A versatile route to single enantiomer verapamil from readily available raw materials is described. The key intermediate, 4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl hexanoic acid (verapamilic acid), was resolved efficiently with r-methyl benzylamine. Stereochemical integrity at the quarternary carbon centre was preserved through subsequent steps to give either (R)-or (S)-verapamil in good overall yield. This sequence incorporated a selective borane-mediated reduction of a tertiary amide. Process scale-up to the pilot plant has been demonstrated successfully for the resolution step.
A synthesis of methyl 3-(2-methoxy-4-pyridy1)propionate ( Z ) , a key intermediate in the synthesis of the potent long-acting histamine H,-receptor antagonist SK&F 93574 ( I ) , is described. The key step in the synthesis of compound (1 ) involves alkylation of 2-methoxy-4-methylpyridine (5) with sodium chloroacetate in the presence of sodamide. The scope and limitations of the alkylation is investigated using a variety of electrophiles. The application of this reaction to other 2-substituted 4-methylpyridines is also discussed.
The 1,2,4,5-tetrathiane (3), readily formed from amido ester (2) and disulphur dichloride, undergoes immediate reaction with potassium hydroxide in ethanol at room temperature to form sulphur and the maleimide salt (6) which is characterised as its S-benzyl and S-methyl (4) derivatives; a mechanism is proposed for this mild carbon-carbon bond forming desulphurisation reaction.
Diazoalkanes react with tetrasulphur tetranitride to give red crystalline, 1,3h462,5,2,4-trithiadiazines [(3), (7), ( 8 ) ] ,representatives of a new ring system with a nearly planar S3N2 unit; the parent compound (3) was independently synthesised from methanebis(sulpheny1 chloride) (11) and sulphur bis(trimethylsi1yl)diimide (12).
Ab initio self-consistent field molecular-orbital calculations confirm that compounds of the type RSNSNSR (1; R = H) exist preferentially as the syn,syn isomer in which the S S distance is significantly shorter than the non-bonded van der Waals value, an effect attributed t o stereoelectronic interactions involving the terminal sulphur lone-pair orbitals. A five-membered ring valence isomer (2) is calculated to be much higher in energy and not a true minimum. A series of related compounds (4) in which the t w o R substituents are replaced by a bridging group (X = S, NH, or CH,) have similarly short S S distances. To account for this, another novel stereoelectronic interaction is proposed between specifically the equatorial orbitals o n X and the adjacent sulphur lone-pair orbitals, which results in bonding electron density in the transannular S S region, and has the greatest effect for X = S. On this basis, it is predicted that the bridging group X = NR will show an axial preference for the R substituent, and that groups such as X = CR, could reveal a discrimination between the axial and equatorial substituents.Both organic ' and inorganic 2 , 3 sulphur-nitrogen systems are
The synthesis of
[3aR,4S,6R,6aS]-6-amino-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide, a
key
single enantiomer intermediate to carbocyclic nucleosides
such
as adenosine agonists, is reported involving a scalable
catalytic
osmium tetraoxide dihydroxylation of
(−)-2-azabicyclo[2.2.1]hept-5-en-3-one. The acetonide-protected diol
[3aS,4R,7S,7aR]-tetrahydro-2,2-dimethyl-4,7-methano-1,3-dioxolo[4,5-c]pyridin-6(3aH)-one is subject to lactam ring opening with
anhydrous
ethylamine to give the carbocyclic key intermediate. The
rate
of this known reaction, carried out in a pressure vessel,
is
considerably enhanced by acid catalysis using
ethylammonium
ion. In addition, the need for a pressure vessel is
circumvented
by using anhydrous ethylamine with acid catalysis.
Alternatively stoichiometric ethylammonium ion in an appropriate
cosolvent can be used to form the key intermediate in high
yield.
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