EP2310365A1

EP2310365A1 - Method for producing n-phenyl-n-(4-piperidinyl)amide salts

Info

Publication number: EP2310365A1
Application number: EP08773829A
Authority: EP
Inventors: Oliver FLÖGEL; Ulrich Weigl
Original assignee: Cilag AG
Current assignee: Cilag AG
Priority date: 2008-07-03
Filing date: 2008-07-03
Publication date: 2011-04-20
Also published as: WO2010000282A1; JP2011526257A; US20110144346A1

Abstract

The invention relates to a method for producing N-phenyl-N-(4-piperidinyl)amide salts, particularly pharmaceutically tolerable addition salts of the compound Remifentanil, in that a compound of the formula (III) is reacted with an acrylic acid alkyl ester of the formula CH2=CH-C(O)-OR: where independently of each other R denotes low-molecular alkyl, preferably (C1-4)alkyl, preferably methyl or ethyl, R1 denotes low-molecular alkyl, preferably (C1-4)alkyl, preferably methyl or ethyl; and HX denotes an inorganic or organic acid, wherein the components are optionally reacted in the presence of a catalyst, preferably at a higher temperature, thereby obtaining the salt of the compound of formula (I).

Description

Process for the preparation of N-phenyl-N- (4-piperidinyl) amide salts

Technical area

The present invention relates to the production of amide salts being selected ^¬ N-phenyl-N- (4-piperidinyl), particularly of salts of the compound remifentanil, in particular of remifentanil hydrochloride.

PRIOR ART EP 0 383 579, Glaxo Welcome Inc., published on 22.08.1990, describes N-phenyl-N- (4-piperidinyl) amides and their salts and their preparation. In particular, compounds of the formula (I) and their salts are:

in which R and R ₁ independently of one another are low molecular weight alkyl. Remifentanil corresponds to the compound of formula (I) wherein R is methyl and R _{x is} ethyl.

Compounds of the formula (I) are synthetic opiods which are used as anesthetics. A preferred method of preparing the salts of compounds of formula (I) is to alkylate a compound of formula (II) by means of an aza-Michael addition and the resulting compound of formula (I) to a pharmaceutically acceptable salt, preferably

BESTATIGUNGSKOPIE - -

into the hydrochloride, converts:

_ _ »- In the F orm el (I) S a lz d the verb in th e F orm el (I)

(I)

The process of aza-Michael addition starting from the free amine of a compound of formula (II) in the presence of a Michael acceptor such as an acrylic acid derivative [eg CH ₂ = CH-C (O) -OR] has significant disadvantages. Thus, according to J. Med. Chem. 32 _. , Page 968 (1989), in the reaction of the piperidine compound of formula (II), an intramolecular shift of the Ri-C (O) substituent to the secondary piperidine nitrogen atom has been observed, resulting in difficultly removable undesired by-products. Furthermore, the compounds of the formula (I) are obtained in liquid form, which are chromatographically purified and then converted into a salt, which is expensive.

Presentation of the invention

It has now been found that it is surprisingly possible to first convert the compound of formula (II) into a salt and this salt [referred to hereinafter as compound (III)] by means of an aza-Michael addition directly into the desired salt of the compound of formula (I), whereby the salt of the compound of formula (I) thus obtained is obtained directly in pure form. This one-step process is simple and has the surprising advantage that there is no intramolecular shift of the Rχ-C (O) substituent to the secondary piperidine nitrogen atom. In addition, no other unwanted side reactions occur, such as the saponification of the ester groups which are contained in the compound of the formula (III), or dimerization Reactions in which two molecules of the compound (II) dimerisieren by the ester group of the one molecule is converted by attack of the piperidine free nitrogen into an amide. These properties are of particular importance, since the compounds of formula (I) belong to the class of highly potent drugs and any additional effort in their preparation for safety reasons is associated with special requirements and the process considerably more expensive.

It is also surprising that the process according to the invention proceeds without the addition of a catalyst, it being possible to add a catalytic amount of a catalyst, for example a base, to the reaction mixture in order to accelerate the reaction. If desired, the pure compound of the formula (I) can subsequently be obtained from the salt in a manner known per se.

The present invention is defined in the claims. In particular, the present invention relates to a process for the preparation of N-phenyl-N- (4-piperidinyl) amide salts, in particular of pharmaceutically acceptable addition salts of the compound remifentanil, in particular remifentanil hydrochloride, which is characterized in that a compound of Formula (III) with an acrylic acid alkyl ester of the formula CH ₂ = CH-C (O) -OR, reacts:

(III)

Salt of the compound (I) wherein - -

R is independently lower alkyl, preferably (CI_ ₄₎ -alkyl, preferably methyl or ethyl, preferably methyl;

Ri is lower alkyl, preferably (CI_ ₄₎ -alkyl, preferably methyl or ethyl, preferably ethyl; and

HX is an inorganic or organic acid, preferably hydrogen halide, preferably HBr, HJ, HCl, preferably HCl; or an organic mono- or dicarboxylic acid, preferably ^¬ as oxalic acid; in which the components are reacted, if appropriate, in the presence of a catalyst, preferably at elevated temperature, and then the reaction mixture is allowed to cool, the salt of the compound of the formula (I) being obtained.

The present invention also relates to the salts of the compound of the formula (I) prepared according to the invention, which are obtained directly in crystalline or amorphous form.

The salts of the compound of the formula (I) prepared according to the invention can also be used for the preparation of the free base of

Using compound of formula (I) by converting a fiction, ^¬ ACCORDANCE prepared salt of the compound of formula (I) in manner known per se into the free base of the compound of formula (I).

The present invention also relates to a process for the preparation of the free base of the compound of the formula (I) which comprises reacting a salt prepared according to the invention of the compound of the formula (I) in a manner known per se into the compound of the formula (I) transforms.

Preferably, remifentanil hydrochloride is prepared, wherein in the compound of the formula (III): R = methyl, R ₁ = ethyl and HX = HCl. An important advantage of the process according to the invention is that the compound of the formula (III) is present as a crystalline or amorphous solid and leads to the end product in a single step. In this sense, the compound of formula (III) can be reacted directly with a Alkylsaurealkylester of the formula CH ₂ = CH-C (O) -OR and use the Acrylsaurealkylester, preferably methyl acrylate, as a solvent. However, preferred is the use of a suitable inert solvent containing the acrylic acid ester in an amount of about 1 to 10 equivalents, calculated on the amount of the compound of formula (III).

As a suitable inert solvent for the reaction of the compound of formula (III) with the acrylic acid alkyl ester of the formula CH ₂ = CH-C (O) -OR is preferably used an alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol; or an ether, for example tert. butyl methyl ether; or tetrahydrofuran (THF); or acetonitrile; or another compound suitable as a solvent or a mixture of these compounds. The selection of a suitable inert

Solvent or a mixture of such solvents can be readily optimized by the skilled person.

In this case, the compound of the formula (III) is dissolved or suspended in an inert solvent or in a mixture of the inert solvents and these are at least an equimolar amount of Acrylsaurealkylester calculated on the molar amount of the compound of formula (III), and optionally also a catalyst, to. The acrylic acid ester is preferably used in an amount of about 1 to 10 equivalents, preferably in an amount of about 3 to 10 equivalents, preferably in an amount of about 3 to 6 equivalents, and more preferably in an amount of about 5 equivalents, calculated on the amount of the compound of the formula (III). In this case, the weight ratio of solvent to alkyl acrylate is preferably - -

in the range of 8: 2 to 2: 8, and preferably in the range of 6: 4 to 4: 6.

The reaction mixture is stirred for a sufficient time at elevated temperature, wherein the compound of formula (I) precipitates immediately and / or upon cooling of the reaction mixture in crystalline or amorphous form and can be filtered off. Preferably, the reaction mixture is treated at a temperature in the range of about 20-120 ⁰ C, depending on the boiling point of the reaction mixture, preferably at a temperature in

Range of about 50-80 ⁰ C, during about 1 hour to 48 hours, preferably for about 4-6 hours. The formed salt of compound (I) usually precipitates immediately or upon cooling of the reaction mixture in crystalline or amorphous form.

Preferably, the catalyst is added to the reaction mixture. The addition of a suitable catalyst significantly accelerates the reaction rate. Suitable catalysts are, for example, metal carbonates, e.g. Sodium carbonate, potassium carbonate, lithium carbonate, magnesium carbonate, calcium carbonate; tertiary amines, e.g. Triethylamine, N-methylmorpholine, Hunig's base (ethyldiisopropylamine), N, N-dimethylbenzylamine; basic inorganic hydroxides, e.g. Alumina, calcium oxide, sodium hydroxide, potassium hydroxide, lithium hydroxide; basic ion exchangers, e.g. Amberlyst A21.

The concentration of the catalyst, for example the tertiary amine, is preferably in the range of 1-10 mol%, preferably about 3-5 mol%, per mole of the compound used of the formula (III). The optimum concentrations for the other catalysts mentioned above are readily determinable by those skilled in the art.

For carrying out the present invention, preference is given to using a compound of the formula (III) and _

a catalytic amount of base, e.g. Triethylamine, dissolved or suspended in an organic solvent. Subsequently, acrylic acid alkyl ester is added. The suspension is heated to boiling for about 4-6 hours. After cooling to room temperature, the product, i. the salt of the compound

(I), filtered off directly, optionally after addition of an antisolvent such as tert. Butyl methyl ether. As a rule, this gives a product with a purity of more than 99%

(> 99%). The moist product as a crude product is preferably dissolved in an organic solvent in the heat and crystallized by the addition of an antisolvent. As a rule, this gives a product with a purity of more than 99.5%.

(> 99.5%).

The following examples illustrate the invention without limiting it.

example 1

0.981 g (3.0 mmol) of the compound of the formula (III) in which R = methyl, R ₁ = ethyl and HX = HCl are treated with triethylamine (9 mg, 0.09 mmol) and isopropanol (1.5 ml). Subsequently, methyl acrylate (1.35 ml, 15.0 mmol) is added. The suspension is heated to boiling for 24 hours. After cooling to room temperature (22 ° C), the precipitate is filtered off and washed with isopropanol (3 ml). The moist product remifentanil hydrochloride is dried in vacuo (70 ⁰ C). This gives 1.03 g (82%) of remifentanil hydrochloride as a colorless solid, in a purity> 99%.

Example 2

0.327 g (1.0 mmol) of the compound of the formula (III) in which R = methyl, R ₁ = ethyl and HX = HCl, are treated with triethylamine (3 mg, 0.03 mmol) and isopropanol (1 ml). Subsequently, methyl acrylate (0.45 ml, 5.0 mmol) is added. The suspension is heated to boiling for 24 hours. After this Cooling to room temperature (22 ⁰ C) is tert. Butyl methyl ether (5 ml) was added and stirred for 1 hour (h) at room temperature (22 ⁰ C). The precipitate is then filtered off and washed with tert-butyl methyl ether (2 ml). The moist product Remifentanil crude (339 mg) is taken up in isopropanol (4 ml) and heated to boiling (0.5 h) and a clear filtration performed. It is allowed to cool overnight (16 h). The precipitate is filtered off, washed with isopropanol (1 ml) and the moist product is dried in vacuo (70 ° C., 24 h). This gives 267 mg (65%) dry product remifentanil as a colorless solid; Purity of> 99.5%.

Example 3

0.327 g (1.0 mmol) of the compound of the formula (III) in which R = methyl, R ₁ = ethyl and HX = HCl, are treated with potassium carbonate (0.7 mg, 0.005 mmol) and isopropanol (1 ml).

Subsequently, methyl acrylate (0.45 ml, 5.0 mmol) is added.

The suspension is heated to boiling for 24 hours (h). After cooling to room temperature (RT) tert. Butylmethyl ether (5 ml) was added and stirred for 1 h at RT. Then the

Precipitate filtered off, with tert. -Butylmethylether (5 ml) washed. 218 mg (53%) of remifentanil are obtained as a colorless solid; Purity> 99%.

Example 4

0.327 g (1.0 mmol) of the compound of the formula (III) in which R = methyl, R ₁ = ethyl and HX = HCl, are treated with potassium carbonate (1.4 mg, 0.01 mmol) and methanol (1 ml). Subsequently, methyl acrylate (0.45 ml, 5.0 mmol) is added. The suspension is heated to boiling for 25 hours (h). After cooling to room temperature (RT) tert. Butyl methyl ether (5 ml) was added and stirred for 2 h at RT. Then the precipitate is filtered off, with tert. -Butylmethylether (5 ml) washed. 303 mg (73%) of remifentanil are obtained as a colorless solid; Purity> 99%. Example 5

0.981 g (3.0 mmol) of the compound of the formula (III) in which R = methyl, R ₁ = ethyl and HX = HCl, are mixed with sodium carbonate (3.2 mg, 0.03 mmol) and isopropanol (3 ml). Subsequently, methyl acrylate (1.35 ml, 15.0 mmol) is added. The suspension is heated to boiling for 24 hours (h). After cooling to room temperature (RT) tert-butyl methyl ether (15 ml) is added and stirred for 0.5 h at RT. Then the precipitate is filtered off, with tert. -Butylmethyl ether (6 ml) washed. 1,196 g (97%) of remifentanil are obtained as a colorless solid; Purity> 99%.

Example 6 8.17 g (10.0 mmol) of the compound of the formula (III) in which

R = methyl, R ₁ = ethyl and HX = HCl, triethylamine (126 mg, 1.25 mmol) and methanol (12.5 ml) are added. Subsequently, methyl acrylate (11.3 ml, 125 mmol) is added. The solution is heated to boiling for 6 hours (h). After cooling to room temperature (RT), the suspension is stirred for a further 16 h at RT. Then tert. Butyl methyl ether (12.5 ml) was added and the suspension was cooled to 0-5 ⁰ C. After 1 h at this temperature, the precipitate is filtered off and washed with tert. -Butylmethylether (25 ml) washed. The moist product remifentanil crude (9.095 g) is taken up in methanol (25 ml) and heated to boiling (1 h) and a clear filtration performed. After cooling to RT (1 h) tert. Butyl methyl ether (25 ml) was added. The suspension is cooled to 0-5 ⁰ C and stirred for 1 h at this temperature. The precipitate is filtered off, with tert. -Butylmethylether (25 ml) and the moist product dried in vacuo (50 ⁰ C, 15h). This gives 8.522 g (83%) dry product Remifentanil API as a colorless solid; Purity> 99.5%. Example 7

8.17 g (10.0 mmol) of the compound of the formula (III) in which R = methyl, R ₁ = ethyl and HX = HCl, are treated with triethylamine (126 mg, 1.25 mmol) and methanol (12.5 ml). Subsequently, methyl acrylate (11.3 ml, 125 mmol) is added. The solution is heated for 6 h at 50 ⁰ C internal temperature. After cooling to RT, the suspension is stirred for a further 16 h at RT. Then the suspension is cooled to 0-5 ⁰ C. After Ih at this temperature, the precipitate is filtered off and washed with tert. -Butylmethylether (25 ml) washed. The moist product remifentanil crude (8.333 g) is taken up in methanol (25 ml), heated to boiling (Ih) and subjected to a clear filtration. After cooling to RT tert. Butyl methyl ether (12.5 ml) was added. The suspension is cooled to 0-5 ⁰ C and stirred for Ih at this temperature. The precipitate is filtered off, with tert. -Butylmethylether (25 ml) and the moist product dried in vacuo (50 ⁰ C, 18h). This gives 7.648 g (74%) dry product Remifentanil API as a colorless solid; Purity> 99.5%.

Example 8

3.27 g (10 mmol) of the compound of the formula (III) in which R = methyl, R ₁ = ethyl and HX = HCl, are treated with methanol (5 ml) and methyl acrylate (4.5 ml, 50 mmol). It is heated for 47.5h at 50 ⁰ C internal temperature. It is then cooled to 0-5 ⁰ C and the suspension for 1 h at 0-5 ⁰ C stirred. The precipitate is filtered off and washed with tert-butyl methyl ether (10 ml). 3.381 g (82%) of remifentanil are obtained as a colorless solid; Purity> 99%.

Example 9

3.27 g (10 mmol) of the compound of the formula (III) in which R = methyl, R ₁ = ethyl and HX = HCl, are treated with triethylamine (51 mg, 0.5 mmol) and acetonitrile (5 ml). Then methyl acrylate (4.5 ml, 50 mmol) is added. It will be for - -

21.5h heated to 50 ⁰ C internal temperature. It is then cooled to 0-5 ° C and the suspension for 1 h at 0-5 ⁰ C stirred. The precipitate is then filtered off and washed with tert-butyl methyl ether (10 ml). 3.617 g (88%) of remifentanil are obtained as a colorless solid; Purity> 98%.

Example 10

3.27 g (10 mmol) of the compound of the formula (III) in which R =

Methyl, R ₁ = ethyl and HX = HCl, triethylamine (51 mg, 0.5 mmol) and methanol (5 ml) are added. Then methyl acrylate (4.5 ml, 50 mmol) is added. It is stirred for 18 h at RT. It is then cooled to 0-5 ° C and the suspension stirred for 45 min at 0-5 ° C. Then the precipitate is filtered off and washed with tert. Butyl methyl ether (10 ml). 3,243 g (79%) of remifentanil are obtained as a colorless solid; Purity> 98%.

Example 11

3.27 g (10 mmol) of the compound of the formula (III) in which R = methyl, R ₁ = ethyl and HX = HCl, with triethylamine

(51 mg, 0.5 mmol) and methyl acrylate (4.5 ml, 50 mmol).

It is heated for 22 h at 50 ⁰ C internal temperature. It is then cooled to RT and the suspension is stirred for 30 min at RT. The precipitate is filtered off and washed with tert-butyl methyl ether (10 ml). One receives 3.512 g

(85%) remifentanil as a colorless solid; Purity> 97%.

Example 12

3.27 g (10 mmol) of the compound of the formula (III) in which R = methyl, R ₁ = ethyl and HX = HCl, are treated with Amberlyst A21 (500 mg) and methanol (5 ml). Then methyl acrylate (4.5 ml, 50 mmol) is added. It is heated for 6.5 h at 50 ⁰ C internal temperature. A hot filtration is subsequently carried out at 50 ⁰ C. The filtrate is cooled to 0-5 ⁰ C and the suspension for 15 min at 0-5 ⁰ C stirred. Then - -

the precipitate is filtered off and washed with tert. -Butylmethyl ether (10 ml) washed. This gives 2.442 g (59%) of remifentanil as a colorless solid; Purity> 99%.

Claims

claims

1. A process for the preparation of N-phenyl-N- (4-piperidinyl) amide salts, in particular of pharmaceutically acceptable addition salts of the compound remifentanil, which comprises reacting a compound of the formula (III) with an alkyl acrylate of the formula CH ₂ = CH- C (O) -OR, converts:

(III) salt of the compound (I) wherein

R is independently lower alkyl, preferably (CI_ ₄₎ alkyl, preferably methyl or ethyl,

Ri is lower alkyl, preferably (C 1-4) alkyl, preferably methyl or ethyl; and HX is an inorganic or organic acid, wherein the components are reacted, if appropriate in the presence of a catalyst, preferably at elevated temperature, to give the salt of the compound of the formula (I).

2. The method according to claim 1, characterized in that R is methyl; R _{1 is} ethyl; and HX is hydrogen halide, preferably HBr, HJ, HCl, preferably HCl; or an organic mono- or dicarboxylic acid, preferably oxalic acid; mean.

3. The method according to claim 1, characterized in that R = methyl, R ₁ = ethyl and HX = HCl mean.

4. The method according to any one of claims 1-3, characterized in that reacting the compound of formula (III) with the acrylic acid alkyl ester of the formula CH ₂ = CH-C (O) -OR and use this Acrylsaurealkylester as a solvent.

5. The method according to any one of claims 1-3, characterized in that reacting the compound of formula (III) with the alkyl acrylate in a suitable inert solvent, and this solvent is preferably an alcohol, preferably methanol, ethanol, n-propanol, isopropanol .

butanol; or an ether, preferably tert. butyl methyl ether; or tetrahydrofuran (THF); or acetonitrile; or a mixture of these compounds.

6. The method according to claim 5, characterized in that the inert solvent or the mixture of inert solvents the Acrylsaurealkylester at least in equimolar amount, preferably in an amount of 1 to 10 equivalents, preferably in an amount of 3 to 10 equivalents, preferably in an amount of about 3 to 6 equivalents, and especially in an amount of about 5 equivalents, calculated on the amount of the compound of formula (III).

7. A process according to any one of claims 1-6, characterized in that the reaction is carried out in the presence of a suitable catalyst, and this catalyst is selected from the group comprising: metal carbonates, preferably sodium carbonate, potassium carbonate, lithium carbonate, magnesium carbonate, calcium carbonate; tertiary amines, preferably triethylamine, N-methylmorpholine, Hunig base (ethyldiisopropylamine), N, N-dimethylbenzylamine; basic inorganic hydroxides, preferably alumina, calcia, sodium hydroxide, potassium hydroxide, lithium hydroxide; basic ion exchangers, preferably Amberlyst A21.

8. The method according to claim 7, characterized in that the concentration of the catalyst in the range of 1-10 mol%, preferably about 3-5 mol%, per mole of the compound of formula (III) used, is.

9. The method according to any one of claims 1-8, characterized in that the reaction mixture at a temperature in the range of about 20-120 ⁰ C, preferably at a temperature in the range of about 50-80 ⁰ C, for about 1 hour to 48 hours, preferably for about 4-6 hours.

10. Salts of the compound of formula (I) in crystalline or amorphous form, prepared according to any one of claims 1-9.

11. Use of the salts according to any one of claims 1-9 prepared the compound of formula (I) for the preparation of the free base of the compound of formula (I) by reacting the salt of the compound of formula (I) in known per se in converts the free base of the compound of formula (I).

12. A process for the preparation of the free base of the compound of formula (I), characterized in that one prepared according to any one of claims 1-9 salt of the compound of formula (I) in a manner known per se in the free base of the compound of formula (I) converts.