WO2013050873A1 - Process for the preparation of lersivirine - Google Patents
Process for the preparation of lersivirine Download PDFInfo
- Publication number
- WO2013050873A1 WO2013050873A1 PCT/IB2012/002449 IB2012002449W WO2013050873A1 WO 2013050873 A1 WO2013050873 A1 WO 2013050873A1 IB 2012002449 W IB2012002449 W IB 2012002449W WO 2013050873 A1 WO2013050873 A1 WO 2013050873A1
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- WO
- WIPO (PCT)
- Prior art keywords
- isophthalonitrile
- reaction
- stage
- pyrazol
- diethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
Definitions
- the present invention is directed to a process for the preparation of lersivirine (a non- nucleoside reverse transcriptase inhibitor (NNRTi) useful for the treatment of HIV infection).
- lersivirine a non- nucleoside reverse transcriptase inhibitor (NNRTi) useful for the treatment of HIV infection.
- NRTi non- nucleoside reverse transcriptase inhibitor
- WO02/085860 discloses a process for the synthesis of lersivirine consisting of the two steps shown below.
- 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 1 19 (with reference to Example 1 14) 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
- step (a) comprises a first stage wherein the reaction is controlled so as to maintain a reaction temperature between 15-30 °C and a second stage wherein the reaction is controlled so as to maintain a reaction temperature between 40-70 °C.
- the first stage is controlled so as to maintain a reaction temperature between 20-25 °C.
- the second stage is controlled so as to maintain a reaction temperature of about 60 °C.
- This stage preferably takes place at a temperature between 15-30 °C, more preferably 20-25 °C.
- the reaction temperature may be controlled by (i) adjusting the rate of addition of one reagent to the other; and/or (ii) adjusting the rate of agitation (e.g. stirring) of the reaction mixture; and/or (iii) cooling the reaction mixture.
- the intermediate compound shown above converts relatively slowly to form 5- ⁇ [3,5-diethyl-1 -(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy ⁇ isophthalonitrile.
- This stage preferably takes place at a temperature between 40-70 °C, more preferably about 60 °C.
- the reaction temperature may be controlled by heating the reaction mixture.
- the principal advantage of maintaining a reaction temperature between 15-30 °C for the first stage of step (a) is that the reaction proceeds without excessive formation of unwanted byproducts (in particular 5-hydroxyisophthalonitrile).
- the principal advantage of maintaining a reaction temperature between 40-70 °C for the second stage of step (a) is that the reaction proceeds without excessive formation of unwanted by-products (in particular the organic ester of 5- ⁇ [3,5- diethyl-1 -(2-hydroxyethyl)-1 H-pyrazol-4-yl]oxy ⁇ isophthalonitrile where an organic acid is used in step (a)).
- the present invention provides a process for the synthesis of lersivirine of high purity (>99.5wt%) in good overall yield (87% isolated yield) with manageable levels of undesirable by-products ( ⁇ 0.22% in total), in particular very low levels of the acetate ester of lersivirine
- Step (a) 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
- step (a) A further advantage of maintaining specified reaction temperatures for step (a) is that the reaction may be performed using acetic acid as the acid for step (a) which is preferred from an environmental standpoint.
- the crystallised solid is granulated, filtered, washed with n-heptane and dried under vacuum to afford 5- ⁇ [3,5-diethyl-1 -(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy ⁇ isophthalonitrile.
- the 5- ⁇ [3,5-diethyl-1-(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy ⁇ isophthalonitrile may be further purified by recrystallisation from isopropyl acetate/n-heptane.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process for the preparation of lersivirine or a pharmaceutically acceptable salt thereof comprising: (a) reacting 5-(2-oxo-1-propanoylbutoxy)isophthalonitrile and 2- hydrazinoethanol, in the presence of an acid, to form 5-{[3,5-diethyl-1 -(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy}isophthalonitrile, and optionally, (b) reacting 5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4- yl]oxy}isophthalonitrile with a suitable reagent so as to form a pharmaceutically acceptable salt of 5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H- pyrazol-4-yl]oxy}isophthalonitrile, characterised in that step (a) comprises a first stage wherein the reaction is controlled so as to maintain a reaction temperature between 15-30 °C and a second stage wherein the reaction is controlled so as to maintain a reaction temperature between 40-70 °C.
Description
PROCESS FOR THE PREPARATION OF LERSIVIRINE
The present invention is directed to a process for the preparation of lersivirine (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 H- pyrazol-4-yl]oxy}isophthalonitrile.
WO02/085860 discloses a process for the synthesis of lersivirine consisting of the two steps shown below.
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 1 19 (with reference to Example 1 14) 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-(2-oxo-1-propanoylbutoxy)isophthalonitrile and 2- hydrazinoethanol, in the presence of an acid, to form 5-{[3,5-diethyl-1-(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy}isophthalonitrile, and optionally,
(b) reacting 5-{[3,5-diethyl-1 -(2-hydroxyethyl)-1 H-pyrazol-4- yl]oxy}isophthalonitrile with a suitable reagent so as to form a
pharmaceutically acceptable salt of 5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H- pyrazol-4-yl]oxy}isophthalonitrile,
characterised in that step (a) comprises a first stage wherein the reaction is controlled so as to maintain a reaction temperature between 15-30 °C and a second stage wherein the reaction is controlled so as to maintain a reaction temperature between 40-70 °C.
More preferably, the first stage is controlled so as to maintain a reaction temperature between 20-25 °C.
More preferably, the second stage is controlled so as to maintain a reaction temperature of about 60 °C.
Without wishing to be bound by any particular theory, it is believed that in the first stage 5- (2-OXO-1 -propanoylbutoxy)isophthalonitrile and 2-hydrazinoethanol react rapidly (and
exothermically) to form the intermediate compound shown below. This stage preferably takes place at a temperature between 15-30 °C, more preferably 20-25 °C.
In the first stage, the reaction temperature may be controlled by (i) adjusting the rate of addition of one reagent to the other; and/or (ii) adjusting the rate of agitation (e.g. stirring) of the reaction mixture; and/or (iii) cooling the reaction mixture.
Without wishing to be bound by any particular theory, it is believed that in the second stage, the intermediate compound shown above converts relatively slowly to form 5-{[3,5-diethyl-1 -(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy}isophthalonitrile. This stage preferably takes place at a temperature between 40-70 °C, more preferably about 60 °C.
In the second stage, the reaction temperature may be controlled by heating the reaction mixture.
The principal advantage of maintaining a reaction temperature between 15-30 °C for the first stage of step (a) is that the reaction proceeds without excessive formation of unwanted byproducts (in particular 5-hydroxyisophthalonitrile). The principal advantage of maintaining a reaction temperature between 40-70 °C for the second stage of step (a) is that the reaction proceeds without excessive formation of unwanted by-products (in particular the organic ester of 5-{[3,5- diethyl-1 -(2-hydroxyethyl)-1 H-pyrazol-4-yl]oxy}isophthalonitrile where an organic acid is used in step (a)). Thus, the present invention provides a process for the synthesis of lersivirine of high purity (>99.5wt%) in good overall yield (87% isolated yield) with manageable levels of undesirable by-products (<0.22% in total), in particular very low levels of the acetate ester of lersivirine
(<0.08%) and very low levels of the starting material 5-hydroxyisophthalonitrile (<0.05%, not detected).
Step (a) 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. A further advantage of maintaining specified reaction temperatures for step (a) is that the reaction may be performed using acetic acid as the acid for step (a) which is preferred from an environmental standpoint.
Example 1
Preparation of 5-(2-oxo-1-propanoylbutoxy)isophthalonitrile
5-Hydroxyisophthalonitrile and triethylamine are combined in 2-methyltetrahydrofuran and heated to reflux, 4-chloroheptane-3,5-dione is then added and the reaction is refluxed until complete. The reaction is cooled and acetic acid and water are added. After allowing the mixture to settle the organic phase is separated and reduced in volume by distillation, propan-2-ol is added and the overall volume is again reduced by distillation. The reaction is seeded and after cooling, the crystallised solid is granulated, filtered, washed with propan-2-ol and dried under vacuum to afford 5-(2-oxo-1 -propanoylbutoxy)isophthalonitrile.
Preparation of 5-{r3,5-diethyl-1-(2-hvdroxyethyl)-1 /-/-pyrazol-4-ylloxy}isophthalonitrile
5-(2-Oxo-1-propanoylbutoxy)isophthalonitrile and acetic acid are combined in isopropyl acetate and are warmed. An aqueous solution of 2-hydrazinoethanol is added at a sufficient rate and with
sufficient mixing to ensure that the reaction temperature is maintained between 20-25 °C during mixing. When mixing is complete, the reaction mixture is warmed to about 60 °C and held at this temperature until reaction is complete. Water and aqueous sodium hydroxide are added to the reaction and after allowing the mixture to settle the organic phase is separated. The organic phase is washed with water and filtered. The solution is then concentrated by distillation to remove 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 5-{[3,5-diethyl-1 -(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy}isophthalonitrile. If necessary, the 5-{[3,5-diethyl-1-(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy}isophthalonitrile may be further purified by recrystallisation from isopropyl acetate/n-heptane.
Claims
1. A process for the preparation of lersivirine or a pharmaceutically acceptable salt thereof comprising:
(a) reacting 5-(2-oxo-1-propanoylbutoxy)isophthalonitrile and 2- hydrazinoethanol, in the presence of an acid, to form 5-{[3,5-diethyl-1 -(2- hydroxyethyl)-1 H-pyrazol-4-yl]oxy}isophthalonitrile, and optionally,
(b) reacting 5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4- yl]oxy}isophthalonitrile with a suitable reagent so as to form a
pharmaceutically acceptable salt of 5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H- pyrazol-4-yl]oxy}isophthalonitrile,
characterised in that step (a) comprises a first stage wherein the reaction is controlled so as to maintain a reaction temperature between 15-30 °C and a second stage wherein the reaction is controlled so as to maintain a reaction temperature between 40-70 °C.
2. The process of claim 1 wherein the first stage is controlled so as to maintain a reaction temperature between 20-25 °C.
3. The process of claim 1 or claim 2 wherein the second stage is controlled so as to maintain a reaction temperature of about 60 °C.
4. The process of any preceding claim wherein the acid is acetic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161544393P | 2011-10-07 | 2011-10-07 | |
| US61/544,393 | 2011-10-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013050873A1 true WO2013050873A1 (en) | 2013-04-11 |
Family
ID=47436122
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2012/002449 Ceased WO2013050873A1 (en) | 2011-10-07 | 2012-10-04 | Process for the preparation of lersivirine |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2013050873A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002085860A1 (en) | 2001-04-10 | 2002-10-31 | Pfizer Limited | Pyrazole derivatives for treating hiv |
-
2012
- 2012-10-04 WO PCT/IB2012/002449 patent/WO2013050873A1/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002085860A1 (en) | 2001-04-10 | 2002-10-31 | Pfizer Limited | Pyrazole derivatives for treating hiv |
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