WO2010032254A1 - Industrial process for cis(+m-2-r(dimethylamino)-methyl-1-(3- methoxyphenyl) cyclohexanol hydrochloride - Google Patents

Industrial process for cis(+m-2-r(dimethylamino)-methyl-1-(3- methoxyphenyl) cyclohexanol hydrochloride Download PDF

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WO2010032254A1
WO2010032254A1 PCT/IN2008/000763 IN2008000763W WO2010032254A1 WO 2010032254 A1 WO2010032254 A1 WO 2010032254A1 IN 2008000763 W IN2008000763 W IN 2008000763W WO 2010032254 A1 WO2010032254 A1 WO 2010032254A1
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tramadol
cis
hydrochloride
novel process
nitric acid
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PCT/IN2008/000763
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French (fr)
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Suhas Vasant Sohani
Pravin Gaj Anan Khochikar
Altaf Abdul Hamid Tamboli
Ramesh Shankar Kulkarni
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Kamud Drugs Pvt . Ltd .
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel process for preparation of Cis(+/-)-2- [(dimethylamino)-methyl]-1-(3-methoxyphenyl) cyclohexanol which is substantially free from the "Trans" isomer. More particularly the present invention relates to a process for producing cis(+/-)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl) cyclohexanol using the nitrate salt as an stable intermediate.
  • Cis (+/-)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl) cyclohexanol is a typical opioid which is a centrally acting analgesic, used for treating moderate to severe pain and most types of neuralgia, including trigeminal neuralgia. It is a synthetic agent and appears to have actions on the ⁇ -opioid receptor as well as the noradrenergic and serotonergic systems.
  • Tramadol is the compound cis(+/-)-2-[(dimethylamino)-methyl]-1-(3-methoxypheny
  • Tramadol hydrochloride assumes a special position among centrally acting analgesics since this active pharmaceutical ingredient acts as a strong inhibitor of pain without the side effects which are known for opioids (T. Phannacol. Exptl. Ther. 267,331 (1993)).
  • US 5414129 provides a process for the purification and separation of cis(+/-)-2- [(dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol-hydrochloride from a reaction mixture containing the cis-racemate-isomer, the trans-racemate-isomer and Grignard reaction side products.
  • the reaction mixture is combined with a solution of hydrochloric acid in a C2 -C3 alcohol or with gaseous hydrogen chloride in the presence of specific solvents.
  • the process is said to effect the selective precipitation of cis(+/-)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol-hydrochloride.
  • isopropanol is given and the process is also said to have been successful using one of the following solvents as an alternative: butyl acetate, MIBK, 1-butanol, 1-pentanol, PAA (primary amyl alcohol mixture), 1-hexanol, cyclohexanol, 1-octanol, 2-ethylhexanol, anisole.
  • the present inventors have surprisingly found a novel process to overcome all the shortcomings of the prior art.
  • the present inventors have found that the preparation of the tramadol nitrate salt is an effective route to achieve good yields of the cis- isomer with a content of the trans isomer as low as 0.5%.
  • the present invention effectively describes a novel process which produces high yields of cis-Tramadol with a trans isomer content of less than 0.2% after purification which happens concurrently during the formation of Hydrochloride salt.
  • Tramadol is the compound cis(+/-)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl) cyclohexanol which, in the form of the hydrochloride salt is widely used as an analgesic.
  • cis- Tramadol means the racemic mixture of cis-Tramadol (RR 1 SS) as shown by the following chemical structures:
  • the present inventors have surprisingly found that pure cis-2- [(dimethylamino)methyl]-1-(3-dimethoxyphenyl) cyclohexanol Nitric acid salt precipitates out selectively from a mixture of cis and trans Tramadol Nitric acid salts accompanied by less than 0.5% of the trans isomer.
  • cis-Tramadol base in anhydrous form at room temperature is an oil.
  • cis-Tramadol Nitric acid salt is a stable derivative, which can be crystallized very easily and selectively and can be used to produce pure cis-Tramadol hydrochloride.
  • the Mannich base is formed by forming a Ma ⁇ nich hydrochloride and liberating the Mannich base.
  • the Mannich hydrochloride is formed by reaction of cyclohexanone with paraformaldehyde and dimethylamine hydrochloride to form dimethylaminomethylcyclohexanone hydrochloride.
  • the Mannich base is liberated by treating the Mannich hydrochloride with a base such as sodium hydroxide in a solvent system which may comprise a mixture of toluene, methyl t-butylether, hexane and water.
  • a base such as sodium hydroxide in a solvent system which may comprise a mixture of toluene, methyl t-butylether, hexane and water.
  • the cis-Tramadol hydrochloride is formed from the cis-Tramadol Nitric acid salt by basification followed by acidification with hydrochloric acid.
  • the invention also provides Tramadol and salts thereof whenever prepared by the process of the invention.
  • Step 1 In the improved process of the invention, the first step is the reaction of cyclohexanone with paraformaldehyde and dimethylamine hydrochloride to form the Mannich base hydrochloride - dimethylaminomethylcyclohexanone hydrochloride - which is recovered from acetone.
  • Step 2 The Mannich hydrochloride formed in Step 1 is treated with sodium hydroxide in a mixture of toluene, methyl t-butyl ether, Hexane and water more preferably with Hexane and water to liberate the Mannich base.
  • Step 3 The Mannich base is reacted with a Grignard reagent to form a crude mixture of cis and trans Tramadol base.
  • the crude mixture of cis and trans Tramadol base thus obtained is converted to the Nitric acid salt using Nitric acid.
  • the Cis - Tramadol Nitric acid salt precipitates out selectively accompanied by less than 0.5 % of the Trans diastereomer.
  • Cis-Tramadol hydrochloride is formed from the cis-Tramadol Nitric acid salt by basification followed by acidification with hydrochloric acid.
  • reaction scheme may be illustrated as follows:
  • a reaction vessel is charged successively with 13 Kg of Magnesium, 80 I of dry
  • a reactor vessel is charged successively with cis-Tramadol Nitric acid salt (94 Kg), soft water (282 I) and Toluene (282 I). The vessel is then cooled to 10 to 15°C and the pH adjusted to 12-13 with aqueous sodium hydroxide solution. After separating the strata the solvent is distilled under vacuum. The vessel is charged with IPA (175 I). IPA. HCI (42 I, 22-25% HCI Content) is added at a low temperature until pH of 1.8- 2.0 is reached. The separated product is centrifuged at this temperature and washed with cold IPA. Thus 64-65Kg of dry cis-Tramadol Hydrochloride is obtained.
  • the overall process produced high yields of cis-Tramadol with a trans isomer content of less than 0.2% which is the pharmacopial limit.

Abstract

The present invention provides a process for the preparation of cis(+/-)-2- [(dimethylamino)-methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride using the stable nitrate salt as an intermediate to give a product containing less than 0.2 % of the undesired "Trans" diastereomer.

Description

INDUSTRIAL PROCESS FOR CIS(+M-2-r(DIMETHYLAMINO)-METHYU-1-(3- METHOXYPHENYL) CYCLOHEXANOL HYDROCHLORIDE
FIELD OF INVENTION
The present invention relates to a novel process for preparation of Cis(+/-)-2- [(dimethylamino)-methyl]-1-(3-methoxyphenyl) cyclohexanol which is substantially free from the "Trans" isomer. More particularly the present invention relates to a process for producing cis(+/-)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl) cyclohexanol using the nitrate salt as an stable intermediate.
BACKGROUND OF THE INVENTION Cis (+/-)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl) cyclohexanol (Tramadol ) is a typical opioid which is a centrally acting analgesic, used for treating moderate to severe pain and most types of neuralgia, including trigeminal neuralgia. It is a synthetic agent and appears to have actions on the μ-opioid receptor as well as the noradrenergic and serotonergic systems.
Tramadol is the compound cis(+/-)-2-[(dimethylamino)-methyl]-1-(3-methoxypheny|) cyclohexanol which, in the form of the hydrochloride salt is widely used as an analgesic.
Tramadol hydrochloride assumes a special position among centrally acting analgesics since this active pharmaceutical ingredient acts as a strong inhibitor of pain without the side effects which are known for opioids (T. Phannacol. Exptl. Ther. 267,331 (1993)).
The compound per se is described in Patent No. US 3652589 and UK 997399. Tramadol is obtained in the cis-racemate form as the major synthetic product. In known processes, the trans-racemate is present as a minor component of the reaction mixture. US 3652589 discloses an isolation process for the pure cis-racemate isomer in which a complex Grignard reaction mixture is distilled and the crude mixture of the isomers is precipitated and filtered. However, there is still a relatively high level of the trans-racemate isomer present in the final product.
US 5414129 provides a process for the purification and separation of cis(+/-)-2- [(dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol-hydrochloride from a reaction mixture containing the cis-racemate-isomer, the trans-racemate-isomer and Grignard reaction side products. In that process, the reaction mixture is combined with a solution of hydrochloric acid in a C2 -C3 alcohol or with gaseous hydrogen chloride in the presence of specific solvents. The process is said to effect the selective precipitation of cis(+/-)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol-hydrochloride. A specific example using isopropanol is given and the process is also said to have been successful using one of the following solvents as an alternative: butyl acetate, MIBK, 1-butanol, 1-pentanol, PAA (primary amyl alcohol mixture), 1-hexanol, cyclohexanol, 1-octanol, 2-ethylhexanol, anisole.
US6469213 describes a method for the preparation of cis-Tramadol hydrochloride by using a base hydrate with a trans isomer content of 0.03% in the base hydrate. The aforesaid patent however does not exemplify the conversion of the base hydrate to hydrochloride salt and the yield thereof.
US5672755 describes a process for the purification and isolation of (RR, SS)-2- dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexanol containing (RS, SR) isomer under acidic conditions and its selective precipitation. This process is however not very efficient in producing the final cis isomer that is completely free of the trans form. Thus it may be summarized that all the prior art procedures suffer from a major disadvantage i.e. relatively low yields of the cis (+/-)-isomer with a high content of the trans (+/-)-isomer.
Looking at the various problems associated with prior art there is therefore a need for a process for preparing the pure cis form of Tramadol without several further purification steps.
The present inventors have surprisingly found a novel process to overcome all the shortcomings of the prior art. The present inventors have found that the preparation of the tramadol nitrate salt is an effective route to achieve good yields of the cis- isomer with a content of the trans isomer as low as 0.5%. The present invention effectively describes a novel process which produces high yields of cis-Tramadol with a trans isomer content of less than 0.2% after purification which happens concurrently during the formation of Hydrochloride salt.
OBJECT OF INVENTION
It is an object of the present invention to provide a novel process for preparing cis- Tramadol hydrochloride.
It is another object of the present invention to provide a novel process for preparing cis-Tramadol hydrochloride by using Nitric acid salt of Tramadol.
It is another object of the present invention to provide a novel process for preparing cis-Tramadol hydrochloride with minimal contamination of "Trans-isomer".
It is yet another object of the present invention to provide the Nitrate salt of cis- Tramadol as an intermediate in a process for preparing Tramadol Hydrochloride. It is a further object of the present invention to provide a process for preparing cis- Tramadol hydrochloride from the cis-Tramadol.
SUMMARY OF INVENTION
According to an aspect of the present invention there is provided a novel process for preparing cis-Tramadol hydrochloride comprising the steps of:
i. reacting a Mannich base with a Grignard reagent to form Tramadol base;
ii. converting the tramadol base to the nitrate salt using Nitric acid in the temperature range of 0 to 200C;
iii. selectively precipitating the cis-Tramadol Nitric acid salt;
iv. Generating cis-Tramadol hydrochloride with a trans isomer content of less than 0.2% from the cis-Tramadol nitrate salt via the Tramadol free base.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
Tramadol is the compound cis(+/-)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl) cyclohexanol which, in the form of the hydrochloride salt is widely used as an analgesic.
Tramadol can exist in either its cis or trans isomer forms. In this specification cis- Tramadol means the racemic mixture of cis-Tramadol (RR1SS) as shown by the following chemical structures:
Figure imgf000006_0001
(1 R.2R) (1S,2S)
Cis-Tramadol
The present inventors have surprisingly found that pure cis-2- [(dimethylamino)methyl]-1-(3-dimethoxyphenyl) cyclohexanol Nitric acid salt precipitates out selectively from a mixture of cis and trans Tramadol Nitric acid salts accompanied by less than 0.5% of the trans isomer.
In comparison cis-Tramadol base in anhydrous form at room temperature is an oil. Surprisingly it was found that cis-Tramadol Nitric acid salt is a stable derivative, which can be crystallized very easily and selectively and can be used to produce pure cis-Tramadol hydrochloride.
In a preferred embodiment of the invention the Mannich base is formed by forming a Maηnich hydrochloride and liberating the Mannich base. Preferably, the Mannich hydrochloride is formed by reaction of cyclohexanone with paraformaldehyde and dimethylamine hydrochloride to form dimethylaminomethylcyclohexanone hydrochloride.
In one embodiment of the invention, the Mannich base is liberated by treating the Mannich hydrochloride with a base such as sodium hydroxide in a solvent system which may comprise a mixture of toluene, methyl t-butylether, hexane and water. In a preferred embodiment of the invention, the cis-Tramadol hydrochloride is formed from the cis-Tramadol Nitric acid salt by basification followed by acidification with hydrochloric acid.
The invention also provides Tramadol and salts thereof whenever prepared by the process of the invention.
The invention will be more clearly understood from the following description thereof given by way of examples.
Step 1: In the improved process of the invention, the first step is the reaction of cyclohexanone with paraformaldehyde and dimethylamine hydrochloride to form the Mannich base hydrochloride - dimethylaminomethylcyclohexanone hydrochloride - which is recovered from acetone. Step 2: The Mannich hydrochloride formed in Step 1 is treated with sodium hydroxide in a mixture of toluene, methyl t-butyl ether, Hexane and water more preferably with Hexane and water to liberate the Mannich base. Step 3: The Mannich base is reacted with a Grignard reagent to form a crude mixture of cis and trans Tramadol base. The crude mixture of cis and trans Tramadol base thus obtained is converted to the Nitric acid salt using Nitric acid. In this process, the Cis - Tramadol Nitric acid salt precipitates out selectively accompanied by less than 0.5 % of the Trans diastereomer.
Step 4: Cis-Tramadol hydrochloride is formed from the cis-Tramadol Nitric acid salt by basification followed by acidification with hydrochloric acid.
In general, the reaction scheme may be illustrated as follows:
In this scheme only the (RR)-enantiomer of the Tramadol Nitric acid salt is illustrated. It will be appreciated that both the (RR) and (SS) enantiomers are present in the same way as cis-Tramadol as defined above. Step l:Formation of Dimethylaminomethyl Cyclohexanone Hydrochloride
Figure imgf000008_0001
Step 2:Formation of Tramadol Mannich Base
Y " N "
Figure imgf000008_0002
' . CH,
Dimethylaminomethyl Mannich Base
Cyclohexanone Hydrochloride
Step 3:Formation of Tramadol Nitric acid salt.
Figure imgf000008_0003
Mannich Base CH3 CH3
Step 4:Formation of Tramadol Base
Figure imgf000008_0004
CH3 Step 4:Formation of Tramadol Hydrochloride
Figure imgf000009_0001
CH3 CH3 CH3 CH3
The invention is further illustrated by the non-limiting examples given below:
EXAMPLES
Example 1 : Cis-Tramadol Nitric acid salt
A reaction vessel is charged successively with 13 Kg of Magnesium, 80 I of dry
Tetrahydrofuran (THF) and 5 Kg of 3-bromoanisole. With careful heating, the reactor temperature is brought up to ca. .60-650C. The Grignard reaction initiates at this point and exotherms to approximately 67°C. A further mixture of 3-bromoanisole (95 Kg) and 150 I dry Tetrahydrofuran are added which maintains reflux. This addition of the remainder of the bromoanisole is carried out slowly so as to sustain a gentle reflux. The reaction is refluxed after complete addition of 3-bromoanisole. The vessel is cooled and Mannich base is added. After completion of addition, the vessel is maintained at room temperature for 6 hours to ensure complete reaction. After cooling to ca. 0-200C, 269 I of water and 103 Kg ammonium chloride are added to quench the reaction. When complete, the solvent is distilled under vacuum. About (96 I) methanol is charged and approximately 21 I of Nitric Acid is added at 0 - 5°C until a pH of 0-1 is reached, at this point the Nitrate salt precipitates out. The product is centrifuged at the same temperature and washed with cold methanol. 94 -95 Kg of cis-Tramadol Nitric acid salt (trans isomer less than 0.5%) is obtained as wet cake. Example 2: Purification
A reactor vessel is charged successively with cis-Tramadol Nitric acid salt (94 Kg), soft water (282 I) and Toluene (282 I). The vessel is then cooled to 10 to 15°C and the pH adjusted to 12-13 with aqueous sodium hydroxide solution. After separating the strata the solvent is distilled under vacuum. The vessel is charged with IPA (175 I). IPA. HCI (42 I, 22-25% HCI Content) is added at a low temperature until pH of 1.8- 2.0 is reached. The separated product is centrifuged at this temperature and washed with cold IPA. Thus 64-65Kg of dry cis-Tramadol Hydrochloride is obtained.
The overall process produced high yields of cis-Tramadol with a trans isomer content of less than 0.2% which is the pharmacopial limit.

Claims

1. A novel process for preparing cis-Tramadol hydrochloride comprising the steps of:
i. reacting a Mannich base with a Grignard reagent to form Tramadol base;
ii. converting the tramadol base to the nitrate salt using Nitric acid in the temperature range of 0 to 200C;
iii. selectively precipitating the cis-Tramadol Nitric acid salt;
iv. Generating cis-Tramadol hydrochloride with a trans isomer content of less than 0.2% from the cis-Tramadol nitrate salt via the Tramadol free base.
2. The novel process for preparing cis-Tramadol hydrochloride as claimed in claim 1 wherein the Tramadol base is formed by reacting Mannich base with a Grignard reagent in tetrahydrofuran.
3. The novel process for preparing cis-Tramadol hydrochloride as claimed in claim 2 wherein the Mannich base is formed from the corresponding Mannich hydrochloride.
4. The novel process for preparing cis-Tramadol hydrochloride as claimed in claim 3 wherein the Mannich hydrochloride is generated by the reaction of cyclohexanone with paraformaldehyde and dimethylamine hydrochloride.
5. The novel process for preparing cis-Tramadol hydrochloride as claimed in claim 2 wherein the Grignard reagent is formed from 3-bromoanisole.
6. The novel process for preparing cis-Tramadol hydrochloride as claimed in claim 1 wherein the nitric acid used in the step ii is fuming Nitric acid or of any other concentration.
7. The novel process for preparing cis-Tramadol hydrochloride as claimed in claim 6 wherein the nitric acid concentration is 70%.
8. The novel process for preparing cis-Tramadol hydrochloride as claimed in claim 1 wherein the preferred temperature range 0 to 5°C.
9. The novel process for preparing cis-Tramadol hydrochloride as claimed in claim 1 wherein the cis-Tramadol Nitric acid salt is selectively precipitated from lower (C1-C4) alcohols.
10. The novel process for preparing cis-Tramadol hydrochloride as claimed in claim 9 wherein the preferred lower (C1-C4) alcohol is methanol.
PCT/IN2008/000763 2008-09-22 2008-11-10 Industrial process for cis(+m-2-r(dimethylamino)-methyl-1-(3- methoxyphenyl) cyclohexanol hydrochloride WO2010032254A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5877351A (en) * 1997-12-24 1999-03-02 Wyckoff Chemical Company, Inc. Preparation and purification process for 2- (dimethylamino) methyl!-1-(3-methoxphenyl)-cyclohexanol and its salts
WO1999036390A1 (en) * 1998-01-14 1999-07-22 Macfarlan Smith Limited Purification of tramadol
WO2000006585A1 (en) * 1998-07-28 2000-02-10 Nicox S.A. Medicine nitrate salts
EP1785412A1 (en) * 2005-11-14 2007-05-16 IPCA Laboratories Limited Tramadol recovery process
BRPI0601938A (en) * 2006-05-29 2008-01-22 Globe Quimica S A process for preparing and purifying the mixture r, r-s, s- (cis) -r, s-s, r (trans) -tramadol and its salts

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5877351A (en) * 1997-12-24 1999-03-02 Wyckoff Chemical Company, Inc. Preparation and purification process for 2- (dimethylamino) methyl!-1-(3-methoxphenyl)-cyclohexanol and its salts
WO1999036390A1 (en) * 1998-01-14 1999-07-22 Macfarlan Smith Limited Purification of tramadol
WO2000006585A1 (en) * 1998-07-28 2000-02-10 Nicox S.A. Medicine nitrate salts
EP1785412A1 (en) * 2005-11-14 2007-05-16 IPCA Laboratories Limited Tramadol recovery process
BRPI0601938A (en) * 2006-05-29 2008-01-22 Globe Quimica S A process for preparing and purifying the mixture r, r-s, s- (cis) -r, s-s, r (trans) -tramadol and its salts

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 200827, Derwent World Patents Index; AN 2008-D66830, XP002564766 *

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