Synthesis method of N-Boc protected L-beta-homopiperidine acid methyl ester

Abstract

The invention relates to the technical field of organic synthesis, in particular to a synthesis method of N-Boc protected L-beta-homopiperidine acid methyl ester. According to the invention, cheap and easily available L-2-amino adipic acid is used as an initial raw material, and the target product N-Boc protected L-beta-homopiperidine acid methyl ester is finally prepared through conversion of five steps. The synthetic route is convenient to operate, good in stereoselectivity, mild in reaction condition, simple in separation and purification, relatively high in total yield and capable of realizing large-scale preparation. The adopted raw materials and reagents are non-toxic, the production process is pollution-free and environment-friendly, and good conditions are created for industrial large-scale production and commercialization of the product.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing N-Boc protected L-beta-homopipecolic acid methyl ester. Background Art

[0002] N-Boc protected L-beta-homopipecolic acid methyl ester (1) is a common key intermediate compound for the synthesis of several natural product molecules such as alkaloids (+)-sedridine, (-)-allosedridine, (+)-pelletierine, Cermizine D, etc. (as shown below).

[0003]

[0004] The methods for preparing compound (1) reported in the literature currently have their own characteristics, but they have many shortcomings: such as expensive chiral catalysts, poor stereoselectivity, inconvenient experimental operations, harsh reaction conditions, and lengthy routes resulting in low overall yields.

[0005] The ideal synthetic route should meet the green chemistry standards: such as the use of renewable resources, mild reaction conditions, good stereoselectivity, and high overall yield. Therefore, how to efficiently use cheap and readily available raw and auxiliary materials to prepare compound (1) is a technical problem that urgently needs to be solved. Summary of the invention

[0006] Based on the above content, the present invention provides a method for synthesizing N-Boc protected L-beta-homopipecolic acid methyl ester. The preparation method of the present invention overcomes the defects of the prior art method for preparing compound (1), and the method of the present invention uses cheap and readily available starting materials, thereby improving the yield of preparing compound (1).

[0007] To achieve the above object, the present invention provides the following solutions:

[0008] The present invention provides a method for synthesizing N-Boc protected L-beta-homopipecolic acid methyl ester, characterized in that it comprises the following steps:

[0009] Step 1, synthesis of compound 3:

[0010] a. Dissolve L-2-aminoadipic acid in methanol, cool to 0°C, add thionyl chloride, then heat under reflux for reaction, and concentrate under reduced pressure to obtain L-2-aminoadipic acid methyl ester hydrochloride.

[0011] b. The L-2-aminoadipate methyl hydrochloride was dissolved in a mixed solvent of tetrahydrofuran and water, solid sodium bicarbonate and Boc anhydride were added, and the reaction was carried out at room temperature to obtain N-Boc-protected L-2-aminoadipate methyl ester;

[0012] c. The N-Boc protected L-2-aminoadipate methyl ester was dissolved in anhydrous tetrahydrofuran, cooled to 0°C, lithium borohydride was added and allowed to stand for 30 min, and then the temperature was naturally raised to room temperature to react to obtain an N-Boc protected amino alcohol;

[0013] d. The N-Boc protected amino alcohol is dissolved in anhydrous dichloromethane, p-toluenesulfonic acid and 2,2-dimethoxypropane are added, and the reaction is carried out at room temperature to obtain a propidene compound;

[0014] e. The propylidene compound was dissolved in anhydrous dichloromethane, imidazole and tert-butyldiphenylsilyl chloride were added, and the reaction was carried out at room temperature to obtain TBDPS silyl ether;

[0015] f. The TBDPS silyl ether was dissolved in acetonitrile, copper chloride dihydrate was added, and the mixture was reacted at 0°C to obtain compound 3;

[0016] The structural formula of the compound 3 is as follows:

[0017]

[0018] Step 2, synthesis of compound 5: dissolving the compound 3 in acetonitrile, adding IBX, heating under reflux to react to obtain N-Boc protected ammaldehyde; dissolving the N-Boc protected ammaldehyde in isopropanol, adding Wittig reagent and potassium carbonate solid, reacting at room temperature to obtain compound 5;

[0019] The structural formula of the compound 5 is as follows:

[0020]

[0021] Step 3, synthesis of compound 6: dissolve the compound 5 in anhydrous dichloromethane, cool to -78°C, add diisobutylaluminum hydride to react to obtain an intermediate primary alcohol; dissolve the intermediate primary alcohol in acetone, cool to 0°C, add p-toluenesulfonic acid to react to obtain compound 6;

[0022] The structural formula of the compound 6 is as follows:

[0023]

[0024] Step 4, synthesis of compound 7: dissolve the compound 6 in a tetrahydrofuran / methanol / water mixed solvent, add solid sodium periodate, and react at room temperature to obtain an intermediate N-Boc protected β 3 -amino acid; N-Boc protected intermediate β 3 -amino acid was dissolved in acetone, solid potassium carbonate and methyl iodide were added, and the mixture was heated under reflux to obtain compound 7; the compound 7 was N-Boc protected β 3 -amino acid methyl esters;

[0025] The structural formula of the compound 7 is as follows:

[0026]

[0027] Step 5, synthesis of N-Boc protected L-beta-homopipecolic acid methyl ester: the compound 7 is dissolved in methanol, solid ammonium fluoride is added, and the reaction is heated under reflux to obtain an intermediate primary alcohol; the intermediate primary alcohol is dissolved in anhydrous dichloromethane, cooled to 0°C, triethylamine and methylsulfonyl chloride are added, and the mixture is allowed to stand for 15 minutes, and then the mixture is naturally heated to room temperature to obtain an intermediate mesylate; the intermediate mesylate is dissolved in anhydrous tetrahydrofuran, cooled to 0°C, and potassium tert-butoxide is added to obtain N-Boc protected L-beta-homopipecolic acid methyl ester.

[0028] The structural formula of the N-Boc protected L-beta-homopipecolic acid methyl ester is as follows:

[0029]

[0030] In a preferred embodiment of the present invention, in step 1, the molar ratio of L-2-aminoadipic acid: dichlorothionyl: sodium bicarbonate: Boc anhydride: lithium borohydride: p-toluenesulfonic acid: 2,2-dimethoxypropane: tert-butyldiphenylsilyl chloride: imidazole: cupric chloride dihydrate is 1.0: 2.0-4.0: 3.0-5.0: 1.0-1.05: 3.0-4.0: 0.05-0.1: 1.5-2.0: 1.0-1.2: 2.0-3.0: 1.5-2.0. More preferably, the molar ratio of L-2-aminoadipic acid: dichlorothionyl: sodium bicarbonate: Boc anhydride: lithium borohydride: p-toluenesulfonic acid: 2,2-dimethoxypropane: tert-butyldiphenylsilyl chloride: imidazole: cupric chloride dihydrate is 1.0:2.0:3.0:1.0:4.0:0.1:2.0:1.1:2.0:1.5.

[0031] In a preferred embodiment of the present invention, the reaction time in step a is 2h-4h (more preferably, 2h), and after the reaction is completed, a reduced pressure concentration step is further included.

[0032] The reaction time in step b is 8h-12h (more preferably, 10h). After the reaction is completed, the process further includes concentrating under reduced pressure, extracting with ethyl acetate, combining the organic phases, washing with saturated brine, separating the phases, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating and drying to obtain N-Boc protected L-2-aminoadipate methyl ester.

[0033] The reaction time in step c is 12h-15h (more preferably, 12h). After the reaction is completed, the reaction is slowly quenched with a saturated sodium sulfate aqueous solution at low temperature (0°C), concentrated under reduced pressure to remove tetrahydrofuran, extracted with ethyl acetate, combined organic phases, washed with saturated brine, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain N-Boc protected amino alcohol.

[0034] The reaction time in step d is 2h-3h (more preferably, 2h). After the reaction is completed, the mixture is slowly quenched with a saturated sodium bicarbonate aqueous solution at low temperature, concentrated under reduced pressure to remove dichloromethane, extracted with ethyl acetate, and the organic phases are combined and washed with saturated brine, separated, and the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain a propylidene compound.

[0035] The reaction time in step e is 5 h-10 h (more preferably, 6 h). After the reaction is completed, the mixture is slowly quenched with water at low temperature, concentrated under reduced pressure to remove dichloromethane, extracted with ethyl acetate, and the organic phases are combined and washed with 1M potassium hydrogen sulfate aqueous solution and saturated brine in sequence. The organic phases are separated, and the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain TBDPS silyl ether.

[0036] The reaction time in step f is 1 h-1.5 h (preferably 1 h). After the reaction is completed, the reaction is slowly quenched with a saturated sodium bicarbonate aqueous solution at low temperature, filtered, and the filtrate is concentrated under reduced pressure to remove the acetonitrile, extracted with ethyl acetate, and the organic phases are combined and washed with saturated brine, separated, and the organic phase is dried over anhydrous sodium sulfate, filtered and concentrated, and a colorless oil is obtained by rapid column chromatography using petroleum ether: ethyl acetate = 2:1 (v / v) as an eluent, i.e., compound 3.

[0037] In a preferred embodiment of the present invention, in step 2, the molar ratio of compound 3: compound 4: potassium carbonate is 1: 1.1-2.0: 1.1-2.0. More preferably, the molar ratio of compound 3: compound 4: potassium carbonate is 1: 1.2: 1.2.

[0038] In a preferred embodiment of the present invention, in step 2, the reaction time at room temperature is 8h-15h (further preferably, 12h). After the reaction is completed, it is directly filtered, and the filter residue is washed with ethyl acetate. After the filtrate is concentrated under reduced pressure, rapid column chromatography is performed using petroleum ether: ethyl acetate = 10: 1 (v / v) as the eluent to obtain a colorless oil, namely compound 5.

[0039] In a preferred embodiment of the present invention, in step 3, the molar ratio of compound 5: diisobutylaluminum hydride: p-toluenesulfonic acid is 1: 2.0-3.0: 1.0-1.2. More preferably, the molar ratio of compound 5: diisobutylaluminum hydride: p-toluenesulfonic acid is 1: 2.0: 1.0.

[0040] In step 3, when preparing the intermediate primary alcohol, the reaction time is 1h-2h (more preferably, 1.5h). After the reaction is completed, it is quenched with a saturated sodium sulfate aqueous solution at -78°C, concentrated under reduced pressure to spin off dichloromethane, and then extracted with ethyl acetate. After the organic phases are combined, they are washed with saturated brine, separated, and the organic phases are dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain the intermediate primary alcohol. The intermediate primary alcohol can be directly used in the next reaction without further purification.

[0041] In step 3, when preparing compound 6, the reaction time is 1h-1.5h (further preferably, 1h). After the reaction is completed, it is quenched with excess triethylamine and then directly concentrated under reduced pressure. Rapid column chromatography using petroleum ether: ethyl acetate = 2: 1 (v / v) as the eluent gives a colorless oil, i.e., compound 6.

[0042] In a preferred embodiment of the present invention, in step 4, the molar ratio of compound 6: sodium periodate: potassium carbonate: methyl iodide is 1.0: 3.0-5.0: 2.0-4.0: 1.5-3.0. More preferably, the molar ratio of compound 6: sodium periodate: potassium carbonate: methyl iodide is 1.0: 4.0: 3.0: 1.5.

[0043] In step 4, the intermediate N-Boc protected β 3 -amino acid, the reaction time is 5h-10h (more preferably, 6h), after the reaction is completed at room temperature, quench with saturated sodium sulfite aqueous solution, concentrate under reduced pressure to spin off tetrahydrofuran and methanol, then add dilute hydrochloric acid to acidify, extract with ethyl acetate, combine the organic phases and wash with saturated brine, separate the liquids, add anhydrous sodium sulfate to dry the organic phase, filter, concentrate and dry to obtain the intermediate N-Boc protected β 3 -amino acid. The intermediate N-Boc protected β 3 -The amino acid can be used directly in the next reaction without further purification.

[0044] In step 4, when preparing compound 7, the heating reflux reaction time is 8h-12h (further preferably, 10h). After the reaction is completed, it is cooled to room temperature and directly filtered. The filter residue is washed twice with ethyl acetate, and the filtrate is concentrated under reduced pressure. Rapid column chromatography using petroleum ether: ethyl acetate = 4: 1 (v / v) as the eluent obtains a colorless oil, i.e., compound 7.

[0045] In a preferred embodiment of the present invention, in step 5, the molar ratio of compound 7: ammonium fluoride: methanesulfonyl chloride: triethylamine: potassium tert-butoxide is 1.0: 20-40: 1.5-2.0: 2.0-3.0: 1.5-3.0. More preferably, the molar ratio of compound 7: ammonium fluoride: methanesulfonyl chloride: triethylamine: potassium tert-butoxide is 1.0: 30: 1.5: 2.0: 2.0.

[0046] In step 5, when preparing the intermediate primary alcohol, the heating reflux reaction time is 5h-10h (further preferably, 6h), and after the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure, and the methanol is spun off, and then quenched with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phases are combined and washed with saturated brine, separated, and the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated, and drained to obtain the intermediate primary alcohol. The intermediate primary alcohol does not need to be further purified and can be directly used in the next step reaction.

[0047] In step 5, the reaction time at room temperature is 1 h-1.5 h (more preferably, 1 h) when preparing the intermediate mesylate. After the reaction is completed, saturated sodium bicarbonate aqueous solution is added to quench, extracted with dichloromethane, the organic phases are combined and washed with saturated brine, separated, the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated and drained to obtain the intermediate mesylate. The intermediate mesylate can be directly used in the next reaction without further purification.

[0048] In step 5, when preparing N-Boc protected L-beta-homopipecolic acid methyl ester, potassium tert-butoxide is added for a reaction time of 2h-3h (more preferably, 2h). After the reaction is completed, saturated aqueous ammonium chloride solution is added to quench the reaction, the mixture is concentrated under reduced pressure to remove tetrahydrofuran, and then extracted with ethyl acetate. The organic phases are combined and washed with saturated brine, separated, and the organic phases are dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to rapid column chromatography using petroleum ether: ethyl acetate = 4:1 (v / v) as an eluent to obtain a colorless oil, i.e., N-Boc protected L-beta-homopipecolic acid methyl ester, i.e., compound (1).

[0049] The present invention discloses the following technical effects:

[0050] 1) The present invention uses cheap and readily available L-2-aminoadipic acid (2) as a starting material, and prepares the final product N-Boc-protected L-beta-homopipecolic acid methyl ester (1) through five steps; the synthesis method has mild reaction conditions, is green and environmentally friendly, has good stereoselectivity, and has a high overall yield.

[0051] 2) The raw materials and various reagents are cheap and easy to obtain, with low cost, simple post-processing, and simple and convenient separation and purification; creating good conditions for industrial-scale production and commercialization of the product.

[0052] 3) The raw materials and auxiliary materials used are non-toxic, the production process is pollution-free, environmentally friendly, and in line with the country's green industry policy. DETAILED DESCRIPTION

[0053] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0054] It should be understood that the terms described in the present invention are only for describing a particular embodiment and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. The intermediate value in any stated value or stated range, and each smaller range between any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0055] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0056] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to the skilled artisan. The present invention description and examples are exemplary only.

[0057] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0058] The "room temperature" described in the present invention, unless otherwise specified, refers to 20-30°C.

[0059] The present invention uses cheap and readily available L-2-aminoadipic acid as a starting material, and finally obtains the target product (1) through five major steps of transformation. The overall synthetic route is as follows:

[0060]

[0061] The present invention uses cheap and readily available L-2-aminoadipic acid (2) as a starting material, firstly obtains compound 3 by a method known in the literature, then oxidizes it with IBX to N-Boc protected aminoaldehyde, and obtains compound 5 by Wittig reaction with phosphonium salt 4. Then, the methyl ester is reduced with DIBAL-H, and then hydrolyzed under acidic conditions to convert the enol methyl ether into α-hydroxy ketone (compound 6). The acid (intermediate N-Boc protected β 3 -amino acid), followed by methyl esterification to give compound 7N-Boc protected β 3-amino acid methyl ester. Next, the TBDPS protecting group is removed, and then the hydroxyl group is activated to obtain the mesylate; finally, tetrahydrofuran is used as solvent and potassium tert-butoxide is used as base to extract the hydrogen and close the ring to obtain the target compound 1N-Boc protected L-beta-homopipecolic acid methyl ester (same as compound (1) below).

[0062] This route is easy to operate, has good stereoselectivity, mild reaction conditions, simple separation and purification, high total yield, and can be scaled up for preparation. The raw materials and reagents used are non-toxic, the production process is pollution-free, and environmentally friendly, creating good conditions for industrial-scale production and commercialization of the product.

[0063] The technical solutions described in the present invention, unless otherwise specified, are all conventional solutions in the art, and the reagents or raw materials used, unless otherwise specified, are purchased from commercial channels or have been disclosed.

[0064] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0065] Example 1-5 The reaction route for the synthesis of N-Boc protected L-beta-homopipecolic acid methyl ester (1) is as follows:

[0066]

[0067] Example 1: Synthesis of Compound 3

[0068]

[0069] 1) Dissolve L-2-aminoadipic acid (2) (10 g, 62.0 mmol) in methanol (300 mL), cool to 0°C in an ice-water bath, slowly dropwise add thionyl chloride (9 mL, 124 mmol), heat under reflux for 2 h after 20 minutes, and concentrate under reduced pressure to obtain L-2-aminoadipic acid methyl ester hydrochloride, which is directly used in the next step.

[0070] 2) The above L-2-aminoadipate methyl ester hydrochloride was dissolved in a tetrahydrofuran / water (1:1, 600mL) mixed solvent, sodium bicarbonate (15.6g, 186mmol) was added, and after stirring evenly, Boc anhydride (14.2mL, 62.0mmol) was slowly added dropwise, and the reaction was stirred at room temperature for 10h, and the tetrahydrofuran was removed by concentrating under reduced pressure, and water (200mL) was added to dilute, and ethyl acetate (300mL) was extracted three times, and the organic phases were combined and washed with saturated brine (200mL), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to obtain N-Boc protected L-2-aminoadipate methyl ester. It was directly used for the next step reaction.

[0071] 3) The above-mentioned N-Boc protected L-2-aminoadipate methyl ester was dissolved in anhydrous tetrahydrofuran (300 mL), cooled to 0°C, and lithium borohydride (5.4 g, 248 mmol) was added. After 30 minutes, the low temperature cooling bath was removed and the temperature was slowly raised to room temperature for reaction for 12 hours. After the reaction was completed, it was slowly quenched with a saturated aqueous sodium sulfate solution at 0°C, concentrated under reduced pressure to spin off tetrahydrofuran, extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain N-Boc protected amino alcohol.

[0072] 4) The above N-Boc protected amino alcohol was dissolved in anhydrous dichloromethane (300 mL), p-toluenesulfonic acid (1.07 g, 6.2 mmol) and 2,2-dimethoxypropane (DMP) (15.2 mL, 124 mmol) were added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the mixture was slowly quenched with a saturated aqueous sodium bicarbonate solution at low temperature, concentrated under reduced pressure to remove dichloromethane, and then extracted three times with ethyl acetate (300 mL). The organic phases were combined and washed with saturated brine (200 mL), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to obtain a propylidene compound. It was directly used for the next step reaction.

[0073] 5) The above propylidene compound was dissolved in anhydrous dichloromethane (300mL), imidazole (8.4g, 124mmol) and tert-butyldiphenylsilyl chloride (TBDPSCl) (17.7mL, 68.2mmol) were added, and the mixture was reacted at room temperature for 6h. After the reaction was completed, the mixture was slowly quenched with water at low temperature, concentrated under reduced pressure to remove dichloromethane, and then extracted three times with ethyl acetate (300mL). After the organic phases were combined, they were washed with 1M potassium hydrogen sulfate aqueous solution (200mL) and saturated brine (200mL) in sequence, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and drained to obtain TBDPS silyl ether. It was directly used for the next step reaction.

[0074] 6) The above TBDPS silyl ether was dissolved in acetonitrile (400 mL), and cupric chloride dihydrate (15.9 g, 93.0 mmol) was added and reacted at 0°C for 1 h. After the reaction was completed, it was slowly quenched with saturated sodium bicarbonate aqueous solution (300 mL) at low temperature, filtered, and the filtrate was concentrated under reduced pressure to spin off the acetonitrile, and then extracted three times with ethyl acetate (300 mL). The organic phases were combined and washed with saturated brine (300 mL), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and a colorless oil was obtained by rapid column chromatography using petroleum ether: ethyl acetate = 2: 1 (v / v) as the eluent, i.e., compound 314.6 g, with a six-step yield of 50%.

[0075] 1HNMR(600MHz, CDCl3)δ7.66(d,J=6.9Hz,4H),7.40(dt,J=24.7,7.1Hz,6H),4.62(d,J=5.0Hz,1H),3.72–3.55(m,4H),3.51(dd,J=10 .2,5.5Hz,1H),1.62–1.54(m,2H),1.48(dd,J=10.3,4.9Hz,2H),1.44(s,9H),1.38(dd,J=13.0,6.3Hz,2H),1.06(d,J=12.3Hz,9H); 13 C NMR (151MHz, CDCl3) δ156.59,135.54,133.95,129.53,127.58,79.57,66.06,63.52,52.84,32.26,31.12,28.35,26.85,22.31,19.17; HR-ESIMS m / z:calculated for C 27 H 41 NO4SiNa + [M+Na] + :494.2697,found494.2699.

[0076] Example 2: Synthesis of Compound 5

[0077]

[0078] 1) The above compound 3 (10 g, 21.2 mmol) was dissolved in acetonitrile (250 mL), 2-iodoacylbenzoic acid (IBX) (6.5 g, 23.2 mmol) was added, and the mixture was heated to reflux for 1 h, cooled to room temperature, and filtered directly. The filter residue was washed twice with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure and then dried to obtain N-Boc protected aminaldehyde; it was used directly in the next step without further purification.

[0079] 2) The above N-Boc protected ammaldehyde was dissolved in isopropanol (250 mL), stirred evenly, and Wittig reagent 4 (11.4 g, 25.5 mmol) and solid potassium carbonate (3.5 g, 25.5 mmol) were added, and the mixture was reacted at room temperature for 12 h, filtered directly, and the filter residue was washed with ethyl acetate (300 mL). After the filtrate was concentrated under reduced pressure, it was subjected to rapid column chromatography using petroleum ether: ethyl acetate = 10: 1 (v / v) as the eluent to obtain a colorless oil, i.e., compound 58.0 g, with a two-step yield of 68%.

[0080] 1H NMR (600MHz, CDCl3) δ7.65 (d, J=7.7Hz, 4H), 7.42–

[0081] 7.36(m,6H),6.04(d,J=8.7Hz,1H),4.65(s,1H),4.52(s,1H),3.78(s,3H),3. 72(s,3H),3.64(t,J=6.3Hz,2H),1.63–1.45(m,6H),1.43(s,9H),1.04(s,9H); 13 C NMR (151MHz,CDCl3)δ

[0082] 163.98,155.02,145.98,135.54,133.97,129.51,128.18,127.58,79.33,63. 49,60.14,51.99,47.08,34.89,32.15,28.38,26.83,21.95,19.17;HR-ESIMS m / z:calculatedfor C 31 H 45 NO6SiNa + [M+Na] + :578.2908, found 578.2912.

[0083] Example 3: Synthesis of Compound 6

[0084]

[0085] 1) The above compound 5 (7.0 g, 12.6 mmol) was dissolved in anhydrous dichloromethane (300 mL), cooled to -78 ° C, diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in hexanes) (25.2 mL, 25.2 mmol) was added, and the reaction was carried out at -78 ° C for 1.5 h, quenched with saturated sodium sulfate aqueous solution (300 mL), concentrated under reduced pressure to remove dichloromethane, diluted with water (200 mL), extracted with ethyl acetate (300 mL) three times, and the organic phases were combined and washed with saturated brine (200 mL), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain the intermediate primary alcohol. It was used directly in the next step without further purification.

[0086] 2) The intermediate primary alcohol was dissolved in acetone (300 mL), cooled to 0°C in an ice-water bath, p-toluenesulfonic acid (2.17 g, 12.6 mmol) was added, and the mixture was reacted at 0°C for 1 h. An excess of triethylamine (3 mL) was added dropwise to quench the reaction, and then the mixture was directly concentrated under reduced pressure. Rapid column chromatography using petroleum ether: ethyl acetate = 2: 1 (v / v) as the eluent gave a colorless oil, i.e., compound 64.66 g, with a two-step yield of 72%.

[0087] 1 HNMR (600MHz, CDCl3) δ7.65 (dt, J=8.0, 1.4Hz, 4H), 7.47–7.34 (m, 6H), 4.72 (d,J=8.1Hz,1H),4.22(dd,J=44.0,19.0Hz,2H),3.90(d,J=5.8Hz,1H),3.67 –3.62(m,2H),3.11(s,1H),2.59(d,J=4.6Hz,2H),1.55(ddd,J=8.6,5.4,2. 5Hz,2H),1.46(dd,J=13.7,5.4Hz,4H),1.43(d,J=13.9Hz,9H),1.04(s,9H); 13 C NMR (151MHz, CDCl3) δ208.60,155.40,135.54,133.92,129.55,127.60,79.56,6 8.67,63.48,47.65,43.51,34.45,32.05,28.31,26.85,22.49,19.18; HR-ESIMS m / z:calculated forC 29 H 43 NO5SiNa + [M+Na] + :536.2803,found 536.2806.

[0088] Example 4: Synthesis of Compound 7

[0089]

[0090] 1) Compound 6 (4.3 g, 8.4 mmol) was dissolved in a tetrahydrofuran / methanol / water mixed solvent (volume ratio 1:1:1, 300 mL), solid sodium periodate (7.2 g, 33.6 mmol) was added, and the mixture was reacted at room temperature for 6 h, and then quenched with a saturated aqueous sodium sulfite solution (200 mL), concentrated under reduced pressure to remove tetrahydrofuran and methanol, and acidified to pH = 5 with dilute hydrochloric acid, extracted three times with ethyl acetate (300 mL), and the organic phases were combined and washed with saturated brine (200 mL), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain an intermediate N-Boc protected β 3 -amino acid. It was used directly in the next reaction without further purification.

[0091] 2) N-Boc protected β 3 -The amino acid was dissolved in acetone (200 mL), potassium carbonate solid (3.5 g, 25.2 mmol) and iodomethane (0.78 mL, 12.6 mmol) were added, and the mixture was heated to reflux for 10 h, cooled to room temperature, and filtered directly. The filter residue was washed with ethyl acetate (200 mL), and the filtrate was concentrated under reduced pressure. The target compound N-Boc protected β 3 -Amino acid methyl ester 73.78 g, two-step yield 88%.

[0092] 1 H NMR (600MHz, CDCl3) δ7.65(dt,J=8.1,1.4Hz,4H),7.39(dt,J=14.3,7.0Hz,6H),4.88(d,J=8.8Hz,1H),3.88(s,1H),3.67(s,3 H),3.64(t,J=6.2Hz,2H),2.49(qd,J=15.5,5.2Hz,2H),1.59–1.52(m,2H),1.50–1.43(m,4H),1.45–1.39(m,9H),1.04(s,9H); 13 C NMR (151MHz, CDCl3) δ172.16,155.33,135.55,133.99,129.51,127.59,79.17,6 3.58,51.60,47.56,39.10,34.30,32.19,28.36,26.85,22.47,19.18; HR-ESIMS m / z:calculated for C 29 H 43 NO5SiNa + [M+Na] +:536.2803,found536.2806.

[0093] Example 5: Synthesis of Compound (1)

[0094]

[0095] 1) Compound 7 (3.0 g, 5.8 mmol) was dissolved in methanol (200 mL), solid ammonium fluoride (6.5 g, 174 mmol) was added, and the mixture was heated under reflux for 6 h, cooled to room temperature, concentrated under reduced pressure to remove methanol, and then quenched with saturated aqueous sodium bicarbonate solution (300 mL); extracted three times with ethyl acetate (300 mL), the organic phases were combined and washed with saturated brine (200 mL), separated, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the intermediate primary alcohol. It was used directly in the next step without further purification.

[0096] 2) The intermediate primary alcohol was dissolved in anhydrous dichloromethane (200 mL), cooled to 0°C, triethylamine (1.6 mL, 11.6 mmol) and methanesulfonyl chloride (0.67 mL, 8.7 mmol) were added, and the low-temperature cooling bath was removed after 15 minutes, and the temperature was slowly raised to room temperature for 1 hour. After the reaction was completed, saturated sodium bicarbonate aqueous solution (200 mL) was added to quench, and the mixture was extracted with dichloromethane (200 mL) three times. The organic phases were combined and washed with saturated brine (200 mL), separated, and the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain the intermediate methanesulfonate. It was used directly in the next step without further purification.

[0097] 3) The intermediate mesylate was dissolved in anhydrous tetrahydrofuran (150 mL), cooled to 0°C, and dried activated potassium tert-butoxide (1.3 g, 11.6 mmol) was added. The mixture was reacted at 0°C for 2 h, quenched with saturated aqueous ammonium chloride solution (200 mL), concentrated under reduced pressure to remove tetrahydrofuran, and then extracted three times with ethyl acetate (300 mL). The organic phases were combined and washed with saturated brine (200 mL), separated, and the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to rapid column chromatography using petroleum ether: ethyl acetate = 4: 1 (v / v) as the eluent to obtain a colorless oil, i.e., compound (1) N-Boc protected L-beta-homopipecolic acid methyl ester 1.1 g. The three-step yield was 75%.

[0098] 1H NMR (600MHz, CDCl3) δ4.66-4.68(m,1H),3.97–3.99(m,1H),3.64(s,3H),2.77–2.74(m,1H) ),2.54(ddd,J=45.2,14.1,7.6Hz,2H),1.66–1.56(m,4H),1.53–1.46(m,2H),1.43(s,9H); 13 C NMR (151MHz, CDCl3) δ171.85,154.68,79.50,51.63,47.82,39.06,35.07,28.35,28.28,25.24,18.82; HR-ESIMS m / z:calculated forC 13 H 23 NO4Na +

[0099] [M+Na] + :280.1519, found 280.1523.

[0100] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A method for synthesizing N-Boc protected L-beta-homopipecolic acid methyl ester, characterized in that: The following steps are involved: Step 1, synthesis of compound 3: a. dissolving L-2-aminoadipic acid in methanol, cooling to 0°C, adding thionyl chloride, and then heating to reflux for reaction, and concentrating under reduced pressure to obtain L-2-aminoadipic acid methyl ester hydrochloride; b. The L-2-aminoadipate methyl hydrochloride was dissolved in a mixed solvent of tetrahydrofuran and water, solid sodium bicarbonate and Boc anhydride were added, and the reaction was carried out at room temperature to obtain N-Boc-protected L-2-aminoadipate methyl ester; c. The N-Boc protected L-2-aminoadipate methyl ester was dissolved in anhydrous tetrahydrofuran, cooled to 0°C, lithium borohydride was added and allowed to stand, and then the temperature was raised to room temperature to react and obtain an N-Boc protected amino alcohol; d. The N-Boc protected amino alcohol is dissolved in anhydrous dichloromethane, p-toluenesulfonic acid and 2,2-dimethoxypropane are added, and the reaction is carried out at room temperature to obtain a propidene compound; e. The propylidene compound was dissolved in anhydrous dichloromethane, imidazole and tert-butyldiphenylsilyl chloride were added, and the reaction was carried out at room temperature to obtain TBDPS silyl ether; f. The TBDPS silyl ether was dissolved in acetonitrile, copper chloride dihydrate was added, and the mixture was reacted at 0°C to obtain compound 3; The structural formula of the compound 3 is as follows: Step 2, synthesis of compound 5: dissolving the compound 3 in acetonitrile, adding IBX, heating under reflux to react to obtain N-Boc protected ammaldehyde; dissolving the N-Boc protected ammaldehyde in isopropanol, adding Wittig reagent and potassium carbonate solid, reacting at room temperature to obtain compound 5; The structural formula of the compound 5 is as follows: Step 3, synthesis of compound 6: dissolve the compound 5 in anhydrous dichloromethane, cool to -78°C, add diisobutylaluminum hydride to react to obtain an intermediate primary alcohol; dissolve the intermediate primary alcohol in acetone, cool to 0°C, add p-toluenesulfonic acid to react to obtain compound 6; The structural formula of the compound 6 is as follows: Step 4, synthesis of compound 7: dissolve the compound 6 in a tetrahydrofuran / methanol / water mixed solvent, add solid sodium periodate, and react at room temperature to obtain an intermediate N-Boc protected β 3 -amino acid; N-Boc protected intermediate β 3 -amino acid was dissolved in acetone, solid potassium carbonate and methyl iodide were added, and the mixture was heated under reflux to obtain compound 7; the compound 7 was N-Boc protected β 3 -amino acid methyl esters; The structural formula of the compound 7 is as follows: Step 5, synthesis of N-Boc protected L-beta-homopipecolic acid methyl ester: dissolve the compound 7 in methanol, add solid ammonium fluoride, heat and reflux to react to obtain an intermediate primary alcohol; dissolve the intermediate primary alcohol in anhydrous dichloromethane, cool to 0°C, add triethylamine and methylsulfonyl chloride, let stand, then heat to room temperature to react to obtain an intermediate mesylate; dissolve the intermediate mesylate in anhydrous tetrahydrofuran, cool to 0°C, add potassium tert-butoxide to react to obtain N-Boc protected L-beta-homopipecolic acid methyl ester; The structural formula of the N-Boc protected L-beta-homopipecolic acid methyl ester is as follows:

2. The method for synthesizing N-Boc protected L-beta-homopipecolic acid methyl ester according to claim 1, characterized in that: In step 1, the molar ratio of L-2-aminoadipic acid: dichlorothionyl: sodium bicarbonate: Boc anhydride: lithium borohydride: p-toluenesulfonic acid: 2,2-dimethoxypropane: tert-butyldiphenylsilyl chloride: imidazole: cupric chloride dihydrate is 1.0: 2.0-4.0: 3.0-5.0: 1.0-1.05: 3.0-4.0: 0.05-0.1: 1.5-2.0: 1.0-1.2: 2.0-3.0: 1.5-2.

0.

3. The method for synthesizing N-Boc protected L-beta-homopipecolic acid methyl ester according to claim 1, characterized in that: In step 2, the molar ratio of compound 3: compound 4: potassium carbonate is 1: 1.1-2.0: 1.1-2.

0.

4. The method for synthesizing N-Boc protected L-beta-homopipecolic acid methyl ester according to claim 1, characterized in that: In step 2, the reaction time at room temperature is 8h-15h.

5. The method for synthesizing N-Boc protected L-beta-homopipecolic acid methyl ester according to claim 1, characterized in that: In step 3, the molar ratio of compound 5: diisobutylaluminum hydride: p-toluenesulfonic acid is 1: 2.0-3.0: 1.0-1.

2.

6. The method for synthesizing N-Boc protected L-beta-homopipecolic acid methyl ester according to claim 1, characterized in that: In step 4, the molar ratio of compound 6: sodium periodate: potassium carbonate: methyl iodide is 1.0: 3.0-5.0: 2.0-4.0: 1.5-3.

0.

7. The method for synthesizing N-Boc protected L-beta-homopipecolic acid methyl ester according to claim 1, characterized in that: In step 5, the molar ratio of compound 7: ammonium fluoride: methanesulfonyl chloride: triethylamine: potassium tert-butoxide is 1.0: 20-40: 1.5-2.0: 2.0-3.0: 1.5-3.0.

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