Process for the preparation of 3-[(1R,2R)-3-(Dimethylamino)-1-ethyl-2-methylpropyl]-phenol

Abstract

A process for the preparation of a compound of formula (I) and of a acid salt (T) wherein R.sup.1 is selected from the group consisting of alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, R.sup.2 and R.sup.3, are, independently of each other, selected from the group consisting of alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, R.sup.4, R.sup.5, R.sup.6 and R.sup.7, are independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein the acid salt is a 2,3-Ditoluoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid salt, 2,3-Dianisoyl tartaric acid salt, 2,3-Dibenzoyl tartaric acid mono(dimethylamide) salt or a mixture of two or more thereof, wherein the tartaric acid salt (T) of the compound of formula (I) contains at least 90% by weight of the tartaric salt of the compound of formula (Ia) based on the total weight of the acid salt of the compound of formula (I).

##STR00001##

Claims

1. A process for the preparation of a compound of formula (I) ##STR00227## the process comprising (a1) providing a compound of formula (II) ##STR00228## (a2) reacting the compound of formula (II) with an amine HN(R.sup.2)(R.sup.3) and reducing the resulting reaction product with hydrogen in the presence of a catalyst, to give the compound of formula (I).

2. The process of claim 1 comprising (a1) providing a compound of formula (II) ##STR00229## (a2) reacting the compound of formula (II) with HN(R.sup.2)(R.sup.3)) in the presence of a reducing agent, thereby forming a compound of formula (III) ##STR00230## (a3) optionally isolating the compound of formula (III), (a4) reducing the compound of formula (III) with hydrogen in the presence of a catalyst, to give the compound of formula (I).

3. A process for the preparation of a compound of formula (I) ##STR00231## the process comprising (aa) providing a compound of formula (IX) ##STR00232## (ab) providing a compound of formula (X) ##STR00233## (ac) reacting the compound of formula (IX) with the compound of formula (X) in the presence of Zn to give a compound of formula (XI) ##STR00234## (ad) dehydrating the compound of formula (XI) to give a compound of formula (XIIa) ##STR00235## and/or a compound of formula (XIIb) ##STR00236## (ae) reducing the compound of formula (XIIa) and/or (XIIb), to give the compound of formula (I).

4-5. (canceled)

6. The process according to claim 1, wherein compound of formula (I) ##STR00237## comprises a diastereomeric mixture of the compounds of formula (Ia) and formula (Ib) ##STR00238##

7. The process of claim 1 wherein the process further comprises (a) providing a compound of formula (I) ##STR00239## comprising a diastereomeric mixture of the compounds of formula (Ia) and formula (Ib) ##STR00240## wherein the providing is by a process according to claim 1, (b) forming an acid salt (T*) of at least part of the compound of formula (I) by treating the compound of formula (I) with a chiral acid in a suitable solvent, and precipitating at least part of the acid salt (T*) formed, thereby obtaining a mixture comprising the precipitated acid salt (T) and the solvent; (c) optionally separating the precipitated acid salt (T) of the compound of formula (I) from the mixture obtained in (b), wherein the acid salt (T) of the compound of formula (I) contains at least 90% by weight of the acid salt of the compound of formula (Ia) based on the total weight of the acid salt (T) of the compound of formula (I),

8-9. (canceled)

10. The process of claim 1, further comprising (i) providing an acid salt (T) of a compound of formula (I) wherein the acid salt (T) is prepared by a process according to claim 7 (ii) (ii) transforming the group —OR.sup.1 to OH, (iii) optionally purifying the compound obtained in (ii) to give the compound of formula (XIV) ##STR00241## (iv) optionally preparing pharmaceutically acceptable salt or solvate of compound (XIV) of (ii) or (iii).

11-15. (canceled)

16. A compound of formula (II) ##STR00242## wherein R.sup.1 is selected from the group consisting of alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, R.sup.4, R.sup.5, R.sup.6 and R.sup.7, are independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl.

17. A compound of formula (III) ##STR00243## wherein R.sup.1 is selected from the group consisting of alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, R.sup.2 and R.sup.3, are, independently of each other, selected from the group consisting of alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, R.sup.4, R.sup.5, R.sup.6 and R.sup.7, are independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl.

18. A compound of formula (IV) ##STR00244## wherein R.sup.8 is —CH(isopropyl).sub.2.

19-20. (canceled)

Description

EXAMPLES

Synthesis of (1E)-1-hydroxy-2-methylpent-1-en-3-one sodium salt

[0602] ##STR00214##

[0603] In 2 L four-necked flask (pre-dried, filled with Ar) equipped with mechanic stirred, dropping funnel 250 mL, termometer and tube with calcium chloride 26 g (1.08 mol) of sodium hydride was placed. 600 mL of toluene was added and flask placed in ice-bath. Methanol (5 mL) was added to toluene, till evolution of gas was clearly seen. Dropping funnel was charged with mixture of 3-pentanon and ethyl formate. Reagents were added to the mixture in such manner, that temperature did not rise above 10° C. Oily, sticky precipitate was formed which imparts stirring. When gas evolution ceases, toluene was replaced with 600 mL of diethyl ether and stirring was continued overnight. The following day white-off precipitate was collected via filtration and dried in rotavapour (HPLC: 100% a/a).

Synthesis of O-Protected Ketenols

[0604] ##STR00215##

[0605] In 2 L roundbottomed flask 1-hydroxypent-1-en-3-on (96.3 g, 0.84 M) is placed. 1.2 L of isopropanol was added along with p-toluenesulfonic acid (8.0 g, 42 mM). Efficient condenser was fitted and mixture was heated for 16 hours (overnight). Solvent was evaporated on rotavapour. Crude reaction mixture was transferred to 250 mL roundbottomed flask. Distillation afforded fraction boiling at 90-95° C. Yield was 74.5 g (56.5%) of yellow oil. HPLC analysis confirmed purity of 84%.

Synthesis of Methyl Derivative

[0606]

TABLE-US-00001 Results Amount N.sup.o Type Reagents [g] Yield [%] Purity [%] 1 E 1-hydroxypent-1-en-3-on sodium salt 0.75 36 95 (2.2 g, 1.62 mmol); methyl iodide (2.3 g, (HPLC) 1.62 mmol); DMF 40 mL 2 E sodium (1E)-2-methyl-3-oxopent-1-en- 74.6 58 98 1-olate 64.1 g (1.0 eq.), citric acid 120 g, (HPLC) pH = 4, separation; methyl iodide 35 mL (1.0 eq) drop wise addition at −78° C. acetone 16 h 3 E 1-hydroxypent-1-en-3-on sodium salt 1.05 82 99 (1.36 g. 1 mmol); p-TsOH 1 mmol; (HPLC) methanol 20 mL 4 U 1-hydroxypent-1-en-3-on (0.66 mol), 73.3 86 60 MeOH 300 mL, p-TsOH cat. reflux, (HPLC) overnight

Synthesis of Ethyl Derivative

[0607]

TABLE-US-00002 Results Amount Yield N.sup.o Type Reagents [g] [%] Purity [%] 1 E 1-hydroxypent-1-en-3-on sodium 1.0 77 77 salt (1.36 g, 1 mmol); p-TsOH (HPLC) 1 mmol; ethanol 20 mL

Synthesis of Isopropyl Derivative

[0608]

TABLE-US-00003 Results Amount Yield N.sup.o Type Reagents [g] [%] Purity [%] 1 E 1-hydroxypent-1-en-3-on sodium salt 1.1 70 98 (1.36 g 1 mmol); p-TsOH 1 mmol; (HPLC) isopropanol 20 mL; distilation 2 E 3.6 g of crude reaction mixture; filtered 3.16 88 97 through silica pad (HPLC) 3 E 10 g of reaction mixture; distillation 4.3 + 3.4 43 (77) 93 (HPLC)

Synthesis of diisopropylcarbinol Derivative

[0609]

TABLE-US-00004 Results Amount Yield N.sup.o Type Reagents [g] [%] Purity [%] 1 E 1-hydroxy-2-methyl-1-en-3-one 21.4 37.6 99 34 g (0.3 mol); (HPLC) 2,4-dimethyl-3-pentanol 69.7 g (0.6 mol); p-TsOH 1.7 g; toluene 250 mL

[0610] Heating of en one with t-butanol gave product is field less than 5%.

Addition of Lithiumorganic Reagents to Carbonyl Function

[0611] ##STR00216##

[0612] In three headed 2 L flask equipped with condenser fitted with calcium chloride containing tube, septum and termomether, bromoanisole 28.7 g (0.154 mol) was dissolved in 280 mL of anhydrous THF (distilled over sodium, with benzophenone as indicator). Flask was placed in acetone-dry ice bath and chilled to −78° C. 96 mL of nBuLi (0.154 mol) solution in hexanes (c=1.6 M) was added dropwise with syringe in such manner that temperature of reaction did not exceed −70° C. Reaction mixture was stirred for 30 minutes. Later 17.4 mL (0.141 mol) of BF.sub.3 etherate was added immediately with syringe. Immediately solution of O-isopropyl-1-hydroxy-penten-3-on in mixture of 20 mL of glyme and 20 mL of THF was added via syringe, in such manner that reaction temperature did not exceed −70° C. Mixture was stirred for 2 hours in acetone-dry ice bath. Ice-cold solution of 13.8 g NH.sub.4Cl (0.256 mol) in 300 mL of water was added and mixture allowed to warm up to room temperature. Mixture was transferred to separating funnel. Organic phase was separated, dried over magnesium sulfate for 10 minutes. Solvent was removed on rotavapour. Crude product was purified by chromatography using mixture of hexanes:ethyl acetate 50:1. Fraction of Rf=0.2 were collected. Yield 18.6 g (70.4%).

TABLE-US-00005 Results Amount Yield N.sup.o Type Reagents [g] [%] Purity [%] 1 P Bromoanisole 86.2 g (0.46 mol); nBuLi 34.2 43.5 90 1.6M in hexane 288 ml (0.46 mol); (HPLC) BF.sub.3-etherate 52.2 mL (0.42 mol); 1,2- dimethoxyethan 40 mL (0.384 mol); O- isopropyl-1-hydroxy-penten-3-on 60 g (0.384 mol); THF 1000 mL aldehyde 1 separated — — — aldehyde 2 separated 14.3 — 90 (HPLC) 2 P Bromoanisole 115 g (0.615 mol); nBuLi 66.4 63.5 94 1.6M in hexane 384 mL (0.615 mol); (HPLC) BF.sub.3-etherate 69.4 mL (0.564 mol); 1,2- dimethoxyethan 53.2 mL (0.512 mol); O-isopropyl-1-hydroxy-penten-3-on 80 g (0.512 mol); THF 1000 mL aldehyde 1 separated 16.8 — 86 (HPLC) aldehyde 2 separated 4.4 84 (HPLC) 3 P Bromoanisole 43 g (0.23 mol); nBuLi 25.2 64.3 93 1.6M in hexane 144 mL (0.23 mol); (HPLC) BF.sub.3-etherate 26.1 mL (0.21 mol); 1,2- dimethoxyethan 20 mL (0.192 mol); O- isopropyl-1-hydroxy-penten-3-on 30 g (0.192 mol); THF 450 mL aldehyde 1 separated — — — aldehyde 2 separated 4.95 — 82 (HPLC) 4 P Bromoanisole 97.5 g (0.52 mol); nBuLi 59.1 66.7 94 1.6M in hexane 325 mL (0.52 mol); (HPLC) BF.sub.3-etherate 59 mL (0.478 mol); 1,2- dimethoxyethan 45 ml (0.43 mol); O- isopropyl-1-hydroxy-penten-3-on 67:,8 g (0.43 mol); THF 1000 ml aldehyde 1 separated 20.1 93 (HPLC) aldehyde 2 separated 6.8 91 (HPLC) 5 P Bromoanisole 56 g (0.30 mol); nBuLi 27.3 54 91 1.6M in hexanes 187 mL (0.30 mol); (HPLC) BF.sub.3-etherate 34 mL (0.275 mol); 1,2- dimethoxyethan 26 ml (0.25 mol); O- isopropyl-1-hydroxy-penten-3-on 38:,9 g (0.249 mol); THF 500 mL aldehyde 1 separated 4.0 75 (HPLC) aldehyde 2 separated 4.3 84 (HPLC) 6 P Bromoanisole 86.2 g (0.46 mol); nBuLi 51.6 65.8 97 1.6M in hexanes 288 mL (0.46 mol); (HPLC) BF.sub.3-etherate 52.2 ml (0.42 mol); 1,2- dimethoxyethan 40 ml (0.384 mol); O- isopropyl-1-hydroxy-penten-3-on 60 g (0.384 mol); THF 900 ml aldehyde 1 separated 22.8 75 (HPLC) aldehyde 2 separated — — — 7 P Bromoanisole 56 g (0.30 mol); nBuLi 45.7 90 90 1.6M in hexanes 187 ml (0.30 mol); (HPLC) BF.sub.3-etherate 34 ml (0.275 mol); 1,2- dimethoxyethan 26 ml (0.25 mol); O- isopropyl-1-hydroxy-penten-3-on 38.9 g (0.249 mol); 450 ml aldehyde 1 separated 17.1 75 (HPLC) aldehyde 2 separated — — — 8 P Bromoanisole 28.7 g (0.154 mol); 18.6 70 97 nBuLi 1.6M in hexanes 96 ml (0.154 mol); (HPLC) BF.sub.3-etherate 17.4 ml (0.141 mol); 1,2-dimethoxyethan 13.3 ml (0.128 mol); O-isopropyl-1-hydroxy-penten-3- on 20 g (0.128 mol); THF 300 ml

Reductive Amination of Aldehyde, Synthesis of OMe-Tapentadol

[0613] ##STR00217##

Reductive Amination Over Palladium on Carbon.

[0614] 3-(3-methoxyphenyl)-2-methylpent-2-enal (10.31 g, 0.05 mol) was dissolved in 100 ml of MeOH pure grade. Dimethyl amine hydrochloride (16.31 g, 0.2 mol) was added and mixture was stirred to dissolve salt of amine. Triethylamine (20.2 g, 0.2 mol) and wetted 10% Pd/C (0.53 g, 0.0005 mole) were added and whole mixture placed in glass cylinder, fitted with Teflon cork containing hole for plastic tube. Tube fitted with o-ring and plastic tube was fitted to cork and bottle placed inside Parr apparatus, and connected via tube with pressured hydrogen tank. Apparatus valve was set to “open”. Valve was fitted with rubber tube, connected to vacuum pump. Pump was started and when pressure dropped below 50 bar apparatus valve was set to “close”. Immediately hydrogen tank was set to “open” and bottle was pressurized slowly with hydrogen at pressure of 1 bar. Hydrogen tank was set to close as soon pressure inside bottle reached 1 bar. Bottle was shaken for 120 hours. During reaction pressure was checked every two hours during daytime and pressure kept at 1 bar. After 120 hours apparatus valve was set to“open” and whole hydrogen slowly released. Methanol from reaction mixture was removed on rotavapour (bath temperature 25° C.). Ethyl acetate (100 ml) and 1 N HCl (100 ml) were added to remaining oil. Organic phase was washed with 1 N HCl (10 ml) until no product was detected in organic phase (usually two or three washings are enough). Organic phase was discarded and aqueous phase was alkalized to pH=8 with sodium bicarbonate 1 N solution (130-140 ml). Aqueous phase was washed three times with 10 ml of ethyl acetate. Organic phase was combined, dried over magnesium sulfate. Removal of solvent yielded 0.5 g (5%) of OMe-Tapentadol with isomer ratio (S,R)+(R,R) 47%, (R,S) 33%, (S,S) 20%.

TABLE-US-00006 Hydride Allylic Allylic OMe- Yield/ No source Base alcohol amine TAP Purity notes relative ratio of isomers (S,R) (R,R) (R,S) (S,S) 1 Pd/C H.sub.2 TEA — 26% 74% 82% 3 atm (E)-aldehyde relative ratio of isomers 45 42 13 2 Pd/C H.sub.2 TEA — — 100%  52% Conversion 2.36 atm full (Z)-aldehyde relative ratio of isomers 47 37 16 3 Pd/C H.sub.2 TEA —  9% 91% 90% 56% 1 atm (E)-aldehyde relative ratio of isomers 48 40 12 4 Pd/C H.sub.2 TEA — 14% 86% 97% 30% 1 atm (E)-aldehyde relative ratio of isomers 45 41 14 5 Pd/C H.sub.2 TEA —  4% 96% 100%  2.36 atm (Z)-aldehyde relative ratio of isomers 40 40 20
Reductive Amination, Synthesis of (2Z,E)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-2-en-1-amine

##STR00218##

[0615] In 100 ml of chloroform pure grade, placed in 250 ml round-bottomed flask, Z-3-(3-methoxyphenyl)-2-methylpent-2-enal (4.08 g 20 mM) was dissolved. Acetic acid (2.4 g 40 mM) and dimethyl amine hydrochloride (8.16 g 100 mM) were added. Mixture was mixed with magnetic bar for 15 minutes to achieve complete dissolution of dimethyl amine hydrochloride. Sodium triacetoxyborohydride (8.5 g, 40 mM) was added and reaction mixture was allowed to react for 4 hours. HPLC analysis shown that full conversion of substrate was obtained and 58% of product formed. Solution was transferred to separating funnel (250 ml) and washed three times with 30 ml of water. Aqueous phases were combined, washed with 20 ml of ether. NaOH 4.4 g was added and mixture was washed three times with ether. Organic extracts were combined, dried over magnesium sulfate for 10 minutes. Ether was removed on rotavapour. Amine was dissolved in ether HPLC grade (50 ml) and slowly, 2.6 M solution of HCl in ether (8 ml) was added with mixing. 4.02 g (75%) of white solid was obtained via filtration and drying.

TABLE-US-00007 Results Amount Yield N.sup.o Type Reagents [g] [%] Purity [%] 1 P dimethylamine hydrochloride 32.58 g (0.4M) 10.7 50 97 acetic acid 9.6 g (0.16M) (HPLC) sodium triacetoxyborohydride 33.88 g (0.16M) Z:E 97:3 3-(3-methoxyphenyl)-2-methylpent-2-enal 16.3 g (0.08M) [Z:E 97:3] NaOH 17.6 g (0.44M) chloroform 2 P dimethylamine hydrochloride 30.98 g (0.38M) 11.9 58 92 acetic acid 9.13 g (0.152M) (HPLC) sodium triacetoxyborohydride 32.21 g (0.152M) Z:E 3-(3-methoxyphenyl)-2-methylpent-2-enal 31:63 15.5 g (0.076M) [Z:E 31:59] NaOH 16.7 g (0.418M) chloroform 3 dimethylamine hydrochloride 30.64 g (0.375M) 12.34 55 97 acetic acid 9.03 g (0.15M) (HPLC) sodium triacetoxyborohydride 31.9 g (0.15M) Z:E 3-(3-methoxyphenyl)-2-methylpent-2-enal 22:75 15.3 g (0.075M) [Z:E 27:51] NaOH 16.5 g (0.413M) chloroform 4 P dimethylamine hydrochloride 8.16 g (100 mM) 4.02 75 (58 >99 acetic acid 2.4 g (40 mM) HPLC) Z:E sodium triacetoxyborohydride 8.5 g (40 mM) 100:0 3-(3-methoxyphenyl)-2-methylpent-2-enal 4.08 g (20 mM) [Z:E 99.7:0.3] NaOH 4.4 g (110 mM) chloroform 5 P dimethylamine hydrochloride 8.16 g (100 mM) 4.25 79 (86 >99 acetic acid 2.4 g (40 mM) HPLC) Z:E sodium triacetoxyborohydride 8.5 g (40 mM) 0:100 3-(3-methoxyphenyl)-2-methylpent-2-enal 4.08 g (20 mM) [Z:E 1:99] NaOH 4.4 g (110 mM) chloroform

Synthesis of 2-bromo-N,N-dimethylpropanamide

[0616] ##STR00219##

[0617] 1 L 3-necked round bottomed flask was placed in ice bath and charged with 500 ml of chloroform. Dimethyl amine hydrochloride 37.8 g (1.5 eq.) and TEA 39.6 g (1.25 eq.) were added and mixing was continued until complete dissolution of hydrochloride. Flask was fitted with termomether and 100 ml dropping funnel. Funnel was charged with bromopropionyl bromide 67.65 g. Bromide was added dropwise while temperature was maintained below 10° C. When all bromide was added reaction was left mixing for 1 hour. Reaction mixture was transferred to 1 L flask and solvent was removed in vacuo. 250 ml of ethyl acetate was added and reaction mixture was transferred to separatory funnel. Organic phase was washed consequently: 3*150 ml 1M HCl, 3*25 ml water, 3*150 ml 1M NaHCO3, 3*25 ml water, 2*25 ml brine. Organic phase was dried over magnesium sulfate for 30 minutes. Solvent was removed in vacuo yielding 41.5 g (74%) of yellowish oil. Purity >99%.

TABLE-US-00008 Yield Yield Purity NMR/ No Type Conditions (%) (g) (%) LCMS 1 U Scale 0.1 mol: 85.5 15.4 >99 OK dimethylamine hydrochloride 12.8 g (1.5 (HPLC) eq.), 2-bromopropionyl bromide 21.6 g (1 eq.), TEA 12.65 g (1.25 eq.) chloroform 500 ml 2 P Scale 0.31 mol: 74 41.5 >99 OK dimethylamine hydrochloride 37.8 g (1.5 (HPLC) eq.), 2-bromopropionyl bromide 67.65 g (1 eq.), TEA 39.6 g (1.25 eq.) chloroform 500 ml

Reformatsky Reaction. Synthesis of 3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide

[0618] ##STR00220##

[0619] In 500 ml three necked flask equipped with condenser and dropping funnel zinc dust 14.66 g was placed. Magnetic bar was placed inside along with iodine crystal. Dust was mixed while heated with hot-gun. Heating was ceased when purple vapours of iodine started to form. When vapours condensed again in form of yellow film dropping funnel was charged with solution of 2-bromo-N,N-dimemethylpropanamide 34.44 g, 3-methoxyphenyl-ethylketone 33.46 g in 250 ml of THF. Solution was added dropwise on still hot zinc dust over 30 minutes. Whenever mixture was not boiling it was heated up again. Solution started to became white and milky. It forms foams when heated up to much. Gentle reflux was sustained overnight. The following day, mixture was decanted from remains of zinc. Solvent removed in vacuo. Crude product was purified on silica gel using mixture of hexanes:ethyl acetate 4:1 as eluent. Product with Rf=0.3 was gathered (one diastereomer), second Rf=0.2 was discarded. Reaction yielded 16.0 g (30%) of product with purity >99%.

Dehydration of 3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide

[0620] ##STR00221##

[0621] Reaction was up-scaled and 20 g of product was produced. After purification by liquid chromatography in eluent hexanes:ethyl acetate 1:6 pure compound was obtained and its structure confirmed. Four isomers of alkene were formed, two with “exo” C═C bond, and two with “endo”:

##STR00222##

[0622] 3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide 27.0 g was placed in 500 ml flask fitted with Dean-Stark trap and condenser. 200 ml toluene were added along with drop of concentrated sulfuric acid. Heating was continued until no more water was condensing in trap. Organic phase was transferred to separatory funnel, washed with 3*20 ml 1 M NaHCO.sub.3 1*20 ml water. Organic phase was dried over magnesium sulfate for 30 minutes and solvent was evaporated. Process yielded 21.3 g (84%) of product with purity 97%.

Reduction of 3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-enamide

[0623] ##STR00223##

[0624] 9.77 g of 3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-enamine was dissolved in dry THF (200 ml). LiAlH.sub.4 1.65 g in pellets (ca. 0.5 g each pellet) was added in one portion. Immediately LAH starts to dissolve and gas evolution is observed. After 45 minutes 1.65 g of water was added, then 3.3 g of saturated solution of NaOH, and again 4.95 g of water. White pellets were formed in solution. Solution was filtered through Schott funnel. THF was removed in vacuo. 7.75 g of crude product was obtained which was purified on silica gel using mixture of hexane:EtOAc 1:5 as eluent. 5.92 g (64%) of product were obtained with purity 94%.

TABLE-US-00009 No. Type Conditions Amount Purity Yield Notes 1 E 3-(3-methoxyphenyl)- 2.25 g 95% 75% Full conversion. N,N,2-trimethylpent- Side products found. 3-enamine 3.21 g LiAlH.sub.41.97 g (4 eq.) r.t. overnight. 2 U 3-(3-methoxyphenyl)- 7.75 g crude 94% 64% LC:EtOAc: n-hexane 5:1 N,N,2-trimethylpent- 5.92 g pure product 3-enamine 9.77 g LiAlH.sub.41.65 g (1.1 eq) 45 minutes. (mixture of isomers used)

Hydrogenation; Synthesis of [3-(3-metoxyphenyl)-2-methylpentyl]-dimethylamine (According to WO 2008/01246)

[0625]

TABLE-US-00010 [00224] No Type Conditions amount purity Yield 1 P. 3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1- 29.1 g 93.7% 96.0% amine (30.52 g, 1.0 eq.), dissolved in EtOH (76 ml) and in Et.sub.2O (4 ml). Pd/C (1.098 g) and HCl (3.5 ml, 0.302 eq.) were added. Reaction continued in parr apparatus overnight. pH.sub.2 = 3.5 atm 2 P. 3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-  4.1 g 94.9% 78.5% amine (5.58 g, 1.0 eq.), dissolved in EtOH (14 ml) and in Et.sub.2O (1 ml). Pd/C (0.2007 g) and HCl (0.65 ml, 0.302 eq.) were added. Reaction continued in parr apparatus overnight. pH.sub.2 = 3.5 atm

Chiral Crystallization of OMe-Tapentadol—Examples

[0626] ##STR00225##

Method A. (One Equivalent of Chiral Acid).

[0627] 0.100 g (0.42 mmol) of O-methyl-Tapentadol was placed in a vial and dissolved in 1 ml of ethyl acetate. 0.153 g (0.42 mmol) of (−)DBTA was placed in a vial and dissolved in 1 ml of ethyl acetate. Solution of (−)DBTA was placed in a syringe and added dropwise to the solution of O methyl-Tapentadol. Immediately crystals started to form. The vial was kept at room temperature for 24 h. Solid residue was filtered off and analyzed.

Method B. (One to 0.4 Equivalent of Chiral Acid. 0.6 Equivalent of Achiral Acid).

[0628] 0.100 g (0.42 mmol) of O-methyl-Tapentadol was placed in a vial and dissolved in 1 ml of ethyl acetate. 0.060 g (0.168 mmol) of (−) DBTA was placed in a vial and dissolved in 1 ml of ethyl acetate. 0.08 ml of 3.1 N solution of HCl in ethyl acetate was added to the solution of (−) DBTA. Solution of (−) DBTA and HCl was placed in a syringe and added dropwise to the solution of O-methyl-Tapentadol. Immediately crystals started to form. Vial was kept at room temperature for 24 h. Solid residue was filtered off and analyzed.

Method C. (One to 0.4 Equivalent of Chiral Acid).

[0629] 0.100 g (0.42 mmol) of O-methyl-Tapentadol was placed in a vial and dissolved in 0.5 ml of ethyl acetate. 0.060 g (0.168 mmol) of (−) DBTA was placed in a vial and dissolved in 0.5 ml of ethyl acetate. Solution of (−) DBTA was placed in a syringe and added dropwise to the solution of O-methyl-Tapentadol. Immediately crystals started to form. The vial was kept at room temperature for 24 h. Solid residue was filtered off and analyzed.

[0630] All O-methyl-Tapentadol chiral resolution analyses were performed on either HPLC Agilent 1200 or HPLC Dionex Ultimate 3000 using Astec Chirobiotic V2 4.6/250 mm 5 micrometer column. Mobile phase 98.5% MeOH. 0.1% AcOH. 0.05% NH3*H2O (28-30% solution). flow 0.4 ml. time 40 min. 10° C.

Example 1

[0631] Crystallization was performed according to method A. 1.09 g of O-methyl-Tapentadol. 1.66 g of (−)DBTA and 50 ml of ethyl acetate was used. Crystallization started at 50° C. and was slowly cooled down to 20° C. and kept at this temperature for 24 hours. Crystals were filtered, collected and analyzed. Process yielded 1.02 g of salt. Isomers ratio (S,R+R,R):(R,S):allylic amine:(S,S) according to chiral HPLC 74:17:3:6.

Example 2

[0632] Crystallization was performed according to method B. 0.380 g of O-methyl-Tapentadol from example 1. 0.425 g of (−)DBTA (0.74 eq.) and 10 ml of ethyl acetate consisting 0.43 mmol of HCl was used. Crystallization started at 50° C. and was slowly cooled down to 20° C. and kept at this temperature for 24 hours. Crystals were filtered, collected and analyzed. Process yielded 0.5755 g. Isomers ratio (S,R+R,R):(R,S):allylic amine:(S,S) according to chiral HPLC 94.5:3:1.5:1.

Example 3

[0633] Crystallization was performed according to method C. 0.139 g of O-methyl-Tapentadol from example 2 0.190 g of (−)DBTA (0.9 eq.) and 5 ml of ethyl acetate was used. Crystallization started at 50° C. and was slowly cooled down to 20° C. and kept at this temperature for 24 hours. Crystals were filtered, collected and analysed. Process yielded 0.219 g of salt. Isomers ratio (%): (R,R):(S,R):(S,S):(R,S)=99.5:0:0:0.5 (according to chiral HPLC).

Example 4

[0634] Crystallization was performed according to method A. 0.3 g (1.26 mmol) of O-methyl-Tapentadol. 0.459 g (1.26 mmol) of (−)DBTA and 25 ml of ethyl acetate was used. Crystallization started at 20° C. and was kept at 20° C. for 24 hours. Crystals were filtered, collected and analyzed. Process yielded 0.1655 g of salt and 0.071 g and amine (after liberation). Isomers ratio (S,R+R,R):(R,S):allylic amine:(S,S) according to chiral HPLC 63.48:9.8:14.4:3.73.

Example 5

[0635] Crystallization was performed according to method B. 0.071 g (0.3 mmol) of O-methyl-Tapentadol from example 4. 0.068 g (0.19 mmol) of (−)DBTA and 1 ml of ethyl acetate consisting 0.11 mmol of HCl. Crystallization started at 20° C. and was kept at 20° C. for 24 hours. Crystals were filtered, collected and analysed. Process yielded 0.0163 g. Isomers ratio (R,R):(S,R):(S,S):(R,S)=93.9:2.3:2.9:0.9 (according to chiral HPLC).

Deprotection, Synthesis Tapentadol

[0636]

TABLE-US-00011 [00226] Yield Nr Scale Conditions (%) Notes 1 2 mmol 3-(3-methoxyphenyl)-2methyl-pentyl-dimethylamine 0.47 g NMR hydrochloride 0.55 g mixture of isomers (S,R) + (R,R) 3:1 OK D,L-Methionin 0.37 g Methanesulfuric acid 2.15 ml 14 hours in 80° C. Crystallization IPrOH:water

[0637] Reaction mixture was dissolved in isopropanol and 1 drop of water was added. The reaction mixture was stirred and heated in 80° C. for 15 minutes. Reaction mixture was cooled down slowly. Crystalline was filtered.

SHORT DESCRIPTION OF THE FIGURES

[0638] FIG. 1 and FIG. 2 show preferred synthesis schemes according to the invention.

CITED PRIOR ART

[0639] WO 2008/012047 [0640] EP 0 693 475 A [0641] WO 2004/108658 [0642] WO 2011/067714 [0643] WO 2011/080736 [0644] WO 2008/01246