WO2006012276A1 - Processus pour préparer des 2-amino-6-(alkyl)amino-4,5,6,7-tétrahydrobenzothiazoles chiralement purs par résolution chromatographique en phase liquide - Google Patents

Processus pour préparer des 2-amino-6-(alkyl)amino-4,5,6,7-tétrahydrobenzothiazoles chiralement purs par résolution chromatographique en phase liquide Download PDF

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Publication number
WO2006012276A1
WO2006012276A1 PCT/US2005/022416 US2005022416W WO2006012276A1 WO 2006012276 A1 WO2006012276 A1 WO 2006012276A1 US 2005022416 W US2005022416 W US 2005022416W WO 2006012276 A1 WO2006012276 A1 WO 2006012276A1
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formula
compound
process according
liquid chromatography
alkyl
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PCT/US2005/022416
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English (en)
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David A. Siesel
Catherine Ramirez
Harold Meckler
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Amr Technology, Inc.
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Publication of WO2006012276A1 publication Critical patent/WO2006012276A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms

Definitions

  • the present invention relates to a process for obtaining single enantiomers of2-amino-6-(alkyl)amino-4,5,6,7-tetrahydrobenzothiazoles by liquid chromatographic resolution.
  • R is hydrogen or acyl
  • R 1 is hydrogen, alkyl, or aralkyl
  • R 2 is hydrogen
  • Some of these compounds are known to have dopamine D-2 agonist activity.
  • Pramipexole is a well-known compound of formula (1). Its chemical name is (5)-2-amino-6-propylamino-4,5,6,7-tetxahydrobenzothiazole, and its chemical structure is:
  • Pramipexole is available commercially (Mirapex , Pfizer,
  • EP 186087 Methods for preparing compounds of formula (1) are described in European Patent Nos. EP 186087 and EP 207696, and Published International Application WO 2004/041797.
  • a common core of these methods is a process comprising ring halogenation (preferably bromination) of a substituted aminoketone (2) and the condensation of the so obtained alpha-halogenated aminoketone (3) with thiourea or iV-acylthiourea to form a 2- aminotetrahydrobenzothiazole ring, as shown in Equation 1.
  • a compound of formula (1), wherein both R 1 and R 2 are hydrogen, is prepared from a compound (2) wherein either R 1 is an amino-protective group such as an acyl or alkoxycarbonyl group and R 2 is hydrogen, or R 1 ZR 2 together form an iminoprotective group such as phthalimidogroup. After halogenation (X) and condensation with thiourea, the protective group is removed in a separate step.
  • a compound of formula (1), wherein R 1 is acyl and R 2 is hydrogen, is prepared from a compound (2) wherein R 1 is acyl and R 2 is hydrogen.
  • a compound of formula (1), wherein R 1 is alkyl or aralkyl and R 2 is hydrogen is either prepared from a compound (2) wherein R 1 is alkyl or aralkyl and R 2 is hydrogen or a protective group (with subsequent deprotection in the latter case), or it can be prepared by alkylation/aralkylation of the compound (1) wherein both R 1 and R 2 is hydrogen, or finally, it can be prepared by metal hydride or borane reduction of the acyl group in a compound of formula (1) wherein R 1 is acyl or arylacyl and R 2 is hydrogen.
  • Equation 2 U.S. Patent Application 2004/0029936 Al discloses a further process for preparing compounds of formula (1).
  • the process (depicted in Equation 2) involves the selective bromination of 1,4-cyclohexanedione (4) in an alcoholic solvent to produce a compound of formula (5), where R 3 and R 4 are either the same, and each of them represents an alkoxy group of 1-4 carbons, or they together can form a C 2 -C 5 alkylenedioxy group or an oxo-group.
  • Condensation of the compound of formula (5), where R 3 and R 4 represent an oxo group) with thiourea produces a compound of formula (6), where R 3 and R 4 are as defined above.
  • Reaction of the compound of formula (6) with a suitable amine under conditions of reductive animation provides a compound of formula (1). Equation 2
  • This process allows the formation of enantiomerically enriched ( ⁇ S)-pramipexole by either using a chiral catalyst for the reductive animation to propylamine, or by using a chiral amine convertible to propylamine as a reagent in the reductive animation.
  • the starting diamino compound can be prepared by a sequence starting from 4-aminocyclohexanol, which is acetylated or phthalidated and subsequently oxidized to yield acetamido- or 4-phthalimidocyclohexanone, which is monobrominated and subsequently reacted with thiourea, to give 6-acetamido or (6-phthalimido)-2-amino-4,5,6,7-tetrahydrobenzothiazole (a compound of formula (1) where R 1 is H and R 2 is COCH3, or R 1 ZR 2 taken together are phthalimido). Finally, the protective acetyl or phthalimido group is removed. [0018] Thus, the overall synthetic sequence, starting from commonly available materials, represents six synthetic steps.
  • Compounds of formula (1) have an asymmetric carbon and they exist either as single enantiomers or in a racemic form. As is often the case, pharmacological activity of compounds of formula (1) is generally connected only or mainly with one stereoisomer. Pramipexole, for example, is marketed as the single S isomer, and the dopaminergic activity of this isomer is reported to be twice as high as that of the R isomer. It is anticipated that the produced racemic compounds of formula (1) may be resolved into its optical isomers by classical chromatography methods, or by fractional crystallization.
  • the produced racemic compounds of formula (1) can be resolved into their optical isomers by adding a subsequent production sequence involving steps of forming a salt with an appropriate optically active acid, resolving the salts by fractional crystallization, and, if necessary, liberating the free base of the resolved product from the salt.
  • An example of such a resolution process for producing optically pure pramipexole is disclosed in Schneider et al., J. Med. Chem. 30:494 (1987). The process uses the diamino derivative (a compound of formula (1) where R, R 1 , and R 2 are each H) as a substrate and L-tartaric acid as a resolution agent.
  • optically active pramipexole is prepared by a two-step propylation of the single enantiomer diamino precursor, which involves reacting the precursor with propionic anhydride, and then reducing the resulting propionyl intermediate.
  • Another known process for producing (>S)-pramipexole is disclosed in Published International Applications WO 02/22591 and WO 04/041797. This process involves converting compounds of formula (1) into their monovalent salts; reacting the monovalent salts with a chiral salt such as a tartaric acid derivative forming diasteromers; and selectively separating the diasteromers by fractional crystallization techniques.
  • ()S)-pramipexole can also be achieved by using chiral agents to carry out enantioselective reductive amination.
  • enantiomerically enriched pramipexole is prepared using (5)-2-hydroxypropyl amine.
  • One aspect of the present invention relates to a process for obtaining a single enantiomer of a compound of formula 10, where R is alkyl.
  • the process involves resolving a compound of formula I by liquid chromatography under conditions effective to produce a compound of formula (S)-I,
  • Another aspect of the present invention relates to a process for obtaining a single enantiomer of a compound of formula I which involves resolving the compound of formula I by liquid chromatography under conditions effective to produce a compound of formula (R)-I,
  • a further aspect of the present invention relates to a process for obtaining a single enantiomer of a compound of formula I which involves resolving a providing a compound of formula II
  • Yet another aspect of the present invention relates to a process for obtaining a single enantiomer of a compound of formula I which involves resolving a compound of formula II by liquid chromatography under conditions effective to produce a compound of formula (K)-II,
  • R 1 is H or acyl.
  • the compound of formula (R)-U is reacted under conditions effective to produce a compound of formula (R)-I.
  • the compound of formula (R)-I is recovered.
  • Still another aspect of the present invention relates to a process for obtaining a single enantiomer of a compound of formula II which involves resolving the compound of formula II by liquid chromatography under conditions effective to produce a compound of formula (S)-H, and recovering the compound of formula (S)-Il.
  • Yet a further aspect of the present invention relates to a process for obtaining a single enantiomer of a compound of formula II which involves resolving the compound of formula II by liquid chromatography under conditions effective to produce a compound of formula (R)-II, and recovering the compound of formula (R)-II.
  • the present invention thus provides a direct process for preparing chirally pure 2-amino-6-(alkyl)amino-4,5,6,7-tetrahydrobenzothiazoles by resolving the corresponding racemic compounds.
  • the chromatographic chiral resolution processes of the present invention are linearly scaleable and reproducible, and provide feasible and efficient alternatives to traditional chemical resolution routes.
  • the present invention provides a direct process for preparing ( ⁇ S)-pramipexole, a particularly valuable 2-amino-6- (alkyl)amino-4,5,6,7-tetrahydrobenzothiazole.
  • the present invention provides a process for obtaining a single enantiomer of a compound of formula I,
  • Alkyl may, for example, include any C 1-20 linear or branched hydrocarbon radicals and combinations thereof.
  • the substituent R may, for example, be methyl, ethyl, n-propyl, isopropyl, /z-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, zs ⁇ -amyl, hexyl, octyl, or the like.
  • R is propyl
  • the compound of formula (S)-I is (5)-pramipexole.
  • the compound of formula I may, for example, be resolved by preparative chiral high performance liquid chromatography ("HPLC").
  • HPLC high performance liquid chromatography
  • HPLC may, for example, include a chiral stationary phase and a mobile phase.
  • the chiral stationary phase may, for example, be tm-3,5-dimethylphenyl carbamate derived amylose coated on silica gel.
  • the mobile phase may, for example, involve polar organic solvents, constituted of, for example, combinations of 2-propanol and acetonitrile or methanol and ethanol, or normal phase solvents, constituted of, for example, a combination of an alcohol and n- heptane or hexanes.
  • polar organic solvents constituted of, for example, combinations of 2-propanol and acetonitrile or methanol and ethanol
  • normal phase solvents constituted of, for example, a combination of an alcohol and n- heptane or hexanes.
  • Alkyl may, for example, include any C 1-20 linear or branched hydrocarbon radicals and combinations thereof, as described above.
  • R is propyl
  • the compound of formula (R)-I is (i?)-pramipexole.
  • the compound of formula I may, for example, be resolved by preparative chiral high performance liquid chromatography, as described above.
  • Scheme 1 illustrates the separation and isolation of the two enantiomers of a compound of formula I by preparative chiral HPLC. The resolution may be on an amylase-based chiral stationary phase using either normal phase or polar organic mobile phases. According to this aspect of the invention, the compounds of formula (7a) and (7b) are produced quantitatively pure, and represent the (S)- and (i?)-enantiomers of the compound of formula I, respectively.
  • a further aspect of the present invention provides a process for preparing a single enantiomer of a compound of formula I, which involves resolving a compound of formula II,
  • Alkyl may, for example, include any C 1-20 linear or branched hydrocarbon radicals and combinations thereof, as described above.
  • R is propyl
  • the compound of formula (S)-I is ( * S)-pramipexole.
  • the compound of formula II may, for example, be resolved by preparative chiral high performance liquid chromatography, as described above.
  • R 1 may, for example, be H, and the reacting may, for example, involve N-acylation, followed by a reduction reaction.
  • R 1 may be acyl, and the reacting may, for example, involve a reduction reaction.
  • Yet another aspect of the present invention provides a process for preparing for a single enantiomer of a compound of formula I, which involves resolving a compound of formula II by liquid chromatography under conditions effective to produce a compound of formula (R)-II,
  • Alkyl may, for example, include any C 1-20 linear or branched hydrocarbon radicals and combinations thereof, as described above.
  • R is propyl
  • the compound of formula (R)-I is (i?)-pramipexole.
  • the compound of formula II may, for example, be resolved by preparative chiral high performance liquid chromatography, as described above.
  • R 1 may, for example, be H, and the reacting may, for example, involve N-acylation, followed by a reduction reaction.
  • R 1 may be acyl, and the reacting may, for example, involve a reduction reaction.
  • Scheme 2 illustrates the separation and isolation of the two enantiomers of a compound of formula II (formula (8)) by preparative chiral HPLC, and the transformation of these chirally pure compounds into the chirally pure target 2-amino-6-(alkyl)amino-4,5,6,7-tetrahydrobenzothiazoles. Resolution may, for example, be on an amylase-based chiral stationary phase using polar organic mobile phases.
  • R 1 is H (formula (9)
  • quantitatively pure compounds of formulas (9a) and (9b) are produced
  • R 1 is acyl (formula (10))
  • quantitatively pure compounds of formulas (10a) and (10b) are produced.
  • Still another aspect of the present invention provides a process for preparing a single enantiomer of a compound of formula II, which involves resolving the compound of formula II by liquid chromatography under conditions effective to produce a compound of formula (S)-IL, and recovering the compound of formula (S)-IL.
  • the compound of formula II may, for example, be resolved by preparative chiral high performance liquid chromatography, as described above.
  • Yet a further aspect of the present invention provides a process for preparing a single enantiomer of a compound of formula II, which involves resolving the compound of formula II by liquid chromatography under conditions effective to produce a compound of formula (R)-LL, and recovering the compound of formula (R)-LL.
  • the mobile phase solutions were prepared from HPLC grade solvents (Fisher Scientific International Inc., Hampton, NH, USA) and certified ACS reagents (Fisher Scientific International Inc., Hampton, NH, USA).
  • the solutions were premixed to contain either 1% diethylamine v/v ("DEA") or trifluoroacetic acid v/v (“TFA”) in alcohol for use in the normal phase screen, while 0.2% DEA (v/v) was added to each solvent during the polar organic solvent screen.
  • DEA diethylamine v/v
  • TSA trifluoroacetic acid v/v
  • the solutions for the column screens were prepared from a suitable sample such as an enantio-enriched materials or a racemate.
  • sample solutions for the amylose and cellulose-based columns screen were prepared by weighing approximately 1 mg of sample and dissolving in 1 mL of 10% 2-propanol in heptane, while acetonitrile ("ACN") was used as diluent for samples run in the polar organic mode.
  • ACN acetonitrile
  • the samples screened on the macrocyclic glycopeptide columns were prepared at 1 mg/mL concentration in MeOH.
  • the compound of the formula (10) was resolved into compounds of formulas (10a) and (10b) using 5-10% EtOH in heptane with an acidic additive (preferably as TFA) as mobile phase.
  • an acidic additive preferably as TFA
  • the EtOH content is about 10%, and about 0.1% v/v of the acidic additive is used.
  • the compound of the formula (9) was resolved into compounds of formulas (9a) and (9b) using 10-60% EtOH in heptane with an amine additive (preferably as DEA) as mobile phase.
  • the mobile phase should contain about 15% EtOH and 0.2% of the amine additive.
  • the column was equilibrated in a premixed mobile phase prepared from HPLC grade solvents and certified ACS grade reagents for at least 15 minutes prior to each injection while monitoring using UV detection.
  • the separation was carried out on isocratic mobile phases running at the direct scaled- up flow rate as general conditions.
  • the sample solution was prepared in the mobile phase at concentrations of 1-10 mg/mL and loaded onto the column.
  • the components of the mixture were collected upon elution and an aliquot of each fraction was analyzed using the corresponding analytical method.
  • Each fraction was independently concentrated to dryness using a rotary evaporator (Buchi, model 114A, BUCHI Labortechnik AG, Flawil, CH) with a bath temperature of 30-35 °C.
  • sample batches of compounds of formulas (7), (9), and (10) were separated into both (R)- and (S)-enantiomers, i.e., compounds of formulas (7a) and (7b), (9a) and (9b), and (10a) and (10b), respectively, using at least one of the methods previously described herein.
  • the recovered tan solid was triturated with isopropyl acetate ("IPAc”), and the solid collected by filtration and washed with IPAc affording (10a) as a white solid.
  • Compound (10a) was then dissolved in THF and heated to 50 °C under a nitrogen atmosphere prior to the addition of BH 3 /THF. After completion of the reaction, the solution was allowed to cool and the THF removed by rotary evaporation. The solution was cooled in an ice bath prior to the addition of aqueous sodium hydroxide (50% NaOH), the IPAc was added dissolving the solids and separating the solution in two layers. All the organic layers were recovered and processed as mentioned above.
  • IPAc isopropyl acetate
  • the crade compound (7a) was slurried in ACN, and the solution was homogenized by heating at 60 °C, allowed to cool down and slowly crystallize. The solids were recovered by filtration and dried on vacuum oven overnight to afford free-based compound (7a). The compound (7a) was further converted into the di- hydrochloride salt. The optical rotation of the obtained material matched that of pramipexole (7a, where R is propyl).
  • a sample solution was prepared by dissolving 100 mg of a compound of formula (9) in 100 mL of ACN with 0.2% DEA.
  • the sample solution was loaded onto the Chiralpak AD column (50 mm x 500 mm) using ACN with 0.2% DEA as mobile phase.
  • the first enantiomer was observed from 38-50 minutes while the second one eluted from 91-110 minutes. Both components were collected and concentrated to dryness using a rotary evaporator with a bath temperature of 30-35 °C.
  • the recovered material was dried under vacuum for at least 12 h to remove residual solvents.
  • Example 5 Preparation of 2-amino-6-(alkyl)amino-4,5,6,7- tetrahydrobenzothiazole Compounds of Formulas (9a) and (9b) Under Polar Organic Conditions on a Chiralpak AD Column [0067]
  • the resolution of the compound of formula (9) was completed as follows. A sample solution was prepared by dissolving 100 mg of a compound of formula (9) in 100 mL of 5:95 IPA/ACN with 0.2% DEA. The sample solution was loaded onto the Chiralpak AD column (50 mm x 500 mm) using 5:95 IPA/ACN with 0.2% DEA as mobile phase. The first component of the mixture was observed from 28-35 minutes while the second one eluted from 56-70 minutes. Both components were collected upon elution and processed as described above. These conditions are preferred for the resolution of large scale batches.
  • Example 8 Preparation of 2-amino-6-(alkyl)amino-4,5,6,7- tetrahydrobenzothiazole Compounds of Formulas (10a) and (10b) Under Polar Organic Conditions on a Chiralpak AD Column
  • the resolution ofthe compound of formula (10) was completed as follows. A sample solution was prepared by dissolving 100 mg of compound of formula (10) in 100 mL of 5:95 IPA/ACN with 0.2% DEA. The sample solution was loaded onto the Chiralpak AD column (50 mm x 500 mm) using the same above-mentioned mobile phase. The first enantiomer was observed from 18.5-22 minutes while the second one eluted from 23.5-27 minutes. Both components were collected and processed as for the normal phase resolution processes in Example 7. This method is preferred for large-scale resolution processes. [0072] Samples ofthe resolved material (1 mg each) from Examples 7 and
  • Example 13 Preparation of 2-amino-6-(alkyl)amino-4,5,6,7- tetrahydrobenzothiazole Compounds of Formula (7a) from Compounds of Formula (10a): Second Step on Example 12 [0078] Compound (10a) [25.7 g, 0.114 mol], was added to THF (175 mL) in a three-neck 1-L RB flask equipped with an overhead stirrer, addition funnel, and a Claisen adapter fitted with a condenser and an internal temperature probe. The mixture was heated to 50 °C purging with N 2 . After holding at 50 °C for 10 min, BH 3 ATHF (340 mL of 1 M in THF, 0.342 mol) was added.
  • the mixture was allowed to cool to 60 °C. After holding at 60 °C for a short time, the mixture was allowed to cool to 50 °C. Upon reaching 52 0 C, product began to precipitate out. The mixture was allowed to cool to ambient in 10 °C increments. The solid was collected by filtration and washed with CH 3 CN. The filtrate from the recrystallization was 68.6% (AUC).

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Abstract

L’invention décrit des processus pour obtenir des énantiomères uniques de 2-amino-6-(alkyl)amino-4,5,6,7-tétrahydrobenzothiazoles par chromatographie en phase liquide.
PCT/US2005/022416 2004-06-30 2005-06-23 Processus pour préparer des 2-amino-6-(alkyl)amino-4,5,6,7-tétrahydrobenzothiazoles chiralement purs par résolution chromatographique en phase liquide WO2006012276A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011021214A2 (fr) * 2009-08-07 2011-02-24 Msn Laboratories Limited Procédé amélioré pour la préparation de (s)-2-amino-4,5,6,7-tétrahydro-6-(propylamino)benzothiazole et de ses sels pharmaceutiquement acceptables
CN104072442A (zh) * 2013-03-28 2014-10-01 成都弘达药业有限公司 一种化合物及其制备方法
CN104177309A (zh) * 2013-05-23 2014-12-03 北京凯瑞科德药物技术研究有限公司 一种普拉克索制备工艺

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0186087A1 (fr) * 1984-12-22 1986-07-02 Dr. Karl Thomae GmbH Tétrahydro-benzothiazoles, leur procédé de préparation et leur utilisation comme intermédiaires ou médicaments

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0186087A1 (fr) * 1984-12-22 1986-07-02 Dr. Karl Thomae GmbH Tétrahydro-benzothiazoles, leur procédé de préparation et leur utilisation comme intermédiaires ou médicaments

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011021214A2 (fr) * 2009-08-07 2011-02-24 Msn Laboratories Limited Procédé amélioré pour la préparation de (s)-2-amino-4,5,6,7-tétrahydro-6-(propylamino)benzothiazole et de ses sels pharmaceutiquement acceptables
WO2011021214A3 (fr) * 2009-08-07 2011-04-28 Msn Laboratories Limited Procédé amélioré pour la préparation de (s)-2-amino-4,5,6,7-tétrahydro-6-(propylamino)benzothiazole et de ses sels pharmaceutiquement acceptables
CN104072442A (zh) * 2013-03-28 2014-10-01 成都弘达药业有限公司 一种化合物及其制备方法
CN104177309A (zh) * 2013-05-23 2014-12-03 北京凯瑞科德药物技术研究有限公司 一种普拉克索制备工艺

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