CN111116597A

CN111116597A - Preparation method of nalbuphine free alkali

Info

Publication number: CN111116597A
Application number: CN201811305007.9A
Authority: CN
Inventors: 朱顺; 戴志成; 潘瀛鹏; 成玲
Original assignee: Yangtze River Pharmaceutical Group Jiangsu Zilong Pharmaceutical Co ltd
Current assignee: Yangtze River Pharmaceutical Group Jiangsu Zilong Pharmaceutical Co ltd
Priority date: 2018-10-31
Filing date: 2018-10-31
Publication date: 2020-05-08

Abstract

The patent discloses a preparation method of nalbuphine free base, (-) -17- (cyclobutanemethyl) -4, 5 α -epoxy morphine-3, 6 α, 14-hydroxyl, and the synthetic route is shown as follows:

Description

Preparation method of nalbuphine free alkali

Technical Field

The invention relates to the field of medicinal chemistry and organic synthesis, in particular to a preparation method of nalbuphine free base (-) -17- (cyclobutylmethyl) -4, 5 α -epoxy morphine-3, 6 α, 14-hydroxyl.

Background

Nalbuphine Hydrochloride is a central analgesic of morphine, has extremely small addiction, can be used for the analgesic treatment of moderate to severe pain caused by various diseases, has high safety and is a second class of psychotropic drugs, has low side effect in the aspects of psychology, sympathomimetic, respiratory depression and the like, is used as an anesthetic adjuvant abroad for preoperative analgesia, postoperative analgesia, production, obstetrical pain in the process of delivery and the like, and has very wide application, the Nalbuphine Hydrochloride is synthesized for the first time by DuPont in 1965, and is originally researched by Hospira, Nalbuphine Hydrochloride (Nalbuphine Hydrochloride), has the chemical name of (-) -17- (cyclobutylmethyl) -4, 5 α -epoxymorphine-3, 6 α, 14-hydroxy Hydrochloride, and has the following structural formula:

at present, there are two main routes for the synthesis of nalbuphine hydrochloride, one of which takes thebaine as a starting material and the other one takes morphine as a raw material, the 6-hydroxy β isomer exists in the finished products synthesized by the two routes, and a large amount of solvent is consumed in the process of refining and removing the 6-hydroxy β isomer, so that the yield is reduced.

For example: in US740531, gamma-MnO is used₂Although the use of photocatalyst to synthesize nalbuphine avoids the use of virulent reagents cyanogen bromide and expensive vinyl chloroformate, the defect is that the obtained product is difficult to realize industrialized production by chromatographic column separation, in US3332950, lithium aluminium hydride is used as a reducing agent, but the reduced product still contains 10% of 6-hydroxy β isomer, and in the synthesis process of nalbuphine hydrochloride disclosed in Zheng Hua chapter and the like, sodium borohydride is used as a reducing agent, but the reduction yield of the free base of nalbuphine is only 75%, and the 6-hydroxy β isomer still exists.

Therefore, in order to improve the yield and increase the reduction selectivity, a new synthesis of the nalbuphine free base is needed.

Disclosure of Invention

The invention overcomes the defects of the prior art and provides a novel synthesis method of nalbuphine free alkali, which can obviously reduce the content of 6-hydroxyl β isomer in the product and improve the yield, and finally ensures that the content of 6-hydroxyl β isomer in the product is lower than 1 percent and the yield can reach 86 percent through the selective reduction.

In an embodiment, the present invention provides a method of preparing a synthetic compound, formula IV, by contacting a compound of formula II with a reducing agent under reaction conditions to form a compound of formula IV:

Detailed Description

Dissolving the compound of the formula II in methanol or ethanol at the temperature of-20-70 ℃, stirring, adding a reducing agent sodium triacetoxyborohydride (accounting for 1-5 times of the substance), and monitoring the reaction in a liquid phase until the compound of the formula II is completely reacted.

Adding a proper amount of water for quenching, concentrating under reduced pressure to remove an organic solvent, then adjusting the pH to 7-14 with alkali, adding a proper amount of water, extracting with ethyl acetate for three times, washing with saturated saline solution, drying with anhydrous sodium sulfate, performing suction filtration, and then concentrating under reduced pressure to obtain the compound shown in the formula IV.

Compound I ═ nalbuphine hydrochloride

Compound II ═ 14-hydroxy-17-cyclobutylmethyl-7, 8-dihydromorphinone

Compound III as β isomer

Compound IV ═ nalbuphine free base

Example 1:

adding 1.01g of compound II and 40mL of absolute ethanol into a 100mL three-neck flask, stirring, controlling the reaction temperature to be 0 ℃, weighing 719mg (1.2eq) of sodium triacetoxyborohydride, adding the sodium triacetoxyborohydride in batches, sampling and controlling every 1h until the compound II finishes reacting, adding 2mL of water to quench the reaction after the reaction is finished, decompressing and concentrating by a rotary evaporator to remove the ethanol, adding a saturated sodium carbonate solution to adjust the pH to be about 9.0, adding 10mL of water, extracting for 3 times by using 10mL of ethyl acetate, collecting an organic phase, washing by using saturated sodium chloride, adding 2g of anhydrous sodium sulfate for drying, and performing rotary drying and concentration to obtain 0.87g of nalbuphine free base, wherein the yield is 86.0%, the purity is 99.01%, and the content of β -nalbuphine is 0.45%.

Example 2:

adding 1.03g of compound II and 40mL of anhydrous ethanol into a 100mL three-neck flask, stirring, controlling the reaction temperature to be 70 ℃, weighing 611mg (1.0eq) of sodium triacetoxyborohydride, adding the sodium triacetoxyborohydride in batches, sampling and controlling every 1h until the compound II finishes reacting, adding 2mL of water to quench the reaction after the reaction is finished, decompressing and concentrating by a rotary evaporator to remove the ethanol, adding a saturated sodium carbonate solution to adjust the pH to be about 9.0, adding 10mL of water, extracting with 10mL of ethyl acetate for 3 times, collecting an organic phase, washing with saturated sodium chloride, adding 2g of anhydrous sodium sulfate to dry, and concentrating by rotary drying to obtain 0.78g of nalbuphine free base, wherein the yield is 75.70%, the purity is 99.12%, and the content of β -nalbuphine is 0.38%.

Example 3:

adding 1.05g of compound II and 40mL of anhydrous methanol into a 100mL three-neck flask, stirring, controlling the reaction temperature to be-20 ℃, weighing 2.49g (4.0eq) of sodium triacetoxyborohydride, adding the mixture into a reaction system in batches, sampling and controlling every 1h until the compound II finishes reacting, adding 2mL of water to quench the reaction after the reaction is finished, decompressing and concentrating by a rotary evaporator to remove the methanol, adding a saturated sodium carbonate solution to adjust the pH to be about 9.0, adding 10mL of water, extracting for 3 times by 10mL of ethyl acetate, collecting an organic phase, washing by saturated sodium chloride, adding 2g of anhydrous sodium sulfate for drying, and performing spin-drying and concentration to obtain 0.76g of nalbuphine free base, wherein the yield is 72.4%, the purity is 99.03%, and the content of β -nalbuphine is 0.52%.

Example 4:

adding 1.00g of compound II and 40mL of absolute ethanol into a 100mL three-neck flask, stirring, controlling the reaction temperature to be 25 ℃, weighing 593mg (1.0eq) of sodium triacetoxyborohydride, adding the reaction system in batches, sampling and controlling every 1h until the compound II finishes reacting, adding 2mL of water to quench the reaction after the reaction is finished, decompressing and concentrating by a rotary evaporator to remove the ethanol, adding a saturated sodium carbonate solution to adjust the pH to be about 9.0, adding 10mL of water, extracting for 3 times by using 10mL of ethyl acetate, collecting an organic phase, washing by using saturated sodium chloride, adding 2g of anhydrous sodium sulfate for drying, and performing rotary drying and concentration to obtain 0.86g of nalbuphine free base, wherein the yield is 86.12%, the purity is 99.09%, and the content of β -nalbuphine is 0.54%.

Example 5:

adding 1.04g of compound II and 40mL of anhydrous methanol into a 100mL three-neck flask, stirring, controlling the reaction temperature to be 70 ℃, weighing 1.85g (2.0eq) of sodium triacetoxyborohydride, adding the reaction system in batches, sampling and controlling every 1h until the compound II finishes reacting, adding 2mL of water to quench the reaction after the reaction is finished, decompressing and concentrating by a rotary evaporator to remove the methanol, adding a saturated sodium carbonate solution to adjust the pH to be about 9.0, adding 10mL of water, extracting for 3 times by using 10mL of ethyl acetate, collecting an organic phase, washing by using saturated sodium chloride, adding 2g of anhydrous sodium sulfate for drying, and performing spin-drying and concentration to obtain 0.82g of nalbuphine free base, wherein the yield is 78.15%, the purity is 98.97%, and the content of β -nalbuphine is 0.60%.

Example 6:

adding 1.01g of compound II and 40mL of anhydrous methanol into a 100mL three-neck flask, stirring, controlling the reaction temperature to be 25 ℃, weighing 1.20g (2.0eq) of sodium triacetoxyborohydride, adding the reaction system in batches, sampling and controlling every 1h until the compound II finishes reacting, adding 2mL of water to quench the reaction after the reaction is finished, decompressing and concentrating by a rotary evaporator to remove the methanol, adding a saturated sodium carbonate solution to adjust the pH to be about 9.0, adding 10mL of water, extracting for 3 times by using 10mL of ethyl acetate, collecting an organic phase, washing by using saturated sodium chloride, adding 2g of anhydrous sodium sulfate for drying, and performing spin-drying and concentration to obtain 0.79g of nalbuphine free base, wherein the yield is 78.16%, the purity is 99.14%, and the content of β -nalbuphine is 0.50%.

Example 7:

adding 1.02g of compound II and 40mL of anhydrous methanol into a 100mL three-neck flask, stirring, controlling the reaction temperature to be 45 ℃, weighing 1.82g (3.0eq) of sodium triacetoxyborohydride, adding the sodium triacetoxyborohydride in batches, sampling and controlling every 1h until the compound II finishes reacting, adding 2mL of water to quench the reaction after the reaction is finished, decompressing and concentrating by a rotary evaporator to remove the methanol, adding a saturated sodium carbonate solution to adjust the pH to be about 9.0, adding 10mL of water, extracting for 3 times by using 10mL of ethyl acetate, collecting an organic phase, washing by using saturated sodium chloride, adding 2g of anhydrous sodium sulfate for drying, and performing rotary drying and concentration to obtain 0.81g of nalbuphine free base, wherein the yield is 79.10%, the purity is 99.03%, and the content of β -nalbuphine is 0.52%.

Example 8:

adding 1.04g of compound II and 40mL of absolute ethanol into a 100mL three-neck flask, stirring, controlling the reaction temperature to be 45 ℃, weighing 1.82g (3.0eq) of sodium triacetoxyborohydride, adding the sodium triacetoxyborohydride in batches, sampling and controlling every 1h until the compound II finishes reacting, adding 2mL of water to quench the reaction after the reaction is finished, decompressing and concentrating by a rotary evaporator to remove the ethanol, adding a saturated sodium carbonate solution to adjust the pH to be about 9.0, adding 10mL of water, extracting for 3 times by using 10mL of ethyl acetate, collecting an organic phase, washing by using saturated sodium chloride, adding 2g of anhydrous sodium sulfate for drying, and performing rotary drying and concentration to obtain 0.85g of nalbuphine free base, wherein the yield is 81.10%, the purity is 99.07%, and the content of β -nalbuphine is 0.55%.

Comparative example 1:

adding 1.01g of compound II and 40mL of absolute ethanol into a 100mL three-neck flask, stirring, controlling the reaction temperature to be 25 ℃, weighing 129mg (1.2eq) of sodium borohydride, adding the sodium borohydride into the reaction system in batches, sampling and controlling every 1h until the compound II is reacted, adding 2mL of water to quench the reaction after the reaction is finished, performing reduced pressure concentration by using a rotary evaporator to remove the ethanol, adding a saturated sodium carbonate solution to adjust the pH to be about 9.0, adding 10mL of water, extracting the mixture for 3 times by using 10mL of ethyl acetate, collecting an organic phase, washing the organic phase by using saturated sodium chloride, adding 2g of anhydrous sodium sulfate, drying the mixture, and performing rotary drying and concentration to obtain 0.77g of nalbuphine free base, wherein the yield is 75.70%, the purity is 70.08%, and the content of β -nalbuphine is 28.06%.

Claims

1. Synthetic method for preparing compound of formula IV

Contacting a compound of formula II with a reducing agent under reaction conditions to form a compound of formula IV, wherein the compound of formula II is:

2. the method of claim 1, wherein the solvent is methanol or ethanol and the mass to volume ratio of the compound of formula II to the solvent is from 1: 10 to 1: 50.

3. The process of claim 1, contacting the compound of formula II with a reducing agent under reaction conditions to form the compound of formula IV, wherein the reaction conditions comprise a temperature between-20 ℃ and 70 ℃.

4. The method of claim 1, wherein the reducing agent is sodium triacetoxyborohydride.

5. The method of claim 1, wherein the ratio of the amount of reducing agent to the substance of the compound of formula II is from 1: 1 to 5: 1.