Preparation method of 1 alpha-hydroxyl dinorhydrin

Abstract

The invention discloses a preparation method of 1alpha-hydroxyl dinorhydrin, the structural formula of the 1alpha-hydroxyl dinorhydrin is shown as a formula (1), the method comprises the following steps: by taking dinorhydrin shown as a formula (2) as a raw material, preparing the 1alpha-hydroxyl dinorhydrin through five steps of acylation, bromination, debromination, epoxidation / hydrolysis and ring opening, and the reaction formula is as follows: # imgabs0 #. All reactions are carried out under normal pressure, reagents with high toxicity are not used in the reaction process, the reaction yield is high, the total yield of the five-step reaction can reach 48.46%, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a method for preparing 1α-hydroxydihydroquinolone, belonging to a method for preparing steroid compounds. Background Art

[0002] Active vitamin D can regulate the physiological activities of human and animal bodies. In addition to promoting the absorption and metabolism of calcium and phosphorus in human and animal bodies, it also has pharmacological effects such as anti-tumor, cardiovascular disease, infectious disease, prevention of hypertension, obesity, etc. At present, the active vitamin D drugs that are widely used in clinical practice include alfacalcidol, calcitriol, calcipotriol, tacalcitol, doxorcalciferol, etc.

[0003] In 2022, patent CN202211507515.1 reported a route for preparing and synthesizing 1α-hydroxycholesterol using 1α-hydroxy-4-cholestene-3-one.

[0004] 1α-Hydroxy-bis-decanoate is the product of 21-hydroxy-20-methyl-pregnane-4-ene-3-one (BA) after the hydroxyl group is introduced into the 1st position of the A ring. Its structure is consistent with that of 1α-hydroxy-4-cholesten-3-one on the steroidal AB ring, so 1α-hydroxycholesterol can be prepared through a similar reaction. The side chain of 1α-hydroxy-bis-decanoate is a hydroxyl group, which can be connected to different side chains through reactions such as Grignard reaction and Wittig reaction for the synthesis of active vitamin D derivatives. Its structural formula is as follows:

[0005]

[0006] There is no report on the synthesis of 1α-hydroxy bis-decanoic acid alcohol using bis-decanoic acid alcohol (BA) as raw material.

[0007] The object of the present invention is to provide a method for synthesizing 1α-hydroxybis-decyl alcohol with simple operation, high process safety, mild reaction conditions and fast reaction rate.

[0008] The technical solution adopted by the present invention is as follows:

[0009] A method for preparing 1α-hydroxy bis-decanoic acid alcohol, using bis-decanoic acid alcohol as a raw material, sequentially undergoing five steps of acylation, bromination, debromination, epoxidation / hydrolysis, and ring opening to prepare the 1α-hydroxy bis-decanoic acid alcohol, specifically comprising the following steps:

[0010] a. Acylation

[0011] The bis-decyl alcohol shown in formula (2) is used as a raw material, and an acylation reaction is carried out with an acylating agent and an acid-binding agent in an organic solvent medium under the action of a catalyst DMAP to obtain a compound shown in formula (3). The reaction process is as follows:

[0012]

[0013] b. Bromine

[0014] Under the action of a free radical initiator, the compound represented by formula (3) prepared in step a undergoes a bromination reaction with a bromination reagent to generate a compound represented by formula (4), and the reaction process is as follows:

[0015]

[0016] c. Debromination

[0017] The compound represented by formula (4) prepared in step b is subjected to a debromination reaction to obtain a trienone product represented by formula (5), and the reaction process is as follows:

[0018]

[0019] d. Epoxidation / hydrolysis

[0020] The trienone represented by formula (5) prepared in step c is reacted with hydrogen peroxide and an inorganic base to obtain a compound represented by formula (6). The reaction process is as follows:

[0021]

[0022] e. Open loop

[0023] The compound represented by formula (6) prepared in step d is subjected to a ring-opening reaction with formic acid under alkaline conditions in the presence of a catalyst to obtain a product 1α-hydroxybis-decyl alcohol represented by formula (1). The reaction process is as follows:

[0024]

[0025] Furthermore, in step a, the molar ratio of the acylating agent to the dihydrochloric acid alcohol is 1 to 3:1, preferably 1.2 to 1.5:1, the molar ratio of the acid-binding agent to the dihydrochloric acid alcohol is 0.5 to 6:1, preferably 1.5 to 2:1; the molar ratio of the catalyst DMAP to the dihydrochloric acid alcohol is 0.01 to 0.1:1, preferably 0.02 to 0.03:1.

[0026] Furthermore, the acylating agent used in step a is one of the following: acyl chloride, acid anhydride, isopropenyl acetate, allyl acetate, preferably acid anhydride; wherein the acid anhydride is one of acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, benzoic anhydride, succinic anhydride or phthalic anhydride; and the acyl chloride is one of acetyl chloride, propionyl chloride, butyryl chloride or benzoyl chloride.

[0027] Furthermore, the acid binding agent used in step a is one or more of the following: DMAP, triethylamine, diethylamine, ethylenediamine, ammonia, piperidine, pyridine, collidine, DBU, DABCO, preferably DMAP, triethylamine.

[0028] Furthermore, the reaction in step a is carried out using dichloromethane, ethyl acetate or n-hexane as solvent, the reaction temperature is 5°C to room temperature, and after the reaction is completed by TLC detection, the following post-treatment steps are also included: adding water to quench, adjusting the pH to neutral, washing the organic phase with water, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, and the obtained crude product is added to methanol for pulping and purification to obtain the compound shown in formula (3).

[0029] Furthermore, in step b, the molar ratio of the brominating agent to the compound represented by formula (3) is 2 to 4:1, preferably 3 to 3.5:1; the brominating agent is one of the following: N-bromosuccinimide, N-chlorosuccinimide, NBPI (N-bromophthalimide), NCPI (N-chlorophthalimide), N,N-dibromo-p-toluenesulfonamide, TBCA, TCCA, dibromohydantoin, dichlorohydantoin, liquid bromine, preferably N-bromosuccinimide or liquid bromine.

[0030] Furthermore, the free radical initiator used in step b is one of the following: dibenzoyl peroxide, azobisisobutyronitrile, azobisisoheptanenitrile, isopropylbenzene hydroperoxide, tert-butyl hydroperoxide, preferably dibenzoyl peroxide.

[0031] Furthermore, the reaction in step b uses 1,4-dioxane as the reaction solvent, the reaction temperature is 10 to 75° C., preferably 35 to 45° C., and after the reaction is completed by TLC detection, the following post-treatment steps are also included: adding sodium bisulfite aqueous solution for quenching, extracting the organic phase with dichloromethane and water, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound represented by formula (4).

[0032] Furthermore, the debromination reaction in step c is carried out in the presence of lithium bromide and lithium carbonate, the molar ratio of lithium bromide to formula (4) is 1 to 8:1, preferably 2 to 4:1, and the molar ratio of lithium carbonate to formula (4) is 1 to 10:1, preferably 2.5 to 3:1.

[0033] Furthermore, the reaction in step c uses DMF as a reaction solvent, the reaction temperature is 50 to 180° C., preferably 140 to 150° C., and after the reaction is completed by TLC detection, the following post-treatment steps are also included: removing insoluble matter in the reaction solution by suction filtration, extracting with ethyl acetate, washing the organic layer with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure and separating by column chromatography, the eluent being a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5 to 10:1, to obtain the trienone product shown in formula (5).

[0034] Furthermore, in step d, the molar ratio of hydrogen peroxide to trienone is 1 to 7:1, preferably 2.5 to 3:1, and the molar ratio of inorganic base to trienone is 0.5 to 2.2:1, preferably 1 to 1.2:1.

[0035] Furthermore, in step d, the inorganic base is one of the following: sodium hydroxide, potassium hydroxide.

[0036] Furthermore, step d uses methanol, ethanol or tetrahydrofuran as the reaction solvent, the reaction temperature is 0°C to room temperature, and after the TLC detection reaction is completed, it also includes the following post-treatment steps: adjusting the pH of the reaction solution to neutral, extracting with dichloromethane, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound represented by formula (6).

[0037] Furthermore, in step e, the molar ratio of formic acid to the compound of formula (6) is 2 to 10:1, preferably 2.5 to 5:1; in step e, the base is triethylamine, and the molar ratio of triethylamine to the compound of formula (6) is 2 to 12:1, preferably 3 to 6:1; the catalyst is palladium carbon with a palladium loading of 5 to 15%, and the ratio of the mass of palladium carbon to the molar amount of the compound of formula (6) is 50 to 100:1, preferably 60 to 70:1, the unit of mass is g, and the unit of molar amount is mol.

[0038] Furthermore, in step e, the reaction temperature is room temperature, and after the reaction is completed by TLC monitoring, the following post-treatment steps are also included: filtering to remove insoluble matter in the reaction solution, adjusting the pH of the reaction solution to neutral, extracting with ethyl acetate, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the target product.

[0039] The 1α-hydroxydihydroquinone synthesized by the invention is a key intermediate for synthesizing vitamin D derivatives.

[0040] By adopting the above technology, the present invention has the following beneficial effects: the present invention has simple operation, mild reaction conditions, fast reaction rate, high reaction yield, and is suitable for large-scale preparation and production. DETAILED DESCRIPTION

[0041] The present invention will be further described below in conjunction with specific embodiments.

[0042] Example 1

[0043] According to the preparation method of the present invention, 1α-hydroxydihydrocholesterol is prepared, and 1α-hydroxycholesterol is further prepared.

[0044] a. Acetylation of acetic anhydride to prepare a compound represented by intermediate formula (3):

[0045] BA (1 mmol), DMAP (0.02 mmol) and triethylamine (1.5 mmol) were dissolved in 5 mL of dichloromethane. Acetic anhydride (1.5 mmol) was added dropwise to the above reaction solution at room temperature. After the addition was completed, the reaction was allowed to proceed for 0.5 h. The reaction progress was monitored by TLC. After the reaction was completed, water was added to quench the reaction. The pH was adjusted to neutral with hydrochloric acid. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was added to methanol for pulping and purification to obtain white solid compound 3 (0.37 g, yield 99%).

[0046] Characterization data:

[0047] 1 H NMR(600MHz,Chloroform-d)δ5.70(s,1H),4.06(dd,1H),3.75(dd,1H),2.44~2.25(m,4H),2.03(s,3H),2.02~1.98( m,2H),1.87~1.17(m,12H),1.16(s,3H),1.12(m,1H),1.02(m,1H),0.99(d,J=6.6Hz,3H),0.92(m,1H),0.72(s,3H).

[0048] 13 C NMR(150MHz,Chloroform-d)δ199.34,171.21,171.17,123.66,69.26,55.41,53.60,52.53,42.40,39. 27,38.41,35.60,35.55,35.47,33.81,32.72,31.84,27.44,24.08,20.85,20.83,17.22,16.94,11.84.

[0049] MS (ESI) m / z 373.62 [M+H] + .

[0050] b. Bromination reaction to prepare an intermediate compound as shown in formula (4):

[0051] The compound (1 mmol) of the intermediate formula (3) prepared in step a and NBS (3.5 mmol) were dissolved in 10 mL of 1,4-dioxane, and BPO (0.02 mmol) was added dropwise to the reaction solution after heating to 45°C, and the reaction was continued for 5 h. The reaction was monitored by TLC. After the reaction was completed, an aqueous sodium bisulfite solution was added to quench the reaction. The organic phase was extracted with dichloromethane and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a black oily liquid compound 4 (0.48 g, yield 90%).

[0052] Characterization data:

[0053] 1 H NMR(400MHz,DMSO-d6)δ6.10(s,1H),5.43(dd,1H),5.37(m,1H),3.99(dd,1H),3.72(dd,1H),2.53(m,2H),2.09(m,2H),2.00(s,3H),1.98~ 1.82(m,2H),1.80~1.63(m,3H),1.56(s,3H),1.52~1.27(m,3H),1.22~1.13(m,2H),1.11~1.00(m,3H),0.97(d,J=6.5Hz,3H),0.73(s,3H).

[0054] 13 C NMR (100MHz, DMSO) δ191.82,170.72,165.97,124.65,68.72,54.08,52.47,52.23,51.92,51.45,4 9.40,42.27,41.57,40.17,38.72,35.42,30.17,27.17,23.97,22.31,20.93,20.55,17.13,11.89.

[0055] MS (ESI) m / z 531.0911 [M+H] + .

[0056] c. Debromination reaction to prepare the intermediate trienone as shown in formula (5):

[0057] The compound (1 mmol) of the intermediate formula (4) prepared in step b, lithium bromide (2 mmol) and lithium carbonate (3 mmol) were dissolved in 10 mL of DMF, and the reaction solution was heated to 150° C. and reacted for 1 h. After TLC detection, the insoluble matter in the reaction solution was removed by suction filtration, extracted with ethyl acetate, and the organic layer was washed with water for many times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 8:1 as an eluent) to obtain a yellow solid compound 5 (0.31 g, yield 85%).

[0058] Characterization data:

[0059] 1H NMR(400MHz,Chloroform-d)δ7.03(d,J=10.1Hz,1H),6.20(m,2H),6.04~5.99(dd,1H),5.99~5.94(d,J=1.9Hz,1H),4.05(dd,1H),3.74 (dd,1H),2.23(m,1H),2.05(m,1H),2.02(s,3H),1.93~1.54(m,5H),1.43~1.18(m,6H),1.16(s,3H),0.99(d,J=6.6Hz,3H),0.77(s,3H).

[0060] 13 C NMR(100MHz,Chloroform-d)δ186.15,171.11,162.44,152.75,138.26,127.90,127.42,123.52,69.07,5 3.09,52.25,48.04,42.92,40.98,39.01,37.94,35.52,27.33,23.52,21.58,20.80,20.51,16.90,11.82.

[0061] MS (ESI) m / z 369.60 [M+H] + .

[0062] d. Epoxidation / hydrolysis reaction to prepare the compound represented by the product formula (6):

[0063] The compound (20 mmol) of the intermediate formula (5) prepared in step c and sodium hydroxide (24 mmol) were weighed and dissolved in 80 mL of methanol, and 30% hydrogen peroxide (the amount added was calculated as 60 mmol of H2O2) was slowly added dropwise, and the reaction was carried out at room temperature for 1 hour. After TLC monitoring, the reaction solution was adjusted to neutral, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid compound 6 (5.4 g, yield 79%).

[0064] Characterization data:

[0065] 1H NMR(400MHz,Chloroform-d)δ6.07(m,2H),5.63(m,1H),3.63(dd,1H),3.57(d,J=4.0Hz,1H),3.42(dd,1H),3.37(dd,1H),2.21(m,1H),2 .08(m,1H),1.95~1.75(m,3H),1.68~1.48(m,4H),1.42~1.34(m,1H),1.30~1.22(m,3H),1.17(s,3H),1.05(d,J=6.6Hz,3H),0.78(s,3H).

[0066] 13 C NMR(100MHz,Chloroform-d)δ194.66,158.76,140.35,127.66,119.25,67.58,59.26,54.52,52. 89,52.03,45.82,42.88,38.92,38.69,38.51,37.37,27.41,23.65,21.00,18.32,16.59,11.76.

[0067] MS (ESI) m / z 343.53 [M+H] + .

[0068] e. Ring-opening reaction to prepare the product 1α-hydroxy dihydrochloride represented by formula (1), namely 1α-hydroxy dihydrochloride:

[0069] The compound (1 mmol) of the intermediate formula (6) prepared in step d and palladium carbon (68 mg) with a Pd loading of 10% were dissolved in 4 mL of THF, and triethylamine (6 mmol) and formic acid (5 mmol) were added in sequence, and the mixture was reacted at room temperature for 24 h. After the reaction was completed by TLC monitoring, the insoluble matter in the reaction solution was filtered out, the reaction solution was adjusted to neutral, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1α-hydroxybis-decanoic acid (0.28 g, yield 81%).

[0070] Characterization data:

[0071] 1H NMR (400MHz, DMSO-d6) δ5.59(s,1H),4.85(m,1H),4.26(s,1H),3.88(s,1H),3.40(d,J=10.5Hz,1H),3.06(t,1H) ,2.66(d,J=16.3Hz,1H),2.43~2.21(m,3H),1.96~1.13(m,15H),1.10(s,3H),0.95(d,J=6.6Hz,3H),0.69(s,3H).

[0072] 13 C NMR (100MHz, DMSO) δ197.05,166.97,122.74,70.62,65.86,55.64,52.52,44.17,43.02,42 .68,42.23,39.28,38.81,34.88,32.46,31.15,27.47,24.25,19.99,18.20,17.13,12.07.

[0073] MS (ESI) m / z 347.2581 [M+H] + .

[0074] Example 2

[0075] According to the steps and methods of Example 1, the only difference is that in step a, triethylamine is removed and the reaction time is adjusted to 1 h. The other operation steps are the same, and the intermediate compound 3 is obtained in a yield of 79%.

[0076] Example 3

[0077] According to the steps and methods of Example 1, the only difference is that in step a, triethylamine is replaced by an equal molar amount of DMAP, and the reaction time is adjusted to 1 h. The other operating steps are the same, and the yield of intermediate compound 3 is 99%.

[0078] Example 4

[0079] According to the steps and methods of Example 1, the only difference is that in step a, acetic anhydride is replaced by an equal molar amount of benzoic anhydride. The other steps are the same, and the yield of intermediate compound 3 is 98%.

[0080] Example 5

[0081] According to the steps and methods of Example 1, the only difference is that in step a, the reaction temperature is adjusted to 5° C. and the reaction time is adjusted to 1 h. The other operation steps are the same, and the yield of intermediate compound 3 is 99%.

[0082] Example 6

[0083] The steps and methods of Example 1 were followed, except that the amount of bromination reagent NBS was reduced in step b, so that the molar ratio of bromination reagent NBS to compound 3 was adjusted to 2.5:1. The other steps were the same, and the yield of intermediate compound 4 was 68%.

[0084] Example 7

[0085] According to the steps and methods of Example 1, the only difference is that in step b, NBS is replaced by an equal molar amount of TBCA, and the other operation steps are the same, and the intermediate compound 4 is obtained with a yield of 91%.

[0086] Example 8

[0087] According to the steps and methods of Example 1, the only difference is that in step b, BPO is replaced by an equal molar amount of AIBN, and the other operation steps are the same, and the intermediate compound 4 is obtained in a yield of 89%.

[0088] Example 9

[0089] According to the steps and methods of Example 1, the only difference is that the reaction temperature is adjusted to 60° C. in step b. The other operation steps are the same, and the yield of intermediate compound 4 is 79%.

[0090] Example 10

[0091] The steps and methods of Example 1 were followed, except that in step c, the amounts of lithium bromide and lithium carbonate were adjusted so that the molar ratio of lithium bromide, lithium carbonate and compound 4 was adjusted to 4:6:1. The other steps were the same, and the yield of intermediate compound 5 was 85%.

[0092] Embodiment 11

[0093] According to the steps and methods of Example 1, the only difference is that in step c, the reaction temperature is adjusted to 130° C. and the reaction time is adjusted to 2 h. The other operation steps are the same, and the yield of intermediate compound 5 is 84%.

[0094] Example 12

[0095] According to the steps and methods of Example 1, the only difference is that in step c, the reaction temperature is adjusted to 110° C. and the reaction time is adjusted to 2 h. The other operation steps are the same, and the yield of intermediate compound 5 is 68%.

[0096] Example 13

[0097] The steps and methods of Example 1 were followed, except that the amounts of hydrogen peroxide and sodium hydroxide were adjusted in step d so that the molar ratio of hydrogen peroxide, sodium hydroxide and compound 5 was adjusted to 5:2.2:1. The other steps were the same, and the yield of intermediate compound 6 was 78%.

[0098] Embodiment 14

[0099] The steps and methods of Example 1 were followed, except that the amount of sodium hydroxide was adjusted in step d so that the molar ratio of sodium hydroxide to compound 5 was adjusted to 0.5:1 and the reaction time was adjusted to 2 h. The other steps were the same, and the yield of intermediate compound 6 was 38%.

[0100] Embodiment 15

[0101] According to the steps and methods of Example 1, the only difference is that in step d, sodium hydroxide is replaced by potassium hydroxide of the same molar amount, and the other operation steps are the same, and the yield of intermediate compound 6 is 77%.

[0102] Example 16

[0103] The steps and methods of Example 1 were followed, except that the amounts of sodium hydroxide and hydrogen peroxide were adjusted in step d so that the molar ratio of hydrogen peroxide, sodium hydroxide and compound 5 was adjusted to 5:2.2:1, the reaction temperature was adjusted to 0°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 46%.

[0104] Embodiment 17

[0105] The steps and methods of Example 1 were followed, except that the amounts of formic acid and triethylamine were adjusted in step e so that the molar ratio of formic acid, triethylamine and compound 6 was adjusted to 2.5:3:1. The other steps were the same, and the yield of the target product 1 was 74%.

[0106] Embodiment 18

[0107] The steps and methods of Example 1 were followed, except that the amounts of formic acid and triethylamine were adjusted in step e so that the molar ratio of formic acid, triethylamine and compound 6 was adjusted to 2:2:1, and the reaction time was adjusted to 36 h. The other operating steps were the same, and the yield of the target product 1 was 50%.

[0108] Application Examples

[0109] The 1α-hydroxydihydrocholesterol prepared in Example 1 can be used to prepare 1α-hydroxycholesterol, and the reaction scheme is as follows:

[0110]

[0111] 1) Sulfonylation to prepare an intermediate compound as shown in formula (7):

[0112] 1α-Hydroxybis-decyl alcohol (1 mmol) was dissolved in 5 mL of DCM, and DMAP (0.2 mmol), triethylamine (4 mmol) and TsCl (2 mmol) were added, and the temperature was raised to 40°C for 2 h. After the reaction was completed by TLC monitoring, the reaction solution was adjusted to neutral, extracted with dichloromethane, 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, volume ratio) to obtain compound 7 (yield 96%).

[0113] Characterization data:

[0114] 1 H 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).

[0115] 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.

[0116] MS (ESI) m / z 501.2667 [M+H] + .

[0117] 2) Acetylation and isomerization to prepare an intermediate compound as shown in formula (8):

[0118] Compound 7 (1 mmol) was dissolved in 6 mL of isopropenyl acetate, and the reaction solution was heated to 90°C, and iodine (0.1 mmol) was added, and the reaction was refluxed for 0.5 h. After the reaction was completed by TLC detection, the solid impurities produced in the reaction solution were filtered out, the filtrate was extracted with ethyl acetate, and washed with saturated sodium bisulfite solution and saturated brine in sequence, 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 = 8: 1, volume ratio) to obtain compound 8 (yield 90%).

[0119] Characterization data:

[0120] 1 H 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),1.41( m,1H),1.32(m,1H),1.27~1.05(m,6H),1.02(s,3H),0.95(d,J=6.6Hz,3H),0.65(s,3H).

[0121] 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.

[0122] MS (ESI) m / z 607.2703 [M+Na] + .

[0123] 3) Reduction and hydrolysis to prepare an intermediate compound as shown in formula (9):

[0124] Anhydrous calcium chloride (5mmol) and DMAP (0.2mmol) were dissolved in 7mL methanol, and then the reaction solution was cooled to -5°C, sodium borohydride (10mmol) was added and stirred for 30min, and then compound 8 (1mmol) was dissolved in 10mL THF and slowly added dropwise to the above reaction solution for 2h. After the reaction was completed by TLC detection, the insoluble matter in the reaction solution was removed by suction filtration, a small amount of dichloromethane was added to the filtrate, and 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 with saturated brine and separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude compound and 0.5 g of potassium hydroxide were added to 8 mL of methanol and reacted at room temperature. After the reaction was completed by TLC, the pH of the reaction solution was adjusted to neutral, extracted with dichloromethane, washed with saturated brine, 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, volume ratio) to obtain compound 9 (total yield of two-step reaction was 70%).

[0125] Characterization data:

[0126] 1 H NMR (400MHz, Chloroform-d) δ7.77(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),5.56(d,J=5.0Hz,1H),3.97(m,2H),3.82(t,1H),3.77(dd,1H ),2.44(s,3H),2.41~2.22(m,2H),2.09~1.89(m,3H),1.75~1.41(m,11H),1.18(m,3H),1.00(s,3H),0.97(d,J=6.5Hz,3H),0.63(s,3H).

[0127] 13 C NMR(150MHz,Chloroform-d)δ144.48,137.17,132.97,129.64,127.78,125.35,75.48,72.75,66.25,56.03,51.64 ,42.29,41.53,41.36,41.22,38.97,38.11,36.06,31.70,31.54,27.28,24.18,21.52,20.06,19.29,16.73,11.66.

[0128] MS (ESI) m / z 525.2632 [M+Na] + .

[0129] 4) coupling reaction to prepare the target product 1α-hydroxycholesterol as shown in formula (10):

[0130] Metal magnesium chips (24 mmol) were added to a reaction flask, 1-bromo-3-methylbutane (12 mmol) was dissolved in 20 mL of anhydrous redistilled THF, and the mixture was added dropwise in two steps. Under nitrogen protection, 1.5 mL of 1-bromo-3-methylbutane tetrahydrofuran solution was first added to the reaction flask, and then 0.1 mL of 1 M methylmagnesium bromide tetrahydrofuran solution was added thereto. The temperature was raised to 65° C. for reflux. When the surface of the magnesium turned slightly black, the reaction solution was moved to room temperature and the remaining 1-bromo-3-methylbutane tetrahydrofuran solution was slowly added. After the addition was completed, the reaction was kept warm for 1 h until the surface of the magnesium chips turned completely black, thereby obtaining a reaction solution containing isopentylmagnesium bromide. Take another reaction bottle, add copper chloride (0.1 mmol) and compound 9 (1 mmol), under nitrogen protection, add 5 mL of anhydrous redistilled THF, cool the reaction solution to 0°C, add the reaction solution containing isopentylmagnesium bromide prepared above, react for 5 hours, and after TLC detection, quench the reaction with hydrochloric acid, adjust the reaction solution to neutral, extract with dichloromethane, wash with saturated brine, separate the liquids, dry the organic layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude compound is separated by column chromatography (eluent PE:EA=2:1, volume ratio) to obtain 1α-hydroxycholesterol (yield 93%).

[0131] Characterization data:

[0132] 1 H NMR(400MHz,Chloroform-d)δ5.58(d,J=5.7Hz,1H),3.97(m,1H),3.84(t,1H),2.40~2.24(m,2H),2.10~1.99(m,2H),1.85~1. 39(m,10H),1.34~1.06(m,10H),1.02(s,3H),0.90(d,J=6.5Hz,3H),0.86(d,J=1.9Hz,3H),0.85(d,J=1.9Hz,3H),0.67(s,3H).

[0133] 13 C NMR(100MHz,Chloroform-d)δ137.20,125.49,72.79,66.24,56.47,55.99,42.16,41.55,41.49,41.21,39.37,3 9.35,38.05,36.04,35.65,31.71,31.65,28.07,27.88,24.21,23.71,22.70,22.43,20.15,19.33,18.60,11.70.

[0134] MS (ESI) m / z 403.3550 [M+H] + .

[0135] 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 1α-hydroxydihydroquinoline, characterized in that The 1α-hydroxy bis-decanoic acid alcohol is prepared by using the bis-decanoic acid alcohol shown in formula (2) as a raw material, sequentially undergoing five steps of acylation, bromination, debromination, epoxidation / hydrolysis, and ring opening, specifically comprising the following steps: a. Acylation The bis-decyl alcohol shown in formula (2) is used as a raw material, and an acylation reaction is carried out with an acylating agent and an acid-binding agent in an organic solvent medium under the action of a catalyst DMAP (4-dimethylaminopyridine) to obtain a compound shown in formula (3). The reaction process is as follows: b. Bromine Under the action of a free radical initiator, the compound represented by formula (3) prepared in step a undergoes a bromination reaction with a bromination reagent to generate a compound represented by formula (4), and the reaction process is as follows: c. Debromination The compound represented by formula (4) prepared in step b is subjected to a debromination reaction to obtain a trienone product represented by formula (5), and the reaction process is as follows: d. Epoxidation / hydrolysis The trienone represented by formula (5) prepared in step c is reacted with hydrogen peroxide and an inorganic base to obtain a compound represented by formula (6). The reaction process is as follows: e. Open loop The compound represented by formula (6) prepared in step d is subjected to a ring-opening reaction with formic acid under alkaline conditions in the presence of a catalyst to obtain a product 1α-hydroxybis-decyl alcohol represented by formula (1). The reaction process is as follows:

2. The method for preparing 1α-hydroxybisphenol A according to claim 1, characterized in that In step a, the molar ratio of the acylating agent to the dihydrochloric acid alcohol is 1 to 3:1, preferably 1.2 to 1.5:1, the molar ratio of the acid binding agent to the dihydrochloric acid alcohol is 0.5 to 6:1, preferably 1.5 to 2:1; the molar ratio of the catalyst DMAP to the dihydrochloric acid alcohol is 0.01 to 0.1:1, preferably 0.02 to 0.03:

1. The acylating agent used in step a is one of the following: acyl chloride, acid anhydride, isopropenyl acetate, allyl acetate, preferably acid anhydride; wherein the acid anhydride is one of acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, benzoic anhydride, succinic anhydride or phthalic anhydride; the acyl chloride is one of acetyl chloride, propionyl chloride, butyryl chloride or benzoyl chloride; The acid binding agent used in step a is one or more of the following: DMAP, triethylamine, diethylamine, ethylenediamine, ammonia, piperidine, pyridine, collidine, DBU, DABCO, preferably DMAP, triethylamine.

3. The method for preparing 1α-hydroxybisphenol A according to claim 1, characterized in that The reaction in step a is carried out using dichloromethane, ethyl acetate or n-hexane as solvent, and the reaction temperature is from 5°C to room temperature. After the reaction is completed by TLC detection, the following post-treatment steps are also included: adding water for quenching, adjusting the pH to neutral, washing the organic phase with water, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, and the obtained crude product is added to methanol for pulping and purification to obtain the compound shown in formula (3).

4. The method for preparing 1α-hydroxybis-decyl alcohol according to claim 1, characterized in that In step b, the molar ratio of the brominating agent to the compound represented by formula (3) is 2 to 4:1, preferably 3 to 3.5:1; the brominating agent is one of the following: N-bromosuccinimide, N-chlorosuccinimide, NBPI, NCPI, N,N-dibromo-p-toluenesulfonamide, TBCA, TCCA, dibromohydantoin, dichlorohydantoin, liquid bromine, preferably N-bromosuccinimide or liquid bromine; The free radical initiator used in step b is one of the following: dibenzoyl peroxide, azobisisobutyronitrile, azobisisoheptanenitrile, isopropylbenzene hydroperoxide, tert-butyl hydroperoxide, preferably dibenzoyl peroxide.

5. The method for preparing 1α-hydroxybisphenol A according to claim 1, characterized in that The reaction in step b uses 1,4-dioxane as the reaction solvent, the reaction temperature is 10 to 75° C., preferably 35 to 45° C., and after the reaction is completed by TLC detection, the following post-treatment steps are also included: adding sodium bisulfite aqueous solution for quenching, extracting the organic phase with dichloromethane and water, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound represented by formula (4).

6. The method for preparing 1α-hydroxybisphenol A according to claim 1, characterized in that The debromination reaction in step c is carried out in the presence of lithium bromide and lithium carbonate, the molar ratio of lithium bromide to formula (4) is 1 to 8:1, preferably 2 to 4:1, and the molar ratio of lithium carbonate to formula (4) is 1 to 10:1, preferably 2.5 to 3:1; The reaction in step c uses DMF (N,N-dimethylformamide) as a reaction solvent, the reaction temperature is 50-180° C., preferably 140-150° C., and after the reaction is completed by TLC detection, the following post-treatment steps are also included: removing insoluble matter in the reaction solution by suction filtration, extracting with ethyl acetate, washing the organic layer with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure and separating by column chromatography, the eluent being a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5-10:1, to obtain the trienone product represented by formula (5).

7. The method for preparing 1α-hydroxybis-decyl alcohol according to claim 1, characterized in that In step d, the molar ratio of hydrogen peroxide to trienone is 1 to 7:1, preferably 2.5 to 3:1, and the molar ratio of inorganic base to trienone is 0.5 to 2.2:1, preferably 1 to 1.2:1; In step d, the inorganic base is one of the following: sodium hydroxide, potassium hydroxide.

8. The method for preparing 1α-hydroxybisphenol A according to claim 1, characterized in that Step d uses methanol, ethanol or tetrahydrofuran as the reaction solvent, the reaction temperature is 0°C to room temperature, and after the reaction is completed by TLC detection, the following post-treatment steps are also included: the pH of the reaction solution is adjusted to neutral, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound represented by formula (6).

9. The method for preparing 1α-hydroxybisphenol A according to claim 1, characterized in that In step e, the molar ratio of formic acid to the compound of formula (6) is 2 to 10:1, preferably 2.5 to 5:1; in step e, the base is triethylamine, and the molar ratio of triethylamine to the compound of formula (6) is 2 to 12:1, preferably 3 to 6:1; the catalyst is palladium carbon with a palladium loading of 5 to 15%, and the ratio of the mass of palladium carbon to the molar amount of the compound of formula (6) is 50 to 100:1, preferably 60 to 70:1, the unit of mass is g, and the unit of molar amount is mol.

10. The method for preparing 1α-hydroxybis-decyl alcohol according to claim 1, characterized in that In step e, the reaction temperature is room temperature. After the reaction is completed by TLC monitoring, the following post-treatment steps are also included: filtering to remove insoluble matter in the reaction solution, adjusting the pH of the reaction solution to neutral, extracting with ethyl acetate, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the target product.

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