Process for producing (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol

1. A process for producing (1R,3R,6R)-6-dimethylaminomethyl- 1-(3-methoxyphenyl)-cyclohexane-1,3-diol, (1S,3S,6S)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclo-hexane-1,3-diol, a mixture thereof, or an acid addition salt thereof, said process comprising:

reacting 3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one (II)

with an α,β-unsaturated ketone to form 2-dimethylaminomethyl-1-(3-methoxyphenyl)hexane-1,5-dione (III)

and cyclizing the 2-dlimethylaminomethyl-1-(3-methoxyphenyl)hexane-1,5-dione (III) to form 4-dimethylaminomethyl-3-hydroxy-3-(3-methoxyphenyl)cyclohexanone (IV)

2. A process according to claim 1 , further comprising reacting 3-methoxyaceto-phenone (I)

with an Eschenmoser salt to form the 3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one (II)

3. A process according to claim 1 , further comprising:

reducing the 4-dimethylaminomethyl-3-hydroxy-3-(3-methoxyphenyl)cyclohexanone (IV) to form (1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclo-hexane-1,3-diol) (Va) or (1S,3S,6S)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol (Vb) or a mixture thereof

and optionally reacting the (1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxyphenyl)cyclo-hexane-1,3-diol (Va) or (1S,3S,6S)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol (Vb) or a mixture thereof with an acid to form the corresponding acid addition salt or salts.

4. A process according to claim 2 , wherein the reacting of 3-methoxyacetophenone (I) is carried out as a Mannich reaction.

5. A process according to claim 4 , wherein the 3-methoxyacetophenone (I) is reacted with an Eschenmoser salt formed from tetramethyl diaminomethane and acetyl chloride.

6. A process according to claim 1 , wherein the reacting of 3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one (II) is carried out as a Michael addition.

7. A process according to claim 1 , wherein the reacting of 3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one (II) and the cyclizing of 2-dimethylaminomethyl-1-(3-methoxyphenyl)hexane-1,5-dione (III) are carried out in a one-pot reaction.

8. A process according to claim 1 , wherein 3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one (II) is reacted with a base and methyl vinyl ketone.

9. A process according to claim 8 , wherein the base is selected from the group consisting of NaOH, KOH, Tri-C 1-4 alkyl amines, sodium methanolate, potassium-tert-butylate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and sodium hydride.

10. A process according claim 3 , wherein sodium borohydride, lithium borohydride or diisobutylaluminium hydride is used as a reducing agent.

11. A process according to claim 1 , wherein a substantially racemic mixture of (1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexane-1,3-diol) (Va) and (1S,3S,6S)-6-dimethylaminomethyl- 1-(3-methoxyphenyl)cyclohexane-1,3-diol (Vb) or of the acid addition salts thereof is obtained.

12. A process according to claim 1 , wherein a phosphate acid addition salt is obtained.