CN116969906A - Bridged amino tetrahydronaphthalene compound and preparation method and application thereof - Google Patents

Abstract

The invention provides a bridged amino tetrahydronaphthalene compound (a compound shown in a formula A), and a preparation method and application thereof.

Description

A bridged aminotetralin compound and its preparation method and use

Technical field

The invention belongs to the field of medicine, and specifically provides a bridged aminotetralin compound (compound of formula A) and its preparation method and use.

Background technique

[5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methylenebenzo Cyclodecen-3-phenol is a typical opioid alkaloid analgesic developed by the Swedish company Astra. It works by stimulating opioid receptors.

In the process of new drug research and development, drug quality is an important criterion for measuring drug quality. The safety of a drug is not only related to its active ingredients, but also to the impurities present, their content and physiological toxicity. The occurrence of many adverse drug reactions is directly related to its impurities. In addition, impurities can also affect the stability of the drug itself, reducing its activity. Therefore, the control of impurities in drugs is an important means to ensure drug safety.

As we all know, single impurities in pharmaceutical raw materials or their preparations need to be controlled within a certain level, such as below 0.5%, below 0.4%, below 0.3%, below 0.2%, below 0.1%, etc. The growth of impurities in pharmaceutical raw materials cannot exceed the aforementioned limits during their storage and validity period.

Contents of the invention

The invention provides a bridged aminotetralin compound (compound of formula A) and its preparation method and use.

A method for preparing bridged aminotetralin compounds (compounds of formula A), including:

Step 1: Under the protection of inert gas (such as nitrogen), (-)-(5R,11S,13S)-13-amino-5,6,7,8,9,10,11,12-octahydro-5 -Methyl-5,11-methylenebenzocyclodecene-3-methoxy-D-tartrate is refluxed in hydrobromic acid to remove the hydrobromic acid. The residue is dissolved in water and filtered by cooling and crystallization. ;

Step 2: Adjust the pH of the mother liquor with ammonia water and suction filtrate. The obtained filter cake is extracted, separated, washed and dried, and then the compound of formula A is separated using a preparative liquid phase system.

Further, the pH in step 2=8~9.

Further, dichloromethane and 10% wtNaOH solution were added to the filter cake in step 2 for extraction.

Further, the washing step in step 2 is: the organic phase obtained by liquid separation is washed with 10% wt NaOH solution and water respectively.

Further, the preparation liquid phase conditions are: octadecylsilane bonded silica gel is used as filler, 0.1% (v/v) formic acid aqueous solution is used as mobile phase A, acetonitrile is used as mobile phase B, elution is carried out, and the detection wavelength is 281nm.

Further, the elution method is gradient elution, and the volume ratio of the initially used mobile phase A is 65% to 100%.

Further, the elution method is gradient elution, and the volume ratio of mobile phase A/mobile phase B is as shown in the following table:

The invention also provides a compound of formula A in [5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5 , 11-methylenebenzocyclodecene-3-phenol or its pharmaceutical salt is used as an impurity reference substance when detecting related substances in raw materials and preparations,

In an alternative embodiment, [5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5, Detection methods for related substances in raw materials and preparations of 11-methylenebenzocyclodecene-3-phenol or its pharmaceutically acceptable salts include:

Preparation of test solution: take [5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5 , 11-methylenebenzocyclodecene-3-phenol, weigh it accurately, add acetonitrile to dissolve it, add an aqueous solution containing triethylamine and adjust the pH value to 2.0-4.0 with phosphoric acid, and dilute to the mark. shake well;

Preparation of the reference solution: Precisely weigh the compound of formula A, first add acetonitrile to dissolve it, and then dilute it to the mark with water to serve as the reference solution; accurately measure the compound of formula A reference solution and other impurity reference solution. Put an appropriate amount into the same measuring flask and dilute to the mark with diluent.

Precisely measure the test solution and the impurity reference solution respectively, and inject them into the liquid chromatograph to record the chromatogram.

Further, in the preparation of the test solution, the aqueous solution contains 0.1%-1% v/v triethylamine, and uses phosphoric acid to adjust the pH value to 2.0-4.0; preferably, it contains 0.25% v/v triethylamine, and uses phosphoric acid to adjust the pH value. to 3.0.

Further, an aqueous solution containing 0.25% v/v triethylamine and whose pH value has been adjusted to 3.0 with phosphoric acid was added to the preparation of the test solution.

Further, the chromatography conditions are: use octadecylsilane bonded silica gel as the filler; use acetonitrile/0.1%-1% (v/v) triethylamine aqueous solution as the mobile phase A, acetonitrile/0.1%-1% ( v/v) triethylamine aqueous solution as mobile phase B; wherein the triethylamine aqueous solution in mobile phase A and mobile phase B is adjusted to pH 2.0-4.0 with phosphoric acid, mobile phase A and mobile phase B perform linear elution, the flow rate It is 0.5-2mL per minute; the detection wavelength is 250-300nm.

Further, the volume ratio of mobile phase A: acetonitrile and 0.1%-1% (v/v) triethylamine solution is 10-20:80-90, and mobile phase B: acetonitrile and 0.1%-1% (v/v) The volume ratio of the triethylamine solution of v) is 60-80:20-40.

Further, the chromatographic conditions are: using octadecylsilane bonded silica gel as the filler; using acetonitrile/0.25% (v/v) triethylamine aqueous solution as the mobile phase A, acetonitrile/0.7% (v/v) triethyl Amine aqueous solution is used as mobile phase B; the triethylamine aqueous solution in mobile phase A and mobile phase B is adjusted to pH 3.0 with phosphoric acid. Mobile phase A and mobile phase B perform linear elution according to the volume ratio in the table below, and the flow rate is per minute. 1.2mL; detection wavelength is 281nm,

Further, the volume ratio of mobile phase A: acetonitrile to 0.25% (v/v) triethylamine solution is 16:84, and the mobile phase B: the volume ratio of acetonitrile to 0.7% (v/v) triethylamine solution It's 70:30.

The invention also provides a kind of 5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11 - The raw material of methylene benzocyclodecene-3-phenol or its pharmaceutically acceptable salt contains the compound of formula A and its mass percentage is less than 0.2%, preferably less than 0.1%, more preferably less than 0.015%.

The present invention also provides a pharmaceutical composition, which contains the above-mentioned [5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro- The raw material of 5-methyl-5,11-methylenebenzocyclodecene-3-phenol or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients.

The invention also provides a bridged aminotetralin compound (compound of formula A),

In non-limiting embodiments, the pharmaceutical composition of the present invention can be further prepared into an injection or a solid preparation, and the solid preparation is selected from but not limited to tablets, pills, granules, freeze-dried powder for injection or capsules.

In non-limiting embodiments, the pharmaceutical composition of the present invention can be further prepared into an injection or a solid preparation, and the solid preparation is selected from but not limited to tablets, pills, granules, freeze-dried powder for injection or capsules.

Further, the excipients in the solid preparation are well known or can be determined by those skilled in the art, and are selected from but not limited to at least one of disintegrants, fillers, binders, and lubricants;

The injection excipients are selected from, but are not limited to, non-toxic physiologically acceptable liquid carriers, such as physiological saline, water for injection, glucose injection, glucose sodium chloride injection, at least one of pH adjusters or preservatives. kind.

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 8-0 (ppm). NMR was measured using a Bruker Avance III 600MHz nuclear magnetic resonance instrument, the measurement solvent was deuterated dimethyl sulfoxide, and the internal standard was tetramethylsilane (TMS); MS was measured using an Agilent 6530Q-TOF mass spectrometer (manufacturer: Agilent company).

Detailed ways

The present invention will be explained in more detail below with reference to examples. The examples of the present invention are only used to illustrate the technical solution of the present invention, and the essence and scope of the present invention are not limited thereto.

Example 1

Under nitrogen protection, 20g (-)-(5R,11S,13S)-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11- Methylene benzocyclodecene-3-methoxy-D-tartrate was refluxed in 150 mL hydrobromic acid for 2 hours, concentrated under reduced pressure to remove the hydrobromic acid, and the residue was refined with 150 mL purified water, and crystallized by cooling. Filter, and obtain the refined mother liquor of dezocine hydrobromide, adjust the pH to 8-9 with ammonia water, and filter with suction. Add 100 mL of methylene chloride and 100 mL of 10% NaOH solution to the obtained filter cake (add 10 g of sodium hydroxide to 100 mL of water), stir and clarify. , separate the liquids, and the organic phase is washed once with 100 mL of 10% NaOH solution (10 g of sodium hydroxide is added to 100 mL of water), once with 100 mL of purified water, dried over anhydrous magnesium sulfate, and spin-dried to obtain a yellow solid, with HPLC purity of about 70-80%. , and separated by C18 column chromatography to obtain the compound of formula A.

The conditions for preparing liquid phase are:

Instrument: Shimadzu LC-20AP preparative liquid phase

Preparation column model: Welch Xtimate C18 (30×250mm, 5μm)

Detection wavelength: 281nm

Flow rate: 30mL/min

Mobile phase: A: 0.1% formic acid aqueous solution (add 1mL formic acid to 1000mL water and mix well)

B: Acetonitrile

The volume ratio gradient elution procedure of mobile phase A and mobile phase B is as follows:

NMR data attribution is as follows:

¹ H-NMR (600MHz, DMSO-d ₆ +DCl): 7.267-7.257(1H), 7.167-7.154(1H), 6.695/6.635(1H), 6.575-6.570(1H), 3.498-3.476(2H), 3.193-3.127(1H), 3.100-3.020(1H), 2.754-2.694(1H), 2.603-2.569(1H), 2.503(1H), 2.427(1H), 1.869-1.838(1H), 1.774(4H), 1.689-1.674(5H), 1.629(1H), 1.458(6H), 1.366(6H), 1.328-1.292(2H), 0.799(1H), 0.637-0.529(3H).

¹³ C-NMR (150MHz, DMSO-d ₆ +DCl): 179.56/179.45, 152.53/152.16, 151.46/151.44, 141.56/141.37, 141.37/141.23, 132.28/131.98, 130.31/130.16, 126.76, 125.21/125.03, 122.33 /122.03, 113.23/112.92, 108.47/108.40, 58.58/58.51, 58.36/58.2847.30, 38.52, 37.85, 36.10/35.93, 35.86, 34.05, 33.79/33.70, 33.64, 33. 39/33.32, 32.48/32.46, 32.29, 28.84 /28.74, 28.17/28.04, 25.96, 23.97/23.85, 22.39/22.33.

Mass spectrum (+)-ESI-TOF/MS: [M+H] ⁺ =543.3583. The molecular formula determined from the molecular weight measured by high-resolution mass spectrometry is (C ₃₅ H ₄₆ N ₂ O ₃ ). Combined with NMR data, this structure can be inferred.

Example 2

Test solution: take [5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11 - 30 mg of methylene benzocyclodecene-3-phenol, weigh accurately, place it in a 20 mL volumetric flask, add 5 mL of acetonitrile to dissolve, then add 2.5 mL of triethylamine to 0.25% triethylamine aqueous solution (1000 mL of water). Adjust the pH value to 3.0 with phosphoric acid) dilute to volume and shake well.

Preparation of the reference substance solution: Precisely weigh 6 mg of the compound of formula A, place it in a 20 mL measuring bottle, first add 16 mL of acetonitrile to dissolve it, and then dilute to the mark with water to serve as the reference substance stock solution; accurately measure the reference substance stock solution of the compound of formula A. Appropriate amounts of each and other impurity reference substance stock solutions are placed in the same 50mL volumetric flask, and diluted to the mark with diluent to obtain.

Chromatographic conditions: Use octadecylsilane bonded silica gel as the filler; use acetonitrile-0.25% triethylamine aqueous solution (add 2.5mL triethylamine to 1000mL water, adjust the pH value to 3.0 with phosphoric acid) (16:84) as the flow Phase A, acetonitrile-0.7% triethylamine aqueous solution (add 7mL triethylamine to 1000mL water, adjust the pH value to 3.0 with phosphoric acid) (70:30) is mobile phase B; the volume ratio of mobile phase A to mobile phase B is as follows: Perform linear elution with a flow rate of 1.2mL per minute; the detection wavelength is 281nm.

Precisely measure 20 μl each of the test solution and the impurity reference solution, and inject them into the liquid chromatograph to record the chromatogram.

Result: [5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methylene The content of the compound of formula A in benzocyclodecene-3-phenol is 0.014% (g/g), and the relative main peak retention time is 4.18.

Although the present invention has been described in detail above, those skilled in the art will understand that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of rights of the present invention is not limited to the detailed description made above, but should belong to the claims.

Claims (10)

1. A method for preparing bridged aminotetralin compounds (compounds of formula A), comprising: Step 1: Under the protection of inert gas, (-)-(5R,11S,13S)-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl- 5,11-methylenebenzocyclodecene-3-methoxy-D-tartrate is refluxed in hydrobromic acid to remove the hydrobromic acid. The residue is dissolved in water and filtered by cooling and crystallization; Step 2: Adjust the pH of the mother liquor with ammonia water and suction filtrate. The obtained filter cake is extracted, separated, washed and dried, and then the compound of formula A is separated using a preparative liquid phase system. 2. The method of claim 1, wherein the pH in step 2 is 8-9. 3. The method according to claim 2, the liquid phase preparation conditions are: octadecylsilane bonded silica gel is used as filler, 0.1% v/v formic acid aqueous solution is used as mobile phase A, acetonitrile is used as mobile phase B, and washing off, the detection wavelength is 281nm. 4. The method of claim 3, wherein the elution method is gradient elution, and the volume ratio of the initially used mobile phase A is 65% to 100%. 5. Compound of formula A in 5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11- Methylene benzocyclodecene-3-phenol or its pharmaceutical salt is used as an impurity reference substance when detecting related substances in raw materials and preparations. 6. A detection method for 5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-ylidene Methods for related substances in raw materials and preparations of methylbenzocyclodecene-3-phenol or its pharmaceutical salts, including: Preparation of test solution: take 5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5, 11-Methylenebenzocyclodecene-3-phenol, weigh accurately, add acetonitrile to dissolve it, add an aqueous solution containing triethylamine and adjust the pH value to 2.0-4.0 with phosphoric acid, dilute to the mark, and shake uniform; Preparation of the reference solution: Precisely weigh the compound of formula A, first add acetonitrile to dissolve it, and then dilute it to the mark with water to serve as the reference solution; accurately measure the compound of formula A reference solution and other impurity reference solution. Put an appropriate amount in the same measuring flask, dilute to the mark with diluent, and you have it; Precisely measure the test solution and reference solution respectively, inject them into the liquid chromatograph and record the chromatogram. 7. The method according to claim 6, characterized in that: an aqueous solution containing 0.25% v/v triethylamine and having adjusted the pH value to 3.0 with phosphoric acid is added to the preparation of the test solution; and/or The chromatographic conditions are: use octadecylsilane bonded silica gel as the filler; use acetonitrile/0.25% v/v triethylamine aqueous solution as mobile phase A, and acetonitrile/0.7% v/v triethylamine aqueous solution as mobile phase B; The triethylamine aqueous solution in mobile phase A and mobile phase B is adjusted to pH 3.0 with phosphoric acid. Mobile phase A and mobile phase B perform linear elution according to the volume ratio in the table below. The flow rate is 1.2mL per minute; the detection wavelength is 281nm. , 8. The method as claimed in claim 7, wherein the volume ratio of mobile phase A: the triethylamine aqueous solution of acetonitrile and 0.25% v/v is 16:84, and the mobile phase B: the triethyl acetonitrile and 0.7% v/v The volume ratio of the amine aqueous solution is 70:30. 9. A 5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methylene The bulk medicine or preparation of benzocyclodecene-3-phenol or its pharmaceutically acceptable salt contains the compound of formula A and its mass percentage is less than 0.2%, preferably less than 0.1%, and more preferably less than 0.015%. 10. A bridged aminotetralin compound (compound of formula A),