.69, N 3.57; found C 64.1, H 6.3, H 6.45, N 6.19; found C 68.7, H 6.2, N 6.1.
N 3.5.
1-{2-[(4-Chlorophenyl)diallyloxymethyl]-4-methylphenyl}-
N-{2-[(4-Chlorophenyl)dipropyloxymethyl]-4-methyl-
3-(4-fluorobenzyl)urea (6c)
phenyl}propylcarbamate (5c)
From 4-fluorobenzyl amine (0.55 g, 5 mmol) and◦ 4f
From n-propanol (3 ml) as described for 5a. Recrystalliza-
tion from n-hexane gives Pale yellow fine crystals (70%). –
M. p. 47 – 48 ◦C. – IR (KBr): ν = 1595 (C=C), 1737 (C=O),
3388 cm−1 (NH). 1H NMR (CDCl3): δ = 0.97 (m, 9H,
3CH3), 1.61 (m, 6H, 3CH2), 2.34 (s, 3H, CH3), 3.21 (m,
4H, 2OCH2), 3.96 (t, 2H, J = 6.5 Hz, OCH2), 7.09 – 7.82
(m, 7H, Ar-H), 8.15 (NH). – 13C NMR (CDCl3): δ = 10.6
(CH3), 11.3 (2CH3), 21.4 (CH3) 22.7 (CH2), 23.1(2CH2),
63.5 (2OCH2), 66.6 (OCH2), 101.5 (OCO), 120.8, 128.3,
128.6, 128.7, 128.9, 130.0, 132.2, 133.6, 134.0, 140.2 (Ar-
C), 154.0 (C=O). – C24H32ClNO4 (434.0): calcd. C 66.42,
H 7.43, N 3.23: found C 66.7, H 7.7, N 2.9.
(1.85 g, 5 mmol), as described for 6a. M.p. 205 – 206 C;
yield (69%). – IR (KBr): ν = 1594 (C=C), 1654 (C=O),
3370 cm−1(NH). – 1H NMR (CDCl3): δ = 2.37 (s, 3H,
CH3), 3.82 (m, 4H, 2OCH2), 4.16 (d, 2H, J = 5.8 Hz, NCH2),
4.36, 7.77 (2NH). 5.15 (dd, 2H, Jcis = 10.5 Hz, 3’-Ha),
5.30 (dd, 2H, Jtrans = 16.8 Hz, 3’-Hb), 5.90 (m, 2H,2’-H),
6.96 – 7.50 (m, 11H, Ar-H). – 13C NMR (CDCl3): δ = 21.5
(CH3), 43.8 (NCH2), 63.4 (2OCH2), 101.5 (OCO), 117.2,
134.3 (2 CH=CH2), 115.6, 115.9, 124.0, 128.6, 128.7, 128.9,
129.3, 129.4,130. 5, 133.6, 133.7, 134.4, 139.6, 164.0 (Ar-
C), 155.1 (C=O). -C28H28ClFN2O3 (495): calcd. C 67.94,
H 5.70, N 5.67; found C 68.2, H 5.8, N 5.4.
General procedure for the preparation of (6a−h)
1-{2-[(4-Chlorophenyl)diallyloxymethyl]-4-methylphenyl}-
3-(4-chlorobenzyl)urea (6d)
A mixture of 4 (5 mmol) and primary amine (5 mmol) in
diethylether (50 ml) is boiled under reflux for 10 min. The
solid product is filtered off and recrystallized from CH2Cl2 /
Et2O to give colourless fine crystals.
From 4-chlorobenzyl amine (0.63 g, 5 mmol) and◦ 4f
(1.85 g, 5 mmol), as described for 6a. M.p. 209 – 210 C;
yield (63%). – IR (KBr): ν = 1594 (C=C), 1661 (C=O),
3391 cm−1(NH). – 1H NMR (CDCl3): δ = 2.37 (s, 3H,
CH3), 3.78 (m, 4H, 2OCH2), 4.16 (d, 2H, J = 5.7 Hz,
NCH2), 4.39, 7.77 (2NH). 5.16 (dd, 2H, Jcis = 10.4 Hz, 3’-
Ha), 5.30 (dd, 2H, Jtrans = 17.0 Hz, 3’-Hb), 5.88 (m, 2H,
2’-H), 6.98 – 7.50 (m, 11H, Ar-H). – 13C NMR (CDCl3):
δ = 21.5 (CH3), 43.8 (NCH2), 63.3 (2OCH2), 101.5 (OCO),
117.2, 134.3 (2CH=CH2), 124.1, 128.6, 128.7, 128.9, 129.0,
129.1, 130. 5, 131.7, 133.0, 133.6, 133.7, 134.4, 137.8,
139.6 (Ar-C), 155.1 (C=O). -C28H28Cl2N2O3 (511.6): calcd.
C 65.75, H 5.52, N 5.49; found C 66.0, H 5.7, N 5.1.
1-{2-[(4-Chlorophenyl)diethoxymethyl]-4-methylphenyl}-3-
benzylurea (6a)
From benzyl amine (0.46 g, 5 mmol) and 4b (1.73 g,
5 mmol) as described before. M.p. 188 – 189 ◦C; yield
(79%). – IR (KBr): ν = 1594 (C=C), 1661 (C=O),
3370 cm−1(NH). – 1H NMR (CDCl3): δ = 1.19 (t, 6H,
J = 7.0 Hz, 2CH3), 2.36 (s, 3H, CH3), 3.28 (m, 4H, 2OCH2),
4.20 (d, 2H, J = 5.6 Hz, NCH2), 4.43, 7.73 (2NH), 7.06 –
7.50 (m, 12H, Ar-H). – 13C NMR (CDCl3): δ = 15.4
(2CH3), 21.4 (CH3), 44.5 (NCH2), 57.6 (2OCH2), 101.2
(OCO), 123.7, 127.6, 127.7, 128.4, 128.5, 128.6, 128.9,
130.2, 132.2, 133.1, 133.7, 134.0, 139.2, 140.1 (Ar-C), 155.3
(C=O). – C26H29ClN2O3 (453.0): calcd. C 68.94, H 6.45,
N 6.19; found C 68.6, H 6.2, N 5.9.
1-{2-[(4-Chlorophenyl)diallyloxymethyl]-4-methylphenyl}-
3-(4-methoxybenzyl)urea (6e)
From 4-methoxybenzyl amine (0.61 g, 5 mmol) and
4f (1.85 g, 5 mmol), as described for 6a. M.p. 191 –
◦
192 C; yield (68%). – IR (KBr): ν = 1591 (C=C), 1657
1-{2-[(4-Chlorophenyl)diethoxymethyl]-4-methylphenyl}-
3-(4-methylphenyl)urea (6b)
(C=O), 3368 cm−1(NH). – 1H NMR (CDCl3): ν = 2.36
(s, 3H, CH3), 3.78 (m, 4H, 2OCH2), 3.80 (s, 3H, OCH3),
From p-toluidine (0.46 g, 5 mmol) and 4b (1.73 g, 4.13 (d, 2H, J = 5.5 Hz, NCH2), 4.31, 7.75 (2NH). 5.15
5 mmol), as described for 6a. M.p. 194 – 195 ◦C; yield (dd, 2H, Jcis = 10.4 Hz, 3’-Ha), 5.29 (dd, 2H, J
=
trans
(72%). – IR (KBr): ν = 1594 (C=C), 1667 (C=O), 17.0 Hz, 3’-Hb), 5.90 (m, 2H, 2’-H), 6.83 – 7.52 (m, 11H,
3370 cm−1(NH). 1H NMR (CDCl3): δ = 1.12 (t, 6H, Ar-H). – 13C NMR (CDCl3): δ = 21.5 (CH3), 44.0 (NCH2),
J = 7.3 Hz, 2CH3), 2.35, 2.37 (2CH3), 3.22 (m, 4H, 55.6 (OCH3), 63.3 (2OCH2), 101.5 (OCO), 117.1, 134.3
2OCH2), 6.14, 7.71 (2NH), 7.00 – 7.65 (m, 11H, Ar-H). – (2CH=CH2), 114.3, 123.9, 128.5, 128.6, 128.8, 129.0, 130.
13C NMR (CDCl3): δ = 15.2 (2CH3), 21.2, 21.4 (2CH3), 5, 131.1, 131.5, 133.3, 133.8, 134.4, 139.6, 159.2 (Ar-
57.5 (2OCH2), 101.1 (OCO), 123.4, 123.9, 128.6, 128.7, C), 155.1 (C=O). C29H31ClN2O4 (507.0): calcd. C 68.70,
130.0, 130.1, 131.8, 133.1, 133.5, 134.0, 134.8, 135.1, 139.7 H 6.16, N 5.54; found C 69.1, H 5.8, N 5.2.
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A. A. Hamed · Convenient Route to Efavirenz Analogues
595
1-{2-[(4-Chlorophenyl)dimethoxyethoxymethyl]-4-methyl-
phenyl}-3-(4-fluorobenzyl) urea (6f)
130.3, 132.4, 133.2, 134.2, 135.0, 138.5, 139.8 (Ar-C), 155.5
(C=O). – C28H32Cl2N2O5 (547.6): calcd. C 61.42, H 5.89,
N 5.13; found C 61.2, H 6.1, N 4.8.
From 4-fluorobenzyl amine (0.55 g, 5 mmol) and 4e
(2.03 g, 5 mmol), as described for 6a. M. p. 140 – 141 ◦C;
yield (65%). – IR (KBr): ν = 1594 (C=C), 1666 (C=O),
3360 cm−1(NH). – 1H NMR (CDCl3): δ = 2.27 (s, 3H,
CH3), 3.29 (s, 6H, 2OCH3), 3.36 – 3.60 (m, 8H, 4OCH2),
4.28 (d, 2H, J = 5.7 Hz, NCH2), 5.00, 8.60 (2NH), 6.96 –
7.7.87 (m, 11H, Ar-H). – 13C NMR (CDCl3): δ = 21.3
(CH3), 43.7 (NCH2), 59.0 (2OCH3), 61.2, 71.8 (4OCH2),
103.6 (OCO), 115.8, 122.7, 128.5, 128.6, 129.2, 129.4,
129.5, 130.3, 132.4, 134.2, 135.1, 139.9, 164.0 (Ar-C), 155.6
(C=O). C28H32ClFN2O5 (531.2): calcd. C 63.33, H 6.07,
N 5.29; found C 62.9, H 5.8, N 4.9.
1-{2-[(4-Chlorophenyl)dimethoxyethoxymethyl]-4-methyl-
phenyl}-3-(4-methoxybenzyl) urea (6h)
From 4-methoxybenzyl amine (0.61 g, 5 mmol) and◦4e
(2.03 g, 5 mmol), as described for 6a. M.p. 83 – 84 C;
yield (73%). – IR (KBr): ν = 1593 (C=C), 1667 (C=O),
3368 cm−1(NH). – 1H NMR (CDCl3): δ = 2.27 (s, 3H,
CH3), 3.28 (s, 6H, 2OCH3), 3.79 (s, 3H, OCH3), 3.35 –
3.60 (m, 8H, 4OCH2), 4.26 (d, 2H, J = 5.5 Hz, NCH2),
4.95, 8.52 (2NH), 6.83 – 7.87 (m, 11H, Ar-H). 13C NMR
(CDCl3): δ = 21.3 (CH3), 43.9 (NCH2), 55.6 (OCH3), 59.0
(2OCH3), 61.2, 71.8 (4OCH2), 103.5 (OCO), 114.2, 122.7,
128.5, 128.6, 128.8, 129.1, 129.2, 130.3, 131.9, 132.2, 134.1,
135.2, 139.8, 159.1 (Ar-C), 155.6 (C=O). -C29H35ClN2O6
(543.2): calcd. C 64.13, H 6.50, N 5.17; found C 63.8, H 6.2,
N 4.9.
1-{2-[(4-Chlorophenyl)dimethoxyethoxymethyl]-4-methyl-
phenyl}-3-(4-chlorobenzyl) urea (6g)
From 4-chlorobenzyl amine (0.63 g, 5 mol) and ◦4e
(2.03 g, 5 mmol), as described for 6a. M. p. 93 – 94 C;
yield (69%). – IR (KBr): ν = 1594 (C=C), 1666 (C=O),
3370 cm−1(NH). – 1H NMR (CDCl3): δ = 2.27 (s, 3H,
CH3), 3.30 (s, 6H, 2OCH3), 3.33 – 3.63 (m, 8H, 4OCH2),
4.28 (d, 2H, J = 5.9 Hz, NCH2), 5.03, 8.61 (2NH), 7.05 –
7.86 (m, 11H, Ar-H). – 13C NMR (CDCl3): δ = 21.3 (CH3),
43.7 (NCH2), 59.0 (2OCH3), 61.2, 71.8 (4OCH2), 103.6
(OCO), 122.7, 128.4, 128.5, 128.6, 128.9, 129.2, 129.4,
Acknowledgements
The author would like to thank Prof. Dr. Erik. B. Pedersen
for valuable discussion and Prof. Dr. Claus Nielsen for deter-
mination of biological activity. Danish International Devel-
opment Agency (DANIDA) is gratefully acknowledged for
financial support.
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