Process for the preparation of optical antipode of vincamine and new indole derivatives

Claim 2

A PROCESS FOR THE PREPARATION OF THE OPTICAL ANTIPODE OF VINCAMINE, WHICH COMPRISES THE STEPS OF: A. OXIDIZING (+)-VINCADIFFORMINE WIH A PERACID UNDER NITROGEN, IN THE ABSENCE OF LIGHT AND IN THE PRESENCE OF A WATER-IMMISCIBLE SOLVENT SELECTED FROM THE GROUP CONSISTING OF AROMATIC SOLVENTS, ALIPHATIC CHLORINATED HYDROCARBONS AND ETHER FOR A TIME AT LEAST SUFFICIENT FOR PRODUCING (+)-1,2-DEHYDRO-16-CARBOMETHOXY-16-HYDROXY-NOXYASPIDOSPERMIDINE, AND B. REDUCING THE (+)-1,2-DEHYDRO-16-CARBOMETHOXY-16HYDROXY-N-OXYASPIDOSPERMIDINE OF STEP (A) IN THE PRESENCE OF A LIQUID LOW MOLECULAR WEIGHT ORGANIC ACID WITH TRIPHENYLPHOSPHINE FOR A TIME AT LEAST SUFFICIENT FOR FORMING A PRODUCT COMPRISING A MIXTURE OF THE OPTICAL ANTIPODES OF:

Claim 3

VICAMINE, 2. 16-EPI-VICAMINE, AND

Claim 4

VICAMINE, 2. 16-EPI-VICAMINE, AND

Claim 5

16-epi-vicamine, and

Claim 6

16-epi-vicamine, and

Claim 7

16-epi-vincamine, and

Claim 8

16-epi-vincamine, and

Claim 9

The process of claim 1 which comprising oxidizing (+) vincadifformine with an equal molar quantity of a peracid for a time at least sufficient to produce (+)-N-oxy-vincadifformine and then treating the (+)-N-oxy-vincadifformiNe with an equal molar quantity of a peracid for a time at least sufficient to produce the (+)-1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxyaspidospermidine.

Claim 10

The process of claim 2 which comprises treating the (+)-N-oxy-vincadifformine with an equimolar quantity of a peracid for 1 to 5 days.

Claim 11

apo-vincamine.

Claim 12

apo-vincamine.

Claim 13

apo-vincamine.

Claim 14

apo-vincamine.

Claim 15

APO-VINCAMINE.

Claim 16

APO-VINCAMINE.

Claim 17

The process of claim 1 which further comprises isolating the optical antipode of vincamine from the mixture by crystallization from a member selected from the group of acetone, methanol, ethanol and propanol.

Claim 18

The process of claim 4 wherein the products of step (b) are separated into fractions by a plurality of successive crystallizations.

Claim 19

The process of claim 1 which further comprises isolating the optical antipode of vincamine from the mixture by chromatography with aluminum-oxide and then crystallization from acetone.

Claim 20

The process of claim 6 wherein the product mixture of step (b) is separated by chromatography into two fractions wherein the more polar fraction consisting essentially to a major extent of said antipode of vincamine and to a minor extent of the optical antipode of 16-epi-vincamine and the less polar fraction consisting essentially of the optical antipode of apo-vincamine, and wherein the constituents of the more polar fraction are separated by crystallization.

Claim 21

The process of claim 1 which comprises reducing the (+)-1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxyaspidospermidine with an approximately equimolar quantity of the reducing agent in solution in a liquid organic acid of low molecular weight at an elevated temperature for 1 to 2 hours under nitrogen.

Claim 22

The process of claim 1 which comprises oxidizing (+)-vincadifformine with about two molar equivalents of a peroxide for a time at least sufficient to form the (+)-1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxy-aspidospermidine.

Claim 23

The process of claim 1 which comprises oxidizing (+)-vincadifformine with about 2 molar equivalents of a peroxide for 1 to 5 days.

Claim 24

A process of claim 1 which comprises oxidizing (+)-vincadifformine for 1 to 5 hours with an equimolar quantity of a peracid at room temperature under nitrogen and in the absence of light.

Claim 25

A process of claim 11 which further comprises washing the reaction solution with aqueous alkaline solution to remove the major part of the peracid and its conversion products, and then distilling the reaction solution to obtain a residue containing (+)-N-oxy-vincadifformine.

Claim 26

The process of claim 11 which comprises treating the (+)-N-oxy-vincadifformine with an equimolar quantity of a peracid for 1 to 5 days.

Claim 27

The process of claim 1 wherein said liquid low molecular weight organic acid is acetic acid.

Claim 28

The process of claim 1 wherein said peracid is selected from the group of peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, p-nitroperbenzoic acid, trifluoro-peracetic acid, performic acid and perphthalic acid.

Claim 29

A process for the preparation of the optical antipode of vincamine, which comprises the steps of a. oxidizing (+)-vincadifformine with an equal molar quantity of a peracid for about 1 to 5 hours under nitrogen, in the absence of light, and in the presence of a water-immiscible organic solvent selected from the group consisting of aromatic solvents, ethers and chlorinated aliphatic hydrocarbons, to produce (+)-N-oxy-vincadifformine; b. washing the reaction solution with aqueous alkaline solution to remove the major part of the peracid and its conversion products; c. distilling the reaction solution to obtain a residue containing (+)-N-oxy-vincadifformine; d. oxidizing the (+)-N-oxy-vincadifformine with an equal molar quantity of a peracid for between 1 and 5 days under nitrogen, in the absence of light, and in the presence of a water-immiscible organic solvent selected from the group consisting of aromatic solvents, ethers, and chlorinated aliphatic hydrocarbons, to produce (+)-1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxy-aspidospermidine; e. the peracid of steps (a) and (d) being selected from the group of peracetic acid, perbenzoic acid, m-chloro-perbenzoic acid, p-nitroperbenzoic acid, trifluoroperacetic acid, performic acid and perphthalic acid; f. reducing the (+)-1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxyaspidospermidine of step (e) with triphenylphosphine in the presence of acetic acid for a time at least sufficient for forming a product comprising a mixture of the optical antipodes of:

Claim 30

A process for the preparation of the optical antipode of vincamine, which comprises the steps of a. oxidizing (+)-vincadifformine with an equal molar quantity of a peracid for about 1 to 5 hours under nitrogen, in the absence of light, and in the presence of a water-immiscible organic solvent selected from the group consisting of aromatic solvents, ethers and chlorinated aliphatic hydrocarbons, to produce (+)-N-oxy-vincadifformine; b. washing the reaction solution with aqueous alkaline solution to remove the major part of the peracid and its conversion products; c. distilling the reaction solution to obtain a residue containing (+)-N-oxy-vincadifformine; d. oxidizing the (+)-N-oxy-vincadifformine with an equal molar quantity of a peracid for between 1 and 5 days under nitrogen, in the absence of light, and in the presence of a water-immiscible organic solvent selected from the group consisting of aromatic solvents, ethers, and chlorinated aliphatic hydrocarbons, to produce (+)-1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxy-aspidospermidine; e. the peracid of steps (a) and (d) being selected from the group of peracetic acid, perbenzoic acid, m-chloro-perbenzoic acid, p-nitroperbenzoic acid, trifluoroperacetic acid, performic acid and perphthalic acid; f. reducing the (+)-1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxyaspidospermidine of step (e) with triphenylphosphine in the presence of acetic acid for a time at least sufficient for forming a product comprising a mixture of the optical antipodes of:

Claim 31

The process of claim 16 wherein said aqueous alkaline solution is aqueous sodium bicarbonate solution.