Method for the preparation of an enantiomerically pure benzazepine

1. A method for the preparation of a cyclic compound according to Formula IIIa, comprising reacting 2-amino-3-benzylpyridine according to Formula lb and a compound according to Formula II,

wherein,

Z 1 and Z 2 are leaving groups, or together form oxygen creating the corresponding aldehyde;

X is a hydrocarbon having a carbon atom attached to the central carbon atom of formula II, comprising a reactive functional group and optionally a nitrogen atom, chosen in view of one or more subsequent reaction steps starting from the compound according to Formula IIIa to a ring closure to form mirtazapine; or X is —CO-Q or —CH 2 -Q, wherein Q is a hydrogen, or halogen, or a hydrocarbon substituent optionally comprising a nitrogen atom, or Q is —NHR or —OR wherein R is hydrogen or a hydrocarbon substituent.

2. The method according to claim 1 wherein the leaving group Z 1 and Z 2 in Formula II each independently are hydroxide, alkoxide, chloride, bromide, iodide, triflate, mesylate, tosylate or besylate.

3. The method according to claim 1 wherein in Formula II

Z 1 and Z 2 are OR 6 and OR 7 respectively wherein R 6 and R 7 are hydrocarbon or hydrogen as indicated in Formula IIa, or

Z 1 and Z 2 are together oxygen creating the corresponding aldehyde as indicated in Formula IIb

4. The method according to claim 1 for the preparation of the compound of Formula IIIb1 in enantiomeric excess

further comprising the steps:

1: subjecting a racemic mixture of said compound to an optical resolution step,

2: separating the desired enantiomer,

3: racemising the undesired enantiomer and

4: recycling the racemised undesired enantiomer to the optical resolution step 1.

5. The method according to claim 4 , wherein the compound of Formula IIIb1 is further reduced to a compound of Formula IIIb2

6. The method according to claim 5 , wherein Q is —NMeC 2 H 4 L, wherein L is a group reactive with the ring amine.

7. The method according to claim 1 , wherein X is —CO-Q or —CH 2 -Q, the reactive group in Q is reacted with an extender compound according to the Formula L-CH 2 —CH 2 —NMe-A, wherein L is a group reactive with the ring amine and A is a group reactive with Q.

8. The method according to claim 7 , wherein Q is a halogen, —NHR or —OR wherein R is hydrogen or a hydrocarbon substituent.

9. A compound according to Formula IIIb in racemic, enantiomeric excess or enantiomeric pure R or S form,

wherein X is a hydrocarbon having a carbon atom attached to the central carbon atom of formula II, comprising a reactive functional group and optionally a nitrogen atom, chosen in view of one or more subsequent reaction steps starting from the compound according to Formula IIIa to a ring closure to form mirtazapine; or X is —CO-Q or —CH 2 -Q, wherein Q is a hydrogen, or halogen, or a hydrocarbon substituent optionally comprising a nitrogen atom, or Q is —NHR or —OR wherein R is hydrogen or a hydrocarbon substituent.

10. A compound according to Formula IVb1 or IVb2 in enantiomeric pure form,

wherein L is a group reactive with the ring amine.