IE20000051A1

IE20000051A1 - Melperone

Info

Publication number: IE20000051A1
Application number: IE20000051A
Authority: IE
Inventors: Helmut Schickaneder; Aggelos Nikolopoulos; Justin Ahern
Original assignee: Russinsky Ltd
Priority date: 1999-02-01
Filing date: 2000-01-21
Publication date: 2000-09-06
Also published as: GB0001785D0; GB2346143A; GB2346143B

Abstract

A novel form of Melperone is obtained in solid crystalline form as the base in high yield and high purity from a crude reaction mixture. Crystalline Melperone base may be used directly in various pharmaceutical formulations or it may be converted into very pure pharmaceutically acceptable salts such as Melperone hydrochloride. The process for preparing Melperone or salts thereof comprises converting a Melperone precursor into a Melperone intermediate ketal and converting the ketal intermediate into Melperone base or a salt thereof.

Description

“MELPERONE” A novel form of Melperone is obtained in solid crystalline form as the base in high yield and high purity from a crude reaction mixture. Crystalline Melperone base may be used directly in various pharmaceutical formulations or it may be converted into very pure pharmaceutically acceptable salts such as Melperone hydrochloride. The process for preparing Melperone or salts thereof comprises converting a Melperone precursor into a Melperone intermediate ketal and converting the ketal intermediate into Melperone base or a salt thereof.

IE 000051 The invention relates to a novel form of Melperone and a process for the manufacture thereof. The invention also relates to the use of the new form of Melperone as a pharmaceutical.

Melperone is l-(4-fluorophenyl)-4-(4-methyl-l-piperidinyl)-l-butanone, a 10 butyrophenone derivative of formula (I): Melperone is disclosed in US 3 816 433. It is a neuroleptic agent that is structurally related to Haloperidol. It is used for the treatment of dementia, schizophrenia, mania or hallucinations. Typically Melperone is produced in the form of the hydrochloride salt which is stable and has a high melting point.

Melperone base is described in the literature as a liquid with a boiling point of bpo.i = 120-125°C (Merck Index 12th edition [1996], page 993).

According to US 3 816 433 Melperone base is obtained by reaction of 4-chloro-pfluorobutyrophenone (II) with 4-methylpiperidine (III) in the presence of potassium iodide (Scheme 1).

„ OPEN YG PUBLIC INSPECTION I UNDER J I SECTION 28 AND RULE 23 S [·'·· I nririunm...... .............................,........... ................. i 7 I NT CL ; ijNL NO IE 000051 RUSS17/C Scheme 1 Generally this process is inconvenient as a number of by-products are formed, which are difficult to remove. The crude product is distilled under vacuum yielding Melperone base as an oil, which is further purified by conversion into the hydrochloride salt. For final purification the Melperone hydrochloride salt is recrystallised.

Statements of the Invention We have unexpectedly found that Melperone can be obtained in a solid crystalline form as the base in high yield and high purity from a crude reaction mixture. The crystalline base is remarkably stable and has a surprisingly high melting point. Crystalline Melperone base may be used directly in various pharmaceutical formulations. Solid crystalline Melperone base rather than an oil base or hydrochloride salt is especially suitable in formulations for percutaneous use. Crystalline Melperone base can also be converted into veiy pure pharmaceutically acceptable salts such as Melperone hydrochloride.

According to the invention there is provided Melperone base in a solid form, especially Melperone base in a crystalline form.

The invention also provides the use of Melperone base in a solid form in the manufacture of a medicament.

IE 000051 RUSS17/C -3The invention further provides a pharmaceutical formulation comprising Melperone base in a solid form and a suitable carrier and/or excipient. Preferably the Melperone base is in a crystalline form.

Ideally the formulation is in a form for percutaneous use, especially a transdermal patch.

The invention also provides a transdermal therapeutic system comprising Melperone base in a crystalline form and optional further substances. The transdermal system typically has a layered structure consisting of a backing layer which is substantially impermeable to Melperone base and a release layer. The release layer may be one or several matrix layers, at least one of the matrix layers containing Melperone base in crystalline form.

The invention also provides a process for preparing Melperone or salts thereof comprising the steps of:converting a Melperone precursor into a Melperone intermediate ketal; and converting the ketal intermediate into Melperone base or a salt thereof.

Preferably the Melperone precursor is ketone obtained from a Friedel Crafts reaction.

The Friedel Crafts reaction product is preferably a ketone of formula II of Scheme 2.

In a preferred embodiment of the invention the ketal intermediate is a compound of the formula IV of scheme 2.

IE 000051 RUSS17/C -4In one embodiment of the invention the ketal intermediate is deprotected to form Melperone base in a solid form.

In one case the ketal intermediate is deprotected to form Melperone base which is converted directly into a salt of Melperone base.

The invention further provides Melperone base in a solid form whenever prepared by a process of the invention.

In addition, the invention provides salts of Melperone whenever prepared by a process of the invention.

The invention further provides a ketal intermediate of Melperone. Preferably the intermediate is a ketal of formula IV or V in scheme 2.

The pharmaceutical may be in the form of tablets, pellets, capsules, transdermal plasters, solutions or suppositories.

Detailed Description of the Invention In the invention Melperone base is crystallised typically as a white to off-white solid from a crude reaction mixture. This is of major advantage both in simplifying the production process and in enabling the production of high quality Melperone hydrochloride and other pharmaceutically acceptable salts. No purification of Melperone base is needed. The crystalline base may also be used as such for various types of medical applications.

The current invention will be more clearly understood from the following reaction schemes and the examples given below.

IE 000051 RUSS17/C Scheme 2: R is represented by alkyl groups, preferably by CrC4 chains. A cyclic ketal may 5 also be formed wherein the bridging unit R-R is represented by -(CH2)n- and n is preferably 2 or 3.

Step 1: A Friedel-Crafts reaction using a Lewis acid, e.g. Aluminium chloride, is performed furnishing compound (II) in quantitative yield.

Step 2: The Friedel-Crafts product ketone (II) is protected as a ketal of type (IV) in quantitative yield. It was found that this is of major advantage over the patent method described in US 3 816 433 in terms final product purity and yield.

Step 3: A substitution reaction is performed under basic conditions in the presence of a phase transfer catalyst furnishing compound (V).

The ketal protected Melperone base (V) can then optionally be converted into Melperone base (I) or directly in a one-pot process into a pharmaceutically acceptable salt of Melperone base, e.g. into the hydrochloride (la) as described in Scheme 3.

IE 000051 RUSS17/C Scheme 3 Step 4: The coupling product (V) is deprotected under acidic conditions liberating Melperone base (I) which may be crystallised as the free base at this stage.

Step 5: Melperone base (I) is converted into a pharmaceutically acceptable salt, e.g. by treatment with hydrochloric acid into the hydrochloride (la).

Optionally step 4 and 5 can be combined converting ketal (V) in a one-pot process into a pharmaceutically acceptable salt. By reaction with an excess of hydrochloric acid the hydrochloride salt of Melperone base can be crystallised.

If very pure crystalline Melperone base is required the combined step 4 and 5 process may he performed first. Melperone base may then be re-liberated from its hydrochloride salt (la) by treatment with a base and final crystallisation.

IE 000051 RUSS17/C -7 Example 1 Preparation of 4-Chloro-p-fluorobutyrophenone (Step 1) A vessel is charged with 501 of fluorobenzene and 30-35 1 of a suitable solvent are added. The solvent is preferably ethylendichloride. The mixture is agitated and cooled, preferably to a temperature between 0°C and 10°C. 72.5 kg of anhydrous aluminium chloride are added prior to the addition of 55 1 of 4-Chlorobutyryl chloride. The temperature is kept ideally below 20°C during addition time. Stirring is continued preferably for 10-15 hours at ambient conditions. The mixture is subsequently quenched with an aqueous hydrochloride solution and basified with 30% sodium hydroxide solution. The organic phase is separated and the solvent removed furnishing the crude product in quantitative yield. The product is suitable for the next reaction step without further purification.

FT-IR: v [cm!] — 2964, 1686, 1598, 1507, 1410, 1365, 1321, 1228, 1157, 836. !H-NMR (270 MHz, CDC13): δ = 2.15-2.25 (m, 2H; CH2), 3.10-3.17 (m, 2H; CH2), 3.64-3.70 (m, 2H; CH2), 7.08-7.16 (m, 2H; H^,), 7.96-8.03 (m, 2H; H^,).

Example 2 Preparation of l-(4-Fluorophenyl')-l,l-dimethoxy-4-chlorobutane (Step 2) A vessel is charged with 50 kg of crude 4-Chloro-p-fluorobutyrophenone (Example 1), 65-70 1 of trimethoxymethane and approximately 20 1 of methanol. 250-300 ml of concentrated sulfuric acid are added. The mixture is agitated for several hours at a temperature preferably between 20 and 30°C and basified with 4-5 1 of triethylamine. The solvent is distilled off under reduced pressure. The crude product is taken up in toluene or any other suitable solvent and a basic wash is performed. After phase separation and removal of the organic solvent the crude product is obtained in quantitative yield.

IE 000051 RUSS17/C -8FT-IR: v[cm·'] = 2945, 2826, 1600, 1503, 1449, 1304, 1223, 1155, 1128, 1082, 1042, 956, 839,580.

Example 3 Preparation of Melperone Base (Step 3 and 4) Step 3: 18-19 kg of sodium hydroxide are dissolved in water to give 5-50% solution, preferably a concentration of 10-20% is prepared. 20 1 of 4Methylpiperidine and a suitable phase transfer catalyst, e.g. 0.8-1 kg of tetrabutyl ammoniumhydrogensulfate are added. The mixture is agitated and heated, preferably to a temperature of 90-105°C. 50 kg of crude l-(4-Fluorophenyl)-l,ldimethoxy-4-chlorobutane (Example 2) are added. The mixture is kept under reflux for 1-10 hours; the preferred reaction time is 7-9 hours. The aqueous layer is separated from the product phase. Optionally unreacted starting material may be removed by distillation under atmospheric pressure or vacuum conditions from the product phase.

Step 4: The intermediate Melperone ketal is deprotected by treatment with acid according to general standard procedures. The mixture is then re-basified with a suitable base such as sodium hydroxide. The aqueous phase is eliminated and Melperone base is crystallised from the organic layer by addition of a suitable solvent, e.g. hexane, heptane or petroleum ether. If necessary seeding material may be added and the solution may be chilled to initiate crystallisation. The overall yield for step 3 and 4 is typically >60%. If required the product can be recrystallised from petroleum ether or any other suitable solvent. (Analytical data for Melperone base are given in Example 5).

IE 000051 RUSSI7/C -9Example 4 Preparation of Melperone hydrochloride from crystalline Melperone base (Step 51 1.00 kg of crystalline Melperone base (Example 3) is dissolved in a suitable solvent such as 3.5-41 of ethyl acetate. The solution is cooled preferably to 0-10°C and acidified with HC1 gas. The mixture is agitated until crystallisation is complete. The product is filtered off and dried under vacuum. The yield is typically >80%.

Mp.: 206-210°C.

FT-IR (KBr): vfcm1] = 2933, 2539, 2485, 1689, 1599, 1509, 1286, 1230, 1212, 1160, 840.

'H-NMR (270 MHz, d^DMSO): δ = 0.93 (d, 3H, CH3), 1.54-1.78 (m, 5H; CH, CH2), 2.04-2.09 (m, 2H; CH2), 2.84-3.06 (m, 4H; CH2), 3.19-3.39 (m, 4H; CH2), 7.36-7.42 (m, 2H, H^), 8.06-8.12 (m, 2H; H^).

Alternatively step 4 and 5 of the reaction sequence can be combined for the preparation of Melperone hydrochloride: The crude Melperone ketal obtained according to Example 3 / Step 3 is taken up in a suitable solvent such as ethyl acetate. The mixture is acidified with HC1 gas in the presence of some water and agitated until product precipitation is complete. The overall yield for the two steps is typically >70%.

Example 5 Preparation of crystalline Melperone base from Melperone hydrochloride 3.00 kg of Melperone hydrochloride are dissolved in 4.5-5 1 of water, preferably under gentle heating. A suitable organic solvent is added, typically 6-7 1 of IE 000051 RUSS17/C -10petroleum ether. The mixture is basified with 30% sodium hydroxide solution. The organic phase is separated from the aqueous layer. Melperone base crystallises from the organic phase as a white to off-white precipitate. Optionally the volume may be reduced prior to crystallisation and seeding material may be used to initiate crystallisation. If necessary the product may be re-crystallised for further purification from petroleum ether or any other suitable solvent. The product is filtered off and dried under vacuum. Typically a yield of >80% and a purity >99% is obtained.

Mp.: 79-80°C.

FT-ER. (KBr): vLcm4] = 2946, 2812, 2759, 1681, 1596, 1507, 1364, 1270, 1225, 1200, 1169, 1125,985,826.

Microanalysis: calc.: C: 72.97 H: 8.42 N: 5.32 found: C: 72.92 H: 8.67 N: 5.54 Ή-NMR (270 MHz, CDC13): δ = 0.85 (d, 3H; CH3), 1.04-1.22 (m, 2H; CH2), 1.23-1.40 (m, 1H; CH), 1.56-1.61 (m, 2H; CH2), 1.86-1.99 (m, 4H; CH2), 2.34-2.40 (m, 2H; CH2), 2.83-2.99 (m, 4H; CH2), 7.07-7.14 (m, 2H, H^), 7.96-8.04 (m, 2H, Haryl).

The Melperone base in a solid crystalline form is obtained in high yield and at a high purity level from a crude reaction mixture. The crystalline base is remarkably stable and has a high melting point. Crystalline Melperone base may be used directly in various pharmaceutical agents, especially as a neurleptic agent used for the treatment of dementia, schizophrenia, mania or hallucinations. Solid crystalline Melperone base is especially suitable in formulations for percutaneous use, especially in a transdermal patch.

IE 000051 RUSS17/C -11The invention is not limited to the embodiments hereinbefore described which may be varied in detail.

Claims

1. Melperone base in a solid form.

2. Melperone base in a crystalline form.

3. The use of Melperone base in a solid form in the manufacture of a medicament.

4. The use as claimed in claim 3 wherein the Melperone base is in a crystalline form.

5. A pharmaceutical formulation comprising Melperone base in a solid form and a suitable carrier and/or excipient.

6. A pharmaceutical formulation as claimed in claim 5 wherein the Melperone base is in a crystalline form.

7. A pharmaceutical formulation as claimed in claim 5 or 6 in a form for percutaneous use.

8. A pharmaceutical formulation as claimed in claim 7 in the form of a transdermal patch.

9. A pharmaceutical formulation substantially as hereinbefore described with reference to the examples.

10. A process for preparing Melperone or salts thereof comprising the steps of:converting a Melperone precursor into a Melperone intermediate ketal; and IE 000051 RUSS17/C -13converting the ketal intermediate into Melperone base or a salt thereof.

11. A process as claimed in claim 10 wherein the Melperone precursor is a ketone obtained from a Friedel Crafts reaction.

12. A process as claimed in claim 11 wherein the Friedel Crafts reaction product is a ketone of formula II of Scheme 2.

13. A process as claimed in any of claims 10 to 12 wherein the ketal intermediate is a compound of the formula IV of scheme 2.

14. A process as claimed in any of claims 10 to 13 wherein the ketal intermediate is deprotected to form Melperone base in a solid form.

15. A process as claimed in any of claims 10 to 13 when the ketal intermediate is deprotected to form Melperone base which is converted directly into a salt of Melperone base.

16. A process substantially as hereinbefore described with reference to the examples.

17. Melperone base in a solid form whenever prepared by a process as claimed in any of claims 10 to 14 or 16.

18. Salts of Melperone whenever prepared by a process as claimed in any of claims 10 to 13,15 or 16.

19. A ketal intermediate of Melperone. IE 000051 RUSSI7/C -1420. A compound of claim 19 wherein the ketal is a compound of formula IV.

20.

21. A compound as claimed in claim 19 wherein the ketal is a compound of formula V.