CN102977105A

CN102977105A - Synthesis method of 3(methyl),7-diazabicyclooctane

Info

Publication number: CN102977105A
Application number: CN2012105000348A
Authority: CN
Inventors: 张福治; 丁炬平; 张仁延; 余强
Original assignee: Cgenetech Suzhou China Co Ltd
Current assignee: Cgenetech Suzhou China Co Ltd
Priority date: 2012-11-30
Filing date: 2012-11-30
Publication date: 2013-03-20

Abstract

The invention discloses a synthesis method of 3(methyl),7-diazabicyclooctane. Aiming at the defects that the traditional synthesis method of 3(methyl),7-diazabicyclooctane has low reaction yield, requires strict conditions and does not easily realize purification, the invention proposes a way of performing addition ring closing between 1-methylpyrrole-2,5-diketone serving as a start raw material and nitromethoxymethylbenzyltrimethylsiliconmethylammonia and reducing with lithium aluminum hydride and finally performing debenzylation to obtain 3(methyl),7-diazabicyclooctane. According to the synthesis method disclosed by the invention, the whole process has high yield and is easy to operate, the product is easy to purify, and column chromatography is avoided; and the method is suitable for industrialization, and the cost of raw materials is greatly reduced.

Description

3 (methyl), 7-diazabicyclo octane synthetic

Technical field

The present invention relates to the 3(methyl), synthesizing of 7-diazabicyclo octane also relates to the synthetic of its intermediate and uses, and belongs to medical, chemical technology field.

Background technology

The 3(methyl), 7-diazabicyclo octane is important chemistry, chemical intermediate, be widely used in medicine and pesticide field, especially aspect antitumor and similar rheumatism new drug synthetic, be seen at present the analogue synthetic route of report seldom, and severe reaction conditions mostly, yield is low, is difficult for purifying, is difficult to industrialization.

Summary of the invention

The present invention is directed to the 3(methyl), 7-diazabicyclo octane synthetic method reaction yield in the past is low, condition is harsh, the deficiency that is difficult for purifying, invented described with 1-methylpyrrole-2, the 5-diketone is that ring is closed in starting raw material and the addition of n-formyl sarcolysine oxygen methyl-benzyl trimethyl silicane methyl ammonia, reduce last debenzylation with Lithium Aluminium Hydride again and obtain the 3(methyl), the route of 7-diazabicyclo octane makes whole process yield high, easy handling, the good purifying of product, avoid column chromatography, be fit to industrialization, raw materials cost reduces greatly.

Described 3(methyl), 7-diazabicyclo octane is synthetic, by 1-methylpyrrole-2, the 5-diketone is that starting raw material becomes (3) catalyst system therefor including but not limited to trifluoroacetic acid with n-formyl sarcolysine oxygen methyl-benzyl trimethyl silicane methyl ammonia addition pass cyclization, tosic acid, sulfuric acid, methylsulfonic acid etc., first-selected trifluoroacetic acid, solvent is including but not limited to tetrahydrofuran (THF), dioxane, methylene dichloride, ethylene dichloride etc., first-selected methylene dichloride, temperature of reaction is not limited to zero degree to 50 degree, first-selected 25 degree, and the time was not limited to 0.5 hour to 48 hours.

Described 3(methyl), 7-diazabicyclo octane is synthetic, revert to (4) reduction reagent including but not limited to Lithium Aluminium Hydride by intermediate (3), borine dimethyl sulphide, sodium borohydride/aluminum chloride, first-selected Lithium Aluminium Hydride, temperature of reaction is not limited to 25 degree to 100 degree, first-selected 65 degree, and the time is not limited to half an hour to 72 hour, first-selected 24 hours, wherein aftertreatment destruction Lithium Aluminium Hydride method was the saturated sodium pyrosulfate aqueous solution.

Above-mentioned with 1-methylpyrrole-2, the 5-diketone is that the chemical reaction route of starting raw material is as follows:

Embodiment

Embodiment:

Preparation compound (3):

Starting raw material 1-methylpyrrole-2,5-diketone 222 grams (2.0 moles) are dissolved in 2.5 liters of methylene dichloride, add n-formyl sarcolysine oxygen methyl-benzyl trimethyl silicane methyl ammonia 522.3 grams (2.2 moles), 5 milliliters of trifluoroacetic acids (catalytic amount), add rear room temperature reaction 24 hours, reaction solution is transferred PH to 11, layering with the sodium hydroxide of 1N, the organic phase washing, the saturated salt washing, anhydrous sodium sulfate drying filters, be spin-dried for, re-crystallizing in ethyl acetate obtains beige solid 327.3 grams (yield 67%).

Preparation compound (4):

Compound (3) 244.3 grams (1.0 moles) that the upper step makes are dissolved in 2.5 liters of anhydrous tetrahydro furans, add Lithium Aluminium Hydride 159.6 grams (4.2 moles) in batches, add rear temperature rising reflux reaction 24 hours, be cooled to subzero 10 degree, the saturated sodium bisulfate about 1 of temperature control dropping is raised to does not have γ-ray emission, continues to stir 1 hour, filter, the tetrahydrofuran (THF) washing, anhydrous sodium sulfate drying is spin-dried for after the filtration and obtains oily matter 181.4 grams (yield 84%).

Preparation compound (5) is the 3(methyl), 7-diazabicyclo octane:

Compound (4) 108 grams (0.5 mole) that the upper step makes are dissolved in 1 liter of methyl alcohol, palladium carbon 10 grams of adding 10%, with reaction 48 hours under 2 atmospheric hydrogen environments 60 degree temperature behind the hydrogen exchange 3 times, cooled and filtered, methyl alcohol is washed, obtain yellow oil crude product 63 grams after being spin-dried for, dissolving crude product is in hydrogenchloride/methyl alcohol of 500 milliliters of 2N, stirred salify 1 hour, a large amount of solids are separated out, and filter and obtain pure product hydrochloride, and hydrochloride extracts after dissociating with the sodium hydroxide of 1N is molten, be spin-dried for and obtain pure 3(methyl), 7-diazabicyclo octane 47 grams (yield 74.6%).

Claims

1. described with 1-methylpyrrole-2, the 5-diketone is that ring is closed in starting raw material and the addition of n-formyl sarcolysine oxygen methyl-benzyl trimethyl silicane methyl ammonia, reduce last debenzylation with Lithium Aluminium Hydride again and obtain the 3(methyl), the route of 7-diazabicyclo octane makes whole process yield high, easy handling, the good purifying of product, avoid column chromatography, be fit to industrialization, raw materials cost reduces greatly.

2. described 3(methyl), 7-diazabicyclo octane is synthetic, by 1-methylpyrrole-2, the 5-diketone is that starting raw material becomes (3) catalyst system therefor including but not limited to trifluoroacetic acid with n-formyl sarcolysine oxygen methyl-benzyl trimethyl silicane methyl ammonia addition pass cyclization, tosic acid, sulfuric acid, methylsulfonic acid etc., first-selected trifluoroacetic acid, solvent is including but not limited to tetrahydrofuran (THF), dioxane, methylene dichloride, ethylene dichloride etc., first-selected methylene dichloride, temperature of reaction is not limited to zero degree to 50 degree, first-selected 25 degree, and the time was not limited to 0.5 hour to 48 hours.

3. described 3(methyl), 7-diazabicyclo octane is synthetic, revert to (4) reduction reagent including but not limited to Lithium Aluminium Hydride by intermediate (3), borine dimethyl sulphide, sodium borohydride/aluminum chloride, first-selected Lithium Aluminium Hydride, temperature of reaction is not limited to 25 degree to 100 degree, first-selected 65 degree, and the time is not limited to half an hour to 72 hour, first-selected 24 hours, wherein aftertreatment destruction Lithium Aluminium Hydride method was the saturated sodium pyrosulfate aqueous solution.