Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
  • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• • 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
  • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
  • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
  • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/76—Unsaturated compounds containing keto groups
  • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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 to ring carbon atoms
  • C07D307/32—Oxygen atoms
  • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form

Definitions

• the present invention relates to a process for the synthesis of tapentadol intermediates, the process comprising the steps of:
• step b) Stereoselective reacting (3S)-4-(3-methoxyphenyl)-3-methyl-4-oxobutanoic acid obtained in step a) in the presence of an organometallic-reagent to obtain (45,5R)-5-ethyl-5-(3- methoxyphenyl)-4-methyldihydrofuran-2(3H)-one
• the invention is directed to the use of different intermediates in the production of tapentadol and the pharmaceutical use of tapentadol HQ synthesized via the inventive route of synthesis.
• Tapentadol and its salt forms act, among other mode of actions, as opioid agonist and as noradrenalin uptake inhibitor. It has valuable pharmacological and therapeutic properties.
• the drug acts centrally as analgesic.
• Tapentadol is chemically known as 3- [(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol (formula I).
• WO 2011 080736 Al describes the preparation of Tapentadol through phenylpent-2-en amide.
• WO 2011 080756 Al consists of the preparation of a cyano-intermediate as key intermediate towards Tapentadol preparation.
• WO 2011 092719 Al describes a method of Tapentadol preparation using the key intermediate (bromopropyl)methoxybenzene .
• WO 2012 001571 Al describes Tapentadol synthesis with a benzyl group as substituent at the amino function.
• WO 2012 089177 Al consists of the description of Tapentadol synthesis of a protected alkene acid as intermediate.
• WO 2012 023147 Al comprises the reaction of (dimethylamino)-2-methylpentan-3-one with anisole-Grignard.
• WO 2012 038974 Al comprises a Tapentadol preparation using l-(3-hydroxyphenyl)propan- 1-one with an appropriate Grignard reagent.
• WO 2012 069004 Al describes the Tapentadol synthesis using Methane sulfonyl esters.
• WO 2012 103799 Al describes the use of Evans auxiliary to generate key chiral intermediates for Tapentadol preparation.
• Such route is inventively achieved by firstly stereoselectively reacting the starting educt, the ketoester (I) in step a) to obtain the stereoselective ketoacid, intermediate (II).
• the starting educt is a C1-C4 alkyl ketoester, wherein the alkyl can for instance be a straight chain methyl, ethyl, propyl, butyl or, if applicable, one of their branched homologues.
• the stereoselective conversion is preferably performed in the presence of a buffered solvent, preferably at least comprising water, and may include one or two process steps addressing the ester hydrolysis and stereoselective conversion.
• Suitable enzymes for performing such reaction and their optimum processing conditions are known to the skilled artisan and can for instance be selected from the group comprising lipases, keto reductases and esterases which may be immobilized on porous organic or inorganic carriers like microporous polypropylene or kaolinite or can be used as soluble enzyme.
• the reaction temperature for the enzymatic conversion may be selected as a function of the used enzyme and may vary from 5 °C up to or below the denaturation temperature of the enzyme, for instance up to 55 °C, preferentially between 20 and 35°C.
• the ester hydrolysis may result as a consequence of the enzymatic reaction conditions or may be achieved separately by acid or base catalyzed hydrolysis before or after the stereoselective conversion.
• the enantiomeric excess (ee) of the desired intermediate (II) obtainable by step a) can be higher than 90%, more specifically higher than 95% or even higher than 98%.
• step b) secondly the stereoselective keto-acid (II) is transformed via the use of an ethyl group transferring organometallic reagent to intermediate (III), a keto-furan-derivative.
• the conversion may be generally performed in a dried aprotic solvent under a protective atmosphere and in general organometallic compounds known as Grignard reagents can be used within this step.
• the cyclisation of the reaction product of the keto-acid (II) and the organometallic compound may be achieved by the addition of a strong acid, resulting in the stereoselective formation of the keto-furan (III).
• Suitable pH- ranges for this conversion may be pH ⁇ 2, preferably ⁇ 1.5 and even more preferred ⁇ 1.0.
• the intermediate (III) can be obtained with diastereomeric ratios of larger than 3:1, preferably larger than 4: 1.
• Step c) thirdly is targeted to the stereoselective conversion of the ketofuran (III) to the (3S,4R)-acid (IV) via metal catalyzed reduction in the presence of an organic base in a hydrogen atmosphere.
• Suitable metal catalysts can be either homogeneous or heterogeneous hydrogenation catalysts, wherein heterogeneous catalysts are preferred. Suitable examples are for instance catalysts comprising Pt, Pd, Rh, Ru, Ni, Co, Fe Cu, Cr or Zn.
• Preferred catalysts comprise platinum, palladium, rhodium, ruthenium or mixtures thereof.
• the metal catalyst may be mounted on a support, preferably a support such as activated carbon, calcium carbonate, barium sulfate, barium carbonate, silicium dioxide, alumina or may for example be present as a colloid in solution.
• the hydrogen can be added just at the beginning of the reaction, added repeatedly, generated in situ or being feed continuously into the reactor, wherein a sequential feeding of the hydrogen is preferred.
• the hydrogen pressure, hydrogenation time and the temperature of conversion is a strong function of the catalyst and the adaption of these reaction conditions is known the skilled artisan.
• Suitable organic bases in step c) may for example be non-nucleophilic bases of moderate strength, i.e. preferably amines and nitrogen heterocycles exhibiting a pKa of the conjugate acid of approximately 10-13.
• Examples for such bases are Diisopropylamine (DIP A), N,N-Diisopropylethylamine (DIPEA), l,8-Diazabicycloundec-7-ene (DBU), 2,6-Di-tert-butylpyridine, or Phosphazene bases, such as t-Bu- P 4 .
• the organic base can be N,N-Diisopropylethylamine.
• the solvent of the reaction in step c) is preferably an alcohol like methanol, ethanol, propanol, isopropanol and butanol, methanol being preferred.
• step d) fourthly the (3S,4R)-acid (IV) is converted to the amine (V).
• This can either be achieved by a modified Curtius- (L), a Hofmann- (ii.) or via a Lossen-reaction, wherein in all three routes an isocyanate reaction intermediate is formed.
• This isocyanate is not stable in aqueous solution and reacts by addition of water to the carbamic acid, followed by decarboxylation to the amine.
• Another possibility in the synthesis route includes the formation of a carbamate by introduction of an alcohol. Therefore, it is also possible to generate a stable intermediate including a protective group. The protective group can later on be removed by the conventional methods known to the skilled in the art.
• an azide in presence of a base and subsequently a pharmaceutically acceptable acid HX are used.
• Suitable azides include, but are not limited to, inorganic or organic azides, for instance alkali salt azide, trimethylsilylazide, tosylazide or trifluoromethylazide.
• Possible pharmaceutically acceptable acids HX can for example be found in the "Handbook of Pharmaceutical Salts: Properties, Selection and Use", Editors P. H. Stahl and C. G. Wermuth, Weinheim/Ziirich:Wiley-VCH/VHCA, 2002.
• hydrochloric acid is used.
• carboxylic acid activating agent a carboxylic acid activating agent
• Common reagents for activation are known to the skilled artisan and can for instance be selected from the group comprising or consisting of thionylchloride, carbodiimide, carbonyldiimidazole, carboxylic acid anhydride, N- Hydroxysuccinimide (NHS) or derivatives thereof.
• Other common coupling/activation reagents can also be used.
• Suitable carbodiimides may for instance be dicyclohexylcarbodiimide (DCC) or 1 -Ethyl - 3-(3-dimethylaminopropyl)carbodiimide (EDC).
• the activated carboxylic acid derivatives are then further reacted with ammonia and a halogen/halogen succinimide according to route ii. or by carboxylic acid chloride or carboxylic acid anhydride according to route iii..
• Suitable halogens are either chloride or bromide and consequently the halogen succinimide may also be a chloride or a bromide succinimide.
• an additional step e) a pharmaceutically acceptable acid HX is added to the compound obtained in step d) in order to obtain the (2R,3R)-3-(3-methoxyphenyl)- 2-methylpentan-l -amine acid salt
• Such reaction step can be advantageous in order to stabilize the amine and for further purification of the intermediate amine V.
• any suitable pharmaceutically acceptable acid HX can be used as mentioned above.
• HX is selected from the group comprising or consisting of HC1, HBr, HI, H 2 S0 4 or mixtures thereof. Such acids result in a significant stabilization of the intermediate and may easily be removed if necessary.
• a further inventive aspect of the process comprises a step a), wherein this step is performed in the presence of a lipase -enzyme.
• this step is performed in the presence of a lipase -enzyme.
• the lipase-enzymes have been found to reliably convert the starting educt to intermediate (II) in high yields and high selectivity.
• the enantiomeric excess (ee) of this reaction step may be larger than 90%, preferably larger than 95% or even 98% and the reaction can for instance be performed using a Lipase PS "Amano" SD in aqueous solution at a pH of 3.5-11.0, preferably at a pH of 7.0-8.0.
• step a) is performed stepwise, wherein in a first step al) R-4-(3-methoxyphenyl)-3-methyl-4-oxobutanoate is stereoselectively reacted in the presence of a keto-reductase enzyme to obtain (35,4R)-4-hydroxy-4-(3- methoxyphenyl)-3-methylbutanoic acid
• keto-ester (I) is subjected to a keto-reductase enzyme solution, preferably also comprising glucose dehydrogenase and a suitable cofactor like NADP. It is preferred to perform the conversion by application of both enzymes and the cofactor at the same time.
• the preferably stereoselectively generated 4-hydroxy ester may afterwards be subjected to an acid or alkaline hydrolysis in order to obtain the 4-hydroxy acid (la). Preferably the alkaline hydrolysis is used for the generation of the free acid.
• the free acid (la) is oxidized via common alcohol oxidizing reagent (e.g. Jones, Collins, Swern, Dess-Martin, Oppenauer or Fetizon procedure) to keto-acid (II).
• common alcohol oxidizing reagent e.g. Jones, Collins, Swern, Dess-Martin, Oppenauer or Fetizon procedure
• free acid (la) is converted in the presence of an oxidation catalyst and preferably a suitable oxidation reagent to obtain the stereoselective preferred keto-acid (II).
• Suitable oxidation catalysts can either be homogeneous or heterogeneous oxidation catalysts or organic peroxides, wherein heterogeneous metallic catalysts are preferred. Suitable examples are for instance catalysts comprising V, Pt, Ag, Ru, Mn, Co, Fe Cu.
• Preferred catalysts comprise platinum, vanadium, ruthenium or mixtures thereof. Especially preferred is ruthenium either as an oxide or halide salt.
• the metal catalyst may be mounted on a support or may be used as a metal salt dissolvable into the reaction medium, the latter alternative being preferred.
• ruthenium has been proven to result in high yields, including products exhibiting a high stereoselectivity and high purity.
• Suitable oxidation reagents are known to the skilled artisan and can for instance be selected from the group comprising hydrogen peroxide, tert.
• oxidation-catalyst in step a2) is selected from the group comprising Ruthenium-halogenides, organic peroxides and mixtures thereof.
• the dissolved ruthenium-salts here especially the halogenides like ruthenium chloride and/or bromide, and the organic peroxides has proven useful for performing the oxidation of the alcohol (la) to the keto-acid (II).
• the ruthenium salts can be used alone or in combination with the organic peroxides.
• Suitable organic peroxides may be hydrogen peroxide, Acetyl acetone peroxide, Acetyl benzoyl peroxide, Ascaridole, tert.
• the oxidation-catalyst in step a2) comprises at least RuCl 3 .
• the ruthenium chloride enables a fast conversion from the alcohol to the ketone resulting in high yields of optical pure product (>90 ee).
• the separation of the catalyst from the reaction mixture is easily achievable and therefore a product of high purity is easily obtainable.
• this process step is performed under acidic conditions.
• the pH may be adjusted to a pH of ⁇ 3.5, preferably to ⁇ 3.0 and even more preferred to ⁇ 2.5.
• An additional embodiment of the invention is related to a process, wherein step d) is performed stepwise, wherein in a first step
• step c) (35,4R)-4-(3-methoxyphenyl)-3-methyl-hexanoic acid obtained in step c) is stereoselectively reacted according to variants i. - iii. at least in the presence of a base and an alcohol Z to obtain Z [(2R,3R)-2-methyl-3-methoxyphenyl pentyl]carbamate
• the alcohol is added in a base catalyzed reaction to the intermediately generated isocyanate.
• These intermediates may for instance be isolated and stored and can easily be further processed afterwards.
• all organic alcohols can be used, preferably C1-C20 alkyl or aryl alcohols.
• the alcohol can either be tert-butanol or benzyl alcohol resulting in the Boc (tert-butoxy carbamate) or CBz (Benzyloxy carbamate) protective groups. These protective groups are preferred, because the deprotection is easily achievable.
• Further protective groups may also be suitable, for instance Trifluoroacetamide, Acetamide (Ac), Formamide, Methyl carbamate, 4-Methoxybenzenesulfonamide, Benzylamine (Bn) protective groups.
• the second step d2) includes the back reaction with an acid induced liberation of the protective group. All pharmaceutical acceptable acids can be used, preferably HC1.
• an extractive workup preferably at least comprising an aqueous phase.
• step c) the metal catalyst is selected from the group consisting of Pt, Pd, Ni, Rh, and Ir and the organic base is selected from the group consisting of primary, secondary or tertiary amines, substituted or non-substituted C1-C50 aliphatic or aromatic N-heterocycles, oxygen containing bases or mixtures thereof.
• the metal catalyst is selected from the group consisting of Pt, Pd, Ni, Rh, and Ir
• the organic base is selected from the group consisting of primary, secondary or tertiary amines, substituted or non-substituted C1-C50 aliphatic or aromatic N-heterocycles, oxygen containing bases or mixtures thereof.
• Such combination of reduction catalyst and organic base has been proven useful in order to achieve high conversion rates at high diastereomeric ratios.
• a Pd catalyst can be used and this catalyst can be mounted on a solid carrier, for example, but not limited to, activated carbon.
• This catalyst enables a reaction at low temperatures and hydrogen pressures, resulting in a high stereoselectivity.
• the base may preferably be selected from the group comprising or consisting of amines, hydroxide salts, carbonate salts or hydrogencarbonate salts.
• the reaction step c) can be performed once or this step can be repeated and the crude product of each cycle can be used as educt for the next cycle. Such cycle can result in the formation of highly pure products exhibiting > 90% ee/de.
• a process can be used, wherein in step b) the organometallic- reagent is a Grignard-reagent selected from the group comprising EtLi, EtMgCl and EtMgBr or mixtures thereof. These group of organometallic -reagents result in a fast and stereoselective cyclisation of the keto-acid (II).
• EtMgBr und EtMgCl can be used.
• step dl) variant i.) the azide is selected from the group comprising Lithium azide, Sodium azide, Potassium azide, Benzyl azide, Tosyl azid, Trifluoromethanesulfonyl azide or diphenylphosphoryl azide or mixtures thereof.
• the azide is selected from the group comprising Lithium azide, Sodium azide, Potassium azide, Benzyl azide, Tosyl azid, Trifluoromethanesulfonyl azide or diphenylphosphoryl azide or mixtures thereof.
• the azide is selected from the group comprising Lithium azide, Sodium azide, Potassium azide, Benzyl azide, Tosyl azid, Trifluoromethanesulfonyl azide or diphenylphosphoryl azide or mixtures thereof.
• Particularly these azides result in a fast conversion with high yields and a low amount of unwanted side-products.
• Another characteristic of the invention is directed to a process, wherein the starting educt (I) R-4-(3- methoxyphenyl)-3-methyl-4-oxobutanoate is obtainable via the synthesis steps i. - iii.: i. Reacting l-(3-methoxyphenyl)propan-l-one and glyoxylic acid in the presence of an acid
• Such pre-steps have been found suitable in order to generate the starting material (I) in an effective and easy way.
• these steps enable an easy work-up of the resulting products, thus clean substances are obtained exhibiting only a low degree of unwanted by-products.
• an intermediate product in the production of tapentadol can comprise (45,5R)-5-ethyl-5- (3 -methoxyphenyl) -4-methyldihydrofur an-2(3H) -one
• an intermediate product in the production of tapentadol can comprise (3S,4R)-4-(3-methoxyphenyl)-3-methylhexanoic acid
• an intermediate product in the production of tapentadol can comprise tert.- butyl [(2R,3R)-2-methyl-3-methoxyphenyl pentyl] carbamate
• Another inventive object reveals the use of a tapentadol HQ synthesized via the inventive intermediates in a pharmaceutical composition.
• Figure 1 depicts the inventive route of synthesis including the pre-steps 1 - 3, which result in the starting educt I of the main synthesis.
• Ketoester (I) 400g
• aq. Keto reductase solution 800g, 2x
• aq. Glucose dehydrogenase solution 400g, lx
• NADP phosphate buffer at pH 7.3
• phosphate buffer at pH 7.3 4.0 L, lOx
• the reaction was monitored with Chiral HPLC analysis (-40% conversion).
• the reaction mixture was extracted with tert.-Butylmethylether iBME (3 x 1.0 L). NaOH solution (10%, 1.05 eq.) was added to above iBME solution to hydrolyze ketoester [(R)-3] and (R,S)-hydroxyl ester.
• the mixture was agitated until all esters were hydrolyzed into the corresponding acids (monitored by HPLC).
• the keto acid was racemized and the aq. layer containing both ketoacid and hydroxyl acid was separated.
• the pH of the aqueous layer was adjusted to pH 2-3 with HC1 solution.
• the (R,S)-(hydroxyl acid) was converted into its corresponding lactone (-1-2 hours, monitoring by HPLC) while the keto acid remained unchanged.
• iBME (3 x 500ml) was charged and the pH of the aqueous layer was adjusted back to pH 8-9 with NaOH solution.
• the organic layer was separated and washed with basic solution to remove the residual keto acid.
• NaOH solution (10%, 0.5-0.6 eq.) was added into the iBME solution and the aqueous solution was separated.
• the pH of the aqueous layer was adjusted to pH 2-3 by addition of HC1.
• the reaction mixture 3 x 500 ml of iBME was added and the pH of the aqueous layer was adjusted to pH 8-9 with NaOH solution.
• the organic layer was separated and washed with basic solution (NaOH solution). Afterwards further NaOH (10% 0.5- 0.6 eq.) was added to the iBME layer and the aqueous layer with intermediate ((R,S)-4) was subjected to the oxidation reaction in next step.
• intermediate (III) 30.4 g
• MeOH 50 mL
• DIPEA 2.6 g
• Pd/C 15.2g, 5 wt% loading (dry basis) on activated carbon, wet support.
• the flask was evacuated and refilled with 1 atm of hydrogen for 4 times.
• the reaction mixture was stirred at room temperature (around 25 °C) for 24 h.
• starting material is less than 1%
• the mixture was filtered, and the Pd/C cake was washed with MeOH (2 x 40 mL).
• the combined filtrate was concentrated to give intermediate (IV) as a yellowish oil (-30.4 g, 100% yield, >99% purity, 93%ee, 94%de).
• Step d) includes for all variants i.-iii. the following product/educt reaction scheme:
• Acetone (3.78 ml, 5.14 mmol) is added at ambient temperature during 30 min and the overall reaction mixture is treated with 20 ml of hexane and cooled to -5°C. The resulting oily solid is isolated. The second crop is obtained by evaporation of the liquids and treating of the remaining residue with hexane.
• the Tapentadol hydrochloride (2.0 g) was charged into a 50 niL flask and then n-butyl alcohol (4 niL) was added. The mixture was heated to reflux for 30min. The mixture was slowly cooled to 5 ⁇ 10°C and stirred for 2h at this temperature. The precipitate was filtered and dried to give 0.8 g of Tapentadol hydrochloride, 40% yield, the main single impurity was decreased from 1.2% to 0.67%.
• the tapentadol hydrochloride (1.0 g) was charged into a 100 mL flask and then MIBC (60 mL) was added. The mixture was heated to reflux for 30min. Then the solvent was concentrated to about 10 mL and the mixture was stirred overnight at rt. The precipitate was filtered and dried to give 0.65 g of Tapentadol hydrochloride, 65% yield, the main single impurity was decreased from 0.97% to 0.71%.
• the tapentadol hydrochloride (1.0 g) was charged into a 50 mL flask and n-butyl alcohol (4 mL) was added. The mixture was heated to reflux for 30min. Then the mixture was stirred at rt overnight. The precipitate was filtered and dried to give 0.8 g of Tapentadol hydrochloride, 80% yield, the main single impurity was decreased from 0.71% to 0.48%.
• the tapentadol hydrochloride (1.0 g) was charged into a 50 mL flask and n-propanol (3 mL) was added. The mixture was heated to reflux for 30min. Then the mixture was stirred at rt overnight. The precipitate was filtered and dried to give 0.7 g of tapentadol hydrochloride, 70% yield, the main single impurity was decreased from 1.5% to 1.1%.

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• 2015
  • 2015-06-16 GB GB1510544.8A patent/GB2539442A/en not_active Withdrawn
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