阅读说明：本技术 一种纳布啡的制备方法及其中间体 (Preparation method and intermediate of nalbuphine ) 是由 李莉娥 张俊 曹路 易斌 付婷婷 廖宗权 于 2021-01-05 设计创作，主要内容包括：本发明公开了一种纳布啡的制备方法及其中间体,所述的制备方法以吗啡为原料,经酰化、催化氧化、钯/碳加氢还原、氯甲酸-1-氯乙酯脱N-甲基、水解脱保护、氮-甲基环丁烷取代而制备纳布啡。该方法从起始原料即引入了手性中心,在整个反应过程中,未采用会影响手性中心的反应和试剂,且整个反应过程仅使用常规的方法和设备,操作简便,条件温和,路线短,总体收率高,适合工业化生产。(The invention discloses a preparation method of nalbuphine and an intermediate thereof, wherein morphine is used as a raw material, and the nalbuphine is prepared through acylation, catalytic oxidation, palladium/carbon hydrogenation reduction, N-methyl removal by chloroformic acid-1-chloroethyl, hydrolysis deprotection and nitrogen-methyl cyclobutane substitution. The method introduces chiral centers from starting materials, does not adopt reactions and reagents which can influence the chiral centers in the whole reaction process, only uses conventional methods and equipment in the whole reaction process, has simple and convenient operation, mild conditions, short route and high overall yield, and is suitable for industrial production.)

1. A method of preparing nalbuphine, said method comprising the steps of:

(a) morphine shown in a formula (I) or an acid salt thereof reacts with an acetylation reagent to generate a compound shown in a formula (II);

(b) reacting the compound of the formula (II) obtained in the step (a) with tert-butyl peroxybenzoate (TBPB) under the action of a cuprous catalyst and a nitrogen ligand to obtain a compound of a formula (III) protected by a 14-hydroxy group;

(c) carrying out catalytic hydrogenation on the compound of the formula (III) obtained in the step (b) by palladium carbon (Pd/C) to obtain a compound of a formula (IV);

(d) reacting the compound of formula (IV) obtained in the step (c) with chloroformic acid-1-chloroethyl ester, and hydrolyzing to obtain a compound (V);

(e) reacting the compound of formula (V) obtained in step (d) with cyclobutylbromomethane to obtain nalbuphine (VI);

wherein Ac in the compounds of the formula (II), the formula (III) and the formula (IV) is acetyl; in the compounds of formula (III) and formula (IV), Bz is benzoyl.

2. The preparation method according to claim 1, wherein in the step (a), the acid salt of morphine can be an inorganic acid salt or an organic acid salt, optionally, the inorganic acid salt is a hydrochloride or a sulfate; the organic acid salt is salicylate or tartrate; and/or

In the step (a), the acetylating reagent is acetic anhydride, acetic acid or acetyl chloride; and/or

In the step (a), the reaction is carried out in the presence of an organic base, wherein the organic base is one or a mixture of more than two of triethylamine, diisopropylethylamine and pyridine, and preferably pyridine.

3. The method of claim 1, wherein the cuprous catalyst is CuBr, CuCl, CuI, and Cu₂One or a mixture of more than two of O, preferably CuI; and/or

In the step (b), the molar ratio of the compound of formula (II) to the cuprous catalyst is 1:0.1 to 1:0.2, preferably, the molar ratio is 1: 0.1.

4. The production method according to claim 1, wherein the nitrogen ligand is one or a mixture of two or more of 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylenediamine, and triethylamine, preferably, the nitrogen ligand is triethylenediamine; and/or

In the step (b), the molar ratio of the compound of the formula (II) to the nitrogen ligand is 1:0.1 to 1:0.2, preferably, the molar ratio is 1: 0.1.

5. The preparation method according to claim 1, wherein the step (b) is carried out in an aprotic organic solvent, wherein the aprotic organic solvent is one or a mixture of two or more of benzene, toluene, 1, 4-dioxane and acetonitrile, preferably, the organic solvent is 1, 4-dioxane; and/or

The reaction temperature of the reaction in the step (b) is 70-100 ℃.

6. The production method according to any one of claims 1 to 5, wherein in the step (b), the nitrogen ligand is triethylenediamine, and the cuprous catalyst is CuI; wherein the molar ratio of the compound of formula (II) to triethylene diamine is 1 (0.1-0.2), preferably the molar ratio is 1: 0.1; the molar ratio of the compound of the formula (II) to the CuI is 1 (0.1-0.2), and preferably the molar ratio is 1: 0.1.

7. The production method according to any one of claims 1 to 5, wherein in the step (b), the nitrogen ligand is DBU, and the cuprous catalyst is CuI; wherein the molar ratio of the compound of formula (II) to DBU is 1 (0.1-0.2), preferably the molar ratio is 1: 0.1; the molar ratio of the compound of the formula (II) to CuI is 1 (0.1-0.2), preferably 1: 0.1.

8. The production method according to any one of claims 1 to 5, wherein in the step (d), the compound of formula (IV) is reacted with 1-chloroethyl chloroformate, and the resulting reaction solution is filtered, and after the filtrate is spin-dried, it is used in the hydrolysis reaction of the step (d).

9. The preparation method according to any one of claims 1 to 5, wherein in the step (e), the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate or a mixture thereof, preferably potassium carbonate.

10. A nalbuphine intermediate compound has a structure shown as a compound in a formula (III):

wherein Ac in the compound of the formula (III) is acetyl; bz is benzoyl;

or, the structure is shown as the compound of formula (IV):

wherein Ac in the compound of the formula (IV) is acetyl; bz is benzoyl.

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method and an intermediate of nalbuphine.

Background

Nalbuphine is a morphinan semi-synthetic opioid receptor mixed agonist-antagonist of formula C₂₁H₂₇NO₄Structurally similar to the opioid receptor antagonist naloxone and the potent opioid analgesic oxymorphone:

nalbuphine is used as an analgesic drug with multiple action mechanisms, has partial antagonism to mu receptors and complete agonism to kappa receptors, and has weaker agonism activity to delta receptors, and the mechanism ensures that the nalbuphine has less adverse reaction and low toxic and side effects compared with other opioid analgesic drugs. Nalbuphine is used for treating moderate and severe pain, such as tumor, cancer, liver and gallbladder pain, and can be used as adjuvant medicine for compound anesthesia for relieving pain before and after operation and delivery, and relieving pain during parturition.

Nalbuphine is generally synthesized starting from natural morphine derivatives, such as morphine, codeine, thebaine, oripavine and the like. In the disclosed synthetic routes, the hydroxyl group at the 6-position is obtained by reducing the carbonyl group at the 6-position, thus introducing a certain amount of β -isomer impurity at the 6-position.

For example, US3332950 discloses a process for the preparation of nalbuphine starting from 14-hydroxynormorphinone wherein the route uses a lithium aluminium hydride reducing agent but the resulting nalbuphine product after reduction contains about 10% of the 6-position β isomer impurity.

WO9532973 discloses a method for preparing nalbuphine by using 14-hydroxymethyl morphinone as a raw material and reducing 6-carbonyl by sodium borohydride, catalytic hydrogenation, 3-and N-protecting group deprotection, amidation and reduction, wherein the content of 6-beta isomer impurities in the nalbuphine product is lower than 1%.

IN2009MU02909 discloses a method for preparing nalbuphine from thebaine as a raw material through oxidation, 14-hydroxy protection, N-methyl protection, 6-carbonyl reduction, hydrolysis deprotection, catalytic hydrogenation, N-protecting group removal, amidation, carbonyl reduction and 3-methoxy demethylation, wherein the yield is 22%, and the content of 6-beta isomer impurities IN the obtained nalbuphine product is lower than 0.1%.

Although the impurity content of the 6-position beta isomer is reduced to be lower than 1 percent, the preparation method of nalbuphine disclosed by the prior art consumes a large amount of solvent in the process of refining and removing the 6-position hydroxyl beta isomer in industrial production, so that the yield is reduced, and the production cost is increased; and the synthesis reported at present generally has the defects of long route, low yield, complicated operation, low economy and the like. Therefore, it is particularly important to develop a nalbuphine synthetic route which has short route, no 6-position beta isomer impurity generation, simple operation and high yield.

Disclosure of Invention

The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the present application.

The invention provides a preparation method of nalbuphine, which has the advantages of short route, no generation of 6-bit beta isomer impurity, simple and convenient operation and suitability for industrial production.

The invention provides a preparation method of nalbuphine, which comprises the following steps:

(a) morphine shown in a formula (I) or an acid salt thereof reacts with an acetylation reagent to generate a compound shown in a formula (II);

(b) reacting the compound of the formula (II) obtained in the step (a) with tert-butyl peroxybenzoate (TBPB) under the action of a cuprous catalyst and a nitrogen ligand to obtain a compound of a formula (III) protected by a 14-hydroxy group;

(c) carrying out catalytic hydrogenation on the compound of the formula (III) obtained in the step (b) by palladium carbon (Pd/C) to obtain a compound of a formula (IV);

(d) reacting the compound of formula (IV) obtained in the step (c) with chloroformic acid-1-chloroethyl ester, and hydrolyzing to obtain a compound (V);

(e) reacting the compound of formula (V) obtained in step (d) with cyclobutylbromomethane to obtain nalbuphine (VI);

wherein Ac in the compounds of the formula (II), the formula (III) and the formula (IV) is acetyl; in the compounds of formula (III) and formula (IV), Bz is benzoyl.

In the above embodiment, in the step (a), the acid salt of morphine may be an inorganic acid salt or an organic acid salt, optionally, the inorganic acid salt is a hydrochloride or a sulfate; the organic acid salt is salicylate or tartrate.

In the above embodiment, in the step (a), the acetylating reagent is acetic anhydride, acetic acid or acetyl chloride.

In some embodiments, in step (a), the reaction is carried out in the presence of an organic base, which is one or a mixture of two or more of triethylamine, diisopropylethylamine, and pyridine, preferably pyridine.

In some embodiments, in step (b), the cuprous catalyst is CuBr, CuCl, CuI, and Cu₂One or a mixture of two or more of O, preferably CuI.

In some embodiments, in step (b), the molar ratio of the compound of formula (II) to the cuprous catalyst is 1:0.1 to 1:0.2, preferably the molar ratio is 1: 0.1.

In some embodiments, in step (b), the nitrogen ligand is 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (DBU), triethylenediamine (D)ABCO) and Triethylamine (Et)₃N), preferably the nitrogen ligand is DABCO. In the above embodiment, the nitrogen ligand can complex with the copper catalyst, increasing the catalytic efficiency of the reaction of step (b).

In some embodiments, in step (b), the molar ratio of the compound of formula (II) to the nitrogen ligand is from 1:0.1 to 1:0.2, preferably the molar ratio is 1: 0.1.

In some embodiments, step (b) is performed in an aprotic organic solvent, wherein the aprotic organic solvent is one or a mixture of two or more of benzene, toluene, 1, 4-dioxane, and acetonitrile, preferably the organic solvent is 1, 4-dioxane.

In some embodiments, the reaction temperature for the reaction in step (b) is from 70 ℃ to 100 ℃.

In some embodiments, in step (b), the nitrogen ligand is 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (DBU), triethylenediamine (DABCO) and triethylamine (Et)₃N) or a mixture of two or more thereof; the cuprous catalyst is CuBr, CuCl, CuI and Cu₂One or a mixture of two or more of O. In the above embodiment, under the action of the cuprous catalyst and the nitrogen ligand, the TPBP is used as the oxidant, and the generated benzoyloxy radical after the TPBP peroxide bond is broken can be effectively combined with the compound of formula (II), so that the 14-benzoyloxy protected compound of formula (III) can be obtained in high yield and high selectivity.

In some embodiments, in step (b), the nitrogen ligand is DABCO and the cuprous catalyst is CuI; wherein the molar ratio of the compound of formula (II) to DABCO is 1 (0.1-0.2), preferably the molar ratio is 1: 0.1; wherein the molar ratio of the compound of the formula (II) to the CuI is 1 (0.1-0.2), preferably 1: 0.1.

In some embodiments, in step (b), the nitrogen ligand is DBU and the cuprous catalyst is CuI; wherein the molar ratio of the compound of formula (II) to DBU is 1 (0.1-0.2), preferably the molar ratio is 1: 0.1; the molar ratio of the compound of the formula (II) to CuI is 1 (0.1-0.2), preferably 1: 0.1.

In some embodiments, in step (d), the compound of formula (IV) is reacted with 1-chloroethyl chloroformate, and the resulting reaction solution is filtered, and after spin-drying the filtrate, it is used in the hydrolysis reaction of step (d).

In some embodiments, in step (e), the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, or a mixture thereof, preferably potassium carbonate.

In one embodiment, the method of preparing the nalbuphine comprises the steps of:

(a) morphine reacts under the action of acetic anhydride and pyridine to generate a compound shown in a formula (II);

(b) reacting the compound of the formula (II) obtained in the step (a) with tert-butyl peroxybenzoate (TBPB) under the action of CuI and DABCO to obtain a compound of a formula (III) with 14-hydroxy protected;

(c) carrying out catalytic hydrogenation on the compound of the formula (III) obtained in the step (b) by palladium carbon (Pd/C) to obtain a compound of a formula (IV);

(d) reacting the compound shown in the formula (IV) with chloroformic acid-1-chloroethyl ester, and hydrolyzing under the action of sodium carbonate to obtain a compound shown in the formula (V);

(e) and (3) reacting the compound shown in the formula (V) with cyclobutylbromomethane under the action of potassium carbonate to obtain the nalbuphine (VI).

In the above embodiment, the molar ratio of the compound of formula (II), CuI, DABCO is 1 (0.1-0.2) to (0.1-0.2); preferably, the molar ratio of the compound of formula (II), CuI and DABCO is 1:0.1: 0.1.

In another aspect, the present invention provides a nalbuphine intermediate compound, the structure of which is shown as formula (III):

wherein Ac in the compound of the formula (III) is acetyl; bz is benzoyl.

In another aspect of the present invention, there is provided another nalbuphine intermediate having the structure represented by the formula (IV):

wherein Ac in the compound of the formula (IV) is acetyl; bz is benzoyl.

The nalbuphine prepared by the method is characterized and detected by technical means such as nuclear magnetic resonance hydrogen spectrum, carbon spectrum, High Performance Liquid Chromatography (HPLC) and the like, and the result proves that the structure of the nalbuphine prepared by the method is consistent with that of a commercially available raw material medicine, and the purity of the nalbuphine prepared by the method reaches more than 99.9%.

Compared with the prior art, the invention has the beneficial effects that:

(1) the preparation method provided by the invention provides a synthesis method of nalbuphine, specifically morphine is used as a starting material, a chiral center is introduced from the starting material, and a reaction and a reagent which can influence the chiral center are not adopted in the whole reaction process, so that the method with higher cost and low efficiency of chiral resolution, chiral catalyst and the like is avoided, and the chiral purity of the product is ensured.

(2) The preparation method provided by the invention provides a synthesis method of nalbuphine, the whole reaction process only uses conventional experimental methods and equipment, the operation is simple and convenient, the condition is mild, and the catalytic oxidation method provided by the step (b) can obtain the compound of the formula (III) protected by 14-hydroxy, so that the whole reaction route is shortened, and the method is suitable for industrial production.

Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the application. Other advantages of the present application may be realized and attained by the instrumentalities and combinations particularly pointed out in the specification and the drawings.

Drawings

The accompanying drawings are included to provide an understanding of the present disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure and together with the examples serve to explain the principles of the disclosure and not to limit the disclosure.

FIG. 1 is an HPLC chromatogram of the compound of formula (VI) prepared in example 5 (main peak retention time of 5.860 minutes, relative peak area of 99.93%).

Detailed Description

Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.

In the embodiments of the present invention, unless otherwise specified,¹H NMR、¹³the detection conditions for C NMR were as follows:

a detector: BRUKER AV-400 type nuclear magnetic resonance spectrometer

Solvent: DMSO-d₆

Measuring temperature: 303K

In the present embodiment, unless otherwise specified, the measurement conditions of High Performance Liquid Chromatography (HPLC) are as follows:

a detector: waters2695 model high performance liquid chromatograph

A chromatographic column: agilent ZORBAX SB-C18

Mobile phase: 0.01mol/L potassium dihydrogen phosphate aqueous solution (containing 0.1% triethylamine, adjusted to pH 2.6. + -. 0.1 with phosphoric acid) -acetonitrile (85: 15)

Column temperature: 35 deg.C

Wavelength: 201nm

EXAMPLE 1 Synthesis of Compound of formula (II)

600mL of pyridine and 900mL of acetic anhydride were added to a 2.50L single-neck flask, 60g (183mmol) of morphine was added under stirring, the resulting reaction solution was stirred at room temperature for 24 hours, and the disappearance of the starting material was monitored by TLC. The reaction solution was poured into 2.5L of ice water, extracted with chloroform (3X 1.5L), the organic layers were combined, washed with 10% sodium hydrogencarbonate (2L) and water (2L), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was partially evaporated and cooled, ether was added, the resulting solid was filtered and dried to obtain 64g of a compound of formula (II) as a white solid in a yield of 94.6%.

HPLC purity 92.63%.

EXAMPLE 2 Synthesis of Compound of formula (III)

Adding 1.0L of 1, 4-dioxane into a 2.5L three-neck flask equipped with a nitrogen protection device, a reflux pipe and a dropping funnel, adding 64g (173mmol) of the compound of formula (II) (from example 1), 1.5g (17.3mmol) of DABCO and 3.3g (17.3mmol) of CuI in turn under stirring, slowly dropping 50g of TBPB (260mmol) through the dropping funnel, replacing with nitrogen after the addition is finished, reacting the reaction mixture at 90 ℃ for 6 hours, filtering the reaction solution with diatomite after cooling, pouring the filtrate into 3L of ice water, and adding 30% K₂CO₃The pH was adjusted to 8, a large amount of solid precipitated, filtered, and the filter cake was washed with water, ether and dried to give 65g of the compound of formula (III) in 77% yield.

HPLC purity 95.24%.

¹H NMR(DMSO-d₆，400MHz)δ：1.55～2.00(m,2H),2.19(s,3H),2.26(s,3H),2.28(s,3H),2.41～2.51(m,2H),2.79～3.04(m,3H),5.22(m,1H),5.59～5.63(m,3H),6.60～6.74(m,2H),7.55～8.03(m,5H)。

EXAMPLE 3 Synthesis of Compound of formula (III)

In a 50mL three-necked flask equipped with a nitrogen blanket, a reflux tube and a dropping funnel, 30mL of 1, 4-dioxane was charged, and 1g (2.7mmol) of the compound of formula (II) (prepared according to example 1), 0.04g (0.27mmol) of DBU and 0.27mmol of copper catalyst (shown in Table 1) were added in this order with stirring, and 0.79 g of TBPB (4.07mmol) was slowly dropped through the dropping funnel, and after the completion of the addition, nitrogen substitution was carried out, and the reaction mixture was reacted at 90 ℃ for 6 hours, and the content data of the final product detected by high performance liquid chromatography were shown in Table 1.

TABLE 1 summary of experimental parameters and final product content results of example 3

Test number	Metal catalyst	Product content (%)
			1	CuBr	39
2	CuCl	43
			3	CuI	67
4	Cu2O	28
			5	CuCl2	13
6	Cu(OAc)2	6

As can be seen from the test results in Table 1 above, the above-mentioned metal salts of copper can be used as catalysts for the above-mentioned reaction, but the catalytic activity of the monovalent copper salt is significantly better than that of the divalent copper salt, and the catalytic activity of cuprous iodide is the best.

EXAMPLE 4 Synthesis of Compound of formula (III)

1, 4-dioxane 30mL was charged into a 50mL three-necked flask equipped with a nitrogen blanket, reflux tube and dropping funnel, 1g (2.7mmol) of the compound of formula (II) (prepared according to example 1), 0.05g (0.27mmol) of CuI and 0.27mmol of ligand (shown in Table 2) were added in this order with stirring, 0.79 g of TBPB (4.05mmol) was slowly dropped through the dropping funnel, the reaction mixture was replaced with nitrogen after the completion of the addition, the reaction mixture was reacted at 90 ℃ for 6 hours, and the content data of the final product detected by high performance liquid chromatography are shown in Table 2.

Table 2 summary of experimental parameters and final product content results of example 4

Test number	Ligands	Product content (%)
			1	Et3N	53
2	DBU	67
			3	DABCO	84

As can be seen from the test results shown in Table 2 above, Et₃N, DBU and DABCO can be used as ligands of the reaction, wherein the catalytic effect is better when the DABCO is matched with the CuI.

EXAMPLE 5 Synthesis of nalbuphine (i.e., a compound of formula (VI)) from a compound of formula (IV)

S1: A5L autoclave was charged with 1.5L of methanol, 65g (133mmol) of the compound of formula (III) (prepared by using DABCO in combination with CuI in example 4) and 5% of wet palladium on charcoal (10g), and the reaction was carried out under hydrogen at room temperature for 9 hours while maintaining the hydrogen pressure at 35Psi, and the completion of the reaction was monitored by TLC, followed by filtration, washing of the filtrate with a small amount of methanol, concentration and evaporation of the filtrate to dryness to give 59g of the compound of formula (IV) in 91% yield.

HPLC purity: 96.52 percent.

¹H NMR(DMSO-d₆，400MHz)δ：1.55～2.00(m,6H),2.02(s,3H),2.26(s,3H),2.28(s,3H),2.41～2.51(m,2H),2.79～3.04(m,3H),5.01(m,1H),5.09～5.11(m,1H),6.60～6.74(m,2H),7.55～7.67(m,5H)。

S2, adding 200mL of dichloroethane into a 1.0L single-neck bottle, adding 59g (12.0mmol) of the compound of the formula (IV) prepared by S1, 8.5g (60mmol) of chloroformic acid-1-chloroethyl ester and 6g of potassium bicarbonate under stirring, heating the obtained mixture to reflux for reaction for 8 hours, cooling to room temperature, filtering, spinning dry the filtrate, adding 5.0g of sodium carbonate and 150mL of methanol into the residue, heating to 70-80 ℃, carrying out hydrolysis reaction for 8 hours, cooling the reaction solution to room temperature, filtering, adjusting the pH of the filtrate to be 9 with 25% ammonia water, stirring to separate out a solid, filtering, washing the filter cake with water and ethanol in sequence, and drying to obtain 30g of the compound of the formula (V) as a light brown solid with the yield of 86%.

HPLC purity: 95.30 percent.

S3: adding 500mL of DMF into a 1L single-neck bottle, sequentially adding 30g (104mmol) of the compound of the formula (V) prepared by S2, 33g (311mmol) of sodium carbonate, 3g (21mmol) of potassium iodide and 19g (125mmol) of cyclobutylbromomethane under stirring, heating the reaction solution to 50 ℃ for reaction for 12 hours, monitoring the completion of the reaction by TLC, cooling the reaction solution to room temperature, slowly adding the reaction solution into 2L of water, stirring, separating out a solid, filtering, sequentially washing a filter cake with water and cyclohexane, drying, recrystallizing the crude product with ethanol to obtain 28g of nalbuphine (namely the compound of the formula (VI)) as a white solid with the yield of 76%.

HPLC purity: 99.93 percent.

The present application describes embodiments, but the description is illustrative rather than limiting and it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of the embodiments described herein.