Efavirenz preparation

For the treatment of AIDS, TDF is now available in three commercial preparations, as such (Viread ), in combmation with emtricitabine (Truvada ) and m combination with emtricitabme and efavirenz (Atripla ). The latter represents a three-drugs-in-once combination piU, which has become available for the treatment of AIDS since July 2006. The different milestones mat marked the development and ultimate commercialization of Atripla (m 2006) smce the original identification of adefovir as an antiretroviral agent (m 1986) have been previously reviewed (De Clercq 2006, 2007a-c). 

Efavirenz (1) is the second NNRTI development candidate at Merck. Prior to the development of 1, we worked on the preparation of the first NNRTI development candidate 2 [2]. During synthetic studies on 2, we discovered and optimized an unprecedented asymmetric addition of an acetylide to a carbon-nitrogen double bond. The novel asymmetric addition method for the preparation of 2 also provided the foundation for the process development of Efavirenz . Therefore, in this chapter we will first discuss chemistries for the preparation of 2 in two parts process development of large scale synthesis of 2 and new chemistries. Then, we will move into process development and its chemistries on Efavirenz . 

Efavirenz (1) was chosen over compound 2 as a developmental candidate in 1993 based on its better antivirus activities, especially against resistant strains [1, 17]. Efavirenz is the first HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) which was approved by the FDA on September 21, 1998. The original Medicinal Chemistry method to prepare Efavirenz is depicted in Scheme 1.14. 

Efavirenz (1) was prepared from 4-chloroaniline (11) rather straightforwardly in seven chemical steps in an overall yield of 12%. Ortho-Trifluoroacetylation of... 

Naturally, we thought our novel asymmetric acetylide addition on ketenimine 5 (Scheme 1.6) could also be applicable in the preparation of Efavirenz . The structure of 36 in Scheme 1.14 is somewhat misleading. We should expect that one of... 

Preparation and isolation of Efavirenz (first manufacturing route). 

Introduction Since we had already developed the novel asymmetric addition of lithium acetylide to ketimine 5, we did not spend any time on investigating any chiral resolution methods for Efavirenz . Our previous method was applied to 41. In the presence of the lithium alkoxide of cinchona alkaloids, the reaction proceeded to afford the desired alcohol 45, as expected, but the enantiomeric excess of 45 was only in the range 50-60%. After screening various readily accessible chiral amino alcohols, it was found that a derivative of ephedrine, (1J ,2S) l-phenyl-2-(l-pyrrolidinyl)propan-l-ol (46), provided the best enantiomeric excess of 45 (as high as 98%) with an excellent yield (vide infra). Prior to the development of asymmetric addition in detail, we had to prepare two additional reagents, the chiral modifier 46 and cyclopropylacetylene (37). 

Obviously, there are two ways to prepare Efavirenz from the pMB protected chiral amino alcohol 50 (i) creation of the benzoxazinone first then removal of the pMB group or (ii) removal of the pMB first then formation of benzoxazinone. Preparation of the benzoxazinone was demonstrated by Medicinal Chemistry from the amino-alcohol with CDI. 

The sample for analysis was prepared by solid-phase extraction of 5 ml of 0-24 h urine obtained from rats after dosing with 800 mg/kg of efavirenz. The extract was dried and reconstituted with 100 ml of 80% D2O and 20% acetonitrile-d3. 

R-(R, S )]-p-Methyl-a-phenyl-1-pyrrolidineethanol is an important chiral mediator for the enantioselective addition of an acetylide to a prochiral ketone.2 3 This reaction has been successfully applied to the synthesis of the reverse transcriptase inhibitor efavirenz (DMP-266) (Scheme 1).3.4 Preparation of the enantiomer, (1S,2R)-N-pyrrolidinylnorephedrine, has been reported.2 The method used potassium carbonate (K2CO3) as base, but the yield of the product was only 33%. The submitters have extensively studied the formation of the pyrrolidinyl ring under various conditions as summarized in Table I. Eventually they found that the reaction was extremely efficient when it was run in toluene using sodium bicarbonate (NaHCC>3) as base (entry 8, Table I),5 which gave [R-(R, S )]-p-methyl-a-phenyl-1-pyrrolidineethanol quantitatively. Enantioselective (up to 99% ee) addition of cyclopropylacetylene to the ketoaniline 1 is achieved when the solution of [R-(R, S )]-p-methyl-a-phenyl-1-pyrrolidineethanol is used as a chiral additive.3 In addition, this method is also applicable to the preparation of a variety of alkylated norephedrines and other amino alcohols in excellent yields as Illustrated in Table II. These amino alcohols are potentially useful in asymmetric syntheses. 

Merck s HIV-1 reverse transcriptase inhibitor Efavirenz 83 is one of the simplest anti-HIV drugs yet produced. The most straightforward synthesis17 is based on closure of the amino alcohol 84 with some phosgene equivalent and the preparation of 84 by asymmetric addition of cyclopropyl-ethynyl-lithium 86 to the ketone 85. 

Delavirdine absorption is reduced by the buffered preparation of didanosine. This interaction would not be expected with the enteric-coated preparation of didanosine. Delavirdine does not affect the pharmacokinetics of zidovudine. There is no pharmacokinetic interaction between efavirenz and zidovudine or lamivudine. There is no ciinicaiiy reievant pharmacokinetic interaction between nevirapine and didanosine, iamivudine, stavudine, zaicit-abine or zidovudine. 

Rifabutin 300 to 600 mg daily for 12 days did not significantly affect the pharmacokinetics of [buffered] didanosine 167 to 250 mg twice daily in 12 patients with AIDS. The steady-state pharmacokinetics of rifabutin were not affected by didanosine (buffered sachet preparation), which suggests that the buffer used in the didanosine preparation had no effect on rifabutin absorption. However, a case has been reported of a patient taking lopinavir/ritonavir, efavirenz, lamivudine and buffered didanosine who had impaired rifabutin absorption. When rifabutin was taken 30 minutes after didanosine, rifabutin levels were undetectable, but when rifabutin was taken 3 hours after didanosine, rifabutin levels were apparent. ... 

A key intermediate (125) en route to anti-HIV drug efavirenz is prepared by enantioselective addition of cyclopropylacetylene to the parent ketone (ArCOCFj), mediated by diethylzinc and a chiral amino-alcohol auxiliary. An efficient flMfocatalytic version has now been developed, giving higher yield (79%) and ee (99.6%) than the stoichiometric version. ... 

Efavirenz 1 and its congeners 2-4 are prepared in a higher than 98% enantiomeric excess on a scale of up to 5,000 kg. All of them either reached a late stage of clinical testing or have been introduced into the regular therapy of AIDS [14, 15]. The remarkable synthetic achievements that resulted in the availability of this valuable drug on the world market are outlined in the following sections. 

Recently, this strategy was applied to the deracemization of propargylic alcohols that are important synthons for the preparation of biologically active compounds such as mifepristone, efavirenz, or petrosynol [63]. A one-pot two-step process employing whole cells from Candida parapsilosis ATCC 7330 was carried out in aqueous medium using short reaction times of 1—4h (Scheme 4.15). Biocatalyzed transformations afforded excellent enantiomeric excess (up to 99%) and isolated yields were from 60-81%. 

NMR experiments. The sample for analysis was prepared by solid-phase extraction of 5 mL of urine obtained from rats after dosing with 800 mg kgr of efavirenz, with 0-24 hr collection. The extract was dried and reconstituted with 100 pL of 80% D2O and 20% acetonitrile-d3. A 40 pL injection was made onto a 3.9 x 150 Waters Symmetry Cjg column. A gradient elution from 80% D2O and 20% ace-tonitrile-d3 to 50% D2O and 50% acetonitrile-d3 over 20 min at a flow rate of 0.8 mL min i was employed for separation. Using a splitter immediately after the column, 95% of the sample went to the UV detector and onto the NMR spectrometer while 5 % went to a Finnigan LCQ ion-trap mass spectrometer equipped with an ESI probe operating in the positive-ion mode. The system was plumbed to allow the peak to reach the UV detector and the mass spectrometer at the same time. 

Scheme 1-157. Enantioselective preparation of alcoholate 214, a key intermediate in an an Efavirenz synthesis.

In the context of a practical synthesis of the HIV reverse transcriptase inhibitor efavirenz (300), the enantioselective addition of metalated terminal acetylenes to ketones was studied and developed at Merck (Scheme 2.37) [184], The key enantioselective addition of the lithium acetylide prepared from 298 to ketone 296 in the presence of amino alcohol 297 proceeded with impressive enantioselectivity additionally, the process can be conducted on multi-kilogram scale. Careful mechanistic studies including spectroscopic work by Collum suggested that the alkyne addition proceeds via the cubic lithium tetramer 301 [185],... 

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