阅读说明：本技术 一种钠离子通道阻滞剂cnv1014802盐酸盐形态的制备方法 (Preparation method of sodium ion channel blocker CNV1014802 hydrochloride form ) 是由 开永平 柴宝红 文兆峰 鲁刚 于 2021-01-20 设计创作，主要内容包括：本发明涉及医药化工领域,具体来说,涉及一种用来抑制钠离子内流的钠离子通道阻滞剂(GSK1014802)CNV1014802盐酸盐的新制备方法,其是一种高选择性的不对称合成方法,通过醛与手性诱导试剂脱水缩合生成席夫碱,然后与锂试剂等进行加成反应,得到高选择性的手性中间体。再通过关环、分步氧化等反应,即可得到目标化合物。较现有报导的合成方法相比,可以实现降低工艺成本、安全性更好、化合物手性纯度更高的效果。(The invention relates to the field of pharmaceutical chemicals, in particular to a novel preparation method of sodium ion channel retarder (GSK1014802) CNV1014802 hydrochloride for inhibiting sodium ion inflow, which is a high-selectivity asymmetric synthesis method, and the high-selectivity chiral intermediate is obtained by dehydrating and condensing aldehyde and a chiral induction reagent to generate Schiff base, and then performing addition reaction with a lithium reagent and the like. And then the target compound can be obtained through reactions such as ring closing, step-by-step oxidation and the like. Compared with the existing reported synthetic method, the method can realize the effects of reducing the process cost, having better safety and higher chiral purity of the compound.)

1. A preparation method of a sodium ion channel agent CNV1014802 hydrochloride form is characterized by comprising the following steps:

1) dissolving alcohol of the compound of formula 1 in a solvent, obtaining aldehyde of the compound of formula 2 through oxidation reaction,

the oxidation reaction is carried out by adopting a PCC oxidant, a Dess-Martin reagent or Stevens oxidation;

2) carrying out dehydration condensation reaction on a compound shown in a formula 2 and a chiral induction reagent under the action of a dehydrating agent to obtain Schiff base of a compound shown in a formula 3, wherein the equivalent ratio of the compound shown in the formula 2 to the dehydrating agent is 1: 1-1: 5; the chiral inducing reagent is (S) -tert-butyl sulfinamide,

3) reacting the compound of formula 4 with the compound of formula 5 under alkaline conditions to produce a compound of formula 6;

4) reacting the compound shown in the formula 6 with butyl lithium or magnesium chips to prepare a lithium reagent or a Grignard reagent, and then performing addition reaction with Schiff base of the compound shown in the formula 3 at low temperature to obtain compounds shown in the formulas 7 and 8;

5) under the action of a metal catalyst and under an alkaline condition, the compound of the formula 8 obtains a compound of a formula 9;

6) the compound of the formula 9 is subjected to acidolysis to obtain a compound of a formula 10;

7) reacting a compound of formula 10 with BOC under basic conditions₂O reaction to obtain the compound of formula 11;

8) the compound in the formula 11 is subjected to oxidation reaction under the action of an oxidant to obtain a compound in a formula 12;

9) reacting the compound of formula 12 under the action of an oxidant to obtain a compound of formula 13;

10) subjecting the compound of formula 13 to a condensation reaction to produce an amide of the compound of formula 14;

11) removing the BOC protecting group from the compound of formula 14 by acidolysis to obtain a compound of formula 15;

2. the preparation method according to claim 1, wherein in step 2), the dehydrating agent is selected from any one of anhydrous copper sulfate/PPTS, isopropyl titanate, ethyl titanate, toluene/PPTS.

3. The method according to claim 1, wherein the equivalent ratio of the compound of formula 4 to the compound of formula 5 in step 3) is 1:1 to 1: 3.

4. The preparation method according to claim 1, wherein in the step 4), the equivalent ratio of the lithium reagent or the Grignard reagent to the Schiff base of the compound of formula 3 is 1: 0.8-1: 1.5, and the DE value of the compound of formula 8 obtained by purification is more than 98%.

5. The method according to claim 1, wherein in the step 5), the metal catalyst is selected from any one of palladium acetate, palladium trifluoroacetate and palladium chloride, and the catalyst is used in an amount of 1 to 15% by mole with respect to the compound of formula 8.

6. The method according to claim 5, wherein in step 5), the base is at least one selected from the group consisting of anhydrous sodium acetate, anhydrous sodium carbonate, anhydrous lithium acetate, and pyridine.

7. The process according to claim 1, wherein in step 6), a solution of hydrogen chloride/1, 4-dioxane or hydrogen chloride/diethyl ether is used for the acid hydrolysis.

8. The method according to claim 1, wherein the base used in the reaction in step 7) is selected from basesSelected from any one of sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine and DMAP, a compound of formula 10 and BOC₂The equivalent ratio of O is 1:1 to 1: 3.

9. The method according to claim 1, wherein in step 8), the oxidizing agent is selected from one of ozone and osmium tetroxide.

10. The method according to claim 1, wherein in step 9), the oxidizing agent is selected from any one of sodium chlorite, potassium permanganate and hydrogen peroxide.

Technical Field

The invention relates to the field of pharmaceutical chemicals, in particular to a novel preparation method of chiral synthesis of sodium ion channel retarder (GSK1014802) CNV1014802 hydrochloride for inhibiting sodium ion inflow.

Background

It is well known that sodium ion channels are the primary initiating bonds for electrical signals in all animal bodies, which are the basis for the control of a series of physiological processes, such as nerve activity and muscle contraction. In humans, there are a total of nine known subtypes of voltage-gated sodium ion channels, which play important roles in different organs and physiological processes. In other words, abnormalities in sodium ion channels can lead to a range of neurological, muscular or cardiovascular related diseases, in particular epilepsy, cardiac arrhythmias and persistent or imperceptible pain. To date, over the years of research, more than one thousand point mutations associated with known diseases have been found in nine sodium channel proteins in humans. Furthermore, it is known that sodium ion channels are also a direct target for many local anesthetics and a number of neurotoxins in nature, such as snake venom, scorpion venom, spider toxins, etc., all of which have adverse consequences due to their action on sodium ion channels. Therefore, there has been much interest in the research on sodium channel blockers.

The sodium ion channel is formed by an internal membrane protein and can allow sodium ions Na⁺Through the cell membrane. In addition, sodium ion channels can be classified into two types, one of which is called a voltage-gated type that starts up according to a change in voltage, depending on the manner of starting up; the other is called ligand-gated, which requires binding to other chemicals (e.g., ligands) before it can be initiated.

The sodium ion channel blocker is a medicine capable of inhibiting sodium ion inflow, thereby inhibiting action potential amplitude and overshoot amplitude of myocardial cells, slowing conduction and prolonging effective refractory period. GSK1014802(CNV1014802) is a novel sodium channel blocker and also a potent anticonvulsant. Studies in rat experiments indicated that: if 20-80 mg/kg of sodium channel blocker (GSK1014802) is orally taken, the reversible learning defect induced by Phencyclidine (PCP) is relieved in a dose-dependent manner, which shows that the GSK1014802 is expected to be used for treating cognitive symptoms of schizophrenia. Although GSK2 is also A potent human MAO-B inhibitor, its pIC50 value was 7.96, but it did not inhibit human MAO-A. GSK2 inhibited MAO-B in rat forebrain with a pKi value of 7.20. While GSK1014802 state-dependently inhibits sodium channels, GSK1014802 selectively acts on the Nav1.7 subtype relative to other Nav subtypes (Nav1.1, Nav1.2, Nav1.3, Nav1.5, Nav1.6 and TTX-R), i.e., GSK-1014802 is a potent inhibitor of the sodium ion channel Nav1.7.

At present, GSK1014802 has been reported to complete a phase II clinical trial for the treatment of lumbosacral radiculopathy, being in phase II clinical trial for the treatment of Trigeminal Neuralgia (TN). In addition, CNV1014802 also received us FDA-granted orphan drug for the treatment of trigeminal neuralgia in 2013.

The GSK1014802 hydrochloride salt form is generally of the formula:

the GSK1014802 synthesis process reported in the literature at present mainly comprises the following two methods:

the method of patent document 1(WO 2008090114a 1):

the method of patent document 2(WO 2007042239 a 1):

as is clear from the synthetic routes of the above patent documents, in both of these processes, catalytic hydrogenation is first required, and the catalyst used is platinum, which is a noble metal. Secondly, in the above synthesis method, after hydrogenation reduction, the DE value of the obtained intermediate is not high, and therefore, when a product with a certain purity is required, column chromatography separation or other chiral separation is still performed subsequently. Therefore, further improvement is urgently needed in view of economy and cost.

Prior art documents

Patent document

Patent document 1: WO 2008090114A1

Patent document 2: WO 2007042239A 1

Disclosure of Invention

The invention provides a new preparation method of sodium ion channel retarder (GSK1014802) CNV1014802 hydrochloride form for solving the existing problems, isomers can be separated by using asymmetric synthesis and a column chromatography method, and the DE value of the intermediate compound of formula 8 is improved to more than 98%. The preparation method avoids catalytic hydrogenation reaction, greatly improves the chiral purity of the compound, and reduces the purification cost. In addition, the preparation method has the advantages of high product yield, good product purity and mild reaction conditions, and is very suitable for large-scale industrial production.

In order to achieve the above object, the present invention provides a preparation method of a sodium channel blocker CNV1014802 hydrochloride form, which comprises the following steps:

(1) synthesis of compounds of formula 2:

the alcohol (4, 5-dienhexanol) of the compound of formula 1 is subjected to the following oxidation reaction to give the aldehyde (4, 5-dienhexanal) of the compound of formula 2.

(chemical formula 1)

The oxidation reaction can be carried out by using a PCC oxidizing agent, a Dess-Martin reagent, Stevens oxidation and the like. Wherein the equivalent ratio of the compound shown in the formula 1 to the oxidant is 1: 1-1: 3; the solvent is more than one of dichloromethane and tetrahydrofuran, and when two solvents are used and mixed, the volume ratio of the dichloromethane to the tetrahydrofuran is 1: 3-1: 20.

The reaction of the above step (1) is preferably:

1) PCC can be used as the oxidant and dichloromethane as the solvent. Reaction conditions are as follows: dissolving the compound shown in the formula 1 in dichloromethane, adding a PCC oxidant in batches, stirring and reacting at room temperature, and detecting the reaction progress by TLC.

2) The compound of formula 1 can be dissolved in dichloromethane/tetrahydrofuran by a schwann oxidation method by using tetrahydrofuran/dichloromethane as a solvent, adding DMSO and oxalyl chloride dropwise, then adding triethylamine dropwise, and detecting the reaction by TLC.

3) Dess-Martin reagent can be used for oxidation, and dichloromethane is used as a solvent. Reaction conditions are as follows: dissolving the compound shown in the formula 1 in dichloromethane, cooling to 0 ℃, adding Dess-Martin oxidant in batches, stirring for reaction at room temperature, and detecting the completion of the reaction by TLC.

The reaction is preferably oxidized by a Dess-Martin reagent, the equivalent ratio of the compound shown in the formula 1 to the oxidant is preferably 1: 1-1: 1.5, the reaction temperature is 0-10 ℃, and the reaction time is 2-3 hours.

(2) Synthesis of compounds of formula 3:

the Schiff base of the compound shown in the formula 3 is obtained by the dehydration condensation reaction of the compound shown in the formula 2 and a chiral inducing reagent under the action of a dehydrating agent, wherein the chiral inducing reagent is (S) -tert-butyl sulfinamide,

(chemical formula 2)

The dehydrating agent in the step (2) can adopt one of anhydrous copper sulfate/PPTS, isopropyl titanate, ethyl titanate and toluene/PPTS; the solvent can be more than one selected from dichloromethane, dichloroethane, tetrahydrofuran and toluene.

The ratio of the compound shown in the formula 2 to the dehydrating agent is 1: 1-1: 5; preferably 1: 1.5-1: 4; further preferably 1:2 to 1: 3;

the ratio of the compound in the formula 2 to the chiral inducer is 1: 1-1: 3; preferably 1:1 to 1: 2.5;

the reaction temperature is 20-70 ℃;

the dehydrating agent for this reaction is preferably anhydrous copper sulfate/PPTS, and the solvent is preferably dichloromethane.

(3) Synthesis of compounds of formula 6:

reacting the compound of formula 4 with the compound of formula 5 (p-bromophenol) under alkaline conditions to produce a compound of formula 6,

(chemical formula 3)

Wherein, in the step (3), the used alkali is selected from one of anhydrous potassium carbonate, anhydrous cesium carbonate, sodium methoxide and potassium tert-butoxide, and the solvent is selected from one of DMF, CAN, acetone, methanol and tetrahydrofuran; the reaction temperature is 0-100 ℃.

In the reaction, the alkali is preferably anhydrous potassium carbonate, and the solvent is preferably acetone;

the equivalent ratio of the compound of the formula 4 to the compound of the formula 5 is 1: 1-1: 3, preferably 1: 1-1: 2;

the reaction temperature is preferably: 40-60 ℃;

(4) synthesis of compounds of formula 7 and 8:

reacting the compound shown in the formula 6 with butyl lithium or magnesium chips to prepare a lithium reagent or a Grignard reagent, reacting at low temperature,

performing addition reaction with Schiff base of the compound of the formula 3 to obtain compounds of the formula 7 and the formula 8,

(chemical formula 4)

In the step (4), the equivalent ratio of the lithium reagent or the Grignard reagent to the Schiff base of the compound of the formula 3 is 1: 0.8-1: 1.5, and the more preferable ratio is 1: 0.8-1: 1.2;

the solvent is selected from more than one of tetrahydrofuran, diethyl ether and toluene;

the low temperature is-90 ℃ to-50 ℃;

the DE value of the compound of the formula 8 reaches more than 98 percent.

(5) Synthesis of a compound of formula 9:

and (3) under the action of alkali and a metal catalyst, the compound of the formula 8 is subjected to reaction to obtain the compound of the formula 9.

(chemical formula 5)

Wherein, in the step (5), the reaction solvent is selected from more than one of toluene, DMSO and tetrahydrofuran;

the metal catalyst used in the reaction is any one of palladium acetate, palladium trifluoroacetate and palladium chloride;

the alkali in the reaction is at least one of anhydrous sodium acetate, anhydrous sodium carbonate, anhydrous lithium acetate and pyridine;

the reaction temperature is 0-100 ℃, and preferably 25-75 ℃;

the amount of the catalyst is 1 to 15 mol%, preferably 2 to 12 mol%, based on the compound of formula 8;

the reaction time is 12-72 hours; the preferable time is 24 to 48 hours.

(6) Synthesis of compounds of formula 10:

the compound of the formula 9 is subjected to acidolysis reaction to obtain the compound of the formula 10, wherein the acidolysis is carried out by using a hydrogen chloride/1, 4-dioxane solution or a hydrogen chloride/diethyl ether solution.

(chemical formula 6)

(7) Synthesis of a compound of formula 11:

reacting a compound of formula 10 with BOC under basic conditions₂And O, obtaining the compound shown in the formula 11.

(chemical formula 7)

In the step (7), the step (c),

the solvent is selected from any one of tetrahydrofuran/water, dichloromethane and isopropanol;

the alkali is selected from any one of sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine and DMAP;

wherein the compound of formula 10 and BOC₂The equivalent ratio of O is 1: 1-1: 3;

the reaction temperature is 0-100 ℃;

in this step, it is preferable that: the solvent is tetrahydrofuran/water (1:1), the alkali is potassium carbonate, and the reaction temperature is 20-70 ℃; more preferably, the reaction temperature is from 35 ℃ to 60 ℃.

(8) Synthesis of a compound of formula 12:

the compound of formula 11 is oxidized under the action of an oxidant to obtain the compound of formula 12.

(chemical formula 8)

The oxidant is selected from one of ozone and osmium tetroxide;

the reaction temperature is-100 ℃ to 25 ℃;

the oxidant in the step is preferably ozone, and the reaction temperature is preferably-90 ℃ to-50 ℃.

(9) Synthesis of a compound of formula 13:

the compound of formula 12 is oxidized by an oxidizing agent to give a compound of formula 13.

(chemical formula 9)

In the step (9), the oxidant is one of sodium chlorite, potassium permanganate and hydrogen peroxide;

the oxidizing agent in this step is preferably sodium chlorite.

(10) Synthesis of a compound of formula 14:

the compound of formula 13 produces an amide of the compound of formula 14 by a condensation reaction.

(chemical formula 10)

In the step (10), the solvent is one selected from tetrahydrofuran, 1, 4-dioxane and N, N-dimethylformamide;

the condensing agent is selected from more than one of 2- (1H-benzotriazol L-1-yl) -1,1,3, 3-tetramethylurea tetrafluoroborate TBTU, 1-hydroxybenzotriazole HOBT and dicyclohexylcarbodiimide DCC;

in this step, the condensing agent is preferably 2- (1H-benzotriazol L-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate TBTU, and the solvent is preferably N, N-dimethylformamide.

(11) Synthesis of a compound of formula 15:

the compound of formula 14 is subjected to acidolysis to remove the BOC protecting group to obtain the compound of formula 15. The acidolysis is carried out in a hydrogen chloride/1, 4-dioxane solution; the DE value of the compound of formula 15 reaches 98.5%.

(chemical formula 11)

The invention obtains the sodium channel retarder CNV1014802 hydrochloride by chiral asymmetric synthesis through the reaction routes of the steps (1) - (11).

In addition, the compound CNV1014802 hydrochloride may be a pharmaceutically acceptable salt, a precursor, or the like for the present invention. It can be administered as a raw chemical or as a composition comprising the CNV1014802 hydrochloride salt form, preferably as an active ingredient in a pharmaceutical preparation.

ADVANTAGEOUS EFFECTS OF INVENTION

According to the invention, the CNV1014802 hydrochloride can be prepared under mild conditions by utilizing asymmetric synthesis and separating isomers of the intermediate compound shown in formula 7 and the intermediate compound shown in formula 8 through a column chromatography method after the addition reaction is finished, and the DE value of the intermediate compound shown in formula 8 is increased to more than 98%, so that the CNV1014802 hydrochloride is a product which is very suitable for industrial production of medicines.

In addition, because the intermediate compound involved in the invention has high optical purity, the chiral purity of the sodium channel blocker CNV1014802 hydrochloride serving as a final product is also high, the DE value reaches 98.5%, and the whole synthesis process is carried out under mild conditions and is easy to operate, so that the production cost can be reduced, and the industrial production is easy.

Drawings

FIG. 1a is an HPLC chromatogram of a mixture of a compound of formula 7 and a compound of formula 8.

FIG. 1b is an HPLC chromatogram of the purified compound of formula 8.

FIG. 2 is a nuclear magnetic hydrogen spectrum H of the compound represented by formula 13¹-NMR。

FIG. 3 is a high performance liquid chromatography HPLC of the compound represented by formula 15 (i.e., CNV1014802 hydrochloride).

FIG. 4 is a nuclear magnetic hydrogen spectrum H of the compound represented by formula 15 (i.e., CNV1014802 hydrochloride)¹-NMR。

Detailed Description

The above summary of the present invention is further illustrated by the following specific examples, which should not be construed as limiting the scope of the present invention in any way. All technical solutions realized based on the above contents of the present invention belong to the scope of the present invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. As is clear to those skilled in the art, the room temperature in the present invention has a technical meaning known in the art, and generally means 20 to 25 ℃ unless otherwise specified; the chemicals are all commercially available.

The various compounds prepared according to the invention are, in the case of chiral separation, purified by known separation methods, for example by preparative HPLC or by chromatography, to give the corresponding isomers after separation.

Examples

Example 1: synthesis of Compound of formula 2

(chemical formula 1)

Dissolving 26 g of (E) -4-hexene-1-alcohol of the compound shown in the formula 1 in 260 ml of dichloromethane in a clean and dried three-neck flask, cooling to 0 ℃, adding 120 g of Dess-Martin oxidant in batches, controlling the temperature to be 0-25 ℃, slowly heating to room temperature after adding, stirring for 1-2 hours, and finishing TLC detection reaction. Filtering, concentrating to obtain crude compound of formula 2 compound aldehyde 40 g, light yellow liquid, without further purification, can directly proceed the next reaction.

Example 2: synthesis of Compounds of formula 3

(chemical formula 2)

And (3) adding the compound of the formula 2, 37.8 g of S-tert-butylsulfinamide and 200 ml of dichloromethane which are the products of the first step into a clean and dried three-neck flask, dissolving, adding 104 g of anhydrous copper sulfate and 1 g of PPTS, heating to 40 ℃, stirring for reaction for 3-4 hours, and detecting the reaction completion by TLC. Filtering, decompressing and concentrating, silica gel column chromatography, decompressing and concentrating to obtain 40 g of the compound in the formula 3, light yellow liquid, the total yield of the two steps is 76.5%.

Example 3: synthesis of Compounds of formula 6

(chemical formula 3)

20 g of p-bromophenol (compound of formula 5) was dissolved in 100 ml of acetone, 24 g of o-fluorobenzyl bromide (compound of formula 4) was added dropwise, heated to 50 ℃ and reacted at that temperature with stirring for 3 to 4 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. To the concentrate was added 250 ml of ethyl acetate to dissolve it, followed by washing with water 2 times, washing with saturated brine 1 time, drying over anhydrous sodium sulfate, and concentrating. Finally, crystallization from ethyl acetate/petroleum ether gave 30 g of the compound of formula 6 as an off-white solid in 84% yield.

Example 4: synthesis of Compounds of formula 8

(chemical formula 4)

Example 4-1:

93 g of the compound shown in the formula 6 is dissolved in 930 ml of anhydrous tetrahydrofuran, the mixture is cooled to-78 ℃ under the protection of nitrogen, 133 ml of 2.5N butyl lithium/N-hexane solution is slowly added dropwise, the temperature is maintained at-78 ℃ after the completion of the cooling, the mixture is stirred for 30 minutes, 60 g of the compound shown in the formula 3 is added dropwise, the mixture is maintained at-78 ℃ after the completion of the cooling, the stirring reaction is carried out for 1 to 2 hours, and the TLC/HPLC detection reaction is completed.

Then quenching the reaction with 10% phosphoric acid aqueous solution, extracting with 1000 ml methyl tert-butyl ether for 2 times, respectively, combining the organic phases, washing with water for 2 times, washing with saturated brine for 1 time, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 130 g of a mixture of the compound of formula 8 and the compound of formula 7 (the content ratio of the compound of formula 8 to the compound of formula 7 is 9: 1). Silica gel column chromatography (eluent is mixed solution of ethyl acetate and petroleum ether) to obtain 66.0 g of compound shown in formula 8, light yellow liquid, yield 54.8%, DE value>98％(Agilent 1100，Zorbax 4.6×75mm C18,210nm,ACN/H₂O/buffer solution: 30% ACN 3.5min to 100% ACN and 100% ACN 3.5min Flow ═ 1.0ml/min), and the chiral purity spectra are shown in fig. 1a and 1 b.

Example 4-2:

dissolving 10 g of a compound shown in the formula 6 in 100 ml of anhydrous tetrahydrofuran, cooling to-78 ℃ under the protection of nitrogen, slowly dropwise adding 14.3 ml of 2.5N butyl lithium/N-hexane solution, maintaining the temperature at-78 ℃ after the completion of the reaction, stirring for 30 minutes, dropwise adding 7.16 g of the obtained compound shown in the formula 3, maintaining the temperature at-78 ℃ after the completion of the reaction, stirring for reacting for 1-2 hours, and detecting the completion of the reaction by TLC/HPLC.

The reaction was then quenched with 10% aqueous phosphoric acid, extracted 2 times with 100 ml of methyl t-butyl ether, respectively, the organic phases were combined, washed 2 times with water, washed 1 time with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 14 g of a mixture of the compound of formula 8 and the compound of formula 7. Silica gel column chromatography (eluent is mixed solution of ethyl acetate and petroleum ether) provides 7.35 g of the compound of formula 8 with the yield of 51.2% (DE value > 98%).

Examples 4 to 3:

dissolving 10 g of the compound shown in the formula 6 in 100 ml of anhydrous tetrahydrofuran, cooling to-78 ℃ under the protection of nitrogen, slowly dropwise adding 14.3 ml of 2.5N butyl lithium/N-hexane solution, maintaining the temperature at-78 ℃ after the completion of the reaction, stirring for 30 minutes, dropwise adding 6.6 g of the compound shown in the formula 3, maintaining the temperature at-50 ℃, stirring for reaction for 1-2 hours, and detecting the completion of the reaction by TLC/HPLC.

Then quenching the reaction with 10% phosphoric acid aqueous solution, extracting with 100 ml methyl tert-butyl ether for 2 times, respectively, combining the organic phases, washing with water for 2 times, washing with saturated brine for 1 time, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 13.5 g of a mixture of the compound of formula 8 and the compound of formula 7 (the content ratio of the compound of formula 8 to the compound of formula 7 is 7: 3). Silica gel column chromatography (eluent is mixed solution of ethyl acetate and petroleum ether) provides 5.6 g of compound of formula 8 with 42.3% yield (DE value > 98%).

Examples 4 to 4:

under the protection of nitrogen, 0.9 g of magnesium chips and 15 ml of anhydrous tetrahydrofuran are placed in a reaction container, 8.38 g of the compound shown in the formula 6 is dissolved in 15 ml of anhydrous tetrahydrofuran, then a little of the mixture is dripped into the reaction container, 0.1 ml of 1, 2-dibromoethane is dripped to initiate reaction, then the tetrahydrofuran solution shown in the formula 6 is dripped continuously and slowly, and the mixture is stirred for 30 minutes for standby after the dripping is finished. Dissolving 5.0 g of the compound of formula 3 in 50 ml of anhydrous tetrahydrofuran in another reaction vessel, cooling to-78 ℃ under the protection of nitrogen, slowly dripping the prepared Grignard reagent into the reaction vessel, keeping the reaction temperature below-50 ℃, continuing stirring for 1-2 hours, and detecting the completion of the reaction by TLC/HPLC.

Then quenching the reaction with ammonium chloride aqueous solution, extracting with 50 ml methyl tert-butyl ether for 2 times, respectively, combining the organic phases, washing with water for 2 times, washing with saturated brine for 1 time, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 12.2 g of a mixture of the compound of formula 8 and the compound of formula 7 (the content ratio of the compound of formula 8 to the compound of formula 7 is 3: 7). Silica gel column chromatography (eluent is mixture of ethyl acetate and petroleum ether) gives 1.6 g of compound of formula 8 in 16% yield (DE > 98%).

Example 5: synthesis of Compounds of formula 9

(chemical formula 5)

66 g of the compound of the formula 8, 5.5 g of palladium trifluoroacetate, 66 g of 3A molecular sieve and DMSO (350 ml) are added into a three-neck flask, oxygen is introduced, and the mixture is stirred, heated to 50 ℃ and reacted for 48 hours. Then 1000 ml of methyl tert-butyl ether was added, and 350 ml of water was added thereto in this order and washed 2 times with saturated saline and 1 time, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 65 g of the compound of formula 9 as a pale yellow liquid. Further purification is not required, and the next reaction can be directly carried out.

Example 6: synthesis of Compounds of formula 10

(chemical formula 6)

Dissolving 65 g of the compound shown in the formula 9 in 300 ml of diethyl ether, adding hydrogen chloride diethyl ether solution at room temperature, stirring for reaction for 1-2 hours, detecting the reaction completion by HPLC, concentrating under reduced pressure, washing for 2-3 times by methyl tert-butyl ether to obtain 45 g of the compound shown in the formula 10 as a white solid, wherein the total yield of the two steps is 82.5%.

Example 7: synthesis of Compounds of formula 11

(chemical formula 7)

Dissolving 45 g of the compound of formula 10 in a mixture of 225 ml of tetrahydrofuran and 225 ml of water, slowly adding 3 equivalents of anhydrous potassium carbonate, adding 1.2 equivalents of BOC₂And O, heating to 50 ℃, and reacting for 2-3 hours. Adding 500 ml methyl tert-butyl ether, layering, washing with 300 ml water for 2 times, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating to obtain 53 g compound of formula 11, white solid, without further purification, and directly performing the next stepShould be used.

Example 8: synthesis of Compounds of formula 12

(chemical formula 8)

Dissolving 22 g of the compound of formula 11 in 1100 ml of methanol, cooling to-78 ℃, and slowly introducing ozone (O)₃) The reaction completion was detected by HPLC and used directly in the next reaction.

Example 9: synthesis of Compounds of formula 13

(chemical formula 9)

132 ml of tert-butyl alcohol, 66 ml of 2-methyl-2-butene, 17.3 g of sodium dihydrogen phosphate and 66 ml of water are added into a reaction vessel, the mixture is cooled to 0 ℃, the compound of the formula 12 is added into the reaction solution, the temperature is controlled to 0 ℃, and 10 g of sodium chlorite is added in batches. The reaction was stirred for 12-24 hours and checked for completion by TLC/HPLC. Concentrating under reduced pressure, adding 250 ml of methyl tert-butyl ether, adjusting pH to 4-5 with 10% phosphoric acid water, layering, washing with water for 2 times, washing with saturated salt water for 1 time, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 18 g of compound of formula 13 as a white solid with a total yield of 78.2% in two steps. H¹-NMR (400MHz, DMSO- δ 6) δ 12.563(s,1H)7.517-7.554(m,1H)7.401-7.458(m,3H)7.187-7.224(m,2H)6.934-6.953(m,2H)5.099-5.111(d,2H)4.619-4.804(m,1H)4.174-4.229(m,1H)2.136-2.259(m,2H)1.688-1.891(m, 2H); 1.054-1.328(d,9H), nuclear magnetism H thereof¹NMR is shown in FIG. 2.

Example 10: synthesis of Compounds of formula 14

(chemical formula 10)

To a reaction vessel were added 17 g of the compound of formula 13, 170 ml of DMF, 10.6 g of N, N-diisopropylethylamine, and 14.5 g of TBTU, and the mixture was stirred at room temperature for 30 minutes. 9.9 g of hexamethyldisilazane was added dropwise, the reaction was stirred for 2 hours, and the completion of the reaction was checked by TLC/HPLC. Then 500 ml of methyl tert-butyl ether and 200 ml of saturated aqueous sodium bicarbonate solution were added to the mixture to separate layers. Washing the organic phase with water for 2 times, washing with salt water for 1 time, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain 17 g of crude product, recrystallizing to obtain 14 g of pure compound of formula 14 as off-white solid with yield of 82.5%.

Example 11: synthesis of Compounds of formula 15

(chemical formula 11)

To 13 g of the compound of formula 14 was added a hydrogen chloride/ether solution, the reaction was stirred for 3 to 5 hours and the reaction was completed as detected by HPLC. Concentrating under reduced pressure, adding 100 ml methyl tert-butyl ether, stirring, filtering to obtain compound of formula 15 9.5 g with yield 86.4%, and determining chiral purity DE value>98.5% and 99.23% chemical purity HPLC (Agilent 1100, Zorbax 4.6X 75mm C18,210nm, ACN/H)₂O/buffer solution: 0% ACN 3.5min to 100% ACN and 100% ACN 3.5min Flow ═ 1.0 ml/min). H¹NMR (400MHz, DMSO-. delta.6) delta. 10.672(s,1H)8.079(s,2H)7.731(s,1H)7.543-7.581(m,1H)7.408-7.500(m,3H)7.226-7.285(m,2H)7.090-7.112(d,2H)5.177(s,1H)4.611(s,1H)4.316(s,1H)2.257-2.504(m,2H)2.135-2.172(m,1H)2.006-2.053(m, 1H). Its high performance liquid chromatography and nuclear magnetic H¹The results of NMR measurements are shown in FIGS. 3 and 4, respectively.

It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is intended to include such modifications and variations. The foregoing examples or embodiments are merely illustrative of the present invention, which may be embodied in other specific forms or in other specific forms without departing from the spirit or essential characteristics thereof. The described embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. The scope of the invention should be indicated by the appended claims, and any changes that are equivalent to the intent and scope of the claims should be construed to be included therein.