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Synthesis of nitrogen mustards of pyrimdine derivatives.

Introduction

Pyrimidine derivatives play a fundamental role in life processes and their chemotherapist potential has given a considerable impetus to their study1,2. In particular, pyrimidine derivatives include a large number of natural products, pharmaceuticals, and functional materials. Several examples of pharmaceutically important compounds include trimethoprim, sulfadiazine, imatinib mesilate and capecitabine. Natural and unnatural polymers also contain pyrimidine derivatives. Important methodologies for the synthesis of pyrimidines enjoys a rich history, the discovery of new strategies for the convergent synthesis of pyrimidines remains a vibrant area of chemical research.

In nature, the pyrimidine ring is synthesized from glutamine, bicarbonate, and aspartate. Way back in 1920's, Gabriel and Colman3 as well as Ross4 has reported that methyl groups at 2,4- and 6- position in the pyrimidine ring undergo easy condensation with benzaldehyde in presence of anhydrous zinc chloride. 2- hydroxy4,6-dimethyl pyrimidine (I) and 2-mercapto-4,6-dimethyl pyrimidine (VI) attracted our attention because one or two nitrogen mustard can be introduced in them. 2hydroxy-4,6-dimethyl pyrimidine (I) and 2-mercapto-4,6-dimethyl pyrimidine (VI) were condensed with benzaldehyde mustard. A number of condensing agents such as iodine, acetic anhydride, piperidine and anhydrous zinc chloride were used and anhydrous zinc chloride was found to be most suitable in inert solvent like benzene, toluene and xylene. This work will give us the idea of the synthesis method which we have adopted.

Materials and Methods

The entire chemicals were of analytical grade and were purchased from CDH chemicals, India. The characterization of the compounds was done at Patna University, Bihar, India. Below are the methods for the preparation of each pyrimidine derivatives

(1) Preparation of 2-hydroxy-4,6-dimethyl pyrimidine (I)--10 g urea was dissolved in alcohol and to the cold solution, acetyl acetone (10 g) and conc. [H.sub.2]S[O.sub.4] (30g) were added as quickly as possible. Well mixed solution when kept in chest for few hours deposited 12 g of sulphate. The solution of sulphate was boiled with an excess of BaCO3 for a few minutes and filtered. The filtrate on concentration gave 2-hydroxy-4,6-dimethyl pyrimidine (I) which was recrystallised from benezene-ethanol having m.p. 197[degrees]C.

(2) Preparation of 2-hydroxy-4-methyl-6-{4'-[N,N-bis(2-chloroethylyl) amino] styryl} pyrimidine (II)--2-hydroxy-4,6-dimethyl pyrimidine (1.24g; 0.01 mole) and benzaldehyde mustard (2.46g; 0.01 mole), anhydrous ZnCl2 (3.0 g) were taken in 80 ml xylene and the mixture was refluxed for 6 h. Crystal was separated from benezene-ethanol . The compound was colourless needle shaped with m.p 193[degrees]C.

(3) Preparation of 2-hydroxy-4-methyl-6-{4'-[N,N-bis(2-chloroethylyl) amino] styryl} pyrimidine hydrochloride(III) - Equimolar quantities of 2-hydroxy-4,6- dimethyl pyrimidine (1.24, 0.01 mole) and benzaldehyde mustard (2.46 g, 0.01 mole) were taken in 80 ml of xylene. Anhydrous Zn[Cl.sub.2] (3g) was added to this solution. The mixture was refluxed for 6 h. The crystals were separated and the mother liquor of the above reaction was diluted with the dry ether (50 ml) and it was saturated with dry HCl gas. Viscous liquid was formed which was separated and exposed to the atmosphere. It was turned dark pink solid with metallic lustre. The compound was recrystallised from alcohol having pink colour crystal appearance with m.p. 90[degrees]c.

(4) Preparation of 2-hydroxy-4-methyl-6-{4'-[N,N-bis(2-chloroethylyl) amino] distyryl} pyrimidine (IV)-2-hydroxy-4,6-dimethyl pyrimidine (1.24, 0.01 mole) was dissolved in a mixture of xylene (70 ml) and absolute alcohol (10 ml). To it benzaldehyde mustard (4.8g. 0.02 moles) and anhydrous zinc chloride (2.5 g) were added and the mixture was refluxed for 4 h. Separated crystals were recrystallized from benzene-ethanol having appearance of colourless needle shape with m.p. 203[degrees]C.

(5) Preparation of 2-hydroxy-4-methyl-6-{4'-[N,N-bis(2-chloroethylyl) amino] distyryl} pyrimidine hydrochloride (V)-The concentrated mother liquor from the above experiments was diluted with ether and dry HCl gas was passed. A viscous oil was obtained which solidified after 3 days. The pink crystal compound was recrystallised from benzene ethanol having m.p. 110[degrees]C.

(6) Preparation 2-mercapto-4,6-dimethyl pyrimidine (VI)--Thiourea (2.0 g) was dissolved in alcohol (40 ml). 2 g of acetyl acetone and 50 drops of conc. [H.sub.2]S[O.sub.4] were added during cooling and the mixture was left for 2 days. Separated crystals were dissolved in water and freshly precipitate BaC[O.sub.3] was added till the solution became neutral. Filtered and filtrate on concentration gave light yellow prisms of 2 -mercapto 4,6-dimethyl pyrimidine (VI). The yield was 80 % after recrystallising from benzene with m.p. 210[degrees]C.

(7) Preparation of 2-mercapto-4-methyl -6-{4'-[N,N-bis(2-chloroethylyl) amino] styryl} pyrimidine (VII)--Equimolar quantities of benzaldehyde mustard (2.4 g) and 2 -mercapto4,6-dimethyl pyrimidine was dissolved in xylene (70 ml) and absolute alcohol (10 ml). Anhydrous Zn[Cl.sub.2] was added to this solution and the mixture was refluxed for 4 h with the arrangement to remove the water during condensation. The crystals started to separate very soon but heating was continued for 5 h. The crystal were filtered, the mother liquor was concentrated (45 ml) and left overnight to separate crystals. The crystals were recrystallised from benezene ethanol. Pale needles like crystal formed with m.p. 203[degrees]C.

(8) Preparation of 2-mercapto-4-methyl -6-{4'-[N,N-bis(2-chloroethylyl) amino] styryl} pyrimidine hydrochloride (VIII)-Equimolar quantities bezaldehyde mustard and 2-mercapto-4,6-dimethyl pyrimidine were dissolved in xylene (70 ml) and absolute alcohol (10ml) and added Zn[Cl.sub.2]. Anhydrous zinc chloride (3g) was added to this solution. The mixture was refluxed for 5 h. The crystals separated and the mother liquor of the above reaction was diluted with the dry ether (50 ml) and it was saturated with dryl HCl gas. Viscous liquid was formed which was separated and exposed to the atmosphere for 4 days. Blood coloured solid was obtained. It was recrystallised from benzene. It was turned dark pink solid with metallic lustre. The compound was recrystallised from alcohol with pink colourless crystal m.p. 120[degrees]c.

(9) Preparation of 2-mercapto-4-methyl -6-{4'-[N,N-bis(2-chloroethylyl) amino] distyryl} pyrimidine (IX) - 2-mercapto-4,6-dimethyl pyrimidine (1.7 g, 0.01 mole) and benzaldehyde mustard (4.86, 0.02 mole) were dissolved in dry benzene (70 ml) and absolute alcohol (10ml) and added ZnCl2. Anhydrous zinc chloride (3g) was added to this solution. The mixture was refluxed for 4 h with the arrangement to remove the water during condensation. The crystals started to separate very soon but heating was continued for 5 h. The crystal were filtered, the mother liquor was concentrated (55 ml) and left overnight to separate crystals. The crystals were recrystallised from benezene-ethanol (charcoal) to form red needles shaped structure. Pale needles crystal was separated with m.p. 192[degrees]C.

(10) Preparation of 2-mercapto-4-methyl -6-{4'-[N,N-bis(2-chloroethylyl) amino] distyryl} pyrimidine hydrochloride (X) - 2-mercapto-4,6-dimethyl pyrimidine (0.01 mole) and benzaldehyde mustard (0.02 mole) were dissolved in dry benezene (70 ml) and absolute alcohol (15ml) and added Zn[Cl.sub.2]. Anhydrous zinc chloride (3g) was added to this solution. The mixture was refluxed for 4 h. The crystals separated and the mother liquor was diluted with dry ether (50 ml and it was saturated with dry HCl gas. The viscous liquid was formed and it was separated from the reaction mixture and left exposed to the atmosphere for 4 days. Red solid mass was obtained and it was recrystallised from benzene ethanol with m.p. 132[degrees]C.

Results and Discussion

Figure 1 to 6 presents the FTIR of the compound I, II, IV, VI, VII, IX. The appearance of sharp absorption band at 1610 [cm.sup.-1] confirms the formation of compound (II). When one mole of 2-hydroxy-4,6-dimethyl pyrimidine and two moles of benzaldehyde mustard were refluxed for 4 h, 2-hydroxy-4-methyl-6-{4'-[N,N- bis(2-chloroethylyl) amino] distyryl} pyrimidine hydrochloride (VI), m.p 203[degrees]C was formed with the disappearance of characteristic band at 1390 [cm.sup.-1] (- C[H.sub.3]).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

[FIGURE 5 OMITTED]

[FIGURE 6 OMITTED]

Table 1 and 2 represent the absorption band of characteristic functional groups. The elemental composition of the compounds mentioned in Table 2 matches completely with the required chemical compositions.

Conclusion

Pyrimidine derivatives were successfully synthesized. The elemental analysis shows the purity of the compound. The study on anticancer properties will be followed subsequently.

References

[1] Raic-Malic S, Svedruzic D, Gazivoda T, Marunovic A, Hergold-Brundic A, Nagl A, Balzarini J, De Clercq E and Mintas M., 2000, "Synthesis and antitumor activities of novel pyrimidine derivatives of 2,3-O,O-dibenzyl-6- deoxy-L-ascorbic acid and 4,5-didehydro-5,6- dideoxy-L-ascorbic acid" J. Med. Chem. 43(25), pp 4806-11.

[2] Hill, M. D., Movassaghi, M., 2008, "New Strategies for the Synthesis of Pyrimidine Derivatives" Chemistry - A European Journal, 14(23), pp 6836-44.

[3] Ross W. C. J., 1948, Some Derivatives of 4-styrylpyrimidine, J. Chem. Soc., pp. 1128-35.

[4] Hale, W. J., 1914, "The Constitution of Acetylacetone-Urea" J. Am. Chem. Soc., 48, pp 104-15.

T Gangawar (1), Sanju Kumari (1) and Rakesh Kumar (2)

(1) Department of Chemistry, A. N. College, Magadh University, Patna-800023, Bihar, India

(2) CSIR Materials Science and Manufacturing, P.O. Box 1124, Port Elizabeth 6000, South Africa,

(2) Email-krrakesh72@gmail.com
Table 1: Important wave numbers of the compounds synthesized.

Compound     Wavenumbers ([cm.sup.-1]) with functional groups

1            3325 (-OH)                       1390 (-[CH.sub.3])
2            3330 (-OH)                       1610 (CH=CH)
4            3350 (-OH)                       1610 (CH=CH)
6            2940 (-SH)                       1390 ([CH.sub.3])
7            2920 (-SH)                       1610 (CH=CH)
9            2980 (-SH)                       1605 (CH=CH)

Compound     Wavenumbers ([cm.sup.-1]) with functional groups

1            1225 (C-N=)
2            1540 ([CH.sub.2]-[CH.sub.2])     1390 (-[CH.sub.3])
4            1450 ([CH.sub.2]-[CH.sub.2])     1325 (-C-N=)
6            1470 ([CH.sub.2]-[CH.sub.2])     1330 (-C-N=)
7            1470 ([CH.sub.2]-[CH.sub.2])     1325 (-C-N=)
9                                             1325 (-C-N=)

Table 2: Represents the elemental analysis of the compounds.

Compound                                            C (%)

[C.sub.6][H.sub.8][N.sub.2]O (1)                58.60 (58.65)
[C.sub.17][H.sub.19][N.sub.3]O[Cl.sub.2] (2)    57.85 (57.95)
[C.sub.17][H.sub.20][N.sub.3]O[Cl.sub.3] (3)         --
[C.sub.28][H.sub.30][N.sub.4]O[Cl.sub.4] (4)    57.81 (57.93)
[C.sub.28][H.sub.31][N.sub.4]O[Cl.sub.5] (5)    54.82 (58.5)
[C.sub.6][H.sub.8][N.sub.2]S (6)                51.30 (51.42)
[C.sub.17][H.sub.19][N.sub.3]S[Cl.sub.2] (7)         --
[C.sub.17][H.sub.30][N.sub.4]O[Cl.sub.4] (4)    50.03 (50.43)
[C.sub.28][H.sub.30][N.sub.4]O[Cl.sub.4] (4)    56.50 (56.66)
[C.sub.28][H.sub.30][N.sub.4]O[Cl.sub.4] (4)    53.71 (53.21)

Compound                                            H (%)

[C.sub.6][H.sub.8][N.sub.2]O (1)                 6.30 (6.46)
[C.sub.17][H.sub.19][N.sub.3]O[Cl.sub.2] (2)     5.40 (5.39)
[C.sub.17][H.sub.20][N.sub.3]O[Cl.sub.3] (3)
[C.sub.28][H.sub.30][N.sub.4]O[Cl.sub.4] (4)     5.18 (5.17)
[C.sub.28][H.sub.31][N.sub.4]O[Cl.sub.5] (5)      5.2 (5.02)
[C.sub.6][H.sub.8][N.sub.2]S (6)                  5.9 (5.4)
[C.sub.17][H.sub.19][N.sub.3]S[Cl.sub.2] (7)         --
[C.sub.17][H.sub.30][N.sub.4]O[Cl.sub.4] (4)     5.34 (4.94)
[C.sub.28][H.sub.30][N.sub.4]O[Cl.sub.4] (4)      5.5 (5.03)
[C.sub.28][H.sub.30][N.sub.4]O[Cl.sub.4] (4)     5.01 (4.9)

Compound                                            N (%)

[C.sub.6][H.sub.8][N.sub.2]O (1)                22.62 (22.58)
[C.sub.17][H.sub.19][N.sub.3]O[Cl.sub.2] (2)    11.70 (11.93)
[C.sub.17][H.sub.20][N.sub.3]O[Cl.sub.3] (3)    10.65 (10.81)
[C.sub.28][H.sub.30][N.sub.4]O[Cl.sub.4] (4)     9.56 (9.65)
[C.sub.28][H.sub.31][N.sub.4]O[Cl.sub.5] (5)         --
[C.sub.6][H.sub.8][N.sub.2]S (6)                20.45 (20.0)
[C.sub.17][H.sub.19][N.sub.3]S[Cl.sub.2] (7)    11.50 (11.41)
[C.sub.17][H.sub.30][N.sub.4]O[Cl.sub.4] (4)         --
[C.sub.28][H.sub.30][N.sub.4]O[Cl.sub.4] (4)     9.12 (9.39)
[C.sub.28][H.sub.30][N.sub.4]O[Cl.sub.4] (4)    11.70 (11.93)

* Data in bracket represents the actual C, H, N ratio of the
compounds.
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Author:Gangawar, T.; Kumari, Sanju; Kumar, Rakesh
Publication:International Journal of Applied Chemistry
Article Type:Report
Geographic Code:1USA
Date:May 1, 2009
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