Method for preparing medicine intermediate for treating osteoarthritis

Abstract

The invention belongs to the technical field of chemical research and development, and particularly relates to a method for preparing a medicine intermediate for treating osteoarthritis. According toa preparing method for a zinc-salt-modified-hydroxyapatite ceric-ammonium-nitrate-loading catalyst, the catalyst is obtained after zinc-salt-modified hydroxyapatite and ceric ammonium nitrate are subjected to ion exchange in an ethanol water solution; the zinc-salt-modified hydroxyapatite is prepared under the alkaline condition with the chemical precipitation method, wherein Ca(NO3)2.4H2O and diammonium hydrogen phosphate serve as raw materials, and Zn(NO3)2.6H2O serves as a modifying agent; the catalyst prepared with the method can catalyze 6-methyl 3-hydroxyhexanoate to prepare medicine cis-capsaicine intermediate 6-carbonyl methyl caproate for treating osteoarthritis. The catalyzing technology is high in yield and environmentally friendly.

Description

technical field

[0001] The invention belongs to the technical field of chemical drug research and development, and in particular relates to a method for preparing a drug intermediate for treating osteoarthritis. Background technique

[0002] Capsaicin (capsaicin) is the main spicy substance in peppers. It has analgesic, anti-inflammatory and anti-oxidative effects. It is mainly used to treat muscle, joint and nerve pain. However, skin burning and stinging are prone to occur at the drug site at the initial stage of administration. Adverse reactions such as flu and flushing limit clinical application. Compared with capsaicin, zucapsaicin, which is artificially synthesized by zucapsaicin, exhibits stronger analgesic activity and lower irritation, and has broad application prospects. WINSTON developed zucapsaicin cream (trade name: zuacta), which was approved for marketing in Canada on July 15, 2010, and the approved indication is the treatment of osteoarthritis (OA).

[0003] ...

Examples

Embodiment 1

[0038] Preparation of zinc salt modified hydroxyapatite supported cerium ammonium nitrate catalyst:

[0039] First with Ca(NO 3 ) 2 .4H 2 O and diammonium hydrogen phosphate as raw materials, Zn(NO 3 ) 2 .6H 2 O is a modifier, and the zinc salt-modified hydroxyapatite is prepared by chemical precipitation under alkaline conditions; then the zinc salt is prepared by ion exchange between the zinc salt-modified hydroxyapatite and cerium ammonium nitrate in ethanol aqueous solution Modified hydroxyapatite supported cerium ammonium nitrate catalyst.

[0040] Concrete preparation process is as follows:

[0041] (A) Preparation of zinc salt modified hydroxyapatite:

[0042] A-1) 10mmol Ca(NO 3 ) 2 .4H2 O and 7mmol Zn(NO 3 ) 2 .6H 2 O was dissolved in 50ml of water, then added dropwise to 100ml of ammonia solution with pH=11 and stirred evenly to obtain a calcium-zinc mixed solution;

[0043] A-2) Add 50 ml of diammonium hydrogen phosphate aqueous solution (containing 10 ...

Embodiment 2

[0052] The Zn / Ce / HAP / X prepared by the present invention is used as a catalyst, and its catalytic performance to methyl 6-hydroxyhexanoate is investigated to generate methyl 6-oxohexanoate. The catalytic process is as follows:

[0053] Add 10mmol methyl 6-hydroxyhexanoate and catalyst (0.15g, ~10%wt) to 20ml ethanol in a parallel synthesizer, then add 30%wt hydrogen peroxide solution (containing 20mmol hydrogen peroxide, 2.0eq), 20-30 Stir the reaction at ℃ (i.e. reaction at room temperature), detect the catalytic effect of different catalysts by GC-MS, and count the reaction status of the reaction solution after the reaction, including the time taken for the reaction to reach equilibrium, the conversion rate of methyl 6-hydroxyhexanoate and the target product The selectivity of methyl 6-carbonylhexanoate, the results are shown in table 1:

[0054] Table 1 Catalytic effects of different catalysts

[0055] catalyst

[0056] The above results show that the catalytic a...

Embodiment 3

[0058] When determining Zn / Ce / HAP / 400 as the catalyst, the reaction solvent, temperature, catalyst dosage, oxidant and its oxidant dosage were further optimized:

[0059] In the parallel synthesizer, 10mmol 6-hydroxyhexanoic acid methyl ester, catalyst Zn / Ce / HAP / 400 (44mg-440mg, 3.0~30%wt) are added in the 20ml solvent, then add oxidizing agent (molar dosage is substrate 6- 1.5-3.0eq of methyl hydroxyhexanoate), stirring reaction at 0-60°C, GC-MS detection of the catalytic effect of different catalysts, statistics of the reaction of the reaction solution after the end of the reaction, including the time used for the reaction to reach equilibrium, 6- The selectivity of methyl hydroxycaproate conversion and target product 6-oxomethylhexanoate, the results are shown in table 2:

[0060] Table 2 List of catalytic system optimization results

[0061]

[0062] Note: DCM refers to dichloromethane; EA refers to ethyl acetate; H 2 o 2 30%wt hydrogen peroxide solution; NaClO is 10...

technical field

[0001] The invention belongs to the technical field of chemical drug research and development, and in particular relates to a method for preparing a drug intermediate for treating osteoarthritis. Background technique

[0002] Capsaicin (capsaicin) is the main spicy substance in peppers. It has analgesic, anti-inflammatory and anti-oxidative effects. It is mainly used to treat muscle, joint and nerve pain. However, skin burning and stinging are prone to occur at the drug site at the initial stage of administration. Adverse reactions such as flu and flushing limit clinical application. Compared with capsaicin, zucapsaicin, which is artificially synthesized by zucapsaicin, exhibits stronger analgesic activity and lower irritation, and has broad application prospects. WINSTON developed zucapsaicin cream (trade name: zuacta), which was approved for marketing in Canada on July 15, 2010, and the approved indication is the treatment of osteoarthritis (OA).

[0003] ...

Examples

Embodiment 1

[0038] Preparation of zinc salt modified hydroxyapatite supported cerium ammonium nitrate catalyst:

[0039] First with Ca(NO 3 ) 2 .4H 2 O and diammonium hydrogen phosphate as raw materials, Zn(NO 3 ) 2 .6H 2 O is a modifier, and the zinc salt-modified hydroxyapatite is prepared by chemical precipitation under alkaline conditions; then the zinc salt is prepared by ion exchange between the zinc salt-modified hydroxyapatite and cerium ammonium nitrate in ethanol aqueous solution Modified hydroxyapatite supported cerium ammonium nitrate catalyst.

[0040] Concrete preparation process is as follows:

[0041] (A) Preparation of zinc salt modified hydroxyapatite:

[0042] A-1) 10mmol Ca(NO 3 ) 2 .4H2 O and 7mmol Zn(NO 3 ) 2 .6H 2 O was dissolved in 50ml of water, then added dropwise to 100ml of ammonia solution with pH=11 and stirred evenly to obtain a calcium-zinc mixed solution;

[0043] A-2) Add 50 ml of diammonium hydrogen phosphate aqueous solution (containing 10 ...

Embodiment 2

[0052] The Zn / Ce / HAP / X prepared by the present invention is used as a catalyst, and its catalytic performance to methyl 6-hydroxyhexanoate is investigated to generate methyl 6-oxohexanoate. The catalytic process is as follows:

[0053] Add 10mmol methyl 6-hydroxyhexanoate and catalyst (0.15g, ~10%wt) to 20ml ethanol in a parallel synthesizer, then add 30%wt hydrogen peroxide solution (containing 20mmol hydrogen peroxide, 2.0eq), 20-30 Stir the reaction at ℃ (i.e. reaction at room temperature), detect the catalytic effect of different catalysts by GC-MS, and count the reaction status of the reaction solution after the reaction, including the time taken for the reaction to reach equilibrium, the conversion rate of methyl 6-hydroxyhexanoate and the target product The selectivity of methyl 6-carbonylhexanoate, the results are shown in table 1:

[0054] Table 1 Catalytic effects of different catalysts

[0055] catalyst

[0056] The above results show that the catalytic a...

Embodiment 3

[0058] When determining Zn / Ce / HAP / 400 as the catalyst, the reaction solvent, temperature, catalyst dosage, oxidant and its oxidant dosage were further optimized:

[0059] In the parallel synthesizer, 10mmol 6-hydroxyhexanoic acid methyl ester, catalyst Zn / Ce / HAP / 400 (44mg-440mg, 3.0~30%wt) are added in the 20ml solvent, then add oxidizing agent (molar dosage is substrate 6- 1.5-3.0eq of methyl hydroxyhexanoate), stirring reaction at 0-60°C, GC-MS detection of the catalytic effect of different catalysts, statistics of the reaction of the reaction solution after the end of the reaction, including the time used for the reaction to reach equilibrium, 6- The selectivity of methyl hydroxycaproate conversion and target product 6-oxomethylhexanoate, the results are shown in table 2:

[0060] Table 2 List of catalytic system optimization results

[0061]

[0062] Note: DCM refers to dichloromethane; EA refers to ethyl acetate; H 2 o 2 30%wt hydrogen peroxide solution; NaClO is 10...

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