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Dear Omprakash, Try structure from site for journal of heterocyclic chemistry. they provide facility for structure search but is restricted only for journal of heterocyclic chemistry. The URL is http://www.jhetchem.com. Best of luck.

Hi Omprakash,

The synthesis for this compound could be done by either selective reactions on the pyrimidine ring or making the pyrimidine ring en-route! So I decided the second option! I went about it as such:-

1-Allowed Acetaldehyde to undergo aldol reaction.

2-Protecting the alcohol in the aldol product with Trimethylsillyl ether (TMS) by reacting the alcohol to

trimethylsillyl chloride.(reagent 1)

3-Reacting the Reagent 1 with benzaldehyde to undergo another aldol reaction and then heating the aldol

product to give the aldol condensation product.

4-Reacting the condensation product with NBS, AIBN and Benzyl Amine under CCl4 to give the Benzyl substituted

amide.

5-Addition of phenyl carbamimidoyl to this benzyl substituted amide would make the phenyl substituted

pyrimidine ring.

6-Removal of TMS group by NaF and then oxidizing the obtained second degree alcohol to ketone by Parikh-

Doering oxidation to give the final precursor.

7-The mild catalytic hydrogenation would give the final product.

I hope this helped! If you have some please let me know.

Thanks

Sid

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Good one Siddharth

thanks mr.rajesh

Sid

Efficient methods for the synthesis of pyrido[2,3-d]pyrimidin-5-ones from 4-amino-5-acetylpyrimidines

A. V. Komkov, B. I. Ugrak, V. S. Bogdanov and V. A. Dorokhov

Russian Chemical Bulletin, 1994, Volume 43, Number 8, Pages 1392-1397

4-Amino-5-acetyl-2,6-diphenylpyrimidine (4) and 4-amino-5-benzoyl-6-methyl-2-phenylpyrimidine (6). A mixture of N-cyanobenzamidine (0.50 g, 3.4 mmol), benzoylacetone (1.10 g, 6.8 mmol), and Ni(OAc)2 (0.60 g, 3.4 mmol) was heated at 135--145 °C for 6 h. The reaction mixture was cooled to ~20 °C then 20 mL of CHCl3 was added, the precipitate was filtered off, the filtrate was concentrated, and the residue was chromatographed on a column with SiO2 (elution was carried out with a C6H6--CHCI3 (1:1) mixture, and then with CHCl3) to give 0.45 g (46 %) of pyrimidine 4 with an admixture of pyrimidine 6 (the 4 to 6 ratio was 8.5:I according to the 1H NMR spectrum) as an oil, which was directly used in the subsequent synthesis. The 1H NMR spectrum of pyrimidine 4 (CDCI3) δ 5:1.90 (s, 3 H, MeCO), 7.62 (br.s, 2 H, NH2), 7.35--7.65 (m, 6 H, Ph), 7.70 (m, 2 H, Ph), 8.50 (m, 2 H, Ph). The 1H NMR spectrum of pyrimidine 6 (CDC13) , 5:2.18 (s, 3 H, Me), 5.85 (br.s, 2 H, NH2), 7.80 (m, 2 H, Ph), 8.42 (m, 2 H, Ph), the signals for other protons were overlapped with the signals of the prevailing pyrimidine 4.

You get a mixture, but it is 8.5/1 for the compound you want (4), and should not be too hard to purify.

Bill

Thank you dear all

I got one more suggestion please tell me whether it will work?

Through retrosynthesis precursors:

benzamidine (benzonitrile + ammonia) + benzoic acid + 1-cyanoacetone. I don't know the exact conditions to use, but this probably will work!

Please see it and tell me if it will work.

Thanks

Hi,

Use benzaldehyde instead of benzoic acid and it might work. The following procedure uses malononitrile and produces the nitrile instead of the acetyl derivative. The actual product is the dihydro-pyrimidine which then air oxidizes to the pyrimidine. Thus, use 1-cyano-acetone (NCCH2COCH3) (and modify the work up as needed), and you should get the acetyl substituted product you want .

14. Sheilbani, H.; Saljoogi, A.S.; Bazgir, A. (2008) Arkivoc (ii): ll5

Three-component process for the synthesis of 4-amino-5- pyrimidinecarbonitriles under thermal aqueous conditions or microwave irradiation

General Procedure for the Preparation of 4-amino-5- pyrimidinecarbonitriles in water at

reflux (Method I) and under microwave irradiation (Method II)

Method I. A mixture of aldehyde 1 (2 mmol), malononitrile 2 (2 mmol), amidine hydrochloride (2 mmol) and sodium acetate (2 mmol) in H20 (50 mL) and ethanol (5 mL) was refluxed with stirring for the time reported in Table 2 [R1=Ph, R2= Ph, 6 h.] (the progress of the reaction being monitored by TLC and using n-hexane/ethyl acetate as an eluent). The product 4a precipitated from the reaction mixture after cooling, and the solid was filtered and recrystallized from ethanol.

Method II. A mixture of aldehyde 1 (2 mmol), malononitrile 2 (2 mmol) and an amidine

hydrochloride (2 mmol) in toluene (5 mL) containing triethylamine (3-4 drops) was placed in a

15 mL high pressure glass tube and placed in a 250 mL beaker. After microwave radiation at

300 W the microwave oven for the period of time shown in Table 1, [40 sec] the reaction mixture was

allowed to cool to ambient temperature. The product was purified as in Method I.

4-Amino-2,6-diphenyl-5-pyrimidinecarbonhrile (4a). White crystals; mp 210-212 °C;

[Found: C, 74.69 ; H, 4.35; N, 20.33% C17H12N4 requires C, 74.98; H, 4.44; N, 20.57%]; νmax

(KBr) 3478, 3344 (NH2), 2212 (CN), 1641, 1617 (C=N), 1542 (Ar) cm-1

Good luck,

Bill

Hi Omprakash,

I must say William Berkowitz is correct about using benzaldehyde rather than benzoic acid. The method described above will work for sure and you should give it a try. However I am not satisfied that it will give better yields. Neither any process in my knowledge would give a good yield considering the starting materials you provided.

My guess is that you must have got the starting material via retrosynthetic disconnection approach! Now here's the thing; Retrosynthesis is brilliant for getting simple starting products but when you work the synthesis forward then the hidden problems such as regioselectively, stereoselectivity, side reactions etc. arises. This is one of the main reasons why retrosynthetic routes are re-revised and modified again and again.

Anyways. For 1-cyanoacetone... you will have to rely on the enol form to do the work for you. Unfortunately; enol are formed less in a solution and even more unfortunate is that the enol form you need is the one which will be produced in still smaller quantities than the other undesirable enol form. Another problem is that the acidic work up may hydrolyze the nitrile to carboxylic acid. Any ways the route I found out for your set of starting materials is attached below as an image.

This is all I could do for you! Let me know if I was of some assistance.

Thanks

Sid

thank you Siddharth and William

Well I will try this reaction for sure.

I am very confused what to do actually I have already spent two years on this compound but I did not get any good result. I tell you what I did on this

I have started the synthesis of desired compound from 4-amino-2,6-diphenylpyrimidine-5-carbonitrile (CN group in place of -COCH3 the reaction told by william) as starting material. I did hydrolysis of CN group in compound 1 under basic conditions. I got the Compound "4-amino-2,6-diphenylpyrimidine-5-carboxylic acid" (CN hydrolysed to COOH) in good yield. From 4-amino-2,6-diphenylpyrimidine-5-carboxylic acid, I wanted to convert the COOH group to COCH3 with the help of Methyl lithium but may be due to presence of free NH2 group the reaction was not successful.

Then I did Boc protection of free NH2 group (on 4-amino-2,6-diphenylpyrimidine-5-carboxylic acid) but I got the double Boc protected compound that on NH2 and COOH both. I did not go further.

I also tried to synthesise the Boc protection 4-amino-2,6-diphenylpyrimidine-5-carbonitrile and then hydrolysis of the resultant product in basic conditions but again I got the 4-amino-2,6-diphenylpyrimidine-5-carboxylic acid. It might be due to Boc is hydrolysing in basic condition and the CN group is hydrolysing to Acid.

I also tried benzylation (with benzyl bromide and NaH in DMF) of compound 2 but the reaction is giving N-Di-benzylated product.

Ultimately I decided to take help from you guys.

Now come to the point latest one

If I will take

benzamidine (benzonitrile + benzaldehyde + acetoacetamide in place of 1-cyanoacetone will it pose the same problem. May be here the fee amide will be a problem.

Please let me know

Thanks

Hi Omprakash,

Thanks for giving the clearer picture.... well if you have trust on this compound then don't give up. The problem I think is that the oxidation level at the carbon which you want to turn to an acetyl group is higher than the acetyl group itself. That is; the carbon atom of a nitrile or a carboxylic acid is attached to an atom(s) with 3 bonds to a heteroatom(s) and that is why you must first reduce your nitrile or carboxylic acid.

Even if you use the acetoacetamide; you will still have problems with the connection... but it is worth trying out for sure. My suggestion is that you use a FMOC protecting group rather than a BOC. Try it... if it works let me know... and even if it doesn't work let me know that also. Lets see how far can we go with this compound.

Or do one thing... If you really don't get it from the ground up... then synthesize it using multiple steps and use a carbonyl protected reagent. Whom you will be able to turn to carbonyl back with ease.

Thanks

Sid

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Dear Omprakash, If you have tried so many reactions with cyano compounds, try one more i.e. treatment with methylmagnesium bromide to give directly acetyl group. But I know that treating your compound with grignard reagent in presence of free NH2 group is not advisable. But you can try one.

Rajesh Sir,

This is really a good solution but worth trying!

Sid

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If tried must be carried out with two equivalents of grignard reagent and not one because one equivalent of grignard reagent will first react with NH2 group to form complex and other will be actually used for desired reaction.

Rejesh Sir! how will we remove the grignard's reagent that ha binded to the amine group?

Thanks

Sid

Hi,

I sent a reply about 2PM, but got a note "reply not parsable", so I'm sending it again;

Yadav and Kenny have it right: I found two papers which directly convert a (pertinent) amino-nitrile to the amino ketone (See below for details). In both cases the (stable) intermediate imide (i.e. C(=NH)-Me) was isolated, then converted to the desired amino-acetyl compound by acid hydrolysis. The Marchetti paper is perhaps the best model, as it starts with a 2,4-diamino-5 cyanopyrimidine.

Bill

Experimentals:

Atkinson, and Marchetti reactions.

1. Triazaphenanthrenes. II. Derivatives of 10-phenyl-1,2,9-triazaphenanthrene Full Text

Atkinson, C. M.; Mattocks, A. R.

Journal of the Chemical Society (1957), 3722-6.

A preparative route to 4-acetyl-3-amino-2-phenylquinoline (I) was developed. Diazotization of I in HCl and subsequent cyclization gave chiefly 4-acetyl-3-chloro-2-phenylquinoline (II), with 10% of the hydroxytriazaphenanthrene (III); an 80% yield of III was obtained by cyclization in an alk. medium. 4-Amino-10-phenyl-1,2,9-triazaphenanthrene (IV) formed a monomethiodide (V) which was biologically inactive. 2-Phenyl-3-phthalimidoquinoline-4-carboxylic acid (VI) (40 g.) refluxed 0.5 hr. with 400 cc. 50% vol./vol. H2SO4 gave 3-amino-2-phenylquinoline (VII), m. 119°. Neutralization of the moth...

The amino-ketone (11; R = Ac, R’ = NH,) was eventually synthesised by a Grignard

reaction with the amino-amide (11; R = CO-NH,, R’ = NH,) or amino-nitrile, the intermediate ketimide being remarkably stable to cold hydrochloric acid but readily decomposed by hot acid or alkali or slowly by contact with alumina.

4-Acetyl-3-amino-2-phenylquinoline.-

(a) 3-Amino-4-cyano-2-phenylquinoline (24 g.) was

added during ½ hr. to a Grignard reagent prepared from magnesium (7.2 g.) and methyl iodide (20

c.c.) in ether (150 c.c.) and benzene (450 c.c.). The solution was heated under reflux for ca. 20 hr.,

cooled, and stirred with ice (1400 g.) and concentrated hydrochloric acid (360 c.c.) for 39 hr.

The organic layer was extracted with 5N hydrochloric acid (2 x 150 c.c.) and the acid solution

was then basified and extracted with benzene (3 x 300 c.c.) . Evaporation of the washed and

dried (MgSO4) extract yielded a sticky solid which gave an almost pure product (22.4 g. ; m. p.

130-133°) when washed with ether. The ketimide, m. p. 133-134°, formed almost colourless

crystals from benzene-light petroleum (b. p. 80-100°) (Found: C, 77.8; H, 5.55; N, 15.1.

C17H15N3 requires C, 78-1; H, 5.8; N, 16.1%). The ketone (13.8 g.) was best prepared by

heating the ketimide (15 g.) under reflux with water and concentrated hydrochloric acid

(120 c.c.; 2 to 1 v/v) for 1 hr. For isolation, the reaction mixture was basified and extracted

with ether, and the residue from evaporation of the washed and dried (Na2SO4) extract was

recrystallised from n-hexane; the pure ketone, m. p. 93-94°, separated as pale yellow needles

or blades (Found: C, 77.7; H, 5.3; N, 10.1. C17H14ON2 requires C, 77.8; H, 5.4; N, 10.7%).

b) 3-Amino-2-phenylquinoline-4-carboxyamide (35 g.) was added with stirring during 15 min.

to a Grignard reagent prepared from magnesium (18 g.) and methyl iodide (54 c.c.) in ether (225

c.c.) and benzene (600 c.c.). The mixture was heated under reflux for 3* hr., then cooled, and

the ketimide (29 g.) was isolated as before and hydrolysed to give the almost pure ketone (25 g.) .

Org. Biomol. Chem., 2010, 8, 2397–2407 | 2

Synthesis and biological evaluation of 5-substituted O4 -alkylpyrimidines as CDK2 inhibitors†

Francesco Marchetti, C´ eline Cano, Nicola J. Curtin, Bernard T. Golding, Roger J. Griffin, Karen Haggerty,

David R. Newell, Rachel J. Parsons, Sara L. Payne, Lan Z.Wang and Ian R. Hardcastle

6-Cyclohexylmethoxy-5-(1-iminoethyl)pyrimidine-2,4-diamine (10)12

To a solution of 9 (0.50 g, 2.02 mmol) in THF (50 mL), under N2, in an ice bath was added dropwise methyl magnesium bromide (3.0 M in THF, 3.37 mL, 10.1 mmol), over 10 min while stirring at 0 ◦C. The mixture was stirred 2 h at 0 ◦C, then heated at reflux for 24 h. Further methyl magnesium bromide (3.0 M in THF, 6.74 mL, 20.2 mmol) was added over the next 48 h with continued heating, until the reaction came to completion. The mixture was cooled to rt, quenched with aq. ammonium chloride (sat, 30 mL),

and extracted with EtOAc (3 X 30 mL). The combined organic layers were washed with water (40 mL), dried (Na2SO4) and concentrated in vacuo yielding a yellow powder. Recrystallisation (EtOAc, petrol) gave 10 as yellow solid (2.35 g, 95%), m.p.: 141–143 ◦C. UV λmax (EtOH): 240, 312 nm; IR γmax 3365, 3210, 3127, 2984, 2914, 1655, 1554, 1418, 1253 cm-1 ; δH (300MHz, d4-MeOD): 0.99–1.32 (5H, m, C6H11), 1.71–180 (6H, m, C6H11), 2.45 (3H, s, CH3), 4.08 (2H, d, J = 6.0 Hz, OCH2); δC (75 MHz, CDCl3)

26.1, 26.8, 30.4, 33.1, 37.9, 72.1, 91.4, 161.4, 165.8, 170.2, 175.3. MS (ESI+) m/z 264.25 [M+H]

+. HRMS (ESI+) m/z:Calc.for C13H21N5O: 264.1819 [M+H]+. Found 264.1821 [M+H]+.

1-(2,4-Diamino-6-cyclohexylmethoxypyrimidin-5-yl)ethanone (11)

A solution of HCl (2M; 10 mL) was added dropwise to a solution of 10 (0.075 g, 0.285mmol) in THF (10mL). The resulting mixture was stirred at rt for 16 h, then neutralised by dropwise addition

of NaOH (2M), and extracted with EtOAc (3 X 30 mL). The combined organic layers were washed with water (30 mL) and dried (Na2SO4) and concentrated in vacuo giving a yellow powder. Recrystallisation (EtOAc, petrol), gave 11 as yellow solid (0.063 g, 84%), m.p. 149–151 ◦C. UV λmax (EtOH): 283 nm. IR γmax 3340, 3221, 2923, 2849, 1683, 1548, 1524, 1431, 1244 cm-1 ; δH (300MHz, CDCl3): 0.93–1.28 (5H, m, C6H11), 1.62–1.77 (6H, m, C6H11), 2.47 (3H, s, CH ), 4.08 (2H, d, J = 6.0 Hz, OCH ), 4.93 (2H, br, NH ex), 5.38 (1H, br, NH ex), 9.27 (1H, br, NH ex); δC (75 MHz, CDCl3): 23.9, 24.6, 28.2, 31.2, 35.6, 70.4, 91.8, 160.3, 164.8, 169.4, 195.1.MS (ESI+) m/z 265.28 [M+H]+; HRMS (ESI+) m/z:Calc. for C13H20N4O2: 265.1659 [M+H]+. Found 265.1656 [M+H]+.

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Just decomposing the reaction mixture in water should break the complex. Its not a big deal. Experimentals mentioned by williams are good one.

Dear william

Can you provide me both the articles you have mentioned, actually I have no access to those articles. If you can please do a favor for me.

Thanks

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Dear Omprakash,

Kindly let me know what happened after trying reaction with methylmagnesium bromide.

Thanks

Rajesh

Sir actually I have to do it with some expert in organic chemistry because I did not perform reactions with methylmagnesium bromide.

But surely I will let you know the status.

Thanks to all for help and support

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Dear Omprakash,

Dont even try to synthesize methylmagnesium bromide. MethylMagnesium bromide 1 N solution in ether or THF is available in Market. The bottle is like the one like butyl lithium 1M in hexane where we use syringe to remove it. Purchase it from market directly or see some one in other labs have the same. Even you can get it from some local companies in India.

Best of luck

Rajesh

Forgive me for the enol comment that i gave........ The desirable enol will be formed in more quantity.

dear Sir,

Thanks for your suggestion

Are you talking about cyanoacetone comment?

Yess about that