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

Abstract

The invention relates to the manufacture of a compound of formula (I)

##STR00001##

wherein R.sup.1 is defined as in the description and in the claims.

Claims

1. A process for the manufacture of a compound of formula (I) ##STR00008## comprising the reaction of a compound of formula (II) ##STR00009## in the presence of hydrogen and a catalyst selected from Raney-Nickel and Raney-Cobalt; wherein R.sup.1 is alkyl; at a pressure between 5 and 20 bar; and wherein around 0.01 to around 0.5 equivalent of Raney-Nickel or Raney-Cobalt is used.

2. A process according to claim 1, wherein the compound of formula (II) is obtained by the reaction of a compound of formula (III) ##STR00010## in the presence of acrylonitrile, wherein R.sup.1 is as defined in claim 1.

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

4. A process according to claim 1, wherein the catalyst is Raney-Nickel.

5. A process according to claim 1, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is done in methanol, tetrahydrofurane, ethanol, i-propanol, toluene, pentan-octane, methyltetrahydrofurane, methyl tert-butyl ether, ethyl acetate, water or dioxane.

6. A process according to claim 1, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is done in methanol or tetrahydrofurane.

7. A process according to claim 1, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is done in the presence of a base.

8. A process according to claim 1, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is done at a temperature between 15 and 100 C.

9. A process according to claim 1, wherein the reaction of the compound of formula (II) in the presence of hydrogen and a catalyst is done at a pressure of around 10 bar.

10. A process according to claim 2, wherein the reaction of a compound of formula (III) in the presence of acrylonitrile is done in methanol, ethanol, n-propanol, isopropanol or butanol.

11. A process according to claim 2, wherein the reaction of a compound of formula (III) in the presence of acrylonitrile is done at a temperature between 15 and 66 C.

12. A process according to claim 1, wherein R.sup.1 is methyl.

13. (canceled)

Description

EXAMPLES

[0051] Abbreviations: MeOH: methanol; THF: tetrahydrofuran; EtOAc: ethyl acetate; GC: gas chromatography; hrs: hours; eq.: equivalent; RaNi: Raney-Nickel; RaCo: Raney-Cobalt; Pd/C: palladium on carbon; Pt/C: platinum on carbon; Rh/Alox: rhodium on aluminum oxide; P: pressure; T: temperature; t: time.

Example 1

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

[0052] The following reaction was carried out under various conditions.

##STR00006##

[0053] The different reaction conditions have been tested on a short time frame, without always letting the reaction going to completion. This was made simply to check efficiently whether or not the reactions are working. Therefore a low conversion rate but high relative yield is indicative of a positive result.

Example 1.1

[0054] 200 mg of 3-(4-methylpiperazin-1-yl)propanenitrile (1.3 mmol) and 2 ml MeOH (Sigma-Aldrich) was transferred together with 20 mg Raney-Cobalt (0.147 mmol, Johnson Matthey A-8B46 Sponge Cobalt) into a 35 mL stainless steel autoclave, which was sealed and 3 times pressurized with 10 bar H.sub.2 and releasing to normal pressure, thereafter charged with 10 bar of hydrogen. The autoclave was heated under program control to 40 C. and shaked for 2 hrs. After this time the autoclave was cooled to room temperature, the pressure released and the reaction mixture filtered. The filtrate was analyzed with GC, showed a conversion of 88% and a selected yield of 85% of 3-(4-methylpiperazin-1-yl)propan-1-amine.

Example 1.2

[0055] This example was run in an analogous manner as example 1.1 but using 64 mg of 3-(4-methylpiperazin-1-yl)propanenitrile (0.41 mmol) and 2 ml 7 N NH.sub.3 in MeOH (Sigma-Aldrich) and 15 mg Raney-Nickel (0.119 mmol, EVONIK B113Z) at 23 C. under 10 bar for 5 hrs. GC analysis showed a conversion of 87% and a yield of 85% of 3-(4-methylpiperazin-1-yl)propan-1-amine.

Example 1.3

[0056] This example was run in an analogous manner as example 1.2 but using 100 g of 3-(4-methylpiperazin-1-yl)propanenitrile (652 mmol) and 1 L 7 N NH.sub.3 in MeOH (Sigma-Aldrich) and 10 g Raney-Nickel (79.6 mmol, EVONIK B113Z) in a 1.5 L autoclave at 40 C. under 10 bar for 5 hrs stirring. GC analysis showed a conversion of 100% and 98.9% yield of 3-(4-methylpiperazin-1-yl)propan-1-amine.

Example 1.4

[0057] This example was run in an analogous manner as example 1.2 but using 200 mg of 3-(4-methylpiperazin-1-yl)propanenitrile (1.3 mmol) and 2 ml MeOH (Sigma-Aldrich) and 20 mg Raney-Nickel (0.159 mmol, EVONIK B113Z) at 40 C. under 10 bar for 1 hrs. GC analysis showed a conversion of 97.6% and 62.8% yield of 3-(4-methylpiperazin-1-yl)propan-1-amine.

Example 1.5

[0058] This example was run in an analogous manner as example 1.2 but using 400 mg of 3-(4-methylpiperazin-1-yl)propanenitrile (2.6 mmol) and 2 ml with NH.sub.3 saturated THF (Self made) and 20 mg Raney-Nickel (0.159 mmol, EVONIK B113Z) at 40 C. under 10 bar for 2 hrs. GC analysis showed a conversion of 31.7% and 28.6% yield of 3-(4-methylpiperazin-1-yl)propan-1-amine.

Example 1.6

[0059] This example was run in an analogous manner as example 1.2 but using 200 mg of 3-(4-methylpiperazin-1-yl)propanenitrile (1.3 mmol) and 2 ml THF and 20 mg Raney-Cobalt (0.147 mmol, Johnson Matthey A-8B46 Sponge Cobalt) at 23 C. under 10 bar for 2 hrs. GC analysis showed a conversion of 13.1% and 12.8% yield of 3-(4-methylpiperazin-1-yl)propan-1-amine.

Comparative Example 1.7

[0060] This example was run in an analogous manner as example 1.1 but using 200 mg of 3-(4-methylpiperazin-1-yl)propanenitrile (1.3 mmol) and 2 ml MeOH and 20 mg 10% Pd/C (0.019 mmol, EVONIK E 101 N/D) at 40 C. under 10 bar for 2 hrs. GC analysis showed a conversion of 100% and 1.8% yield of 3-(4-methylpiperazin-1-yl)propan-1-amine.

Comparative Example 1.8

[0061] This example was run in an analogous manner as example 1.7 but using 200 mg of 3-(4-methylpiperazin-1-yl)propanenitrile (1.3 mmol) and 2 ml MeOH and 38.6 mg 5% Rh/Alox (0.019 mmol, EVONIK G 213 XKR/D) at 40 C. under 10 bar for 2 hrs. GC analysis showed a conversion of 100% and 13.6% yield of 3-(4-methylpiperazin-1-yl)propan-1-amine.

Comparative Example 1.9

[0062] This example was run in an analogous manner as example 1.7 but using 200 mg of 3-(4-methylpiperazin-1-yl)propanenitrile (1.3 mmol) and 2 ml MeOH and 73.3 mg 5% Pt/C (0.019 mmol, EVONIK F 101 R/D) at 40 C. under 10 bar for 2 hrs. GC analysis showed a conversion of 19.2% and 0.54% yield of 3-(4-methylpiperazin-1-yl)propan-1-amine.

Example 1.10

[0063] This example was run in an analogous manner as example 1.1 but using 100 g of 3-(4-methylpiperazin-1-yl)propanenitrile (652 mmol) and 1 L MeOH and 10 mg Raney-Cobalt (73.6 mmol, Johnson Matthey A-8B46 Sponge Cobalt) in a 1.5 L autoclave at 40 C. under 10 bar for 4 hrs stirring. GC analysis showed a conversion of 100% and 93.7% yield of 3-(4-methylpiperazin-1-yl)propan-1-amine.

[0064] The above results, as well as other experiments are summarized in Table 1 below.

TABLE-US-00001 Starting T P t Conversion Yield Experiment Example material Solvent Catalyst [ C.] [bar] [hrs] [%] [%] 1 1.2 64 mg 2 ml 7N 15 mg, 23 10 5 87 85 NH3 in 0.29 eq. MeOH RaNi 2 88 mg 2 ml 7N 22 mg, 40 10 5 100 97.4 NH3 in 0.305 eq. MeOH RaNi 3 100 g 1 L 7N 25 g, 40 10 2 100 99 NH3 in 0.305 eq. MeOH RaNi 4 100 mg 2 ml 7N 25 mg, 40 10 0.5 93.1 91.4 NH3 in 0.305 eq. MeOH RaNi 5 1.3 100 g 1 L 7N 10 g, 40 10 5 100 98.9 NH3 in 0.122 eq. MeOH RaNi 6 1.4 200 mg 2 ml 20 mg, 40 10 1 97.6 62.8 MeOH 0.122 eq. RaNi 7 1.5 400 mg 2 ml 20 mg, 40 10 2 31.7 28.6 saturated 0.061 eq. NH3 in RaNi, THF No. 313 8 400 mg 2 ml 20 mg, 23 5 2 43.9 34.4 MeOH 0.061 eq. RaNi 9 200 mg 2 ml 20 mg, 23 5 1 21.7 18.6 saturated 0.122 eq. NH3 in RaNi THF 10 400 mg 2 ml THF 20 mg, 40 5 1 2.4 1.8 0.060 eq. RaCo 11 1.6 200 mg 2 ml THF 20 mg, 23 10 2 13.1 12.8 0.113 eq. RaCo 12 1.7 200 mg 2 ml 20 mg 40 10 2 100 1.8 MeOH 0.0144 eq. 10% Pd/C 13 1.8 200 mg 2 ml 38.6 mg, 40 10 2 100 13.6 MeOH 0.0144 eq. 5% Rh/Alox 14 1.9 200 mg 2 ml 73.3 mg, 40 10 2 28.8 0.67 MeOH 0.0144 eq. 5% Pt/C 15 1.1 200 mg 2 ml 20 mg, 40 10 2 88 85 MeOH 0.113 eq. RaCo 16 1.1 100 g 1 1 MeOH 10 g, 40 10 4 100 93.7 0.113 eq. RaCo 17 200 mg 1 eq 20 mg, 40 10 2 100 96.6 NaOH in 0.113 eq. 2 ml RaCo MeOH 18 200 mg 12.2 mg, 20 mg, 40 10 2 13.4 13 0.113 eq 0.113 eq. NaOAc in RaCo 2 ml EtOAc

Example 2

Telescoped Process for the Preparation of 3-(4-methylpiperazin-1-yl)propan-1-amine

[0065] ##STR00007##

Step 1

[0066] Acrylonitrile (35.56 g, 1.05 eq.) was added within one hour at 25 C. to a solution off N-methyl-piperazine (63.90 g, 1.00 eq.) in MeOH (240 mL) and the resulting mixture was stirred for 3 hours at 25 C. The mixture was concentrated at 35 C./250 mbar unless no more solvent was distilled off and the residue (100 g) was directly used in the next step.

Step 2

[0067] The above residue (100 g) was dissolved in methanol containing ammonia (7N, 1000 mL in total) and hydrogenated in the presence of 10 g of Raney-Nickel (at 40 C. and 10 bar for 5 hours). The catalyst was filtered off and the filtrate was concentrated at 32-37 C./400 mbar to dryness. The residue (104.9 g) was purified by fractional distillation to afford 88.30 g (88% yield over two steps) of 3-(4-methylpiperazin-1-yl)propan-1-amine with a purity of 99.97% (measured by GC).