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Preparation process method of gadobutrol epoxy side chain intermediate

A preparation process, alcohol epoxy technology, applied in the direction of organic chemistry, etc., can solve the problems of insufficient product purity, reduce production costs, and cannot realize green and pollution-free promotion of mutual benefit, so as to improve product purity and product quality, improve purity and quality , Reduce the effect of equipment anti-corrosion level and process equipment cost

Active Publication Date: 2017-07-21
穆云
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the current existing preparation methods, either using concentrated sulfuric acid as a catalyst cannot achieve green pollution-free promotion and mutual benefit in the post-treatment stage, or there are deficiencies in yield and product purity, or in reducing production costs and enabling green industrial production There are still deficiencies

Method used

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  • Preparation process method of gadobutrol epoxy side chain intermediate
  • Preparation process method of gadobutrol epoxy side chain intermediate
  • Preparation process method of gadobutrol epoxy side chain intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Embodiment 1, the preparation process of gadobutrol epoxy side chain intermediate

[0072] step 1:

[0073] (1) Add 300g of compound A-1 in the reaction flask;

[0074] (2) Add 450g of compound A-2;

[0075] (3) Add the p-toluenesulfonic acid monohydrate of 0.9g;

[0076] (4) Stir and heat to 70°C, distill 219g of methanol, and heat and distill methanol for 3 hours at the same time;

[0077] (5) heating up to 120°C, distilling off excess compound A-2;

[0078] (6) be heated up to 170 degrees centigrade, and atmospheric distillation separates the fraction impurity before separating, and collection distillation range is 80-142 ℃;

[0079] (7) Compound A-3 (354 g, purity 96.2%) of components with a distillation range of 142-147° C. was collected.

[0080] Step 2:

[0081] (1) Add 338g of compound A-3, 315g of acetonitrile, 270g of methanol and 330g of water in the reaction flask, then add 2.4g of disodium hydrogen phosphate;

[0082] (2) stirring and heating the rea...

Embodiment 2

[0090] Embodiment 2, the preparation process of gadobutrol epoxy side chain intermediate

[0091] step 1:

[0092] (1) Add 180g of compound A-1 in the reaction flask;

[0093] (2) adding 319g of compound A-2;

[0094] (3) Add 0.4g of p-toluenesulfonic acid monohydrate;

[0095] (4) Stir and heat to 70°C, distill 128g of methanol, and heat and distill methanol for 2 hours at the same time;

[0096] (5) heating up to 120°C, distilling off excess compound A-2;

[0097] (6) be warming up to 170 degrees centigrade, the cut impurity before atmospheric pressure distillation is separated,;

[0098] (7) Compound A-3 (212 g, purity 96.3%) was collected with a distillation range of 142-147°C.

[0099] Step 2:

[0100] (1) Add 180g of compound A-3, 190g of acetonitrile, 157g of methanol and 198g of water in the reaction flask; then add 1.4g of disodium hydrogen phosphate;

[0101] (2) stirring and heating the reaction solution;

[0102] (3) Add 210g of 30% hydrogen peroxide dropwi...

Embodiment 3

[0110] Example 3, workshop scale-up preparation process of gadobutrol epoxy side chain intermediate

[0111] step 1:

[0112] (1) Add 186kg of compound A-1 in the reactor;

[0113] (2) Add 330kg of compound A-2 again;

[0114] (3) Add the p-toluenesulfonic acid monohydrate of 372g;

[0115] (4) Stir and heat to 80° C., distill methanol; heating and separating methanol continue for 3 hours at the same time;

[0116] (5) heating up to 120° C., distilling off excess compound A-2 to obtain crude compound A-3;

[0117] (6) The crude compound A-3 was distilled under reduced pressure to obtain compound A-3 (216 kg, purity 96.2%).

[0118] Step 2:

[0119] (1) Add 215kg of compound A-3, 208kg of acetonitrile, 178kg of methyl alcohol and 217kg of water in the reactor, then add 1.6kg of disodium hydrogen phosphate;

[0120] (2) stirring and heating the reaction solution;

[0121] (3) Add 257kg of 27% hydrogen peroxide and 103kg of 1M sodium hydroxide aqueous solution into the rea...

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Abstract

The invention disclose a 4,4-dimethyl 3,5,8-trioxabic [5,1,0]ycloctane and particularly relates to a preparation process method of a gadobutrol epoxy side chain intermediate. According to the preparation process method disclosed by the invention, by adjusting the weight ratio of feeding materials, optimizing reaction conditions and improving post treatment and purification methods, the impurity content of an obtained gadobutrol epoxy side chain intermediate product is low; the quality of the intermediate product is greatly improved while the yield is increased, so that the difficulty of process control of the gadobutrol crude drugs during the production process is reduced, and the quality and the qualification rate of the gadobutrol crude drugs are improved. The preparation process method disclosed by the invention has the advantages of simple operation methods in all process steps, safe and feasible solvent and technological conditions, realization of green and environmental-friendly production and wide application prospect.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, more specifically, to a synthesis method of a gadobutrol epoxy side chain intermediate. Background technique [0002] Magnetic resonance imaging (MRI) is a diagnostic technique that uses radio frequency radiation in a magnetic field to reconstruct images, which is superior to X-rays in visualizing anatomical structures and soft tissue lesions. However, in the early 1980s, MRI was not very specific for viewing tissue structures. An MRI contrast agent is a compound that can affect the relaxation time of its surrounding tissue. Since it will produce different signal intensities in different tissues, accurate images can be obtained. [0003] Paramagnetic ions have unpaired electrons in the central atom or outer shell of the ion, making them suitable magnetic resonance contrast agents. Gadolinium (Gd) has 7 unpaired electrons in its outer shell, so it is a powerful ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04
CPCC07D493/04
Inventor 不公告发明人
Owner 穆云
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