CN104558008A - Method for synthesizing paricalcitol intermediate - Google Patents

Abstract

The invention provides a method for synthesizing a paricalcitol intermediate, which comprises the following steps: (1) reacting methyl triphenyl phosphorus iodide with alkali, and adding a compound to initiate Wittig reaction, thereby obtaining a compound II; (2) carrying out alkene double decomposition reaction on the compound II and a compound III under the catalytic action of a ruthenium-containing catalyst to obtain a compound IV; (3) selectively removing triethyl silyl protecting group from the compound IV under the catalytic action of Lewis acid to obtain a compound V; and (4) oxidizing the compound V with an oxidizer to obtain the intermediate VI for synthesizing paricalcitol. The method has the advantages of simple preparation process, fewer reaction steps, higher total yield and favorable stereoselectivity of double decomposition reaction for alkene, can obtain a single-configuration product of which the side chain is trans double bond, and simplifies the purification process of the product.

Description

A kind of method for the intermediate of synthetic paricalcitol

technical field

The present invention relates to a kind of synthetic method of compound, particularly a kind of synthetic method about the intermediate of paricalcitol, and its structure is as shown in formula 1 below:

technical background

Secondary hyperthyroidism (SHPT) is a serious complication in patients with end-stage renal disease, which can lead to cardiovascular disease and increase mortality. Paricalcitol is a new vitamin D analogue, which can inhibit the synthesis of parathyroid hormone and prevent hyperplasia of parathyroid glands. It has little effect on bone and intestinal tract, and does not increase blood calcium and phosphorus levels. At present, Paricalcitol has become the most widely used drug for the prevention and treatment of SHPT in clinical practice. It has shown good preventive and therapeutic effects on SHPT in patients with stage III and IV chronic kidney disease before dialysis and transplantation. .

Paricalcitol is mainly prepared by multi-step chemical synthesis, one of the important preparation methods is to use the intermediate of Paricalcitol and the sulfone compound to undergo Julia-Lythgoe coupling, and then remove the protecting group to prepare Well, its synthetic route is:

The methods for the preparation of such paricalcitol intermediates reported so far mainly include the following. These methods all use vitamin D2 as the starting material, undergo several steps of transformation to obtain the five- and six-membered ring skeleton, and then use different strategies to construct the most critical and most difficult trans double bond in the side chain, and finally remove the protection. base, oxidation, to obtain intermediates of such paricalcitol:

Method 1: In method 1, the author introduced a trans double bond in the side chain through the _SN 2' reaction (The Journal of Organic Chemistry, 1986, 51, 1264-1269). This is the first report on the preparation of a synthetic intermediate of paricalcitol.

However, the steps of this method are cumbersome, requiring 6 steps of reaction to complete the establishment of the trans double bond, and the cost is relatively high.

Method 2: Method 2 is an improvement to Method 1 (The Journal of Organic Chemistry, 1997, 62, 6344-6352).

Compared with method 1, although the reaction steps of method 2 are shortened to some extent, it still takes 3 steps to obtain the side chain containing trans double bond, and because the stereoselectivity of the first step nucleophilic addition reaction is not high, resulting in The overall yield of this method is low.

Method 3: Method 3 uses 6-step reactions such as 1,3-dipolar cycloaddition, reduction, and Hoffman elimination to construct the required side chain (The Journal of Organic Chemistry, 1986, 51, 3098-3108 ).

This method simultaneously introduces a trans double bond and a 25-position hydroxyl group, but the synthetic route is relatively long, the stereoselectivity of the 1,3-dipolar cycloaddition reaction is not good, and the product is not easy to purify.

Method 4: Method 4 uses the Julia-Lythgoe reaction to create the desired trans double bond (ES 2380477A).

The operation of this method is relatively simple, but the stereoselectivity of the Julia-Lythgoe reaction is poor, and the atom economy is not high.

Contents of the invention

In order to overcome the shortcomings of the existing preparation methods, the invention provides a method for synthesizing an intermediate of paricalcitol with convenient and easy-to-obtain raw materials, simple operation, few reaction steps and high stereoselectivity.

The technical solution adopted by the present invention to realize the above object is that the synthetic route of the method is:

Concretely comprise following reaction steps:

(1) Preparation of compound II

Dissolve methyltriphenylphosphine iodide in the first solvent and react with a strong base at a molar ratio of 1:0.8-1.2 for 15-60 minutes at a temperature of -78°C to 15°C, and add compound I to cause a Wittig reaction 0.5~10h, the molar ratio of compound I to methyltriphenylphosphine iodide is 1:1~2, and purified to obtain compound II;

(2) Synthesis of compound IV

Compound II and compound III are mixed according to the molar ratio of 1:1.2~3 and then dissolved in the second solvent, and olefin metathesis reaction occurs under the catalysis of ruthenium-containing catalyst under the temperature condition of 60°C-150°C, and compound II and ruthenium-containing catalyst The molar ratio is 1:0.02-0.2, the reaction time is 15-48 hours, and purified to obtain compound IV;

(3) Synthesis of Compound V

The compound IV is dissolved in the third solvent, and the triethylsilyl protecting group is catalyzed by a Lewis acid at a temperature of -20°C to 55°C, and the catalytic time is 3 to 24 hours. The molar ratio of the compound IV to the Lewis acid 1:0.005～0.15, purified to obtain compound V;

(4) Synthesis of the synthetic intermediate VI of Paricalcitol

Dissolve compound V in the fourth solvent, add hypervalent chromium or hypervalent iodine oxidizing agent, and oxidize compound V at a temperature of -10°C to 50°C for 2 to 24 hours, the mole of compound V and hypervalent chromium or hypervalent iodine oxidizing agent Ratio is 1:1～3, purify, obtain the synthetic intermediate VI of Paricalcitol;

The above-mentioned first solvent is tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether or dioxane;

The above-mentioned second solvent is dichloromethane, 1,2-dichloroethane, benzene or toluene;

The above-mentioned third solvent is methanol, ethanol, acetonitrile, water or a mixture thereof in any proportion;

The above-mentioned fourth solvent is dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide or dimethyl sulfoxide.

Further, in step (1), it is preferred to dissolve methyltriphenylphosphine iodide in the first solvent and the strong base at a molar ratio of 1:0.9 to 1 at a temperature of -20°C to 0°C under nitrogen protection conditions. React for 20 to 60 minutes, add compound I to cause Wittig reaction for 0.5 to 5 hours, the molar ratio of compound I to methyltriphenylphosphine iodide is 1:1 to 1.5, add saturated ammonium chloride solution to the reaction solution to quench After reaction, petroleum ether was added for extraction, the organic layer was dried with magnesium sulfate, all solvents were evaporated under reduced pressure, and the residue was purified by column chromatography to obtain compound II. The strong base used can be selected from n-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide or potassium bistrimethylsilylamide.

Further, in step (2), it is preferable to mix compound II and compound III according to the molar ratio of 1:1.5~2 under the protection of nitrogen, and then dissolve them in the second solvent under the condition of 90°C~120°C under the catalysis of a ruthenium-containing catalyst. Olefin metathesis reaction, the molar ratio of compound II to the ruthenium-containing catalyst is 1:0.05-0.1, the reaction time is 24-36 hours, filtered through diatomaceous earth, and all solvents are evaporated under reduced pressure, and the residue is purified by column chromatography. Compound IV is obtained.

The ruthenium-containing catalyst in the above step (2) can be selected from first-generation Grubbs catalyst, second-generation Grubbs catalyst, first-generation Hoveyda-Grubbs catalyst or second-generation Hoveyda-Grubbs catalyst.

Further, preferably in step (3), the compound IV is dissolved in a third solvent at a temperature of 0°C to 40°C to catalyze the removal of the triethylsilyl protecting group with a Lewis acid, and the catalytic time is 5 to 24 hours, and the compound The molar ratio of IV to Lewis acid is 1:0.005-0.1, filtered through basic alumina, and all solvents are evaporated under reduced pressure, and the residue is purified by column chromatography to obtain compound V.

The above-mentioned Lewis acid is sodium tetrachloroaurate dihydrate, indium trichloride, ferric chloride or scandium trifluoromethanesulfonate.

Further, preferably in the above step (4), compound V is dissolved in the fourth solvent, and a hypervalent chromium or hypervalent iodine oxidant is added to oxidize compound V at a temperature of 0° C. to 35° C. for 3.5 to 15 hours. The molar ratio is 1:1~2, filtered through diatomaceous earth, all the solvents are evaporated under reduced pressure, and the residue is purified by column chromatography to obtain the synthetic intermediate VI of Paricalcitol.

The above-mentioned hypervalent chromium oxidizing agent can be pyridinium chlorochromate or pyridinium dichromate, and the hypervalent iodine oxidizing agent can be selected from 2-iodylbenzoic acid or (1,1,1-triacetoxy)-1,1-dihydro -1,2-Phenyliodyl-3(1H)-one.

The method for synthesizing the intermediate of Paricalcitol in the present invention is to utilize iodide methyltriphenylphosphine to react with an alkali, and then add compound I prepared by a known method from cheap natural vitamin D2 to undergo a Wittig reaction to obtain Compound II, Compound II and Compound III, which is conveniently prepared by commercial reagents, undergo olefin metathesis reaction under the catalysis of a ruthenium-containing catalyst, stereospecifically obtain Compound IV with a trans double bond in the side chain, and obtain Compound IV in Lewis Under the catalysis of acid, the triethylsilyl protecting group is selectively removed to obtain compound V, and the compound V is oxidized with an oxidizing agent to obtain the synthetic intermediate VI of paricalcitol, which is based on the convenient and easy-to-obtain compound I and Compound III, as a starting material, provides a method for preparing an intermediate of Paricalcitol with simple operation, few reaction steps and high stereoselectivity, and its main advantages are:

1) The structure of raw material compound I and raw material compound III is relatively simple, and it is easy to prepare in large quantities;

2) The experiment is easy to operate, no highly toxic reagents are used in all steps, and the safety is high;

3) The stereoselectivity of the olefin metathesis reaction is good, and the product whose side chain is a trans double bond can be obtained with a specific configuration, which simplifies the purification process of the product;

4) The reaction steps are few, and the overall yield is relatively high.

Therefore, the present invention is easier to realize the large-scale preparation of the paricalcitol intermediate.

Detailed ways

The technical solutions of the present invention will be further described below in conjunction with the examples, but the present invention is not limited to the following embodiments.

The intermediate VI of Paricalcitol of the present invention is synthesized according to the following synthetic route:

Step (1): Preparation of Compound II

The synthetic route for compound II is:

Concrete synthetic reaction conditions can refer to following several schemes:

Scheme a: Dissolve methyltriphenylphosphine iodide (2.020g, 5mmol) in 10mL of anhydrous tetrahydrofuran under nitrogen protection, and add strong base n-butyllithium (3.13mL, 5mmol, 1.6M), stirred and reacted for 20 minutes, and then compound I (1.625g, 5mmol) was dissolved in 10mL of anhydrous tetrahydrofuran, and added dropwise to the above reaction system, Wittig reaction occurred at 0°C, and reacted for 30 minutes, After the reaction is over, add saturated ammonium chloride solution to the reaction solution to quench the reaction, add petroleum ether for extraction, dry the organic layer with magnesium sulfate, spin off all solvents at 10-20mmHg under reduced pressure, and purify the residue by column chromatography , the stationary phase is silica gel, and the eluent is petroleum ether to obtain 1.502 g of compound II with a yield of 93%.

The above-mentioned compound I can be prepared by using vitamin D2 as a raw material through a known synthetic method (Journal of Medicinal Chemistry, 2000, 43, 3581-3586);

¹ H NMR (600MHz, CDCl ₃ ) δ = 5.66 (ddd, J = 8.4, 10.2, 16.8 Hz, 1H), 4.89 (dd, J = 16.8, 1.2 Hz, 1H), 4.81 (dd, J = 10.2, 1.8 Hz,1H),4.03(br s,1H),2.09–2.03(m,1H),1.95–1.92(m,1H),1.86–1.78(m,1H),1.68–1.57(m,3H),1.38 –1.29(m,3H),1.27–1.21(m,2H),1.15–1.05(m,2H),1.00(d,J＝6.6Hz,3H),0.95(t,J＝7.8Hz,9H), 0.93(s,3H),0.55(q,J＝7.8Hz,6H).

ESI-HRMS calc: C ₂₀ H ₃₈ OSiNa [(M+Na) ⁺ ] 345.2590, found: 345.2588.

Scheme b: Dissolve methyltriphenylphosphine iodide (3.030g, 7.5mmol) in 15mL of anhydrous dioxane under the protection of nitrogen, and add a strong base bistrimethazine dropwise to the above solution at -10°C Sodium silylamide (3.38mL, 6.75mmol, 2M), stirred for 30 minutes, then compound I (1.625g, 5mmol) was dissolved in 10mL of anhydrous dioxane, and added dropwise to the above reaction system,- Wittig reaction occurs at 10°C and reacts for 1 hour. After the reaction is over, add saturated ammonium chloride solution to the reaction solution to quench the reaction, add petroleum ether for extraction, dry the organic layer with magnesium sulfate, and reduce pressure at 10-20mmHg All the solvent was evaporated by rotary evaporation, and the residue was purified by column chromatography, the stationary phase was silica gel, and the eluent was petroleum ether to obtain 1.421 g of compound II with a yield of 88%.

¹ H NMR (600MHz, CDCl ₃ ) δ = 5.66 (ddd, J = 8.4, 10.2, 16.8 Hz, 1H), 4.89 (dd, J = 16.8, 1.2 Hz, 1H), 4.81 (dd, J = 10.2, 1.8 Hz,1H),4.03(br s,1H),2.09–2.03(m,1H),1.95–1.92(m,1H),1.86–1.78(m,1H),1.68–1.57(m,3H),1.38 –1.29(m,3H),1.27–1.21(m,2H),1.15–1.05(m,2H),1.00(d,J＝6.6Hz,3H),0.95(t,J＝7.8Hz,9H), 0.93(s,3H),0.55(q,J＝7.8Hz,6H).

ESI-HRMS calc: C ₂₀ H ₃₈ OSiNa [(M+Na) ⁺ ] 345.2590, found: 345.2588.

Scheme c: Dissolve methyltriphenylphosphine iodide (2.222g, 5.5mmol) in 10mL of anhydrous ethylene glycol dimethyl ether under the protection of nitrogen, and add a strong base bis Lithium trimethylsilylamide (5.23mL, 5.23mmol, 1M), stirred for 40 minutes, and then compound I (1.625g, 5mmol) was dissolved in 10mL of anhydrous ethylene glycol dimethyl ether, and added dropwise to the above In the reaction system, a Wittig reaction occurs at -20°C for 5 hours. After the reaction, a saturated ammonium chloride solution is added to the reaction solution to quench the reaction, petroleum ether is added for extraction, and the organic layer is dried with magnesium sulfate. All the solvent was evaporated under reduced pressure at 10-20 mmHg, and the residue was purified by column chromatography with silica gel as the stationary phase and petroleum ether as the eluent to obtain 1.454 g of compound II with a yield of 90%.

¹ H NMR (600MHz, CDCl ₃ ) δ = 5.66 (ddd, J = 8.4, 10.2, 16.8 Hz, 1H), 4.89 (dd, J = 16.8, 1.2 Hz, 1H), 4.81 (dd, J = 10.2, 1.8 Hz,1H),4.03(br s,1H),2.09–2.03(m,1H),1.95–1.92(m,1H),1.86–1.78(m,1H),1.68–1.57(m,3H),1.38 –1.29(m,3H),1.27–1.21(m,2H),1.15–1.05(m,2H),1.00(d,J＝6.6Hz,3H),0.95(t,J＝7.8Hz,9H), 0.93(s,3H),0.55(q,J＝7.8Hz,6H).

ESI-HRMS calc: C ₂₀ H ₃₈ OSiNa [(M+Na) ⁺ ] 345.2590, found: 345.2588.

Scheme d: Add methyltriphenylphosphine iodide (3.032g, 7.5mmol) into 15mL of anhydrous ether under nitrogen protection, and add a strong base lithium diisopropylamide dropwise to the above solution at 15°C (4.5mL, 9mmol, 2M), stirred and reacted for 15 minutes, then dissolved compound I (1.948g, 6mmol) in 12mL of anhydrous ether, added dropwise to the above reaction system, Wittig reaction occurred at 15°C, and the reaction After 30 minutes, after the reaction is over, add saturated ammonium chloride solution to the reaction solution to quench the reaction, add petroleum ether for extraction, dry the organic layer with magnesium sulfate, and spin off all solvents at 10-20mmHg under reduced pressure, and the residue is passed through the column Purified by chromatography, the stationary phase was silica gel, and the eluent was petroleum ether to obtain 1.665 g of compound II with a yield of 86%.

¹ H NMR (600MHz, CDCl ₃ ) δ = 5.66 (ddd, J = 8.4, 10.2, 16.8 Hz, 1H), 4.89 (dd, J = 16.8, 1.2 Hz, 1H), 4.81 (dd, J = 10.2, 1.8 Hz,1H),4.03(br s,1H),2.09–2.03(m,1H),1.95–1.92(m,1H),1.86–1.78(m,1H),1.68–1.57(m,3H),1.38 –1.29(m,3H),1.27–1.21(m,2H),1.15–1.05(m,2H),1.00(d,J＝6.6Hz,3H),0.95(t,J＝7.8Hz,9H), 0.93(s,3H),0.55(q,J＝7.8Hz,6H).

ESI-HRMS calc: C ₂₀ H ₃₈ OSiNa [(M+Na) ⁺ ] 345.2590, found: 345.2588.

Scheme e: Add methyltriphenylphosphine iodide (2.525g, 6.25mmol) into 12.5mL anhydrous tetrahydrofuran, and add a strong base potassium bistrimethylsilylamide dropwise to the above solution at -78°C (5mL, 5mmol, 1M), stirred and reacted for 60 minutes, then compound I (1.016g, 3.13mmol) was dissolved in 6mL of anhydrous tetrahydrofuran, added dropwise to the above reaction system, Wittig reaction occurred at -78°C, React for 10 hours. After the reaction is over, add saturated ammonium chloride solution to the reaction liquid to quench the reaction, add petroleum ether for extraction, dry the organic layer with magnesium sulfate, and spin off all the solvent at 10-20mmHg under reduced pressure. Purified by column chromatography with silica gel as the stationary phase and petroleum ether as the eluent to obtain 0.868 g of compound II with a yield of 86%.

The strong bases and the first solvent used in the above schemes a to e can be replaced with each other, and the reaction conditions can also be adjusted within the range of the above schemes, and the yields of the obtained products are all above 86%.

Step (2): Preparation of Compound IV

Compound IV is synthesized by the following synthetic route:

Concrete synthetic reaction conditions can refer to following several schemes:

Scheme a: Compound II (1.454g, 4.5mmol) and Compound III (2.056g, 9mmol) were dissolved in 15mL of anhydrous toluene under nitrogen protection, and the second generation Grubbs catalyst (382mg, 0.45mmol) was added to the reaction solution As a ruthenium-containing catalyst, the reaction solution was placed in an oil bath at 120°C for reflux reaction for 24 hours to complete the olefin metathesis reaction. After the reaction, it was filtered through diatomaceous earth, and all solvents were evaporated under reduced pressure at 10-20mmHg, and the residue was Purified by column chromatography, the stationary phase is silica gel, and the eluent is petroleum ether to obtain 1.389 g of compound IV with a yield of 59%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.28(dd, J=15.6,8.4Hz,1H),5.18(dd,J=15.6,8.4Hz,1H),4.03(br s,1H),2.03–1.97 (m,2H),1.95–1.91(m,1H),1.86–1.78(m,1H),1.69–1.55(m,3H),1.38–1.19(m,6H),1.15(s,3H),1.10 (s,3H),1.06(q,J=9.6Hz,1H),0.98–0.92(m,18H),0.87(s,9H),0.55(q,J=7.8Hz,6H),0.07(s, 6H).

ESI-HRMS calc.: C ₃₁ H ₆₂ O ₂ Si ₂ Na [(M+Na) ⁺ ] 545.4186, found: 545.4190.

Above-mentioned compound III can adopt following method to prepare:

① Dissolve commercially available compound A (2.324g, 10mmol) and sodium acetate (2.870g, 35mmol) in 20mL of anhydrous dichloromethane, add pyridinium chlorochromate (3.234g, 15mmol) to the above solution, and React for 12 hours. After the reaction is over, filter through diatomaceous earth, dichloromethane is evaporated under reduced pressure at 10-20mmHg, and the residue is purified by column chromatography. The stationary phase is silica gel, and the eluent is V _{petroleum ether} /V _{acetic acid Ethyl ester} = 20:1, to obtain 2.120g of compound B, 92%.

②Dissolve methyltriphenylphosphine iodide (3.717g, 9.2mmol) in 19mL of anhydrous tetrahydrofuran under nitrogen protection, and add n-butyllithium (5.75mL, 9.2mmol, 1.6M in hexane), stirred for 30 minutes, then dissolved compound B (2.120g, 9.2mmol) in 19mL of anhydrous tetrahydrofuran, added dropwise to the above reaction system, and reacted for 1 hour at 0°C. Add saturated ammonium chloride solution to the solution to quench the reaction, add petroleum ether to extract, dry the organic layer with magnesium sulfate, and spin off all solvents at 10-20mmHg under reduced pressure, and the residue is purified by column chromatography. The stationary phase is silica gel. The eluent was petroleum ether, and 1.723 g of compound III was obtained with a yield of 82%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.83(ddd,J=8.4,10.8,16.8Hz,1H),4.99–4.94(m,2H),2.12–2.06(m,1H),1.17(s,3H ),1.14(s,3H),1.00(d,J=7.2Hz,3H),0.87(s,9H),0.07(s,3H),0.07(s,3H).

Scheme b: under nitrogen protection, compound II (1.454g, 4.5mmol) and compound III (1.542g, 6.75mmol) were dissolved in 15mL of anhydrous benzene, and the second-generation Hoveyda-Grubbs catalyst (141mg, 0.225mmol) as a ruthenium-containing catalyst, the reaction solution was placed in an oil bath at 100°C for reflux reaction for 24 hours, and the olefin metathesis reaction was completed. After the reaction was completed, it was filtered through diatomaceous earth, and all solvents were rotary evaporated at 10-20mmHg under reduced pressure. The residue was purified by column chromatography with silica gel as the stationary phase and petroleum ether as the eluent to obtain 1.176 g of compound IV with a yield of 50%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.28(dd, J=15.6,8.4Hz,1H),5.18(dd,J=15.6,8.4Hz,1H),4.03(br s,1H),2.03–1.97 (m,2H),1.95–1.91(m,1H),1.86–1.78(m,1H),1.69–1.55(m,3H),1.38–1.19(m,6H),1.15(s,3H),1.10 (s,3H),1.06(q,J=9.6Hz,1H),0.98–0.92(m,18H),0.87(s,9H),0.55(q,J=7.8Hz,6H),0.07(s, 6H).

ESI-HRMS calc.: C ₃₁ H ₆₂ O ₂ Si ₂ Na [(M+Na) ⁺ ] 545.4186, found: 545.4190.

The above compound III was prepared according to the method in scheme a.

Scheme c: Dissolve compound II (1.454g, 4.5mmol) and compound III (1.851g, 8.1mmol) in 15mL of anhydrous 1,2-dichloroethane under nitrogen protection, and add the first generation Hoveyda-Grubbs catalyst (203mg, 0.338mmol) is used as a ruthenium-containing catalyst, and the reaction solution is placed in an oil bath at 100°C for reflux reaction for 36 hours to complete the olefin metathesis reaction. All the solvent was distilled off by rotary distillation, and the residue was purified by column chromatography, the stationary phase was silica gel, and the eluent was petroleum ether to obtain 1.130 g of compound IV, with a yield of 48%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.28(dd, J=15.6,8.4Hz,1H),5.18(dd,J=15.6,8.4Hz,1H),4.03(br s,1H),2.03–1.97 (m,2H),1.95–1.91(m,1H),1.86–1.78(m,1H),1.69–1.55(m,3H),1.38–1.19(m,6H),1.15(s,3H),1.10 (s,3H),1.06(q,J=9.6Hz,1H),0.98–0.92(m,18H),0.87(s,9H),0.55(q,J=7.8Hz,6H),0.07(s, 6H).

ESI-HRMS calc.: C ₃₁ H ₆₂ O ₂ Si ₂ Na [(M+Na) ⁺ ] 545.4186, found: 545.4190.

The above compound III was prepared according to the method in scheme a.

Scheme d: Compound II (1.454g, 4.5mmol) and Compound III (1.233g, 5.4mmol) were dissolved in 15mL of dichloromethane under nitrogen protection, and the second generation Grubbs catalyst (77mg, 0.09mmol) was added to the reaction solution ) as a ruthenium-containing catalyst, the reaction solution was heated and placed in a 60°C oil bath for reflux reaction for 48 hours to complete the olefin metathesis reaction. After the reaction was completed, it was filtered through diatomaceous earth, and all solvents were rotary evaporated at 10 to 20mmHg under reduced pressure. The compound was purified by column chromatography, the stationary phase was silica gel, and the eluent was petroleum ether to obtain 0.964 g of compound IV with a yield of 41%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.28(dd, J=15.6,8.4Hz,1H),5.18(dd,J=15.6,8.4Hz,1H),4.03(br s,1H),2.03–1.97 (m,2H),1.95–1.91(m,1H),1.86–1.78(m,1H),1.69–1.55(m,3H),1.38–1.19(m,6H),1.15(s,3H),1.10 (s,3H),1.06(q,J=9.6Hz,1H),0.98–0.92(m,18H),0.87(s,9H),0.55(q,J=7.8Hz,6H),0.07(s, 6H).

ESI-HRMS calc.: C ₃₁ H ₆₂ O ₂ Si ₂ Na [(M+Na) ⁺ ] 545.4186, found: 545.4190.

The above compound III was prepared according to the method in scheme a.

Scheme e: Compound II (1.454g, 4.5mmol) and Compound III (3.083g, 13.5mmol) were dissolved in 15mL of toluene under nitrogen protection, and the first generation Grubbs catalyst (740mg, 0.9mmol) was added to the reaction solution as Containing ruthenium catalyst, put the reaction solution in an oil bath at 150°C for reflux reaction for 15 hours to complete the olefin metathesis reaction. After the reaction, filter through diatomaceous earth, and rotate all the solvents under reduced pressure at 10-20mmHg, and the residue is passed through the column Purified by chromatography, the stationary phase was silica gel, and the eluent was petroleum ether to obtain 1.035 g of compound IV with a yield of 44%.

The above compound III was prepared according to the method in scheme a.

The catalysts in the schemes a to e of step (2) synthesizing compound IV can be replaced with each other, and the reaction conditions can also be adjusted appropriately within the scope of the above-mentioned schemes, and the yields of the obtained compound IV are all above 41%.

Step (3): Preparation of compound V

The synthetic route of compound V is:

Concretely can carry out with reference to following several concrete implementation schemes:

Scheme a: Compound IV (785mg, 1.5mmol) was dissolved in 3mL of methanol, and sodium tetrachloroaurate dihydrate (3mg, 0.0075mmol) was added to the above solution as a Lewis acid catalyst, and reacted at 25°C for 24 hours to remove three Ethyl silicon-based protective agent, after the reaction, filter through basic aluminum oxide, and rotate all the solvents under reduced pressure at 10-20mmHg, the residue is purified by column chromatography, the stationary phase is silica gel, and the eluent is V _{petroleum Ether} /V _{ethyl acetate} = 5:1 to obtain 582 mg of compound V with a yield of 95%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.30(dd, J=15.0,8.4Hz,1H),5.18(dd,J=15.6,8.4Hz,1H),4.07(br s,1H),2.04–1.95 (m,3H),1.86–1.78(m,2H),1.72–1.64(m,1H),1.57–1.40(m,5H),1.37–1.32(m,1H),1.29–1.30(m,2H) ,1.18–1.13(m,4H,including 1.15(s,3H)),1.10(s,3H),0.98(d,J＝6.0Hz,3H),0.96(d,J＝7.2Hz,3H),0.95 (s,3H),0.87(s,9H),0.07(s,6H).

ESI-HRMS calc: C ₂₅ H ₄₈ O ₂ SiNa [(M+Na) ⁺ ] 431.3321, found: 431.3320.

Scheme b: Dissolve compound IV (785mg, 1.5mmol) in 3mL of ethanol, add ferric trichloride (24mg, 0.15mmol) to the above solution as a Lewis acid catalyst, and react at 25°C for 5 hours to remove triethylsilicon base protecting agent, after the reaction is finished, filter through basic alumina, and rotate all the solvents under reduced pressure at 10-20mmHg, and the residue is purified by column chromatography, the stationary phase is silica gel, and the eluent is V _{petroleum ether} /V _{Ethyl acetate} =5:1, 563 mg of compound V was obtained, and the yield was 92%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.30(dd, J=15.0,8.4Hz,1H),5.18(dd,J=15.6,8.4Hz,1H),4.07(br s,1H),2.04–1.95 (m,3H),1.86–1.78(m,2H),1.72–1.64(m,1H),1.57–1.40(m,5H),1.37–1.32(m,1H),1.29–1.30(m,2H) ,1.18–1.13(m,4H,including 1.15(s,3H)),1.10(s,3H),0.98(d,J＝6.0Hz,3H),0.96(d,J＝7.2Hz,3H),0.95 (s,3H),0.87(s,9H),0.07(s,6H).

ESI-HRMS calc: C ₂₅ H ₄₈ O ₂ SiNa [(M+Na) ⁺ ] 431.3321, found: 431.3320.

Scheme c: Compound IV (785 mg, 1.5 mmol) was dissolved in 3 mL of acetonitrile and water mixed solution (volume ratio of acetonitrile and water 1:1), and indium trichloride (3.2 mg, 0.015 mmol) was added to the above solution As a Lewis acid catalyst, react at 40°C for 8 hours to remove the triethyl silicon-based protective agent. After the reaction is completed, filter through basic alumina, spin evaporate all the solvent at 10-20mmHg under reduced pressure, and pass the residue through the column layer Analysis and purification, the stationary phase is silica gel, and the eluent is V _{petroleum ether} /V _{ethyl acetate} = 5:1 to obtain 550 mg of compound V with a yield of 90%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.30(dd, J=15.0,8.4Hz,1H),5.18(dd,J=15.6,8.4Hz,1H),4.07(br s,1H),2.04–1.95 (m,3H),1.86–1.78(m,2H),1.72–1.64(m,1H),1.57–1.40(m,5H),1.37–1.32(m,1H),1.29–1.30(m,2H) ,1.18–1.13(m,4H,including 1.15(s,3H)),1.10(s,3H),0.98(d,J＝6.0Hz,3H),0.96(d,J＝7.2Hz,3H),0.95 (s,3H),0.87(s,9H),0.07(s,6H).

ESI-HRMS calc: C ₂₅ H ₄₈ O ₂ SiNa [(M+Na) ⁺ ] 431.3321, found: 431.3320.

Scheme d: Compound IV (785 mg, 1.5 mmol) was dissolved in 3 mL of acetonitrile, and scandium trifluoromethanesulfonate (37 mg, 0.075 mmol) was added to the above solution as a Lewis acid catalyst, and reacted at 0°C for 5 hours. After the reaction, Filtrate through basic aluminum oxide, rotary evaporate all the solvent at 10-20mmHg under reduced pressure, and purify the residue by column chromatography, the stationary phase is silica gel, and the eluent is V _{petroleum ether} /V _{ethyl acetate} =5:1, 550 mg of compound V was obtained with a yield of 90%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.30(dd, J=15.0,8.4Hz,1H),5.18(dd,J=15.6,8.4Hz,1H),4.07(br s,1H),2.04–1.95 (m,3H),1.86–1.78(m,2H),1.72–1.64(m,1H),1.57–1.40(m,5H),1.37–1.32(m,1H),1.29–1.30(m,2H) ,1.18–1.13(m,4H,including 1.15(s,3H)),1.10(s,3H),0.98(d,J＝6.0Hz,3H),0.96(d,J＝7.2Hz,3H),0.95 (s,3H),0.87(s,9H),0.07(s,6H).

ESI-HRMS calc: C ₂₅ H ₄₈ O ₂ SiNa [(M+Na) ⁺ ] 431.3321, found: 431.3320.

Scheme e: Compound IV (785 mg, 1.5 mmol) was dissolved in 3 mL of a mixed solution of ethanol and water (the volume ratio of ethanol and water was 1:5), and ferric chloride (36 mg, 0.225 mmol) was added to the above solution As a Lewis acid catalyst, it was reacted at -20°C for 24 hours. After the reaction, it was filtered through basic alumina, and all solvents were evaporated under reduced pressure at 10-20 mmHg. The residue was purified by column chromatography. The stationary phase was silica gel. The lotion was V _{petroleum ether} /V _{ethyl acetate} =5:1, and 537 mg of compound V was obtained with a yield of 88%.

Scheme f: Compound IV (785mg, 1.5mmol) was dissolved in 3mL of a mixture of methanol and acetonitrile (the volume ratio of methanol to acetonitrile was 1:2), and scandium trifluoromethanesulfonate (110mg, 0.225mmol) was added to the above solution , react at -20°C for 10 hours, after the reaction, filter through basic alumina, and evaporate all the solvent under reduced pressure at 10-20mmHg, the residue is purified by column chromatography, the stationary phase is silica gel, and the eluent is V _{Petroleum ether} /V _{ethyl acetate} =5:1 to obtain 525 mg of compound V with a yield of 86%.

Scheme g: Dissolve compound IV (785mg, 1.5mmol) in 3mL of water, add sodium tetrachloroaurate dihydrate (30mg, 0.075mmol) to the above solution as a Lewis acid catalyst, react at 55°C for 3 hours, after the reaction, Filtrate through basic aluminum oxide, rotary evaporate all the solvent at 10-20mmHg under reduced pressure, and purify the residue by column chromatography, the stationary phase is silica gel, and the eluent is V _{petroleum ether} /V _{ethyl acetate} =5:1, 538 mg of compound V was obtained with a yield of 88%.

The third solvent and the Lewis acid catalyst used in the schemes a to g of the above preparation of compound V can be replaced with each other, and the reaction conditions can also be adjusted within the scope of the above scheme, and the yield of the obtained compound V is above 86%.

Step (4): Synthesis of the synthetic intermediate VI of Paricalcitol

Synthesize intermediate VI according to the following synthetic route:

Concrete reaction condition can be implemented with reference to following several schemes:

Scheme a: Dissolve compound V (409mg, 1mmol) in 5mL of anhydrous dichloromethane, add pyridinium chlorochromate (431mg, 2mmol) to the above solution, and react at 25°C for 15 hours. After soil filtration, all solvents were evaporated under reduced pressure at 10-20 mmHg, and the residue was purified by column chromatography, the stationary phase was silica gel, and the eluent was V _{petroleum ether} /V _{ethyl acetate} =7:1 to obtain 376 mg of compound VI, Yield 92%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.33(dd, J=15.6,8.4Hz,1H),5.19(dd,J=15.6,8.4Hz,1H),2.47–2.42(m,1H),2.30– 2.18(m,2H),2.10–1.86(m,5H),1.77–1.66(m,2H),1.62–1.58(m,1H),1.52–1.44(m,2H),1.35–1.24(m,1H ),1.15(s,3H),1.10(s,3H),1.04(d,J=6.6Hz,3H),0.95(d,J=6.6Hz,3H),0.86(s,9H),0.65(s ,3H),0.06(s,6H).

ESI- _HRMS calc: _C25H46O2SiNa [(M+Na) ⁺ ] _429.3165 , found: 429.3170.

Scheme b: Dissolve compound V (409mg, 1mmol) in 5mL of anhydrous 1,2-dichloroethane, add pyridinium dichromate (564mg, 1.5mmol) to the above solution, react at 35°C for 8 hours, and react After the end, filter through diatomaceous earth, rotary evaporate all the solvent at 10-20mmHg under reduced pressure, and purify the residue by column chromatography, the stationary phase is silica gel, and the eluent is V _{petroleum ether} /V _{ethyl acetate} =7:1 , to obtain 362 mg of compound VI, with a yield of 89%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.33(dd, J=15.6,8.4Hz,1H),5.19(dd,J=15.6,8.4Hz,1H),2.47–2.42(m,1H),2.30– 2.18(m,2H),2.10–1.86(m,5H),1.77–1.66(m,2H),1.62–1.58(m,1H),1.52–1.44(m,2H),1.35–1.24(m,1H ),1.15(s,3H),1.10(s,3H),1.04(d,J=6.6Hz,3H),0.95(d,J=6.6Hz,3H),0.86(s,9H),0.65(s ,3H),0.06(s,6H).

ESI- _HRMS calc: _C25H46O2SiNa [(M+Na) ⁺ ] _429.3165 , found: 429.3170.

Scheme c: Dissolve compound V (409mg, 1mmol) in 5mL N,N-dimethylformamide, add (1,1,1-triacetoxy)-1,1-dihydro- 1,2-Phenyliodyl-3(1H)-one (424mg, 1mmol) was reacted at 0°C for 4 hours. After the reaction was completed, it was filtered through diatomaceous earth, and all solvents were evaporated under reduced pressure at 1~5mmHg, and the residue Purified by column chromatography, the stationary phase is silica gel, and the eluent is V _{petroleum ether} /V _{ethyl acetate} =7:1 to obtain 368 mg of compound VI with a yield of 90%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.33(dd, J=15.6,8.4Hz,1H),5.19(dd,J=15.6,8.4Hz,1H),2.47–2.42(m,1H),2.30– 2.18(m,2H),2.10–1.86(m,5H),1.77–1.66(m,2H),1.62–1.58(m,1H),1.52–1.44(m,2H),1.35–1.24(m,1H ),1.15(s,3H),1.10(s,3H),1.04(d,J=6.6Hz,3H),0.95(d,J=6.6Hz,3H),0.86(s,9H),0.65(s ,3H),0.06(s,6H).

ESI- _HRMS calc: _C25H46O2SiNa [(M+Na) ⁺ ] _429.3165 , found: 429.3170.

Scheme d: Dissolve compound V (409 mg, 1 mmol) in 5 mL of anhydrous dimethyl sulfoxide, add 2-iodobenzoic acid (420 mg, 1.5 mmol) to the above solution, and react at 25°C for 3.5 hours. After the reaction, Filtrate through diatomaceous earth, rotate all the solvents under reduced pressure at 1-5mmHg, and purify the residue by column chromatography, the stationary phase is silica gel, and the eluent is V _{petroleum ether} /V _{ethyl acetate} = 7:1 to obtain the compound VI 360mg, yield 88%.

¹ H NMR (600MHz, CDCl ₃ ) δ=5.33(dd, J=15.6,8.4Hz,1H),5.19(dd,J=15.6,8.4Hz,1H),2.47–2.42(m,1H),2.30– 2.18(m,2H),2.10–1.86(m,5H),1.77–1.66(m,2H),1.62–1.58(m,1H),1.52–1.44(m,2H),1.35–1.24(m,1H ),1.15(s,3H),1.10(s,3H),1.04(d,J=6.6Hz,3H),0.95(d,J=6.6Hz,3H),0.86(s,9H),0.65(s ,3H),0.06(s,6H).

ESI- _HRMS calc: _C25H46O2SiNa [(M+Na) ⁺ ] _429.3165 , found: 429.3170.

Scheme e: Compound V (409 mg, 1 mmol) was dissolved in 5 mL of dichloromethane, and (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodide was added to the above solution Acyl-3(1H)-ketone (530mg, 1.25mmol) was reacted at -10°C for 24 hours. After the reaction was completed, it was filtered through diatomaceous earth, and all solvents were evaporated under reduced pressure at 10-20mmHg, and the residue was subjected to column chromatography. For purification, the stationary phase was silica gel, and the eluent was V _{petroleum ether} /V _{ethyl acetate} =7:1 to obtain 347 mg of compound VI with a yield of 85%.

Scheme f: Dissolve compound V (409mg, 1mmol) in 5mL 1,2-dichloroethane, add pyridinium dichromate (1.128g, 3mmol) to the above solution, react at 50°C for 2 hours, after the reaction , filtered through diatomaceous earth, all solvents were evaporated under reduced pressure at 10-20mmHg, the residue was purified by column chromatography, the stationary phase was silica gel, and the eluent was V _{petroleum ether} /V _{ethyl acetate} =7:1, to obtain Compound VI 343 mg, yield 84%.

The hypervalent chromium or hypervalent iodine used in the scheme a～f of synthetic intermediate compound VI can be replaced mutually, and reaction temperature and reaction time also can be adjusted in the scope between above-mentioned scheme a～f, and its yield is all in 84% above.

In summary, the method for synthesizing the intermediate of Paricalcitol of the present invention has the advantages of easy-to-obtain raw materials, simple operation, few reaction steps, and high stereoselectivity, and can be realized by arbitrarily combining various schemes of the above-mentioned various steps. Synthesis of intermediates of paricalcitol of the present invention.

Claims (9)

1. a method for the intermediate of synthetic Paricalcitol, it is characterized in that the synthetic route of this method is: Concretely comprise following reaction steps: (1) Preparation of compound II Dissolve methyltriphenylphosphine iodide in the first solvent and react with a strong base at a molar ratio of 1:0.8-1.2 for 15-60 minutes at a temperature of -78°C to 15°C, and add compound I to cause a Wittig reaction 0.5~10h, the molar ratio of compound I to methyltriphenylphosphine iodide is 1:1~2, and purified to obtain compound II; (2) Synthesis of Compound IV Compound II and compound III are mixed according to the molar ratio of 1:1.2~3 and then dissolved in the second solvent, and olefin metathesis reaction occurs under the catalysis of ruthenium-containing catalyst under the temperature condition of 60°C-150°C, and compound II and ruthenium-containing catalyst The molar ratio is 1:0.02-0.2, the reaction time is 15-48 hours, and purified to obtain compound IV; (3) Synthesis of Compound V The compound IV is dissolved in the third solvent, and the triethylsilyl protecting group is catalyzed by a Lewis acid at a temperature of -20°C to 55°C, and the catalytic time is 3 to 24 hours. The molar ratio of the compound IV to the Lewis acid 1:0.005～0.15, purified to obtain compound V; (4) Synthesis of the synthetic intermediate VI of Paricalcitol Dissolve compound V in the fourth solvent, add hypervalent chromium or hypervalent iodine oxidizing agent, and oxidize compound V at a temperature of -10°C to 50°C for 2 to 24 hours, the mole of compound V and hypervalent chromium or hypervalent iodine oxidizing agent Ratio is 1:1～3, purify, obtain the synthetic intermediate VI of Paricalcitol; The above-mentioned first solvent is tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether or dioxane; The above-mentioned second solvent is dichloromethane, 1,2-dichloroethane, benzene or toluene; The above-mentioned third solvent is methanol, ethanol, acetonitrile, water or a mixture thereof in any proportion; The above-mentioned fourth solvent is dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide or dimethyl sulfoxide. 2. the method for the intermediate of synthetic paricalcitol according to claim 1, is characterized in that, in step (1), at-20 DEG C～0 DEG C of temperature, under nitrogen protection condition, iodide methyl Dissolve triphenylphosphine in the first solvent and react with a strong base according to the molar ratio of 1:0.9~1 for 20~60min, add compound I to undergo Wittig reaction for 0.5~5h, compound I and iodide methyl triphenylphosphine The molar ratio is 1:1~1.5, adding saturated ammonium chloride solution to the reaction solution to quench the reaction, adding petroleum ether for extraction, drying the organic layer with magnesium sulfate, and rotary evaporating all solvents under reduced pressure, and the residue is subjected to column chromatography Purification affords compound II. 3. the method for the intermediate of synthetic paricalcitol according to claim 1, is characterized in that: the strong base in step (1) is n-butyllithium, lithium diisopropylamide, bistrimethyl Lithium silylamide, sodium bistrimethylsilylamide, or potassium bistrimethylsilylamide. 4. the method for the intermediate of synthetic paricalcitol according to claim 1, is characterized in that: in step (2), under nitrogen protection, compound II and compound III are according to molar ratio 1:1.5～2 After mixing, it is dissolved in the second solvent at a temperature of 90°C to 120°C, and the olefin metathesis reaction occurs under the catalysis of a ruthenium-containing catalyst. The molar ratio of compound II to the ruthenium-containing catalyst is 1:0.05-0.1, and the reaction time is 24-36 hours , filtered through diatomaceous earth, all the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to obtain compound IV. 5. the method for the intermediate of synthetic Paricalcitol according to claim 1 is characterized in that, the ruthenium-containing catalyst in step (2) is the first generation Grubbs catalyst, the second generation Grubbs catalyst, the first generation Grubbs catalyst First-generation Hoveyda-Grubbs catalyst or second-generation Hoveyda-Grubbs catalyst. 6. the method for the intermediate of synthetic paricalcitol according to claim 1, is characterized in that, in step (3), compound IV is dissolved in the 3rd solvent at 0 ℃～40 ℃ temperature with The Lewis acid catalyzes the removal of the triethylsilyl protecting group, the catalytic time is 5 to 24 hours, the molar ratio of compound IV to Lewis acid is 1:0.005 to 0.1, it is filtered through basic alumina, and all solvent, and the residue was purified by column chromatography to obtain compound V. 7. the method for the intermediate of synthetic paricalcitol according to claim 1, is characterized in that, the Lewis acid in step (3) is sodium tetrachloroaurate dihydrate, indium trichloride, trichloroaurate iron oxide or scandium triflate. 8. the method for the intermediate of synthetic paricalcitol according to claim 1 is characterized in that: in step (4), compound V is dissolved in the 4th solvent, adds hypervalent chromium or hypervalent iodine oxidizing agent in Oxidize compound V for 3.5 to 15 hours at a temperature of 0°C to 35°C, the molar ratio of compound V to oxidant is 1:1 to 2, filter through diatomaceous earth, spin off all solvents under reduced pressure, and the residue is subjected to column chromatography After purification, the synthetic intermediate VI of Paricalcitol was obtained. 9. the method for the intermediate of synthetic paricalcitol according to claim 1, is characterized in that: the high valence chromium oxidizing agent described in step (4) is pyridinium chlorochromate or pyridinium dichromate, high valence The iodine oxidizing agent is 2-iodylbenzoic acid or (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodyl-3(1H)-one.