WO2019035775A1 - Method for the preparation of tapentadol and its intermediates - Google Patents
Method for the preparation of tapentadol and its intermediates Download PDFInfo
- Publication number
- WO2019035775A1 WO2019035775A1 PCT/SK2018/000005 SK2018000005W WO2019035775A1 WO 2019035775 A1 WO2019035775 A1 WO 2019035775A1 SK 2018000005 W SK2018000005 W SK 2018000005W WO 2019035775 A1 WO2019035775 A1 WO 2019035775A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- reaction
- salt
- compound
- prepared
- mixture
- 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
Links
- 0 CC(CNC*)C(c1cc(OC)ccc1)=O Chemical compound CC(CNC*)C(c1cc(OC)ccc1)=O 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- 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
- 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
- C07C213/08—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 not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- 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
- C07C217/64—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 further substituted by singly-bound oxygen atoms
- C07C217/66—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 further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
- C07C217/72—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 further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain 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
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified 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
- C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified 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 having amino groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present disclosure relates to a new method for the preparation of tapentadol in the form of a base or its hydrogen chloride, whic involves the preparation of a salt (III.) from a mixture of diastereomers (H) by crystallization-induced asymmetric transformation (CIAT) with a high degree of diastereoselectivity through oxo-enol tautomeric equilibrium of covalent!y linked diastereomers, shifted towards the desired diastereomer without the use of chiral resolution wit c iral earboxyl acids.
- the desired derivative (III) is isolated from the mixture by simple filtration in high yield and high diastereomeric purity.
- (R)-phenySethylamine as a chirality mediator leads to the generation of the required stereogenie centre at the ot-posiiion to carbonyl and at the same time it enables a simple analytical cheek of the process as well as of subsequent stereoselective transformations without the use of chiral HPLC. This solution thus enables to increase the yield of this step of synthesis and subsequently also the total yield of tapentadol synthesis.
- the originator's and others' synthesis preferably uses the Mannich reaction from the appropriate 3-substxtuted propiophenone, formaldehyde and dimethylarnine under acidic conditions.
- cleavage of the racemic mixture of Mannich salts with enantiomerieaHy pure acid is used.
- the enanliomerically pure Mannich base is subjected to the diastereoselective Grignard reaction, in which the content of the undesired diastereomer needs to be cheeked. Its elimination by crystallization leads to yield losses and requires more demanding analytical instrumentation for the checking of undesired raeemization (chiral HPLC). Equally less stereodiscriminating ⁇ , ⁇ -dimethyIamino group lowers the diastereoselectivity of this reaction stage (addition of ethylmagnesium halide to the carbonyl group of the Mannich base), which lowers the total yield and increases the labour intensity of purifying ' this intermediate of tapentadol synthesis.
- the object of the present invention is a new method for tapentadol synthesis, whether in the form of a base or its salt, which involves the process of preparing diastereomerically and enantiottierically highly enriched Mannich salts (III) with covalently linked chirality mediator— (S)-phenylethylamine via the process of crystallization-induced asymmetric transformation (CIAT), which represents a transformation of an equilibrating mixture of two or more diastereomers in the reaction mixture by crystallization of one of them under reactio conditions.
- chirality mediator— (S)-phenylethylamine via the process of crystallization-induced asymmetric transformation (CIAT), which represents a transformation of an equilibrating mixture of two or more diastereomers in the reaction mixture by crystallization of one of them under reactio conditions.
- the synthesis of tapeniadol thus preferably begins from the propiophenone of oramla (I)
- This reaction known as the Mannich reaction takes place in a suitable solvent or without a solvent, it uses formalin, parafonnaldehyde or 1 ,3,5-trioxane as a formaldehyde source and a suitable acid.
- a polar aprotie solvent such as acetonitriie, aliphatic alcohols or lower aliphatic earboxyl acids may be used as a solvent.
- the reaction preferably takes place without the use of a solvent in the presence of concentrated hydrochloric acid at a temperature of 50-85 °C.
- a mixture of diastereomers (II) is obtained in the form of a base after the alkalization of a reaction mixture in a diastereomeric ratio close to 1 : 1.
- a strong acid HX such as hydrochloric acid, bydrobrornie acid, sulphuric acid, preferably hydrochloric acid
- suitable solvent system effective equilibration between the Mannich salt diastereomers, however, takes place through oxo-enol tautomeric equilibrium, as indicated in the diagram
- the equilibrium is shifted towards the desired salt (10) by stirring and its elimination from the reaction mixture in a suitable solvent or solvent mixture.
- the final product is isolated from the reaction mixture by simple filtration in high yield and high diastereomeric purity.
- the solvents used in this asymmetric transformation can be selected from aliphatic ketones, aliphatic alcohols, , ethers, non-pola aromatic hydrocarbons or mixtures thereof,
- the object of the present disclosure represents a new method for tapentadol synthesis, which uses diastereomerically pure Mannich salt (III) prepared by CiAT and involves the following steps;
- bases are selected from the hydroxides or carbonates of alkali metals:
- the organic solvent is selected from toluene, MTBE,. 2- mefhyltetrahydrofuran, methyl isobutyl ketone or methyl cyclopentyl ether.
- Fig. 1 Crystalline structure of Mannich salt III (X - CI)
- aminium chloride (III) (83%) (d.r. 99:1) is obtained.
- the catalyst is filtered off, washed with 2-methylietrahydiOfuran (100 ml), and the filtrate is subsequently concentrated at a temperature of 50 °C and a pressure of lO mbars,
- a solution of sodium hydroxide (30.6 g, 0.765 mol) in water (300 ml) is added, and the mixture is extracted using methyl isobutyi ketone (2 x 500 ml).
- the combined extracts are partially concentrated at a temperature of 70 °C and a pressure of 100 mbars.
- Hydrogen chloride (12,3 g, 0.337 mol) is introduced to the residue while stirring at a temperature of 10 °C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
La présente invention concerne un procédé de préparation de tapentadol sous forme d'une base ou de son chlorure d'hydrogène, ledit procédé implique la préparation d'un sel (III) à partir d'un mélange de diastéréomères (II) au moyen d'une transformation asymétrique induite par cristallisation (CIAT) par l'intermédiaire d'un équilibre tautomérique oxo-énol de diastéréomères liés de manière covalente, décalés vers le diastéréoisomère souhaité sans utilisation de résolution chirale avec des acides carboxyliques chiraux.The present invention relates to a process for preparing tapentadol in the form of a base or its hydrogen chloride, said process involves the preparation of a salt (III) from a mixture of diastereomers (II) by means of crystallization-induced asymmetric transformation (CIAT) via a tautomeric oxo-enol equilibrium of covalently linked diastereomers, shifted to the desired diastereoisomer without the use of chiral resolution with chiral carboxylic acids.
Description
Method for the preparation of tapentadol and its intermediates Field of inventio
The present disclosure relates to a new method for the preparation of tapentadol in the form of a base or its hydrogen chloride, whic involves the preparation of a salt (III.) from a mixture of diastereomers (H) by crystallization-induced asymmetric transformation (CIAT) with a high degree of diastereoselectivity through oxo-enol tautomeric equilibrium of covalent!y linked diastereomers, shifted towards the desired diastereomer without the use of chiral resolution wit c iral earboxyl acids.
S. Hi and (R, )~IS
The desired derivative (III) is isolated from the mixture by simple filtration in high yield and high diastereomeric purity. The use of (R)-phenySethylamine as a chirality mediator leads to the generation of the required stereogenie centre at the ot-posiiion to carbonyl and at the same time it enables a simple analytical cheek of the process as well as of subsequent stereoselective transformations without the use of chiral HPLC. This solution thus enables to increase the yield of this step of synthesis and subsequently also the total yield of tapentadol synthesis.
Background of the invention
Tapentadol of the structural formula (VIII)
iii
is a centrally acting analgesic with a dual mode of action as an opioid μ-agonist an at the same time a norepinepiiiine re-uptake inhibitor and is used for the treatment of moderate to severe acute pain.
The preparation of homochiral tapentadol requires gradual building of stereogenic centres and stringent checking of diastereomeric purity of individual reaction stages. Synthesis methods have bee described in detail in literature (P.P, Graezyk; O. Zbrpjkiewitz; S. Nerdinger: Tetrahedron: Asymmetry, 2017, 28 (3), 387-400.)
For the building of tapentadol molecule the originator's and others' synthesis preferably uses the Mannich reaction from the appropriate 3-substxtuted propiophenone, formaldehyde and dimethylarnine under acidic conditions. For the preparation of optically pure Mannich base, cleavage of the racemic mixture of Mannich salts with enantiomerieaHy pure acid is used.
Most ofte L-DBTA (EP 2046724, CN102320984) is used. Higher cleavage yields in these eases are provided, by modified Mannich intermediates (WO2G08G 12047, EP2049464, WQ2011/067714, WQ2014/005546), however, their preparation is more demanding and increases the cost of the synthesis. The main disadvantage of these processes is that all require enantioseparation of the subsequent intermediates, increase the number of reaction steps and use expensive reagents.
The use of covalently linked stereoisomers in the Mannich reaction with racemic 1 - phenylethylamine is indicated in the patent application WO 2013/11116.1. However, the authors do not define the absolute nor relative configuration of the Mannich base, and the given Mannich base with racemic 1-phenyiethyl amine is not even described in the experiment nor in the patent claims. Similarly, no method of isolation of the desired diastereomer after the Mannich reaction is specified.
In the next step, the enanliomerically pure Mannich base is subjected to the diastereoselective Grignard reaction, in which the content of the undesired diastereomer needs to be cheeked. Its elimination by crystallization leads to yield losses and requires more demanding analytical instrumentation for the checking of undesired raeemization (chiral HPLC). Equally less stereodiscriminating Ν,Ν-dimethyIamino group lowers the diastereoselectivity of this reaction stage (addition of ethylmagnesium halide to the carbonyl
group of the Mannich base), which lowers the total yield and increases the labour intensity of purifying 'this intermediate of tapentadol synthesis.
This problem is partially solved by patent EP 2 588 429, which uses N- methyibenzylamine instead of dimethylamine, achieving hig diastereomeric purity of the Grignard adduct in favour of the desired (2S,3R)~diastereomer. The disadvantage is. however, low yield of the starting optically pure Mannich base through cleavage with R)-maridelic acid.
The developing of a new method that would lead to high yields of the desired stereoisomer while maintaining excellent diastereoselectivity in the addition of a Grignard reagent to an optically pure Mannich base would enable to significantly increase the yield of the entire process.
Summary of the invention
The object of the present invention is a new method for tapentadol synthesis, whether in the form of a base or its salt, which involves the process of preparing diastereomerically and enantiottierically highly enriched Mannich salts (III) with covalently linked chirality mediator— (S)-phenylethylamine via the process of crystallization-induced asymmetric transformation (CIAT), which represents a transformation of an equilibrating mixture of two or more diastereomers in the reaction mixture by crystallization of one of them under reactio conditions. The advantage of such transfomiation, as opposed to the classical cleavage of racemate through diastereomeric salts, is a 'high yield of the desired diastereomer, theoretically reaching up to 100% (Anderson, 'N. Org. Process Res. Dev. 2005, 9, 800-813,).
(SJRtfl and (R,R)»ti
The advantage of such CIAT process is that in contrast with the cleavage by means of chiral organic acids it uses cheap HX achiral acids, such as HCI, HBr, H2SQ4. Higher stereomductio connectal with covaleMly linked diastereomers, such as in the case of diastereomeric salts, results in high yield and high diastereornerie purity of the final crystalline salt (III), which is obtained by simple filtration from a reaction mixture of equilibrating diastereomers. Checking the CIAT process of covalently linked diastereomers requires simpler analytical instrumentation.
The synthesis of tapeniadol according to the patent thus preferably begins from the propiophenone of oramla (I)
The compound of formula (I) is subjected to a reaction with (R)-phenylethyl formaldehyde and hydrochloric acid to give a mixture of diastereomers (II)
(S,R)-fl (FU*H<
This reaction known as the Mannich reaction takes place in a suitable solvent or without a solvent, it uses formalin, parafonnaldehyde or 1 ,3,5-trioxane as a formaldehyde source and a suitable acid. A polar aprotie solvent such as acetonitriie, aliphatic alcohols or lower aliphatic earboxyl acids may be used as a solvent. The reaction preferably takes place without the use of a solvent in the presence of concentrated hydrochloric acid at a temperature of 50-85 °C.
A mixture of diastereomers (II) is obtained in the form of a base after the alkalization of a reaction mixture in a diastereomeric ratio close to 1 : 1.
By the action of a strong acid HX, such as hydrochloric acid, bydrobrornie acid, sulphuric acid, preferably hydrochloric acid, in suitable solvent system, effective equilibration between the Mannich salt diastereomers, however, takes place through oxo-enol tautomeric equilibrium, as indicated in the diagram
til.
The equilibrium is shifted towards the desired salt (10) by stirring and its elimination from the reaction mixture in a suitable solvent or solvent mixture. The final product is isolated from the reaction mixture by simple filtration in high yield and high diastereomeric purity.
The solvents used in this asymmetric transformation can be selected from aliphatic ketones, aliphatic alcohols,, ethers, non-pola aromatic hydrocarbons or mixtures thereof,
The structure of the isolated salt ΪΠ was unequivocally proved by an X-ray analysis (Fig. 1).
Furthermore, the object of the present disclosure represents a new method for tapentadol synthesis, which uses diastereomerically pure Mannich salt (III) prepared by CiAT and involves the following steps;
A) The suspension of the salt (III) in the mixture of water and a suitable organic sol vent and the release of the corresponding free Mannich base (S,R)-II by the addition of a base. According to the present disclosure, bases are selected from the hydroxides or carbonates of alkali metals: The organic solvent is selected from toluene, MTBE,. 2- mefhyltetrahydrofuran, methyl isobutyl ketone or methyl cyclopentyl ether.
B) The alkylation of the base obtained in the previous step by means of ethylmagnesium. halide to give (2S,3R)-3~(3-methoxyphenyl)~2-methyi-l~(((R)-l- phenyle†hyl)ammo)pentan~3-ol (IV), as indicated in the following diagram:
This stage is characterised by high diastereoselectivity thanks to the presence of sterically bulky 1 -phenyl ethyl group on nitrogen. It has been surprisingl discovered that acidification of aminocarbinol (IV) with hydrochloric acid in a suitable solvent and subsequent crystallization result in significant enantiomeric and diastereomeric. enrichment of the final salt (V), which is obtained in yield and stereoisomeric purity of more than 99% ee and 99% de. Such synthetic sequence thus enables, compared to the existing processes, to significantly increase the total yield of tapentadpl synthesis.
C) Reductive methylation of the salt (IV) in a system of formaldehyde, formic acid in a suitable solvent, that sing with a base
V
D) Acylation of the isolated derivative from the previous step by trifluoroacetic anliydride in a suitable solvent to give a
E) Subsequent catalytie debenzylation of intermediate VI in hydrogen environment, in the presence of transition metals-based catalyst, preferably palladium, and finally reductive N-mefhylation by formaldehyde addition in hydrogen atmosphere, preferably with the same catalyst as in the previous step and in a single receptacle. After alkalization of the reaction mixture the product is isolated by extraction and converted to a salt by a reaction with hydrogen chloride in a suitable solvent.
(VII)
F) Finally O-demethylation of thus prepared derivative (VII) is done and optionally the demethy!ated product is converted to tapentadol acid addition salt (VIII)
Brief description of the drawings
Fig. 1 : Crystalline structure of Mannich salt III (X - CI)
Examples of realization Example 1
The Mannich reaction: preparation of a mixture of diastereomers 1 -(3-raetiioxyphenyl)-2>- metliyi-3-(((R)-l-phersylethyl)ammo)propan-l-on ((S,R)~iI d (R, )-1I)
To a solution of (R)-l~pheiiylaniine (121.2 g, 1 mol) i EtOH (600 ml) 36% hydrochloric acid (94.4 ml, 1.1 mol) is added while cooling at a temperature of 25-30 °C. Subsequently 3-niethoxy-propiophenone (164,2 g, 1 mol) and 37% solution of formaldehyde in water (82.3 ml, 1.1 mol) are added. The reaction mixture is subsequently ref!uxed for 24 hours. The alcohol is distilled off at reduced pressure, toluene (700 ml) is added to the residue and while stirring and cooling at a temperature of 25 -30 GC a solution of sodium hydroxide (52 g, 13 mo!) in water (600 ml) is added. The stirring is continued for 30 minutes and the toluene layer is separated. To the aqueous layer further 700 ml of toluene is added and the mixture is stirred for 30 minutes. By concentrating of the combined toluene extracts 282 g of l-(3- methoxyphenyl)-2~methyl-3-(((R)-l-phenylethyl)amino)propaii-l-on (95%) is obtained, as a mixture of diastereomers in a ratio of 1 :1. The concentrate will be used in the next stage.
Example 2
(S)-3-(3-meί o >φhenyl)-2-methyl-3-o o-N~((R)-l-phen lem l o an-l~aminium chloride (III)
To a solution of a mixture of diastereomers l-(3-methoxyphenyl)-2-meth.yl-3-(((R)-l- plienylethyl)an ino)propan-l-on from the previous step in methyl isobutyl ketone (MIBK) (1000 ml.) a solution of hydrogen chloride (54, 7 g, 1 ,5 mol) in MIBK (500 ml) Is added, and the mixture is heated to 80 °C. The reaction mixture is subsequently stirred for 24 hours at 40 °C. The product is filtered off, washed with MIBK (250 ml) and dried at 60 °C and a pressure of
SO nibars. 263 g of (S)-3«(3-niemox> henyl)~2~^
aminium chloride (III) (83%) (d.r. 99:1) is obtained.
¾ NMR (300 MHz, dmso-d6) δ 10.40 (s, ΪΗ), 9.08 (s, IH), 7.71-7.61 (m, IH), 7.61-7.36 (in, 6H), 7.33-7.21 (m, 1H), 4.41 (s, IH), 4.25 (dd, J - 12.1 , 7.3 Hz, 1H), 3.85 (s, 3H), 3.04 (s, IH), 2.90 (s, IH), 1.65 (d, J = 6.8 Hz, 3H), 1,15 (d? J - 7.2 Hz, 3H).
C NMR (75 MHz, dmso-d6) δ 200.74, 160.01, 137.79, 136.89, 130.58, 129.37, 129.30, 128.31, .121.34, 120.04, 1 13,46, 58.55, 55.94, 47.10, 38.45, 20.19, 17.38.
m.p> = 189 °C
a20- ÷36.6° (MeOH, C=2.0) Example 3
(S)-3»(3-methoxyphenyl)-2-methyl-3-oxo-N-((l )- 1 -phenylethyl)propan~ 1 -aminium chloride (HI)
To a solution of a mixture of diastereomers l-(3-methoxyphenyl)-2-methyI-3-(((R)-l- phenylethyl)ainino)piOpan-l-on (0.3 mol) from example 1 in cyclopentyl methyl ether (CPME) (300 ml) a solution of hydrogen chloride (16.4 g, 0.45 mol) in CPME (150 mi) is added, and the mixture is heated to 80 °C. The reaction mixture is subsequently stirred for 48 hours at 30 °C. Tl e product is filtered off, washed with CPME (TOO ml) and dried at 60 °C and a pressure of 50 mbars, 88.2 g of (S)-3-(3-methox> henyl)-2~metliyl-3-oxo~N-((R)~l-phenylethyl)propan~l^ aminium chloride (III) (88%) (d.r. 98:2) is obtained. m.p. = 189-190 °C Example 4
(S)-l-(3-methoxyphenyl)-2-memyl-3-(((R)-l-phenylethyl)amino)propan ((S,R)-II)
To a suspension of (S)-3-(3-mei'hoxyphenyl)-2-methyl-3-oxo-N-((R)-l - phenylethyl)propan-i-aminiu3T5 chloride (1Π) (168 g, 0.503 mol) in diethyl ether (500 ml) a solution of sodium carbonate (63.98 g, 0.604 mol) in water (600 ml) is added and the mixture is stirred until the solid part is dissolved. The ether layer is separated, and diethyl ether (300 mi) is added to the aqueous one, and the mixture is stin'ed for 30 minutes. The combined ether extracts are dried with magnesium sulphate, and it is concentrated to half volume, A solution of ($)- 1 -(3-methox}?phenyl)-2-methyl-3-(((R)- 1 -phenylethyl)amino)propan- 1 -on in ether, which will be used in the next step, is obtained.
Example 5
(2S,3R)~3~(3-methoxyphenyl)-2-m (IV)
To a mixture of magnesium (36.7 g, 1.51 mo!) and diethyl ether (100 ml) a solution of bromoethane (164.4 g, 1.51 mol) in diethyl eiher (900 ml) is added, while the temperature of the reaction mixture is maintained at temperature of 30-35 °C> Subsequently the cooling is stopped and the stirring is continued for 2 hours. A solution of eihylmagnesium bromide is cooled, and at. a temperature of 5 °C a solution of (S)-l-(3-memox}^henyl)-2-methyl-3-(((R)-l~ phenylethyl)ammo)propan-l-on in diethyl ether from the previous ste is added, and the stirring is continued for 30 min. To the reaction mixture a solution of ammonium chloride in water (1000 ml) at a temperature of 25-30 °C is added. The stirring is continued for 1 hour, until complete dissolution of the magnesium salts. The ether layer is separated, and the aqueous one is in addition extracted using ether (400 ml). The combined extracts are concentrated and (2$ 3R)~3-(3-memox>phenyI)~2-methyl- 1 -((l~phenylethyl)amino)pentan-3-oi (164.5 g), which will be used in the next step, is obtained.
Example 6
(2 S ,3R)-3 ~hydroxy~3 -(3-raethQxyphenyl)-2-methyl~N- ( 1 ~phenyletliyl)pentan-l~aminium chloride (IV.MC1)
To a solution of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-((l- phenylethyl)amino)pentan-3~ol (164.5 g, 0.503 mol) in isopropanoi (1000 ml) gaseous hydrogen chloride (20.2 g, 0.553 mol) is introduced at a temperature of 25-30 °C. The resulting suspension is cooled to -15 °C and left to stand at this temperature for 15 hours. The product is filtered off, washed using cooled isopropanoi (200 mi) and dried at 50 °C for 24 hours. 150,2 g of (2 S ,3R)-3-hydroxy-3-(3-methox phenyl)~2-meihyl-N-( 1 -phenylethyl)penian- 1 -aminium chloride (V) (82%) is obtained.
¾ NMR (300 MHz, dmso-d6) δ 9.68 (s, IH), 9,03 (s, IH), 7.67 (dd, J = 7.8, 1.7 Hz, 2H), 7,54- 7.42 (m, 3H), 7.18 (t, J = 7,9 Hz, IH), 6.82-6,69 (m, 3H)3 5.04 (s, IH), 434 (s, IH), 3.71 (s, 3H), 2.87 (s, IH), 2.41 s, IH), 2.33-2.22 (m, I H), 1.88-1.70 (m, 2H), 1.66 (d, J - 6.8 Hz, 3H), 0.80 (d, J « 6.8 Hz, 3H), 0.61 (t, J - 7.2 Hz, 3H).
i3C NMR (75 MHz, dmso~d6) δ .159.27, 145.99, 137.92, 129.33, 129.29, 128.98, 128.42, 118.80, 1 12.78, 111.70, 78.16, 58.40, 55.36, 48.15, 39.88, 32.00, 20.09, 14.76, 8.26.
m.p. = 221 °C
α20= +57.9° (Me OH, C=2.0)
Example 7
(2S,3R)-3-(3~meihoxyphen> )-2-^ (V)
To (2S,3R)-3-hydroxy-3-(3-methox phenyl)~2-metl yl-N-( 1 -phenyl ethyl)pentan- 1 - aminium chloride (150.2 g, 0.413 niol) a solution of sodium hydroxide (24.8 g, 0.619 mol) in water (500 ml) is added, and the mixture is extracted using toluene (2 x 500 ml). The combined organic extracts .are concentrated, and formic acid (75.99 g, 1.651 mol) and 37% solution of formaldehyde in water (100.5 g, 1.238 mol) are added to the concentrate. The mixture is heated at reflux for 4 hours to 85 °C. To the cooled reaction mixture a solution of sodium hydroxide (66,04 g, 1.651 mol) in water (400 ml) is added, while the temperature of the reaction mixture is maintained at 25-30 °C. The reaction mixture is extracted using toluene (2 x 300 ml). The combined extracts are filtered through silica gel (10 g) and concentrated at reduced pressure. (2S,3R)-3-(3-methoxyphenyl)-2-methyl- 1 ~(methyl((R)-l -phenyl ethyl ) amino)pentan-3 -ol , 141 g (quant.), is obtained in the form of colourless viscose oil.
!H NMR (300 MHz, dmso-d6) δ 7.42-7.27 (m, 5H), 7.24 (t, J = 8.0 Hz, IH), 7.01 (dd, J = 2.4, 1.6 Hz, 1H), 6.96-6.91 (m, 1H), 6.79 (ddd, J - 8.1 , 2.6, 0.7 Hz, IH), 6.65 (s, 1H), 3.81 (q, J = 6.9 Hz, 1 H), 3.75 (s, 3H), 2.30 (dd, J = 14.1, 9.9 Hz, I H), 2.20 -2.07 (m, 2H)5 2.03 (s, 3H), 1.98-1.71 (m, 2H), 1.29 (d, J = 6,9 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H), 0.69 (t, J = 7.3 Hz, 3H). i3C NMR (75 MHz, dmso-d6) δ 159.18, 147.34, 142.14, 128.71, 128.54, 128.27, 127.39, 119.41, 1 13.38, 1 1 3.25, 79.47, -61.96, 58.20, 55.28, 39.40, 36.87, 32.93, 15.05, 14.59, 8.27. a20- +86.6° (Me OH, C-2.0)
Example 8
Trifluoroacetylation of (2S,3R)-3-(3-methoxyphenyl)-2-methyl- 1 -(methyl((R)- 1 - phenyl ethyl)amino)pentan-3-oL The preparation of trifiuoroaeetoxy derivative (VI)
To a solution of intermediate from the previou step (5 g, 14.64 mmol) in - methyltetrahydrofuran (30 ml) trifiuoroacetic anhydride (3.23 g, 15.37 mmol) is added during 30 minutes while cooling at a temperature of 5-10 °C. The mixture is subsequently stirred for 30 minutes at 25 °C; after the completion of acylation the content of the starting substance is less than 1% HPLC. To the mixture a solution of sodium carbonate (3.88 g, 36.6 mmol) in water (50 ml) is added, and the mixture is extracted using methylte t ahydrofuran ( 50 ml). By
concentrating the extract a tr fluoroacetoxy derivative (VI) (99%) in the form of viscose oil is obtained.
Example 9
(2 ,3R)-3~(3-methoxyphenyl)- , ,2-trimethyipentan-l-aniiniw chloride (VII)
To a solution of intermediate from the previous step (104.5 g, 0.306 mo!) in 2- methylteti'ahydrofura (500 ml) trifiuoroacetic anhydride (77.1 g, 0.367 mol) is added during 30 minute while cooling at a temperature of 5-10 °C. The mixture is subsequently stirred fo 30 minutes at 25 °C. To the reaction mixture 5% Pd C (5.23 g) is added, and the mixture is hydrogenated using hydrogen at a pressure of 10 bars for 48 hours at a laboratory temperature. To the reaction mixture 37% solution of formaldehyde in water (37.3 g, 0.459 mol) is added, and the hydrogenation is continued at pressure of 10 bars for a period of 4 hours at a laboratory temperature. The catalyst is filtered off, washed with 2-methylietrahydiOfuran (100 ml), and the filtrate is subsequently concentrated at a temperature of 50 °C and a pressure of lO mbars, To the residue a solution of sodium hydroxide (30.6 g, 0.765 mol) in water (300 ml) is added, and the mixture is extracted using methyl isobutyi ketone (2 x 500 ml). The combined extracts are partially concentrated at a temperature of 70 °C and a pressure of 100 mbars. Hydrogen chloride (12,3 g, 0.337 mol) is introduced to the residue while stirring at a temperature of 10 °C. The mixture is left to crystallize for a period of 15 hours at a temperature of -20 °C, and subsequently the product is filtered off, washed with cold methyl isobutyi ketone (200 ml) and dried, 64.1 g of (2R,3R)-3-(3-methoxypheiiyl)-NiNi,2-trimethylpentan-l-aminium chloride (77%) is obtained, in the form of a colourless crystalline substance.
¾ NMR (300 MHz, dmso-d6) 6 10.53 (s, IH), 7.26 (t, J - 8.1 Hz, IH), 6.91-6.71 (m, 3H), 3.77 (s, 3H), 2.96-2.73 (m, 2H), 2.6 (d, J - 4.1 Hz, 3H), 2.64 (d, J = 4.2 Hz, 3H), 2.45 (ddd, J = 10.8, 6.9, 3.9 Hz, IH), 2.26-2.08 (m, IH), 1.83-1.68 (m, I B), 1.67-1.51 (m, IH), 1,09 (d, J - 6.6 Hz, 3H), 0.69 (t, J - 7.3 Hz, 3H).
i3C NMR (75 'MHz, dmso-d6) δ 159.78, 144.50, 129.80, 120.95, 1 14.69, 1 12.01 , 61.87, 55.43, 50.62, 44.67, 41.75, 34.15, 23.94, 16.31, 12.50.
m.p. = 1 3 °C
a20- -24.5° (Me OH, C-2.0) Example 10
(2R,3R)-3-(3-hydroxyphenyl)-N,N,2 rimethylpentai-l -aininiuxn chloride (VIII)
A mixture of (2R,3R)~3~(3-m.elhQxy henyl)-^ chloride (50 g, 0.184 mol) and 48% hydrobromic acid (500 g, 2.966 mol) is stirred at a temperature of 110 °C for a period of 4 hours. To the cooled reaction mixture 25% solution of ammonium in water (313 g, 4.6 mol) is added at a temperature of 25-30" °CS and the mixture is subsequently extracted using toluene (3 x 200 ml). The combined extracts are concentrated and the residue is dissolved in isopropanol (300 ml). Gaseous hydrogen chloride (7.38 g, 0.202 mol) is introduced into the solution while stirring at a temperature of 5-10 °C. The resulting suspension is stirred for 2 hours at 5 °C, and subsequently the product is filtered off and washed with cold isopropanol (50 ml). 43,2 g of (2R.3R)-3-(3-hydroxyphenyI)-N,N!2-trimethyipentan-l-aminium chloride (92%) is obtained, in the form of a colourless crystalline substance.
¾ NM (600 MHz, dmso-d6 δ 10.19 (s, 1 H), 9.39 (s, IB), 7.08 (t, J = 7.7 Hz, 1H), 6,63 (ddd, J = 8.1, 2.3, 0.9 Hz, IE), 6.61 -6.57 (m, 2H , 2.84-2.71 (m, 2H), 2.65 (s, 3H), 2,59 (s, 3H), 2.30 (ddd, J - 10.8, 6.9, 3.8 Hz, 1H), 2.09-2.01 (m, 1H), 1.69 (dqd, J = 14.6, 7.3, 3,9 Hz, 1H), 1.55— 1.45 (m, 1 H), 1.02 (d, J = 6.6 Hz, 3H), 0.64 (t, J = 7.3 Hz, 3H),
13C NMR (151 MHz, dmso-d6) δ 157.82, 144.14, 129.66, 1 19.12, 115.72, 1 13.87, 6.1.87, 50,54, 44.69, 41.68, 34.14, 24.01 , 16.16, 2.46,
m.p. = 204 °C
a20- -24.5° (Me OH, O2.0)
Claims
1. The method of preparatio of l R,2R)-3-(3-dimethylaiBino-l-ethyl-2-m.ethylpropyl}phe!riol or its salt with an added acid by reaction of 3-methoxyi3ropiopherione with 1- phenylethyl amine, characterised in that this method comprises the following steps:
a) reaction of 3-methoxypropiophenone of f rmula I
ί
with (R)-l -phenyleihylamine or its salt, fonTtal ehyde and a suitable acid under the conditions of the Maraiich reaction followed by
b) crystallization-induced asymmetric transformation (CIAT), as depicted, of the obtained compound of the general formula (H)
in the presence of a mineral aeid selected from the group of HC1, HBr or H2SO with a subsequent separation of thus prepared diastereomeric salt of the general formula (III), where X represents CI, Br or HSO4
c) this is followed by a release of a base and a reaction of thus obtained enamiomerically pure aminoketone with ethylmagnesium halide in an inert reaction medium under the conditions of the Grignard reaction.
d) this is followed by the transformation of thus prepared compound of the general formula (IV)
IV
to its crystalline salt (IV.HCI) and its reductive animation, by which a compound of formula (V) is prepared.
e) in the next step, acyiation of compound (V) is done using trifluoroaeetic anhydride in a suitable solvent to give compound (VI)
f) which is by catalytic debenzylation in hydrogen environment, in the presence of a transition metals-based catalyst, preferably palladium, and finally by reductive N- inethylation by adding formaldehyde in hydrogen atmosphere, preferably with the same catalyst as in the previous step and in one receptacle, transformed to compound (V!I); after alkalization of the reaction mixture the product is isolated by extraction and converted to a salt by a reaction with hydrogen chloride in a suitable solvent
(VII)
g) finally Q-dernethyiation of thus prepared derivative (VO) and optionally conversion of the demethylated product to tapentadol acid addition salt (VIII) are done
2, The method according to claim 1, characterised in that the mixture of diastereomeric Mannich bases (II) prepared in step a) from propiophenone,. ■R)-phenyiethylamine> formaldehyde and a corresponding acid by the Mannich reactio is i ste b) acted upon by a mineral acid from the group of HC1, HBr or H2SO4 under the conditions of crystallization- induced as mmetric transformation. (CIAT) in a suitable solvent and at a suitable temperature
with a subsequent separation of thus prepared diastereomeric salt of the general formula (III), where X represents CI, Br or HS04.
3, The method according to claim 1, characterised in that Grignard addition product (IV) obtained in step b) is subjected in step d) to the crystallisation by which enantiomerically and diastereomerically highly pure salt of an inoalcohol (IV.HCI) is prepared for the subsequent reductive methylatipn to give derivative (V).
4, The method according to claim 1, cfearacterised In that derivative (V) obtained in step d) is subjected to the "one-pot" reaction sequence based on the O-aeylation of derivative V using trifluoroacetic anhydride to give derivative (VI) and its catalytic O-debenzylation and N- debenzyiaiion, and the subsequent reductive animation of the debenzylated intermediate to give product (VII).
5. Chemical compounds of formu . (Ill), where X represents CI, Br, HSO4,
iSi as intermediates of tapentadol preparation.
6. Chemical compound of formula (IV) or its
as intermediates of tapentadol preparation,
7. Chemical compound of formula (V) or its
as intermediates of tapentadol preparation.
8. Chemical compound of formul
as intermediates of tapen tadol preparation.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EA202090197A EA202090197A1 (en) | 2017-08-18 | 2018-08-14 | METHOD FOR PRODUCING TAPENTADOL AND ITS INTERMEDIATE COMPOUNDS |
| EP18769245.4A EP3713911A1 (en) | 2017-08-18 | 2018-08-14 | Method for the preparation of tapentadol and its intermediates |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SK81-2017A SK812017A3 (en) | 2017-08-18 | 2017-08-18 | Method for preparing of tapentadol and its intermediates |
| SKPP00081-2017 | 2017-08-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2019035775A1 true WO2019035775A1 (en) | 2019-02-21 |
Family
ID=65362569
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SK2018/000005 Ceased WO2019035775A1 (en) | 2017-08-18 | 2018-08-14 | Method for the preparation of tapentadol and its intermediates |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP3713911A1 (en) |
| EA (1) | EA202090197A1 (en) |
| SK (1) | SK812017A3 (en) |
| WO (1) | WO2019035775A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN119176758A (en) * | 2024-11-26 | 2024-12-24 | 苏州盛迪亚生物医药有限公司 | Method for preparing tapentadol or pharmaceutically acceptable salt thereof by immobilized catalysis |
| CN119192000A (en) * | 2024-11-26 | 2024-12-27 | 苏州盛迪亚生物医药有限公司 | Method for preparing tapentadol or its pharmaceutically acceptable salt by continuous flow reaction |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008012047A1 (en) | 2006-07-24 | 2008-01-31 | Grünenthal GmbH | Process for the preparation of (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol |
| WO2008012283A1 (en) * | 2006-07-24 | 2008-01-31 | Janssen Pharmaceutica Nv | Preparation of (2r,3r)-3-(3-methoxyphenyl)-n,n,2-trimethylpentanamine |
| EP2049464A1 (en) | 2006-07-24 | 2009-04-22 | Grünenthal GmbH | Preparation of 3-ý(1r,2r)-3-(dimethylamino)-1ethyl-2-methylpropyl¨phenol |
| WO2011067714A1 (en) | 2009-12-01 | 2011-06-09 | Archimica Srl | New process for the preparation of tapentadol and intermediates thereof |
| CN102320984A (en) | 2011-07-25 | 2012-01-18 | 江苏恩华药业股份有限公司 | Preparation method of (R)-3-(3-methoxy phenyl)-N,N,2-trimethylpent-3-ene-1-amine |
| WO2013111161A2 (en) | 2012-01-10 | 2013-08-01 | Msn Laboratories Limited | Process for the preparation of 3-aryl-2-methyl-propanamine derivatives and polymorphs thereof |
| WO2014005546A1 (en) | 2012-07-06 | 2014-01-09 | 江苏恩华药业股份有限公司 | Preparation method of tapentadol hydrochloride and compounds for preparation of tapentadol hydrochloride |
-
2017
- 2017-08-18 SK SK81-2017A patent/SK812017A3/en unknown
-
2018
- 2018-08-14 WO PCT/SK2018/000005 patent/WO2019035775A1/en not_active Ceased
- 2018-08-14 EP EP18769245.4A patent/EP3713911A1/en not_active Withdrawn
- 2018-08-14 EA EA202090197A patent/EA202090197A1/en unknown
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008012047A1 (en) | 2006-07-24 | 2008-01-31 | Grünenthal GmbH | Process for the preparation of (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol |
| WO2008012283A1 (en) * | 2006-07-24 | 2008-01-31 | Janssen Pharmaceutica Nv | Preparation of (2r,3r)-3-(3-methoxyphenyl)-n,n,2-trimethylpentanamine |
| EP2046724A1 (en) | 2006-07-24 | 2009-04-15 | Grünenthal GmbH | Process for the preparation of (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol |
| EP2049464A1 (en) | 2006-07-24 | 2009-04-22 | Grünenthal GmbH | Preparation of 3-ý(1r,2r)-3-(dimethylamino)-1ethyl-2-methylpropyl¨phenol |
| WO2011067714A1 (en) | 2009-12-01 | 2011-06-09 | Archimica Srl | New process for the preparation of tapentadol and intermediates thereof |
| CN102320984A (en) | 2011-07-25 | 2012-01-18 | 江苏恩华药业股份有限公司 | Preparation method of (R)-3-(3-methoxy phenyl)-N,N,2-trimethylpent-3-ene-1-amine |
| WO2013111161A2 (en) | 2012-01-10 | 2013-08-01 | Msn Laboratories Limited | Process for the preparation of 3-aryl-2-methyl-propanamine derivatives and polymorphs thereof |
| WO2014005546A1 (en) | 2012-07-06 | 2014-01-09 | 江苏恩华药业股份有限公司 | Preparation method of tapentadol hydrochloride and compounds for preparation of tapentadol hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| ANDERSON, N., ORG. PROCESS RES. DEV., vol. 9, 2005, pages 800 - 813 |
| P.P. GRACZYK; O. ZBROJKIEWITZ; S. NERDINGER, TETRAHEDRON: ASYMMETRY, vol. 28, no. 3, 2017, pages 387 - 400 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN119176758A (en) * | 2024-11-26 | 2024-12-24 | 苏州盛迪亚生物医药有限公司 | Method for preparing tapentadol or pharmaceutically acceptable salt thereof by immobilized catalysis |
| CN119192000A (en) * | 2024-11-26 | 2024-12-27 | 苏州盛迪亚生物医药有限公司 | Method for preparing tapentadol or its pharmaceutically acceptable salt by continuous flow reaction |
| CN119176758B (en) * | 2024-11-26 | 2025-05-09 | 苏州盛迪亚生物医药有限公司 | A method for preparing tapentadol or its pharmaceutically acceptable salt by solid-support catalysis |
Also Published As
| Publication number | Publication date |
|---|---|
| EA202090197A1 (en) | 2020-05-27 |
| SK812017A3 (en) | 2019-03-01 |
| EP3713911A1 (en) | 2020-09-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11434201B2 (en) | Processes for preparing pyrrolidine compounds | |
| EP0947498B1 (en) | Optically active nitro alcohol derivatives, optically active amino alcohol derivatives, and process for preparing the same | |
| CN107382783B (en) | A kind of chiral beta-amino acid derivative and preparation method thereof | |
| ES2640313T3 (en) | New procedure for the preparation of tapentadol and its intermediates | |
| EP2588429B1 (en) | New process for the synthesis of tapentadol and intermediates thereof | |
| EP2123628B1 (en) | A process for preparing optical pure milnacipran and its pharmaceutically accepted salts | |
| EP3199516B1 (en) | Process for the preparation of metaraminol | |
| WO2019035775A1 (en) | Method for the preparation of tapentadol and its intermediates | |
| US20200406243A1 (en) | Bifunctional chiral organocatalytic compound having excellent enantioselectivity, preparation method therefor, and method for producing non-natural gamma-amino acid from nitro compound by using same | |
| JP4045722B2 (en) | Amine compounds, intermediates, production methods and optical resolution agents | |
| EP2221300B1 (en) | Methods for resolution of the mixture of the optical isomers, especially the racemate of pinocembrin | |
| KR20130107698A (en) | A PROCESS FOR PREPARING HIGH PURITY OF (s)-METOPROLOL | |
| JP6113826B2 (en) | (S)-Improved method for producing equol | |
| US5942629A (en) | Process for producing optically active pyrrolidine derivatives | |
| JPH09268146A (en) | Method for producing optically active fluorine-containing hydroxy compound | |
| JP6666213B2 (en) | (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl ) Method for producing tartrate, and (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbo using the tartrate Method for producing nitrile and its salt | |
| JP4339074B2 (en) | Process for producing optically active 1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine | |
| WO1996027581A1 (en) | Enantioselective synthesis of cyclic amino alcohols | |
| Beliaev et al. | Approaches to Enantiomerically Pure 3, 4-Dihydro-2H-1-Benzopyran-3-Amines | |
| WO2014016852A1 (en) | Asymmetric synthesis of (-)-venlafaxine using organocatalyst | |
| JP2016536367A (en) | A novel intermediate of tapentadol | |
| JP2017519832A (en) | Novel method for the synthesis of optically pure β-aminoalcohols | |
| EP4116288A1 (en) | Racemization of (s) and/or (r)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1- one and its mixtures | |
| JP2001106661A (en) | Amine compounds, intermediates, production methods and optical resolution agents | |
| CA2491020A1 (en) | Phenol derivatives and method of use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18769245 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| ENP | Entry into the national phase |
Ref document number: 2018769245 Country of ref document: EP Effective date: 20200318 |