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Preparation method of butenol

A technology of butanol and intermediates, which is applied in the field of preparation of high-purity butanol, can solve problems such as unfavorable quality control, difficult purification, cumbersome process, etc., and achieve improved atom economy, easy recrystallization and purification, and simple quality research Effect

Pending Publication Date: 2022-08-05
SHANGHAI JIANHE PHARM & TECH CO LTD +1
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  • Summary
  • Abstract
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AI Technical Summary

Problems solved by technology

Specifically disclosed three routes in Inorg.Chem.1997,36,6086~6093: route 1 side reaction is less, but the physicochemical property of intermediate is not good and does not have strong ultraviolet absorption (is not conducive to carrying out quality control), and needs Use resin for purification; route 2 has many side reactions, low yield and poor purity, and is difficult to purify; route 3 uses flammable and explosive reagents, which is suitable for laboratory preparation and is not suitable for industrial scale-up
Patent CN109293592A improved route 1, adopted recrystallization to purify the intermediate, got rid of column chromatography or ion exchange resin, but did not change the ultraviolet absorption problem of intermediate; patent CN107001294B has improved route 2, adopted resin purification and heavy The crystallization method is combined with the purification of the intermediate, but the problem of ultraviolet absorption of the intermediate is not changed. At the same time, both patent routes require the step of preparing the relevant intermediate after the protection of the ring ring and tenin ring, and then the step of removing the protecting group. The process is still relatively cumbersome.

Method used

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  • Preparation method of butenol
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preparation example Construction

[0056] Preparation of epoxy side chains

[0057] Preparation of 4,4-dibenzyl-3,5,8-trioxabicyclo[5,1,0]octane:

[0058]

[0059] 2,2-Dimethoxypropane-1,3-diyl-diphenyl

[0060] 1,3-diphenylacetone (25.7g), trimethyl orthoformate (26g), iron p-toluenesulfonate (1.4g) and methanol (150g) were added to the reaction flask, all the materials were dissolved, the reaction was carried out at room temperature, and the system There was solid precipitation, TLC tracked the reaction progress, after the reaction, filtered and dried to obtain 2,2-dimethoxypropane-1,3-diyl-diphenyl (white solid, 26.9 g, yield: 85.9%) ,HPLC:99.13%). 1 H NMR (400MHz, Chloroform-d) δ 7.56-7.41 (m, 6H), 7.26-7.11 (m, 4H), 3.35 (s, 6H), 2.86 (s, 4H). MS: m / e 257.1[ (M+H) + ].

[0061] 2,2-Dibenzyl-4,7-dihydro-1,3-dioxoheptane

[0062] Into the reaction flask were added 2,2-dimethoxypropane-1,3-diyl-diphenyl (22.7g), iron p-toluenesulfonate (0.5g), maleic-1,4-diol (10g) and dichloromethane (100g), all th...

Embodiment 1

[0082] The reaction equation is as follows:

[0083]

[0084] Preparation of Compound Ⅰ-A

[0085] Under nitrogen protection, cyclamenine (10 g) and 4,4-dibenzyl-3,5,8-trioxabicyclo[5,1,0]octane (10 g) were mixed in ethanol (50 mL) , stirred, heated to reflux, followed the progress of the reaction by HPLC, stopped heating, added to purified water, filtered, and dried to obtain 13.6 g of crude product, which was added to ethyl acetate and ethanol for recrystallization to obtain compound Ⅰ-A: 10 g, yield Yield: 63.3%, HPLC: 99.1%. 1 H NMR (400MHz, Chloroform-d) δ 7.31–7.21(m, 6H), 7.18–7.14 (m, 2H), 7.10–7.06 (m, 2H), 4.25–3.60 (m, 6H), 2.87 (s) ,4H),2.80–2.42(m,16H).MS: m / e469.3[(M+H) + ]. Preparation of compound Ⅱ-A

[0086] Intermediate I-A (8 g) and acetonitrile (40 mL) were added to the three-necked flask, stirred, potassium carbonate (11.8 g) and tert-butyl chloroacetate (8.5 g) were added, and the system was heated to 55° C. to react for 3 hours. Cool the temperat...

Embodiment 2

[0090] The reaction equation is as follows:

[0091]

[0092] Preparation of compound I-B

[0093] Into the reaction flask was added cyclamenine (50g), 4,4-diphenyl-3,5,8-trioxabicyclo[5,1,0]octane (50g) and acetonitrile (500mL), Stir, heat to reflux, follow the reaction process by HPLC, stop heating, add the reaction solution to purified water, filter with suction, wash, and dry to obtain 80 g of crude product. The crude product was recrystallized from methanol / ethyl acetate system to obtain compound I-B: 70.6 g, yield: 86%, HPLC: 98.9%. 1 H NMR (400MHz, DMSO-d6) δ 7.50 (d, J=7.7Hz, 4H), 7.31 (t, J=7.5Hz, 4H), 7.23 (d, J=7.2Hz, 2H), 3.71–3.22 (m,6H),2.71–2.34(m,16H).MS: m / e 441.3[(M+H) + ].

[0094] The following compounds were prepared with reference to the same method

[0095]

[0096]

[0097] Preparation of compound Ⅱ-B

[0098] Intermediate I-B (50g) and acetonitrile (800mL) were added to the three-necked flask, stirred, potassium carbonate (63g) and tert-...

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of high-purity bufol. The preparation method comprises the following steps: (1) reacting cycleanine with an epoxy side chain to generate an intermediate I, (2) carrying out nitrogen alkylation on the intermediate I and an alpha-substituted acetic acid side chain to generate an intermediate II, and (3) hydrolyzing an ester group and acetal (ketone) of the intermediate II to obtain the bufol.

Description

Technical field: [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of high-purity butanol. Background technique: [0002] Gadobutrol, developed by Bayer, was first marketed in Switzerland in 1998 and has been approved in more than 100 countries. It was approved by the U.S. Food and Drug Administration (FDA) on March 14, 2011, and was approved by the China Food and Drug Administration (CFDA) on July 13, 2014, and was approved for marketing on March 26, 2015. Approved by the Japan Pharmaceutical and Medical Devices Agency (PMDA), it is marketed by Bayer under the trade names of Gadavist, Galexian and Gadovist. [0003] Gadobutrol is a non-ionic gadolinium chelate with paramagnetic properties as a magnetic resonance contrast agent. It is mainly distributed in the extracellular fluid, but does not cross the blood-brain barrier, is administered intravenously only, and is used in diagnostics for CNS, kidney a...

Claims

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Application Information

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IPC IPC(8): C07D257/02C07D405/04
CPCC07D257/02C07D405/04
Inventor 尹建新何爱国张南陈义朗沈伟艺年四钧陈林渺
Owner SHANGHAI JIANHE PHARM & TECH CO LTD
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