The 2007

ChemBark is dead.

So is Kinase Pro, Atompusher, Totally Synthetic, Heterocyclic Chemistry, Organometallic Current, Totally Medicinal and Jungfreundlich

Today I settled all family business.

Just don’t tell me you’re innocent.

Come on – you think I’d make my sister a widow? I’m Godfather to your son. Admit what you did.
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Update: Turns out Paulie Boy is stil alive. No way we can get to him now. Roth has played this one beautifully.

Frustrating: Meet the Bricks

  Credit: Adolf Born

Orally active drugs need to dissolve in water or in lipids. When the compounds are crashing out even from straight ethyl acetate one should urgently look for better-behaved analogues before going too far down the SAR potency/selectivity road. One should not hope to fix the solubility later – there is only so much that the solubilizing side-chains can do. And when a poorly-soluble polycyclic molecule is decorated with amines a mirage of improved solubility and potency in cell-based assay may appear but very little of it usually goes towards a sound SAR.  (Also the PK of such series is most likely going to be awful). 

Compounds generally appear more soluble when prepared in form of a lyophilisate. Scaling-up a poorly-soluble clinical candidate that was never before prepared in a pure crystalline form is bound to produce unpleasant surprises…

Developing poorly soluble compounds is a frequent source of frustration in kinase projects; the kinase ligand-binding sites naturally like polyheterocyclic compounds. Nowadays many medchem programs start with the high-throughput screening of chemical  libraries – the lead compounds obtained from combichem/parallel-synthesis are notorious for the high number of NH bonds. Also, over-optimistic crystallography-driven drug design can lead to terrible molecules: X-ray co-crystal picture offers the illusion of a great insight (“we should try to pick a H-bond here and reach a pocket back there”)  and it encourages decorating the molecule with too large greasy or excessively-polar substituents – the fast way into potent undruggable series. 

When trying to fix a poor compound solubility:

1. Abandon the series and work on something else – the most reliable option. One should consider this seriously when the compounds are so terribly insoluble that they form gels.
2. Get rid of some NH bonds – alkylate the nitrogens, replace them with  C or O, etc. Tertiary amides are less troublesome than primary, secondary amides or sulfonamides. Stay away from N,N’-diaryl ureas. Amine NHs are fine.
3. If you must have the NH bonds in your molecule, put some groups right next to the NH, to shield it  – in ortho or alpha positions. An ortho methyl substituent can make all the difference.
4. Get rid of some hydrogen bond acceptors  – remove sulfonyls, carbonyls etc.
5. Avoid a combination of el deficient with el rich aromatic rings within the same molecule – the charge transfer between electronically unequal partners produces exceptionally strong pi-stacking. (Picric acid forms a stable co-crystal with naphtalene)
6. Mess up the symmetry: Avoid big symmetrical substituents like p-Br-phenyl, try to add some ortho substituents to keep rings out of plane
7. Add solubilizing side-chains containing tertiary (or secondary) amines or try to pro-drug
8. Disconnect rings or replace aromatic rings with non-aromatic ones. Polycyclic aromatic systems with more than 2 rings are Very Bad
9. Reduce the size of the molecule
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Purifying insoluble compounds is hard, especially when some structurally-related impurity carries over into the solids. You cannot do a silica column and the reverse-phase prep HPLC purification is no picnic either (you inject your material in DMF solution – then pray it wont crash out in the injection loop, autoinjector needle, connecting tubing or on the top of the very expensive column). If you must make poorly-soluble compounds, it is best to rigorously purify the intermediates right up to the moment when the material becomes very insoluble (such as the deprotection or coupling step) and spend enough time optimising the reaction conditions and workup in the following steps so that the impurities are kept at low levels from then on.

Glow in the dark

I got a C grade from the radiochemistry labs once. It troubled me a great deal: I wanted no C on my transcript. The overbearing fellow in charge of the labs was throwing tantrums because of some weakly-labeled sulfur spilled on my bench. (A soft emitter less active than plain KCl, I argued – but the bossman would have none of it)

And I fought hard and requested extra weeks in that basement lab: I would redo everything, on those noisy detectors.
Thus I earned the second C from the radiochemistry dudde – proving his point that I was an exemplary failure.

I prayed for this man’s suffering. A swimming accident – fast comes a boat with two cruel propellers…

Now I see only a disappointed man, trying to discipline kids. The years in a basement lab with obsolete instruments

3-amino-6-bromoisoquinoline

 

A solution of 25% wt sodium methoxide in methanol 3.0mL (12.8 mmol) was added dropwise to a solution of diethoxyacetonitrile 6.2g (48 mmol) in anh methanol 15mL with cooling on ambient water bath over 5 min period. The mixture was stirred at RT under Ar for 26 hours. [Note 1] To this solution containing (EtO)2CHC(OMe)=NH, solid p-bromobenzylamine hydrochloride 5.04g (22.65 mmol) was added followed by additional 25% NaOMe 3.0mL (12.8mmol). The mixture was refluxed under Ar at 70C on oil bath for 17 hours (overnight). The reaction mixture was evaporated, the residue was diluted with tert-BuOMe 50mL, the salts were removed by filtration (washed with additional TBME) and the filtrates were evaporated. The residue was dried on highvac (50C, 0.5Torr, 1 hour) to yield the crude amidine 7.64g as a dark brown honey.

The crude amidine was slowly added in a thin stream into vigorously stirred conc. sulfuric acid 50 mL with cooling on ice bath. The flask after amidine was rinsed with additional conc. sulfuric acid (2x10mL, then 4 mL) and these washings were also added to the reaction mixture. The cooling bath was removed and the dark mixture was stirred at RT under Ar for 1 day. The reaction mixture was poured onto ice (250 g) in a 1L beaker, the flask was washed with water and washings were added to the mixture. The mixture was made alkaline by careful addition of conc. aqueous ammonia (approx 220mL, exothermic!) with external cooling on water bath. When the mixture has cooled to RT the precipitated product was collected by filtration, washed with water and dried by suction. The obtained crude product was suspended in a mixture of ethanol 400mL and water 100mL. 6M HCl 4mL was added and the mixture was heated and sonicated until complete dissolution took place. Charcoal (3 spoons) was added, the mixture was heated to a brief reflux (2 min) then cooled to RT and filtered. The charcoal was washed with ethanol+water mixture (1:1, 1oomL). The filtrates were made basic by addition of conc. ammonia 3mL and gradually concentrated down to approx 125mL volume to remove ethanol. The precipitated product was collected by filtration, washed with water and dried by suction, then on highvac. Y=3.943g (78% overall) of a pure product as a light tan solid.

1H(d6-DMSO, 400MHz): 8.809(s, 1H), 7.793(app d, 1.8Hz, 1H), 7.730(d, 8.7Hz, 1H), 7.215(dd, 8.7Hz, 1.9Hz, 1H), 6.553(s, 1H), 6.112(br s, 2H); 13C(d6-DMSO, 100MHz): 157.12, 151.74, 139.61, 130.03, 125.90, 124.44, 124.17, 120.63, 95.85; LC/MS(+ESI): 223, 225 (M+1)

Note 1: The progress of  methyl imidate formation from nitrile can be readily followed on NMR – by diluting samples of react mixture with CD3OD + TMS standard: (EtO)2CHC(OMe)=NH : 4.836(s, 1H), 3.760(s, 3H), 3.590(m, 4H), 1.213(t, 7.1Hz, 6H); (EtO)2CHCN: 5.490(s, 1H), 3.699(m, 4H), 1.239(t, 7.1Hz, 6H)

Note 2: A slightly more optimised version follows: 12 mL of 25% wt NaOMe in MeOH was added to a water-cooled solution of (EtO)2CHCN 11.81g in anh. MeOH 30mL over 10 min. After 12 hours at RT, solid p-bromobenzylamine hydrochloride 10.17g was added and the mix was refluxed under Ar at 70C for 14 hours, then evaporated. The residue was re-dissolved in TBME 50mL, filtered (salts washed with additional TBME) the filtrates were evaporated and the residue dried on highvac at 50C. The obtained crude amidine (15.19g) was slowly poured into ice-cooled conc. sulfuric acid 100mL, the flask was washed with additional H2SO4 (2×20 then 5mL) and the washings were combined with the reaction mixture. The mix was stired at RT for 11 hours, then poured on ice (0.5kg) and carefully alkalised with conc aq. ammonia 450mL (with cooling: exothermic). Upon cooling to RT, the precipitated crude product was collected by filtration, washed with water and dried by suction. The crude product was refluxed with EtOH 0.5L and water 0.25L mixture acidified with 6M HCl 8mL until complete dissolution took place (30min). The solution was cooled, charcoal 2.5g was added, the mix was brought to brief reflux again (5 min), cooled to RT and filtered, the charcoal washed with additional EtOH. The filtrates were concentrated to about half volume, made basic with conc. ammonia 8mL, concentrated slowly down to approx 220mL. The precipitated product was collected by filtration, washed with water, dried by suction and on highvac.
Y = 8.455g (83%) of a light tan solid (96% pure by HPLC, NMR)