WO2013050884A1

WO2013050884A1 - Process for the preparation of lersivirine

Info

Publication number: WO2013050884A1
Application number: PCT/IB2012/002903
Authority: WO
Inventors: Flavien SUSANNE
Original assignee: Phivco Uk Limited
Priority date: 2011-10-07
Filing date: 2012-10-04
Publication date: 2013-04-11

Abstract

The present invention relates to a process for the preparation of lersivirine or a pharmaceutically acceptable salt thereof characterised in that it uses the base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the solvent acetonitrile.

Description

PROCESS FOR THE PREPARATION OF LERSIVIRINE

The present invention is directed to a process for the preparation of the chemical compound lersivirine which is a non-nucleoside reverse transcriptase inhibitor (NNRTi) useful for the treatment of HIV infection. The structure of lersivirine is shown below. Its chemical name is 5-{[3,5-diethyl-1- (2-hydroxyethyl)-1 /-/-pyrazol-4-yl]oxy}i

WO02/085860 discloses a process for the synthesis of lersivirine in two steps as shown in Scheme 1 below.

Scheme 1

Step A is specifically described in Preparation 45 (with reference to Preparation 9) and generically described on page 14. Step B is specifically described in Example 119 (with reference to Example 114) and Example 282 and generically described on pages 1 1 and 12.

The present invention provides a process for the preparation of lersivirine or a

pharmaceutically acceptable salt thereof comprising:

A. reacting 5-hydroxyisophthalonitrile and 4-haloheptane-3,5-dione, in the

presence of a base, to form 5-(2-oxo-1-propanoylbutoxy)isophthalonitrile, and

B. reacting 5-(2-oxo-1 -propanoylbutoxy)isophthalonitrile and 2- hydrazinoethanol, in the presence of an acid, to form lersivirine, and, optionally,

C. reacting lersivirine with a suitable reagent so as to form a pharmaceutically acceptable salt of lersivirine,

characterised in that the base for step A comprises 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the solvent for steps A and B comprises acetonitrile.

The principal advantage of the use of DBU as the base for step A and acetonitrile as the solvent for steps A and B is that the resulting reaction kinetics makes it possible to carry out the reaction in a continuous manner. DBU accelerates the rate of reaction for step A such that it approaches the rate of reaction for step B. Acetonitrile effectively solubilises all starting materials, intermediates and by-products (e.g. DBU.HCI) so as to provide a homogenous solution which flows efficiently throughout a continuous reaction system. Thus, the present invention provides a

"continuous" process for the synthesis of lersivirine of high purity (98.9wt%) in good overall yield (70-75% isolated yield) with manageable levels of undesirable by-products (0.63% or less).

Manufacturing by a continuous process is well known in other industries such as the car and food industries. However, pharmaceutical products are generally still manufactured by batch processes due to the difficulty of applying continuous processing techniques to complex organic reactions which usually occur in a liquid phase.

The ability to conduct the synthesis of lersivirine in a continuous manner results in numerous advantages. As illustrated in Scheme 2 below, rather than perform Steps A and B and subsequent separation of the lersivirine product in separate sequential steps, these steps run in parallel resulting in significant time (and therefore cost) savings. Also, there is no inventory build up between each step when these are linked as a continuous flow. Furthermore, the reactions may be run on a smaller scale when operating in a continuous manner which means that smaller amounts of hazardous materials are in use at any one time. The main advantage however is throughput, a reactor with a relatively low volume (<5L) and footprint is capable of producing several metric tonnes of product per annum. Scheme 2

Lot

12 units of time for one

In a preferred embodiment, step A is conducted at elevated temperature. Preferably, at a temperature from 70 - 80 °C, most preferably at about 74 °C.

Step B is conducted in the presence of an acid. Suitable acids include any straight chain or branched chain aliphatic acid, any mineral acid or any straight chain or branched chain

halogenated aliphatic acid. Preferred acids are hydrochloric acid and acetic acid.

In a preferred embodiment, step B is conducted at elevated temperature. Preferably, at a temperature from 80 - 90 °C, most preferably at about 85 °C.

The 4-haloheptane-3,5-dione may be 4-chloroheptane-3,5-dione, 4-bromoheptane-3,5- dione or 4-iodoheptane-3,5-dione. 4-chloroheptane-3,5-dione is preferred.

The process may be performed using commercially available hardware designed for performing continuous reactions. For more information, reference is made to Anderson, Neal G; Organic Pocess Research & Development 2001, 5, 613-621 and the references cited therein.

In one embodiment, the product of step B or optional step C may be collected and then further processed (i.e. separated and purified) in a batch fashion. Preferably, however, the separation and purification (e.g. crystallisation) steps are also conducted in a continuous manner. This may be achieved by the use of continuous separation and purification techniques known in the art. Examples of commercial equipment include (i) centrifugal separators such as those manufactured by CINC industries (http://www.cincmfg.com/) and disclosed in United States Patents 4,175,040, 4,959,158 and 5,591 ,340, and (ii) rotating disk and baffle tray columns such as those manufactured by Koch Modular Process Systems, LLC (http://www.liquid-extraction.com/karr- column.htm).

Figure 1 schematically illustrates a suitable plug flow reactor system which may be used for the present invention. Tank 1 contains 5-hydroxyisophthalonitrile and DBU in acetonitrile and tank 2 contains 4-haloheptane-3,5-dione in acetonitrile. These reagents are mixed and pumped through the first plug flow reactor (PFR - Step A) where they react to form to form 5-(2-oxo-1- propanoylbutoxy)isophthalonitrile. The outflow is mixed with HCI and 2-hydrazinoethanol from tanks 3 and 4 respectively and pumped through the second plug flow reactor (PFR - Step B) where they react to form to form lersivirine. The outflow is passed to a continuous extraction apparatus 8 which is fed with water and isopropyl acetate from tanks 5 and 6 respectively. The organic extract is switched between two batch crystallisation tanks 9 which are fed with heptanes from tank 7 to assist recrystallisation. The crystalline batches are then filtered (10) and dried (1 1 ) in batch mode.

Example 1

Step A. Preparation of 5-(2-oxo-1-propanoylbutoxy)isophthalonitrile

5-Hydroxyisophthalonitrile and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are combined in acetonitrile in a head tank and the resulting solution is pumped in to a mixing chamber where 4- chloroheptane-3,5-dione is introduced, also by pumping. The combined flow is then rapidly heated and flowed along a tube reactor to effect the desired reaction. After the determined aging time the flow is combined with the step B reagents.

Step B. Preparation of 5-fr3,5-diethyl-1-(2-hvdroxyethyl)-1 /-/-pyrazol-4-ylloxy}isophthalonitrile (lersivirine)

An aqueous hydrochloric acid solution is prepared in a head tank and the resulting solution is pumped in to a mixing chamber where meets the flow from step A. Cooling is applied to remove the heat of reaction. After a short path the reaction flow is combined with an aqueous solution of 2-hydrazinoethanol which is also pumped. The combined flow is then rapidly heated and flowed along a tube reactor to effect the desired reaction. After the determined aging time the flow is combined with pumped solution of aqueous sodium hydroxide and collected in a receiving tank. In batch mode, isopropyl acetate and aqueous sodium carbonate are added to the receiving tank and the phases are mixed. After allowing the mixture to settle the organic phase is separated. The organic phase is washed several times with water and filtered. The solution is then concentrated by distillation to remove water. Further isopropyl acetate is added and the solution is then concentrated by distillation to remove further water. n-Heptane is added and the reaction is seeded and cooled. After cooling, the crystallised solid is granulated, filtered, washed with n-heptane and dried under vacuum to afford lersivirine. If necessary, the lersivirine may be further purified by recrystallisation from isopropyl acetate/n-heptane.

Claims

THAT WHICH IS CLAIMED:

1. A process for the preparation of lersivirine or a pharmaceutically acceptable salt thereof comprising:

A. reacting 5-hydroxyisophthalonitrile and 4-haloheptane-3,5-dione, in the presence of a base, to form 5-(2-oxo-1 -propanoylbutoxy)isophthalonitrile, and

B. reacting 5-(2-oxo-1-propanoylbutoxy)isophthalonitrile and 2- hydrazinoethanol, in the presence of an acid, to form lersivirine, and, optionally,

2. The process of claim 1 wherein the acid is hydrochloric acid.

3. The process of claim 1 or claim 2 wherein the 4-haloheptane-3,5-dione is 4-chloroheptane- 3,5-dione.