Novel organic intermediate as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic synthesis or drug synthesis, and particularly relates to a novel organic intermediate as well as a preparation method and application thereof. The structural formula of the novel organic intermediate is as shown in a formula III: imgabs0 # III. The novel organic intermediate shown in the formula III contains amino, carbonyl and cyano and has richer chemical reactivity, and a simple and convenient synthesis method of the novel organic intermediate lays a solid foundation for structural design and drug property modification of more innovative drugs and also lays a foundation for design and synthesis of other novel compounds with special functions.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis or drug synthesis, and specifically relates to a novel organic intermediate and a preparation method and application thereof. Background Art

[0002] Studies have shown that the 3-azabicyclo[3.2.1]octane fragment (as shown in Formula VII) has functions such as regulating metabolism and transmitting information, which has attracted the attention of chemists and pharmacists: VII.

[0003] For example, Joshua I. Gosling et al. (ChemMedChem 2012, 7, 1191-1201) reported that the bicyclo[3.2.1]octane framework has a series of interesting biological activities. This structural motif has been widely studied in the stereospecific synthesis of peptide mimetics and the development of ligands for various CNS-related receptors. They used this framework to synthesize a series of N 6 -(3-azabicyclo[3.2.1]octan-6-yl)adenosine compounds, and it is demonstrated that they all have the efficacy of A1R agonists.

[0004] Invention patent CN115894367 discloses a new drug containing a 3-azabicyclo [3.2.1] octane fragment, which has good inhibitory activity against complement factor D and has excellent pharmacokinetic and pharmacodynamic activity. In 2023, invention patent WO2023015240 disclosed a new anticancer drug containing a 3-azabicyclo [3.2.1] octane fragment, and patent WO2023086399 disclosed a new bifunctional degradation drug of hematopoietic stem cell kinase containing a 3-azabicyclo [3.2.1] octane fragment. Invention patent WO 2024054469 discloses a new PI3K inhibitor containing a 3-azabicyclo [3.2.1] octane fragment, which can treat diseases related to elevated or activated PI3K pathways. The new drugs disclosed in these invention patents show that in order to improve the functions of anti-cancer and hematopoietic stem cells, the 3-azabicyclo [3.2.1] octane fragment is one of the indispensable fragments for some innovative drugs in the future.

[0005] The innovative drug disclosed in the above invention patents not only contains a 3-azabicyclo[3.2.1]octane fragment, but also has a hydroxyl group (carbonyl reduction transformation), a cyano group and a formyl group (cyano hydrolysis transformation) at the 6- or 7-position of the bridge in the fragment (refer to formula VII). For example, the 6-position of the 3-azabicyclo[3.2.1]octane fragment in the innovative drug disclosed in the invention patent CN117881397 contains a hydroxyl group, which can be used to inhibit KRAS G12D inhibitors and can be used to treat diseases such as cancer. The 6-position of the 3-azabicyclo[3.2.1]octane fragment in the innovative drug disclosed in the invention patent WO2023018812 contains a nitrile or formamide functional group, which is a new drug for treating cancer that can be used to inhibit KRAS G12D.

[0006] Invention patent CN117624169 discloses an agonist with a new structure and strong affinity for 5-HT2A receptors containing a 3-azabicyclo[3.2.1]octane fragment, which is a new drug for treating 5-HT2A receptor-related diseases. Its structural feature is that the 6-position and 7-position of the 3-azabicyclo[3.2.1]octane fragment are combined with the pyrrole ring, opening up the innovative drug of combining the five-membered heterocyclic ring at the bridge position (6-position and 7-position) in 3-azabicyclo[3.2.1]octane. Among the five-membered heterocyclic rings, the imidazole ring, triazole ring and six-membered heterocyclic ring are the most common heterocyclic rings in chemical drugs. Therefore, the presence of two functional groups at the bridge position (6-position and 7-position) in 3-azabicyclo[3.2.1]octane can facilitate the synthesis of two or more five-membered heterocyclic rings and six-membered heterocyclic rings.

[0007] In order to introduce 3-azabicyclo[3.2.1]octane fragment into drug compounds, various intermediates have been synthesized in the prior art. For example, Joshua I. Gosling et al. (ChemMedChem 2012, 7, 1191-1201) synthesized and used the intermediate , WO2005007655 synthesized and used the intermediate , US20230072276 synthesized and used intermediates , CN116829151 synthesized and used the intermediate However, each of these intermediate compounds requires a multi-step complex reaction to be prepared, which involves different synthetic raw materials, complex processes, harsh reaction conditions, and consumes a lot of costs. In addition, each of them is only suitable for the preparation of specific target drug compounds, which also limits its scope of application.

[0008] Therefore, there is a need in the art to develop a novel organic intermediate that can be used to introduce 3-azabicyclo[3.2.1]octane fragments into different target drug compounds and can also be further functionalized at the bridge positions (6- and 7-positions), which can provide a convenient and solid foundation for the structural design and performance modification of more innovative drugs. Summary of the invention

[0009] In order to solve the above problems, the present invention provides a novel organic intermediate, whose structural formula is shown in Formula III: III, wherein G includes any one of the following: (1) benzyl and substituted benzyl (e.g. p-methoxybenzyl, 2,4-dimethoxybenzyl, etc.); (2) C2-C7 acyl; (3) allyl; (4) benzyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, butyloxycarbonyl; (5) trityl.

[0010] Furthermore, in Formula III, G is benzyl, and the obtained novel organic intermediate is 3-benzyl-7-oxo-3-azabicyclo[3.2.1]octane-6-carbonitrile, and its structural formula is shown in Formula VI: VI.

[0011] The present invention also provides a method for preparing the novel organic intermediate as described herein, which comprises the following steps:

[0012] (1) reacting a compound of formula I with a haloacetonitrile in the presence of a base and a phase transfer catalyst in a solvent 1 to obtain a compound of formula II:

[0013] ;

[0014] (2) reacting the compound of formula II in the presence of lithium halide in solvent 2 to obtain a compound of formula III:

[0015] .

[0016] Furthermore, the molar ratio of the compound of formula I, the haloacetonitrile and the base is 1:1.0~2.0:1.0~2.0, preferably 1:1.2~1.4:1.2~1.4.

[0017] Furthermore, the amount of the phase transfer catalyst used is 1 to 10 mol %, preferably 4 to 6 mol % of the compound of formula I.

[0018] Furthermore, the volume usage of the solvent 1 is 3 to 15 times, preferably 5 to 10 times, the mass of the compound of formula I.

[0019] Furthermore, the haloacetonitrile includes at least one of chloroacetonitrile and bromoacetonitrile, preferably chloroacetonitrile.

[0020] Furthermore, the base includes at least one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium tert-butoxide, potassium tert-butoxide, and lithium diisopropylamide, preferably at least one of sodium tert-butoxide and potassium tert-butoxide.

[0021] Furthermore, the mass concentration of the sodium hydroxide aqueous solution is 35% to 50%, and the mass concentration of the potassium hydroxide aqueous solution is 35% to 60%.

[0022] Furthermore, the phase transfer catalyst includes at least one of triethylbenzylammonium chloride, trimethylbenzylammonium chloride, tetrabutylammonium chloride, triethylbenzylammonium bromide, trimethylbenzylammonium bromide, and tetrabutylammonium bromide, preferably triethylbenzylammonium chloride.

[0023] Furthermore, the solvent 1 comprises at least one of tetrahydrofuran, acetonitrile, DMF and dioxane, preferably at least one of tetrahydrofuran and acetonitrile.

[0024] Furthermore, the reaction temperature of the reaction in step (1) is -10 to 100°C, preferably 15 to 35°C, and the reaction time is 1 to 8 hours, preferably 2 to 5 hours.

[0025] Furthermore, the molar ratio of the compound of formula II to the lithium halide is 1:1.0-2.5, preferably 1:1.2-1.8.

[0026] Furthermore, the volume usage of the solvent 2 is 3 to 15 times, preferably 4 to 10 times, the mass of the compound of formula II.

[0027] Furthermore, the lithium halide is lithium bromide, lithium chloride or lithium iodide.

[0028] Further, the solvent 2 includes at least one of tetrahydrofuran, acetonitrile, DMF, N,N-dimethylacetamide, and dioxane, preferably at least one of DMF and acetonitrile. For example, the solvent 2 may include a mixed solvent composed of any two of the above solvents in any proportion.

[0029] Furthermore, the solvent 2 also includes a mixed solvent composed of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran or dioxane and water in any proportion, preferably a mixed solvent of N,N-dimethylformamide and water, wherein the volume ratio of N,N-dimethylformamide to water is 1:1.0~2.5, preferably 1:1.2~1.4.

[0030] Furthermore, the reaction temperature of the reaction in step (2) is 10°C to 100°C, preferably 25°C to 85°C, more preferably 60°C to 80°C, and the reaction time is 1 to 9 hours, preferably 5 to 9 hours.

[0031] The present invention also provides the use of the novel organic intermediate as described herein in the preparation of a medicament comprising a 3-azabicyclo[3.2.1]octane fragment.

[0032] Furthermore, the drug further comprises functional modifications at the bridge positions (6-position and / or 7-position) of the 3-azabicyclo[3.2.1]octane fragment.

[0033] Advantageous Effects of the Invention

[0034] The present invention provides a novel intermediate (III) and a novel synthesis process thereof. The synthesis process is simple, safe, environmentally friendly and has a high yield.

[0035] The novel organic intermediate of formula III designed by the present invention contains an amino group, a carbonyl group and a cyano group, and has richer chemical reactivity. Combined with its simple synthesis method, it lays a solid foundation for the structural design and drug property modification of more innovative drugs, and also lays a foundation for the design and synthesis of other novel compounds with special functions.

[0036] As mentioned above, various intermediates have been synthesized in the prior art to introduce 3-azabicyclo[3.2.1]octane structure into drug compounds, including , , , and However, each of these intermediate compounds requires a multi-step complex reaction to be prepared, which involves different synthetic raw materials, complex processes, harsh reaction conditions, and consumes a lot of costs. In addition, each of them is only suitable for the preparation of specific target drug compounds, which also limits its scope of application.

[0037] The present invention solves this technical problem of the prior art. All the intermediates reported in the prior art can be obtained by conventional organic reactions using only the intermediate shown in formula III prepared by a simple process of the present invention. This makes it possible to introduce 3-azabicyclo[3.2.1]octane fragments into different target drug compounds in a simpler and more convenient manner, thereby preparing more innovative drugs.

[0038] The intermediate represented by formula VI of the present invention Taking (VI) as an example, the different intermediates reported in the above prior art can be conveniently prepared by the conventional synthetic route shown below:

[0039] Intermediates Available synthetic routes:

[0040] ;

[0041] Intermediates Available synthetic routes:

[0042] ;

[0043] Intermediates Available synthetic routes:

[0044] ;

[0045] Intermediates Available synthetic routes:

[0046] . BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The mass spectrum of the compound of formula V prepared in Example 1 is shown.

[0048] Figure 2 The compound of formula V prepared in Example 1 is shown 1 H NMR spectra.

[0049] Figure 3 The compound of formula V prepared in Example 1 is shown 13 C NMR spectrum.

[0050] Figure 4 The mass spectrum of the novel intermediate VI prepared in Example 3 is shown.

[0051] Figure 5 The novel intermediate VI prepared in Example 3 is shown 1 H NMR spectra.

[0052] Figure 6 The novel intermediate VI prepared in Example 3 is shown 13 C NMR spectrum. DETAILED DESCRIPTION

[0053] The present invention provides a novel synthesis process of a novel organic intermediate (III), which can be implemented by the following steps:

[0054] (1) reacting a compound of formula I with a haloacetonitrile in the presence of a base and a phase transfer catalyst in a solvent 1 to obtain a compound of formula II:

[0055] ;

[0056] (2) reacting the compound of formula II in the presence of lithium halide in solvent 2 to obtain a compound of formula III:

[0057] .

[0058] When G in the above formula is benzyl, the present invention provides a novel synthesis process of a novel organic intermediate (VI), which can be implemented by the following steps:

[0059] Step 1: 3-Benzyl-3-azabicyclo[3.1.1]heptan-6-one (IV) and halogenated acetonitrile are reacted in a solvent such as THF in the presence of a base and a phase transfer catalyst to obtain an intermediate compound (V).

[0060] The structures of V and VI are as follows:

[0061]

[0062] IV V

[0063] Step 2: V obtained in step 1 is reacted with a lithium halide such as lithium bromide in a solvent to obtain a novel intermediate (VI), the structure of which is as follows:

[0064]

[0065] VI.

[0066] The present invention is further described below with reference to specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0067] Example 1: Synthesis of the compound of formula V {3-benzyl-3-azaspiro(bicyclo[3.1.1]heptane-6,2'-epoxy)-3'-carbonitrile)}

[0068] Under nitrogen protection, chloroacetonitrile (18.12 g, 0.24 mol, 1.2 eq), potassium tert-butoxide (31.4 g, 0.28 mol, 1.4 eq), triethylbenzylammonium chloride (2.12 g, 9.30 mmol) and THF (200 mL) were added to the reaction flask in sequence, stirred at 20-30°C for 10 minutes, and a solution of 3-benzyl-3-azabicyclo[3.1.1]heptane-6-one (40.00 g, 0.20 mol, 1 eq) and THF (140 mL) was added. After the addition was complete, the reaction was continued to stir for 3.5 h. After the reaction was completed, the reaction solution was concentrated, and water (200 mL) and ethyl acetate (160 mL) were added to the residue and stirred for 5 min. The organic phase was separated and washed with saturated NaCl (3×150 mL). The obtained organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure below 55°C to remove the solvent and purified to obtain a compound of formula V (39.0 g, purity 99% by HPLC). Figure 1 As shown in the mass spectrum in, the molecular weight of the compound of formula V is analyzed to be 241.20 (calculated value is 240.31, hydrogenated ion is 241.31). The nuclear magnetic resonance hydrogen spectrum of the compound of formula V ( 1 H NMR) and carbon nuclear magnetic resonance spectroscopy ( 13 C NMR) see Figure 2 and Figure 3 .

[0069] Example 2: Synthesis of the compound of formula V {3-benzyl-3-azaspiro(bicyclo[3.1.1]heptane-6,2'-epoxy)-3'-carbonitrile)}

[0070] Under nitrogen protection, chloroacetonitrile (13.60 g, 0.18 mol, 1.2 eq), sodium tert-butoxide (20.18 g, 0.21 mol, 1.4 eq), triethylbenzylammonium chloride (1.60 g, 7.00) and THF (160 mL) were added to the reaction flask in sequence, stirred at 20-30°C for 10 minutes, and a solution of 3-benzyl-3-azabicyclo[3.1.1]heptane-6-one (30.00 g, 0.15 mol, 1 eq) and THF (100 mL) was added. After the addition was complete, the reaction was continued to stir for 3.5 h. After the reaction was completed, the reaction solution was concentrated, and water (140 mL) and ethyl acetate (120 mL) were added to the residue and stirred for 5 min. The organic phase was separated and washed with saturated NaCl (3×120 mL). The obtained organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure below 55°C to remove the solvent and purified to obtain a light yellow oily liquid, i.e., the compound of formula V (28.6 g, purity 97.8% by HPLC).

[0071] Example 3: Synthesis of novel organic intermediate VI (3-benzyl-7-oxo-3-azabicyclo[3.2.1]octane-6-carbonitrile)

[0072] Under nitrogen protection, DMF (125 mL) and lithium bromide (10.42 g, 0.12 mol, 1.2 eq) were added to a dry reaction bottle in sequence, and stirred evenly to obtain a colorless transparent solution. The compound of formula V (24.10 g, 0.10 mol, 1.0 eq) obtained in Example 1 was added, and the temperature was raised to 60-62°C for reaction for 4.5 h under stirring. After the reaction was completed, the reaction solution was concentrated, and saturated brine (150 mL) and ethyl acetate (100 mL) were added to the residue and stirred for 5 min. The organic phase was separated, and the organic phase was washed with saturated brine (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure below 55°C to remove the solvent, and purified to obtain a new intermediate VI (21.6 g, HPLC purity 99%). Figure 4 As shown in the mass spectrum in, the molecular weight of the new intermediate VI after water addition is 258.20 (calculated value is 240.31, after water addition is 258.31). 1 H NMR) and carbon nuclear magnetic resonance spectroscopy ( 13 C NMR) see Figure 5 and Figure 6 .

[0073] Example 4: Synthesis of novel organic intermediate VI (3-benzyl-7-oxo-3-azabicyclo[3.2.1]octane-6-carbonitrile)

[0074] Under nitrogen protection, acetonitrile (140 mL) and lithium bromide (6.95 g, 0.08 mol, 1.6 eq) were added to a dry reaction bottle in sequence, and stirred evenly to obtain a colorless transparent solution. The compound of formula V (12.05 g, 0.05 mol, 1.0 eq) obtained in Example 1 was added, and the temperature was raised to 60-62°C with stirring for 6 h. After the reaction was completed, the reaction solution was concentrated, and saturated brine (80 mL) and ethyl acetate (80 mL) were added to the residue and stirred for 5 min. The organic phase was separated, and the organic phase was washed with saturated brine (3×60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure below 55°C to remove the solvent, and purified to obtain a new intermediate VI (10.3 g, purity 97.8% by HPLC).

[0075] Example 5: Synthesis of novel organic intermediate VI (3-benzyl-7-oxo-3-azabicyclo[3.2.1]octane-6-carbonitrile)

[0076] Under nitrogen protection, DMF (60 mL), water (60 mL) and lithium bromide (6.95 g, 0.08 mol, 1.6 eq) were added to the reaction bottle in sequence, and stirred evenly to obtain a colorless transparent solution. The compound of formula V (12.05 g, 0.05 mol, 1.0 eq) obtained in Example 1 was added, and the temperature was raised to 60-62°C under stirring for 8 h. After the reaction was completed, the reaction solution was concentrated, and saturated brine (90 mL) and ethyl acetate (100 mL) were added to the residue and stirred for 5 min. The organic phase was separated, and the organic phase was washed with saturated brine (3×65 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure below 55°C to remove the solvent, and purified to obtain a new intermediate VI (9.8 g, purity 98.4% by HPLC).

[0077] It should be noted that the preferred embodiments of the present invention are given in the specification and drawings of the present invention. However, the present invention can be implemented in many different forms and is not limited to the embodiments described in this specification. These embodiments are not used as additional limitations on the content of the present invention. The purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive. In addition, the above-mentioned technical features continue to be combined with each other to form various embodiments not listed above, which are all regarded as the scope of the present invention; further, for ordinary technicians in this field, they can be improved or transformed according to the above description, and all these improvements and transformations should belong to the protection scope of the claims attached to the present invention.

Claims

1. A novel organic intermediate, characterized in that: The structural formula of the novel organic intermediate is shown in the following formula III: Ⅲ Wherein G includes any of the following: (1) Benzyl and substituted benzyl; (2) C2~C7 acyl group; (3) Allyl; (4) benzyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, methoxycarbonyl; (5) Trityl.

2. A method for preparing the novel organic intermediate according to claim 1, characterized in that: The preparation method comprises the following steps: (1) reacting a compound of formula I with a haloacetonitrile in the presence of a base and a phase transfer catalyst in a solvent 1 to obtain a compound of formula II: ； (2) reacting the compound of formula II in the presence of lithium halide in solvent 2 to obtain a compound of formula III: 。 3. The preparation method according to claim 2, characterized in that: The molar ratio of the compound of formula I, the haloacetonitrile and the base is 1:1.0~2.0:1.0~2.0; The amount of the phase transfer catalyst is 1-10 mol % of the compound of formula I; The volume usage of the solvent 1 is 3 to 15 times the mass of the compound of formula I.

4. The preparation method according to claim 2, characterized in that: The haloacetonitrile comprises at least one of chloroacetonitrile and bromoacetonitrile; The base includes at least one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium tert-butoxide, potassium tert-butoxide, and lithium diisopropylamide; The phase transfer catalyst comprises at least one of triethylbenzylammonium chloride, trimethylbenzylammonium chloride, tetrabutylammonium chloride, triethylbenzylammonium bromide, trimethylbenzylammonium bromide and tetrabutylammonium bromide; The solvent 1 includes at least one of tetrahydrofuran, acetonitrile, DMF and dioxane.

5. The preparation method according to claim 2, characterized in that: The reaction temperature of the reaction in step (1) is 15-35°C, and the reaction time is 2-5h.

6. The preparation method according to claim 2, characterized in that: The molar ratio of the compound of formula II to the lithium halide is 1:1.0-2.5; The volume amount of the solvent 2 is 3 to 15 times the mass of the compound of formula II.

7. The preparation method according to claim 2, characterized in that: The lithium halide is lithium bromide, lithium chloride or lithium iodide; The solvent 2 includes at least one of tetrahydrofuran, acetonitrile, DMF, N,N-dimethylacetamide, and dioxane; The solvent 2 further includes a mixed solvent composed of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran or dioxane and water in any proportion.

8. The preparation method according to claim 2, characterized in that: The reaction temperature of the reaction in step (2) is 60-80° C., and the reaction time is 5-9 h.

9. Use of the novel organic intermediate as claimed in claim 1 in the preparation of a medicament comprising a 3-azabicyclo[3.2.1]octane fragment.

10. The use according to claim 9, characterized in that: The drug further comprises functional modifications at the 6-position and / or 7-position of the 3-azabicyclo[3.2.1]octane fragment.

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