WO2011000217A1 - Synthetic method of key intermediate for preparation of camptothecin-like compounds - Google Patents

Abstract

A synthetic method of (S)-4-ethyl-4-hydroxy-1,7-dihydro-4H-pyrano[3,4-c]pyrid-3,8-one, which is a key intermediate for preparation of camptothecin-like compounds, is disclosed. In the method, a nicotinic acid derivative is used as a starting material, and (2R)-1,2-O-isopropylidenedioxo-3-pentanone is used as a chiral inducing agent. The method includes the following steps: performing nucleophilic reaction to the nicotinic acid derivative and (2R)-1,2-O-isopropylidenedioxo-3-pentanone in the presence of a lithium reducing agent, and treating with dilute hydrochloric acid to obtain a lactone compound; reducing the lactone compound into a diol compound; protecting the diol compound; removing the acetonide group to obtain an o-diol compound; oxidizing the resulting compound into an aldehyde; further oxidizing into an acid; removing hydroxyl protecting groups; and performing hydrolysis and tautomerization.

Description

 Key intermediate synthesis method for the preparation of camptothecin compounds

 The present invention relates to camptothecin and an intermediate of 'Wangzhong, relating to (S)-4-ethyl-4-hydroxy-1,7-dihydro-4hydro-pyran[3,4-c]pyridine-3 A new method for the synthesis of 8-ketones belongs to the field of organic synthesis technology.

Background technique

Camptothecin (CPT) is an alkaloid. In 1966, the American scientist Wall was isolated from the Chinese plant, which is a unique species. Camptothecin has significant activity on the rat leukemia L1210 system. Camptothecin is structurally an alkaloid containing a pyridone structure. The specific structure is shown below. Compound 1 :

 The structure contains a pentacyclic structure in which the ring E is a - lactone ring of a water-membered ring, and the lactone ring contains an alpha group having an absolute configuration of S. After the isolation of camptothecin, it has attracted great interest because of its good anti-leukemia L1210 activity.

Subsequently, a series of derivatives of camptothecin have become new anticancer drugs that have been marketed or are in different stages of development due to their unique bioactive mechanisms and good pharmaceutical properties, such as 10-hydroxycamptothecin (Compound 2). , has been widely used in clinical practice in China.

Another example is 10-hydroxy-9-dimethylaminomethylcamptothecin (Compound 3, Topotecan), which was launched in 1996 as a second-line treatment for patients with ovarian cancer. The US FDA approved it as a small cell lung cancer in 1999. (SCLC) second-line treatment drugs.

Further, as Compound 4 (SN-38) has excellent antitumor activity, its water-soluble prodrug, Irinotecan (Compound 5), was marketed in 1994 for the treatment of colorectal cancer.

 Therefore, camptothecin derivatives have formed a large class of very active chemical drugs. However, since many of the camptothecin derivatives are synthesized at the present stage by using camptothecin as a raw material, and the content of camptothecin in the natural plant camptotheca is very low, a commercial production of camptothecin and The process of its derivatives is necessary.

There have been many reports on the total synthesis of camptothecin in the literature. Since the 1970s, hundreds of literatures have published about the total synthesis of camptothecin and its derivatives. The following methods are divided into the following methods: 1) The synthesis method of camptothecin B/C ring is constructed by the free radical series-closed loop reaction of [4+1] (Journal of the American Chemical Society 1992, 114, 5863; Tetrahedron 1997, 53, 8881. ); 2) Synthesis of camptothecin and its derivatives by Friedlander quinoline synthesis (Journal of Medicinal Chemi stry 1986, 29, 1553; Tetrahedron Letters 1989, 30, 2639; Journal of the Chemical Society, Perkin Transactions 1 1990, 27.); 3) Fully synthetic method for constructing D/E loops using intramolecular Michael addition (Angewandte Chemie International Edition 1990, 35, 1692; Tetrahedron 1997, 32, 11049; Targets in Heterocyclic Systems 2000, 4, 25.); 4) Fully synthetic method for constructing D/E ring by intramolecular Michael addition (Tetrahedron Letters 1998, 39, 6745); 5) Synthesis method for constructing B/C ring by intramolecular aza DA reaction (Tetrahedron Letters 1996, 37, 5679; Journal of the American Chemical Society 1998 120, 1218. ); 6) Construction of a full-synthesis strategy for camptothecin D/E rings using the addition reaction of pyridinium salts (Journal of the Chemical Society, Chemical Communications 2000, 2459; The Journal of Organic Chemistry 2002, 67, 7465. ); 7) The complete synthetic route of camptothecin for the D/E ring using pyridine derivatives as raw materials developed by Comin Group (Journal of the American Chemical Society 1992, 114, 10971; Tetrahedron Letters 1994, 30, 5331; The Journal of Organic Chemi stry 1994, 59, 5120). In addition, Glaxo Wel lcome's Fang and colleagues, Bigg group, Murata group, Bowman group, Greene group and other research teams have also repeatedly expressed the full synthesis of camptothecin.

 Although many important advances have been made in the total synthesis of camptothecin, it is regrettable that the process of total synthesis of camptothecin has not yet made a substantial breakthrough. The current synthetic routes generally have the following disadvantages: (1) long synthetic routes; (2) low overall yield; (3) high production costs, many of which are always applied to very expensive reagents such as t-butyl Lithium, such as an expensive chiral induction reagent, induces chiral (-)-8-phenylmenthol, (-)-trans-2-(2-isopropylphenyl)-cyclohexanol, etc.; (4) reaction 2%, ie, the ee value is greater than 99. 6 %, the ee value of the final product is only about 99%. . There is therefore a need for a synthetic method that is highly stereoselective and low in cost.

Summary of the invention

 The object of the present invention is to provide a key intermediate for the preparation of camptothecin compounds with less enthalpy, high yield and high stereoselectivity: (S) -4-ethyl-4-hydroxy-1, 7 - A method for synthesizing dihydro-4 hydrogen-pyran [3, 4_c]pyridine-3, 8-one, and using this intermediate, a camptothecin compound having a complete stereo configuration can be obtained.

The object of the invention is achieved in this way: A key intermediate for the preparation of camptothecin compounds (S)-4-ethyl-4-hydroxy-1,7-dihydro-4hydro-pyran[3,4-c]pyridine-3, A method for synthesizing 8-ketone, characterized in that the intermediate is a nicotinic acid derivative, and (2R)-1, 2-0-isopropylidenedioxy-3-pentanone is used as a chiral induction reagent. , after the following steps:

 a. The intermediate formed by the treatment of the niacin derivative by the lithium reagent is subjected to a nucleophilic reaction with a chiral induction reagent, and then treated with dilute hydrochloric acid to obtain a lactone compound;

 b. reducing the lactone to a diol compound;

 c, protection of the diol compound;

 d, removal of the acetone fork protecting group;

 e, the o-diol compound is oxidized to an aldehyde group;

 f, oxidation of the aldehyde group to an acid;

 g, removal of the alcohol protecting group;

 h, hydrolysis of ether to hydroxyl group, tautomerization to obtain the target (S)-4-ethyl-4-hydroxy-1,7-dihydro-4hydro-pyran [3, 4-c]pyridine- 3, 8_ ketone;

Among them, the nicotinic acid derivative (I) has the following structure:

Wherein R is an alkoxy group or a benzyloxy group.

 The various nucleophilic reactions of the nicotinic acid derivatives are carried out at the 4-position of the pyridine ring.

 The lithium reagent is lithium diisopropylamide (LDA) reagent or lithium 2,2,4,4-tetramethylpiperidine. The reduction of the lactone to a diol compound is carried out using one of the following reduction systems:

a) sodium borohydride, lanthanum chloride and anhydrous ethanol systems; b) lithium aluminum hydride and tetrahydrofuran systems;

c) sodium borohydride, anhydrous lithium chloride and tetrahydrofuran systems;

d) sodium borohydride, hydrazine chloride heptahydrate and anhydrous ethanol system and aluminum isopropoxide and isopropanol systems. The diol compound is protected by using a diol compound to react with one of the following systems: a) a benzyl protecting system;

b) MOM (-CH ₂ 0CH ₃ ) based protection system;

c) Ester-based protection system.

The removal of the acetone fork protecting group is carried out by using a diol compound with one of the following systems: a) an alcohol and a hydrochloric acid system;

b) Acetic acid system.

The oxidation of the o-diol compound to an aldehyde group employs one of the following oxidation systems:

a) sodium periodate, water and polar aprotic solvents (acetonitrile, DMF) systems;

b) Periodic acid, water and ethyl acetate systems.

The oxidation of the aldehyde group to an acid employs one of the following oxidation systems:

a) sodium hypochlorite and NM0 system;

b) sodium hypochlorite and TEMPO systems;

c) sodium chlorite and buffer systems;

d) Sodium chlorite, buffer systems and 2-methyl-2-butene systems.

The removal of the alcohol protecting group is the reaction of the acid with one of the following removal systems:

a) palladium carbon hydrotreating system;

b) Strong acid such as concentrated hydrochloric acid, hydrobromic acid and other heating systems.

Hydrolysis of the ether to a hydroxyl group is carried out by hydrolyzing methyl ether to a hydroxyl group under strong acid conditions, and undergoing tautomerization. To the target (S)-4-ethyl-4-hydroxy-1,7-dihydro-4hydro-pyran[3,4-c]pyridine-3, 8-one. The specific synthetic route of the present invention is as follows (R is selected from 2-methoxynicotinic acid):

i) Chiral induction reagent screening: The chiral induction reagent of the present invention is: (2R)-1, 2-0-isopropylidenedioxy-3-pentanone reagent (Compound 6), which can be used with this chiral reagent. The product of a single configuration is well induced, and the configuration is determined to be the S configuration required by the present invention, making the present invention a breakthrough.

 Compound 6

Ii) 2-methylnicotinic acid (compound (A)) derivative intermediate treated with lithium reagent and chiral induction reagent (2R) -1, 2-0-isopropylidenedioxy-3-pentyl The ketone is subjected to a nucleophilic reaction and treated with dilute hydrochloric acid to obtain a lactone compound (B). The lithium reagent used in the present invention is an organoammonia lithium compound such as lithium diisopropylamide (LDA) reagent or lithium 2,2,4,4-tetramethylpiperidine reagent.

 Iii) In the reduction reaction of the lactone, the diol compound (C) is formed, and the reduction system used for the hydrazine reaction is: (a) sodium borohydride, a ruthenium chloride and an anhydrous ethanol system, and (b) hydrogenation. Lithium aluminum and tetrahydrofuran system, (c) sodium borohydride, anhydrous lithium chloride and tetrahydrofuran system or (d) sodium borohydride, arsenic chloride and anhydrous ethanol system and aluminum isopropoxide and isopropanol system . The obtained diol product (C) can obtain a very pure compound without column chromatography, which simplifies the entire operation.

Iv) In the protection of the diol, benzyl protection, MOM (-CH ₂ 0CH ₃ ) group protection or ester group protection or the like is employed, with a benzyl protecting group being preferred.

 V) In the removal of the acetone fork protecting group, a certain amount of acid is added to the alcohol system, so that the reaction can proceed smoothly, and the obtained product (E) has good purity, high yield, and simplifies the whole. Operation is conducive to mass production.

 Vi) When the oxidized o-diol is an aldehyde-based compound (F), the reaction conditions employed are: sodium periodate oxidation to obtain a product, in which the obtained product is substantially not purified, and the crude product can be directly input into the sputum reaction. In the middle, the operation is greatly simplified and the cost is reduced, which is advantageous for industrialization.

 ϋ) In the oxidation of aldehyde to acid (G) system, the following methods are used: (a) sodium hypochlorite and 匪0 (N-methyl-N-oxidized morpholine) system, (b) sodium hypochlorite and TEMPO (2, 2, 6, 6_tetramethylpiperidine-1 oxygen-free radical system, (c) sodium chlorite and buffer system or (d) sodium chlorite, buffer system and 2-methyl-2-butyl Alkene system. The obtained acid has a high yield and a good purity, and is directly supplied to the lower hydrazine reaction without purification.

 Viii) Deprotection group In the hydrazine reaction, a conventional benzyl removal method such as Pd/C hydrodebenzylation or a strong acid such as concentrated hydrochloric acid or hydrobromic acid is used, and Pd/C is preferred. Hydrodebenzylation gives the lactone compound (H).

Ix ) Hydrolysis of methyl ether to hydroxyl group under strong acid conditions, tautomerization to obtain target (S) -4-B 4--4-hydroxy-1,7-dihydro-4hydro-pyran[3,4-c]pyridine-3,8-one, the product is purified by absolute ethanol to obtain a purity of 99% or more, ee% >99% of target products.

 The invention has the advantages of high yield and high stereoselectivity.

detailed description

 The present invention is described in more detail in the following examples, but the examples are not intended to limit the invention. Example

 a, 1-{(4R)-2,2-dimethyl-[1,3] Dioxolane_4_yl[(1S)-ethyl]-4-methoxy-1H-furan [3 , 4-c] pyridin-3-one

 Under a nitrogen atmosphere, add 500 ml of anhydrous THF, 14.4 ml of 2, 2,6,6-tetramethylpiperidine and 58.5 ml of n-butyllithium (2.5 M in-hexane) solution to a 500 ml three-necked flask, and cool to _70. After the reaction at ° C for a while, 100 ml of a solution containing 5 g of 2-methoxynicotinic acid in anhydrous THF was added thereto, and the reaction was continued for a while, and then 15.0 g of (2R)-1, 2-0- was added dropwise thereto. Isopropyldioxy-3-pentanone was then reacted at room temperature. After completion of the reaction, 100 ml of 2 N diluted hydrochloric acid was added to quench the reaction. After stirring vigorously, the mixture was separated and the aqueous phase was extracted with 60 ml of ethyl acetate. The organic phase was combined, and the organic phase was washed with water and then washed and washed with brine, dried over anhydrous sodium sulfate, and filtered, and then evaporated.

¹匪R (CDC1 ₃ ) (ppm) 8.40( 1H, d), 7.05( 1H, d), 4.17 (1H, m), 4.14(3H, s), 4.04 (2H, m) , 2.22 (1H, m ), 2.06 (1H, m), 1.41 (3H, t), 1.30 (3H, t), 0.66 (3H, t).

 b, (lS)-l-{l-{(4R)-(2,2-dimethyl-[1,3]dioxolan-4-yl)}-l-(3-hydroxymethyl- 2-methoxy-pyridin-4-yl) }-propan-1-ol

At room temperature, 1.3 g of LiAlH _{4 was} dispersed in 40 ml of anhydrous THF, and then a solution of 3.0 g of the upper hydrazine product in 50 ml of THF was slowly added dropwise thereto. After the completion of the dropwise addition, the reaction was continued for 2 hours to stop the reaction, and the reaction system was destroyed with a sodium hydroxide solution. After filtration, the filter cake was washed 3 times with THF, and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration and rotary distillation gave the title product 2.33 g without purification, yield 75%.

3⁄4 NMR (CDC1 ₃ ) (ppm) 8.03 (lH, d), 6.72 (lH, d), 4.92 (2H, m), 4.55 (1H, m), 3.96 (3H, s), 3.73 (IH, t), 3.60 (IH, t), 3.26 (lH, s, br), 3.00 (lH, s), 1.96 (2H, m), 1.69 (3H, t), 1.40 (3H, t), 0.78 (3H, t) .

 c, 4-{ [(IS)-1-benzyloxy]- 1-[(4R)-2,2-dimethyl-[1,3]dioxolan-4-yl]-propyl} -3-benzyloxy-2-methoxy-pyridine

 Under nitrogen protection, in 2.0 ml of anhydrous THF, 2.0 g of crude decanediol and 0.5 g of sodium hydride were reacted at room temperature for a period of time, then 1.5 ml of benzyl bromide was added, and after heating for 1 h, the reaction was stopped and cooled to room temperature. The reaction was quenched by the addition of aq. EtOAc EtOAc. EtOAc. liquid. Yield: 87.5%.

 3⁄4 NMR (CDCI3) (ppm) 8.10 (1H, d), 7.12—7.34 (10H, m) 7.12 (1H, d), 4.88 (lH,d), 4.80 (1H, t), 4.68 (2H, t), 4.88 (lH,d), 4.45 (2H, s), 3.99 (IH, t), 3.96 (3H, s), 3.87 (IH, t), 2.31 (IH, m), 2.20 (IH, m), 1.35 (6H, s), 0.87 (3H, t).

 d, (2R, 3S)-3-benzyloxy-3-(3-benzylmethoxy-2-methoxy-pyridin-4-yl)-pentane-1,2-diol

 At room temperature, 2.5 g of 4-{[(1S)-1-benzyloxy] 1-[(4R) -2, 2_dimethyl-[1,

3] Dioxol-4-yl]-propyl}_3-benzyloxy-2-methoxy-pyridine dissolved in 50 ml of methanol, then added dropwise 6 ml of concentrated hydrochloric acid, continue to react at room temperature for a while, stop After the reaction, the mixture was evaporated to give EtOAc (EtOAc).

3⁄4 NMR (CDCI3) (ppm) 8.09 ( 1H, d), 7.26-7.42 ( 10H, m) 6.88 ( 1H, d), 4.96 (lH,d), 4.74 (1H, d), 4.67 (1H, d), 4.53 (1H, d), 4.44 (lH, d), 4.35 (lH,d), 4.11 (1H, m), 3.99 (1H, s, br), 3.93 (3H, s), 3.54 (1H, m), 3.31 (1H, m), 2.45 (1H, m) , 2.30 (lH, s, br), 2.16 (1H, m), 0.90 (3H, t).

 e, (2S)-Benzyloxy-2-(3-benzylmethoxy-2-methoxy-pyridin-4-yl)-butanal

 0.58g (2R, 3S) -3-benzyloxy-3-(3-benzylmethoxy-2-methoxy-pyridin-4-yl)-pentane-1,2-diol is dissolved in 25ml In a mixed solvent of acetonitrile and 4 ml of water, 0.6 g of sodium periodate was added thereto, and after reacting at room temperature for 2 hours, the reaction was stopped, water was added to the reaction system, and the organic phase was extracted, washed with water, and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate and filtered and evaporated to give a pure product (0.5 g, yield: 93.1%).

¹诵R (CDC1 ₃ ) (ppm) 9.67 (1H, s), 8.16 (1H, d) , 7.23-7.34 (10H, m) 7.12 (lH,d), 4.58 (2H,dd), 4.43 (2H, s), 4.30 (2H, dd), 3.96 (3H, s), 2.25 (2H, m), 0.91 (3H, t).

 f, (2S)-benzyloxy-2-(3-benzylmethoxy-2-methoxy-pyridin-4-yl)-butyric acid at room temperature, 1. lg (2S)-benzyloxy- 2-(3-Benzylmethoxy-2-methoxy-pyridin-4-yl)-butanal, 1.7 g of sodium dihydrogen phosphate, 10 ml of 2-methyl-2-butene dissolved in 30 ml of tert-butanol and 10 ml In a mixed solvent of water, after stirring for a while, add 1.0 g of sodium chlorite, continue the reaction for 2 h, then stop the reaction, adjust the pH to about 2 with dilute hydrochloric acid, extract with dichloromethane, combine the organic phase, wash with water, and saturate the salt. The mixture was washed with water, dried over anhydrous sodium sulfate and filtered and evaporated to give the crude product 1.

3⁄4 NMR (CDC1 ₃ ) (ppm) 8.15 (1H, d), 7.22—7.36 (10H, m) 7.12 (1H, d), 4.70 (2H, dd), 4.45 (2H, dd), 4.40 (2H, s) , 3.96 (3H, s), 2.26 (2H, m), 0.91 (3H, t).

g, (S)-ethyl-4-hydroxy-8-methoxy-1,4-dihydro-pyran[3,4-c]pyridin-3-one upper hydrazine product (2S)-benzyloxy Base-2-(3-benzylmethoxy-2-methoxy-pyridin-4-yl)-butyric acid 1.0 g dissolved in 50 ml of methanol, added 0.2 g of O% Pd / C, hydrogenation reaction at room temperature for 12 h After Filtration, rotary distillation to obtain a crude product, which was obtained by column chromatography to give a pure product of 0.51 g.

 3⁄4 NMR (CDCI3) (ppm) 8.20 (1H, d), 7.16 (1H, d), 5.58 (1H, d), 5.29 (1H, d),

4.10(3H,s), 3.66 (lH,s), 1.80 (2H, m), 0.98 (3H, t).

 h, (S)-4-ethyl-4-hydroxy-1,7-dihydro-4hydro-pyran[3,4-c]pyridine_3, 8-ketone 0.5g (S)-ethyl- 4-Hydroxy-8-methoxy-1,4-dihydro-pyrano[3,4-c]pyridine-3-enone was dispersed in 25 ml of 3N diluted hydrochloric acid, and the mixture was heated to reflux for 3 h, then the reaction was stopped and cooled to room temperature. The solvent was evaporated to give a crude material.

(ee%=99.1%, [a] ²⁵ _d =110.5)

¹匪R (DMSO-D ⁶ ) (ppm) 11.8 (1H, s, br), 7.43 (lH,d), 6.36 (lH,d), 6.25

(1H, s), 5.22 (2H, s), 1.75 (2H, m), 0.80 (3H, t).

 i, (S) -7-(2-bromo-quinolin-3-ylmethyl)-4-ethyl-4-hydroxy-1,7-dihydro-4H-pyran [3, 4-c] Pyridine-3, 8_dione

 (S)-4-Ethyl-4-hydroxy-1,7-dihydro-4-hydrogen-pyrano[3,4-c]pyridine-3, 8-one 0.18g dispersed in 15ml dry at room temperature under nitrogen In DME, a solution of potassium tert-butoxide in THF was added dropwise thereto, and the reaction was continued for 30 min. Then, 0.32 g of 2-bromo-3-methylbromomethylquinoline was added, and the mixture was heated under reflux for 3 h, then the reaction was stopped and cooled to room temperature. Hydrochloric acid adjusted to pH=2, extracted with dichloromethane, combined with organic phase, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. %.

 3⁄4 NMR (CDCI3) (ppm) 8.16 (1H, s), 8.02 (1H, t), 7.99 (1H, d), 7.75 (1H, t), 7.63 (1H, d), 7.58 (1H, q), 6.59 (1H, d), 5.61 (1H, dd),

5.44 (1H, dd), 5.34 (1H, dd), 5.20 (1H, dd), 3.61 (1H, s), 1.80 (2H, m), 0.97 (3H, t)

Claims

Rights request

 1. A key intermediate for the preparation of camptothecin compounds (S)-4-ethyl-4-hydroxy-1,7-dihydro-4hydro-pyrano[3,4-c]pyridine- A method for synthesizing 3, 8-ketone, characterized in that the intermediate is a nicotinic acid derivative and (2R)-1,2-0-isopropylidenedioxy-3-pentanone is a chiral The induction reagent is synthesized by the following steps:

 a. The intermediate formed by the treatment of the niacin derivative by the lithium reagent is subjected to a nucleophilic reaction with a chiral induction reagent, and then treated with dilute hydrochloric acid to obtain a lactone compound;

 b. reducing the lactone to a diol compound;

 c, protection of the diol compound;

 d, removal of the acetone fork protecting group;

 e, the o-diol compound is oxidized to an aldehyde group;

 f, oxidation of the aldehyde group to an acid;

 g, removal of the alcohol protecting group;

 h, hydrolysis of ether to hydroxyl group, tautomerization to obtain the target (S)-4-ethyl-4-hydroxy-1,7-dihydro-4hydro-pyran [3, 4-c]pyridine- 3, 8_ ketone;

Among them, the nicotinic acid derivative (I) has the following structure:

The method of synthesis according to claim 1, wherein the various nucleophilic reactions of the nicotinic acid derivative are carried out at the 4-position of the pyridine ring.

3. The method according to claim 1, wherein the lithium reagent is lithium diisopropylamide (LDA) reagent or lithium 2,2,4,4-tetramethylpiperidine reagent.

The method according to claim 1, wherein the reduction of the lactone to a diol compound is carried out by using one of the following reduction systems:

 a) sodium borohydride, lanthanum chloride and anhydrous ethanol systems;

 b) lithium aluminum hydride and tetrahydrofuran systems;

 c) sodium borohydride, anhydrous lithium chloride and tetrahydrofuran systems;

 d) sodium borohydride, hydrazine chloride heptahydrate and anhydrous ethanol system and aluminum isopropoxide and isopropanol systems.

The method according to claim 1, wherein the diol compound is protected by a diol compound which reacts with one of the following systems:

 a) benzyl protection system;

b) MOM (-CH ₂ 0CH ₃ ) based protection system;

 c) Ester-based protection system.

 6. A method of synthesis according to claim 1 wherein the removal of the acetone fork protecting group is carried out by reacting a diol compound with one of the following systems:

 a) an alcohol and hydrochloric acid system;

 b) Acetic acid system.

 The method according to claim 1, wherein the oxidation of the o-diol compound to an aldehyde group is carried out by using one of the following oxidation systems:

 a) sodium periodate, water and polar aprotic solvents (acetonitrile, DMF) systems;

 b) Periodic acid, water and ethyl acetate systems.

 The method according to claim 1, wherein the oxidation of the aldehyde group to an acid employs an oxidation system as follows:

 a) sodium hypochlorite and NM0 system;

b) sodium hypochlorite and TEMPO systems; c) sodium chlorite and buffer systems;

 d) Sodium chlorite, buffer systems and 2-methyl-2-butene systems.

 9. A method of synthesis according to claim 1 wherein the removal of the alcohol protecting group is an acid reaction with one of the following removal systems:

 a) palladium carbon hydrotreating system;

 b) Strong acid such as concentrated hydrochloric acid, hydrobromic acid and other heating systems.

 10. The method according to claim 1, wherein the hydrolysis of the ether to a hydroxyl group is carried out by hydrolyzing the methyl ether to a hydroxyl group under strong acid conditions, and tautomerizing to obtain the target (S)-4-ethyl- 4-Hydroxy-1,7-dihydro-4hydro-pyran [3,4-c]pyridine-3, 8-one.