# US 5,352,798 A · Process for preparing dithio-ethylanino 9A-methoxymitosanes

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- Number: US 5,352,798 A
- Document ID: US5352798A
- Status: Granted
- Kind: A
- Application number: 07/945,793
- Filed: 1992-09-16
- Granted: 1994-10-04
- Earliest claimed: 1990-03-08
- Assignees: Bristol-Myers Squibb Company
- Inventors: Daniel A. Benigni; Kenton L. Shultis
- Web page: https://patentgrep.com/patent/US5352798A

## CPC

- C07D 487/14: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

7-(Diphenylmethyl)oxy-9a-methoxymitosane is a novel intermediate for conversion into 7-amino and 7-oxy-9a-methoxymitosanes and is also useful for inhibiting mammalian tumor growth. The compound is prepared by reacting 7-hydroxy-9a-methoxymitosane with diazodiphenylmethane. In a preferred reaction, the compound is prepared from mitomycin C via 7-hydroxy-9a-methoxymitosane without drying (water removal). The intermediate is advantageously converted to the very effective anti-tumor agent 7-[2-(4-nitrophenyldithio)ethylamino]-9a-methoxymitosane in unexpectedly high yields using a two step process where the first step constitutes conversion to 7-[2-(2-pyridyldithio)ethylamino]-9a-methoxymitosane or 7-[2-(3-nitro-2-pyridyldithio)ethylamino]-9a-methoxymitosane.

## Claims

### Claim 1

Process for producing 7-[2-(4-nitrophenyldithio)ethylamino]-9a-methoxymitosane from 7-(diphenylmethyl)oxy-9a-methoxymitosane comprising the steps of
(a) reacting 7-(diphenylmethyl)oxy-9a-methoxymitosane with 2-pyridyldithioethylamine to produce 7-[2-(2-pyridyldithio)ethylamino]-9a-methoxymitosane, and
(b) reacting the product of step (a) with p-nitrothiophenol to produce 7-[2-(4-nitrophenyldithio)ethylamino]-9a-methoxymitosane.

### Claim 2

Process for producing 7-[2-(4-nitrophenyldithio)ethylamino]-9a-methoxymitosane from 7-(diphenylmethyl)oxy-9a-methoxymitosane comprising the steps of
(a) reacting 7-(diphenylmethyl)oxy-9a-methoxymitosane with 2-(3-nitro-2-pyridyldithio)ethylamine to produce 7-[2-(3-nitro-2-pyridyldithio)ethylamino]-9a-methoxymitosane, and
(b) reacting the product of step (a) with p-nitrothiophenol to produce 7-[2-(4-nitrophenyldithio)ethylamino]-9a-methoxymitosane.

### Claim 3

Process for producing 7-[2-(3-nitro-2-pyridyldithio)ethylamino]-9a-methoxymitosane which comprises reacting 7-(diphenylmethyl)oxy-9a-methoxymitosane with 2-(3-nitro-2-pyridyldithio)ethylamine to produce 7-[2-(3-nitro-2-pyridyldithio)ethylamino]-9a-methoxymitosane.

### Claim 4 (depends on 1)

The process of claim 1 wherein step (a) comprises dissolving the 7-(diphenylmethyl)oxy-9a-methoxymitosane in methanol and adding to this a solution of 2-pyridyldithioethylamine hydrochloride in methanol and triethylamine in sufficient amount to convert the hydrochloride to the free base and reacting at a temperature ranging from 15.degree. C. to 25.degree. C.

### Claim 5 (depends on 2)

The process of claim 2 wherein step (a) comprises dissolving the 7(diphenylmethyl)oxy-9a-methoxymitosane in methanol and adding to this a solution of 2-(3-nitro-2-pyridyldithio)ethylamine hydrochloride in methanol and triethylamine in sufficient amount to convert the hydrochloride to the free base and reacting at a temperature ranging from 0.degree. to 30.degree. C.