阅读说明：本技术 一种磷丙泊酚钠及其中间体的合成方法与应用 (Synthesis method and application of fospropofol disodium and intermediate thereof ) 是由 梁莉 刘爱玲 李亚玲 张玉良 李守军 吴燕子 于 2021-07-29 设计创作，主要内容包括：本发明提供了一种磷丙泊酚钠及其中间体的合成方法,包括中间体B和中间体C,以及利用所述合成方法制备得到的磷丙泊酚钠在动物用麻醉剂镇静剂中的应用。本发明提供的磷丙泊酚钠合成方法避免了使用剧毒试剂氯溴甲烷,安全性高；制备得到的甲磷丙泊酚中间体反应条件温和,操作简便,质量收率:＞97%,易于工业化生产,利用本发明所提供的合成方法合成的磷丙泊酚钠制备得到的丙泊酚前药能够产生与市售丙泊酚乳状注射液相同的临床效果,并且未发生磷丙泊酚麻醉所导致的心肌抑制反应。(The invention provides a synthesis method of fospropofol disodium and an intermediate thereof, which comprises an intermediate B and an intermediate C, and application of fospropofol disodium prepared by the synthesis method in an animal anesthetic sedative. The synthesis method of fospropofol disodium provided by the invention avoids using a highly toxic reagent, namely chlorobromomethane, and has high safety; the methylpropofol intermediate prepared by the method has mild reaction conditions, simple and convenient operation and mass yield of more than 97 percent, is easy for industrial production, and the propofol prodrug prepared by the fospropofol sodium synthesized by the synthetic method provided by the invention can generate the same clinical effect as that of the commercially available propofol emulsion injection and does not generate myocardial inhibition reaction caused by fospropofol anesthesia.)

1. A method for synthesizing a fospropofol disodium intermediate takes propofol as an initiator, and is characterized by comprising the following steps of:

step 1: takes propofol as an initiator to synthesize an intermediate B through methylation reaction,

step 2: the intermediate B is subjected to chlorination reaction to obtain an intermediate C,

wherein the compound A is propofol, the compound B is an intermediate B, and the compound C is an intermediate C.

2. The synthesis method of claim 1, wherein in step 1, propofol is dissolved in the first solvent, the reaction solution is cooled under alkaline conditions, a methylating agent is added dropwise while stirring, and after the addition, the reaction is carried out under heat preservation, and an intermediate B is obtained after the reaction is finished.

3. The synthesis method according to claim 2, wherein the first solvent is one or more selected from dichloromethane, chloroform, carbon tetrachloride, acetonitrile, acetone, dimethyl sulfoxide, DMF, tetrahydrofuran, toluene and benzene; the methylation reagent is one of methyl iodide, methyl chloride and methyl bromide; the alkaline condition is obtained by adding one or more solutions of potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine, N-diisopropylethylamine and triethylamine.

4. The method of claim 2, wherein the incubation temperature is selected from the range of 20-80 ℃.

5. The method of claim 1, wherein in step 2, the chlorination reaction is performed by dissolving compound B in a second solvent, adding a chlorinating agent, and heating to obtain intermediate C.

6. The synthesis process according to claim 5, characterized in that the chlorinating reagent is selected from phosphorus pentachloride and/or phosphorus trichloride; the second solvent is selected from one or more of dimethyl sulfoxide, DMF, chlorobenzene, toluene and benzene.

7. The method of synthesis according to claim 5, wherein the temperature of the heating reaction is selected from the range of 50-120 ℃.

8. A method for synthesizing fospropofol disodium, characterized in that intermediate B and intermediate C are synthesized according to the method of any one of claims 1 to 7, and then fospropofol disodium is synthesized according to the following steps:

and step 3: mixing acetonitrile, triethylamine and phosphoric acid, adding the intermediate C, and heating to react to obtain an intermediate D;

and 4, step 4: adding ethanol into the intermediate D, adjusting the pH value to 7.5-8.5, and separating out a solid to obtain fospropofol disodium;

the structural formula of the intermediate D is。

9. An animal anesthetic and sedative agent, characterized in that it is prepared from fospropofol sodium prepared from intermediate B and intermediate C synthesized by the fospropofol sodium intermediate synthesis method of any one of claims 1 to 7, or prepared from fospropofol sodium prepared from the fospropofol sodium synthesis method of claim 8.

Technical Field

The invention belongs to the field of drug synthesis and application, and relates to synthesis and application of a propofol prodrug.

Background

Propofol is a phenol derivative, has a sedative-hypnotic effect after intravenous injection, is widely used for induction and maintenance of anesthesia or sedation, is approved to be used on animals in China, is a fat emulsion, can cause local pain after injection and can also cause vascular embolism, and is inconvenient to transport, store and use as the fat emulsion. Fospropofol sodium and its hydrates are water-soluble prodrugs of propofol, which are metabolized in vivo by endothelial cell surface alkaline phosphatase to produce the active drug propofol, which rapidly reaches equilibrium in brain tissue, thus exerting a dose-dependent sedative-hypnotic effect.

The structural formula of fospropofol disodium is:

at present, the research on the method for preparing fospropofol sodium by using propofol as a raw material is more, the name of the foreign patent US6872838 is 'Water soluble prodrugs of deeply hydrolyzed alcohol or phenols', and the method relates to a synthetic mode of Water-soluble prodrugs, and the process route is shown as follows:

wherein Z is hydrogen or a pharmaceutically acceptable salt.

The domestic reported synthetic methods of the propofol water-soluble prodrug are different in large and small, and the main process route is shown as follows;

however, in the traditional process, the compound synthesis mostly uses a highly toxic reagent of chlorobromomethane, and has large side effect and lower biological safety.

Disclosure of Invention

The invention provides a synthesis method of a fospropofol sodium intermediate, which takes propofol as an initiator and comprises an intermediate B and an intermediate C. The intermediate B or C prepared by the method provided by the invention is used for preparing fospropofol disodium. In the invention, after the reaction, the solution is concentrated and separated out to obtain the intermediate B or intermediate C solid (intermediate B or intermediate C crude product) which is convenient to store, can be used as a raw material for producing the fospropofol disodium and provides reference for a mass production mode of the fospropofol disodium.

Preferably, the synthesis of intermediate B or C comprises the following steps:

step 1: taking propofol as an initiator, and synthesizing an intermediate B through methylation reaction;

step 2: and performing chlorination reaction on the intermediate B to obtain an intermediate C.

Any one of the above preferable ones is that in step 1, compound a (propofol) is dissolved in a first solvent, the reaction solution is cooled under an alkaline condition, a methylating agent is added dropwise while stirring, after the addition, the reaction is kept at a constant temperature, and after the reaction is completed, intermediate B is obtained by post-treatment. Preferred work-up procedures include precipitation of solids, as well as filtration and drying steps. Preferably, intermediate B is precipitated by diluting the solution after the reaction of step 1 into ice water. Preferably, the intermediate B solid is obtained by extraction and then concentrating the organic phase to dryness, and a further preferable scheme is that ethyl acetate is added into the solution after the reaction in the step 1, extraction and liquid separation are carried out, and the organic phase is concentrated to dryness. The alkaline conditions described herein refer to solutions having a pH of > 10. And (3) cooling the reaction liquid under an alkaline condition, preferably, cooling to 0-5 ℃, so that the reaction yield can be improved, and the diluted feed liquid is uniformly dispersed in a stirring state. Preferably, the propofol dissolved in the first solvent is in a volume to mass ratio of 2-10v/w (mL/g) (first solvent to compound a), and more preferably in a volume to mass ratio of 2, 4, 6, 8, 9, 10v/w (mL/g) (first solvent to compound a). Preferably, the dropping rate of the methylating agent is less than or equal to 1mL/min, and the temperature is seriously increased when the methylating agent is dropped too fast. In a preferred embodiment of the present invention, the dropping rate is preferably 1 mL/min. In the present invention, the volume-to-mass ratio is expressed in mL/g unless otherwise specified.

Any one of the above is preferable, the first solvent is one or more selected from dichloromethane, chloroform, carbon tetrachloride, acetonitrile, acetone, dimethyl sulfoxide, DMF (N, N-dimethylformamide), tetrahydrofuran, toluene, and benzene. In a preferred embodiment of the invention, the first solvent is preferably DMF.

Any one of the above is preferred, wherein the methylating agent is one of methyl iodide, methyl chloride and methyl bromide. In a preferred embodiment of the invention, the methylating agent is preferably methyl iodide. The amount of the methylating agent to be used is preferably 1.05eq to 2.5eq (molar ratio) based on the compound a, and more preferably 1.05eq, 1.26eq, 1.38eq, 1.51eq, 1.72eq, 1.92eq, 2.04eq, 2.33eq, or 2.49eq (molar ratio) based on the compound a.

Any one of the above is preferable, the alkaline condition is obtained by adding one or more of potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine, N-diisopropylethylamine and triethylamine, and in a preferable embodiment of the present invention, the alkaline condition is preferably obtained by adding potassium carbonate solution. Preferably, the alkaline condition is such that the reaction system has a PH >10 by adding the above-mentioned preferred reagents to the reaction system.

Any of the above is preferred, the reaction temperature (the temperature at which the reaction is maintained after completion of the dropwise addition) is selected from the group consisting of 20 to 80 ℃, preferably 20 to 30 ℃, 30 to 50 ℃, 25 to 60 ℃, and 40 to 80 ℃.

In any of the above cases, in the step 2, the chlorination reaction is to dissolve the compound B in the second solvent, add a chlorinating agent, heat and react, and obtain the intermediate C after post-treatment. Preferably, the post-treatment comprises the steps of filtration, concentration, precipitation of solids, washing or drying. In a preferred embodiment of the invention, the method comprises the following steps: filtering the solution after the reaction is finished, concentrating the filtrate, adding water and ethyl acetate into the residual liquid, separating the liquid, and respectively using 1M HCl solution and saturated NaHCO solution for an organic phase₃The solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give intermediate C. Preferably, the second solvent is added in an amount of 2 to 10v/w (mL/g) (volume to mass ratio: second solvent to Compound B), and more preferably in a volume to mass ratio of 2, 4, 6, 8, 10v/w (mL/g) (second solvent to Compound B).

Preferably, in any one of the above cases, the chlorinating agent is selected from phosphorus pentachloride and/or phosphorus trichloride. In a preferred embodiment of the invention, the chlorinating agent is preferably phosphorus pentachloride. The amount of the chlorinating agent to be added is preferably 1.05 to 2.5eq by mole (relative to the compound B), and more preferably 1.05, 1.25, 1.38, 1.47, 1.59, 1.72, 1.88, 1.92, 2.06, 2.22, 2.45eq by mole (relative to the compound B).

Any one of the above is preferable, the second solvent is selected from one or more of dimethyl sulfoxide, DMF, chlorobenzene, toluene and benzene. In a preferred embodiment of the invention, the second solvent is preferably DMF.

Any of the above is preferred, the temperature of the heating reaction in the chlorination reaction is selected from 50 to 120 ℃, preferably 70 to 80 ℃.

The invention also provides a synthesis method of fospropofol disodium, which comprises the steps of synthesizing an intermediate B and an intermediate C according to any one of the methods, and then synthesizing fospropofol disodium according to the following steps:

and step 3: mixing acetonitrile, triethylamine and phosphoric acid, adding the intermediate C, and heating to react to obtain an intermediate D;

and 4, step 4: and adding ethanol into the intermediate D, adjusting the pH value to 7.5-8.5, and separating out a solid to obtain the fospropofol disodium.

In a preferred embodiment of the present invention,

and step 3: mixing acetonitrile, triethylamine and phosphoric acid, adding the intermediate C, heating to 60-65 ℃ for reaction to obtain an intermediate D;

and 4, step 4: and adding ethanol into the intermediate D, adjusting the pH value to 7.5-8.5 by adopting NaOH, separating out a solid, cooling to 0-5 ℃, stirring for 2h, and filtering to obtain a target product E phosphorus propofol sodium.

Chemical name of intermediate D: methylphosphinopropofol

The chemical formula is as follows: c₁₃H₂₁O₅P

Structural formula (xvi):

preferably, acetonitrile, triethylamine and phosphoric acid are added in the following amounts: acetonitrile (8-12V: the volume mass ratio of acetonitrile to the compound C is 8-12 mL/g), triethylamine (1.0-1.4 eq: the molar ratio of triethylamine to the compound C is 1.0-1.4), and phosphoric acid (1.0-1.4 eq: the molar ratio of phosphoric acid to the compound C is 1.0-1.4). Further preferred in preferred embodiments of the present invention are: acetonitrile (10V: volume-to-mass ratio of acetonitrile to compound C10 mL/g), triethylamine (1.2 eq: molar ratio of triethylamine to compound C1.2), and phosphoric acid (1.2 eq: molar ratio of phosphoric acid to compound C1.2).

The invention also provides fospropofol disodium prepared from the intermediate B and the intermediate C synthesized by the synthesis method of fospropofol disodium, and fospropofol disodium prepared by the synthesis method of fospropofol disodium, and application of fospropofol disodium as an anesthetic and a sedative for animals.

Compared with the prior art, the invention has the following advantages:

1. the method disclosed by the invention avoids the highly toxic reagents of the chlorobromomethane used in the traditional process of the compounds, so that the potential safety hazard caused by trace residue of the highly toxic reagents is avoided.

2. The methylphosphorofol intermediate prepared by the method has mild reaction conditions, simple and convenient operation, high mass yield of more than 97 percent and easy industrial production.

3. The method for synthesizing the methylprotopropofol by taking propofol as an initial material according to the report of the invention has the advantages of simple process operation, mild conditions, higher yield compared with the currently reported literature, and suitability for industrial production.

4. According to clinical test data, the propofol prodrug can produce the same clinical effect as the commercial propofol emulsion injection, and in all animal experiments carried out by the invention, myocardial inhibition reaction caused by phosphorus propofol anesthesia does not occur.

Detailed Description

The present invention will be more clearly and completely described in the following embodiments, but the described embodiments are only a part of the embodiments of the present invention, and not all of them. The examples are provided to aid understanding of the present invention and should not be construed to limit the scope of the present invention.

Example 1

A preparation method of water-soluble propofol prodrug fospropofol sodium comprises the following steps:

example 1-a

Dissolving a compound A (propofol) in DMF (5V: the volume mass ratio of DMF to the compound A is 5 mL/g), adding potassium carbonate (2.0 eq: the molar ratio of potassium carbonate to the compound A is 2.0), cooling the reaction solution to 0-5 ℃, and dropwise adding CH while stirring₃I（2.0eq：CH₃Molar ratio of I to compound a 2.0) DMF (1V: DMF relative to CH₃I volume to mass ratio of 1 mL/g), heating to room temperature after finishing dropping, reacting for 2-3h, monitoring by a TLC plate layer, taking reaction liquid to dilute in ice water after the reaction is finished, precipitating a large amount of solid, filtering,Drying to obtain a crude product of the compound B, wherein the mass yield is 106.8 percent, and the crude product is directly used for the next reaction without further purification.

Example 1 b

Dissolving the compound B in DMF (5V: the volume mass ratio of DMF to the compound B is 5 mL/g), adding phosphorus pentachloride (1.0 eq: the molar ratio of phosphorus pentachloride to the compound B is 1.0), heating to 70 ℃, reacting for 3-4h, monitoring by a TLC plate layer, filtering after the reaction is finished, concentrating the filtrate, adding water and ethyl acetate into the residual liquid, separating, and respectively using 1M HCl solution and saturated NaHCO solution as organic phases₃The solution and saturated saline solution are washed, dried by anhydrous sodium sulfate and concentrated to be dry, and the crude product of the compound C is obtained with the mass yield of 115.9%.

Examples 1 to c

Adding acetonitrile (10V: the volume mass ratio of the acetonitrile to the compound C is 10 mL/g), triethylamine (1.2 eq: the molar ratio of the triethylamine to the compound C is 1.2) and phosphoric acid (1.2 eq: the molar ratio of the phosphoric acid to the compound C is 1.2) into a three-necked bottle, then adding the obtained compound C, heating to 60-65 ℃ for reaction for 6 hours, concentrating after the reaction is finished, adding water and ethyl acetate into the residual liquid, extracting, concentrating the organic phase under reduced pressure to dryness to obtain an intermediate D crude product, and directly carrying out the next reaction without further purification.

Examples 1 d

Adding ethanol (2V: the volume mass ratio of the ethanol to the intermediate D is 2 mL/g), adjusting pH with 6M NaOH =7.5-8.5, precipitating a large amount of solid, cooling the reaction solution, cooling to 0-5 deg.C, stirring for 2h, filtering to obtain target product E, i.e. fospropofol sodium, with a total mass yield of 148.7%,¹HNMR (600 MHz, DMSO) δ 1.11 (d, J =6.6Hz, 12H); 3.36 (m, J =27.6Hz, 2H); 5.01 (d, J =12.0Hz, 2H); 7.06 (m, J =22.8, 3H), the following steps of example c and d are the same as example 1.

Example 2

A preparation method of water-soluble propofol prodrug fospropofol sodium comprises the following steps:

example 2-a

Dissolving Compound A (Propofol) in dichloromethane: (5V: to a volume-to-mass ratio of dichloromethane to compound a of 5mL/g was added sodium carbonate (2.0 eq: the mol ratio of the sodium carbonate to the compound A is 2.0), the temperature of the reaction liquid is reduced to 0-5 ℃, and CH is dripped under stirring₃Br（2.0eq：CH₃Br to compound a molar ratio of 2.0) in dichloromethane (1V: methylene chloride relative to CH₃Br volume mass ratio of 1 mL/g), heating to room temperature after the dropwise addition, reacting for 2-3h, after the reaction is finished, taking the reaction solution to dilute into ice water, separating, and concentrating the organic phase to dryness to obtain a crude compound B, wherein the mass yield is 105.9%, and the crude compound B is directly used for the next reaction without further purification.

Example 2 b

Dissolving the compound B in dichloromethane (5V: the volume mass ratio of the dichloromethane to the compound B is 5 mL/g), adding phosphorus trichloride (1.0 eq: the molar ratio of the phosphorus trichloride to the compound B is 1.0), heating to 40 ℃ for reaction for 3-4h, monitoring by a TLC plate layer, filtering after the reaction is finished, concentrating the filtrate, adding water and ethyl acetate into the residual liquid, separating the liquid, and respectively using 1M HCl solution and saturated NaHCO solution to the organic phase₃The solution and saturated saline solution are washed, dried by anhydrous sodium sulfate and concentrated to be dry to obtain a crude compound C product with the mass yield of 116.2%.

Example 3

Example 3-a

Dissolving a compound A (propofol) in tetrahydrofuran (5V: the volume mass ratio of the tetrahydrofuran to the compound A is 5 mL/g), adding triethylamine (2.5 eq: the molar ratio of the triethylamine to the compound A is 2.5), cooling a reaction liquid to 0-5 ℃, and dropwise adding CH while stirring₃I（2.0eq：CH₃Molar ratio of I to compound a 2.0) tetrahydrofuran (1V: tetrahydrofuran relative to CH₃Volume-mass ratio of I is 1 mL/g), after the dropwise addition is finished, the temperature is raised to 40 ℃ for reaction for 2 hours, a TLC plate layer is used for monitoring, after the reaction is finished, reaction liquid is diluted into ice water, a large amount of solid is separated out, and a crude compound B is obtained after filtration and drying, wherein the mass yield is 106.7%, and the crude compound B is directly used for the next reaction without further purification.

Example 3 b

Dissolving the compound B in toluene (5V: the volume-mass ratio of toluene to the compound B is 5 mL/g), adding phosphorus pentachloride (1.0 eq: the molar ratio of phosphorus pentachloride to the compound B is 1.0), heating to 70 ℃ for reaction for 3-4h, monitoring by a TLC plate layer, filtering after the reaction is finished, concentrating the filtrate, adding water and ethyl acetate into the residual liquid, separating, washing the organic phase with 1M HCl solution, saturated NaHCO3 solution and saturated saline solution respectively, drying with anhydrous sodium sulfate, concentrating to dryness to obtain a crude compound C, and performing column chromatography to obtain a pure compound C with the mass yield of 117.1%.

Example 4

Example 4 a

Dissolving a compound A (propofol) in toluene (5V: the volume mass ratio of the toluene to the compound A is 5 mL/g), adding N, N-diisopropylethylamine (2.0 eq: the molar ratio of the N, N-diisopropylethylamine to the compound A is 2.0), cooling the reaction liquid to 0-5 ℃, and dropwise adding CH while stirring₃I（2.0eq：CH₃Molar ratio of I to compound a 2.0) in toluene (1V: toluene relative to CH₃Volume-mass ratio of I is 1 mL/g), after the dropwise addition, the solution is heated to room temperature for reaction for 2-3h, a TLC plate layer is used for monitoring, after the reaction is finished, ethyl acetate is added into the reaction solution, extraction and liquid separation are carried out, an organic phase is concentrated to be dry, a crude compound B is obtained, the mass yield is 107.2%, and the crude compound B is not further purified and is directly used for the next reaction.

Example 4 b

Dissolving the compound B in dimethyl sulfoxide (3V: the volume mass ratio of the dimethyl sulfoxide to the compound B is 3 mL/g), adding phosphorus pentachloride (1.0 eq: the molar ratio of the phosphorus pentachloride to the compound B is 1.0), heating to 70 ℃, reacting for 3-4h, monitoring by a TLC plate layer, filtering after the reaction is finished, adding water and ethyl acetate into the residual liquid, separating, and respectively using 1M HCl solution and saturated NaHCO solution as organic phases₃Washing the solution with saturated saline solution, drying the solution with anhydrous sodium sulfate, concentrating the solution until the solution is dried to obtain a crude compound C, and performing column chromatography to obtain a pure compound C product with the mass yield of 115.8%.

Example 5

Example 5 a

Dissolving compound A (propofol) in acetonitrile (5V: the volume mass ratio of the acetonitrile to the compound A is 5mL/g) To (1), pyridine (2.0 eq: the molar ratio of pyridine to the compound A is 2.0), the temperature of the reaction liquid is reduced to 0-5 ℃, and CH is dropwise added under stirring₃I（2.0eq：CH₃Molar ratio of I to compound a 2.0) acetonitrile (1V: acetonitrile to CH₃Volume-mass ratio of I is 1 mL/g), heating to room temperature after finishing dropping, reacting for 2-3h, monitoring by a TLC plate layer, after the reaction is finished, taking reaction liquid to dilute into ice water, precipitating a large amount of solid, filtering, drying to obtain a crude compound B, wherein the mass yield is 105.8%, and the crude compound B is directly used for the next reaction without further purification.

Example 5 b

Dissolving the compound B in DMF (5V: the volume mass ratio of DMF to the compound B is 5 mL/g), adding phosphorus trichloride (1.0 eq: the molar ratio of phosphorus trichloride to the compound B is 1.0), heating to 70 ℃ for reaction for 3-4h, monitoring by a TLC plate layer, filtering after the reaction is finished, concentrating the filtrate, adding water and ethyl acetate into the residual liquid, separating the liquid, washing the organic phase by using 1M HCl solution, saturated NaHCO3 solution and saturated saline solution respectively, drying by anhydrous sodium sulfate, concentrating to dryness to obtain a crude compound C, and carrying out column chromatography to obtain a pure compound C with the mass yield of 116.3%.

Example 6

The synthesis method is adopted to obtain the fospropofol sodium salt for clinical anesthesia of beagle dogs, an electrocardiograph monitor is adopted to continuously record indexes such as heart rate, respiratory rate, body temperature, blood oxygen saturation and the like, the beagle dog for experiment is 15-20kg in weight, the administration concentration is 10mg/mL, the administration dosage is 8mg/mL, a commercially available propofol emulsion injection and a propofol water-soluble prodrug are adopted to carry out clinical comparison experiments, experimental data show that after 1min after single intravenous injection of the water-soluble propofol prodrug fospropofol sodium (PP) by the beagle dogs, animals begin to unconscious, the heart rate of the animals before administration is 120-130 times/min, the respiratory rate is 18-25 times/min, the blood oxygen saturation is 95-100, the blood pressure is about 85/130, the body temperature is 38.8 ℃, the heart rate after administration is 150 times/min, the respiratory rate is 15-40 times/min, the blood oxygen saturation is 95-100, the blood pressure is about 55/130, the body temperature is about 38.5 ℃, the experimental animal wakes up 7min after administration, the heart rate and the respiratory rate are obviously accelerated after administration, the body temperature is slightly reduced, the experimental result shows that the propofol prodrug can enable beagle dogs to generate sleepiness and sedation. In general, the water-soluble prodrug of propofol, fospropofol disodium, is a safer sedative and anesthetic agent for veterinary use that can replace propofol injection.

The phosphorus propofol sodium salt prepared by the method does not contain trace residues of highly toxic reagents such as bromochloromethane and the like, so that the safety is higher. In this example, 50 animals were used for clinical studies, the sudden death rate of cardiac arrest due to side effects was 0, and the safety was high, and the water-soluble prodrug of propofol produced according to the present invention was used as a veterinary anesthetic.

Example 7

Embodiment 7 provides a fospropofol sodium anesthetic, comprising fospropofol sodium, a pH buffer regulator, an osmotic pressure regulator, and an antioxidant, wherein the pH is 8.5-10.5. Specifically, the fospropofol disodium prepared in examples 1-5 is prepared according to the prescription amount, the 0.1mol/L pH buffer regulator is sodium bicarbonate, the antioxidant citric acid is 0.2 percent, and the osmotic pressure regulator is 0.5 percent of sodium chloride and water for injection. The fospropofol sodium anesthetic provided in example 7 can be used to anesthetize animals. Also can be used as sedative hypnotic agent for Monitoring Anesthetic Care (MAC) sedation of animals undergoing diagnostic or therapeutic procedures.

Example 8

Example 8 provides a method of synthesizing fospropofol sodium similar to examples 1-5, except that the first solvent is preferably chloroform.

Example 9

Example 9 provides a method of synthesis of fospropofol sodium similar to examples 1-5, except that the first solvent is preferably carbon tetrachloride.

Example 10

Example 10 provides a method of synthesizing fospropofol sodium, similar to examples 1-5, except that the first solvent is preferably acetone

Example 11

Example 11 provides a method of synthesis of fospropofol sodium similar to examples 1-5, except that the first solvent is preferably dimethyl sulfoxide.

Example 12

Example 12 provides a method of synthesis of fospropofol sodium similar to examples 1-5, except that the first solvent is preferably benzene.

Example 13

Example 13 provides a method of synthesis of fospropofol sodium similar to examples 1-5, except that the methylating agent is methyl chloride.

Example 14

Example 14 provides a method of synthesis of fospropofol sodium similar to examples 1-5, except that the alkaline conditions are obtained by addition of sodium hydroxide and potassium hydroxide solutions.

Example 15

Example 15 provides a method of synthesis of fospropofol sodium similar to examples 1-5, except that the second solvent is selected from chlorobenzene and benzene.