Substance table begins on page 18.

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization WO 2007/105233 A2

International Bureau

(43) International Publication Date P in T d*) International Publication Number

20 September 2007 (20.09.2007) WO 2007/105233 A2
(51) International Patent Classification: Not classified (81) Designated States (unless otherwise indicated, fo r every
kind o f national protection available). AE, AG, AL, AM,
(21) International Application Number: AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
PCT /IN2007/000103 CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS,
(22) International Filing Date: 12 March 2007 (12.03.2007) JP, RE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
LT, LU, LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ,
(25) Filing Language: English NA, NO, NI, NO, NZ, OM, PO, PH, PL, PT, RO, RS, RU,
SC, SD, SE, SG, SR, SL, SM, SV, SY, TJ, TM, TN, TR,
(26) Publication Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.

(30) Priority Data: (84) Designated States (unless otherwise indicated, fo r every
668/DEL/2006 10 March 2006 (10.03.2006) IN kind o f regional protection available). ARIPO (BW, GH,
GM, RE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
(71) Applicant (for all designated States except US). COUN ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
CIL OF SCIENTIFIC & INDUSTRIAL RESEARCH European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
[IN/IN]; Anusandhan Bhawan, Rafi Marg, New Delhi 110 FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL,
WO 2007/105233
010 (IN).A2 PT, RO, SE, SI, SR, TR), OAPI (BF, BJ, CF, CO, Cl, CM,
GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
(72) Inventors; and
(75) Inventors/Applicants (for US only). BORDOLOI, Declaration under Rule 4.17:
Manobjyti [IN/IN]; Natural Products Chemistry Division, o f inventorship (Rule 4.17(iv))
Regional Research Laboratory, Jorhat 785 006, Assam
(IN). ROY, Dipak, Kumar [IN/IN]; Natural Products Published:
Chemistry Division, Regional Research Laboratory, Jorhat without international search report and to be republished
785 006, Assam (IN). upon receipt o f that report

(74) Agent: DHAWAN, Ramesh, Chander; Lall Lahiri & Sal- For two-letter codes and other abbreviations, refer to the "Guid
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Al
WO 2007/105233

(54) Title: AN IMPROVED PROCESS FOR THE PREPARATION OF 4,5,6-SUBSTITUTED 3,4-DIHYDROPYRIMIDIN-2-

ONES AND THEIR 2-THIOXO ANALOGUES

(57) Abstract: The present invention relates to an improved process for the preparation of 4,5,6-substituted 3,4-dihydropyrim-
idin-2-ones and their 2-thioxo analogues wherein substitution at 4,5 and 6 is selected from the group consisting of H, alkyl, aryl,
cycloalkyl, alkyl or aryl carboxylate group, polyhydroxy alkyl and polyhydroxy aryl catalyzed by tin (IV) chloride pentahydrate and
silver triflate.
 WO 2007/105233 PCT/IN2007/000103

AN IMPROVED PROCESS FOR THE PREPARATION OF 4,5,6-SUBSTITUTED

3,4-DIHYDROPYRIMIDIN-2-ONES AND THEIR 2-THIOXO ANALOGUES

Fieldofthelnvention
5 The present invention relates to an improved process for the
IDreparation of 4,5,6-substituted 3,4-dihydropyrimidin-2-ones and their 2-thioxo
analogues. Particularly, the present invention relates to a process for the
preparation of 4, 5, 6-substituted 3, 4-dihydropyrimidin-2-ones and their 2-
thioxo analogues catalyzed by tin (IV) chloride pentahydrate and silver triflate.
io More particularly, the present invention relates to a process for the
production of potential bioactive 4,5,6-substituted 3,4-dihydropyrimidin-2-ones
and their 2-thioxo analogues wherein substitution at 4,5 and 6 is selected
from the group consisting of H, alkyl, aryl, cycloalkyl, alkyl or aryl carboxylate
group, polyhydroxy alkyl and polyhydroxy aryl,.
15

Background of the invention

4,5,6-substituted 3,4-dihydropyrimidin-2-ones and their 2-thioxo
analogues wherein substitution at 4,5 and 6 is selected from the group
consisting of H, alkyl, aryl, cycloalkyl, alkyl or aryl carboxylate group,
20 polyhydroxy alkyl and polyhydroxy, are biologically active with wide spectrum
of biological activity of commercial importance such as calcium channel
modulator, Dradrenoreceptorselective antagonists, useful as treatment of
benign prostatic hyperplasia, anti-HIV and anti-viral agents, anti-cancer drug
as mitotic kinesin inhibitors, inhibitor of Walker carcinosarcoma, etc.
25 The process will be useful for the syntheses of 3,4-dihydropyrimidin-2-
ones and its 2-thioxo analogues biologically active as calcium channel
modulator, ai-adrenoreceptorseiective antagonists, useful as treatment of
benign prostatic hyperplasia, anti-HIV agents, mitotic kinesin inhibitors,
inhibitor of Walker carcinosarcoma, etc. The process of the present invention
30 does not involve the use of any high boiling solvent and also does not involve
the use of costly and environmentally toxic catalysts. Except production of
water vapour, the process is hundred percent atoms economic and therefore,
green in nature. The process when utilizes microwave irradiation, the use of
solvent is not required and reaction time is very short. When the process is
35 used under reflux condition, the recovery of the catalyst as well as solvent is
 WO 2007/105233 PCT/IN2007/000103
2

also possible which makes the process simple and economic. In earlier
inventions, the production of potential bioactive 4,5,6-trisubstituted 3,4-
dihydropyrimidin-2-ones and their 2-thioxo analogues wherein substitution at
4,5 and 6 may be alkyl, aryl, cycloalkyl, alkyl or aryl carboxylate group,
5 polyhydroxy alkyl, polyhydroxy aryl, etc. of the general formula 1 are
described as follows:
Michael Brands et al have reported synthesis and pharmacological
evaluation of Pyrimidinone Antibioticsantibiotic TAN 1057 active against a
number of Gram-positive bacteriae. (Michael Brands et al, Bioorganic &
10 Medicinal Chemistry Letters 13 (2003) 2641-2645).
C. Oliver Kappe has reviewed various 4-Aryldihydropyrimidines via the
Biginelli Condensation to Aza-Analogs of Nifedipine-Type Calcium Channel
Modulators (C. Oliver Kappe Molecules 1998, 3, 1 - 9).
Kappe, C.O. et al has reported the synthesis of monastrol by
15 microwave-promoted three-component Biginelli condensation. Monastrol is a
new anti-cancer drug which inhibits mitotic kinin Eg5. (Kappe, C.O., Shishkin,
O.V., Uray, G., Verdino, P., Tetrahedron, Mar 2000).
B Lagu et al have reported the synthesis of furo 3,4-
dihydropyrimidinones as selective a-1a-receptor antagonists (Biorganic &
20 Medicinal Chemistry Letters, 2000, 10(2), 175-178).
M Brands et al has reported the synthesis of 3,4-dihydropyrimidine
based antistaphilococcal antibiotics (Biorganic & Medicinal Chemistry Letters,
2003,13(2),241-245).
Thus compounds of these class, that is, 4,5,6-substituted 3,4-
25 dihydropyrimidin-2-ones and their 2-thioxo analogues are important and
useful as biologically active and hence related to human health commercially.
Reference may be made to the report of the synthesis of 3,4-
dihydropyrimidin-2-ones and their 2-thioxo analogues wherein these
compounds were synthesized by catalysis of costly, hazardous, strongly
30 acidic, difficult to handle and the use environmentally toxic solvents are
necessary:
(1) C.O.Kappe et al. Dec 2000, (http://www.unibas.ch/mdpi/ecsoc-
3/b0008/b0008.htm)
(2) Sabhita et al Tetrahedron Letters, 2003, 44(34), 6497-6499).
 WO 2007/105233 PCT/IN2007/000103
3

(3) Choudhury et al, Catalysis Communication, 19 July, 2003).

(4) Ji-Tai Li et al, Ultrasonics Sonochemistry, 2003, 10(3), 119-122.
(5) Nan-Yan Fu et al, Journal of Organometallic Chemistry, 2003, 672 (1-2),
52-57.
5 (6) Kappe, C.O.., Bioorganic & Medicinal Chemistry Letters, Jan 2000.
(7) P Salehi et al, Tetrahedron Letters, 2003, 44 (14), 2889-2891.
(8) G Maiti et al Tetrahedron Letters, 2003, 44, 2757.
(9) C Venkateswar Reddy et al Tetrahedron Letters, 2002, 43, 2657-2659.
(10) A Dondoni and A Massi Tetrahedron Letters, 2001, 42, 7975-7978.
io (11) Jun Lu et al Tetrahedron Letters, 2000, 41, 9075-9078.
(12) BC Hamper et al Tetrahedron Letters, 1999, 40, 4973-49-76.

Objectives of the invention

The main object of the present invention, therefore, is to provide an
15 improved process for the preparation of 4,5,6-substituted 3,4-
dihydropyrimidin-2-ones and their 2-thioxo analogues, wherein substitution at
4,5 and 6 is selected from the group consisting of H, alkyl, aryl, cycloalkyl,
alkyl or aryl carboxylate group, polyhydroxy alkyl, polyhydroxy aryl and
oligosaccharides.
20. Yet another object of the present invention .is to provide an improved
process for the production of 4,5,6-substituted 3,4-dihydropyrimidin-2-ones
and their 2-thioxo analogues, which is simple, economical and is of
environmentally acceptable nature.

25 Summary of the invention

Accordingly the present invention provides an improved process for the
preparation of 4,5,6-substituted-3,4-dihydropyrimidin-2-ones and their 2-thioxo

analogues of formula 1,
 WO 2007/105233 PCT/IN2007/000103
4

Rl= OMe, alkyl o r aryi

Rv= H 1 ABqdarcUtyl
Ry= H1aB q d a ra rrl
R+= O o rS
Rf= H 1 ABqdoraqrl
Rf= H 1 ABqdoraqrl
RlR <= cydoalkares

which comprises the reacting the aliphatic or aromatic aldehyde, urea or

thiourea and beta-dicarbonyl compound, optionally in the solution in the
presence of mild lewis acid, either under reflux condition for a period of 2-8
5 hours or under microwave irradiation, at a frequency in the range of 2-3
GHz, at a power of about 50-60%, for a period of 2-3 minute, precipitating
the resultant product from the above said reaction mixture with water
followed by filtration and crystallization with alcohol by known method to
obtain the desired product,
io In an embodiment of the present invention the aliphatic or aromatic
aldehyde used is selected from benzaldehyde and substituted benzaldehyde
selected from the group consisting of hydroxybenzaldehyde, p-
chlorobenzaldehyde, p-methoxybenzaldehyde and m-hydroxybenzaldehyde.
In another embodiment the beta-dicarbonyl compound used is selected
15 from the group consisting of ethyl acetoacetate, acetyl acetone, acetoacetic
acid ethyl ester.
In yet another embodiment the solvent used for reaction is selected
from the group consisting of methanol, ethanol, acetonitrite, propionitrile and
water.
20 In yet another embodiment the mild lewis acid used is selected from
silver triflate and tin (IV) chloride.
In yet another embodiment the organic solvent used for crystallization
is selected from methanol and ethanol.
In still another embodiment the yield of the 4,5,6-substituted-3,4~
25 dihydropyrimidin-2-ones and their 2-thioxo analogues is in the range of 90-98
percent.

Detail description of the invention

The process of the present invention has utilized three types of
30 chemicals namely, (i) urea or thiourea (ii) acetylacetone, ethylacetoacetate or
 WO 2007/105233 PCT/IN2007/000103
5

any beta-dicarbonyl compound and (iii) aliphatic or aromatic aldehydes and a

catalyst namely tin (IV) chloride pentahydrate or silver triflate of any
commercial grade.
The product 4,5,6-substituted 3,4-dihydropyrimidin-2-ones and their 2-
5 thioxo analogues and similar derivatives of the formula 1 can be isolated from
the reaction mixture by diluting with ice cold water followed by crystallization
of the precipitated product.
The product 4,5,6-substituted 3,4-dihydropyrimidin-2-ones and their 2-
thioxo analogues and similar derivatives of the formula 1 can also be isolated
io from the reaction mixture by addition of water, followed by extraction with
solvents selected from a group consisting of hydrocarbons such as hexane,
heptane, petroleum ether, benzene, toluene, and then with halogenated
solvents such as chloroform, dichloromethane, ethylene dichloride, methyl
acetate, ethyl acetate and propyl acetate and distillation of the solvents under
15 vacuum to afford a crude.
The crude as mentioned above is chromatographed over silica gel or
alumina or other chromatographic solid phase to get pure product of 4,5,6-
substituted 3,4-dihydropyrimidin-2-ones and its 2-thioxo analogues of the
structure 1.
20

Ei= OMe, alkyl or aryl

Ej= H1 Alkyl oiraiyl
Ey= H1alM or aryl
E(= O o r S
Ef= H1 Aik,! or ar/1
Ef= H1 Alkyl or aoyl
EiEi = cydoalkares

2
 WO 2007/105233 PCT/IN2007/000103
6

ICH3

10

10
 WO 2007/105233 PCT/IN2007/000103
7

The process comprises:

The production of 4,5,6-substituted 3,4-dihydropyrimidin-2-ones and
their 2-thioxo analogues wherein substitution at 4,5 and 6 may be alkyl, aryl,
cycloalkyl, alkyl or aryl carboxylate group, polyhydroxy alkyl, polyhydroxy aryl,
5 oligosaccharides, etc. of the general formula 1 was obtained from the reaction
of an aldehyde, urea or thiurea and a betadicarbonyl compound in presence
of tin (IV) chloride pentahydrate or silver triflate in acetonitrile or ethanol under
reflux for two to six hours. The same may also be conducted under microwave
irradiation of 2.45 GHz with solvent or without solvent at a suitable power for 1
io to 10 minutes. Then the crude reaction products are obtained by diluting or
dissolving the reaction mixture with water followed by extraction with a
suitable solvent selected from a group consisting of hydrocarbons such as
hexane, heptane, petroleum ether, benzene, toluene, and then with
halogenated solvents such as chloroform, dichloromethane, ethylene
15 dichloride etc. or lower fatty acid esters such as methyl acetate, ethyl acetate,
propyl acetate and evaporation of the dried extract. The pure reaction
products are obtained by purifying the crude by crystallization, or
chromatographic methods such as column chromatography, medium pressure
liquid chromatography (MPLC), high pressure liquid chromatography (HPLC)
20 or other chromatographic methods. Purification can also be affected with
fractional distillation, short path distillation etc.

The following examples are given by way of illustration of the working

of the invention in actual practice and therefore these should not be construed
25 to limit the scope of the present invention:

EXAMPLE 1:
106 mg of benzaldehyde, 78 mg of urea and 130mg ethyl acetoacetate were
mixed thoroughly with 70 mg of tin (IV) chloride pentahydrate and few drops
30 of acetonitrile in a conical flask and the content of the flask was irradiated with
microwave at 2.45 GHz for 3 minutes with 60% power. Then the reaction
product was precipitated out with water followed by filtration and crystallization
with ethanol to get 246 mg (95%) of pure product methyl 6-methyl-2-oxo-4-
phenyl-1, 2,3,4-tetrahydro-5-pyrimidine-carboxylate 3.
 WO 2007/105233 PCT/IN2007/000103
8

EXAMPLE 2:

106 mg of benzaldehyde, 76 mg of thiourea and 130 mg ethyl acetoacetate

5 were mixed thoroughly with 70 mg of tin (IV) chloride pentahydrate in conical
flask and the content of the flask was irradiated with microwave at 2.45 GHz
for 3 minutes with 60% power. Then the reaction product was precipitated out
with water followed by filtration and crystallization with ethanol to get 251 mg
(91%) of pure product methyl 6-methyl-2-thioxo-4-phenyl-1, 2,3,4-tetrahydro-
io 5-pyrimidine-carboxylate 4.

EXAMPLE 3:
A mixture of 53 mg of benzaldehyde, 39 mg of urea and 50 mg acetyl
acetone were mixed thoroughly with 35 mg of tin (IV) chloride pentahydrate in
15 conical flask and the content of the flask was irradiated with microwave at
2.45 GHz for 3 minutes with 60% power. Then the reaction product was
precipitated out with water followed by filtration and crystallization with ethanol
to get 106mg (93%) of pure product compound 5.

20
EXAMPLE 4:
A mixture of 53 mg of benzaldehyde, 38 mg of thiourea and 50 mg
acetylacetone were mixed thoroughly with 35 mg of tin (IV) chloride
pentahydrate in conical flask and the content of the flask was irradiated with
25 microwave at 2.45 GHz for 3 minutes with 60% power. Then the. reaction
product was precipitated out with water followed by filtration and crystallization
with ethanol to get 109 mg (89%) of pure product 6.

30 EXAMPLE 5:
A mixture of 61 mg of meta hydroxybenzaldehyde, 40 mg of thiourea and 65
mg acetoacetic acid ethyl ester were mixed thoroughly with 35 mg of tin (IV)
chloride pentahydrate in conical flask and the content of the flask was
irradiated with microwave at 2.45 GHz for 3 minutes with 60% power. Then
35 the reaction product was precipitated out with water followed by filtration and
crystallization with ethanol to get 134 (92%) of pure product 2.
 WO 2007/105233 PCT/IN2007/000103
9

EXAMPLE 6:
A mixture of 70 mg of p-chlorobenzaldehyde, 39 mg of urea and 65 mg
acetoacetic acid ethyl ester were mixed thoroughly with 35 mg of tin (IV)
5 chloride pentahydrate in conical flask and the content of the flask was
irradiated with microwave at 2.45 GHz for 3 minutes with 60% power. Then
the reaction product was precipitated out with water followed by filtration and
crystallization with ethanol to get 143mg (97%) of pure product 7.

io EXAMPLE 7:
A mixture of 70 mg of p-chlorobenzaldehyde, 39 mg of urea and 50 mg
acetyl acetone were mixed thoroughly with 35 mg of tin (IV) chloride
pentahydrate in conical flask and the content of the flaskwas irradiated with
microwave at 2.45 GHz for 3 minutes with 60% power. Then the reaction
15 product was precipitated out with water followed by filtration and crystallization
with ethanol to get 126 mg (95%) of pure product 8.

EXAMPLE 8:
A mixture of 70 mg of p-chlorobenzaldehyde, 49 mg of thiourea and 65
20 mg acetoacetic acid ethyl ester were mixed thoroughly with 35 mg of tin (IV)
chloride pentahydrate in conical flask and the content of the flask was
irradiated with microwave at 2.45 GHz for 3 minutes with 60% power. Then
the reaction product was precipitated out with water followed by filtration and
crystallization with ethanol to get 144 mg (93%) of pure product 9.
25
EXAMPLE 9:
A mixture of 106 mg of p-methoxybenzaldehyde, 39 mg of urea and 65 mg
ethylacetoacetate were mixed thoroughly with 35 mg of tin (IV) chloride
pentahydrate in conical flask and the content of the flask was irradiated with
30 microwave at 2.45 GHz for 3 minutes with 60% power. Then the reaction
product was precipitated out with water followed by filtration and crystallization
with ethanol to get 273 mg (94%) of pure product 10.

35
 WO 2007/105233 PCT/IN2007/000103
10

EXAMPLE 10:
106 mg of benzaldehyde, 78 mg of urea and 130mg ethyl acetoacetate were
mixed thoroughly with 51 mg of silver triflate and few drops of acetonitrile in a
conical flask and the content of the flask was irradiated with microwave at
5 2.45 GHz for 3 minutes with 60% power. Then the reaction product was
precipitated out with water followed by filtration and crystallization with ethanol
to get 251 mg (97%) of pure product methyl 6-methyl~2-oxo-4-phenyl-1, 2,3,4-
tetrahydro-5-pyrimidine-carboxylate 3.

io EXAMPLE 11:
A mixture of 53 mg of benzaldehyde, 39 mg of urea and 50 mg
acetylacetone were mixed thoroughly with 26 mg of silver triflate in conical
flux and the content of the flux was irradiated with microwave at 2.45 GHz for
3 minutes with 60% power. Then the reaction product was precipitated out
15 with water followed by filtration and crystallization with ethanol to get 108mg
(95%) of pure product compound 5.

EXAMPLE 12:
A mixture of 70 mg of p-chlorobenzaldehyde, 39 mg of urea and 50 mg
20 acetyl acetone were mixed thoroughly with 26 mg of silver triflate in conical,
flask and the content of the flask was irradiated with microwave at 2.45 GHz
for 3 minutes with 60% power. Then the reaction product was precipitated out
with water followed by filtration and crystallization with ethanol to get 127 mg
(96%) of pure product 8.
25
EXAMPLE 13:
A mixture of 106 mg of p-methoxybenzaldehyde, 39 mg of urea and 65 mg
ethylacetoacetate were mixed thoroughly with 51 mg of silver triflate in conical
flask and the content of the flask was irradiated with microwave at 2.45 GHz
30 for 3 minutes with 60% power. Then the reaction product was precipitated out
with water followed by filtration and crystallization with ethanol to get 273 mg
(94%) of pure product 10.
 WO 2007/105233 PCT/IN2007/000103
11

EXAMPLE 14:
A mixture of 61 mg of metahydroxybenzaldehyde, 40 mg of thiourea and 65
mg acetoacetic acid ethyl ester were mixed thoroughly with 26 mg of silver
triflate in conical flask and the content of the flask was irradiated with
5 microwave at 2.45 GHz for 3 minutes with 60% power. Then the reaction
product was precipitated out with water followed by filtration and crystallization
with ethanol to get 134 (92%) of pure product 2.

EXAMPLE 15:
io 106 mg of benzaldehyde, 78 mg of urea and 130mg ethyl acetoacetate were
mixed thoroughly with 70 mg of tin (IV) chloride pentahydrate and few drops
of acetonitrile in a conical flask and the content of the flask was irradiated with
microwave at 2.45 GHz for 3 minutes with 60% power. Then the reaction
product was precipitated out with water followed by filtration and crystallization
15 with ethanol to get 245 mg (95%) of pure product methyl 6-methyl-2-oxo-4-
phenyl-1, 2,3,4-tetrahydro-5-pyrimidine-carboxylate 3.

EXAMPLE 16:
106 mg of benzaldehyde, 78 mg of urea and 130mg ethyl acetoacetate were
20 mixed thoroughly with 70 mg of tin (IV). chloride pentahydrate and few drops
of acetonitrile in a conical flask and the content of the flask was irradiated with
microwave at 2.45 GHz for 3 minutes with 60% power. Then the reaction
product was precipitated out with water followed by filtration and crystallization
with ethanol to get 246 mg (95%) of pure product methyl 6-methyl-2-oxo-4-
25 phenyl-1, 2,3,4-tetrahydro-5-pyrimidine-carboxylate 3.

EXAMPLE 17: t

106 mg of benzaldehyde, 78 mg of urea and 130mg ethyl acetoacetate were ,

mixed thoroughly with 70 mg of tin (IV) chloride pentahydrate and few drops
30 of acetonitrile in a conical flask and the content of the flask was irradiated with
microwave at 2.45 GHz for 3 minutes with 60% power. Then the reaction
product was precipitated out with water followed by filtration and crystallization
with ethanol to get 246 mg (95%) of pure product methyl 6-methyl-2-oxo-4-
phenyl-1, 2,3,4-tetrahydro-5-pyrimidine-carboxylate 3.
 WO 2007/105233 PCT/IN2007/000103
12

EXAMPLE 18:
106 mg of benzaldehyde, 78 mg of urea and 130mg ethyl acetoacetate were
mixed thoroughly with 51 mg of silver triflate and few drops of acetonitrile in a
conical flask and the content of the flask was irradiated with microwave at
2.45 GHz for 3 minutes with 60% power. Then the reaction product was
precipitated out with water followed by filtration and crystallization with ethanol
to get 250 mg (97%) of pure product methyl 6-methyl-2-oxo-4-phenyl-1, 2,3,4-
tetrahydro-5-pyrimidine-carboxyIate 3.
10

EXAMPLE 19.
106 mg of benzaldehyde, 78 mg of urea and 130mg ethyl acetoacetate were
mixed thoroughly with 51 mg of silver triflate and few drops of acetonitrile in a
conical flask and the content of the flask was irradiated with microwave at
15 2.45 GHz for 3 minutes with 60% power. Then the reaction product was
precipitated out with water followed by filtration and crystallization with ethanol
to get 251 mg (97%) of pure product methyl 6-methyl-2-oxo-4-phenyl-1, 2,3,4-
tetrahydro-5-pyrimidine-carboxylate 3.

20 EXAMPLE 20:
106 mg of benzaldehyde, 78 mg of urea and 130mg ethyl acetoacetate were
mixed thoroughly with 51 mg of silver triflate and few drops of acetonitrile in a
conical flask and the content of the flask was irradiated with microwave at
2.45 GHz for 3 minutes with 60% power. Then the reaction product was
25 precipitated out with water followed by filtration and crystallization with ethanol
to get 251 mg (97%) of pure product methyl 6-methyl-2-oxo-4-phenyl-1, 2,3,4-
tetrahydro-5-pyrimidine-carboxylate 3.

EXAMPLE 21:
30 A mixture of 106 mg of benzaldehyde, 78 mg of urea, 130 mg ethyl
acetoacetate and 51 mg of silver triflate was dissolved in acetonitrile in a
round-bottomed flask and refluxed for 8 hours. Then the reaction mixture was
cooled and precipitated out with water followed by filtration and crystallization
 WO 2007/105233 PCT/IN2007/000103
13

with ethanol to get 245 mg (95%) of pure product methyl B-methyi-^-oxo-^-

phenyl-1, 2,3,4-tetrahydro-5-pyrimidine-carboxylate 3.

EXAMPLE 22:
5 A mixture of 106 mg of benzaldehyde, 78 mg of urea, 100 mg acetyl acetone
and 51 mg of silver triflate was dissolved in acetonitrile in a round-bottomed
flask and refluxed for 8 hours. Then the reaction mixture was cooled and
precipitated out with water followed by filtration and crystallization with ethanol
to get 209 mg (92%) of pure product 5.
10
EXAMPLE 23:
A solution of 106 mg of benzaldehyde, 78 mg of urea, 130 mg ethyl
acetoacetate and 70 mg of tin (IV) chloride pentahydrate in acetonitrile was
placed in a round bottomed flask-and refluxed for 8 hours. Then the reaction
15 mixture was cooled and precipitated out with water followed by filtration and
crystallization with ethanol to get 243 mg (94%) of pure product methyl 6-
methyl-2-oxo-4-phenyI-1, 2,3,4-tetrahydro-5-pyrimidine-carboxylate 3.

EXAMPLE 24:
20
.106 mg of benzaldehyde, 76 mg of thiourea, 130 mg ethyl acetoacetate and
70 mg of tin (IV) chloride pentahydrate was dissolved in acetonitrile in a
conical flask and the content of the refluxed for 8 hours. Then the reaction
mixture was cooled and product was precipitated out with water followed by
25 filtration and crystallization with ethanol to get 251 mg (91%) of pure product
methyl 6-methyl-2-thioxo-4-phenyl-1, 2,3,4-tetrahydro-5-pyrimidine-
carboxylate 4.
WO 2007/105233 P C T /IN 2007/000103
14

The main advantage of the present invention are:

1. The presnt invention is simple, economic and environmetally acceptable
process for the production of mitotic kinesin inhibitor monastrol of the
formula 2 and other potential bioactive 4,5,6-substituted 3,4-
dihydropyrimidin-2-ones and their 2-thioxo analogues wherein substitution
at 4,5 and 6 may be alkyl, aryl, cycloalkyl, alkyl or aryl carboxylate group,
polyhydroxy alkyl, polyhydroxy aryl, oligosaccharides, etc.
2. The present invention does not require use of solvent when irradiated with
microwave to initiate and completion of the reaction.
3. The reaction time of the present invention is very short, only 3 minutes
when irradiated with microwave to initiate and completion of the reaction.
4. The process uses mild Lewis acids e.g. tin (IV) chloride and silver triflate.
5. When the process is run under reflux condition, it requires time 6-7 hours
only.
6. After the reaction is over, the recovery of product is very simple and uses
only water to precipitate out the product.
7. The process does not use any high boiling liquid nor any costly material.
8. The process does not require any acid promoter to initiate the reaction.
WO 2007/105233 PCT/IN2007/000103
15
CLAIMS
1. An improved process for the preparation of 4,5,6-substituted-3,4~
dihydropyrimidin-2-ones and their 2-thioxo analogues of formula 1,

I
El= GMa, alkyl or aryl
Rj= H 1 A lijia ra is rI
Ej= H1 waiyl
Ej= OorS
R= H1 ABqi or aiyl
Ei,= H1 A lljia r aryl
RlEs=cydoaIkaiias

which comprises the reacting the aliphatic or aromatic aldehyde, urea or

thiourea and beta-dicarbonyl compound, optionally in the solution in the
presence of mild lewis acid, either under reflux condition for a period of 2-8
hours or under microwave irradiation, at a frequency in the range of 2-3
GHz, at a power of about 50-60%, for a period of 2-3 minute, precipitating
the resultant product from the above said reaction mixture with water
followed by filtration and crystallization with alcohol by known method to
obtain the desired product.

2. A improved process as claim in claimed in claim 1, wherein the aliphatic or

aromatic aldehyde used is selected from benzaldehyde and substituted
benzaldehyde selected from the group consisting of
hydroxybenzaldehyde, p-chlorobenzaldehyde, p-methoxybenzaldehyde
and m-hydroxybenzaldehyde.

3. An improved process as claim in claimed in claim 1, wherein the beta-

dicarbonyl compound used is selected from the group consisting of ethyl
acetoacetate, acetyl acetone, acetoacetic acid ethyl ester.
WO 2007/105233 PCT/IN2007/000103
16

4. An improved process as claim in claimed in claim 1, wherein the solvent

used for reaction is selected' from the group consisting of methanol,
ethanol, acetonitrite, propionitrile and water.

5. An improved as claim in claimed in claim 1, wherein the mild lewis acid

used is selected from silver triflate and tin (IV) chloride.

6. An improved as claim in claimed in claim 1, wherein the organic solvent

used for crystallization is selected from methanol and ethanol.

7. An improved as claim in claimed in claim 1, wherein the yield of the 4,5,6-

substituted-3,4-dihydropyrimidin-2-ones and their 2-thioxo analogues is in
the range of 90-98%.
Key Substances in Patent

Mark Page # CAS RN Name Structure

11 p.8 100-52-7 Benzaldehyde

12 p.8 141-97-9 Butanoic acid, 3-oxo-, ethyl ester

13 p.8 123-54-6 2,4-Pentanedione

p.9

4 p.9 33458-26-3 5-Pyrimidinecarboxylic acid, 1,2,3,4-

tetrahydro-6-methyl-4-phenyl-2-thioxo-,
ethyl ester

5 p.9 25652-50-0 2(1H)-Pyrimidinone, 5-acetyl-3,4-dihydro-6-

methyl-4-phenyl-

14 p.9 100-83-4 Benzaldehyde, 3-hydroxy-

2 p.9 329689-23-8 5-Pyrimidinecarboxylic acid, 1,2,3,4-

tetrahydro-4-(3-hydroxyphenyl)-6-methyl-2-
thioxo-, ethyl ester

15 p.10 104-88-1 Benzaldehyde, 4-chloro-

7 p.10 5948-71-0 5-Pyrimidinecarboxylic acid, 4-(4-

chlorophenyl)-1,2,3,4-tetrahydro-6-methyl-
2-oxo-, ethyl ester

8 p.10 133894-11-8 2(1H)-Pyrimidinone, 5-acetyl-4-(4-

chlorophenyl)-3,4-dihydro-6-methyl-
9 p.10 154866-92-9 5-Pyrimidinecarboxylic acid, 4-(4-
chlorophenyl)-1,2,3,4-tetrahydro-6-methyl-
2-thioxo-, ethyl ester

16 p.10 123-11-5 Benzaldehyde, 4-methoxy-

10 p.10 161374-07-8 5-Pyrimidinecarboxylic acid, 1,2,3,4-

tetrahydro-4-(4-methoxyphenyl)-6-methyl-2-
oxo-, ethyl ester

805 p.12 28777-87-9 Benzaldehyde, hydroxy-

p.16

802 p.13 57-13-6 Urea

p.13

808 p.14 75-05-8 Acetonitrile

p.14
803 p.14 62-56-6 Thiourea
p.16

807 p.14 64-17-5 Ethanol

p.14
3 p.14 5395-36-8 5-Pyrimidinecarboxylic acid, 1,2,3,4-
p.14 tetrahydro-6-methyl-2-oxo-4-phenyl-, ethyl
ester

810 p.15 2923-28-6 Methanesulfonic acid, 1,1,1-trifluoro-,

p.17 silver(1+) salt (1:1)

811 p.15 7646-78-8 Stannane, tetrachloro-

p.17

804 p.16 7732-18-5 Water

p.17
809 p.17 107-12-0 Propanenitrile

806 p.17 67-56-1 Methanol

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