HK1262579A1 - Process for the manufacture of 3-piperazin-1-yl-propylamine derivatives - Google Patents

Description

Process for preparing 3-piperazin-1-yl-propylamine derivatives

The present invention relates to a process for the preparation of 3-piperazin-1-yl-propylamine derivatives.

The invention relates in particular to a process for the preparation of compounds of formula (I)

Comprising reacting a compound of formula (II)

Reacting in the presence of hydrogen and a catalyst selected from Raney nickel and Raney cobalt;

wherein R is¹Is an alkyl group.

Several methods for preparing compounds of formula (I) are known in the art (WO 2014/104272; Ma, Lichao et al, Synthesis 2013,45(1) 45-52; Ovat, Ashi et al, journal of Medicinal Chemistry2010,53(17), 6326-.

However, the known processes have a number of disadvantages and cannot be used industrially. They have particularly low yields, use expensive metals, require cumbersome work-up to remove residual reagents or by-products, or employ conditions that cannot be used on a large scale.

The compounds of formula (I) are building blocks for the synthesis of several biologically active compounds.

Therefore, there is a need for a convenient and efficient process for obtaining compounds of formula (I) on a large industrial scale.

This problem has been solved by the method of the present invention.

In the present specification, the term "alkyl", alone or in combination, denotes a straight or branched alkyl group having 1 to 8 carbon atoms, in particular a straight or branched alkyl group having 1 to 6 carbon atoms, more in particular a straight or branched alkyl group having 1 to 4 carbon atoms. Straight and branched C₁-C₈Examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyl, the isomeric hexyl, the isomeric heptyl and the isomeric octylSpecifically methyl, ethyl, propyl, butyl and pentyl, more specifically methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl and isopentyl. A specific example of an alkyl group is methyl.

The invention specifically relates to:

the process of the invention, wherein the compound of formula (II) is obtained by reacting a compound of formula (III) in the presence of acrylonitrile

Wherein R is¹As defined above;

the process of the invention, wherein the compound of formula (II) is not isolated and is directly converted into the compound of formula (I);

the process of the invention wherein the catalyst is raney nickel;

the process of the present invention, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out in methanol, tetrahydrofuran, ethanol, isopropanol, toluene, pentane-octane (pentan-octane), methyl tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, water or dioxane;

the process of the invention, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out in methanol or tetrahydrofuran, in particular methanol;

the process of the invention, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out in the presence of a base;

the process of the invention, wherein the base is ammonia, sodium acetate or an alkali metal hydroxide;

the process of the present invention, wherein the alkali metal hydroxide is NaOH;

the process of the invention wherein the catalyst is Raney cobalt and the base is NaOH;

the process of the invention wherein the catalyst is raney nickel and the base is ammonia;

the process of the invention wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out at a temperature of from 15 to 100 ℃, specifically from 25 to 65 ℃, more specifically from 30 to 50 ℃, more specifically at about 40 ℃;

the process of the invention, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out at a pressure of from 0.1 to 200 bar, more particularly from 5 to 20 bar, more particularly about 10 bar;

the process of the present invention wherein about 0.01 to about 0.5 equivalents of raney nickel or raney cobalt are used;

the process of the invention, wherein the reaction of the compound of formula (III) in the presence of acrylonitrile is carried out in methanol, ethanol, n-propanol, isopropanol or butanol;

the process of the invention, wherein the reaction of the compound of formula (III) in the presence of acrylonitrile is carried out at a temperature of from 15 to 66 ℃; and

the process of the invention, wherein R¹Is methyl, i.e. wherein the compound of formula (III) is

The process of the invention, in which the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out at a temperature of about 40 ℃ is particularly advantageous.

The process of the invention, in which the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out at a pressure of about 10 bar, is particularly advantageous.

The process of the invention, in which the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out at a temperature of about 40 ℃ and a pressure of about 10 bar, is particularly advantageous.

The reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is advantageously carried out in about 2 to 6 hours.

The process of the invention, in which the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out in about 4 to 5 hours, is particularly advantageous.

The process of the invention, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out at a temperature of about 40 ℃ and a pressure of about 10 bar for about 4 to 5 hours, is particularly advantageous.

The process of the invention, in which the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out at a temperature of about 40 ℃ and a pressure of about 10 bar for about 4 to 5 hours, is particularly advantageous in methanol.

The process of the invention, in which the reaction of the compound of formula (II) in the presence of hydrogen and Raney nickel is carried out at a temperature of about 40 ℃ and a pressure of about 10 bar for about 4 to 5 hours, is particularly advantageous in methanol and ammonia.

The process of the invention, in which the reaction of the compound of the formula (III) in the presence of acrylonitrile is carried out in methanol, is particularly advantageous.

The process of the invention, wherein the reaction of the compound of formula (III) in the presence of acrylonitrile is advantageously carried out for about 2 to 6 hours, more particularly for about 3 to 5 hours, more particularly for about 3 hours.

The process of the invention, in which the reaction of the compound of formula (III) in the presence of acrylonitrile is carried out at about 25 ℃ is particularly advantageous.

The process of the invention, in which the reaction of the compound of formula (III) in the presence of acrylonitrile is carried out in methanol at about 25 ℃ for about 3 hours, is particularly advantageous.

When the compound of formula (II) is not isolated or purified and directly converted into the compound of formula (I), in particular a compound of formula (I) is obtained in very high yield and purity.

When the compound of formula (II) is not isolated or purified, the reaction mixture containing the compound of formula (II) may advantageously be concentrated, for example by distillation, and the compound of formula (II) is then converted into the compound of formula (I).

The reaction mixture containing the compound of the formula (II) can advantageously be concentrated until the solvent is no longer distilled off, and the compound of the formula (II) is then converted into the compound of the formula (I).

When the catalyst is Raney cobalt, it is preferred that no base is used.

When the catalyst is Raney cobalt and if a base is used, the base is advantageously NaOH.

When the catalyst is raney nickel, it is advantageous to add a base, in particular ammonia.

As an alternative to raney nickel and raney cobalt, Spongy nickel/cobalt or skelestal nickel/cobalt may of course be used. Accordingly, the present invention also relates to a process as defined above, wherein the catalyst is a skelethal nickel catalyst, a skelethal cobalt catalyst, a Spongy nickel catalyst or a Spongy cobalt catalyst.

The concentration of the compound of formula (II) in the hydrogenation reaction is advantageously between 10% and 20% (w/solvent volume), more particularly about 10% (w/solvent volume).

The base is advantageously used in an amount of 0.1 to 10 equivalents.

The invention will now be illustrated by the following examples, which are not intended to be limiting in nature.

Examples

Abbreviations: MeOH: methanol; THF: tetrahydrofuran; EtOAc: ethyl acetate; GC: gas chromatography; hrs: hours; eq.: equivalent weight; Ra-Ni: raney nickel; Ra-Co: raney cobalt; Pd/C: palladium on carbon; Pt/C: platinum on carbon; Rh/Alox: rhodium on alumina; p: pressure; t: (ii) temperature; t: time.

Example 1

Synthesis of 3- (4-methylpiperazin-1-yl) propan-1-amine

The following reactions were carried out under various conditions.

Different reaction conditions have been tested in a short time frame, but not always allowed to complete. This was done only to effectively check whether the reaction was running (working). Thus, a low conversion but a high relative yield indicates a positive result.

Example 1.1

200mg of 3- (4-methylpiperazin-1-yl) propionitrile (1.3mmol) and 2mL of MeOH (Sigma-Aldrich) are transferred together with 20mg of Raney Cobalt (0.147mmol, Johnson Matthey A-8B46Sponge Cobalt) into a 35mL stainless steel autoclave, which is sealed and freed from 10 bar of H₂The pressure was increased 3 times and released to normal pressure, then 10 bar of hydrogen was added. The autoclave was heated to 40 ℃ under program control and shaken for 2 hours. After this time, the autoclave was cooled to room temperature, the pressure was released and the reaction mixture was filtered. Analysis of the filtrate by GC showed 88% conversion and 85% selective yield of 3- (4-methylpiperazin-1-yl) propan-1-amine.

Example 1.2

This example was carried out in a similar manner to example 1.1, but using 64mg of 3- (4-methylpiperazin-1-yl) propionitrile (0.41mmol) and 2ml of 7N NH₃MeOH (Sigma-Aldrich) and 15mg of Raney nickel (0.119mmol, EVONIKB113Z) were run at 23 ℃ at 10 bar for 5 h. GC analysis showed 87% conversion and 85% yield of 3- (4-methylpiperazin-1-yl) propan-1-amine.

Example 1.3

This example was carried out in a similar manner to example 1.2, but using 100g of 3- (4-methylpiperazin-1-yl) propionitrile (652 mm)ol) and 1L 7N NH₃MeOH (Sigma-Aldrich) and 10g Raney nickel (79.6mmol, EVONIK B113Z) in a 1.5L autoclave, stir at 10 bar for 5 h at 40 ℃. GC analysis showed 100% conversion and 98.9% yield of 3- (4-methylpiperazin-1-yl) propan-1-amine.

Example 1.4

The example was carried out in a similar manner to example 1.2, but using 200mg of 3- (4-methylpiperazin-1-yl) propionitrile (1.3mmol) and 2ml of MeOH (Sigma-Aldrich) and 20mg of Raney nickel (0.159mmol, EVONIK B113Z) at 40 ℃ for 1 h at 10 bar. GC analysis showed 97.6% conversion and 62.8% yield of 3- (4-methylpiperazin-1-yl) propan-1-amine.

Example 1.5

This example was carried out in a similar manner to example 1.2, but using 400mg of 3- (4-methylpiperazin-1-yl) propionitrile (2.6mmol) and 2ml of NH₃Saturated THF (in house) and 20mg Raney nickel (0.159mmol, EVONIK B113Z) were held at 10 bar for 2 hours at 40 ℃. GC analysis showed 31.7% conversion and 28.6% yield of 3- (4-methylpiperazin-1-yl) propan-1-amine.

Example 1.6

The example was carried out in a similar manner to example 1.2, but using 200mg of 3- (4-methylpiperazin-1-yl) propionitrile (1.3mmol) and 2ml of THF and 20mg of Raney cobalt (0.147mmol, Johnson Matthey A-8B46SpongeCobalt) at 23 ℃ for 2 hours at 10 bar. GC analysis showed 13.1% conversion and 12.8% yield of 3- (4-methylpiperazin-1-yl) propan-1-amine.

Comparative example 1.7

The example was carried out in a similar manner to example 1.1, but using 200mg of 3- (4-methylpiperazin-1-yl) propionitrile (1.3mmol) and 2ml of MeOH and 20mg of 10% Pd/C (0.019mmol, EVONIK E101N/D) at 40 ℃ for 2 h at 10 bar. GC analysis showed 100% conversion and 1.8% yield of 3- (4-methylpiperazin-1-yl) propan-1-amine.

Comparative example 1.8

The example was carried out in analogy to example 1.7, but using 200mg of 3- (4-methylpiperazin-1-yl) propionitrile (1.3mmol) and 2ml of MeOH and 38.6mg of 5% Rh/Alox (0.019mmol, EVONIK G213 XKR/D) at 40 ℃ for 2 hours at 10 bar. GC analysis showed 100% conversion and 13.6% yield of 3- (4-methylpiperazin-1-yl) propan-1-amine.

Comparative example 1.9

The example was carried out in a similar manner to example 1.7, but using 200mg of 3- (4-methylpiperazin-1-yl) propionitrile (1.3mmol) and 2ml of MeOH and 73.3mg of 5% Pt/C (0.019mmol, EVONIK F101R/D) at 40 ℃ for 2 h at 10 bar. GC analysis showed 19.2% conversion and 0.54% yield of 3- (4-methylpiperazin-1-yl) propan-1-amine.

Example 1.10

The example was carried out in a similar manner to example 1.1, but using 100g of 3- (4-methylpiperazin-1-yl) propionitrile (652mmol) and 1L of MeOH and 10mg of Raney cobalt (73.6mmol, Johnson Matthey A-8B46SpongeCobalt) in a 1.5L autoclave at 40 ℃ for 4 h at 10 bar. GC analysis showed 100% conversion and 93.7% yield of 3- (4-methylpiperazin-1-yl) propan-1-amine.

The above results and other experiments are summarized in table 1 below.

Example 2

Intussusception process for the preparation of 3- (4-methylpiperazin-1-yl) propan-1-amine

Step 1

Acrylonitrile (35.56g,1.05eq.) was added to a solution of N-methyl-piperazine (63.90g,1.00eq.) in MeOH (240mL) over 1 hour at 25 ℃ and the resulting mixture was stirred for 3 hours at 25 ℃. The mixture was concentrated at 35 ℃/250 mbar until no more solvent was distilled off and the residue (100g) was used directly in the next step.

Step 2

The above residue (100g) was dissolved in ammonia-containing methanol (7N, 1000mL total) and hydrogenated in the presence of 10g Raney nickel (40 ℃ C. and 10 bar, 5 hours). The catalyst was filtered off and the filtrate was concentrated to dryness at 32-37 ℃ C./400 mbar. The residue (104.9g) was purified by fractional distillation to give 88.30g (two-step yield 88%) of 3- (4-methylpiperazin-1-yl) propan-1-amine with a purity of 99.97% (measured by GC).

Claims (13)

1. A process for the preparation of a compound of formula (I)

Comprising reacting a compound of formula (II)

Reacting in the presence of hydrogen and a catalyst selected from Raney nickel and Raney cobalt;

wherein R is¹Is an alkyl group.

2. The process of claim 1, wherein the compound of formula (II) is obtained by reacting a compound of formula (III) in the presence of acrylonitrile

Wherein R is¹As defined in claim 1.

3. The process of claim 2, wherein the compound of formula (II) is not isolated and is directly converted to the compound of formula (I).

4. The process of any of claims 1-3, wherein the catalyst is Raney nickel.

5. The process of any one of claims 1-4, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out in methanol, tetrahydrofuran, ethanol, isopropanol, toluene, pentane-octane, methyl tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, water, or dioxane.

6. The process of any one of claims 1-5, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out in methanol or tetrahydrofuran.

7. The process of any one of claims 1-6, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out in the presence of a base.

8. The process of any of claims 1-7, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out at a temperature of 15 to 100 ℃.

9. The process of any of claims 1-8, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is carried out at a pressure of 0.1 to 200 bar.

10. The process of any one of claims 2-9, wherein the reaction of the compound of formula (III) in the presence of acrylonitrile is carried out in methanol, ethanol, n-propanol, isopropanol, or butanol.

11. The process of any one of claims 2-10, wherein the reaction of the compound of formula (III) in the presence of acrylonitrile is carried out at a temperature of 15 to 66 ℃.

12. The method of any one of claims 1-11, wherein R¹Is methyl.

13. The invention as described in the present application.