Iodide-catalyzed reductions: development of a synthesis of phenylacetic acids.

A new convenient and scalable synthesis of phenylacetic acids has been developed via the iodide catalyzed reduction of mandelic acids. The procedure relies on in situ generation of hydroiodic acid from catalytic sodium iodide, employing phosphorus acid as the stoichiometric reductant.

Facile conversion of tetracycline antibiotics to 4,11a-bridged derivatives via oxidative mannich cyclization.

Treatment of a variety of tetracyclines (tigecycline, minocycline, tetracycline and doxycycline) with Ag(2)CO(3)/EDTA or Hg(OAc)(2) cleanly gave the 4,11a-bridged derivatives in high yields. The reactions proceeded through a novel, intramolecular Mannich cyclization of an iminium species generated by oxidation of the tertiary dimethylamino group at C(4) by Ag(I) or Hg(II). Tetracyclines without 5-OH-substitution (tigecycline, tetracycline and minocycline) gave the 4-OH-substituted, 4,11a-bridged compound, whereas doxycycline gave the 4-dimethylamino-substituted, 4,11a-bridged product. In the case of tetracycline, the 4,11a-bridged compound can equilibrate further to a 4,6-bridged hemiketal. Some of the bridged compounds underwent a novel decarboxylation--rearrangement sequence under acidic conditions to give tricyclic, open chain 1,4-quinoid compounds.

Stereoselective synthesis of a MCHr1 antagonist.

Melanin-concentrating hormone (MCH) is implicated in the feeding behavior in mammals affording a potential target to control overeating in people. Compound 1 (AMG 076) has been identified as a potent MCHr1 antagonist for the treatment of obesity. A synthesis suitable for the large-scale preparation of this lead candidate was developed to support preclinical studies. A Robinson annulation of benzylpiperidone and resolution of the desired enone from a mixture of the diastereomers afforded key intermediate 6 after a stereoselective hydrogenation. Subsequent Fischer indole synthesis with hydrazine 5 then provided the advanced intermediate, indole 2. Two complementary reductive amination strategies employing either aldehyde 3 or lactol 4 led to the synthesis of title compound 1.

Survey of doctors prescribing diamorphine (heroin) to opiate-dependent drug users in the United Kingdom.

AIM: To determine the scale and practice of diamorphine (heroin) prescribing for opiate dependence in the United Kingdom in 2000. DESIGN: Postal survey. SETTING: England, Scotland and Wales. PARTICIPANTS: One hundred and eleven of the 164 doctors in the United Kingdom on the Home Office record as holding a licence to prescribe diamorphine (response rate 68%), and 59 of the 108 doctors in the United Kingdom eligible to hold a licence (working in drug clinics), but not doing so (response rate 54%). MEASUREMENTS: The characteristics of doctors (a) holding a licence and (b) currently prescribing; the number of opiate users receiving a prescription; current treatment delivery, clinical criteria for patient eligibility; and reasons for prescribing or not prescribing diamorphine. FINDINGS: Seventy of the 111 doctors actually held a licence. While the majority were consultant psychiatrists, five were general practitioners. Forty-six were currently prescribing to 448 patients. The majority of prescribers reported that they had not initiated a prescription for diamorphine but had inherited patients already receiving such a prescription. Most of those who prescribed considered that in selected cases it could produce clinical and social improvement. There were great variations in clinical criteria for patient eligibility, prescribing practice, daily dose prescribed (range 5-1500 mg) and the daily dose-equivalent of 100 mg methadone (range 50-900 mg). Many respondents cited lack of appropriate resources as a reason for not prescribing to more patients. Reasons for non-prescribing varied from lack of resources to little evidence of its effectiveness. CONCLUSIONS: The prescribing of diamorphine to opiate dependent drug users remains rare in the United Kingdom. Not all eligible doctors seek a licence to prescribe, and not all those with licences actually prescribe it. There is no clear consensus on who should be treated with diamorphine and in what way.