Can you specify how you worked out for separation of chloroquinaz. !!

Go for SOCl2 in comparison to POCL3 which is more toxic and produce less yield.

I'd go for POCl3 neat with a base (typically it's N,N-dimethylaniline). heat at 100°C for a couple hours. These reaction can take up to 72h to complete.

Hi Waleed, with POCl3 system, I normally wash excess with hot ligroin and yellow ppt crushes out, which i normally then wash with 10% Na2CO3 and extract with EtOAc, only to find that i recovered the starting material. with SOCl2/cat DMF system, I directly vac excess SOCl2 on rotary evaporator then treat the remaining brown liquid with 10% Na2CO3 and extract under basic condition (around pH 9). Pierre-André, I'll definitely give that a shot for about 36hrs just to check and update but do you use catalytic amount of base and perhaps in what order do you add reagents? I think there is a particular order especially when it comes to basidifying or acidifying like Murugappa suggests.

I remember we used POCl3 for similar transformations in the lab where I worked some 8 years ago... But, if your idea is to displace the chlorine with an amine in the next step; in our hands, it worked quite fine for similar substrates starting directly from the oxo-compound and using BOP and DBU, if I still get it right (I would have to check the details...).

Yes Eduard you are correct, please do so. I appreciate.

in my opinion, Lebusetsa Taleli, i think you should control the temperature when you neutralize with a base as sod. carbonate (the temp is to be around zero). otherwise rapid hydrolysis occur to the hdroxy form. all the chlorinating reagents can work without significant difference in yield.

regards

Here's a prep I've used to convert a molecule containing 2 hydroxypyridines to the corresponding chlorides. Starting material names are erased for confidentiality purpose... :

XXXX (1.709 mmol) was dissolved in POCl3 (19.66 g, 11.95 mL, 128.2 mmol) and the mixture was cooled to -40°C. Hunigs base (2.209 g, 2.977 mL, 17.09 mmol) was added dropwise and the reaction mixture was refluxed for 8h. No more starting material is observed, but the desired product is not observed either. Reflux was pursued for further 72h and complete conversion to the desired product was observed. The reaction mixture was poured into ice-water and the aq. phase was extracted with EtOAc. The combined organic phase was washed with aq. NaHCO3, dried over MgSO4, filtered and the filtrate evaporated under reduced pressure, affording XXXX (1.026 mmol, 60.06%) as a tan solid.

As for how/when to neutralize, in your case you'd probably have to do it during extraction. I would just dump the reaction mixture in ice/water, add EtOAc and neutralizer with NaHCO3. If you have your compound in a biphasic system, once you deprotonate the pyrimidine ion, the product will go in the organic phase rapidly and you should not have any hydrolysis issues. Anyways, I'm not worried about hydrolysis in this case. I would be surprised if you can hydrolyse the chloro-pyrimidine at pH 8 in a biphasic system at room temperature in a couple of minutes...

In a lab I worked for, they were doing the conversion of 2-hydroxypyridines to 2-chloropyridines with PhP(O)Cl2, it apparently gave better yields than POCl3.

But as it was said earlier, your problem may just be that your compound is prone to hydrolysis. In this case, can't you perform the following reaction in the same pot, just on the crude?

Thanks Pierre-André, this sounds interesting, let me give it a try and I'll update.

Here is then a 'BOP' procedure, taken from U.S. Pat. Appl. Publ., 20090036430 : Synthesis of 2-amino-4-(N-piperazin-1-yl)-6-chloropyrido(3,2-d)pyrimidine. To a solution of 2-amino-6-chloro-pyrido[3,2-d]pyrimidin-4(3H)-one (example 20,100 mg, 0.51 mmol) in DMF (20 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 115 μl, 0.76 mmol), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP, 0.66 mmol, 292 mg) and piperazine (1.53 mmol, 131 mg). The solution was stirred for 3 hours at room temperature. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 3:97 with 0.5% aq. NH3 solution), yielding the title compound as a white powder (85 mg, 63%) which was characterised as follows: 2-amino-4-(N-piperazin-1-yl)-6-chloropyrido(3,2-d)pyrimidine, yield (85 mg, 63%). MS (m/z): 266 ([M+H]+, 100). So, the substrate is a pyrido[3,2-d]pyrimidin-4(3H)-one rather than a quinazolin-4(3H)-one , but I suppose it's worth trying...

The nitro group completely alters the reactivity of the quinazolone -- the problem has been noticed before:

J. S. Morley and J. C. E. Simpson, J. Chem. Soc., 1948, 360-366.

You could try deprotonating it with NaH/THF . . . the anion should react well with any of the usual chlorinating reagents. I wouldn't hazard a guess about whether you'd get reaction at O or N, but it's worth a try. I'd also consider diazotizing the 4-amino compound, for a taste of that old-time chemistry.

Take one gram of quinazolinone with 5 ml of POCl3 and 2 gram of PCl5 and this a mixture was fused on water bath for 6-8 h. Cool, the mixture then poured it on ice-water and stirring for 30 min. filter off and crystallized.

Thanks everyone for your input. I am still trying the reaction under basic conditions as suggested. Tarik, these conditions are the same to J. Chem. Soc., 1948, 360-366 that James has mentioned. Taking into consideration that I might be blown away by hydrolysis or possibly phosphorylated intermediates which I then need to give the reaction extra-time and perhaps use excess ice-water this time around.

In the paper J Med Chem 1995, Vol. 38, No. 18, 3483, "Scheme 3", the authors did not explain why they did one-pot reaction to the corresponding arylamine??? Prof van Otterlo has just send me the J. Org. Chem. 2011, 76, 1653–1661, which is detailed on chlorinating quinazolones with POCl3 under basic conditions. Hopefully, these conditions will work...

Two suggestions:

First, to ensure that the reaction is going to completion and forming the chloride, follow the procedure(s) in this reference:

Robins, M. J. U., Bogdan, Can. J. Chem. 1981, 59, 2601-2607.

This is a nice paper that demonstrates well the LaChatlier effect of exogenous chloride source. However, make sure that you dry the Et4NCl. Vacuum oven at 90-100 C overnight works well.

Alternately, why do you need the chloride? Are you going to displace it with amines? If so, you can use a direct activation strategy as in this reference:

Wan, Z.-K. W., Sumrit; Levins, Christopher G.; Lin, Melissa; Tabei, Keiko; Mansour, Tarek S., J. Org. Chem. 2007, 72, (26), 10194-10210.

Note the need for benzotriazole-1-yl-oxy-tris(dimethylamino) phosphonium hexafluoro phosphate (BOP). Other coupling reagents are inferior.

Hope that helps.

Looking for the structure of your target compound it is expected that the nitro group [EWG] will activate the electrophilicity of the N=C-Cl carbon atom, so you have to avoid the presence of water (moisture) during your work up and perform the experiment under dry condition. See, the procedure of the chlorination of the 6-fluoro analogue [EWG at the 6 position too]

---European Journal of Medicinal Chemistry, Volume 46, Issue 7, July 2011, Pages 2709-2721, Mann-Jen Hour, Jai-Sing Yang, Tai-Lin Chen, Kuan-Tin Chen, Sheng-Chu Kuo, Jing-Gung Chung, Chi-Cheng Lu, Chia-Yi Chen, Yi-Hsuan Chuang

Good luck

A great paper exploring this transformation J. Org. Chem. 2011, 76(6), 1653-1661. DOI:10.1021/jo102262k.

Phosphoryllation is base-mediated, chlorination is acid-mediated. Run the reaction uder basic conditions, then add a little water to hydrolyse excess POCl3 forming HCl and promoting the chlorination.

The reaction proceed well with Hunig's base, mixing all regents in ice-water bath and stirring at 80 °C for about 3 hrs. beyond -10 °C everything else in the reaction mixture just seem to freeze, and a lot excess POCl3 just seem to drag the reaction longer. Thanks a lot everyone, your contribution is much appreciated.

Steven Raw · 25.82 · 101.11 · AstraZeneca

A great paper exploring this transformation J. Org. Chem. 2011, 76(6), 1653-1661. DOI:10.1021/jo102262k.

paper of Dr Adel Amer

-European Journal of Medicinal Chemistry, Volume 46, Issue 7, July 2011, Pages 2709-2721, Mann-Jen Hour, Jai-Sing Yang, Tai-Lin Chen, Kuan-Tin Chen, Sheng-Chu Kuo, Jing-Gung Chung, Chi-Cheng Lu, Chia-Yi Chen, Yi-Hsuan Chuang

What about CCl4/PPh3 protocol (classical Appel)? I have no experience on quinazolones, but quinolones and purine bases work well... Even with PPh3 on solid support (even on Merrifield resin)

As an alternative, you could try a phosphotriazolide reaction. For example, see J. Chem. Soc. Perkin Trans. 1 1984, 1263-1271.

Basically, Add POCl3 to a 3.1 fold excess of 1,2,4-triazole in the presence of Et3N or DIPEA (gives a more soluble HCl salt as byproduct, compared to Et3N.HCl, and allows homogenous reaction) in THF or MeCN as solvent. This forms phosphotriazolide. Then add your quinazoline and heat. This should transform your quinazolone to its triazolide derivative. This can then be reacted in a manner analogous to the corresponding chloride. This method is used extensively in nucleoside chemistry, but I have applied it to several heterocycles, including benzisoxazolones, pyridopyrimidinediones and quinazolones. This procedure has several advantages:

1. The triazolide derivative of your substrate is usually highly crystaline.

2. The triazolide derivative is usually more stable to hydrolysis than the corresonding chloride derivative.

3. The ditriazolophosphate moeity is a much better leaving group than chloride, so you should get enhanced reactivity

4. Given you have an intrinsically reactive quinazoline, there should be no issue with the slightly deminished reactivity of triazolide intermediate vs. the usual chloride.

Some final points:

A. Whether you use POCl3 or phosphotriazolide, I'd be inclined to try to telescope your activation and substitution stages as it's likely your product will be sensitive to hydrolysis.

B. Regarding James Denners idea of deprotonating with NaH but not knowing the selectivity (N or O phosphoryllation). I don't expect it would be an issue as it has been shown [J. Org. Chem. 2011, 76(6), 1653-1661. DOI:10.1021/jo102262k, as above] that phosphorylated quinazolones exist as an exquilibrium mixture of several phosphorylated species (including N and O) that interconvert during the reaction.

you can reflux the quinazolinone with POCl3-Xylene on an oil bath (200`C) for about eight hrs ,

Taleli, do you have any luck with your reaction?

Please, test pouring your reaction mixture onto cold NaHCO3 in portions. As I mentioned to you earlier your compound is very sensitive to hydrolysis and pouring onto water creates an acidic medium which enhances this process.

Good luck

PPH3 (3eq), Cl3CCN (1.2 eq), in toluene at reflux

Tetrahedron Letters 53 (2012) 674–677

The quinazolone can chlorinated by in excess of POCl3 under mild reflux conditiion without solvent.

Reaction works well in presence of organic base (amines) and POCl3 without solvent. Take care which quenching the reaction. Recover maximum of POCl3 after reaction completion and quench at lower temperature (may be at 0 °C).

Thanks for all the good answers, POCl3 only does an excellent job....if POCl3 happens to be wet, though still colourless and fuming, this reaction will never work ... again, if you happen to be unlucky with POCl3 for this reaction, get a fresh bottle although some may prefer to distil under inert & anhydrous conditions, the reaction is not that sensitive to hydrolysis during a work up stage.

My favorite protocol for dehydroxy-chlorination of 2-oxoazaheterocycles like pyridones, pirimidinones etc.: 15-20% solution/suspension of starting material in anh. sulfolan and 1.5 eq POCl3 is heated and stirred at 70-75C (no more! decomposition may occur) until reaction completion (by LCMS of probe quenched with 1-methyl-piperazine to analyze LCMS-visible corresponding piperazine derivative  if chloro-derivative is hydrolytically unstable). Usually this takes 0.5-1.5 h. Catalytic amount of organic bases (e.g. DMP) or DMF can be used to accelerate the reaction.  The mixture is transferred into ice (ice excess is required to avoid two phases formation because of low water solubility of sulfolan). Precipitate is filtered off, washed with ice water, and dried by lyophilization.

This protocol works perfectly for synthesizing of sulfonyl chlorides from sulfoacids.  Dehydroxy-chlorination of carboxylic acids also occurs efficiently under mentioned conditions, but the protocol cannot be used for acyl chloride synthesis because water workup procedure is required. However, if you quench r.m. with amines, you will get amides in good yield.

Good luck! 

best for chlorinating quinazolones using POCl3 under gentle refluxing for 4 hs & then removing excess of POCl3  under reduced pressure.

For converting quinazolones into chloro group you should ensure that the moisture content in the quinazolones is less than

I confirm and support Dr Adel Amer answer

Lebu :) :)