Synthesis method of beta3-amino acid derivative

Abstract

The invention relates to the technical field of organic synthesis, in particular to a synthesis method of a beta3-amino acid derivative. Natural alpha-amino acid is selected as an initial raw material, and a final product beta 3-amino acid derivative is prepared through nine-step reaction; the synthesis method is mild in reaction condition, green and environment-friendly, good in stereoselectivity and relatively high in total yield. The raw materials and various reagents adopted by the method are cheap and easy to obtain, the cost is low, the post-treatment is simple, and the separation and purification are simple and convenient; the raw materials and the auxiliary materials adopted by the method are non-toxic, the production process is pollution-free and environment-friendly, and the method conforms to the national green industrial policy.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a β 3 -Synthesis of amino acid derivatives. Background Art

[0002] β 3 -Amino acid refers to an amino acid whose amino group is attached to the β position of the carboxylic acid. 3 - A polypeptide is a sequence containing β 3 -amino acid polypeptide molecule, the structural formula is as follows:

[0003]

[0004] β 3 -Amino acids, as an important structural skeleton, are widely present in many biologically active molecules, drugs and natural products, as shown below:

[0005]

[0006] Sitagliptin is a new anti-type 2 diabetes drug developed by Merck in the United States. Clinical studies have shown that it is an orally effective drug with good market prospects, high safety, good tolerance, and few adverse reactions. Natural product molecules Chondramide C, Leucyl-3-epi-deoxynegamycin, Blasticidin S, and TAN-1057A all have excellent biological activity. Somatostatin analogues can bind to somatostatin receptors with high strength and specificity, and their biological activity is very good.

[0007] In addition, because such a skeleton can increase metabolic stability, β 3 -Amino acids are also widely used in the construction of bioactive peptides and peptidomimetics. 3 -The efficient synthesis of amino acids and their derivatives is of great significance in organic chemistry and medicinal chemistry.

[0008] Starting from cheap and readily available natural α-amino acids, the current 3 - The synthesis methods of amino acids and their derivatives are mainly reported in the following two routes in domestic and foreign literature:

[0009] The Arndt-Eistert reaction is a homologation of carboxylic acids (addition of a CH 2 ) reaction, the reaction of acyl chloride or mixed anhydride with diazomethane, and then heating with water under the catalysis of silver oxide to obtain a carboxylic acid with an additional carbon. It is a very useful method for the synthesis of carboxylic acid carbon chain growth. The synthesis route is as follows: The only drawback of this synthetic route is that a large amount of diazomethane must be used in the reaction. Diazomethane is an unstable yellow gas at room temperature, and its ether solution is generally used. Diazomethane is very dangerous, easily exploded, and is toxic when inhaled. Sharp tips, metal powders, or scratched glassware may cause diazomethane to explode, and it must be prepared in advance before use.

[0010] Using N-protected α-amino alcohol as the starting material, the hydroxyl group is first activated to obtain a sulfonate, which is then subjected to a nucleophilic substitution reaction with sodium cyanide or potassium cyanide to synthesize a nitrile, and finally hydrolyzed with a strong acid at high temperature to obtain a β-amino alcohol. 3 -Amino acid, the synthesis route is as follows: The method has simple steps and a high total yield, but its disadvantage is also obvious, that is, it requires a large amount of highly toxic sodium cyanide or potassium cyanide, whose oral lethal dose is 1-2 mg / kg. The state has implemented a strict management system for it, and it is illegal to manufacture, sell, transport, and store cyanide without authorization.

[0011] The preparation of β 3 -Although the methods of amino acids have their own characteristics, they still have many shortcomings: such as expensive chiral catalysts, poor stereoselectivity, inconvenient experimental operation, harsh reaction conditions, and lengthy routes leading to low overall yields.

[0012] The ideal synthetic route should meet the standards of green chemistry: such as using renewable resources, being recyclable, using less toxic reagents, and having little environmental pollution after the reaction is processed. In addition, there are also requirements: high overall yield, good stereoselectivity, low cost, simple and convenient separation and purification, and can be used for large-scale preparation. So how to efficiently use cheap and readily available natural compounds to prepare β 3 -Amino acids and their derivatives are issues that need to be addressed urgently. Summary of the invention

[0013] Based on the above content, the present invention provides a β 3 - A method for synthesizing amino acid derivatives. The method of the invention uses cheap and readily available starting materials, thereby increasing the yield of the product.

[0014] To achieve the above object, the present invention provides the following solutions:

[0015] The present invention provides a β 3 - A method for synthesizing an amino acid derivative, comprising the following steps:

[0016] Step 1, synthesis of compound 2:

[0017] a. Dissolve the α-amino acid in methanol, cool in an ice-water bath to below 5°C, add thionyl chloride, heat under reflux, and concentrate under reduced pressure to obtain α-amino acid methyl ester hydrochloride;

[0018] b. dissolving the α-amino acid methyl ester hydrochloride in a tetrahydrofuran / water mixed solvent, adding solid sodium bicarbonate and Boc anhydride to react to obtain an N-Boc protected amino acid methyl ester;

[0019] c. The N-Boc protected amino acid methyl ester was dissolved in anhydrous tetrahydrofuran, cooled to -78 ° C, lithium aluminum tetrahydride was added and allowed to stand for 30 minutes, and the temperature was slowly raised to room temperature to obtain an N-Boc protected amino alcohol;

[0020] d. The N-Boc protected amino alcohol was dissolved in acetonitrile, IBX was added, and the reaction was heated under reflux to obtain compound 2 (N-Boc protected amino aldehyde);

[0021] The structural formula of compound 2 is as follows:

[0022] Step 2, synthesis of compound 4:

[0023] The compound 2 is dissolved in isopropanol, and Wittig reagent and solid potassium carbonate are added to react at room temperature to obtain compound 4;

[0024] The structural formula of the compound 4 is as follows:

[0025] Step 3: Synthesis of compound 5:

[0026] The compound 4 is dissolved in anhydrous dichloromethane, cooled to -78°C, diisobutylaluminum hydride (DIBAL-H) ​​is added, and reacted at -78°C to obtain an intermediate primary alcohol;

[0027] The intermediate primary alcohol is dissolved in acetone, cooled to 0°C, and p-toluenesulfonic acid is added to react to obtain compound 5;

[0028] The structural formula of the compound 5 is as follows:

[0029] Step 4: Synthesis of compound 6:

[0030] The compound 5 was dissolved in a tetrahydrofuran / methanol / water mixed solvent, solid sodium periodate was added, and the reaction was carried out at room temperature to obtain an intermediate N-Boc protected β 3 - amino acids;

[0031] The intermediate N-Boc protected β 3 - The amino acid was dissolved in acetone, solid potassium carbonate and methyl iodide were added, and the mixture was heated under reflux to obtain compound 6;

[0032] The compound 6 is β 3 -Amino acid derivatives, the structural formula is as follows:

[0033] In compounds 1 to 6, R is an alkyl group, a benzyl group, a phenyl group or a heterocyclic ring.

[0034] In a preferred embodiment of the present invention, in step 1, the molar ratio of α-amino acid: dichlorothionyl: sodium bicarbonate: Boc anhydride: lithium aluminum hydroxide: IBX is 1: 2.0-4.0: 3.0-5.0: 1.0-1.05: 1.5-2.0: 1.1-1.5 (further preferably 1.0: 2.0: 3.0: 1.0: 1.5: 1.2).

[0035] The reaction time in step a is 2 h-4 h (more preferably 2 h). After the reaction is completed, the mixture is concentrated under reduced pressure, and the obtained α-amino acid methyl ester hydrochloride is directly used in the next reaction.

[0036] The reaction time in step b is 8h-12h (more preferably 10h). After the reaction is completed, the mixture is concentrated under reduced pressure, extracted with ethyl acetate, the organic phases are combined and washed with saturated brine, separated, the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain N-Boc protected amino acid methyl ester.

[0037] The reaction time in step c is 1 h-3 h (more preferably 1 h). After the reaction is completed, the reaction is slowly quenched with a saturated sodium sulfate aqueous solution at low temperature, concentrated under reduced pressure to remove tetrahydrofuran, 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 N-Boc protected amino alcohol.

[0038] The reaction time in step d is 1 h-2 h (preferably 1 h). After the reaction is completed, the mixture is cooled to room temperature and filtered directly. The residue is washed twice with ethyl acetate. The filtrate is concentrated under reduced pressure and then dried to obtain compound 2. Compound 2 is used directly in the next reaction without further purification.

[0039] In a preferred embodiment of the present invention, in step 2, the molar ratio of compound 2:Wittig reagent:potassium carbonate is 1:1.1-2.0:1.1-2.0 (further preferably 1:1.2:1.2).

[0040] The reaction time in step 2 is 8h-15h (more preferably 12h). After the reaction is completed, it is directly filtered and the filter residue is washed with ethyl acetate. The filtrate is concentrated under reduced pressure and then subjected to rapid column chromatography using petroleum ether: ethyl acetate = 10: 1 (v / v) as the eluent to obtain a colorless oil, namely compound 4.

[0041] In a preferred embodiment of the present invention, in step 3, the molar ratio of compound 4: diisobutylaluminum hydride: p-toluenesulfonic acid is 1: 2.0-3.0: 1.0-1.2 (more preferably 1.0: 2.0: 1.0).

[0042] In step 3, the reaction time for preparing the intermediate primary alcohol is 1h-2h (more preferably 1.5h). After the reaction is completed, the mixture is quenched with a saturated aqueous sodium sulfate solution at -78°C, concentrated under reduced pressure to remove dichloromethane, 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, and dried to obtain the intermediate primary alcohol. It is not further purified and is directly used in the next step.

[0043] When preparing compound 5 in step 3, the reaction time is 1h-1.5h (more 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, namely compound 5.

[0044] In a preferred embodiment of the present invention, the molar ratio of compound 5: sodium periodate: potassium carbonate: methyl iodide is 1.0: 3.0-5.0: 2.0-4.0: 1.5-3.0 (further preferably 1.0: 4.0: 3.0: 1.5).

[0045] 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, 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. It can be used directly in the next reaction without further purification.

[0046] When preparing compound 6 in step 4, the reaction time is 8h-12h (more 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 as the eluent obtains a colorless oil, namely compound 6.

[0047] The present invention discloses the following technical effects:

[0048] 1) The present invention uses natural α-amino acids as starting materials and prepares the final product β-amino acids through nine steps of reaction. 3 -amino acid derivatives; the synthesis method has mild reaction conditions, is green and environmentally friendly, has good stereoselectivity, and has a high overall yield.

[0049] 2) The raw materials and various reagents used in the method of the present invention are cheap and easily available, low in cost, simple in post-processing, and simple and convenient in separation and purification; thus, good conditions are created for the industrial-scale production and commercialization of the product.

[0050] 3) The raw materials and auxiliary materials used in the method of the present invention are non-toxic, the production process is pollution-free, environmentally friendly, and in line with the country's green industry policy. DETAILED DESCRIPTION

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0056] The present invention uses cheap and readily available natural α-amino acids as starting materials, and finally obtains the target product β-amino acid through nine-step transformation. 3 -Amino acid derivative (Compound 6), the general synthesis route is as follows:

[0057]

[0058] The present invention provides a synthetic β 3 - A new method for the preparation of amino acid derivatives, starting from cheap and readily available natural α-amino acids, firstly obtains N-Boc protected aminoaldehyde 2, and then undergoes Wittig reaction with phosphonium salt 3 to obtain compound 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 5. Finally, it is oxidized with sodium periodate to obtain the acid, and then methylated to obtain the target compound 6β 3 -Amino acid derivatives.

[0059] The synthetic route of the method of the present invention 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.

[0060] 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.

[0061] 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.

[0062] The "room temperature" described in the present invention, unless otherwise specified, refers to 20-30°C.

[0063] The present invention prepares β 3 -The synthetic route of amino acid derivatives (compounds 6a to 6k) is as follows:

[0064]

[0065] Example 1: Synthesis of Compound 2a

[0066]

[0067] 1) Dissolve L-norvaline 1a (5 g, 42.7 mmol) in methanol (200 mL), cool to 0°C in an ice-water bath, add thionyl chloride (6.2 mL, 85.4 mmol), heat under reflux for 2 h after 10 minutes of dropwise addition, and concentrate under reduced pressure to obtain L-norvaline methyl ester hydrochloride, which is used directly in the next step.

[0068] 2) The above L-norvaline methyl ester hydrochloride was dissolved in a tetrahydrofuran / water (1:1, 400 mL) mixed solvent, sodium bicarbonate (10.8 g, 128 mmol) was added, and after stirring evenly, Boc anhydride (9.8 mL, 42.7 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 10 h, and the tetrahydrofuran was removed by decompression and concentration, and water (200 mL) was added for dilution, and the mixture was 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 under reduced pressure, and dried in vacuo to obtain N-Boc protected L-norvaline methyl ester. It was directly used in the next step.

[0069] 3) The above N-Boc protected L-norvaline methyl ester was dissolved in anhydrous tetrahydrofuran (250 mL), cooled to -78 ° C, and lithium aluminum tetrahydride (2.5 g, 65 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 1 hour. After the reaction was completed, it was cooled to -78 ° C again, and quenched slowly with saturated sodium sulfate aqueous solution (200 mL), concentrated under reduced pressure, and tetrahydrofuran was removed, and water (200 mL) was added to dilute, and extracted three times with ethyl acetate (300 mL). After the organic phase was combined, it was washed with saturated brine (200 mL), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried in vacuo to obtain N-Boc protected L-norvaline alcohol. It was directly used for the next step reaction.

[0070] 4) The above N-Boc protected L-norvalinol was dissolved in acetonitrile (250 mL), IBX (14.3 g, 51.2 mmol) was added, and the mixture was heated to reflux for 1 h, cooled to room temperature, and filtered directly. The residue was washed twice with ethyl acetate (200 mL), and the filtrate was concentrated under reduced pressure and then dried to obtain N-Boc protected L-norvalinaldehyde (Compound 2a). Compound 2a was used directly in the next step without further purification.

[0071] Example 2: Synthesis of Compound 4a

[0072]

[0073] The crude product compound 2a (42.7 mmol) was dissolved in isopropanol (300 mL), and Wittig reagent 3 (22.8 g, 51.2 mmol) and solid potassium carbonate (7.1 g, 51.2 mmol) were added. The mixture was reacted at room temperature for 12 h, and filtered directly. The filter residue was washed with ethyl acetate (300 mL). The filtrate was concentrated under reduced pressure and then 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 4a 8.0 g, with a five-step yield of 65%.

[0074] 1H NMR (600 MHz, CDCl 3 )δ6.04(d,J=8.8Hz,1H),4.66(s,1H),4.53(s,1H),3.77(s,3H),3.72(s,3H ),1.59–1.47(m,2H),1.42(s,9H),1.37–1.31(m,2H),0.91(t,J=7.3Hz,3H); 13 C NMR (151 MHz, CDCl 3 )δ164.04,154.84,145.96,128.33,79.31,60.16,52.00,46.88,37.36,28.38,18.90,13.77; HR-ESIMS m / z:calculated forC 14 H 25 NO 5 Na + [M+Na] + :310.1625, found 310.1629.

[0075] Example 3: Synthesis of Compound 5a

[0076]

[0077] 1) The above compound 4a (6.0 g, 20.9 mmol) was dissolved in anhydrous dichloromethane (200 mL), cooled to -78 ° C, diisobutylaluminum hydride (DIBAL-H, 1.0 M hexane solution) (42 mL, 42 mmol) was added, and the reaction was carried out at -78 ° C for 1.5 h, quenched with saturated sodium sulfate aqueous solution (200 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 under reduced pressure, and dried in vacuo to obtain the intermediate primary alcohol. It was not further purified and was directly used in the next step.

[0078] 2) The intermediate primary alcohol was dissolved in acetone (300 mL), cooled to 0°C in an ice-water bath, p-toluenesulfonic acid (3.6 g, 20.9 mmol) was added, and the mixture was reacted at 0°C for 1 h. An excess of triethylamine (4 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, namely, compound 5a 3.85 g, with a two-step yield of 75%.

[0079] 1 H NMR (600 MHz, CDCl 3)δ4.74(d,J=6.7Hz,1H),4.23(q,J=19.0Hz,2H),4.01–3.88(m,1H),3.13(s,1H),2.62(s,2H),1 .72(s,1H),1.55–1.46(m,2H),1.41(d,J=11.7Hz,9H),1.38–1.27(m,2H),0.91(t,J=7.3Hz,3H); 13 C NMR (151 MHz, CDCl 3 )δ208.68,155.43,79.56,68.70,47.46,43.60,36.94,28.31,19.36,13.71; HR-ESIMS m / z:calculated for C 12 H 23 NO 4 Na + [M+Na] + :268.1519, found 268.1522.

[0080] Example 4: Synthesis of Compound 6a

[0081]

[0082] 1) Compound 5a (2.0 g, 8.2 mmol) was dissolved in a tetrahydrofuran / methanol / water mixed solvent (1:1:1, 150 mL), solid sodium periodate (7.0 g, 32.8 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 under reduced pressure, and dried in vacuo to obtain an intermediate N-Boc protected β 3 -amino acid. It was used directly in the next reaction without further purification.

[0083] 2) N-Boc protected β 3 -The amino acid was dissolved in acetone (200 mL), potassium carbonate solid (3.4 g, 24.6 mmol) and iodomethane (0.77 mL, 12.3 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 (Compound 6a) 1.7 g, two-step yield 85%.

[0084] 1 H NMR (600 MHz, CDCl 3 )δ4.90(d,J=7.7Hz,1H),3.90(d,J=4.9Hz,1H),3.67(s,3H),2.50(qd,J=15.4,5.3Hz,2 H),1.47(dd,J=12.6,6.1Hz,2H),1.42(s,9H),1.38–1.30(m,2H),0.90(t,J=7.3Hz,3H); 13 C NMR (151 MHz, CDCl 3 )δ172.18,155.36,79.14,51.57,47.34,39.16,36.74,28.35,19.33,13.77; HR-ESIMS m / z:calculated for C 12 H 23 NO 4 Na + [M+Na] + :268.1519, found 268.1524.

[0085] The present invention uses the same steps and methods as Examples 1 to 4 to synthesize the following compounds:

[0086]

[0087] The yield in five steps is 63%. 1 H NMR (600 MHz, CDCl 3 )δ6.04(d,J=9.1Hz,1H),4.75(s,1H),4.50(d,J=6.1Hz,1H),3.78(s,3H),3.72(s,3H),1.57(s,1H),1. 50–1.46(m,1H),1.43(d,J=9.7Hz,9H),1.15–1.07(m,1H),0.91(t,J=7.4Hz,3H),0.87(d,J=6.8Hz,3H); 13 C NMR (151 MHz, CDCl 3 )δ164.03,155.11,146.51,126.07,79.28,60.15,52.03,51.06,39.44,28.39,25.56,14.93,11.54; HR-ESIMS m / z:calculated forC 15 H27 NO 5 Na + [M+Na] + :324.1781, found 324.1785.

[0088]

[0089] The two-step yield was 73%. 1 H NMR (600 MHz, CDCl 3 )δ4.78(d,J=8.3Hz,1H),4.24(dd,J=61.5,18.9Hz,2H),3.89–3.81(m,1H),2.63–2.49(m,2H),1.57(d,J=9.3 Hz,1H),1.46(s,1H),1.40(s,9H),1.09(dt,J=14.6,7.7Hz,1H),0.89(t,J=7.4Hz,3H),0.85(d,J=6.8Hz,3H); 13 C NMR (151 MHz, CDCl 3 )δ209.01,155.52,79.52,77.21,77.00,76.79,68.47,51.73,40.87,38.59,38.44,28.26,25.34,15.33,11.39; HR-ESIMS m / z:calculated for C 13 H 25 NO 4 Na + [M+Na] + :282.1676,found 282.1679.

[0090]

[0091] The two-step yield was 87%. 1 H NMR (600 MHz, CDCl 3 )δ4.88(d,J=8.6Hz,1H),3.83(dd,J=12.2,5.4Hz,1H),3.67(s,3H),2.47(ddd,J=22.4,15.2,5.8Hz,2H),1.60–1.54(m ,1H),1.50(dd,J=15.7,9.3Hz,1H),1.46–1.40(m,9H),1.15–1.07(m,1H),0.90(t,J=7.4Hz,3H),0.86(d,J=6.8Hz,3H);13 C NMR (151 MHz, CDCl 3 )δ172.48,155.42,79.14,77.21,77.00,76.79,51.88,51.68,38.28,36.59,28.36,25.43,15.27,11.44; HR-ESIMS m / z:calculated for C 13 H 25 NO 4 Na + [M+Na] + :282.1676,found 282.1681.

[0092]

[0093] Five-step yield 67% 1 H NMR (600 MHz, CDCl 3 )δ7.32–7.20(m,5H),6.11(d,J=8.6Hz,1H),4.80(d,J=14.6Hz,2H),3.79(s,3H),3.56(s,3H),2.97–2.82(m,2H),1.42(s,9H); 13 C NMR (151 MHz, CDCl 3 )δ199.38,163.81,154.92,146.00,137.02,129.53,129.31,128.41,126.80,126.65,79.51,59.88,52.04,48.30,41.04,28.33; HR-ESIMS m / z:calculated for C 18 H 25 NO 5 Na + [M+Na] + :358.1625, found 358.1630.

[0094]

[0095] The two-step yield was 75%. 1 H NMR (600 MHz, CDCl 3) δ 7.27 (ddd, J = 58.0, 32.0, 6.4 Hz, 5H), 4.96 (d, J = 6.4 Hz, 1H), 4.27–4.12 (m, 3H), 3.14 (s, 1H), 2.98 (dd, J = 12.0, 5.7 Hz, 1H), 2.87–2.81 (m, 1H), 2.61 (d, J = 4.9 Hz, 2H), 1.42 (s, 9H); 13 C NMR (151 MHz, CDCl 3 ) δ 208.71, 155.20, 137.48, 129.18, 128.64, 126.77, 79.68, 68.59, 48.63, 41.63, 40.34, 28.27; HR-ESIMS m / z: calculated for C 16 H 23 NO 4 Na + [M + Na] + : 316.1519, found 316.1525.

[0096]

[0097] The two-step yield is 85%. 1 H NMR (600 MHz, CDCl 3 ) δ 7.33–7.19 (m, 5H), 5.07 (d, J = 6.6 Hz, 1H), 4.18 (s, 1H), 3.71 (s, 3H), 2.96 (dd, J = 12.8, 5.7 Hz, 1H), 2.83 (dd, J = 13.4, 7.8 Hz, 1H), 2.50 (ddd, J = 42.2, 15.9, 5.6 Hz, 2H), 1.43 (s, 9H); 13 C NMR (151 MHz, CDCl 3 ) δ 172.12, 155.11, 137.68, 129.35, 128.49, 126.57, 79.35, 77.21, 77.00, 76.79, 51.67, 48.75, 40.34, 37.50, 28.32; HR-ESIMS m / z: calculated for C 16 H 23 NO 4 Na + [M + Na] + : 316.1519, found 316.1524.

[0098]

[0099] The total yield is 70%. 1 H NMR (400 MHz, CDCl 3 )δ7.64(dd,J=6.2,5.6Hz,4H),7.44–7.35(m,6H),6.21(d,J=8.4Hz,1H),5. 05(s,1H),4.69(s,1H),3.78(s,3H),3.63(s,3H),1.45(s,9H),1.07(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ163.68,155.15,146.20,141.79,135.57,135.52,129.80,127.73,127.70,107.3 4,94.18,79.45,65.84,60.01,51.97,48.87,28.36,26.81,26.53,19.25; HR-ESIMS m / z:calculated forC 28 H 39 NO 6 SiNa + [M+Na] + :536.2439, found 436.2445.

[0100]

[0101] The two-step yield was 72%. 1 H NMR (400 MHz, CDCl 3 )δ7.69–7.50(m,4H),7.44–7.37(m,6H),4.97(s,1H),4.19(s,2H),4.11(s,1H) ,3.71(d,J=4.1Hz,2H),2.68(dt,J=15.9,8.1Hz,2H),1.42(s,9H),1.06(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ208.30,155.07,135.50,132.81,129.96,127.85,79.80,68.44,65.04,48.61,40.01,28.31,26.88,19.26; HR-ESIMS m / z: calculated for C 26 H 37 NO 5 SiNa+ [M+Na] + :494.2333,found494.2339.

[0102]

[0103] The two-step yield was 84%. 1 H NMR (400 MHz, CDCl 3 )δ7.62(d,J=6.9Hz,4H),7.45–7.35(m,6H),5.05(s,1H),4.11(s,1H),3. 70(s,2H),3.64(s,3H),2.64(d,J=4.8Hz,2H),1.43(s,9H),1.06(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ171.90,154.83,135.53,133.01,129.80,127.75,79.29,77.32,77.00,76.68,64.93,51.63,48.85,35.91,28.35,26.83,19.27; HR-ESIMS m / z:calculated for C 26 H 37 NO 5 SiNa + [M+Na] + :494.2333,found494.2338.

[0104]

[0105] The total yield is 62%. 1 H NMR (400 MHz, CDCl 3 )δ7.02(d,J=8.3Hz,2H),6.80(d,J=8.3Hz,2H),6.06(d,J=8.3Hz,1H),4.71(s,2H),3.76(s,3 H),3.55(s,3H),2.80(qd,J=13.6,6.3Hz,2H),1.40(s,9H),1.26–1.19(m,3H),1.09(m,18H); 13 CNMR (101MHz, CDCl 3)δ163.85,154.95,154.84,145.93,130.38,130.15,129.35,127.18,119.82 ,107.74,79.81,59.95,51.98,48.45,40.27,28.35,17.88,12.63; HR-ESIMS m / z:calculated for C 27 H 45 NO 6 SiNa + [M+Na] + :530.2908, found 530.2915.

[0106]

[0107] The two-step yield was 75%. 1 H NMR (400 MHz, CDCl 3 )δ6.98(d,J=8.3Hz,2H),6.80(d,J=8.4Hz,2H),4.85(d,J=15.3Hz,2H),4.14(t,J=12.2Hz,2H),3.10(s,1H),2.86(dd,J=1 3.3, 6.6Hz, 1H), 2.73 (dd, J=13.5, 7.8Hz, 1H), 2.56 (d, J=5.0Hz, 2H), 1.40 (s, 9H), 1.27–1.20 (m, 3H), 1.10–1.05 (m, 18H); 13 C NMR (101 MHz, CDCl 3 )δ208.76,155.25,154.93,130.05,120.07,103.90,79.66,68.56,48.80,41.71,39.56,28.30,17.86,12.61; HR-ESIMS m / z: calculated for C 25 H 43 NO 5 SiNa + [M+Na] + :488.2803,found488.2810.

[0108]

[0109] The two-step yield was 82%. 1 H NMR (400 MHz, CDCl 3)δ7.01(d,J=8.3Hz,2H),6.80(d,J=8.4Hz,2H),4.97(s,1H),4.09(s,1H),3.68(s,3H),2.84(dd,J=13.5,6.2Hz,1H),2.73(dd,J=13.6,7.7Hz,1H),2.45(qd,J=15.8,5.6Hz,2H),1.41(s,9H),1.23(dd,J=14.9,7.1Hz,3H),1.09(d,J=7.2Hz,18H); 13 C NMR(101MHz,CDCl 3 )δ171.83,155.13,154.76,130.20,119.89,79.29,51.62,48.89,39.53,37.55,28.35,17.89,12.64;HR-ESIMS m / z:calculated for C 25 H 43 NO 5 SiNa + [M+Na] + :488.2803,found 488.2812.

[0110]

[0111] The total yield was 64%. 1 H NMR(400MHz,CDCl 3 )δ7.97(d,J=8.2Hz,1H),7.75(d,J=8.3Hz,2H),7.56(d,J=7.7Hz,1H),7.43(s,1H),7.27(ddd,J=24.8,16.1,7.9Hz,4H),6.09(d,J=8.4Hz,1H),4.87(d,J=7.4Hz,2H),3.79(s,3H),3.46(s,3H),3.09–2.88(m,2H),2.34(s,3H),1.44(s,9H); 13 C NMR(101MHz,CDCl 3)δ163.52,154.89,144.76,135.13,135.06,130.88,129.77,126.73,126.29,124.70,124.22 ,123.12,119.69,118.12,113.56,79.66,59.69,52.00,46.94,30.49,28.28,21.46; HR-ESIMS m / z:calculated for C 27 H 32 N 2 O 7 SNa + [M+Na] + :551.1822, found 5510.1829.

[0112]

[0113] The two-step yield was 76%. 1 H NMR (400 MHz, CDCl 3 )δ8.01(d,J=8.2Hz,1H),7.77(d,J=8.3Hz,2H),7.56(d,J=7.8Hz,1H),7.42–7.23(m,5H),4.99(d,J =6.4Hz,1H),4.22–4.11(m,2H),3.09–2.92(m,2H),2.64(d,J=2.5Hz,2H),2.36(s,3H),1.44(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ208.55,155.17,144.92,135.21,135.15,130.64,129.83,126.74,124.93,124.17,123 .32,119.51,118.61,113.74,79.86,68.55,47.18,41.74,29.69,28.25,21.50; HR-ESIMS m / z:calculated for C 25 H 30 N 2 O 6 SNa + [M+Na] + :509.1717, found 509.1721.

[0114]

[0115] The two-step yield was 90%. 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 7.7 Hz, 1H), 7.43 (s, 1H), 7.27 (ddd, J = 24.8, 16.1, 7.9 Hz, 4H), 6.09 (d, J = 8.4 Hz, 1H), 4.87 (d, J = 7.4 Hz, 2H), 3.79 (s, 3H), 3.46 (s, 3H), 3.09–2.88 (m, 2H), 2.34 (s, 3H), 1.44 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ 171.95, 155.11, 144.78, 135.23, 135.18, 130.83, 129.79, 126.74, 124.78, 124.27, 123.24, 119.68, 118.82, 113.69, 79.53, 51.69, 47.25, 37.47, 29.64, 28.29, 21.48; HR-ESIMS m / z: calculated for C 25 H 30 N 2 O 6 SNa + [M + Na] + : 509.1717, found 509.1721.

[0116]

[0117] The total yield was 65%. 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (d, J = 6.4 Hz, 4H), 7.42–7.38 (m, 6H), 6.08 (d, J = 8.7 Hz, 1H), 4.84 (s, 1H), 4.55 (s, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.68 (d, J = 6.3 Hz, 2H), 1.68–1.57 (m, 4H), 1.44 (s, 9H), 1.06 (s, 9H); 13 C NMR (101 MHz, CDCl 3)δ163.93,155.05,145.87,135.47,133.74,129.53,127.57,79.26,63.33,60.06,51.94,46.98,31.42,28.59,28.35,26.81,19.13; HR-ESIMS m / z:calculatedfor C 30 H 43 NO 6 SiNa + [M+Na] + :564.2752,found 564.2759.

[0118]

[0119] The two-step yield was 72%. 1 H NMR (400 MHz, CDCl 3 )δ7.67–7.63(m,4H),7.40(ddd,J=16.6,9.6,4.7Hz,6H),4.85(d,J=7.6Hz,1H),4.22(q,J=19.0Hz,2H),3 .91(s,1H),3.67(s,2H),3.15(s,1H),2.61(d,J=5.4Hz,2H),1.65-1.53(m,4H),1.42(s,9H),1.05(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ208.53,155.43,135.50,133.73,129.61,127.63,79.55,68.67,63.46,63.25,47.59,43.62,31.04,29.03,28.30,26.84,19.15; HR-ESIMS m / z:calculated for C 28 H 41 NO 5 SiNa + [M+Na] + :522.2646, found 522.2651.

[0120]

[0121] The two-step yield was 85%. 1 H NMR (400 MHz, CDCl 3) δ 7.65 (dd, J=7.8, 1.5 Hz, 4H), 7.44–7.35 (m, 6H), 4.95 (d, J=8.3 Hz, 1H), 3.92 (d, J=17.4 Hz, 1H), 3.67 (s, 3H), 3.67–3.58 (m, 2H), 2.51 (d, J=5.3 Hz, 2H), 1.64–1.53 (m, 4H), 1.43 (s, 9H), 1.04 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ 172.06, 155.38, 135.52, 133.84, 129.56, 127.61, 79.20, 63.41, 51.60, 47.54, 39.26, 30.89, 29.13, 28.36, 26.84, 19.18; HR-ESIMS m / z: calculated for C 28 H 41 NO 5 SiNa + [M + Na] + : 522.2646, found 522.2651.

[0122]

[0123] The total yield was 62%. 1 H NMR (400 MHz, CDCl 3 ) δ 6.15 (d, J=8.9 Hz, 1H), 4.98 (d, J=7.0 Hz, 1H), 4.48 (s, 1H), 3.89 (d, J=4.7 Hz, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 1.44 (s, 9H), 1.17 (d, J=6.2 Hz, 3H), 0.88 (s, 9H), 0.02 (d, J=9.2 Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 163.91, 155.56, 145.48, 127.92, 79.37, 70.61, 60.27, 52.39, 51.96, 28.39, 25.76, 20.78, 17.97, -4.50, -5.04; HR-ESIMS m / z: calculated for C 19 H 37 NO 6 SiNa + [M + Na] + : 426.2282, found 426.2286.

[0124]

[0125] The two-step yield was 72%. 1 H NMR (600 MHz, CDCl 3 )δ4.82(d,J=8.8Hz,1H),4.25(dd,J=11.3,4.3Hz,2H),3.95(dd,J=13.9,6.8Hz,2H),3.13(s,1H),2. 61(qd,J=15.4,6.7Hz,2H),1.43(s,9H),1.15(d,J=6.1Hz,3H),0.89(s,9H),0.05(d,J=18.9Hz,6H); 13 C NMR (151 MHz, CDCl 3 )δ208.15,155.78,79.73,69.19,68.42,52.46,41.86,28.32,25.82,20.59,17.98,-4.24,-4.93; HR-ESIMS m / z:calculated for C 17 H 35 NO 5 SiNa + [M+Na] + :384.2177, found 384.2180.

[0126]

[0127] The two-step yield was 88%. 1 H NMR (600 MHz, CDCl 3 )δ4.81(d,J=9.1Hz,1H),3.92(dd,J=14.6,6.7Hz,2H),3.66(s,3H),2.50(d,J=7. 0Hz,2H),1.44(s,9H),1.14(d,J=6.1Hz,3H),0.89(s,9H),0.05(d,J=10.6Hz,6H); 13 C NMR (151 MHz, CDCl 3 )δ171.93,155.64,79.34,68.89,52.83,51.65,37.51,28.35,25.82,20.67,17.97,-4.31,-5.07; HR-ESIMS m / z:calculated for C 17 H 35 NO5 SiNa + [M+Na] + :384.2177, found 384.2180.

[0128]

[0129] The total yield is 66%. 1 H NMR (600 MHz, CDCl 3 )δ7.70–7.64(m,4H),7.45–7.38(m,6H),6.22(d,J=7.9Hz,1H),5.72(s,1H),4.74(dd,J=7.7,4.6Hz,1H), 3.78(s,3H),3.76(s,1H),3.73(s,3H),3.71(s,1H),1.89(s,1H),1.77(s,1H),1.43(s,9H),1.07(s,9H); 13 C NMR (151 MHz, CDCl 3 )δ163.88,155.22,145.40,135.54,133.03,129.86,129.77,129.12,127.79,12 7.74,79.06,61.49,59.99,51.95,46.25,36.05,28.42,26.77,19.03; HR-ESIMS m / z:calculated for C 29 H 41 NO 6 SiNa + [M+Na] + :550.2595,found550.2598.

[0130]

[0131] The two-step yield was 74%. 1 H NMR (600 MHz, CDCl 3) δ 7.69–7.58 (m, 4H), 7.42 (dt, J=28.1, 7.3 Hz, 6H), 5.49 (d, J=6.1 Hz, 1H), 4.20 (t, J=4.3 Hz, 2H), 4.16–4.06 (m, 1H), 3.78–3.69 (m, 2H), 3.11 (t, J=4.2 Hz, 1H), 2.79 (dd, J=15.6, 5.2 Hz, 1H), 2.59 (dd, J=15.6, 6.3 Hz, 1H), 1.85 (d, J=3.9 Hz, 1H), 1.76 (d, J=5.0 Hz, 1H), 1.41 (s, 9H), 1.06 (s, 9H); 13 C NMR (151 MHz, CDCl 3 ) δ 208.43, 155.45, 135.53, 135.51, 133.01, 129.83, 127.78, 79.38, 68.62, 61.29, 46.42, 43.11, 35.76, 28.32, 26.81, 19.03; HR-ESIMS m / z: calculated for C 27 H 39 NO 5 SiNa + [M + Na] + : 508.2490, found 508.2493.

[0132]

[0133] The two-step yield is 86%. 1 H NMR (600 MHz, CDCl 3 ) δ 7.70–7.62 (m, 4H), 7.41 (dt, J=26.8, 7.4 Hz, 6H), 5.44 (d, J=7.3 Hz, 1H), 4.16–4.06 (m, 1H), 3.80–3.75 (m, 1H), 3.70 (dt, J=10.6, 5.2 Hz, 1H), 3.67 (d, J=16.7 Hz, 3H), 2.71 (dd, J=15.4, 4.6 Hz, 1H), 2.53 (dd, J=15.5, 6.7 Hz, 1H), 1.86 (d, J=5.3 Hz, 1H), 1.76 (dd, J=12.8, 5.3 Hz, 1H), 1.42 (s, 9H), 1.05 (s, 9H); 13 C NMR (151 MHz, CDCl 3)δ172.06,155.26,135.54,135.53,133.24,129.71,127.71,79.06,61.30,51.57,46.30,38.85,35.80,28.36,26.79,19.05; HR-ESIMS m / z: calculated for C 27 H 39 NO 5 SiNa + [M+Na] + :508.2490, found 508.2493.

[0134]

[0135] The total yield is 68%. 1 H NMR (600 MHz, CDCl 3 )δ7.65(d,J=7.7Hz,4H),7.42–7.36(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 CNMR (151MHz, CDCl 3 )δ163.98,155.02,145.98,135.54,133.97,129.51,128.18,127.58,79.33,63 .49,60.14,51.99,47.08,34.89,32.15,28.38,26.83,21.95,19.17; HR-ESIMS m / z:calculated for C 31 H 45 NO 6 SiNa + [M+Na] + :578.2908, found 578.2912.

[0136]

[0137] The two-step yield was 72%. 1 H NMR (600 MHz, CDCl 3) δ 7.65 (dt, J = 8.0, 1.4 Hz, 4H), 7.47–7.34 (m, 6H), 4.72 (d, J = 8.1 Hz, 1H), 4.22 (dd, J = 44.0, 19.0 Hz, 2H), 3.90 (d, J = 5.8 Hz, 1H), 3.67–3.62 (m, 2H), 3.11 (s, 1H), 2.59 (d, J = 4.6 Hz, 2H), 1.55 (ddd, J = 8.6, 5.4, 2.5 Hz, 2H), 1.46 (dd, J = 13.7, 5.4 Hz, 4H), 1.43 (d, J = 13.9 Hz, 9H), 1.04 (s, 9H); 13 C NMR (151 MHz, CDCl 3 ) δ 208.60, 155.40, 135.54, 133.92, 129.55, 127.60, 79.56, 68.67, 63.48, 47.65, 43.51, 34.45, 32.05, 28.31, 26.85, 22.49, 19.18; HR-ESIMS m / z: calculated for C 29 H 43 NO 5 SiNa + [M + Na] + : 536.2803, found 536.2806.

[0138]

[0139] The two-step yield is 88%. 1 H NMR (600 MHz, CDCl 3 ) δ 7.65 (dt, J = 8.1, 1.4 Hz, 4H), 7.39 (dt, J = 14.3, 7.0 Hz, 6H), 4.88 (d, J = 8.8 Hz, 1H), 3.88 (s, 1H), 3.67 (s, 3H), 3.64 (t, J = 6.2 Hz, 2H), 2.49 (qd, J = 15.5, 5.2 Hz, 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 (151 MHz, CDCl 3)δ172.16,155.33,135.55,133.99,129.51,127.59,79.17,63.58,51.60,47.56,39.10,34.30,32.19,28.36,26.85,22.47,19.18; HR-ESIMS m / z:calculated for C 29 H 43 NO 5 SiNa + [M+Na] + :536.2803,found 536.2806.

[0140]

[0141] The total yield is 65%. 1 H NMR (600 MHz, CDCl 3 )δ7.15(d,J=8.5Hz,2H),6.85–6.80(m,2H),6.32(d,J=8.5Hz,1H),5.65(s,1H),5.04(s,1H), 3.77(s,3H),3.67(s,3H),1.43(s,9H),1.23(dt,J=14.9,7.5Hz,3H),1.08(d,J=7.4Hz,18H); 13 CNMR (151MHz, CDCl 3 )δ163.95,155.58,154.86,145.72,132.87,127.66,127.42,120.02,79.69,60.04,52.05,50.09,28.35,17.87,12.61; HR-ESIMS m / z:calculated forC 26 H 43 NO 6 SiNa + [M+Na] + :516.2752,found 516.2754.

[0142]

[0143] The two-step yield was 40%. 1 H NMR (600 MHz, CDCl 3) δ 7.15 (d, J = 8.5 Hz, 2H), 6.85–6.80 (m, 2H), 6.32 (d, J = 8.5 Hz, 1H), 5.65 (s, 1H), 5.04 (s, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 1.43 (s, 9H), 1.23 (dt, J = 14.9, 7.5 Hz, 3H), 1.08 (d, J = 7.4 Hz, 18H); 13 C NMR (151 MHz, CDCl 3 ) δ 207.91, 155.64, 155.04, 132.94, 127.25, 120.13, 79.92, 68.81, 50.78, 44.92, 28.27, 17.84, 12.58; HR-ESIMS m / z: calculated for C 24 H 41 NO 5 SiNa + [M + Na] + : 474.2646, found 474.2649.

[0144]

[0145] The two-step yield is 84%. 1 H NMR (600 MHz, CDCl 3 ) δ 7.15 (d, J = 8.5 Hz, 2H), 6.85–6.80 (m, 2H), 6.32 (d, J = 8.5 Hz, 1H), 5.65 (s, 1H), 5.04 (s, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 1.43 (s, 9H), 1.23 (dt, J = 14.9, 7.5 Hz, 3H), 1.08 (d, J = 7.4 Hz, 18H); 13 C NMR (151 MHz, CDCl 3 ) δ 171.43, 155.36, 154.99, 133.10, 127.19, 119.91, 79.57, 51.65, 50.72, 40.91, 28.29, 17.84, 12.58; HR-ESIMS m / z: calculated for C 24 H 41 NO 5 SiNa + [M + Na] + : 474.2646, found 474.2649.

[0146] 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 beta 3 - A method for synthesizing an amino acid derivative, characterized in that The following steps are involved: Step 1, synthesis of compound 2: a. Dissolve the α-amino acid in methanol, cool in an ice-water bath to below 5°C, add thionyl chloride, heat under reflux, and concentrate under reduced pressure to obtain α-amino acid methyl ester hydrochloride; b. dissolving the α-amino acid methyl ester hydrochloride in a tetrahydrofuran / water mixed solvent, adding solid sodium bicarbonate and Boc anhydride to react to obtain an N-Boc protected amino acid methyl ester; c. The N-Boc protected amino acid methyl ester was dissolved in anhydrous tetrahydrofuran, cooled to below -50 ° C, lithium aluminum tetrahydride was added and allowed to stand, and the temperature was raised to room temperature to react to obtain an N-Boc protected amino alcohol; d. dissolving the N-Boc protected amino alcohol in acetonitrile, adding IBX, and heating under reflux to obtain compound 2; The structural formula of compound 2 is as follows: Step 2, synthesis of compound 4: The compound 2 is dissolved in isopropanol, and Wittig reagent and solid potassium carbonate are added to react to obtain compound 4; The structural formula of the compound 4 is as follows: Step 3: Synthesis of compound 5: The compound 4 is dissolved in anhydrous dichloromethane, cooled to -78°C, and diisobutylaluminum hydride is added to react to obtain an intermediate primary alcohol; The intermediate primary alcohol is dissolved in acetone, cooled to 0°C, and p-toluenesulfonic acid is added to react to obtain compound 5; The structural formula of the compound 5 is as follows: Step 4: Synthesis of compound 6: The compound 5 was dissolved in a tetrahydrofuran / methanol / water mixed solvent, solid sodium periodate was added, and the reaction was carried out at room temperature to obtain an intermediate N-Boc protected β 3 - amino acids; The intermediate N-Boc protected β 3 - The amino acid was dissolved in acetone, solid potassium carbonate and methyl iodide were added, and the mixture was heated under reflux to obtain compound 6; The compound 6 is β 3 -Amino acid derivatives, the structural formula is as follows: In compounds 1 to 6, R is an alkyl group, a benzyl group, a phenyl group or a heterocyclic ring.

2. The β according to claim 1 3 - A method for synthesizing an amino acid derivative, characterized in that In step 1, the molar ratio of α-amino acid: thionyl chloride: sodium bicarbonate: Boc anhydride: lithium aluminum tetrahydride: IBX is 1: 2.0-4.0: 3.0-5.0: 1.0-1.05: 1.5-2.0: 1.1-1.

5.

3. The β according to claim 1 3 - A method for synthesizing an amino acid derivative, characterized in that In step 2, the molar ratio of compound 2:Wittig reagent:potassium carbonate is 1:1.1-2.0:1.1-2.

0.

4. The β according to claim 1 3 - A method for synthesizing an amino acid derivative, characterized in that In step 3, the molar ratio of compound 4: diisobutylaluminum hydride: p-toluenesulfonic acid is 1: 2.0-3.0: 1.0-1.

2.

5. The β according to claim 1 3 - A method for synthesizing an amino acid derivative, characterized in that In step 4, the molar ratio of compound 5: sodium periodate: potassium carbonate: methyl iodide is 1.0: 3.0-5.0: 2.0-4.0: 1.5-3.0.

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