WO2016038422A1

WO2016038422A1 - Process for the preparation of optically enriched adrenaline

Info

Publication number: WO2016038422A1
Application number: PCT/IB2014/064407
Authority: WO
Inventors: Guy Piacenza; Emmanuelle QUERON
Original assignee: Rouver Investment S.À.R.L
Priority date: 2014-09-11
Filing date: 2014-09-11
Publication date: 2016-03-17

Abstract

A process for the production of (-)-adrenaline and (-)-adrenaline-L-tartrate is provided. The process provides for a new, efficient and commercially feasible process for the optical resolution of racemic adrenaline. In one aspect, a one pot process for the synthesis of (-)-adrenaline is provided. The process provides a simple and less expensive 5 process that can be used to prepare commercial scale batches of (-)-adrenaline and (-)-adrenaline-L-tartrate of API quality. The process avoids the use of expensive and unpredictable chiral catalysts.

Description

PROCESS FOR THE PREPARATION OF OPTICALLY ENRICHED ADRENALINE

TECHNICAL FIELD

[001] The present invention relates to adrenaline. More particularly, the present invention relates to processes for preparing optically enriched adrenaline and its related salts.

BACKGROUND

[002] Adrenaline is a hormone secreted by the adrenal glands. Adrenaline is known by a variety of names including epinephrine and adrenalin. The chemical name for adrenaline in the U.S. is 1,2-Benzenediol, 4-[l-hydroxy-2-(methylamino)ethyl]-, (R)-;(-)- 3,4-dihydroxy-a-[(methylamino)methyl]benzyl alcohol. Adrenaline, once in the bloodstream, initiates several different responses in various cells in the body. Generally, the collective response to adrenaline is to provide energy to the muscles so that the body can respond to a perceived threat. Adrenaline is used to treat a variety of medical conditions such as cardiac arrest, anaphylaxis, and superficial bleeding.

[003] Adrenaline is a chiral molecule and has two stereoisomers: (-)-adrenaline and (+)-adrenaline (also referred to as the L and D isomers respectively). While sometimes administered as a racemic mixture, the form most commonly used for medical purposes is (-)-adrenaline or pharmaceutically acceptable salt, such as (-)-adrenaline tartrate (also known as 1,2-benzenediol, 4-[l-hydroxy-2-(methylamino)ethyl]-, (R)-, [R-(R*, R*)-2,3- dihydroxybutanedioate (1 : 1) (salt). Although synthetic methods for preparing (-)- adrenaline are known, commercial production offadrenaline is typically accomplished by first synthesizing racemic adrenaline and subsequently resolving the stereoisomers to obtain the (-)-adrenaline. Currently known processes for resolving or producing (-)- adrenaline from racemic adrenaline (or any mixture of (-)-adrenaline and (+)-adrenaline) suffer from a number of disadvantages that make commercial scale production problematic and expensive. This is primarily due to the requirement of a chiral catalyst, which drives the cost and quality of the end product.

[004] Known processes have uncertain reproducibility due to the variation of quality and stability of the catalyst, particularly the Rhodium catalysts. Further, the chiral catalysts required are expensive. Moreover, the known processes that require high pressure, for the hydrogenation step (20bars) for example, are not useful in an industrial setting. [005] Accordingly, there is a need for an improved process for the preparation of (-)-adrenaline and its salts. There is a need for an improved process for commercial scale resolution of (-)-adrenaline from a mixture of (+-) -adrenaline.

SUMMARY

[006] The present invention provides for an efficient and economical process for optically enriching or purifying adrenaline and adrenaline salts. In one aspect, an industrial scale process for the preparation of (-)-adrenaline and (-)-adrenaline-L-tartrate is provided. In one aspect the enantiomeric purity of (-)-adrenaline is > 98.0%. The process may be used to prepare commercial scale batches of (-) -adrenaline and (-)-adrenaline-L- tartrate. The process avoids the use of expensive and unpredictable chiral catalysts typically used for optically purifying (-)-adrenaline and (-)-adrenaline salts.

[007] Accordingly, in one aspect a process preparing of optically enriching or purifying adrenaline or adrenaline tartrate is provided. The process includes

[008] (a) reacting a mixture of (-)-adrenaline and (+)-adrenaline with L(+)- tartaric acid to form adrenaline tartrate; and

[009] (b) contacting the adrenaline tartrate with less than 1 equivalent of ammonium hydroxide.

[0010] According to another aspect of the process the ratio of the mixture of (-)- adrenaline and (+)-adrenaline is about 1: 1, i.e. a racemic mixture. The amount of ammonium hydroxide may be less than 1 equivalent and greater than 0.9 equivalents. In another aspect, the amount of ammonium hydroxide is in the range of 0.92 to 0.94 equivalents.

[0011] In another aspect, the process steps (a) and (b) may be repeated one or more times to further increase the optical purity of the resulting (-)-adrenaline.

[0012] Once purified to the desired optical purity, the (-)-adrenaline may be converted to (-)-adrenaline-L-tartrate by reacting the (-)-adrenaline with L-(+) tartaric acid.

[0013] The process of the invention provides many advantages over known techniques to resolve the stereoisomers of adrenaline. The process of the invention does not require the expensive, unpredictable and unstable chiral catalysts. The process of the invention is efficient even for kilogram sized batches, making the process ideal for the commercial production of adrenaline and adrenaline salts. [0014] These and further aspects and preferred embodiments of the invention are described in the following sections and in the appended claims.

DETAILED DESCRIPTION

[0015] In an aspect of the invention, there are provided processes for the preparation of (-) -adrenaline (Formula I), including derivatives thereof such as salts, in particular (-)-adrenaline-L-tartrate (Formula II). The processes can be completed without the use of any chiral catalysts.

[0016]

[0017] A general preparation of (-)-adrenaline according to embodiments of the present invention proceeds as shown in reaction Scheme I. The processes claimed herein are preferably carried out in suitable solvents which may be readily selected by one of ordinary skill in the art. A given step may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular step may be selected. Preferred solvents for specific steps are discussed in more detail below. [0018]

[0019] Scheme I illustrates the process leading to (-) -adrenaline (Formula I), the compound shown in Formula I. In Scheme I, the starting material is adrenaline. The adrenaline is a mixture of the two stereoisomers of adrenaline, i.e.,(-) -adrenaline and (+)- adrenaline (referred herein generally as starting adrenaline or adrenaline mixture). The starting adrenaline may be a racemic mixture, i.e. the ratio of (-)-adrenaline and (+)- adrenaline is 1: 1. The starting adrenaline, however, need not be racemic and the ratio may be different from 1 : 1. In one embodiment, the process is used to optically purify an adrenaline mixture that is already enriched with a greater amount of (-)-adrenaline than (+)-adrenaline. For the purpose of the invention, the terms "optically purify" and

"optically enrich" are used interchangeably and refer to the process of increasing the amount of a particular stereoisomer from a mixture.

[0020] The process begins with reacting adrenaline with L-(+) tartaric acid in a reactor. The adrenaline is preferably dissolved in a solvent such as, for example, methanol to produce adrenaline tartrate. The solvent is removed by filtration of the salt and then the adrenaline tartrate is contacted with ammonium hydroxide to convert the salt back to adrenaline. The amount of ammonium hydroxide is less than one equivalent (of the adrenaline tartrate). Preferably, the amount of ammonium hydroxide is in the range of less than one equivalent and greater than or equal to 0.9 equivalents. More preferably, the ammonium hydroxide is between 0.92 and 0.94 equivalents. The resulting adrenaline is optically enriched with (-)-adrenaline. In this regard, optically enriched with (-)- adrenaline means that there is a higher ratio of (-)-adrenaline than was present in the adrenaline tartrate starting material.

[0021] Scheme I uses L-(+) tartaric acid to produce the intermediate adrenaline tartrate. Other chiral acids, however, may be used as a substitute. [0022] While not bound to any theory, the use of less than one equivalent of ammonium hydroxide is critical to optically enriching the product with (-)-adrenaline. The use of one equivalent or more will convert the tartrate back to the adrenaline base but will not function to optically enrich the adrenaline with respect to the optical purity of the starting adrenaline tartrate.

[0023] The resulting product, referred herein as crude (-)-adrenaline is then preferably washed and dried. Depending on the desired level of optical purity, the process (of making the adrenaline tartrate and contacting with ammonium hydroxide) can be repeated one or more times on the crude (-)-adrenaline in order to further increase the optical purity of the crude (-) -adrenaline.

[0024] In another embodiment, the crude (-)-adrenaline can optionally be converted to a salt, such as a pharmaceutically acceptable salt. For example, the crude (-)- adrenaline can be converted to a tartrate, as shown in Scheme II.

[0025]

(")- a^ safe - L - artrate

Sdsssts E

[0026] In Scheme II, the crude (-)-adrenaline is reacted with L-(+) tartaric acid in a reactor to produce (-)-adrenaline-L-tartrate (Formula II). The crude (-)-adrenaline is preferably dissolved in a solvent such as, for example, methanol for the reaction. The product is preferably washed and dried. Optionally, the product may be again dissolved in a solvent and refluxed one or more times.

[0027] Optionally, the resulting (-)-adrenaline-L-tartrate (Formula II) may, if desired, be converted back to the (-) -adrenaline base. For example, the (-)-adrenaline-L- tartrate can be converted to the base according to Scheme III. [0028]

Fomsiia I]

[0029] In Scheme III, the (-)-adrenaline-L-tartrate (Formula II), preferably the product from Scheme II, is contacted with aqueous ammonium hydroxide to convert the salt to the base (-)-adrenaline. As in Scheme I, the amount of ammonium hydroxide is less than one equivalent. Preferably, the amount of ammonium hydroxide is in the range of less than one equivalent and greater than or equal to 0.9 equivalents. More preferably, the ammonium hydroxide is between 0.92 and 0.94 equivalents. Although, to the extent that the optical purity of the (-)-adrenaline-L-tartrate is satisfactory, the amount of ammonium hydroxide can be one equivalent or more at this step to maximize the yield. The use of ammonium hydroxide in an amount of one equivalent or more will not affect the optical purity one way or the other. The resulting (-)-adrenaline may then optionally be purified by typical means known to those skilled in the art.

[0030] The process of the invention described in Scheme I begins with a starting material of a mixture of the two stereoisomers of adrenaline, i.e., (-) -adrenaline and (+)- adrenaline. While the process of the invention can be applied to any such mixture regardless of the source and regardless of the ratio of (-)-adrenaline to (+)-adrenaline, Scheme IV provides an embodiment where the starting material is synthesized and produces a racemic mixture of adrenaline. [0031]

[0032] Scheme IV shows one synthetic pathway to racemic adrenaline which may be used in Scheme I and optionally in Schemes II and III. Step 1 of the reaction proceeds by aqueous methylamine on CDHA (2-Chloro-3',4'-dihydroxyacetophenone) to produce adrenalone hydrochloride. Step 2 of the reaction is a hydrogenation of adrenalone hydrochloride to produce racemic adrenaline. Additional details of this embodiment for the synthesis of racemic adrenaline are provided below in the Examples.

EXAMPLES

[0033] Certain specific aspects and embodiments of the present disclosure will be explained in more detail with reference to the following examples, which are provided solely for purposes of illustration and are not to be construed as limiting the scope of the disclosure in any manner. The amounts used do not represent a limitation and the process can be scaled up to produce larger batches of (-)-adrenaline and (-)-adrenaline-L-tartrate. Example 1

[0034] Optical enrichment of a mixture of (-) -adrenaline and (+)-adrenaline

[0035] In a reactor 25 ± 2 L of methanol was added and regulated at a temperature of 20°C. About 2.5 kg of racemic adrenaline was added and agitated. The reactor was placed under nitrogen and protected from light. 4.15 ± 1.00 kg of tartaric acid was added and agitated for at least 20 hours at a temperature of about 20°C resulting in a suspension. The suspension was filtered, washed with 2.5 ± 0.5 L of methanol and dried under vacuum at 50°C to produce adrenaline tartrate. The optical purity of the adrenaline tartrate was > 70% (-)-adrenaline as measured by chiral HPLC. The loss on drying of the product as measured by halogen desiccator was < 2.0%.

[0036] The dried adrenaline tartrate was then placed in the reactor regulated at a temperature of 20°C. 12 ± 2 L of purified water was added and the mixture agitated. The reactor was placed under nitrogen and protected from light. The mixture was then filtered for at least 30 minutes through a 0.2 μπι cartridge to remove insoluble particles.

[0037] The mixture was cooled down to a temperature of 10°C ± 5°C. Then, 0.81 ± 0.02 kg of aqueous ammonium hydroxide 28% (0.92 equivalents) was added over 20 minutes at a temperature of 10°C ± 5°C. The suspension was agitated for 3 hours at the same temperature. The suspension was then filtered, washed with 1.25 ± 0.04 L of purified water and 1.25 ± 0.04 L of methanol and dried under vacuum at 50 °C to produce crude (-)-adrenaline. The optical purity of the crude (-) -adrenaline was > 80% (-)- adrenaline as measured by chiral HPLC. The water content of the product as measured by Karl Fischer was < 2%.

[0038] The crude (-)-adrenaline batch size was about 0.68 kg; the molar yield was about 27%.

Example 2

[0039] Preparation of (-)-adrenaline-L-tartrate

[0040] In the reactor, about 0.68 kg of the crude (-)-adrenaline is mixed with 6.8 ± 0.6 L of methanol at a temperature of 20°C and agitated. 1.13 ± 0.02 kg of L(+)-tartaric acid is added and the mixture is agitated for at least 20 hours at 20°C. The suspension is then filtered, washed with 0.34 ± 0.10 L of methanol and dried under vacuum at 50°C resulting in (-)-adrenaline-L-tartrate. The loss on drying of the product is < 2.0%. The optical purity of the (-)-adrenaline-L-tartrate was > 97.0% as measured by chiral HPLC.

[0041] Purification of (-)-adrenaline-L-tartrate.

[0042] The (-)-adrenaline-L-tartrate product obtained was then purified. The product was first introduced in the reactor regulated at a temperature of 20°C with a mixture of 6.9 ± 0.2 L of methanol / 0.36 ± 0.10 L of purified water to form a suspension. The suspension was agitated at 20°C, heated at reflux for 30 minutes and then cooled down to a temperature of 20°C with a slope of -0.5°C/ minute. The suspension was filtered and washed with 0.52 ± 0.10 L of methanol and dried under vacuum at 50°C. The loss on drying was < 2.0%.

[0043] The product was once again introduced in the reactor regulated at a temperature of 20°C with a mixture of 5.5 ± 0.2 L of methanol / 0.29 ± 0.10 L of purified water. The suspension was agitated at 20°C, heated at reflux for 30 minutes and cooled down to a temperature of 20°C with a slope of -0.5°C/ minute. The suspension was filtered and washed with 0.41 ± 0.10 L of methanol and dried under vacuum at 50°C. The loss on drying < 0.30%. The final batch size was about 0.67 kg with a molar yield of about 54%. The optical purity of the (-)-adrenaline-L-tartrate API was > 98.0% as measured by chiral HPLC.

Example 3

[0044] Preparation of API grade (-)-adrenaline

[0045] This last step was performed to convert the (-)-adrenaline-L-tartrate back to (-)-adrenaline suitable for use as an API (active pharmaceutical ingredient). In the reactor about 0.50 kg of (-)-adrenaline-L-tartrate from the last step is added to 2.5 ± 0.5 L of purified water regulated at a temperature of 20°C. The reactor is placed under nitrogen and protected from light. The mixture is agitated and filtered for at least 10 minutes through a 0.2 μπι cartridge to remove insoluble particles. Then the mixture is cooled down to a temperature of 10°C ± 5°C. Aqueous ammonium hydroxide 28% was added after about 20 minutes at a temperature of 10°C ± 5°C until the pH of the mixture is greater than 9 producing a suspension. The suspension was agitated for about 3 hours at the same temperature, then filtered, washed with 0.25 ± 0.05 L of purified water and 0.25 ± 0.05 L of methanol and dried under vacuum at 50 °C. The resulting (-)-adrenaline had an optical purity was > 98.0% (-)-adrenaline as measured by chiral HPLC. The water content as measured by Karl Fischer was < 0.5%. The final batch size was about 0.26 kg. The molar yield was about 93%. The (-)-adrenaline obtained was packed in double PE bags with desiccant in metallic drums. Drums are stored at room temperature.

Example 4

[0046] Synthesis of racemic adrenaline

[0047] In the reactor, 10.0 ± 0.5 kg of the starting material 2-chloro-3',4'- dihydroxyacetophenone (CDHA) was mixed with 60 ± 5 L of acetonitrile and regulated at a temperature of 20°C. The mixture was agitated at 100 rpm and cooled down to a temperature of 0°C ± 5°C. 20.6 ± 0.5 kg of aqueous methylamine 40% was introduced in 30 minutes minimum at a temperature of 5°C ± 5°C. The mixture was heated at a regulated temperature of 35°C ± 5°C and kept in contact at this temperature for at least 2 hours and 30 minutes.

[0048] The mixture was cooled down to a temperature of 10°C ± 5°C with a slope of -0.3°C per minute. When the temperature was reached, 20 ± 5 L of acetonitrile was added and the cooling was maintained. The suspension was filtered under a filter-dryer and washed with 20 ± 5 L of acetonitrile. The product was dried under vacuum at 20°C for at least 1 hour.

[0049] In a filter-dryer regulated at a temperature of 20°C, 40 ± 5 L of ethanol was added to the product. After contact under brewing at 20 rpm for at least 1 hour at 20°C, the suspension was filtered and washed with 20 ± 5 L of ethanol before drying under vacuum at 60°C. The crude adrenalone was obtained. The loss on drying was < 5%.

[0050] In the reactor regulated at a temperature of 20°C, the crude product obtained was introduced, then 35 ± 4 kg of methanol was added and the mixture agitated at 100 rpm. The mixture was cooled down to a temperature of 10°C ± 5°C. 9.65 ± 0.5 kg of HC1 isopropanol was introduced over 30 minutes minimum at 10°C ± 5°C, heated at a temperature of 20°C ± 5°C and kept in contact at this temperature for at least 1 hour.

[0051] The obtained suspension is filtered under a filter dryer, washed with 15 ± 5 L of methanol and then dried under vacuum at 60°C. The loss on drying was < 1.0%. The adrenalone hydrochloride batch size was about 6.5kg with a molar yield of about 56%.

[0052] The first isolated intermediate adrenalone hydrochloride is obtained and packed in double PE bags with desiccant in HDPE drums. Drums are stored at room temperature.

[0053] In the reactor, about 6.5 kg of the adrenalone hydrochloride obtained in the previous step is added and regulated at a temperature of 15°C. 15 ± 5 L of purified water and 50 ± 5 L of methanol was added and agitated at 100 rpm and regulated to a temperature of 10°C. 0.13 ± 0.07 kg of palladium hydroxide was added and agitated at 150 rpm. The reactor was put under hydrogen at 0.2 bars and heated at a regulated temperature of 30°C ± 10°C and put in contact with the hydrogen by agitation for at least 16 hours.

[0054] Then, the mixture is cooled down to a temperature of 20°C ± 5°C and 4.0 ± 0.1 kg of dicalite are added and the suspension is filtered in the crystallization reactor regulated at a temperature of 20°C, washed with 20 ± 5 L of methanol. [0055] The obtained filtrate was filtered twice for at least 1.5 hours each time under an activated carbon cartridge. Each cartridge was washed with 10 ± 5 L of methanol and the crystallization reactor was cooled at a temperature of 10 °C ± 5°C. 3.8 ± 0.5 kg of aqueous ammonium hydroxide 28% was added over at least 30 minutes and heated to 25 ± 5°C and put in contact under agitation for at least 1 hour.

[0056] The obtained suspension is filtered in the filter-dryer, washed with 20 ± 5 L of methanol and dried under vacuum at 50°C. The water content as measured by KF was < 1%. The resulting racemic adrenaline had a batch size of about 3.5 kg with a molar yield of about 64%.

[0057] The isolated intermediate racemic adrenaline was then optically purified by the processes described above.

[0058] Unless defined otherwise, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Any methods and materials similar or equivalent to those described herein also can be used in the practice or testing of the present disclosure.

[0059] It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural references unless the context clearly dictates otherwise.

[0060] While the present disclosure has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

1. A process for the preparation of optically enriched adrenaline or adrenaline tartrate comprising the steps of:

(a) reacting a mixture of (-)-adrenaline and (+)-adrenaline with L(+)-tartaric acid to form adrenaline tartrate;

(b) contacting the adrenaline tartrate with less than 1 equivalent of ammonium hydroxide.

2. A process according to claim 1, wherein the ratio of the mixture of (-)-adrenaline and (+)-adrenaline is about 1 : 1.

3. A process according to claim 1, wherein the amount of ammonium hydroxide is in the range of 0.9 to 1.0 equivalent.

4. A process according to claim 1, wherein the amount of ammonium hydroxide is in the range of 0.92 to 0.94 equivalents.

5. A process according to claim 1, further comprising repeating steps (a) and (b) one or more times.

6. A process according to claim 1, comprising the additional step of reacting the (-)- adrenaline with L(+)-tartaric to produce (-)-adrenaline-L-tartrate.

7. A process for optically purifying a mixture of (-)-adrenaline and (+)-adrenaline comprising the steps of (a) reacting the mixture with a chiral acid to form adrenaline salt;

(b) contacting the adrenaline salt with less than 1 equivalent of ammonium hydroxide.

8. A process according to claim 7, wherein the chiral acid is L(+)-tartaric acid.

9. A process according to claim 7, wherein the ratio of the mixture of (-)-adrenaline and (+)-adrenaline is about 1 : 1.

10. A process according to claim 7, wherein the amount of ammonium hydroxide is in the range of 0.9 to 1.0 equivalent.

11. A process according to claim 7, wherein the amount of ammonium hydroxide is in the range of 0.92 to 0.94 equivalents.

12. A process according to claim 7, further comprising repeating steps (a) and (b) one or more times.

13. A process according to claim 7, comprising the additional step of reacting the (-)- adrenaline with L(+)-tartaric to produce (-)-adrenaline-L-tartrate.