阅读说明：本技术 一种盐酸丁氧明及其制备方法 (Butoxymin hydrochloride and preparation method thereof ) 是由 陈海龙 钟武坤 岳峰 曾少群 柯海媚 黄灿中 于 2020-12-24 设计创作，主要内容包括：本发明属于药物化学合成技术领域,具体涉及一种心血管药物盐酸丁氧明的制备方法,以2-羟基-5-甲氧基苯丙酮为原料,经过丁基化、肟化、氢化还原反应制得盐酸丁氧明；本发明通过对盐酸甲氧明合成过程中产生的副产物盐酸丁氧明进行进一步合成利用,提高副产物的利用率；此外,本发明制备盐酸丁氧明的反应条件温和、工艺过程简单,适于工业化生产。(The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of cardiovascular drug butoxyramine hydrochloride, which takes 2-hydroxy-5-methoxy propiophenone as a raw material and prepares the butoxyramine hydrochloride through butylation, oximation and hydrogenation reduction reactions; the method further synthesizes and utilizes the byproduct butoxyramine hydrochloride generated in the synthesis process of the methoxamine hydrochloride, so that the utilization rate of the byproduct is improved; in addition, the reaction condition for preparing the butoxymine hydrochloride is mild, the process is simple, and the method is suitable for industrial production.)

1. The butoxymine hydrochloride is characterized in that the molecular structure of the butoxymine hydrochloride is as follows:

2. a process for the preparation of butoxymine hydrochloride according to claim 1, comprising the steps of:

(1) putting 2-hydroxy-5-methoxy propiophenone, a butylation reagent and an acid-binding agent in a solvent according to a molar ratio of 1 (1-4) to (1-3.5), and carrying out a butylation reaction to obtain an intermediate I;

(2) placing the intermediate I and nitrite in a solvent according to a molar ratio of 1 (2-6), and carrying out oximation reaction to obtain an intermediate II;

(3) putting the intermediate II into an acid system, and reducing by using a reducing agent to prepare an intermediate III;

(4) and reducing the intermediate III by a reducing agent to prepare the butoxyramine hydrochloride.

3. The method for preparing butoxymin hydrochloride according to claim 2, wherein the molecular structure of the intermediate I is:the molecular structure of the intermediate II is as follows:or a hydrochloride salt thereof; the molecular structure of the intermediate III is as follows:

4. the method for preparing butoxymine hydrochloride according to claim 3, wherein the butylating reagent in step (1) is 1-bromobutane or 1-chlorobutane; the acid-binding agent is any one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.

5. The method for preparing butoxymin hydrochloride according to claim 4, wherein the nitrite in the step (2) is any one of butyl nitrite, isobutyl nitrite and methyl nitrite.

6. The method for preparing butoxymine hydrochloride according to claim 5, wherein the reducing agent is any one of hydrogen, sodium borohydride and potassium borohydride.

7. The method of claim 6, wherein the solvent is chloroform or dichloromethane.

Technical Field

The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a cardiovascular drug butoxyramine hydrochloride and a preparation method thereof.

Background

Methoxamine hydrochloride is a selective alpha receptor agonist, is a common booster in surgical operations, and has been applied to clinic for half a century. The butoxymin hydrochloride is a process impurity in the preparation process of the methoxamine hydrochloride, has a structure similar to that of the methoxamine hydrochloride, and is expected to be developed into a novel alpha receptor agonist so as to make up the defects of the methoxamine hydrochloride in clinical application. In addition, the butoxymin hydrochloride is used as a process by-product of the methoxymin hydrochloride, the reuse of the process by-product butoxymin hydrochloride is beneficial to improving the utilization rate of the by-product in the preparation process of the methoxymin hydrochloride, and the treatment of the by-product butoxymin hydrochloride is also beneficial to improving the purity of the methoxymin hydrochloride.

Disclosure of Invention

The invention aims to provide butoxymine hydrochloride and a preparation method thereof, and based on the aim, the invention adopts the following technical scheme:

in a first aspect, the invention provides a butoxymine hydrochloride, the molecular structure of which is:

in a second aspect, the present invention provides a method for preparing butoxymine hydrochloride having the above molecular structure, wherein the preparation process comprises the following steps:

(1) putting 2-hydroxy-5-methoxy propiophenone, a butylation reagent and an acid-binding agent in a solvent according to a molar ratio of 1 (1-4) to (1-3.5), and carrying out a butylation reaction to obtain an intermediate I; the molar ratio range of the 2-hydroxy-5-methoxypropiophenone, the butylated reagent and the acid-binding agent is selected, all raw materials can fully react in the molar ratio range, few byproducts are generated, the yield of the prepared intermediate I is relatively high, and the yield of the final product butoxymine hydrochloride is improved.

(2) Placing the intermediate I and nitrite in a solvent according to a molar ratio of 1 (2-6), and carrying out oximation reaction to obtain an intermediate II; the molar ratio of the intermediate I to the nitrite is selected in the range, wherein the raw materials can be fully reacted, the generated by-products are less, the yield of the prepared intermediate II is relatively high, and the yield of the final product butoxymine hydrochloride is improved.

(3) Putting the intermediate II into an acid system, and reducing by using a reducing agent to prepare an intermediate III;

(4) and reducing the intermediate III by a reducing agent to prepare the butoxyramine hydrochloride.

The invention takes 2-hydroxy-5-methoxy propiophenone as a raw material, and prepares the butoxydim hydrochloride through the reactions of butylation, oximation and hydrogenation reduction, the reaction condition is mild, the process is simple, and the invention is suitable for industrial production.

Further, the molecular structure of the intermediate I is:the molecular structure of the intermediate II is as follows:or a hydrochloride salt thereof; the molecular structure of the intermediate III is as follows:

further, in the step (1), the butylation reagent is 1-bromobutane or 1-chlorobutane; the acid-binding agent is any one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.

Further, the nitrite in the step (2) is any one of butyl nitrite, isobutyl nitrite and methyl nitrite.

Further, the reducing agent is any one of hydrogen, sodium borohydride and potassium borohydride.

Further, the solvent is chloroform or dichloromethane.

The reaction principle for preparing the butoxydim hydrochloride by using the 2-hydroxy-5-methoxy propiophenone as the raw material is as follows:

compared with the prior art, the invention has the following beneficial effects:

(1) according to the invention, the molar ratio of the intermediate I to the intermediate II as raw materials is adjusted, and a proper molar ratio range is selected, so that the yield of the intermediate I and the intermediate II is improved, and the yield of the final product butoxymine hydrochloride is improved.

(2) The method further synthesizes and utilizes the byproduct butoxyramine hydrochloride generated in the synthesis process of the methoxamine hydrochloride, so that the utilization rate of the byproduct is improved; in addition, the method for preparing the butoxymine hydrochloride has mild conditions and simple process, and is suitable for industrial production.

Detailed Description

To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples. The raw materials used in the following examples are all commercially available general-purpose products unless otherwise specified.

Example 1

The molecular structure of the butoxymine hydrochloride is as follows:

the preparation method of the butoxymine hydrochloride with the molecular structure comprises the following steps:

(1) preparation of intermediate I

Placing 18g of 2-hydroxy-5-methoxy propiophenone, 27.4g of 1-bromobutane and 20.7g of potassium carbonate in 180mL of trichloromethane, stirring, heating and refluxing for 5h, adding 90mL of purified water, extracting and layering, collecting a lower organic layer, adding anhydrous sodium sulfate into the organic layer, drying for 3h, filtering and collecting a filtrate, and concentrating the filtrate to dryness to obtain a pale yellow intermediate I19.6g, wherein the yield is 83%.

The prepared intermediate I is detected by electrospray ionization mass spectrometry (ESI/MS) and nuclear magnetic resonance hydrogen spectrum to obtain the intermediate I with the relative molecular weight of 236, and the specific ion information and chemical shift parameters are as follows: MS (ESI) M/z 237.1[ M + H ]]⁺；¹H NMR(500MHz,CDCl₃)δ7.30(d,J＝3.2Hz,1H)；7.12(dd, J＝9.1,3.2Hz,1H)；6.90(d,J＝9.1Hz,1H)；3.96(t,J＝6.7Hz,2H)；3.79(d,J＝3.2 Hz,3H)；3.02(2H,q)；1.72(dq,J＝9.1,6.8Hz,2H)；1.47–1.38(m,2H)；1.24(3H, t)；0.97(t,J＝7.4Hz,3H)。

(2) Preparation of intermediate II

Placing 16.5g of intermediate I and 250mL of methyl tert-butyl ether in a reaction bottle, introducing hydrogen chloride gas into the reaction bottle, dropwise adding 28.8g of n-butyl nitrite into the reaction bottle, reacting for 3 hours, and filtering to obtain 17.8g of pale yellow intermediate II, wherein the yield of the intermediate II is 96%.

And detecting the prepared intermediate II by electrospray ionization mass spectrometry (ESI/MS) and nuclear magnetic resonance hydrogen spectrum to obtain the intermediate II with the relative molecular weight of 265, wherein the specific ion information and chemical shift parameters are as follows: MS (ESI) M/z 266.3[ M + H ]]⁺；¹H NMR(500MHz,CDCl₃)；δ6.97(dd,J＝9.0,3.1Hz,1H)； 6.91(d,J＝3.1Hz,1H)；6.85(d,J＝9.0Hz,1H)；6.66(brs,:1H)；3.89(t,J＝6.4Hz, 2H)；3.76(s,3H)；2.12(s,3H)；1.64(dt,J＝14.4,6.5Hz,2H)；1.37(dd,J＝15.0, 7.5Hz,2H)；0.91(t,J＝7.4Hz,3H)。

(3) Preparation of intermediate III

Putting 15.9g of intermediate II, 9.6g of Raney nickel, 6mL of concentrated hydrochloric acid and 160mL of ethanol into a reaction bottle, vacuumizing the reaction bottle, continuously introducing hydrogen into the reaction bottle, performing hydrogenation reduction on the intermediate II by using the hydrogen, filtering and collecting filtrate after the reaction is finished, concentrating the filtrate to 80mL, then performing crystallization at 10 ℃ for 12 hours, and filtering to obtain 14.4g of white solid, namely preparing the intermediate III, wherein the yield of the prepared intermediate III is 83%.

And detecting the prepared intermediate III by electrospray ionization mass spectrometry (ESI/MS) and nuclear magnetic resonance hydrogen spectrum to obtain the intermediate III with the relative molecular weight of 251, wherein the specific ion information and chemical shift parameters are as follows: MS (ESI) M/z 252.2[ M + H ]]⁺；¹H NMR(500MHz,DMSO-d₆)δ8.37(s,3H)；7.25(d,J＝2.1Hz, 1H)；7.25–7.23(m,1H)；7.22–7.18(m,1H)；4.85(s,1H)；4.14–4.07(m,2H)； 3.75(s,3H),3.31(s,3H)；1.79–1.72(m,2H)；1.57–1.41(m,2H)；1.38(d,J＝7.2 Hz,3H)；0.96(t,J＝7.4Hz,3H)。

(4) Preparation of butoxymin hydrochloride

Putting 13.8g of the intermediate III, 6.9g of palladium-carbon, 5mL of concentrated hydrochloric acid and 280mL of ethanol into a reaction bottle, vacuumizing the reaction bottle, introducing hydrogen into the vacuumized reaction bottle, performing hydrogenation reduction on the intermediate III by using the hydrogen, filtering and collecting filtrate after the reaction is finished, concentrating the filtrate to 70mL, crystallizing at 10 ℃ for 12 hours, and filtering to obtain 12.7g of white solid, namely butoxymine hydrochloride, wherein the yield of the butoxymine hydrochloride is 91%.

The prepared butoxymin hydrochloride is detected by electrospray ionization mass spectrometry (ESI/MS) and nuclear magnetic resonance hydrogen spectrum to obtain the relative molecular weight of 253, and the specific ion information and chemical shift parameters are as follows: MS (ESI) M/z 254.1[ M + H ]]⁺；¹H NMR(500MHz,DMSO-d₆)δ8.13(s,3H)；7.01(d,J ＝3.1Hz,1H)；6.91(d,J＝8.9Hz,1H)；6.80(dd,J＝8.8,3.1Hz,1H)；5.90(d,J＝ 4.4Hz,1H)；5.16–5.10(m,1H)；4.00–3.87(m,2H)；3.71(s,3H)；3.44(s,1H)； 1.74–1.66(m,2H)；1.50–1.40(m,2H)；0.94(t,J＝7.4Hz,3H)；0.89(d,J＝6.8Hz, 3H)。

Example 2

In this embodiment, the molecular structure of butoxymine hydrochloride is the same as that in the embodiment, but the preparation process parameters of butoxymine hydrochloride are different, and the preparation process of butoxymine hydrochloride in this embodiment is as follows:

(1) preparation of intermediate I

Placing 18g of 2-hydroxy-5-methoxypropiophenone, 13.9g of 1-chlorobutane and 8g of potassium carbonate in 180mL of dichloromethane, stirring, heating, refluxing for 10h, adding 90mL of purified water, extracting, layering, collecting a lower organic layer, adding anhydrous sodium sulfate into the organic layer, drying for 3h, filtering, collecting a filtrate, and concentrating the filtrate to dryness to obtain a light yellow intermediate I18.8g with the yield of 80%.

(2) Preparation of intermediate II

Placing 16.5g of intermediate I and 250mL of diethyl ether in a reaction bottle, introducing hydrogen chloride gas into the reaction bottle, dropwise adding 17.1g of methyl nitrite into the reaction bottle, reacting for 8 hours, and filtering to obtain 17.8g of pale yellow intermediate II, wherein the yield of the intermediate II is 92%.

(3) Preparation of intermediate III

Putting 15.9g of intermediate II, 9.6g of palladium-carbon, 6mL of concentrated hydrochloric acid and 160mL of methanol into a reaction bottle, vacuumizing the reaction bottle, continuously introducing hydrogen into the reaction bottle, carrying out hydrogenation reduction on the intermediate II by using the hydrogen, filtering and collecting filtrate after the reaction is finished, concentrating the filtrate to 60mL, then carrying out crystallization at 10 ℃ for 12h, filtering to obtain 14.6g of white solid, namely preparing the intermediate III, wherein the yield of the prepared intermediate III is 84%.

(4) Preparation of butoxymin hydrochloride

Putting 13.8g of the intermediate III and 280mL of methanol into a reaction bottle, adding 3.6g of sodium borohydride into the reaction bottle for three times, carrying out hydrogenation reduction reaction for 4 hours, filtering to collect filtrate after the reaction is finished, adding 5mL of concentrated hydrochloric acid into the filtrate, concentrating the filtrate to 60mL, crystallizing at 10 ℃ for 12 hours, and filtering to obtain 13.1g of white solid, namely butoxymine hydrochloride, wherein the yield of the butoxymine hydrochloride is 94%.

Example 3

Referring to example 1, the molar ratio of each raw material for preparing intermediate I was adjusted to investigate the effect of different molar ratios on the yields of intermediate I and butoxymine hydrochloride, and the molar ratios between each sample and each raw material are shown in table 1, wherein the molar ratio in table 1 refers to the molar ratio of 2-hydroxy-5-methoxypropiophenone, 1-bromobutane and potassium carbonate.

Table 1 influence of the molar ratio between the different starting materials on the yield of intermediate I and butoxymine hydrochloride

As can be seen from Table 1, the yield of intermediate I can be increased by increasing the amount of 1-bromobutane, and the yield of butoxymine does not increase with the increase of the amount of 1-bromobutane. This is because excess 1-bromobutane can produce other impurities which cannot be removed in the process for the preparation of intermediate I and which are removed in the preparation of intermediate II, with a drop in overall yield. Comprehensively considering, the molar ratio of the 2-hydroxy-5-methoxy propiophenone to the 1-bromobutane to the potassium carbonate is controlled to be 1 (1-4): (1-3.5).

Example 4

Referring to the method for preparing butoxyramine hydrochloride in example 1, the molar ratio between the raw materials with the highest yield of butoxyramine hydrochloride in example 3, namely the molar ratio between 2-hydroxy-5-methoxypropiophenone, 1-bromobutane and potassium carbonate is selected to be 1:1:1, the molar ratio between the raw materials for preparing the intermediate II is adjusted, the influence of the raw materials with different molar ratios on the yields of the intermediate II and the butoxyramine hydrochloride is investigated, and the molar ratios between each sample and each raw material are shown in Table 2, wherein the molar ratio in Table 2 refers to the molar ratio between the intermediate I and n-butyl nitrite.

TABLE 2 influence of molar ratio of intermediate I to n-butyl nitrite on the yield of intermediate II and butoxymin hydrochloride

As can be seen from Table 2, the yield of intermediate II and butoxymine was not significantly increased by increasing the amount of n-butyl nitrite, and the molar ratio of intermediate I to n-butyl nitrite was determined to be 1 (2-6) from the economical viewpoint.

Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.