Preparation method of calcipotriol intermediate

Abstract

The invention discloses a preparation method of a calcipotriol intermediate, the structural formula of the calcipotriol intermediate is shown as a formula (1), and the method comprises the following steps: by taking 1alpha-hydroxyl dinorhydrin shown as a formula (2) as a raw material, carrying out sulfonylation, isomerization, reduction / acylation, oxidation, Wittig, hydrolysis and the like to prepare the calcipotriol intermediate. The process for preparing the calcipotriol intermediate is simple in process, mild in reaction condition, good in selectivity and relatively high in reaction yield.

Description

Technical Field

[0001] The invention relates to a method for preparing a calcipotriol intermediate, belonging to a method for preparing steroidal compounds. Background Art

[0002] Calcipotriol is a derivative of vitamin D that regulates calcium and phosphorus metabolism in the body, promotes the absorption and utilization of calcium and phosphorus, and maintains bone health. In addition to regulating calcium and phosphorus metabolism, calcipotriol also has anti-inflammatory and immunomodulatory effects. It is widely used to treat some immune diseases, such as psoriasis, vitiligo, chronic eczema, rheumatoid arthritis, etc. It is currently the most commonly used first-line vitamin D derivative topical treatment for psoriasis and one of the earliest developed topical drugs.

[0003] In 1987, Calverley et al. (Tetrahedron, 1987, 43(20): 4609-4619) synthesized calcipotriol for the first time using vitamin D2 as raw material through a 12-step reaction. However, the raw materials of this scheme were relatively expensive, the reaction steps were complicated, and the overall yield of the product was not high.

[0004] In 2010, Rumbo et al. (J Steroid Biochem Mol Biol, 2010, 121(1-2): 68-70.) reported a new method for preparing vitamin D2 precursor. The route first synthesizes the alkyne intermediate through the Wittig-Horner reaction, reduces it with dicyclohexylborane and treats it with ethyl zinc reagent to obtain the organic zinc intermediate, and then adds cyclopropylcarboxaldehyde under the catalysis of (+)-DAIB, and then uses tetrabutylammonium fluoride to remove the tert-butyldimethylsilyl to obtain the product calcipotriol. However, the reaction conditions of this reaction are relatively harsh and are not suitable for industrial large-scale production.

[0005] Compound 1 is an important intermediate of calcipotriol, and its structural formula is as follows:

[0006]

[0007] At present, there is no report on the synthesis method of preparing calcipotriol intermediate from 1α-hydroxybisphenol A. Summary of the invention

[0008] The object of the present invention is to provide a method for synthesizing a calcipotriol intermediate with simple operation, high process safety, mild reaction conditions and fast reaction rate.

[0009] The technical solution adopted by the present invention is as follows:

[0010] A method for preparing a calcipotriol intermediate, wherein the intermediate has a structural formula as shown in formula (1), and is prepared by sequentially reacting sulfonylation, isomerization, reduction / acylation, oxidation, Wittig, hydrolysis and the like with 1α-hydroxydiol as shown in formula (2) as a raw material, and specifically comprising the following steps:

[0011] a. Sulfonylation

[0012] The 1α-hydroxydihydroquinone represented by formula (2) is used as a raw material, and a sulfonylation reaction is carried out with a sulfonylating agent and an acid-binding agent in an organic solvent medium under the action of a catalyst to obtain a compound represented by formula (3). The reaction formula is as follows:

[0013]

[0014] b. Acetylation, isomerization

[0015] Under the catalysis of iodine, the compound (3) prepared in step a is subjected to an acylation reaction with an acylating agent and an enol rearrangement is simultaneously carried out to prepare a compound as shown in formula (4), and the reaction formula thereof is shown below:

[0016]

[0017] c. Reduction / acylation

[0018] Under the action of catalyst DMAP, the compound (4) prepared in step b undergoes a reduction reaction with a reducing agent in an organic solvent medium to obtain a crude compound, which is then subjected to an acetylation reaction after post-treatment to obtain a compound as shown in formula (5), and the reaction formula thereof is shown below:

[0019]

[0020] d. Oxidation

[0021] The compound (5) prepared in step c is dissolved in an organic solvent medium and subjected to an oxidation reaction to generate a compound as shown in formula (6), the reaction formula of which is shown below:

[0022]

[0023] e. Wittig reaction

[0024] The compound (6) prepared in step d is dissolved in an organic solvent medium, and reacts with the phosphorus ylide reagent shown in formula (8) to generate a compound shown in formula (7), and the reaction formula is as follows:

[0025]

[0026] f. Hydrolysis

[0027] The compound (7) prepared in step e is dissolved in an organic solvent medium to undergo a hydrolysis reaction to obtain a calcipotriol intermediate product as shown in formula (1), the reaction formula of which is shown below:

[0028]

[0029] Furthermore, in step a, the sulfonylating agent is one of the following: p-toluenesulfonyl chloride, benzenesulfonyl chloride and methanesulfonyl chloride, preferably p-toluenesulfonyl chloride; the molar ratio of the sulfonylating agent to compound (2) is 1 to 3:1, preferably 1.8 to 2:1.

[0030] Furthermore, the acid binding agent used in step a is one or more of the following: triethylamine, DMAP, pyridine, collidine, preferably triethylamine; the molar ratio of the acid binding agent to compound (2) is 2 to 6:1, preferably 3.5 to 4:1.

[0031] Furthermore, the catalyst in step a is DMAP, and the molar ratio of DMAP to compound (2) is 0.05 to 0.4:1, preferably 0.1 to 0.2:1.

[0032] Furthermore, the reaction temperature in step a is 25 to 40° C., and step a uses DCM as the reaction solvent. After the reaction in step a is completed, the following post-treatment step is also included: adjusting the pH of the reaction solution to neutral, adding dichloromethane for extraction, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, and the crude product is separated by column chromatography, and the eluent is a PE-EA mixed solvent with a volume ratio of 0.5 to 2:1, thereby obtaining compound (3).

[0033] Furthermore, the acylating agent used in step b is isopropenyl acetate IPA or allyl acetate; the mass ratio of the volume of the acylating agent to the compound represented by formula (3) is 5 to 20 mL / g.

[0034] Furthermore, the molar ratio of the catalyst iodine to the compound (3) used in step b is 0.05 to 0.3:1, preferably 0.1 to 0.15:1.

[0035] Furthermore, the reaction temperature in step b is 20 to 95° C., preferably 85 to 90° C.; after the reaction in step b is completed, the following post-treatment step is also included: the reaction solution is extracted with ethyl acetate, washed with saturated sodium bisulfite solution and saturated brine in sequence, and the liquid is separated, the organic layer is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, the crude product is separated by column chromatography, and the eluent is a PE-EA mixed solvent with a volume ratio of 5 to 10:1, so as to obtain compound (4).

[0036] Furthermore, the reducing agent used in step c is one of the following: sodium borohydride, calcium borohydride, potassium borohydride, preferably calcium borohydride.

[0037] Furthermore, in step c, the molar ratio of the reducing agent to the compound (4) is 3 to 12:1, preferably 5 to 7:1; the molar ratio of the catalyst DMAP to the compound (4) is 0.1 to 0.4:1, preferably 0.2 to 0.25:1.

[0038] Furthermore, the temperature of the reduction reaction in step c is -10 to 0°C, preferably -5 to -2°C; the reaction solvent of the reduction reaction in step c is methanol-THF in a volume ratio of 0.5 to 1:1, and the following post-treatment steps are included after the reduction reaction is completed: removing insoluble matter in the reaction solution by suction filtration, adding dichloromethane to the filtrate and slowly dropping dilute hydrochloric acid under vigorous stirring, the reaction solution will slowly change from turbid to clear liquid during the dropping process, when the liquid becomes clear, stop dropping dilute hydrochloric acid, wash with saturated sodium bicarbonate solution and saturated brine in turn, separate the liquids, dry the organic layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product, which is directly used in the next step of preparing the acetylation reaction of compound (5).

[0039] Furthermore, the acetylation reaction in step c is carried out in the presence of DMAP / triethylamine with acetic anhydride, with DCM as the reaction solvent, and the molar ratio of DMAP to compound (4) in the acetylation reaction is 0.1 to 0.4:1, preferably 0.2 to 0.25:1; the molar ratio of triethylamine or acetic anhydride to compound (4) in the acetylation reaction is 1 to 3:1, preferably 2 to 2.5:1.

[0040] Furthermore, the acetylation reaction in step c is carried out at room temperature, and after the reaction is completed, the following post-treatment steps are also included: the reaction solution is washed with saturated brine and separated, the organic layer is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, and the crude product compound is separated by column chromatography, and the eluent is a PE-EA mixed solvent with a volume ratio of 5 to 15:1, thereby obtaining compound (5).

[0041] Furthermore, the oxidation reaction in step d is carried out in the presence of a base, which is one of the following: pyridine, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, preferably triethylamine; the molar ratio of the base in step d to compound (5) is 1 to 5:1, preferably 3 to 4:1.

[0042] Furthermore, the reaction temperature in step d is 80 to 140° C., preferably 100 to 110° C.; step d uses DMSO as the reaction solvent and oxidant, and the volume amount of DMSO is 4 to 8 mL / mmol based on the amount of compound (5). After the reaction is completed, the following post-treatment steps are also included: adjusting the pH of the reaction solution to neutral, adding ethyl acetate for extraction, washing with water and saturated brine in sequence, drying the organic layer over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, and the crude compound is separated by column chromatography, and the eluent is a PE-EA mixed solvent with a volume ratio of 10 to 20:1, so as to obtain compound (6).

[0043] Furthermore, the molar ratio of the phosphorus ylide reagent in step e to the compound represented by formula (6) is 1 to 6:1, preferably 1.8 to 2:1.

[0044] Furthermore, the reaction temperature in step e is 65 to 130° C., preferably 100 to 110° C.; step e uses DMSO as the reaction solvent, and after the reaction is completed, the following post-treatment steps are also included: adding ethyl acetate for extraction, washing with water and saturated brine in sequence, drying the organic layer over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, and the crude compound is separated by column chromatography, and the eluent is a PE-EA mixed solvent with a volume ratio of 10 to 20:1, to obtain compound (7).

[0045] Furthermore, in step f, the hydrolysis reaction is carried out in the presence of an inorganic base, and the inorganic base is one or both of the following: sodium carbonate or potassium carbonate. The molar ratio of the inorganic base in step f to compound (7) is 2 to 10:1, preferably 7 to 8:1.

[0046] The compound 1 synthesized by the present invention is a key intermediate for synthesizing calcipotriol.

[0047] By adopting the above technology, the present invention has the following beneficial effects: the process of the present invention is simple, the reaction conditions are mild, the selectivity is good, and the reaction yield is high. DETAILED DESCRIPTION

[0048] The present invention will be further described below in conjunction with specific embodiments.

[0049] Example 1

[0050] The calcipotriol intermediate is prepared according to the preparation method of the present invention.

[0051] a. Sulfonylation to prepare the compound represented by intermediate formula (3):

[0052] 1α-Hydroxybis-decyl alcohol (0.35 g, 1 mmol) was dissolved in 5 mL DCM, and DMAP (0.02 g, 0.2 mmol), triethylamine (0.40 g, 4 mmol) and TsCl (0.38 g, 2 mmol) were added, and the temperature was raised to 40°C for 2 h. After the reaction was completed by TLC monitoring, the pH of the reaction solution was adjusted to neutral, and dichloromethane was added for extraction, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude compound was separated by column chromatography (eluent: PE:EA=1:1, v / v) to obtain compound 3, with a reaction yield of 96%.

[0053] Characterization data:

[0054] 1H NMR(400MHz,Chloroform-d)δ7.75(d,J=8.4Hz,2H),7.32(d,J=8.0Hz,2H),5.75(s,1H ),4.05(t,1H),3.95(dd,1H),3.75(dd,1H),2.70(dd,1H),2.57~2.50(m,1H),2.43(s,3 H),2.38~2.28(m,2H),1.91(m,1H),1.75(m,1H),1.69~1.49(m,6H),1.42~1.33(m,1H), 1.24~1.17(m,3H),1.15(s,3H),1.10~1.00(m,3H),0.95(d,J=6.6Hz,3H),0.66(s,3H).

[0055] 13 C NMR(100MHz,Chloroform-d)δ197.03,167.40,144.49,132.89,129.62,127.70,123.08,75.34,71.65,55.24,51.64 ,44.41,42.96,42.54,42.33,38.86,35.97,35.03,32.80,30.80,27.18,24.03,21.46,20.11,18.34,16.63,11.71.

[0056] MS (ESI) m / z 501.2667 [M+H] + .

[0057] b. Acetylation and isomerization to prepare an intermediate compound as shown in formula (4):

[0058] The compound represented by the intermediate formula (3) prepared in step a (0.50 g, 1 mmol) was dissolved in 6 mL IPA, and the reaction solution was heated to 90°C, and iodine (11 mg, 0.1 mmol) was added and reacted for 0.5 h. After the reaction was completed by TLC detection, the reaction solution was extracted with ethyl acetate, washed with saturated sodium bisulfite solution and saturated brine in sequence, and the liquid was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude compound was separated by column chromatography (eluent: PE:EA=8:1, v / v) to obtain compound 4, with a reaction yield of 90%.

[0059] Characterization data:

[0060] 1H NMR(400MHz,Chloroform-d)δ7.77(d,J=8.4Hz,2H),7.33(d,J=7.8Hz,2H),5.78( d,J=2.3Hz,1H),5.56(dd,1H),5.04(dd,1H),3.95(dd,1H),3.79(dd,1H),2.74(m, 1H),2.44(s,3H),2.28~2.13(m,2H),2.10(s,3H),2.02(s,3H),1.91(m,1H),1.72 ~1.57(m,5H),1.42~1.05(m,8H),1.02(s,3H),0.95(d,J=6.6Hz,3H),0.65(s,3H).

[0061] 13 C NMR(100MHz,Chloroform-d)δ170.77,169.11,144.45,142.97,135.97,133.01,129.62,127.75,126.62,116.50,75.41,71.78,56. 17,51.58,42.36,41.08,39.02,38.61,35.98,31.43,31.38,30.72,27.25,23.96,21.49,21.01,20.83,20.31,19.08,16.69,11.76.

[0062] MS (ESI) m / z 607.2703 [M+Na] + .

[0063] c. Reduction and acetylation to prepare an intermediate compound as shown in formula (5):

[0064] Anhydrous calcium chloride (0.55 g, 5 mmol) and DMAP (0.02 g, 0.2 mmol) were dissolved in 7 mL of methanol, and the reaction solution was cooled to -5 °C, sodium borohydride (0.38 g, 10 mmol) was added and stirred for 30 min, sodium borohydride reacted with calcium chloride to generate calcium borohydride reducing agent (5 mmol), and then the compound (0.58 g, 1 mmol) of the intermediate formula (4) prepared in step b was dissolved in 10 mL of THF and slowly added dropwise to the above reaction solution, and reacted at -5 °C for 2 h. After TLC detection, the insoluble matter in the reaction solution was removed by suction filtration, 5 mL of dichloromethane was added to the filtrate, and 1 M dilute hydrochloric acid was slowly added dropwise under vigorous stirring. During the addition process, the reaction solution will slowly change from turbid to clear liquid. When the liquid becomes clear, stop adding dilute hydrochloric acid. The filtrate was washed and separated with saturated sodium bicarbonate solution and saturated brine in turn, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude compound was added to 8 mL of DCM, and DMAP (0.02 g, 0.2 mmol), triethylamine (0.20 g, 2 mmol) and acetic anhydride (0.20 g, 2 mmol) were added in sequence. The mixture was reacted at room temperature for 1 h. After completion of the reaction by TLC, the mixture was extracted with dichloromethane, washed with saturated brine, and separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude compound was separated by column chromatography (eluent: PE:EA=10:1, v / v) to obtain compound 5. The total yield of the two-step reaction was 70%.

[0065] Characterization data:

[0066] 1 H NMR(400MHz,Chloroform-d)δ7.76(d,J=8.3Hz,2H),7.33(d,J=8.1Hz,2H),5.50(dt,1H),5.03(t,1H),4.90(m,1H),3.94(dd,1H),3.77(dd,1H),2.51~2 .45(m,1H),2.44(s,3H),2.38~2.26(m,1H),2.08(m,1H),2.04(s,3H),2.01( s,3H),1.95~1.10(m,16H),1.05(s,3H),0.94(d,J=6.6Hz,3H),0.62(s,3H).

[0067] 13C NMR(100MHz,Chloroform-d)δ170.22,170.19,144.44,135.87,132.94,129.61,127.73,124.86,75.41,74.34,69.19,56.10,51.5 2,42.21,41.81,40.17,39.03,37.10,35.97,31.75,31.48,31.36,27.22,24.03,21.49,21.17,20.95,20.14,19.22,16.67,11.65.

[0068] MS (ESI) m / z 609.2869 [M+Na] + .

[0069] d. Oxidation to prepare the compound represented by the product formula (6):

[0070] The compound represented by the intermediate formula (5) prepared in step c (0.59 g, 1 mmol) was dissolved in 6 mL DMSO, triethylamine (0.40 g, 4 mmol) was added, and the reaction solution was heated to 100° C. and reacted for 2 h. After the reaction was completed by TLC detection, the pH of the reaction solution was adjusted to neutral, extracted with ethyl acetate, washed with water twice, and washed with saturated brine once, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product compound was separated by column chromatography (eluent: PE:EA=15:1, v / v) to obtain compound 6, with a reaction yield of 88%.

[0071] Characterization data:

[0072] 1 H NMR(400MHz,Chloroform-d)δ9.55(d,J=3.3Hz,1H),5.52(dt,1H),5.05(t,1H),4.91(m,1H),2.47(m,1H),2.34(m,2H),2.0 8(m,1H),2.05(s,3H),2.01(s,3H),1.96~1.82(m,3H),1.69~1.16(m,12H),1.10(d,J=6.8Hz,3H),1.08(s,3H),0.71(s,3H).

[0073] 13C NMR(100MHz,Chloroform-d)δ204.79,170.23,170.21,135.92,124.85,74.38,69.20,55.79,50.79,49.27,42. 77,41.97,40.26,39.14,37.14,31.79,31.55,31.43,26.86,24.47,21.18,20.98,20.19,19.27,13.31,12.10.

[0074] MS (ESI) m / z 453.2631 [M+Na] + .

[0075] e. Wittig reaction to prepare the compound represented by formula (7):

[0076] The phosphorus ylide reagent is a compound having a structure shown in formula (8):

[0077] After the phosphorus ylide reagent (0.69 g, 2 mmol) was protected by nitrogen, the compound represented by the intermediate formula (6) prepared in step d (0.43 g, 1 mmol) was dissolved in 10 mL DMSO and added thereto, and the reaction solution was heated to 110°C and reacted for 5 h. After the reaction was completed by TLC detection, it was extracted with ethyl acetate, washed with water twice, and washed with saturated brine once, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude compound was separated by column chromatography (eluent: PE:EA=15:1, v / v) to obtain compound 7 with a reaction yield of 86%.

[0078] Characterization data:

[0079] 1 H NMR(400MHz,Chloroform-d)δ6.71(dd,1H),6.11(d,J=15.7Hz,1H),5.49(dt,1H),5.02(t,1H),4.88(m,1H),2.45(m,1H),2.36~2.21(m,2H),2.12~ 2.04(m,2H),2.03(s,3H),1.99(s,3H),1.94(m,2H),1.83~1.12(m,13H),1 .07(d,J=6.3Hz,3H),1.06(s,3H),1.03(m,2H),0.85(m,2H),0.68(s,3H).

[0080] 13C NMR(100MHz,Chloroform-d)δ200.44,170.18,170.16,151.95,135.81,127.93,124.87,74.33,69.16,56.24,54.74,42.46,41 .85,40.18,39.74,39.21,37.06,31.71,31.47,31.35,27.93,24.05,21.12,20.93,20.14,19.20,19.16,18.51,11.94,10.80.

[0081] MS (ESI) m / z 497.3270 [M+H] + .

[0082] f. hydrolysis to prepare the product calcipotriol intermediate represented by the product formula (1), i.e., calcipotriol intermediate:

[0083] The compound represented by the intermediate formula (7) prepared in step e (0.50 g, 1 mmol) and potassium carbonate (1.11 g, 8 mmol) were dissolved in 16 mL of methanol and 2 mL of water, and reacted at room temperature for 5 h, and then the reaction solution was heated to 35° C. and reacted for 2 h. After the reaction was completed by TLC detection, the pH of the reaction solution was adjusted to neutral, extracted with dichloromethane, separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude compound was separated by column chromatography (eluent: PE:EA=1:1, v / v) to obtain compound 1, with a reaction yield of 89%.

[0084] Characterization data:

[0085] 1 H NMR(400MHz,Chloroform-d)δ6.76(dd,1H),6.14(d,J=15.7Hz,1H),5.59(dt,1H),3.98(m,5.0Hz,1H),3.85(t,1H),2.42~2.25(m,3H),2.13~1.94 (m,4H),1.78~1.62(m,4H),1.56~1.45(m,5H),1.30~1.22(m,4H),1.12(d ,J=6.6Hz,3H),1.08~1.05(m,2H),1.04(s,3H),0.89(m,2H),0.73(s,3H).

[0086] 13C NMR(100MHz,Chloroform-d)δ200.67,152.19,137.16,128.05,125.41,72.78,66.24,56.26,54.86,42.56,41. 56,41.46,41.22,39.87,39.19,38.10,31.70,31.57,28.02,24.22,20.11,19.32,19.25,18.51,11.98,10.89.

[0087] MS (ESI) m / z 413.3047 [M+H] + .

[0088] Example 2

[0089] The steps and methods of Example 1 were followed, except that the amount of the acid-binding agent triethylamine was adjusted in step a, the molar ratio of p-toluenesulfonyl chloride to the acid-binding agent to the compound represented by formula (2) was adjusted to 2:3:1, and the reaction time was adjusted to 5 h. The other operating steps were the same, and the intermediate compound 3 was obtained in a yield of 83%.

[0090] Example 3

[0091] According to the steps and methods of Example 1, the only difference is that DMAP is removed in step a, and the other steps are the same, and the intermediate compound 3 is obtained in a yield of 65%.

[0092] Example 4

[0093] The steps and methods of Example 1 were followed, except that in step a, the amounts of p-toluenesulfonyl chloride and the acid-binding agent triethylamine were adjusted, the molar ratio of p-toluenesulfonyl chloride to the acid-binding agent to the compound represented by formula (2) was adjusted to 2.3:5:1, and the reaction temperature was adjusted to room temperature. The other operating steps were the same, and the intermediate compound 3 was obtained with a yield of 78%.

[0094] Example 5

[0095] The steps and methods of Example 1 were followed, except that the amount of iodine was adjusted in step b, and the molar ratio of iodine to the compound represented by formula (3) was adjusted to 0.3:1. The other steps were the same, and the yield of intermediate compound 4 was 90%.

[0096] Example 6

[0097] According to the steps and methods of Example 1, the only difference is that in step b, the reaction temperature is adjusted to 70° C. and the reaction time is adjusted to 2 h. The other operation steps are the same, and the yield of intermediate compound 4 is 87%.

[0098] Example 7

[0099] According to the steps and methods of Example 1, the only difference is that in step b, the reaction temperature is adjusted to room temperature and the reaction time is adjusted to 2 h. The other operation steps are the same, and the yield of intermediate compound 4 is 65%.

[0100] Example 8

[0101] The steps and methods of Example 1 were followed, except that the amounts of anhydrous calcium chloride and sodium borohydride were adjusted in step c so that the molar ratio of the calcium borohydride reducing agent to the compound represented by formula (4) was adjusted to 3:1, and the reaction time was adjusted to 3 h. The other operating steps were the same, and the yield of the intermediate compound 5 was 57%.

[0102] Example 9

[0103] The steps and methods of Example 1 were followed, except that the amounts of anhydrous calcium chloride and sodium borohydride were adjusted in step c so that the molar ratio of the calcium borohydride reducing agent to the compound represented by formula (4) was adjusted to 12:1, the DMAP in the first step was removed, and the reaction time was adjusted to 3 h. The other operating steps were the same, and the intermediate compound 5 was finally obtained with a total yield of 70% in the two-step reaction.

[0104] Comparison of the experimental results of Example 9 with those of Example 1 shows that: in step c, the DMAP catalyst is not added during the reduction reaction, but the reaction can be carried out normally by significantly increasing the amount of calcium borohydride reducing agent. However, in Example 1, the use of DMAP catalyst for the reduction reaction can significantly reduce the molar equivalent of calcium borohydride.

[0105] Example 10

[0106] The steps and methods of Example 1 were followed, except that the amount of triethylamine was adjusted in step d, the molar ratio of the base to the compound represented by formula (5) was adjusted to 3:1, and the reaction time was adjusted to 3 h. The other steps were the same, and the yield of intermediate compound 6 was 88%.

[0107] Embodiment 11

[0108] According to the steps and methods of Example 1, the only difference is that in step d, triethylamine is replaced by an equal molar amount of pyridine. The other operation steps are the same, and the intermediate compound 6 is obtained in a yield of 78%.

[0109] Example 12

[0110] The steps and methods of Example 1 were followed, except that the amount of triethylamine was adjusted in step d, the molar ratio of the base to the compound represented by formula (5) was adjusted to 3:1, the reaction temperature was adjusted to 80°C and the reaction time was adjusted to 3 h. The other operating steps were the same, and the yield of intermediate compound 6 was 65%.

[0111] Example 13

[0112] The steps and methods of Example 1 were followed, except that the amount of the phosphorus ylide reagent was adjusted in step e, and the molar ratio of the phosphorus ylide reagent to the compound represented by formula (6) was adjusted to 4:1. The other steps were the same, and the yield of the intermediate compound 7 was 86%.

[0113] Embodiment 14

[0114] The steps and methods of Example 1 were followed, except that in step e, the solvent was changed to an equal volume of THF, the amount of the phosphorus ylide reagent was adjusted, the molar ratio of the phosphorus ylide reagent to the compound represented by formula (6) was adjusted to 4:1, and the reaction temperature was adjusted to 65°C. The other operating steps were the same, and the intermediate compound 7 was obtained with a yield of 69%.

[0115] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. A method for preparing a calcipotriol intermediate, characterized in that The structural formula of the intermediate is shown in formula (1), which is prepared by using 1α-hydroxydihydroquinone as shown in formula (2) as a raw material, and sequentially undergoing sulfonylation, isomerization, reduction / acylation, oxidation, Wittig, and hydrolysis steps, specifically comprising the following steps: a. Sulfonylation The 1α-hydroxydihydroquinone represented by formula (2) is used as a raw material, and a sulfonylation reaction is carried out with a sulfonylating agent and an acid-binding agent in an organic solvent medium under the action of a catalyst to obtain a compound represented by formula (3). The reaction formula is as follows: b. Acetylation, isomerization Under the catalysis of iodine, the compound (3) prepared in step a is subjected to an acylation reaction with an acylating agent and an enol rearrangement is simultaneously carried out to prepare a compound as shown in formula (4), and the reaction formula thereof is shown below: c. Reduction / acylation Under the action of catalyst DMAP, the compound (4) prepared in step b undergoes a reduction reaction with a reducing agent in an organic solvent medium to obtain a crude compound, which is then subjected to an acetylation reaction after post-treatment to obtain a compound as shown in formula (5), and the reaction formula thereof is shown below: d. Oxidation The compound (5) prepared in step c is dissolved in an organic solvent medium and subjected to an oxidation reaction to generate a compound as shown in formula (6), the reaction formula of which is shown below: e. Wittig reaction The compound (6) prepared in step d is dissolved in an organic solvent medium, and reacts with the phosphorus ylide reagent shown in formula (8) to generate a compound shown in formula (7), and the reaction formula is as follows: f. Hydrolysis The compound (7) prepared in step e is dissolved in an organic solvent medium to undergo a hydrolysis reaction to obtain a calcipotriol intermediate product as shown in formula (1), the reaction formula of which is shown below:

2. The method for preparing a calcipotriol intermediate according to claim 1, characterized in that In step a, the sulfonylating agent is one of the following: p-toluenesulfonyl chloride, benzenesulfonyl chloride and methanesulfonyl chloride, preferably p-toluenesulfonyl chloride; the molar ratio of the sulfonylating agent to compound (2) is 1 to 3:1, preferably 1.8 to 2:1; The acid-binding agent used in step a is one or more of the following: triethylamine, DMAP, pyridine, trimethylpyridine, preferably triethylamine; the molar ratio of the acid-binding agent to compound (2) is 2 to 6:1, preferably 3.5 to 4:1; The catalyst in step a is DMAP, and the molar ratio of DMAP to compound (2) is 0.05 to 0.4:1, preferably 0.1 to 0.2:

1.

3. The method for preparing a calcipotriol intermediate according to claim 1, characterized in that The reaction temperature in step a is 25 to 40° C., and step a uses DCM as a reaction solvent. After the reaction in step a is completed, the following post-treatment step is also included: adjusting the pH of the reaction solution to neutral, adding dichloromethane for extraction, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, and the crude product is separated by column chromatography, and the eluent is a PE-EA mixed solvent with a volume ratio of 0.5 to 2:1, thereby obtaining compound (3).

4. The method for preparing a calcipotriol intermediate according to claim 1, characterized in that The acylating agent used in step b is isopropenyl acetate IPA or allyl acetate; the mass ratio of the volume of the acylating agent to the compound represented by formula (3) is 5 to 20 mL / g; The molar ratio of the catalyst iodine to the compound (3) used in step b is 0.05 to 0.3:1, preferably 0.1 to 0.15:1; The reaction temperature in step b is 20 to 95° C., preferably 85 to 90° C.; after the reaction in step b is completed, the following post-treatment step is further included: the reaction solution is extracted with ethyl acetate, washed with saturated sodium bisulfite solution and saturated brine in sequence, and the liquid is separated, the organic layer is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, and the crude product is separated by column chromatography, and the eluent is a PE-EA mixed solvent with a volume ratio of 5 to 10:1, so as to obtain compound (4).

5. The method for preparing a calcipotriol intermediate according to claim 1, characterized in that The reducing agent used in step c is one of the following: sodium borohydride, calcium borohydride, potassium borohydride, preferably calcium borohydride; The molar ratio of the reducing agent to the compound (4) in step c is 3 to 12:1, preferably 5 to 7:1; the molar ratio of the catalyst DMAP to the compound (4) is 0.1 to 0.4:1, preferably 0.2 to 0.25:

1.

6. The method for preparing a calcipotriol intermediate according to claim 1, characterized in that The temperature of the reduction reaction in step c is -10 to 0°C, preferably -5 to -2°C; the reaction solvent of the reduction reaction in step c is methanol-THF in a volume ratio of 0.5 to 1:1, and the following post-treatment steps are included after the reduction reaction is completed: removing insoluble matter in the reaction solution by suction filtration, adding dichloromethane to the filtrate and slowly dropping dilute hydrochloric acid under vigorous stirring, the reaction solution will slowly change from turbid to clear liquid during the dropping process, when the liquid becomes clear, stop dropping dilute hydrochloric acid, wash with saturated sodium bicarbonate solution and saturated brine in turn, separate the liquids, dry the organic layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product, which is directly used in the next step of acetylation reaction for preparing compound (5).

7. The method for preparing a calcipotriol intermediate according to claim 1, characterized in that The acetylation reaction in step c is carried out by reacting with acetic anhydride in the presence of DMAP / triethylamine, using DCM as the reaction solvent, and the molar ratio of DMAP to compound (4) in the acetylation reaction is 0.1 to 0.4:1, preferably 0.2 to 0.25:1; the molar ratio of triethylamine or acetic anhydride to compound (4) in the acetylation reaction is 1 to 3:1, preferably 2 to 2.5:1; The acetylation reaction in step c is carried out at room temperature. After the reaction is completed, the following post-treatment steps are further included: the reaction solution is washed with saturated brine and separated, the organic layer is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product compound is separated by column chromatography, and the eluent is a PE-EA mixed solvent with a volume ratio of 5 to 15:1, thereby obtaining compound (5).

8. The method for preparing a calcipotriol intermediate according to claim 1, characterized in that The oxidation reaction in step d is carried out in the presence of a base, which is one of the following: pyridine, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, preferably triethylamine; the molar ratio of the base in step d to compound (5) is 1 to 5:1, preferably 3 to 4:1; The reaction temperature in step d is 80 to 140° C., preferably 100 to 110° C.; step d uses DMSO as the reaction solvent and oxidant, and the volume amount of DMSO is 4 to 8 mL / mmol based on the amount of compound (5). After the reaction is completed, the following post-treatment steps are also included: adjusting the pH of the reaction solution to neutral, adding ethyl acetate for extraction, washing with water and saturated brine in sequence, drying the organic layer over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, and the crude compound is separated by column chromatography, and the eluent is a PE-EA mixed solvent with a volume ratio of 10 to 20:1, so as to obtain compound (6).

9. The method for preparing a calcipotriol intermediate according to claim 1, characterized in that The molar ratio of the phosphorus ylide reagent in step e to the compound represented by formula (6) is 1 to 6:1, preferably 1.8 to 2:1; The reaction temperature in step e is 65 to 130° C., preferably 100 to 110° C.; step e uses DMSO as the reaction solvent, and after the reaction is completed, the following post-treatment steps are also included: adding ethyl acetate for extraction, washing with water and saturated brine in sequence, drying the organic layer over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, and the crude compound is separated by column chromatography, and the eluent is a PE-EA mixed solvent with a volume ratio of 10 to 20:1, so as to obtain compound (7).

10. The method for preparing a calcipotriol intermediate according to claim 1, characterized in that In step f, the hydrolysis reaction is carried out in the presence of an inorganic base, and the inorganic base is one or both of the following: sodium carbonate or potassium carbonate. The molar ratio of the inorganic base in step f to compound (7) is 2 to 10:1, preferably 7 to 8:1.

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