Preparation method of drug intermediate azaspiro [4.5] decane derivative

Abstract

The invention relates to a preparation method of a drug intermediate azaspiro [4.5] decane derivative, and belongs to the technical field of drugs and chemistry. The invention provides a preparation method of a drug intermediate azaspiro [4.5] decane derivative shown as a formula 3. The reaction is as follows: # imgabs0 # comprises the following steps: step 1, reacting a compound shown as a formula 1 with a phosphorus reagent in the presence of alkali to obtain a compound shown as a formula 2; and step 2, obtaining a compound shown in a formula 3 from the compound shown in the formula 2 under the action of trichloroacetic acid and a halogenated alkane solvent. The method provided by the invention has the advantages of good selectivity, good reproducibility, short time consumption, economy and high conversion rate, is suitable for industrial production, and thus has good market value and profound practical significance.

Description

Technical Field

[0001] The invention relates to a method for preparing a drug intermediate azaspiro[4.5]decane derivative, belonging to the technical field of drugs and chemistry. Background Art

[0002] Azaspiro[4.5]decane derivatives are an important class of nitrogen-containing spirocyclic compounds with a wide range of medical and other uses. 2-Formyl-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester is one of them, and its structure is as follows:

[0003]

[0004] The compound of formula 3 is often used as an important heterospirocyclic core fragment in a variety of drugs such as GPR120 agonists, CD70 inhibitors, RET inhibitors, CDK7 degraders, etc. There are many reports in the prior art showing that a series of new compounds derived from this compound have therapeutic potential, and its synthesis has received widespread attention.

[0005] WO2014059232 discloses that compound 105-2 is oxidized by a Dess-Martin periodinane to obtain compound 105-3 (i.e., compound 3), and the reaction formula is as follows:

[0006]

[0007] The cost of the Dess-Martin oxidant used in the patented method is too high, and the processing process is complicated and the oxidant consumption is high, which is not suitable for industrial scale-up production.

[0008] However, there is no report on the preparation of tert-butyl 2-formyl-8-azaspiro[4.5]decane-8-carboxylate in the prior art. Therefore, there is an urgent need for a method for synthesizing the compound of formula 3 that is economical, fast, easy to operate, simple to post-process, high in yield and high in purity.

[0009] The invention provides a method for preparing a drug intermediate azaspiro[4.5]decane derivative, which avoids the use of an oxidant and has the advantages of being economical, quick, simple to operate, simple to post-process, high conversion rate and high atom utilization rate, and is suitable for industrial production. Therefore, it has good market value and far-reaching practical significance. Summary of the invention

[0010] In view of the above technical background, the present invention provides a method for preparing a drug intermediate azaspiro[4.5]decane derivative. The preparation method of the present invention is simple to operate, has good selectivity, high conversion rate, short time consumption, reduced cost, and is conducive to industrial production.

[0011] The first aspect of the present invention provides a method for preparing a drug intermediate azaspiro[4.5]decane derivative of formula 3, the reaction is as follows:

[0012]

[0013] The steps include:

[0014] Step 2: The compound of formula 2 is reacted with trichloroacetic acid and a halogenated alkane solvent to obtain a compound of formula 3;

[0015] As a further improvement of the present invention, including but not limited to, the compound of formula 2 in step 2 is first dissolved in a halogenated alkane solvent, and then trichloroacetic acid is added at -5 to 5°C to react to obtain a compound of formula 3;

[0016] As a further improvement of the present invention, including but not limited to, the molar ratio of the compound of formula 2 to trichloroacetic acid in step 2 is 1:(1.5-6), preferably 1:(2-5);

[0017] As a further improvement of the present invention, including but not limited to, the halogenated alkane solvent in step 2 is one or more of chloroform, 1,2-dichloroethane, and dichloromethane;

[0018] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 2 is -5 to 40°C, preferably -5 to 35°C;

[0019] As a further improvement of the present invention, including but not limited to, the reaction time of step 2 is 1 to 8 hours, preferably 1 to 6 hours;

[0020] As a further improvement of the present invention, including but not limited to, the volume of the reaction solvent in step 2 is 2 to 15 times, preferably 2 to 10 times, the mass of the compound of formula 2 in mL;

[0021] As a further improvement of the present invention, in certain embodiments, after the reaction of step 2 is completed, the reaction solution is poured into ice water for quenching, an organic solvent is added, and extraction, washing, separation, drying, and concentration are performed to obtain a crude product of the compound of formula 3;

[0022] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane;

[0023] As a further improvement of the present invention, in certain embodiments, the crude product can be further subjected to column chromatography to obtain a pure product of the compound of formula 3, and the column chromatography eluent is, for example, petroleum ether / ethyl acetate = 5:1.

[0024] As a further improvement of the present invention, the use of trichloroacetic acid in step 2 is more gentle than the method of using trifluoroacetic acid and hydrochloric acid in the prior art reaction, and the product yield is particularly high.

[0025] As a further improvement of the present invention, the inventors found that when trifluoroacetic acid or hydrochloric acid is used in step 2, very little target product is obtained, and basically all the products obtained are the products of first removing BOC. Therefore, the method of the present invention has the advantages of high selectivity, high conversion rate, simple operation, mild reaction, short time consumption, good reproducibility, and high atom utilization, and is suitable for industrial production.

[0026] The second aspect of the present invention provides a method for preparing an azaspiro[4.5]decane derivative of formula 3, the reaction is as follows:

[0027]

[0028] The steps include:

[0029] Step 1: The compound of formula 1 reacts with a phosphorus reagent in the presence of a base to obtain a compound of formula 2;

[0030] Step 2: The compound of formula 2 is reacted with trichloroacetic acid and a halogenated alkane solvent to obtain a compound of formula 3;

[0031] As a further improvement of the present invention, including but not limited to, the base in step 1 is selected from one or more of sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium hydroxide, sodium hydroxide, lithium bistrimethylsilylamide (LiHMDS), sodium bistrimethylsilylamide (NaHMDS), lithium diisopropylamide (LDA) or n-butyl lithium, preferably one or more of lithium diisopropylamide (LDA), lithium bistrimethylsilylamide (LiHMDS), sodium bistrimethylsilylamide (NaHMDS), n-butyl lithium, sodium hydride or potassium hydride;

[0032] As a further improvement of the present invention, including but not limited to, in step 1, the molar ratio of the compound of formula 1, the base and the phosphorus reagent is 1: (1.2-6): (1.1-3), preferably 1: (1.5-5): (1.1-2.5);

[0033] As a further improvement of the present invention, including but not limited to, the step 1 is carried out in a reaction solvent, and the reaction solvent is one or more of tetrahydrofuran, petroleum ether, dichloromethane, dichloroethylene, chloroform, ethyl acetate, toluene, DMSO, ether, and DME, preferably one or more of tetrahydrofuran, ether, DME, and toluene;

[0034] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 1 is -5 to 70°C, preferably -5 to 60°C;

[0035] As a further improvement of the present invention, including but not limited to, the reaction time of step 1 is 1 to 8 hours, preferably 1 to 6 hours;

[0036] As a further improvement of the present invention, including but not limited to, the volume of the reaction solvent in step 1 is 5 to 40 times, preferably 5 to 30 times, the mass of the compound of formula 1;

[0037] As a further improvement of the present invention, it includes but is not limited to, in step 1, compound 1 is first dissolved in a reaction solvent, a base is added under ice bath, and the reaction is carried out at 0°C to 30°C for 1 to 3 hours, and then a phosphorus reagent is added and the reaction is carried out at 30°C to 60°C for 1 to 4 hours;

[0038] As a further improvement of the present invention, it includes but is not limited to that the phosphorus reagent in step 1 is selected from one of methoxymethyltriphenylphosphonium bromide and methoxymethyltriphenylphosphonium chloride;

[0039] As a further improvement of the present invention, in certain embodiments, after the reaction of step 1 is completed, the reaction solution is poured into ice water for quenching, an organic solvent is added, and extraction, washing, separation, drying, and concentration are performed to obtain a crude product of the compound of formula 2;

[0040] As a further improvement of the present invention, including but not limited to, the above-mentioned organic solvent includes one of ethyl acetate and dichloromethane;

[0041] As a further improvement of the present invention, in certain embodiments, the crude product of the compound of formula 2 can be further subjected to column chromatography to obtain a pure product of the compound of formula 2.

[0042] The preferred technical solution of the present invention, step 2 can all refer to the entire technical solution of step 2 of the preparation method of the drug intermediate azaspiro [4.5] decane derivative formula 3 provided in the first aspect of the present invention.

[0043] Beneficial technical effects of the present invention:

[0044] 1. The inventors found that there are technical problems in using trifluoroacetic acid and hydrochloric acid in step 2, which will directly remove BOC first, and the target product is basically not produced, resulting in reaction failure. The inventors unexpectedly solved the technical defects of the prior art by using trichloroacetic acid through creative work, shortened the reaction time, and improved the conversion rate.

[0045] 2. The present invention provides a novel method for preparing tert-butyl 2-formyl-8-azaspiro[4.5]decane-8-carboxylate, which avoids the use of an oxidant, reduces production costs, is economical and fast, is easy to operate, has simple post-processing, and has a high yield, and is conducive to promoting industrial production.

[0046] 3. After many experiments, the inventors surprisingly found that the reaction yield of step 2 in a halogenated alkane solvent is significantly higher than that of an ether solvent and acetonitrile. For example, when dichloromethane is used as a solvent, the yield is increased by 17.8% compared with acetonitrile as a solvent. Compared with the use of an ether solvent tetrahydrofuran, the yield is increased by 14.3%. Halogenated alkane solvents are particularly suitable for the substrates and reagents of the present invention, and it is difficult to expect that the yield can be significantly improved relative to other conventional solvents such as ether solvents and acetonitrile; and the solvent used in the present invention does not require special equipment for disposal, is simple to post-process, has good reproducibility, and is suitable for industrial production.

[0047] 4. More importantly, the present invention has finally determined the appropriate solvent, the creative acidic reagent and the important process parameters of the demethylation reaction, such as the addition conditions of the acidifying reagent trichloroacetic acid at a suitable temperature, and the determination of adjusting the reaction temperature and time, etc. through hundreds of creative labors. On this basis, a creative purification technology is further used for purification, so that the present invention provides a compound of formula 3 of tert-butyl 2-formyl-8-azaspiro[4.5]decane-8-carboxylate of the present invention that can be prepared under a variety of different conditions.

[0048] 5. The method of the present invention has the advantages of good selectivity, good reproducibility, short time consumption, economy and high conversion rate, and is suitable for industrial production. Therefore, it has good market value and far-reaching practical significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 This is the HNMR spectrum of the product obtained in Example 2 of the present invention. DETAILED DESCRIPTION

[0050] The present invention will be further described in conjunction with specific examples. It should be understood that the following detailed description of the technical solution of the present invention with examples will help to further understand the advantages and effects of the technical solution of the present invention, and the examples do not limit the protection scope of the present invention, which is determined by the claims.

[0051] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers.

[0052] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0053] Unless otherwise specified, the reagents were used directly without purification. All solvents were purchased from commercial suppliers, such as Aldrich, and used directly without further treatment.

[0054] Embodiment 1:

[0055]

[0056] Compound 1 (80 g, 315.78 mmol) was dissolved in THF (1 L), and 237 mL of lithium diisopropylamide (2 M tetrahydrofuran solution) was added dropwise under ice bath, and then reacted at room temperature for 2 h. Methoxymethyl triphenylphosphonium bromide (169 g, 436.41 mmol) was added. The temperature was raised to 60 ° C and reacted for 2 hours. After the raw material reacted completely, it was poured into ice water, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain compound 2 (56 g, yield 73.7%).

[0057] Embodiment 2:

[0058]

[0059] Compound 2 (56 g, 199.01 mmol) was dissolved in DCM (200 mL), trichloroacetic acid (115 g, 703.85 mmol, 3.5 eq) was added under ice bath, and then reacted at room temperature for 2 hours. After the reaction of the raw material was complete, it was poured into ice water, and DCM (200 mL*3) was added for extraction. The organic phases were combined, washed with saturated sodium chloride solution, separated, dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 3 (30 g, yield 56.4%, purity 95%). 1 H-NMR spectrum Figure 1 shown.

[0060] Embodiment 3:

[0061]

[0062] Compound 2 (2 g, 7.11 mmol) was dissolved in tetrahydrofuran (20 mL), trichloroacetic acid (4.07 g, 22.91 mmol, 3.5 eq) was added under ice bath, and then reacted at room temperature for 5 hours. After the raw material reacted completely, the insoluble matter was removed by filtration, poured into ice water, and extracted with DCM (100 mL*3), the organic phases were combined, washed with saturated sodium chloride solution, separated, dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 3 (800 mg, yield 42.1%, purity 95%).

[0063] Embodiment 4:

[0064]

[0065] Compound 2 (3 g, 10.66 mmol) was dissolved in acetonitrile (50 mL), trichloroacetic acid (6.10 g, 37.33 mmol, 3.5 eq) was added under ice bath, and then reacted at room temperature overnight. After the raw material reacted completely, the insoluble matter was filtered out, poured into ice water, and extracted with DCM (100 mL*3), the organic phases were combined, washed with saturated sodium chloride solution, separated, dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 3 (1.1 g, yield 38.6%, purity 95%).

[0066] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing an azaspiro[4.5]decane derivative of formula 3, comprising the following steps: It is characterized in that The steps include: Step 2: The compound of formula 2 is reacted with trichloroacetic acid and a halogenated alkane solvent to obtain a compound of formula 3.

2. A method for preparing an azaspiro[4.5]decane derivative of formula 3, comprising the following steps: It is characterized in that The steps include: Step 1: The compound of formula 1 reacts with a phosphorus reagent in the presence of a base to obtain a compound of formula 2; Step 2: The compound of formula 2 is reacted with trichloroacetic acid and a halogenated alkane solvent to obtain a compound of formula 3.

3. The preparation method according to claim 1 or 2, characterized in that In the step 2, the compound of formula 2 is first dissolved in a halogenated alkane solvent, and then trichloroacetic acid is added at -5 to 5°C to react to obtain the compound of formula 3.

4. The preparation method according to claim 1 or 2, characterized in that In step 2, the molar ratio of the compound of formula 2 to trichloroacetic acid is 1:(1.5-6), preferably 1:(2-5).

5. The preparation method according to claim 1 or 2, characterized in that The halogenated alkane solvent in step 2 is one or more of chloroform, 1,2-dichloroethane and dichloromethane.

6. The preparation method according to claim 1 or 2, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The reaction temperature of step 2 is -5 to 40°C, preferably -5 to 35°C; (2) The reaction time of step 2 is 1 to 8 hours, preferably 1 to 6 hours; (3) The volume of the reaction solvent in step 2 is 2 to 15 times, preferably 2 to 10 times, the mass of the compound of formula 2.

7. The preparation method according to claim 1 or 2, characterized in that: After the reaction of step 2 is completed, the reaction solution is poured into ice water to quench, and an organic solvent is added, extracted, washed, separated, dried, and concentrated to obtain a crude product of the compound of formula 3; the crude product of the compound of formula 3 can optionally be further subjected to column chromatography to obtain a pure product of the compound of formula 3.

8. The preparation method according to claim 2, characterized in that: In the step 1, the base is selected from one or more of sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium hydroxide, sodium hydroxide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, lithium diisopropylamide or n-butyl lithium, preferably one or more of lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, n-butyl lithium, sodium hydride or potassium hydride.

9. The preparation method according to claim 2 or 8, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The phosphorus reagent in step 1 is selected from methoxymethyltriphenylphosphonium bromide or methoxymethyltriphenylphosphonium chloride; (2) In step 1, the molar ratio of the compound of formula 1, the base and the phosphorus reagent is 1:(1.2-6):(1.1-3), preferably 1: (1.5～5)：(1.1～2.5)； (3) Step 1 is carried out in a reaction solvent, wherein the reaction solvent is one or more of tetrahydrofuran, petroleum ether, dichloromethane, dichloroethylene, chloroform, ethyl acetate, toluene, DMSO, diethyl ether, and DME, preferably one or more of tetrahydrofuran, diethyl ether, DME, and toluene; (4) The reaction temperature of step 1 is -5 to 70°C, preferably -5 to 60°C; (5) The reaction time of step 1 is 1 to 8 hours, preferably 1 to 6 hours; (6) The volume of the reaction solvent in step 1 is 5 to 40 times, preferably 5 to 30 times, the mass of the compound of formula 1; (7) In step 1, compound 1 is first dissolved in a reaction solvent, a base is added under ice bath, and the mixture is reacted at 0°C to 30°C for 1 to 3 hours, and then a phosphorus reagent is added and the mixture is reacted at 30°C to 60°C for 1 to 4 hours.

10. The preparation method according to claim 2 or 8, characterized in that: After the reaction of step 1 is completed, the reaction solution is poured into ice water to quench, and an organic solvent is added, extracted, washed, separated, dried, and concentrated to obtain a crude product of the compound of formula 2; the crude product of the compound of formula 2 can optionally be further subjected to column chromatography to obtain a pure product of the compound of formula 2.

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