An organic intermediate, its preparation method and application

Abstract

The present invention belongs to the technical field of organic synthesis or pharmaceutical synthesis, and particularly relates to a novel organic intermediate and its preparation method and application. The structural formula of the novel organic intermediate is shown in Formula III: III. The novel organic intermediate of Formula III designed by the present invention contains amino, carbonyl and cyano groups, has richer chemical reactivity, and together with its simple synthesis method, lays a solid foundation for the structural design and property modification of more innovative drugs, and also lays a foundation for the design and synthesis of other novel compounds with special functions.

Description

Technical Field

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

[0002] Research has 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. A series of N 6 -(3-azabicyclo[3.2.1]oct-6-yl)adenosine compounds were synthesized using this framework, and it was demonstrated that they all have the efficacy of A 1 R agonists.

[0004] Patent CN115894367 discloses a novel drug containing a 3-azabicyclo[3.2.1]octane fragment, which has good inhibitory activity against complement factor D and excellent pharmacokinetic and pharmacodynamic activities. In 2023, patent WO2023015240 discloses an anticancer new drug containing a 3-azabicyclo[3.2.1]octane fragment, and patent WO2023086399 discloses a new drug of a hematopoietic stem cell kinase bifunctional degrader containing a 3-azabicyclo[3.2.1]octane fragment. Patent WO 2024054469 discloses a novel PI3K inhibitor containing a 3-azabicyclo[3.2.1]octane fragment, which can treat diseases related to the elevation or activation of the PI3K pathway. The new drugs disclosed in these patents indicate 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 future innovative drugs.

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

[0006] The invention patent CN117624169 discloses an agonist with a brand-new structure containing the 3-azabicyclo[3.2.1]octane fragment and having a strong affinity for the 5-HT2A receptor, which is a brand-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 fused with a pyrrole ring, opening up innovative drugs with a five-membered heterocycle fused at the bridge positions (6-position and 7-position) of 3-azabicyclo[3.2.1]octane. Imidazole rings, triazole rings and six-membered heterocycles in the five-membered heterocycle are the most common heterocycles in chemical drugs. Therefore, containing two functional groups simultaneously at the bridge positions (6-position and 7-position) of 3-azabicyclo[3.2.1]octane can facilitate the synthesis of two or more five-membered heterocycles and six-membered heterocycles.

[0007] In order to introduce the 3-azabicyclo[3.2.1]octane fragment into drug compounds, a variety of different 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 the intermediate , 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, consumes a large amount of costs, and each of them is only applicable to the preparation of specific target drug compounds, which also limits their application scope.

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

[0009] To solve the above problems, the present invention provides a novel organic intermediate, the structural formula of which is shown in Formula III: III, wherein G includes any one of the following: (1) benzyl and substituted benzyl (such as p-methoxybenzyl, 2,4-dimethoxybenzyl, etc.); (2) acyl groups with 2 to 7 carbon atoms; (3) allyl; (4) benzyloxycarbonyl, allyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl; (5) trityl.

[0010] Further, when G in Formula III is benzyl, 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 preparation method of the novel organic intermediate as described herein, which includes the following steps:

[0012] (1) Reacting the compound of Formula I and haloacetonitrile in the presence of a base and a phase transfer catalyst in Solvent 1 to obtain the compound of Formula II:

[0013] ;

[0014] (2) Reacting the compound of Formula II in the presence of lithium halide in Solvent 2 to obtain the compound of Formula III:

[0015] .

[0016] Further, the molar ratio of the compound of Formula I, haloacetonitrile and the base is 1:1.0 to 2.0:1.0 to 2.0, preferably 1:1.2 to 1.4:1.2 to 1.4.

[0017] Further, the dosage of the phase transfer catalyst is 1 to 10 mol% of the compound of Formula I, preferably 4 to 6 mol%.

[0018] Further, the volume dosage of Solvent 1 is 3 to 15 times the mass of the compound of Formula I, preferably 5 to 10 times.

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

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

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

[0022] Further, the phase transfer catalyst includes at least one of benzyltriethylammonium chloride, benzyltrimethylammonium chloride, tetrabutylammonium chloride, benzyltriethylammonium bromide, benzyltrimethylammonium bromide, and tetrabutylammonium bromide, preferably benzyltriethylammonium chloride.

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

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

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

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

[0027] Further, 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 can include a mixed solvent composed of any two of the above solvents in any proportion.

[0029] Further, 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, where the volume ratio of N,N-dimethylformamide to water is 1:1.0 - 2.5, preferably 1:1.2 - 1.4.

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

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

[0032] Further, the drug further comprises a functionalized modification at the bridge positions (6-position and / or 7-position) of the 3-azabicyclo[3.2.1]octane fragment.

[0033] Advantages of the invention

[0034] The present invention provides a novel intermediate (III) and a new 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. Coupled with its simple synthesis method, it lays a solid foundation for the structural design and 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 described above, the prior art has synthesized a variety of intermediates to introduce a 3-azabicyclo[3.2.1]octane structure into drug compounds, including , , , and etc. However, each of these intermediate compounds requires the use of multi-step complex reactions to be prepared, which involves different synthetic raw materials, complex processes, and harsh reaction conditions, consumes a large amount of costs, and each of them is only applicable to the preparation of specific target drug compounds, which also limits their application scope.

[0037] The present invention solves this technical problem of the prior art. Only by using the intermediate of formula III prepared by the present invention through a simple process, all the intermediates reported in the above prior art can be obtained through conventional organic reactions, which enables the 3-azabicyclo[3.2.1]octane fragment to be introduced into different target drug compounds in a simpler and more convenient manner, thereby preparing more innovative drugs.

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

[0039] Intermediate Synthetic routes that can be adopted:

[0040] ;

[0041] Intermediate Synthetic routes that can be adopted:

[0042] ;

[0043] Intermediate Synthetic routes that can be adopted:

[0044] ;

[0045] Intermediate Synthetic routes that can be adopted:

[0046] . Description of the Drawings

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

[0048] Figure 2 Shows the 1 1H NMR spectrum of the compound of formula V prepared in Example 1.

[0049] Figure 3 Shows the 13 13C NMR spectrum of the compound of formula V prepared in Example 1.

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

[0051] Figure 5 Shows the 1 1H NMR spectrum of the novel intermediate VI prepared in Example 3.

[0052] Figure 6 Shows the 13 13C NMR spectrum of the novel intermediate VI prepared in Example 3. Detailed Description of the Invention

[0053] The present invention provides a new synthetic process for a novel organic intermediate (III), which can be implemented through the following steps:

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

[0055] ;

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

[0057] .

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

[0059] Step 1: React 3-benzyl-3-azabicyclo[3.1.1]heptan-6-one (IV) and haloacetonitrile 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: React V obtained in Step 1 with a lithium halide such as lithium bromide in a solvent to obtain a novel intermediate (VI), and the structure of VI is as follows:

[0064]

[0065] VI.

[0066] The following specific examples are used to further illustrate the present invention, 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 technical field.

[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 successively added to the reaction flask. The mixture was stirred at 20 - 30 °C for 10 minutes, and then a solution composed of 3-benzyl-3-azabicyclo[3.1.1]heptan-6-one (40.00 g, 0.20 mol, 1 eq) shown in Formula IV and THF (140 mL) was added. After the addition, the mixture was continuously stirred and reacted for 3.5 h. After the reaction was completed, the reaction solution was concentrated. Water (200 mL) and ethyl acetate (160 mL) were added to the residue, and the mixture was stirred for 5 min. The organic phase was separated, washed with saturated NaCl (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure below 55 °C. After purification, the compound of Formula V (39.0 g, HPLC purity 99%) was obtained. As Figure 1 shown in the mass spectrum in 1 , the molecular weight of the compound of Formula V plus a hydrogen ion was 241.20 (the calculated value was 240.31, plus a hydrogen ion was 241.31). The proton nuclear magnetic resonance spectrum ( 13 1H NMR) and carbon nuclear magnetic resonance spectrum ( Figure 2 and Figure 3 ) of the compound of Formula V are shown in

[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 successively added to a reaction flask. The mixture was stirred at 20 - 30 °C for 10 minutes. Then, a solution composed of 3-benzyl-3-azabicyclo[3.1.1]heptan-6-one (30.00 g, 0.15 mol, 1 eq) shown in Formula IV and THF (100 mL) was added. After the addition, the stirring was continued for 3.5 h. After the reaction was completed, the reaction solution was concentrated. Water (140 mL) and ethyl acetate (120 mL) were added to the residue, and the mixture was stirred for 5 min. The organic phase was separated, washed with saturated NaCl (3 × 120 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure below 55 °C. After purification, a light yellow oily liquid, i.e., the compound of Formula V (28.6 g, HPLC purity 97.8%), was obtained.

[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 successively added to a dry reaction flask. The mixture was stirred evenly to obtain a colorless transparent solution. The compound of Formula V obtained in Example 1 (24.10 g, 0.10 mol, 1.0 eq) was added, and the temperature was raised to 60 - 62 °C with stirring for 4.5 h. After the reaction was completed, the reaction solution was concentrated. Saturated brine (150 mL) and ethyl acetate (100 mL) were added to the residue, and the mixture was stirred for 5 min. The organic phase was separated, washed with saturated brine (3 × 100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure below 55 °C. After purification, novel intermediate VI (21.6 g, HPLC purity 99%) was obtained. As shown in the mass spectrum in Figure 4 , the molecular weight of novel intermediate VI plus water was analyzed to be 258.20 (the calculated value was 240.31, plus water was 258.31). The proton nuclear magnetic resonance spectrum ( 1 H NMR) and carbon nuclear magnetic resonance spectrum ( 13 C NMR) of novel intermediate VI are shown in 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 successively added to a dry reaction flask and stirred evenly to obtain a colorless transparent solution. The compound of formula V obtained in Example 1 (12.05 g, 0.05 mol, 1.0 eq) was added, and the temperature was raised to 60 - 62 °C under stirring for reaction for 6 h. After the reaction was completed, the reaction solution was concentrated. Saturated brine (80 mL) and ethyl acetate (80 mL) were added to the residue and stirred for 5 min. The organic phase was separated, washed with saturated brine (3 × 60 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure at a temperature below 55 °C. The novel intermediate VI (10.3 g, HPLC purity 97.8%) was obtained by purification.

[0075] Example 5: Synthesis of the 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 successively added to a reaction flask and stirred evenly to obtain a colorless transparent solution. The compound of formula V obtained in Example 1 (12.05 g, 0.05 mol, 1.0 eq) was added, and the temperature was raised to 60 - 62 °C under stirring for reaction for 8 h. After the reaction was completed, the reaction solution was concentrated. Saturated brine (90 mL) and ethyl acetate (100 mL) were added to the residue and stirred for 5 min. The organic phase was separated, washed with saturated brine (3 × 65 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure at a temperature below 55 °C. The novel intermediate VI (9.8 g, HPLC purity 98.4%) was obtained by purification.

[0077] It should be noted that the description and drawings of the present invention give preferred embodiments 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 do not serve as additional limitations to the content of the present invention. The purpose of providing these embodiments is to make the understanding of the disclosed content of the present invention more thorough and comprehensive. Furthermore, the above technical features continue to be combined with each other to form various embodiments not listed above, which are all regarded as within the scope described in the specification of the present invention; further, for those of ordinary skill in the art, improvements or changes can be made according to the above description, and all such improvements and changes should fall within the protection scope of the appended claims of the present invention.

Claims

1. An organic intermediate, characterized in that The structural formula of the organic intermediate is shown in the following formula III: In the formula, G is benzyl.

2. A method for preparing an organic intermediate as claimed in 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 to 10 mol% of the compound of formula I; The volume amount 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 is at least one of chloroacetonitrile and bromoacetonitrile; The base is 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 is at least one of triethylbenzylammonium chloride, trimethylbenzylammonium chloride, tetrabutylammonium chloride, triethylbenzylammonium bromide, trimethylbenzylammonium bromide and tetrabutylammonium bromide; The solvent 1 is 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 2-5 h.

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 is at least one of tetrahydrofuran, acetonitrile, DMF, N,N-dimethylacetamide and dioxane.

8. The preparation method according to claim 2, characterized in that: The solvent 2 is a mixed solvent composed of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran or dioxane and water in any proportion.

9. 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 hours.

10. Use of the organic intermediate according to claim 1 in the preparation of a compound containing a 3-azabicyclo[3.2.1]octane fragment, wherein the compound containing a 3-azabicyclo[3.2.1]octane fragment is:

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