Merck synthesis

Schiff base-Cu(II) complexes, 2, by Aratani and co-workers [3-6] led to high enantioselectivi-ties in selected intermolecular cyclopropanation reactions, one of which was the critical asymmetrization step in the Sumotomo-Merck synthesis of cilastatin (Eq. 5.2). 

If the cyclisation is not worked up, the product is the alkynyl-lithium that can be added directly to 55 to give the alcohol 54. In the Merck synthesis of efavirenz, this step is used to make a single enantiomer of 64 and this chemistry is discussed in Strategy and Control.16... 

The final stages of the Merck synthesis involved differential oxidation of the C(9), the C(10) and the C(22) secondary hydroxyl groups. Initially, the C(9)-/>"methoxybenzyl group was oxidatively cleaved with 2,3-di-chloro-5,6-dicyano-1,4-benzoquinone (DDQ), and the C(10)-triethylsilyl... 

The TES group is the most labile of the common silyl protecting groups, apart from TMS, and can usually be removed in the presence of TBS, triisopropylsilyl (TIPS) and rerf-butyldiphenylsijyl (TBDPS) groups. Selective deprotection of a TES ether using aqueous trifluoroaoetic acid left two TBS ethers and two TIPS ethers intact in the Merck synthesis of the immunosuppressant FK-506 [Scheme 4.19].22 Weaker acids such as H2O-HOAC-THF (3 5 11) at room temperature,33 HF pyridine24 and pyridinium p-toluenesulfonate [Scheme 4.2Q]23 can accomplish similar transformations. 

Strong protic acids cleave phenolic methyl ethers. Thus hydrogen bromide accomplished the same double demethylation as that depicted in Scheme 4.104.189 The final step in a Merck synthesis of the potent dopamine agonist (A,R)-4-pro-pyl-9-hydroxy naphthoxazine (106 2), a phenolic ether deprotection was accomplished on a large scale using methanesulfonic acid in the presence of methionine as the nucleophile [Scheme 4.106]. 190 191... 

The Nazarov cyclization has also been used industrially. In the Merck synthesis of (+)-indacrinone the indanone unit is formed by an aromatic Nazarov cyclization. ... 

A second example of this methodology comes from the Merck synthesis of homo-tyrosine, an intermediate for a potent do >amine agonist (Scheme 27). The Grignard reagent is added to a solution of 2 equiv. of diethyl oxalate at -20 C. 

In a more direct comparison of the phosphine oxide elimination with the sulfone, Schreiber employed a identical system to Danishefsky, but used the phosphine oxide (422). Reaction with isobutyralde-hyde and subsequent elimination resulted in a 1 1 mixture of the ( )- and (Z)-alkenes (421 equation 98). It appears from the more complex example of the Merck synthesis and from this example, that the Julia coupling proceeds with higher ( )-selectivity, in similar yield. 

This topically active carbonic anhydrase inhibitor is a powerful controller of the elevated intraocular pressure associated with glaucoma, and has been prepared by Merck in > 32% yield in a multistep synthesis starting from (R)-3-hydroxybutyrate [49]. Although the key ketone reduction step has been recently improved by researchers at Zeneca by replacing a chemical process with a biological one [50], the Merck synthesis well illustrates the potentialities of the approach to enantiomerically pure drugs based on the use of chiral non-racemic substrates. 

Scheme 2. Modified Merck synthesis of chaetomellic acids.

Insertion into N-H bond. Of major importance is the recently developped intramolecular carbene insertion into N-H bond, which is the key step in the Merck Synthesis of the 1-carbapenam ring system from diazo precursors. Yields are high, and the reaction is always very selective in one isomer. 

SCHEME 2.18. Merck synthesis of endothelin receptor antagonist 114. 

SCHEME 2.19. Merck synthesis of neurokinin-1 (NKi) receptor antagonist 120. 

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