Highly flexible and efficient synthesis of the GABAB enhancer 4-(2-hexylsulfanyl-6-methyl-pyrimidin-4-ylmethyl)-morpholine

Article abstract of DOI:10.1016/j.tetlet.2006.11.090

In the course of establishing a flexible synthesis of 2,4,6-substituted pyrimidines, we discovered that 2-hexyl-isothiourea hydrobromide reacts at ambient temperature and in a mildly exothermic fashion with 5,5-diethoxy-pent-3-yn-2-one upon treatment with 2 equiv of triethylamine in tetrahydrofuran to afford 4-diethoxymethyl-2-hexylsulfanyl-6-methyl-pyrimidine in 80% isolated yield. The methodology was developed in the search for an improved synthesis of the GABA_B enhancer 4-(2-hexylsulfanyl-6-methyl-pyrimidin-4-ylmethyl)-morpholine.

Full text of DOI:10.1016/j.tetlet.2006.11.090

Tetrahedron Letters 48 (2007) 377–380
Highly flexible and efficient synthesis of the GABAB enhancer
4-(2-hexylsulfanyl-6-methyl-pyrimidin-4-ylmethyl)-morpholine
Julien Verron, Paricher Malherbe, Eric Prinssen, Andrew W. Thomas,
Nadine Nock and Raffaello Masciadri*
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Discovery Chemistry, CH-4070 Basel, Switzerland
Received 6 October 2006; revised 10 November 2006; accepted 14 November 2006
Available online 4 December 2006
Abstract—In the course of establishing a flexible synthesis of 2,4,6-substituted pyrimidines, we discovered that 2-hexyl-isothiourea
hydrobromide reacts at ambient temperature and in a mildly exothermic fashion with 5,5-diethoxy-pent-3-yn-2-one upon treatment
with 2 equiv of triethylamine in tetrahydrofuran to afford 4-diethoxymethyl-2-hexylsulfanyl-6-methyl-pyrimidine in 80% isolated
yield. The methodology was developed in the search for an improved synthesis of the GABAB enhancer 4-(2-hexylsulfanyl-6-
methyl-pyrimidin-4-ylmethyl)-morpholine.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The non-fused pyrimidine ring is an important scaffold
in medicinal chemistry. According to the Derwent World
Drug Indexꢁ close to 100 drugs with a non-fused pyrim-
idine ring have been launched in the pharmaceutical
market and several of these drugs have reached block-
buster status including trimethoprim, buspirone, bosen-
tan, and imatinib. The vitamin thiamine belongs to the
same structural class.
gyl amine 1,10 which was purified on large scale directly
by distillation. Propargyl amine 1 was treated with iso-
propyl magnesium chloride at low temperature which
led to the formation of the corresponding acetylenic
Grignard reagent under the liberation of propane. The
Grignard reagent was cannulated slowly into a cold
solution of the commercial Weinreb amide 2.11 The
purification of the resulting acetylenic ketone 3 proved
to be difficult and unreacted starting material could not
The chemistry of the non-fused pyrimidines has been
exhaustively reviewed in monographs.1,2 Many publica-
tions of more recent solution3–6 and solid phase synthe-
ses7 have appeared in the literature.
O
O
O
O
N
HN
N
Br
2
In the course of a medicinal chemistry program aimed at
the discovery of novel GABAB receptor enhancers,8 we
were in need of a flexible synthesis of 2,4,6-substituted
pyrimidines. We opted for a previously reported method9
which uses the condensation of a alkynone with a
thiuronium salt.
a
b
55%
75%
1
O
O
4
N
N
NH2
In order to resynthesize our lead compound 5, we first
chose the pathway shown in Scheme 1. Morpholine
was readily alkylated with propargyl bromide and
potassium carbonate in methanol to afford the propar-
HBr
S
NH
N
c
S
N
O
30%
Keywords: 2,4,6-Substituted pyrimidines; 2-Hexyl-isothiourea hydro-
bromide; 5,5-Diethoxy-pent-3-yn-2-one; Modular pyrimidine synthe-
sis; GABAB enhancer.
3
5
Scheme 1. Reagents and conditions: (a) K2CO3, MeOH, 0–20 ꢂC; (b)
(i) i-PrMgCl (1 equiv), THF, À20 ꢂC, (ii) AcNMeOMe, THF, À10 ꢂC
(inverse addition); (c) DIPEA (4 equiv), DMF, 24 h, 20 ꢂC.
*
Corresponding author. Tel.: +41 61 688 7504; fax: +41 61 688
6459; e-mail: raffaello.masciadri@roche.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.090

378
J. Verron et al. / Tetrahedron Letters 48 (2007) 377–380
EtO
N
OEt
be removed by chromatography. Therefore the acetyl-
enic ketone 3 was purified by Kugelrohr distillation, but
it soon became apparent that the intermediate 3 had lim-
ited chemical stability. Probably as a consequence, the
condensation of 3 with the thiuronium salt 4 with
pathway B
O
B
H13C6S
NH2
EtO
OEt
9
Hunig’s base in DMF proceeded in low yield.9
¨
HBr
10%
A
NH2
NH
H13C6S
+
Despite the shortness of this pathway, a better synthesis
(Scheme 2) was imperative in view of the preparation of
libraries with ample variation of the substituents in 2-, 4-,
and 6-position of the pyrimidine. Since we planned to
incorporate a wide variety of amines via reductive ami-
nation, we chose a protected aldehyde as intermediate,
which in the end turned out to be highly beneficial.
EtO
OEt
4
O
80%
N
7
H13C6S
N
pathway A
8
Scheme 3.
Luckily, 5,5-diethoxy-pent-3-yn-2-one (6), a commercial
item, could also be obtained on larger scale. Grignard
formation and inverse addition to a solution of the
Weinreb amide 2 proceeded in 70% yield. The resulting
acetylenic ketone 7 proved to be a stable synthetic inter-
mediate. On a small scale, screening of solvents and bases
for the condensation reaction of 7 with the thiuronium
salt 4 indicated that triethylamine in THF was the best
choice. On a large scale (15 g), the reaction was mildly
exothermic (30 ꢂC) and afforded pyrimidine 8 at ambient
temperature in 80% yield. This transformation was
accompanied by formation of by-product 9, which could
be isolated in 10% yield. Refluxing of the reaction mixture
did not convert by-product 9 into pyrimidine 8. Forma-
tion of by-product 9 occurred via Michael addition of the
thiuronium salt 4 to acetylenic ketone 7 (pathway B,
Scheme 3), while main product 8 was formed via car-
bonyl addition (pathway A, Scheme 3).
fact that the diethoxy acetal function sterically and elec-
tronically suppresses the Michael addition pathway B
and thus favors the carbonyl addition pathway A
(Scheme 3). Furthermore, we speculate that the Michael
addition occurred in syn fashion and therefore led to E-
geometry of the double bond in by-product 9 precluding
subsequent cyclization to pyrimidine 8.
Moreover, we found that the thiuronium salt 4 with its
long lipophilic tail was the best nucleophile. Thiuronium
salts with shorter lipophilic appendices (e.g., Me only),
resulted in lower yield. The role of the hexyl chain may
be two-fold: first it increases the solubility of the thiuro-
nium salt 4, and secondly, it enhances the nucleophilicity
of the azathioenol ether substructure. Thus in retrospect,
a number of unanticipated features contributed to the
optimal outcome of the originally planned reaction.
This behavior triggered the interesting thought that the
high yield observed in this reaction may be due to the
Acetal 8 was cleaved with 4 N sulfuric acid in THF at
50 ꢂC overnight to afford aldehyde 10 in 74% yield.
The latter was reductively aminated with a range of sec-
ondary amines. In the case of morpholine, Borch reduc-
tion12 or pyridine borane reduction13 was convenient for
parallel chemistry with direct purification of the prod-
ucts by preparative HPLC, but with more sterically
demanding secondary amines, the Ti(OiPr)4–NaBH3CN
method14 was necessary to bring about efficient coupling
of the reaction partners. The yields of the reductive
aminations were not optimized. Detailed experimental
procedures for the preparation of compounds 1–10 are
listed in Ref. 15.
O
NH2
NH
N
H13C6S
HBr
EtO
OEt
2
EtO
OEt
O
4
b
a
65%
7
6
O
EtO
OEt
EtO
N
OEt
+
8
9
N
O
80%
10%
H13C6S
H13C6S
N
NH2
In conclusion we have discovered a flexible and high
yielding synthesis of 2,4,6-trisubstituted pyrimidines
which proceeds through the utilization of 5,5-diethoxy-
pent-3-yn-2-one as the key building block, and we have
gained mechanistic insight into the factors governing the
maximally achievable yield of the addition of 2-hexyl-
isothiourea to this key intermediate.
74%
O
c
O
O
N
HN
d
N
N
20-50%
H13C6S
N
H13C6S
N
10
11
Acknowledgments
Scheme 2. Reagents and conditions: (a) (i) i-PrMgCl (1.1 equiv), (ii)
AcNMeOMe, THF, À20 to 0 ꢂC, 2 h; (b) TEA (2.2 equiv), THF, 5 h,
20 ꢂC; (c) 4 N H2SO4, THF, 24 h, 50 ꢂC; (d) NaBH3CN, EtOH/AcOH
10:1, 24 h, 20 ꢂC.
We would like to thank the analytical department
PRBD-E for measuring and interpreting H NMR and
MS spectra.
1

J. Verron et al. / Tetrahedron Letters 48 (2007) 377–380
379
Weinreb amide solution at À10 ꢂC via Teflon tubing under
slightly positive nitrogen pressure. There was no exo-
therm. Stirring at À10 ꢂC to 0 ꢂC was continued for 2 h.
The resulting white suspension was poured on a 1:1
mixture of ice and saturated NH4Cl solution (400 mL).
Extraction: 2 · AcOEt, 1 · saturated NaCl solution. One
obtained yellow oil (26.1 g, 89%). Chromatography on
silica gel in heptane/ethyl acetate 1:2 gave 19.4 g (66%) of
a brown oil which was distilled in the Kugelrohr at 130 ꢂC/
References and notes
1. Brown, D. J. The Pyrimidines 1962.
2. Brown, D. J.; Evans, R. F.; Cowden, W. B.; Fenn, M. D.
The Chemistry of Heterocyclic Compounds, Vol. 16, The
Pyrimidines, 1985.
3. Herrera, A.; Martinez-Alvarez, R.; Chioua, R.; Chioua,
M. Tetrahedron Lett. 2003, 44, 2149–2151.
4. Herrera, A.; Martinez-Alvarez, R.; Chioua, R.; Benabde-
louahab, F.; Chioua, M. Tetrahedron 2004, 60, 5475–5479.
5. Stanetty, P.; Hattinger, G.; Schnuerch, M.; Mihovilovic,
M. D. J. Org. Chem. 2005, 70, 5215–5220.
6. Zanatta, N.; Flores, D. C.; Madruga, C. C.; Flores, A. F.
C.; Bonacorso, H. G.; Martins, M. A. P. Tetrahedron Lett.
2006, 47, 573–576.
7. Pathak, R.; Roy, A. K.; Kanojiya, S.; Batra, S. Tetra-
hedron Lett. 2005, 46, 5289–5292.
8. Malherbe, P.; Masciadri, R.; Prinssen, E.; Spooren, W.;
Thomas, A. W. U.S. Patent 2005197337, 2005; Chem.
Abstr. 2005, 266950.
9. Chucholowski, A.; Masquelin, T.; Obrecht, D.; Stadlwie-
ser, J.; Villalgordo, J. M. Chimia 1996, 50, 525–530.
10. Verkruijsse, H. D.; Bos, H. J. T.; De Noten, L. J.;
Brandsma, L. Rec. Trav. Chim. Pays-Bas 1981, 100, 244–
246.
1
0.2 mbar. One obtained 15.8 g (53%) of a yellow oil. H
NMR (400 MHz, CDCl3): d = 2.36 (s, 3H, COCH3), 2.58
(t, J = 4.8 Hz, 4H, CH2N), 3.47 (s, 2H, CCCH2), 3.74 (t,
J = 4.8 Hz, 4H, CH2O); MS (ISP): m/z = 168 (M+H).
2-Hexyl-isothiourea hydrobromide (4). Caution: Because
of its pungent odor, all manipulations with this reagent
should be run in a well ventilated laboratory hood, and all
glassware that has been in contact with this reagent should
be rinsed with 10% sodium hypochlorite solution before
putting into the washing machine. Thiourea (50 g,
657 mmol) and 1-bromohexane (119 mL, 723 mmol) were
heated at reflux under nitrogen in ethanol (500 mL) for
20 h. Ethanol was evaporated, and the thick oil stirred in
diethyl ether (500 mL). The product precipitated sponta-
neously. After filtration one obtained 144.5 g (91%) of
white crystals, mp 75 ꢂC.
4-(2-Hexylsulfanyl-6-methyl-pyrimidin-4-ylmethyl)-morpho-
line (5). 5-Morpholin-4-yl-pent-3-yn-2-one (3) (1 g,
6 mmol) and 2-hexyl-isothiourea hydrobromide (4)
(1.06 g, 7 mmol) were dissolved under nitrogen in DMF
(10 mL), then N-ethyldiisopropylamine (4.1 mL, 24 mmol)
was added and stirring at the room temperature continued
for 18 h. DMF was evaporated. The product was
extracted with AcOEt (2 · 50 mL), saturated solution of
NH4Cl (2 · 50 mL), dried and concentrated. The residue
was purified by flash chromatography on an aminated
silica gel column with a heptane/AcOEt gradient. One
obtained 440 mg (24%) of a yellow liquid. 1H NMR
(250 MHz, CDCl3): d = 0.9 (m, 3H, S(CH2)5CH3), 1.32
(m, 4H, SCH2(CH2)4CH3), 1.45 (m, 2H, SCH2(CH2)4CH3),
1.72 (quin, J = 7.2 Hz, 2H, SCH2(CH2)4CH3), 2.44 (s, 3H,
ArCH3), 2.52 (m, 4H, NCH2CH2O), 3.14 (t, J = 7.2 Hz,
2H, SCH2(CH2)4CH3), 3.52 (s, 2H, ArCH2N), 3.74 (m,
4H, NCH2CH2O), 6.98 (s, 1H, ArH); MS: m/z = 310
(M+H).
5,5-Diethoxy-pent-3-yn-2-one (7). Propargylaldehyde di-
ethylacetal (40 g, 312 mmol) was dissolved in THF
(200 mL) under argon and cooled to À70 ꢂC. Then a
1.6 M solution of n-butyl lithium in hexane (234 mL,
374 mmol) was added and stirring continued for 30 min at
À30 ꢂC. Then N-methoxy-N-methylacetamide (38.6 g,
374 mmol) in THF (10 mL) was added. After 30 min at
À30 ꢂC, the reaction was quenched by addition of
saturated NH4Cl solution (20 mL). The product was
extracted with AcOEt (2 · 200 mL), saturated solution of
NH4Cl (2 · 200 mL), dried and concentrated. Chroma-
tography on silica gel with a heptane/AcOEt gradient
100:0 to 95:5 gave 38.5 g (72%) of a colorless oil. 1H NMR
(400 MHz, CDCl3): d = 1.25 (t, J = 7.2 Hz, 6H, OCH2CH3),
2.37 (s, 3H, COCH3), 3.62 (q, J = 7.2, OCH2CH3), 3.75 (q,
J = 7.2, OCH2CH3), 5.38 (s, 1H, CH(OEt)2); GC/MS:
m/z = 232(M).
11. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini,
G.; Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett.
1995, 36, 5461–5464.
12. Borch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673.
13. Moormann, A. E. Synth. Commun. 1993, 23, 789–795.
14. Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A.
J. Org. Chem. 1990, 55, 2552–2554.
15. Experimental procedures: 4-Prop-2-ynyl-morpholine (1).
Morpholine (100 mL, 1.148 mol) was dissolved in MeOH
(1 L) and cooled in ice under nitrogen, then potassium
carbonate (120 g, 0.63 mol) and propargyl bromide
(124 mL, 1.148 mol) were added while stirring in ice.
Stirring without cooling was continued for 4 h. The white
suspension was filtered through paper and the solids were
washed with MeOH (100 mL), and MeOH was carefully
evaporated. The white precipitate was suspended in DCM
(400 mL), filtered through paper, and carefully evapo-
rated. Finally the oil was distilled at 60 ꢂC/16 mbar. One
obtained 100 g (70%) of a colorless oil. 1H NMR
(300 MHz, CDCl3): d = 2.27 (t, J = 2.4 Hz, 1H, CCH),
2.57 (t, J = 4.5 Hz, 4H, CH2N), 3.29 (d, J = 2.4 Hz, 2H,
CCCH2), 3.75 (t, J = 4.5 Hz, 4H, CH2O).
N-Methoxy-N-methyl-acetamide (2). N,O-Dimethyl-
hydroxylamine HCl (100 g, 1025 mmol) was suspended
under nitrogen in DCM (1000 mL) and cooled in ice.
Triethylamine (300 mL, 2152 mmol) was added slowly,
then acetyl chloride (76.5 mL, 1076 mmol) was added
slowly, and the temperature reached 20 ꢂC despite ice
cooling and slow addition. Stirring without cooling was
continued for 30 min. Extraction: 1 · DCM, 1 · 1 N HCl,
2 · saturated NaCl solution. Distillation at 42 ꢂC/20 mbar
gave 69 g (65%) of a colorless oil. 1H NMR (400 MHz,
CDCl3): d = 2.13 (s, 3H, COCH3), 3.18 (s, 3H, CONCH3),
3.69 (s, 3H, OCH3).
5-Morpholin-4-yl-pent-3-yn-2-one (3). 4-Prop-2-ynyl-mor-
pholine (1) (22 g, 176 mmol) was dissolved under nitrogen
in THF (40 mL) and cooled to À40 ꢂC. Then a 2 M
solution of isopropyl magnesium chloride in THF (97 mL,
193 mmol) was added while keeping the temperature
below À20 ꢂC. Stirring at À40 ꢂC to À30 ꢂC was contin-
ued for 30 min. In a separate flask, N-methoxy-N-methyl-
acetamide (20 g, 193 mmol) was dissolved under nitrogen
in THF (40 mL) and cooled to À10 ꢂC in ice/MeOH. The
Grignard solution prepared above was transferred to the
4-Diethoxymethyl-2-hexylsulfanyl-6-methyl-pyrimidine (8)8
and 1-((E)-1-diethoxymethyl-3-oxo-but-1-enyl)-2-hexyl-
isothiourea (9). 5,5-Diethoxy-pent-3-yn-2-one (7) (15 g,
88 mmol) and 2-hexyl-isothiourea hydrobromide (23 g,
97 mmol) were dissolved under nitrogen in THF (150 mL).
Then triethylamine (27 mL, 194 mmol) was added slowly
while cooling with an ice bath to keep the temperature at
20 ꢂC. The suspension was stirred without cooling for 5 h.

380
J. Verron et al. / Tetrahedron Letters 48 (2007) 377–380
The product was extracted with AcOEt, satd NH4Cl
heated at 50 ꢂC for 33 h. After cooling, the reaction
mixture was poured into cold 10% Na2CO3 solution
(400 mL) and extracted with ethyl acetate and a satd
solution of NaCl. The crude oil was purified by silica gel
chromatography with a heptane/DCM gradient of 100:0
to 67:33. One obtained 10.7 g (74%) of a yellow oil. 1H
NMR (400 MHz, CDCl3): d = 0.90 (t, J = 4 Hz, 3H,
S(CH2)5CH3), 1.33 (m, 4H, SCH2(CH2)4CH3), 1.48 (m,
2H, SCH2(CH2)4CH3), 1.76 (m, 2H, SCH2(CH2)4CH3),
2.55 (s, 3H, ArCH3), 3.21 (t, J = 7.6 Hz, 2H, SCH2-
(CH2)4CH3), 7.28 (s, 1H, ArH). MS (EI): m/z = 239
(M+H).
Library Synthesis via reductive amination: 4-(2-Hex-
ylsulfanyl-6-methyl-pyrimidin-4-ylmethyl)-morpholine (5).
Aldehyde 10 (0.1 g, 0.42 mmol) was dissolved in EtOH
(1 mL) and AcOH (0.1 mL). Then morpholine (0.087 mL,
1 mmol) and NaBH3CN (26 mg, 0.4 mmol) were added
slowly at 20 ꢂC and stirring was continued for 24 h. The
reaction mixture was evaporated to dryness and dissolved
in a minimal amount of DMF (0.8 mL) and directly
purified by preparative HPLC chromatography on a
YMC combiprep ODS-AQ column (75 · 20 mm iD,
S-5 lM, 12 nm) with an acetonitrile–water gradient. One
obtained 34.7 mg (28%) of a yellow liquid. MS: m/z = 310
(M+H).
solution, dried, and concentrated. The residue was purified
by silica gel chromatography in heptane/AcOEt 20:1. One
obtained 22.3 g (80%) of 8 as colorless oil and 2.8 g (10%)
of 9 as yellow oil. Compound 8: 1H NMR (400 MHz,
CDCl3): d = 0.89 (t, J = 4 Hz, 3H, S(CH2)5CH3), 1.25
(t, J = 7.2 Hz, 6H, OCH2CH3), 1.31 (m, 4H, SCH2-
(CH2)4CH3), 1.45 (m, 2H, SCH2(CH2)4CH3), 1.72 (m,
2H, SCH2(CH2)4CH3), 2.45 (s, 3H, ArCH3), 3.15 (t,
J = 7.6 Hz, 2H, SCH2(CH2)4CH3), 3.61 (m, 2H, OCH2-
CH3), 3.72 (m, 2H, OCH2CH3), 5.25 (s, 1H, CH(OEt)2),
7.06 (s, 1H, ArH); MS (ISP): m/z = 313 (M+H). Com-
pound 9: 1H NMR (400 MHz, DMSO-d6): d = 0.86 (t,
J = 4 Hz, 3H, S(CH2)5CH3), 1.16 (t, J = 7.2 Hz, 6H,
OCH2CH3), 1.25 (br, 2H, NH2), 1.26 (m, 4H, SCH2-
(CH2)4CH3), 1.33 (m, 2H, SCH2(CH2)4CH3), 1.49 (m, 2H,
SCH2(CH2)4CH3), 2.15 (s, 3H, COCH3), 3.01 (t, J =
7.6 Hz, 2H, SCH2(CH2)4CH3), 3.48 (m, 2H, OCH2CH3),
3.58 (m, 2H, OCH2CH3), 5.16 (s, 1H, CH(OEt)2), 6.56 (s,
1H, C@CH); MS (EI): m/z = 288 (M–COCH2), 259 (M–
Et), 243 (M–OEt), 213 (M–SC6H13), 103 (CH(OEt)2).
2-Hexylsulfanyl-6-methyl-pyrimidine-4-carbaldehyde (10).
4-Diethoxymethyl-2-hexylsulfanyl-6-methyl-pyrimidine (8)
(19 g, 60.8 mmol) was dissolved in THF (100 mL), 4 N
aqueous H2SO4 (100 mL) was added and the mixture was