Patent Description:
Trabectedin (ecteinascidin-<NUM>), Et-<NUM>) is a marine natural product with an extremely complex structure from the marine tunicate animal mangrove Ecteinascidia turbinata. Since its approval in the EU in <NUM> for the treatment of advanced soft tissue tumors, Trabectedin has achieved hundreds of millions of dollars in sales due to its remarkable efficacy. As the first modern marine drug, the anti-tumor activity of Trabectedin is <NUM>-<NUM> orders of magnitude higher than that of the currently widely used anti-tumor drugs in clinical practice. It is currently considered to be the most effective drug for the treatment of ovarian cancer. Spanish company Zeltia Pharma found that the compound exhibits significant effects on rectal cancer, breast cancer, lung cancer, melanoma, etc.
<CHM>.

Studies found that the highest amount of Trabectedin (Et-<NUM>) extracted from sea squirts is <NUM>%. This makes it hardly possible to directly obtain the compound from nature drug source. Several synthetic routes have been reported, of which mainly are started from sesame phenol or its derivatives. For example, the route developed by Prof. Corey comprises <NUM> steps in total, the yield of which was <NUM>% (<NPL>. ); and the route provided by Prof. Fukuyama comprises <NUM> steps in total, while the yield was <NUM>%. Due to the long route and low total yield, and the poor operability of some steps, the application of these synthetic routes into production is also extremely limited. <CHM>
<CHM>.

Currently, the drug is obtained through semi-synthesis by using cyanosafracin B as a raw material, which is obtained from Pseudomonas fluorescens by fermentation. Even if the method is a semi-synthesis route, it still needs <NUM> steps of reaction and the total yield is only <NUM>%. Such a method for obtaining the compound makes the Trabectedin production very costly.

In summary, there is still a lack of a low-cost, high-efficiency method for preparing Trabectedin in this field.

The object of the present invention is to provide a low-cost, high-efficiency method for preparing Trabectedin.

In the first aspect of the present invention, a method for preparing Et-<NUM> is provided:
<CHM>
wherein it comprises the steps:.

In another preferred example, in the step (a), the reaction is performed in an inert solvent (preferably toluene: DCM: TFE = <NUM>: <NUM>: <NUM>), in the presence of AcOH and 4A MS, and at <NUM> to obtain compound <NUM>.

In another preferred example, in the step (b), the reaction comprises: (<NUM>) conducting a reaction in CH<NUM>CN / THF mixed solvent, and in the presence of HCHO, NaBH<NUM>CN and AcOH, then (<NUM>) conducting a reaction in acetone solvent with allylBr in the presence of K<NUM>CO<NUM> under reflux to compound <NUM>.

In another preferred example, in the step (c), the reaction comprises (<NUM>) after reacting under Swern oxidation conditions, reacting DIPEA with compound <NUM> in DCM, and then with TMSCN to obtain compound <NUM>.

In another preferred example, in the step (d), compound <NUM> with BCl<NUM> in DCM at -<NUM>, and then with TMSCN to obtain compound <NUM>.

In another preferred example, in the step (e), compound <NUM> is subjected to a reaction with (PhSeO)<NUM>O in DCM at -<NUM> to obtain compound <NUM>.

In another preferred embodiment, in the step (f), in the presence of EDCI and DMAP, compound <NUM> is subjected to a reaction with
<CHM>
in dichloromethane to obtain compound <NUM>.

In another preferred example, in the step (g), the reactions are sequentially performed in (<NUM>) DMSO solvent, reacting compound <NUM> with Tf<NUM>O; (<NUM>) reacting with DIPEA at <NUM>; (<NUM>) reacting with tBuOH at <NUM>; (<NUM>) reacting with
<CHM>
at room temperature; and (<NUM>) reacting with Ac<NUM>O at room temperature to obtain compound <NUM>.

In another preferred example, the preparation method includes the following steps:.

Deprotecting the compound <NUM> to obtain compound <NUM>:
<CHM>.

Preferably, the step comprises: in DCM, in the presence of AcOH, reacting Pd(PPh<NUM>)<NUM> and Bu<NUM>SnH with compound <NUM> to obtain compound <NUM>.

In another preferred example, the preparation method further includes the following steps:
Oxidating compound <NUM> to obtain compound <NUM>:
<CHM>.

Preferably, the step includes (<NUM>) reacting compound <NUM> with
<CHM>
at room temperature in DMF, (<NUM>) continously reacting with DBU, and (<NUM>) reacting with oxalic acid to obtain compound <NUM>.

In another preferred example, the preparation method further includes the following steps:
reacting compound <NUM> with compound <NUM> to obtain compound <NUM>:
<CHM>.

Preferably, the step includes (<NUM>) reacting compound <NUM> with compound <NUM> in absolute ethanol in the presence of NaOAc to obtain compound <NUM>.

In another preferred example, the preparation method further includes the following steps:
subjecting compound <NUM> to the following reaction to provide compound <NUM> (Et-<NUM>):
<CHM>.

Preferably, the step includes (<NUM>) reacting compound <NUM> with AgNO<NUM> in an acetonitrile / water mixed solvent to obtain compound <NUM>.

Also disclosed is an intermediate compound of Et-<NUM> which is selected from the group consisting of:
<CHM>
<CHM>
wherein,.

In the forth aspect of the present invention, a method for the preparation of compound of formula <NUM> is provided, wherein the method comprises the steps:
(vi) subjecting compound <NUM> to the following reaction to obtain compound <NUM>:
<CHM>.

The above method may also comprise a method for the preparation of compound of formula <NUM> wherein the method comprises:.

or the method comprises the following steps:.

In another preferred example, in the step (i), the method includes: under blue light, reacting compound <NUM> in an inert solvent (preferably THF) to provide compound <NUM>.

In another preferred example, in the step (ii), the method includes: conducting a reaction with BnBr in the presence of K<NUM>CO<NUM> to obtain compound <NUM>; preferably, the method is carried out at <NUM>-<NUM> in acetone solvent.

In another preferred example, in the step (iii), the method includes: (<NUM>) conducting a reaction in the presence ofNaOH, in MeOH solvent at <NUM>; (<NUM>) in DCM solvent reacting with
<CHM>
in the presence of NEt<NUM>; (<NUM>) in the presence of NEt<NUM>, reacting with AcCl to obtain compound <NUM>.

In another preferred example, in the step (iv), the method includes: (<NUM>) conducting a reaction in the presence of POCl<NUM>, at <NUM> in CH<NUM>CN; (<NUM>) at <NUM>, reacting with NaBH<NUM> to obtain compound <NUM>.

In another preferred example, in the step (v), the method includes: reacting with (Boc)<NUM>O in the presence of NEt<NUM> to obtain compound <NUM>.

In another preferred example, in the step (vi), the method includes: oxidizing compound <NUM> in the presence of Swern oxidant to obtain compound <NUM>.

In another preferred example, in the step (i-a), the method includes: in an inert solvent (preferably DCM / TFE = <NUM>: <NUM>), reacting the compound <NUM> with BnOCH<NUM>CHO to obtain compound <NUM>. Preferably, the method is carried out in the presence of AcOH at <NUM>, and in the presence of 4A molecular sieve.

In another preferred example, in the step (ii-a), the method includes: in an inert solvent (preferably DCM), in the presence of NEt3, reacting Boc<NUM>O with compound <NUM> to obtain compound <NUM>.

In another preferred example, in the step (iii-a), the method includes: in an inert solvent (preferably CH<NUM>CN), reacting the compound <NUM> with Salcomine oxidant and oxygen to obtain the compound <NUM>.

In another preferred example, in the step (iv-a), the method includes: under blue light, reacting compound <NUM> in an inert solvent (preferably THF) to provide compound <NUM>.

In another preferred example, in the step (v-a), the method includes: reacting compound <NUM> in an inert solvent (preferably acetone) at <NUM> to obtain compound <NUM>; and preferably, the reaction was carried out in the presence of BnBr and K<NUM>CO<NUM>.

In another preferred example, the method further comprises a step:
subjecting compound <NUM> to the following reaction to obtain compound <NUM>:
<CHM>.

In another preferred example, the reaction comprises: in CH<NUM>CN, oxidizing compound <NUM> with Salcomine reagent / O<NUM> at room temperature to obtain compound <NUM>.

In another preferred example, the compound <NUM> is prepared by using tyrosine as a raw material.

The above method may also comprise a method for the preparation of compound of formula <NUM> wherein the method includes:
In an inert solvent, under a blue light, subjecting compound <NUM> to a photochemical reaction to obtain the compound <NUM>;
<CHM>.

In another preferred example, the inert solvent is selected from the group consisting of Et<NUM>O, MeCN, toluene, t-BuOH, THF, DMF, acetone, or the combinations thereof.

In another preferred example, the blue light is a light with a wavelength in the range of <NUM>-<NUM>.

The above method may also comprise a method for the preparation of compound of formula <NUM> wherein the method comprises
In an inert solvent, under a blue light, subjecting compound <NUM> to a photochemical reaction to obtain the compound <NUM>;
<CHM>.

The above method may also comprise a method for the preparation of compound of formula <NUM> wherein the method comprises.

In another preferred example, in the step (a), the reaction is performed in the presence of a catalyst (preferably selected from TFA, BF<NUM>·OEt<NUM>, HCOOH, TsOH, AcOH, Yb(OTf)<NUM>), and preferably, the catalyst is AcOH.

In another preferred example, the step (a) is carried out in the presence of 4A molecular sieve.

In another preferred example, the reaction is carried out at <NUM>-<NUM>.

In another preferred example, the reaction is performed in a solvent selected from the group consisting of toluene, DCM, TFE, or the combinations thereof; and preferably, the reaction is performed in DCM: TFE = <NUM>-<NUM>: <NUM> (preferably <NUM>-<NUM>: <NUM>) (v: v) solvent mixture.

In another preferred example, in the step (a), the reaction is carried out at <NUM>-<NUM>.

In another preferred example, the reaction is carried out in toluene: DCM: TFE = <NUM>-<NUM>: <NUM>-<NUM>: <NUM> (v: v: v)) solvent.

In the ninth aspect of the present invention, a method for the preparation of compound <NUM> is provided, wherein the method comprises:
(c) subjecting compound <NUM> to the following reaction to obtain compound <NUM>:
<CHM>.

In another preferred example, in the step (c), the method includes: after the reaction conducted under Swern oxidation condition, the ring is closed in the presence of TFA, DCM, and TMSCN.

The above method may also comprise a method for the preparation of compound <NUM> wherein the method comprises
(g) subjecting compound <NUM> to the following reaction to obtain compound <NUM>:
<CHM>.

In another preferred example, in the step (g), the reaction comprises:
Sequentially reacting compound <NUM> in (<NUM>) Tf<NUM>O, DMSO; (<NUM>) DIPEA, <NUM>; (<NUM>) tBuOH, room temperature; (<NUM>)
<CHM>
, and (<NUM>) Ac<NUM>O, room temperature, thereby obtaining compound <NUM>.

It should be understood that, in the present invention, each of the technical features specifically described above and below (such as those in the Examples) can be combined with each other, thereby constituting new or preferred technical solutions which need not be specified again herein.

After long-term and in-depth research, the present inventors have developed a synthetic method for Trabectedin. The method uses tyrosine as the starting substrate and can complete the synthesis within <NUM> steps of reaction. The raw materials and reagents used are relatively easy to be obtained, and the reaction conditions are relatively mild, thus enabling large-scale preparation. The present invention is completed on this basis.

Currently, the drug is obtained through semi-synthesis by using cyanosafracin B as a raw material, which is obtained from Pseudomonas fluorescens by fermentation. Even if the method is a semi-synthesis route, it still needs <NUM> steps of reaction and the total yield is only <NUM>%. Such way for obtaining the compound makes the Trabectedin production very costly.

The present invention provides a novel synthetic route that uses tyrosine as the starting substrate and natural chiral source, and the five-membered ring is closed through a simple and efficient photocatalytic reaction. The first tetrahydroisoquinoline ring is formed by Bischler-Napieralski reaction, or the first tetrahydroisoquinoline ring is closed by Pictet-Spengler reaction, and then the five-membered ring is closed by a highly efficient photocatalytic reaction. The two fragments are connected by Pictet-Spengler reaction into a closed loop to construct the second tetrahydroisoquinoline ring in the molecular framework. The piperazine ring in the molecular framework structure is closed by intramolecular Strecker reaction to complete the molecule construction of the five-ring skeleton. Afterwards, the product is deprotected, a cysteine side chain is connected through condensation, the ten-membered thiolactone ring is closed, and the last tetrahydroisoquinoline structure was formed by a second Pictet-Spengler reaction, thereby completing the synthesis of the molecule. This route uses a convergent synthesis strategy, starts from the readily available natural chiral source tyrosine, and completes the full synthesis of Et-<NUM> within at minimum <NUM> steps. The raw materials and reagents used in the synthetic route are relatively easy to be obtained, and used reaction conditions are mild, thus enabling large-scale preparation.

According to the new route of the present invention, compounds <NUM> and <NUM> can be synthesized separately from tyrosine, and these two compounds can form key intermediates <NUM> through P-S reaction. Then compound <NUM> was obtained through multiple steps of transformation (all the above steps are new developed synthetic route). Then the compound <NUM> was converted into an reported high-level intermediate through deprotection, and Et-<NUM> was synthesized using the previously reported route. As reported in the known publications, compound <NUM> is synthesized from L-tyrosine in <NUM> steps (<NPL>.

Compound <NUM> is obtained by deprotecting compound <NUM> by hydrogenation.

Compound <NUM> is prepared from compound <NUM> through a multi-step reaction via compounds <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. Structure of each new compound is determined by <NUM>H NMR, <NUM>C NMR, MS structure, and the cis-trans structure of compound <NUM> is determined by Noesy.

The photocatalytic reaction from compound <NUM> to compound <NUM> is a critical and novel reaction, which can complete the conversion that normally require <NUM> steps in one step with good yield and the reaction conditions are simple, thus being suitable for large-scale preparation.

Compound <NUM> can also be prepared according to the following route: preparing compound <NUM> from compound <NUM>, and then compound <NUM> is prepared by compound <NUM>:
<CHM>.

The inventors optimized the conditions for the two photoreactions, in which compound <NUM> is prepared from compound <NUM> and compound <NUM> is prepared from compound <NUM>. The results are as follows:
<CHM>.

Based on the above results, it is found that the preferred light source is blue light. The following solvents are screened: DMF, acetone, acetonitrile, t-butanol, toluene, etc., and the preferred solvent is THF.

The two fragments (compounds <NUM> and <NUM>) are connected through Pictet-Spengler reaction into a closed loop to construct the second tetrahydroisoquinoline ring in the molecular framework. The piperazine ring in the molecular framework structure is closed through intramolecular Strecker reaction to complete the molecule construction of the five-ring skeleton (preparation of compound <NUM> from compound <NUM>). Then compound <NUM> is obtained through deprotection, a cysteine side chain is connected through condensation to obtain compound <NUM>, and the ten-membered thiolactone ring is closed to obtain compound <NUM>:
<CHM>.

According to the method reported in <NPL>), the last tetrahydroisoquinoline structure is connected through Pictet-Spengler reaction to complete the synthesis of Et-<NUM> molecule from compound <NUM>.

In the method of the present invention, a series of intermediate compounds that can be used to prepare Et-<NUM> are obtained:
<CHM>
wherein,.

The preferred intermediate structures are as follows:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

Among them, compound <NUM> can also be synthesized using the following several intermediates with different protecting groups.

The present invention will be further illustrated below with reference to the specific examples. It should be understood that these examples are only to illustrate the invention but not to limit the scope of the invention. The experimental methods with no specific conditions described in the following examples are generally performed under the conventional conditions, or according to the manufacturer's instructions. Unless indicated otherwise, parts and percentage are calculated by weight.

As reported in the known publications, compound <NUM> is synthesised from L-tyrosine in <NUM> steps (<NPL>.

Compound <NUM> (<NUM>, <NUM> mmol) was dissolved in methanol, and <NUM> of <NUM>% Pd / C was weighed in a <NUM> flask. Methanol was injected under the protection of argon into the system, and the atomsphere was exchanged with hydrogen for <NUM> times, the reaction was performed at room temperature for <NUM> hours at <NUM> atm. The point on the TLC plate (DCM: MeOH = <NUM>: <NUM>) showed that the raw material was consumed. Pd / C was filtered off with celite, and the solvent was removed under reduced pressure to obtain <NUM> of compound <NUM>, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CD<NUM>OD) δ <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CD<NUM>OD) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

HRMS (ESI): calcd. for C<NUM>H<NUM>NO<NUM> [M+H]+ <NUM>; found <NUM>.

The atomsphere of raw material <NUM> (<NUM>, <NUM> mmol) was exchanged with oxygen, and the solvent acetonitrile was added under the oxygen atmosphere to dissolve raw material <NUM>. The catalyst salcomine (<NUM>, <NUM> mmol) was added, and the reaction was stirred under an oxygen atmosphere at room temperature. The mixture was black, and the reaction was completed after <NUM>. The black catalyst was removed by filtration through celite, and the solvent was removed under reduced pressure, and purified by flash column chromatography (EA: PE = <NUM>: <NUM>) to obtain <NUM> of bright yellow solid <NUM>, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM>- <NUM> (m, <NUM>), <NUM> (s, <NUM>),<NUM>-<NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>(s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

The yellow compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous THF solvent under the protection of argon, and stirred at room temperature under blue light irradiation. The reaction was completed after <NUM>. The THF solvent was removed under reduced pressure. Flash column chromatography purification (EA: PE = <NUM>: <NUM>) was performed to afford <NUM> of white solid product <NUM> in <NUM>% yield.

The compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of acetone, K<NUM>CO<NUM> (<NUM>, <NUM> mmol) and BnBr (<NUM>, <NUM> mmol) were added, and the reaction was refluxed at <NUM> for two hours. The reaction was completed as determined by TLC, and acetone was distilled off under reduced pressure. Water was added, and extracted three times with ethyl acetate, the combined organic phases was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and flash column chromatography (EA: PE = <NUM>: <NUM>) purification was performed to afford <NUM> of product. Yield <NUM>%.

The compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of methanol, and <NUM> of <NUM> NaOH aqueous solution was added. The cloudy mixture was heated to <NUM> to reflux, and the system gradually turned to clear. The reaction was completed after <NUM> hours, the methanol was distilled off under reduced pressure, and the resulting system was extracted with ethyl acetate. The combined organic phases was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in <NUM> of anhydrous dichloromethane, and NEt<NUM> was added (<NUM>, <NUM> mmol). Benzyloxyacetyl chloride (<NUM>, <NUM> mmol) dissolved in <NUM> of dichloromethane was slowly added dropwise at <NUM> in <NUM> minutes. The reaction was completed and (Ac)<NUM>O (<NUM>, <NUM> mmol) was added and reacted for another <NUM> hours at room temperature. After the reaction was completed, the mixture was extracted with dichloromethane for three times, and the combined organic phases was distilled to remove the solvent under reduced pressure. Flash column chromatography (EA: PE = <NUM>: <NUM>) purification was performed to afford <NUM> of white solid compound <NUM>, two-step yield was <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Under argon protection, the compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous acetonitrile. POCl<NUM> (<NUM>, <NUM> mmol) was added and warmed to <NUM> to reflux for <NUM> hours. After the reaction was completed, saturated NaHCO<NUM> solution was added until the reaction solution was neutral, and extracted with ethyl acetate for three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dried. The obtained crude product was dissolved in <NUM> of anhydrous methanol, and NaBH<NUM> (<NUM>, <NUM> mmol) was added in portions at <NUM> and reacted for <NUM> hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained crude product was used in the next reaction.

Compound 14a: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>).

Compound 14b: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ddd, J= <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

The crude compound <NUM> obtained in the previous step was dissolved in <NUM> of dichloromethane, and (Boc)<NUM>O (<NUM>, <NUM> mmol) and NEt<NUM> (<NUM>, <NUM> mmol) were added. The reaction was stirred at room temperature for <NUM> hours. After the reaction was completed, <NUM> of water was added, extracted with dichloromethane for three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and flash column chromatography (EA: PE = <NUM>: <NUM>) purification was performed to afford <NUM> of colorless oily compound <NUM> with a yield of <NUM>% in three steps.

Compound <NUM>: <MAT> (c = <NUM>, CHCl<NUM>) <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (t, J= <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Compound <NUM>: <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

HRMS (ESI): calcd. for C<NUM>H<NUM>NO<NUM>Na [M+Na]+ <NUM>; found <NUM>.

(COCl)<NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous dichloromethane, and DMSO (<NUM>, <NUM> mmol) dissolved in <NUM> of dichloromethane was slowly added dropwise at -<NUM> under the protection of argon. The reaction was kept at this temperature for <NUM>, then compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of dichloromethane, and slowly added dropwise to the system. The reaction was kept at -<NUM> for another <NUM> hour, and afterwards, DIPEA (<NUM>, <NUM> mmol) was added, and reacted at -<NUM> for <NUM>. After the reaction was completed, <NUM> of saturated ammonium chloride solution was added and extracted for three times with dichloromethane. The combined organic phases was dried with anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and flash column chromatography (EA: PE = <NUM>: <NUM>) purification was performed to obtain <NUM> compound <NUM>, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Under the protection of argon, compound <NUM> (<NUM>, <NUM> mmol) and compound <NUM> (<NUM>, <NUM> mmol), 4A molecular sieve (<NUM>) were mixed and dissolved in <NUM>/<NUM>/<NUM> = toluene: DCM: TFE solvent mixture. AcOH (<NUM>, <NUM> mmol) was added and the reaction was performed overnight at <NUM>. After the reaction was completed, the molecular sieve was removed by filtration through diatomaceous earth. The solvent was distilled off under reduced pressure, and flash column chromatography (EA: PE = <NUM>: <NUM>) purification was performed to afford <NUM> of compound <NUM>, yield <NUM>%.

Compound <NUM>: <MAT> (c = <NUM>, CHCl<NUM>) <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

HRMS (ESI): calcd. for C<NUM>H<NUM>N<NUM>O<NUM> [M+H]+ <NUM>; found <NUM>.

For the above reaction, the inventors conducted conditional screening on the solvent system and the acid, and the screening results are as follows:
Screening for acid and reaction temperature:.

Screening for reaction solvent and acid equivalents:.

The optimal conditions were: the reaction solvent being DCM / TFE = <NUM>: <NUM>, the AcOH equivalent being <NUM> equivalents, and the reaction temperature being <NUM>.

Under argon protection, the compound <NUM> (<NUM>, <NUM> mmol) was dissolved in a mixed solvent of CH<NUM>CN / THF (<NUM>: <NUM>), <NUM>% formaldehyde solution (<NUM>, <NUM> mmol) was added, and the reaction was stirred at room temperature for <NUM> minutes. NaBH<NUM>CN (<NUM>, <NUM> mmol) was added, and the reaction was stirred at room temperature for <NUM> minutes. AcOH (<NUM>, <NUM> mmol) was added, and the reaction was stirred at room temperature for <NUM> minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and saturated sodium bicarbonate was added. The solution was extracted three times with dichloromethane, and the combined organic phases was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was dissolved in <NUM> of acetone, and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) and allyl bromide (<NUM>, <NUM> mmol) were added, and reacted at <NUM> under reflux for <NUM> hours. After the reaction was completed, the acetone solvent was distilled off under reduced pressure. Water was added and resulting system was extracted for three times with dichloromethane. The combined organic phases was dried over anhydrous sodium sulfate. The solution was filtered and the solvent was distilled off under reduced pressure, and flash column chromatography (EA: PE = <NUM>: <NUM>) purification was performed to afford <NUM> of compound <NUM> with a two-step yield of <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s,<NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI): calcd. for C<NUM>H<NUM>N<NUM>O<NUM> [M+H]+ <NUM>; found <NUM>.

(COCl)<NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous dichloromethane, and DMSO (<NUM>, <NUM> mmol) dissolved in <NUM> of dichloromethane was slowly added dropwise under the protection of argon at -<NUM>. The reaction was kept at this temperature for <NUM>, then compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of dichloromethane, and slowly added dropwise to the system. The reaction was kept at -<NUM> for another <NUM> hour, and afterwards, DIPEA (<NUM>, <NUM> mmol) was added, and was reacted at -<NUM> for <NUM>. After the reaction was completed, <NUM> of saturated ammonium chloride solution was added and extracted for three times with dichloromethane. The combined the organic phases was dried over anhydrous sodium sulfate, filterd, and the solvent was distilled off under reduced pressure. The crude product obtained was dissolved in <NUM> DCM / TFA = <NUM>: <NUM> solvent mixture, and stirred to react at room temperature for <NUM> hours. TMSCN (<NUM>, <NUM> mmol) was added, and the reaction was stirred at room temperature for <NUM> hours. Then saturated sodium bicarbonate solution was slowly added, and extracted with dichloromethane for three times. The combined organic phases was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and flash column chromatography (EA / PE = <NUM>: <NUM>) purification was performed to afford <NUM> of compound <NUM> with a two-step yield of <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (ddt, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s,<NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Under argon protection, the compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous dichloromethane, and cooled to -<NUM> ° C. <NUM> BCl<NUM> solution in dichloromethane (<NUM>, <NUM> mmol) was added dropwise, and the temperature was maintained for <NUM> hour. After the reaction is completed, <NUM> of methanol was added to quench the reaction at -<NUM> ° C, the solvent was distilled off under reduced pressure, and saturated sodium bicarbonate solution was added, and extracted three times with dichloromethane. The combined organic phases was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Flash column chromatography (DCM / MeOH = <NUM>: <NUM>) was performed to give <NUM> of compound <NUM> in <NUM>% yield.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (ddd, J= <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (ddt, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (t, J= <NUM>, <NUM>), <NUM> (s,<NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>).

Compound <NUM>: <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Under argon protection, the compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous dichloromethane, and cooled to -<NUM>. (PhSeO)<NUM>O (<NUM>, <NUM> mmol) was dissolved in <NUM> of dichloromethane, slowly added to the reaction system and reacted at -<NUM> for <NUM> minutes. After the reaction was completed, saturated sodium bicarbonate solution was added and extracted three times with dichloromethane. The combined organic phases was dired with anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Flash column chromatography (EA / PE = <NUM>: <NUM>) purification was performed to afford <NUM> of compound <NUM>, yield <NUM>%.

Compound <NUM> isomer <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (ddt, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (ddt, J= <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (ddt, J= <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI): calcd. for C<NUM>H<NUM>N<NUM>O<NUM> [M+H]+ <NUM>; found <NUM>.

Compound <NUM> isomer <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (ddt, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>).

Under argon protection, compound <NUM> (<NUM>, <NUM> mmol), compound <NUM> (<NUM>, <NUM> mmol), EDCI (<NUM>, <NUM> mmol) and DMAP (<NUM>, <NUM> mmol) were mixed and dissolved in <NUM> of anhydrous dichloromethane, and stirred at room temperature for <NUM> hours. After the reaction was completed, saturated ammonium chloride solution was added and extracted for three times with dichloromethane. The combined organic phases was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Flash column chromatography (EA / PE = <NUM>: <NUM>) purification was performed to afford <NUM> of compound <NUM>, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

HRMS (ESI): calcd. for C<NUM>H<NUM>N<NUM>O<NUM>S [M+H]+ <NUM>; found <NUM>.

Under the protection of dry argon, Tf<NUM>O (<NUM>µL, <NUM> mmol) was added to a reaction flask, and DMSO in <NUM> dry methylene chloride (<NUM>µL, <NUM> mmol) was slowly added. The mixture was kept at the temperature for <NUM>, then compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous dichloromethane, and slowly added to the system while the system was maintained at -<NUM> ° C. After the addition was completed, the system was warmed to -<NUM> for <NUM>, then DIPEA (<NUM>µL, <NUM> mmol) was slowly added dropwise. The system was warmed to <NUM> ° C for <NUM>, then tBuOH (<NUM>µL , <NUM> mmol) was added at <NUM> ° C for <NUM>. The mixture was moved to room temperature after the reaction was completed, and (MeN)<NUM>C = N- tBu (<NUM>µL, <NUM> mmol) was added at room temperature for <NUM>. (Ac)<NUM>O (<NUM>µL, <NUM> mmol) was added and stirred at room temperature for <NUM>. After the reaction was completed, saturated ammonium chloride solution was added and extracted for three times with dichloromethane. The combined organic phases was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and flash column chromatography (EA / PE = <NUM>: <NUM>) purification was performed to afford <NUM> of compound <NUM>, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Under argon protection, the compound <NUM> (<NUM>, <NUM> mmol) and Pd (PhPPh<NUM>)<NUM> (<NUM>, <NUM> mmol) were dissolved in <NUM> of dichloromethane. Bu<NUM>SnH (<NUM>, <NUM> mmol) and AcOH (<NUM>, <NUM> mmol) were added and stirred at room temperature for <NUM> hours. After the reaction was completed, saturated sodium bicarbonate solution was added, and extracted three times with dichloromethane. The combined organic phases was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Flash column chromatography (DCM / MeOH = <NUM>: <NUM>) purification was performed to afford <NUM> of compound <NUM>, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI): calcd. for C<NUM>H<NUM>N<NUM>O<NUM>S [M+H]+ <NUM>; found <NUM>.

Under the protection of argon, the compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous DMF. The compound <NUM> (<NUM>, <NUM> mmol) dissolved in <NUM> of DCM was added to the system and stirred at room temperature for <NUM> hours. DBU (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous DCM, and slowly added to the system at <NUM>. At this time, the reaction solution was black. After <NUM> minutes, <NUM> of saturated oxalic acid solution was added at <NUM>, and the reaction was allowed to stand at room temperature for <NUM>. After the reaction was completed, sodium bicarbonate solution was added under <NUM>, and extracted three times with ether. The combined organic phases was dried with anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Flash column chromatography (EA / PE = <NUM>: <NUM>) purification was performed to afford <NUM> of compound <NUM>, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Under the protection of argon, compound <NUM> (<NUM>, <NUM> mmol), compound <NUM> (<NUM>, <NUM> mmol) and NaOAc (<NUM>, <NUM> mmol) were mixed and dissolved in <NUM> of anhydrous ethanol, and the reaction was stirred at room temperature for <NUM> hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and water was added. The mixture was extracted three times with ethyl acetate, and the combined organic phases was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Flash column chromatography (DCM / MeOH = <NUM>: <NUM>) purification was performed to afford <NUM> of compound <NUM>, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Under the protection of argon, the compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of a mixed solvent of acetonitrile and water prepared in proportion. AgNO<NUM> (<NUM>, <NUM> mmol) was added, and the reaction was stirred at room temperature for <NUM>. <NUM> saturated sodium chloride and saturated sodium bicarbonate solution were added respectively, and stirred for <NUM>. The mixture was extracted three times with ethyl acetate, and the combined organic phases was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Flash column chromatography (DCM / MeOH = <NUM>: <NUM>) purification was performed to afford <NUM> of compound <NUM> (Et-<NUM>). Yield <NUM>%.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

HRMS (ESI): calcd. for C<NUM>H<NUM>N<NUM>O<NUM>S [M-OH]+ <NUM>; found <NUM>.

Compound <NUM> can also be synthesized from compound <NUM> according to the following optimized route. Specific operation examples and compound data are as follows:.

Under the protection of argon, the compound <NUM> (<NUM>, <NUM> mmol) was dissolved in a mixed solvent of DCM (<NUM>) and TFE (<NUM>). Benzyloxyacetaldehyde (<NUM>, <NUM> mmol) and 4A MS (<NUM>. <NUM>) were added, and AcOH (<NUM>, <NUM> mmol) was slowly added dropwise at -<NUM>. The reaction was maintained at -<NUM> for <NUM> hours, and then warmed to <NUM> for another <NUM> hours. After the reaction was completed, the molecular sieve was removed by filtration through celite. Saturated sodium bicarbonate solution was added, extracted three times with dichloromethane, and the organic phases was combined. After the solvent was distilled off under reduced pressure, the residue was purified through flash column chromatography (DCM / MeOH = <NUM>: <NUM>) to afford <NUM> of white solid compound <NUM>, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J= <NUM>, <NUM>), <NUM> (t, J= <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI): calcd. for C<NUM>H<NUM>NO<NUM>[M+H]+ <NUM>; found <NUM>.

Under argon protection, the compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous DCM, (Boc)<NUM>O (<NUM>, <NUM> mmol) and NEt<NUM> (<NUM>, <NUM> mmol) were added, and stirred at room temperature for <NUM> hours. After the reaction was completed, <NUM> of water was added, extracted three times with dichloromethane. The combined organic phases was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and flash column chromatography (EA / PE = <NUM>: <NUM>) purification was performed to provide <NUM> of white foam product <NUM>, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM> (s), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM><NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

The compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous acetonitrile, a salcomine catalyst (<NUM>, <NUM> mmol) was added, and the atomsphere was exchanged with oxygen for <NUM> times, so that the reaction was conducted for <NUM> hour under oxygen atmosphere. The black solid catalyst was filtered off after the reaction was completed, and acetonitrile was distilled off under reduced pressure. The target product which appeared yellow on a column was purified through flash column chromatography (EA / PE = <NUM>: <NUM>) to give <NUM> of yellow product <NUM>, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Under argon protection, the compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of anhydrous tetrahydrofuran, and the mixture was stirred at room temperature for <NUM> hours under blue light irradiation. After the reaction was completed, the solvent was distilled off under reduced pressure, and flash column chromatography (EA / PE = <NUM>: <NUM>) purification was performed to afford <NUM> of compound <NUM> as a white foamy solid, yield <NUM>%.

Compound <NUM>: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

The compound <NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of acetone, BnBr (<NUM>, <NUM> mmol) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) were added, and the reaction was refluxed at <NUM> for <NUM> hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was extracted three times with dichloromethane. The combined organic phases was dried over anhydrous sodium sulfate, the solvent was distilled off by rotary evaporation under reduced pressure, and flash column chromatography (EA / PE = <NUM>: <NUM>) purification was performed to afford <NUM> viscous compound <NUM>, yield <NUM>%.

Claim 1:
A method for preparing Et-<NUM>:
<CHM>
wherein the method comprises the steps:
(a) reacting compound <NUM> with compound <NUM> to obtain compound <NUM>:
<CHM>
(b) subjecting compound <NUM> to the following reaction to obtain compound <NUM>:
<CHM>
(c) subjecting compound <NUM> to the following reaction to obtain compound <NUM>:
<CHM>
(d) subjecting compound <NUM> to the following reaction to obtain compound <NUM>:
<CHM>
(e) subjecting compound <NUM> to the following reaction to obtain compound <NUM>:
<CHM>
(f) reacting compound <NUM> with
<CHM>
to obtain compound <NUM>:
<CHM>
(g) subjecting compound <NUM> to the following reaction to obtain compound <NUM>:
<CHM>
and preparing Et-<NUM> from compound <NUM>.