BACKGROUND OF THE INVENTION

Field of the Invention

[0001 ] This invention broadly relates to a method for synthesizing 1-amino piperidine (N-aminoρiρeridine). By selecting a proper molar ratio of the starting materials and closely regulating the reaction temperature and the method of product isolation, a high product conversion has been achieved.

Description of Related Art

[0002] German Patent 338608 describes reacting piperidine (P) with hydroxylamine-0-sulfonic (HOS) acid in an aqueous alkaline solution (potassium hydroxide) at a mole ratio of P:HOS of about 1.5:1. The HOS was added at a temperature of about 50-70 ⁰ C over a period of about 30 minutes. Thereafter, the reaction mixture was heated to boiling and held for about 10 minutes, cooled and acidified (ph 2- 3) using hydrochloric acid. The acidified mixture is concentrated by evaporation and then the isolated solid is extracted several times using warm ethanol. After combining the liquids and adjusting to a pH of 8-9 using a potassium hydroxide solution in ethanol, N-aminopiperidine is obtained.

[0003] More efficient ways of producing 1-arninopiperidine is of value to the pharmaceutical arts as it constitutes an important raw material.

SUMMARY OF THE INVENTION

[0004] The present invention is directed to a method of producing 1- aminopiperidine (also known as piperidine- 1-ylamine, N-aminopiperidine, N- piperidylamine, 1-piperidinamine and N,N-pentamethylenehydrazine or N ₅ N- pentamethylenehydrazone) from piperidine.

[0005] The present invention is based on the following reaction between piperidine (P) with hydroxylamine-O-sulfonic acid (HOS):

[0006] According to the method, freshly prepared, aqueous hydroxylamine-O- sulfonic (HOS) acid is added, such as in a stepwise fashion, to an aqueous; alkaline (caustic) solution of piperidine. The HOS is added over about a 1 to 4 hour time period, preferably over about a 2 to 3 hour time period. While the HOS could be added in a continuous fashion over that period, it is suitable to add individual portions of HOS, for example in 2 to 5 different equal spaced apart portions over that time with stirring of the reaction mixture between the separate additions.

[0007] The cumulative mole ratio of the piperidine (P) to the aqueous hydroxylamine-O-sulfonic (HOS), i.e., P:HOS, is at least 2:1, preferably at least 2.5:1 and more preferably at least 3:1. The P :HOS ratio will typically be below about 6:1, usually below about 5 : 1 and often below about 4:1. A cumulative mole ratio of about 3 : 1 is particularly preferred. The product 1-aminopiperidine is recovered as a solution in excess piperidine (organic phase) after several aqueous sodium hydroxide extractions.

DETAILED DESCRIPTION OF THE INVENTION

[0008] In one embodiment of the invention, hydroxylamine-O-sulfonic acid

(HOS) is freshly prepared in water. Five portions of HOS (each portion of 28.6 kg, i.e., 252 mol/portion) for a total amount of about 143 kg (260 mol) in water (57 kg per portion, total amount of 285 kg).

[0009] A reactor is charged with sodium hydroxide (88 kg, 2210 mol) and water

(48 kg, 2650 mol) and then heated to a temperature of 65±5 ⁰ C to dissolve the sodium hydroxide completely. The sodium hydroxide solution then is cooled to a temperature of 55±5 ⁰ C and piperidine (327 kg, 3850 mol) is added. The solution is stirred at a temperature of 55 + 5 ⁰ C for 15 min to ensure complete dissolution and then cooled to a temperature of about 40±5°C.

[0010] The five separate portions of the aqueous hydroxylamine-O-sulfonic acid, described above, is added into the reaction mixture at a temperature of 55±5°C over a period of 180±60 min. After the addition of the last portion of HOS, the mixture is stirred at 55±5°C for an additional time period of 15±5 min.

[0011] At this point additional sodium hydroxide in an amount of 87 kg (2175 mol) is added and the mixture is stirred at 55±5 ⁰ C for an additional time period of 30±10 min. The contents of the reactor then is emptied and the liquid is pumped back into the reactor at a temperature of 55±5°C.

[0012] Thereafter, four additional charges of sodium hydroxide are made over time in an amount respectively of 43, 21, 21, 21 kg. The reaction mixture is maintained at a temperature of about 55±5°C as these portions of sodium hydroxide are separately added. Before each additional portion of sodium hydroxide is added, the previous addition of sodium hydroxide should be totally dissolved. This may require about 5 to 10 min of stirring before the next portion is added. Once all of the sodium hydroxide has been added and thoroughly mixed, the organic and aqueous phases are allowed to separate. The lower aqueous phase is removed and can be discarded.

[0013] Another (fifth) charge of sodium hydroxide (21 kg) then is added at a temperature of about 55±5°C and stirred for about 20 min. Any undissolved sodium hydroxide is filtered off at 55±5°C and the phases are allowed once again to separate. As before, the lower water phase is removed and discarded.

[0014] The recovered organic phase then is cooled to a temperature of about 0 to

7 ⁰ C and stirred slowly for a time period of 4±1 hours. Any precipitates that form are filtered off and the liquid containing the desired 1-aminopiperidine is recovered.

[0015] In accordance with another embodiment of the invention, a freshly prepared portion of Hydroxylamine-0-sulfonic acid, 113 kg, is subdivided into three portions of about 38 kg each (i.e., 0.33 kmol/portion). Each portion is individually added to a previously prepared concentrated aqueous alkaline solution of piperidine (piperidine 272 kg (3.20 kmol), sodium hydroxide 128 kg (3.20 kmol) and water 36 kg (1.99 kmol)). The alkaline piperidine solution is maintained at a temperature of about 55 ± 5 ⁰ C during the HOS addition. After the addition of all three portions is completed, the mixture is stirred at a temperature of about 55 ± 5 ⁰ C for about 15 ± 5 minutes.

[0016] After completing the reaction, the reactor is emptied and the liquid is pumped back into the reactor at a temperature of about 50 + 5 °C. The aqueous and organic phases are separated at 50 + 5 ^Q C and the lower aqueous phase is removed. The upper organic phase contains the desired 1-aminoρiperidine product and is kept at 50 ± 5 °C for processing. The lower water phase is discarded.

[0017] Sodium hydroxide 48 kg (1.20 kmol) is added to the organic phase at a temperature of 50 ± 5 ⁰ C and stirred for 20 min. Any undissolved sodium hydroxyde is filtered off at 50 ± 5 ⁰ C, and the aqueous and organic phases which form are separated at 50 ± 5 ⁰ C. Again, the lower aqueous phase is removed.

[0018] Another portion of sodium hydroxide 22 kg (0.55 kmol) is added to the organic phase at a temperature of about 50 ± 5 ⁰ C and stirred for 20 min. Any undissolved sodium hydroxyde is filtered off at a temperature of 50 ± 5 ⁰ C, and the phases are allowed to separate at a temperature of 50 ± 5 ⁰ C. Once again, the lower aqueous phase is removed and discarded.

[0019] At this point, the organic phase is cooled to a temperature of about 5 +2

⁰ C and stirred slowly. During this time, solid impurities and sodium hydroxide precipitates form and they are filtered off at a temperature of 5+ 2 ⁰ C. The remaining organic liquid phase contains the desired N-Aminopiperidine in unreacted piperidine and is recovered as the product.

[0020] When practicing the present invention, the resulting piperidine solution typically will contain about 20-25 % by weight of the 1-aminopiperidine. If desired, the 1 -aminopiperidine can be recovered from the piperidine solution using known techniques.

[0021] The initial addition of HOS to the aqueous alkaline piperidine solution and the initial reaction between the HOS and piperidine is preferably conducted at an elevated temperature {i.e., above room temperature), such as between 25 and 70 ⁰ C. Such initial addition and initial reaction is more usually conducted at a temperature between 30 and 60 ⁰ C, and generally at a temperature of between 35 and 45 ⁰ C.

[0022] Preferably, the initial aqueous alkaline piperidine contains piperidine at a concentration of at least one mole of piperidine per mole of water and preferably at least about 1.5 mole of piperidine per mole of water. While it may be possible to conduct the reaction in other polar solvents, water is preferred,

[0023] Preferably, the piperidine is added to an aqueous alkaline solution to establish the initial reaction mixture. While potassium hydroxide can be used for preparing the aqueous alkaline solution, it is preferred to use sodium hydroxide. Generally the same base will be used both for initially preparing the reaction solution and for the subsequent product work-up. The reaction mixture will preferably contain from about 50% of saturation up to a substantially saturated solution of base, e.g., sodium hydroxide. Thus, about 0.5 to 1.0 mole of base, e.g., sodium hydroxide, per mole of piperidine is present in the initial reaction mixture solution.

[0024] Methods of preparing HOS are well known and need not be described in detail. For example, HOS can be prepared by the reaction of hydroxylamine sulfate with chlorosulfonic acid.

[0025] In one aspect, the invention constitutes the preparation of 1- aminopiperidine by reaction between piperidine and HOS at a cumulative mole ratio of piperidine (P) to the aqueous hydroxylamine-O-sulfonic (HOS), i.e., P:HOS, of at least 2:1, preferably at least 2.5:1 and more preferably at least 3:1, but below about 6:1, usually below about 5: 1 and often below about 4:1. As noted above, a cumulative mole ratio of about 3:1 is particularly preferred.

[0026] In another aspect, the invention constitutes the preparation of 1 - amiaopiperidine by reaction between piperidine and HOS by the slow addition of HOS to a concentrated aqueous alkaline solution of piperidine. The HOS preferably is added to the concentrated aqueous alkaline solution containing piperidine over about a 1 to 4 hour time period, preferably over about a 2 to 3 hour time period. While the HOS can be added to the piperidine in a continuous fashion over that period, it is suitable, if not desirable to add separate individual portions of HOS to the piperidine. For example, from 2 to 5 separate but equal spaced apart portions of the HOS reagent can be added individually to the concentrated aqueous alkaline piperidine over the above-noted time period with stirring of the reaction mixture between the separate additions.

[0027} In. still another aspect, the invention constitutes the preparation of 1- aminopiperidine by reaction between piperidine and HOS by the slow addition of HOS to a concentrated aqueous alkaline solution of piperidine at an elevated temperature (i.e., above room temperature), such as between 25 and 70 ⁰ C. The initial addition of the HOS and the initial reaction between HOS and piperidine is more usually conducted at a temperature between 30 and 60 ⁰ C, and generally at a temperature of between 35 and 45 ⁰ C.

[0028] In yet another aspect of the present invention, the product is worked up by a series of alkaline extractions, preferably using the same base used for preparing the initial reaction solution. Sodium hydroxide is preferred. The alkaline extractions are

typically conducted at a temperature between 40 and 70 ⁰ C, more usually at a temperature between 45 and 60 ⁰ C, and most often about 55 ⁰ C.

[0029] Final product recovery is conducted by isolating and cooling the organic piperidine phase to a temperature below about 10 ⁰ C, and typically in the range of 0 to 7 ⁰ C, for a time sufficient to precipitate any residual base, e.g., sodium hydroxide, and other solid impurities. Usually a time period of about 1 to about 5 hours should be sufficient. The 1-aminopiperidine is recovered in excess piperidine. Further processing of the piperidine solution does not form a part of the present invention.

[0030] The present invention has been described with reference to specific embodiments. However, this application is intended to cover those changes and substitutions that may be made by those skilled in the art without departing from the spirit and the scope of the invention. Unless otherwise specifically indicated, all percentages are by weight. Also, unless to context shows otherwise, the term "about" is intended to encompass + or - 5% throughout the specification.