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WO2006115456A1 - Synthese de la 1-aminopiperidine - Google Patents

Synthese de la 1-aminopiperidine Download PDF

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Publication number
WO2006115456A1
WO2006115456A1 PCT/SE2006/000499 SE2006000499W WO2006115456A1 WO 2006115456 A1 WO2006115456 A1 WO 2006115456A1 SE 2006000499 W SE2006000499 W SE 2006000499W WO 2006115456 A1 WO2006115456 A1 WO 2006115456A1
Authority
WO
WIPO (PCT)
Prior art keywords
piperidine
aqueous
hydroxylamine
aminopiperidine
added
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/SE2006/000499
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English (en)
Inventor
Ba-Vu Nguyen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nobel Chemicals AB
Original Assignee
Cambrex Karlskoga AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cambrex Karlskoga AB filed Critical Cambrex Karlskoga AB
Publication of WO2006115456A1 publication Critical patent/WO2006115456A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/30—Nitrogen atoms non-acylated

Definitions

  • This invention broadly relates to a method for synthesizing 1-amino piperidine (N-amino ⁇ i ⁇ eridine). 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.
  • 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.
  • 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.
  • 1- aminopiperidine also known as piperidine- 1-ylamine, N-aminopiperidine, N- piperidylamine, 1-piperidinamine and N,N-pentamethylenehydrazine or N 5 N- pentamethylenehydrazone
  • 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.
  • 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.
  • 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
  • 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.
  • the mixture is stirred at a temperature of about 55 ⁇ 5 0 C for about 15 ⁇ 5 minutes.
  • 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-amino ⁇ iperidine product and is kept at 50 ⁇ 5 °C for processing.
  • the lower water phase is discarded.
  • 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.
  • 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.
  • 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.
  • an elevated temperature ⁇ i.e., above room temperature
  • 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.
  • 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,
  • the piperidine is added to an aqueous alkaline solution to establish the initial reaction mixture.
  • potassium hydroxide can be used for preparing the aqueous alkaline solution, it is preferred to use sodium hydroxide.
  • the reaction mixture will preferably contain from about 50% of saturation up to a substantially saturated solution of base, e.g., sodium hydroxide.
  • base e.g., sodium hydroxide.
  • base e.g., sodium hydroxide
  • 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.
  • 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.
  • a cumulative mole ratio of about 3:1 is particularly preferred.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Cette invention concerne un procédé pour synthétiser la 1-aminopipéridine (N-aminopipéridine) qui sélectionne un rapport molaire approprié des matériaux de départ, de préférence un rapport de moles cumulatif de pipéridine sur de l’hydroxylamine-O-sulfonique aqueuse d’au moins 2 :1, et régule étroitement la température de réaction et le procédé d’isolation du produit pour réaliser une conversion élevée du produit.
PCT/SE2006/000499 2005-04-26 2006-04-26 Synthese de la 1-aminopiperidine Ceased WO2006115456A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US67467905P 2005-04-26 2005-04-26
US60/674,679 2005-04-26

Publications (1)

Publication Number Publication Date
WO2006115456A1 true WO2006115456A1 (fr) 2006-11-02

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2006/000499 Ceased WO2006115456A1 (fr) 2005-04-26 2006-04-26 Synthese de la 1-aminopiperidine

Country Status (1)

Country Link
WO (1) WO2006115456A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010142810A1 (fr) * 2009-06-12 2010-12-16 Centre National De La Recherche Scientifique (Cnrs) Synthese d'hydrazines à partir de l'acide hydroxylamine-o-sulfonique

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE338609C (de) * 1919-10-15 1921-06-22 Fritz Sommer Dr Verfahren zur Darstellung von Hydrazin und dessen Alkyl- oder Arylsubstitutionsprodukten
GB866681A (en) * 1958-05-22 1961-04-26 May & Baker Ltd N-substituted piperidines
US3583979A (en) * 1969-05-06 1971-06-08 Upjohn Co Process for preparing n-aminohexamethyleneimine
EP0230895A2 (fr) * 1986-01-17 1987-08-05 BASF Aktiengesellschaft Procédé de préparation d'acide sulfonic-0-hydroxylamine
EP0249452A1 (fr) * 1986-06-13 1987-12-16 Ube Industries, Ltd. Procédé pour la préparation de N-aminohexaméthylène-imine
WO2005035496A1 (fr) * 2003-10-03 2005-04-21 Aventis Pharmaceuticals Inc. Procede de preparation de composes heterocycliques a substitution n-amino

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE338609C (de) * 1919-10-15 1921-06-22 Fritz Sommer Dr Verfahren zur Darstellung von Hydrazin und dessen Alkyl- oder Arylsubstitutionsprodukten
GB866681A (en) * 1958-05-22 1961-04-26 May & Baker Ltd N-substituted piperidines
US3583979A (en) * 1969-05-06 1971-06-08 Upjohn Co Process for preparing n-aminohexamethyleneimine
EP0230895A2 (fr) * 1986-01-17 1987-08-05 BASF Aktiengesellschaft Procédé de préparation d'acide sulfonic-0-hydroxylamine
EP0249452A1 (fr) * 1986-06-13 1987-12-16 Ube Industries, Ltd. Procédé pour la préparation de N-aminohexaméthylène-imine
WO2005035496A1 (fr) * 2003-10-03 2005-04-21 Aventis Pharmaceuticals Inc. Procede de preparation de composes heterocycliques a substitution n-amino

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GÖSL R.: "Synthesis of substituted hydrazones from amines with hydroxylamino-O-sulfonic acid", CHEMISCHE BERICHTE, vol. 92, 1959, pages 2521 - 2531, XP003001381 *
SOMEI M. ET AL.: "A novel N-amination method and its application to the preparation of N-aminoheterocycles", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 26, no. 8, 1978, pages 2522 - 2534, XP003001382 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010142810A1 (fr) * 2009-06-12 2010-12-16 Centre National De La Recherche Scientifique (Cnrs) Synthese d'hydrazines à partir de l'acide hydroxylamine-o-sulfonique
FR2946651A1 (fr) * 2009-06-12 2010-12-17 Centre Nat Rech Scient Synthese d'hydrazines a partir de l'acide hydroxylamine-o- sulfonique.

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