CN111560045A - Method for synthesizing lithocholic acid by taking BA as raw material - Google Patents
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- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
Abstract
The invention discloses a method for synthesizing lithocholic acid, which adopts 21-hydroxy-20-methyl pregn-4-alkene-3-ketone (BA) as a raw material to synthesize the lithocholic acid through oxidation reaction, Wittig reaction and reduction reaction. The synthetic method of lithocholic acid is environment-friendly, simple in steps, less in side reaction, high in yield, cheap and easily available in raw materials, and suitable for industrial production; solves the problems of high synthesis cost, low yield and unsuitability for large-scale industrial production in the prior art.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a method for synthesizing lithocholic acid by taking 21-hydroxy-20-methyl pregn-4-ene-3-one (BA) as a raw material.
Background
Lithocholic acid (3 alpha-hydroxy-5 beta-cholanic acid, formula (4)) is a secondary bile acid, also called as cholanic acid, is present in bile of higher vertebrates, and the content change of the cholanic acid has important reference value in liver diagnosis. Lithocholic acid has a wide range of biological activities, such as activation of vitamin D receptors (j.lipid res.2005, 46, 46-57.), inhibition of the activity of the diabetes-associated target PTP1B (bioorg.med.chem.lett.2012, 22, 7237-. Particularly, the compound also has anti-tumor activity, and in recent years, lithocholic acid is found to inhibit mutation of DNA polymerase beta and reduce the probability of tumor occurrence caused by mutation of the DNA polymerase beta; in 2011, scientists, led by concodia university, and including both the university of mcgill, the davis institute of montreal kosher, and the university of Saskatchewan, published in the Oncotarget journal: lithocholic acid can selectively kill several types of cancer cells, such as those found in brain tumors and breast cancers, without affecting normal cells, suggesting a great prospect for use as a chemotherapeutic drug (Oncotarget2011,2, 761-782).
Journal of Biological Chemistry,1946,162,555-563, reported that after methyl esterification with deoxycholic acid, the 3-hydroxyl group was protected with benzoyl chloride, and then the benzoyl chloride was reacted with the 7-hydroxyl group, followed by alkaline hydrolysis of methyl ester and the benzoyl group at the 3-position, methyl esterification, high-temperature pyrolysis dehydration, alkaline hydrolysis of methyl ester, and hydrogenation of platinum oxide, to obtain lithocholic acid. The reaction formula is as follows:
the method needs high-temperature pyrolysis to remove benzoyl in the lithocholic acid preparation process, has complicated route and low yield, has the total yield of only 23.5 percent, and is not suitable for large-scale production.
In 2016, the patent (CN201610369086.4) filed by the present invention task group reports that deoxycholic acid is used as a raw material, and lithocholic acid is synthesized by methyl esterification protection, acetic anhydride protection of 3-hydroxy group, dehydration, hydrogenation, hydrolysis and other reactions. The reaction formula is as follows:
although the method has the advantages of easily available raw materials and high yield, and the total yield is 76.3%, the route is still long, and the industrial application of the route is limited to a certain extent.
The existing synthetic routes reported at present have the problems of complicated steps, low yield, high cost and the like, and animal cholic acid deoxycholic acid is taken as a starting material in all the reported existing synthetic routes, but due to the occurrence of diseases such as avian influenza, mad cow disease, swine streptococcosis, African swine fever and the like, people have doubt on the safety of animal-derived raw materials, so that the research and development of a method for efficiently synthesizing the lithocholic acid by taking a plant source as the raw material has important significance and industrial value.
Disclosure of Invention
In order to overcome the defects in the prior art, the lithocholic acid LCA is synthesized by taking 21-hydroxy-20-methyl pregn-4-en-3-one ((20S) -21-hydroxy-20-methyl pregn-4-en-3-one) as a raw material through oxidation reaction, Wittig reaction and reduction reaction. The synthetic method of lithocholic acid has the advantages of simple steps, environmental friendliness, less side reactions, yield up to 87.4%, cheap and easily available raw materials, and suitability for industrial production.
The raw material 21-hydroxy-20-methylpregn-4-en-3-one ((20S) -21-hydroxy-20-methylpregn-4-en-3-one) used by the invention is also called BA (bisnalcohol), is derived from the fermentation of the waste plant sterol of the oil technology, is a green raw material of plant source, has annual output reaching kiloton grade at present, has low price, and can well avoid the infection problem of pathogenic bacteria and viruses in the prior art.
The invention provides a method for synthesizing lithocholic acid by using 21-hydroxy-20-methyl pregn-4-ene-3-one (BA) as a raw material, which comprises the following steps:
step (a): in a first solvent, BA shown in a formula (1) is subjected to oxidation reaction to obtain a compound shown in a formula (2);
step (b): in a second solvent, carrying out a Wittig reaction on the compound shown in the formula (2) to obtain a compound shown in the formula (3);
step (c): in a third solvent, carrying out reduction reaction on the compound of the formula (3) to obtain lithocholic acid of the compound of the formula (4);
the reaction process is shown as the following reaction formula (i):
in step (a) of the present invention, the oxidation reaction specifically comprises: in a first solvent, BA shown in a formula (1), TEMPO (2,2,6, 6-tetramethyl piperidine oxide), sodium bicarbonate, tetrabutyl ammonium bromide and an oxidant are subjected to oxidation reaction to obtain a compound shown in a formula (2).
In the step (a), the oxidation reaction is carried out under the action of an oxidant, wherein the oxidant is selected from one or more of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), 2-iodosylbenzoic acid (IBX) and the like; preferably, it is N-chlorosuccinimide (NCS).
In the step (a), the molar ratio of BA, TEMPO, sodium bicarbonate, tetrabutylammonium bromide and an oxidizing agent shown in the formula (1) is 1: (0-1): (0-20): (0-1): (1-5); preferably, 1: (0.01-1): (1.35-20): (0.1-1): (1.15-5); further preferably, is 1: 0.01: 1.35: 0.1: 1.15.
in the step (a), the first solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide, water and the like; preferably, it is a mixed solvent of dichloromethane and water.
In the step (a), the temperature of the oxidation reaction is 0-30 ℃; preferably, it is 0 ℃.
In the step (a), the time of the oxidation reaction is 2-8 h; preferably, it is 5 h.
In one embodiment, the step of synthesizing the compound of formula (2) comprises: dissolving BA shown in the formula (1) in a first solvent, adding TEMPO, sodium bicarbonate, tetrabutylammonium bromide and NCS, and carrying out oxidation reaction to obtain a compound shown in the formula (2).
In the step (b), the Wittig reaction is specifically as follows: in a second solvent, the compound of the formula (2) and carbethoxy methylene triphenylphosphine are subjected to a Wittig reaction to obtain a compound of the formula (3).
Wherein the mol ratio of the compound shown in the formula (2) to the carbethoxymethylene triphenylphosphine is 1: (1-5); preferably, 1: 2.
wherein the second solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, hexane and the like; preferably, it is toluene.
Wherein the temperature of the Wittig reaction is 80-130 ℃; preferably, it is 110 ℃.
Wherein the Wittig reaction time is 2-8 h; preferably, it is 4 h.
Or, in the step (b), the Wittig reaction is specifically: in a second solvent, carrying out Wittig reaction on the compound shown in the formula (2), sodium hydride and triethyl phosphonoacetate to obtain the compound shown in the formula (3).
Wherein the second solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, hexane and the like; preferably, tetrahydrofuran.
Wherein the molar ratio of the compound shown in the formula (2), sodium hydride and triethyl phosphonoacetate is 1: (1-5): (1-5); preferably, 1: 1.5: 1.5.
wherein the temperature of the Wittig reaction is 0-30 ℃; preferably, it is 0 ℃.
Wherein the Wittig reaction time is 2-8 h; preferably, it is 4 h.
In one embodiment, the step of synthesizing the compound of formula (3) comprises: dissolving the compound of the formula (2), carbethoxy methylene triphenylphosphine or the compound of the formula (2), sodium hydride and triethyl phosphonoacetate in a second solvent to perform a Wittig reaction to obtain the compound of the formula (3).
In the step (c), the reduction reaction is specifically: dissolving the compound of formula (3), sodium tert-butoxide, Raney nickel (Raney Ni) in a third solvent, H2Pressurization after replacementCarrying out reduction reaction to obtain lithocholic acid as a compound shown in a formula (4);
wherein the molar ratio of the compound shown in the formula (3) to the sodium tert-butoxide is 1: (1-5); preferably, 1: 2.
wherein the mass ratio of the compound of the formula (3) to the Raney nickel is 1: (0.1-5); preferably, 1: 1.
wherein the third solvent is selected from one or more of isopropanol, n-butanol, ethanol, methanol, tert-butanol, etc.; preferably, it is isopropanol.
Wherein the pressure of the reduction reaction is 1-10 MPa; preferably, it is 4 MPa.
Wherein the temperature of the reduction reaction is 40-120 ℃; preferably, it is 90 ℃.
Wherein the time of the reduction reaction is 5-48 h; preferably 24 h.
The preparation method of lithocholic acid has the beneficial effects that the raw material BA is a plant source raw material, so that the infection problem of pathogenic bacteria and viruses is avoided, and the lithocholic acid is cheap and easy to obtain; the lithocholic acid has the advantages of simple and convenient synthesis steps, less side reactions, high yield of 87.4 percent, environmental friendliness and convenient realization of industrial and industrialized production; solves the problems of high synthesis cost, low yield and unsuitability for large-scale industrial production in the prior art.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
In the following examples, the structures of the compounds were determined by NMR; the reagent is mainly provided by Shanghai national drug chemical reagent company; the product purification is mainly carried out by column chromatography, silica gel (200-.
EXAMPLES preparation of Compounds of formula (2)
(1-1) A500 mL single-neck flask was charged with BA (10.00g,30.26mmol), TEMPO (47mg,0.30mmol), 100mL of DCM, and NaHCO in that order3(3.43g,40.85mmol), tetrabutylammonium bromide (977mg,3.03mmol) in H2O (40mL) solution and NCS (4.65g, 34.80mmol) were reacted at 0 ℃ for 5 h. TLC detection of complete reaction of starting materials, sodium thiosulfate pentahydrate solution (1.3g sodium thiosulfate pentahydrate/25 mL H) was added2O), stirring at 10 ℃ for 20min, separating, extracting the aqueous phase with dichloromethane (50mL × 3), combining the organic phases, adding 120mL of 1% sodium hydroxide solution, stirring for 30min, separating, back-extracting the aqueous phase with dichloromethane (50mL) once, washing with water, and concentrating under reduced pressure to obtain compound 2 (light yellow solid, 9.50g, 95% molar yield).
(1-2) in a 250mL single-neck flask were added BA (5.0g, 15.13mmol), IBX (8.5g, 30.26mmol), 50mL THF and 50mL DMSO in this order, reacted at room temperature for 5 h.after the reaction was detected by TLC, water was added, suction filtration, extraction with dichloromethane (50mL × 3), washing with water (50mL × 2) and with a saturated sodium bicarbonate solution (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA 3/1, v/v) to give compound 2(4.9g, white solid, 98% molar yield), mp: 155-.1H NMR(400MHz,CDCl3)9.55(s,1H),5.71(s,1H),2.45-2.23(m,5H),1.99(t,J=13.7Hz,2H),1.91-1.78(m,2H),1.68(t,J=10.2Hz,2H),1.43(m,5H),1.30-1.19(m,2H),1.17(s,3H),1.11(d,J=5.5Hz,3H),1.06-0.89(m,3H),0.75(s,3H).13C NMR(100MHz,CDCl3)205.00,199.65,171.31,123.99,55.25,53.84,51.04,49.54,43.10,39.39,38.68,35.80,35.68,34.06,32.93,32.05,27.11,24.64,21.06,17.48,13.53,12.44.HRMS(ESI):calcdfor C22H32NaO2[M+Na]+,351.2295,found351.2292.
EXAMPLE two preparation of Compound (3)
(2-1) Compound 2(1.0g, 3.04mmol), ethoxycarbonylmethylenetriphenylphosphine (2.12g, 6.08mmol) and toluene (15mL) were placed in a 100mL single-neck flask in this order, and the reaction was refluxed for 4 hours. After completion of TLC reaction, the reaction was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA 3/1, v/v) to obtain compound 3(1.15g, white solid, molar yield 98%).
(2-2) in a 250mL single-neck flask, sodium hydride (913mg,22.83mmol) and 50mL THF were added in this order, and after stirring for 15min, triethyl phosphonoacetate (4.5mL,22.83mmol), compound 2(5.00g,15.22mmol) and reacted at 0 ℃ for 4 h. TLC detection of the starting material reaction was completed, and then concentrated under reduced pressure and slurried with methanol to obtain Compound 3 (white solid, 5.76g, 95% molar yield).
(2-3) Compound 2(1.0g, 3.04mmol), ethoxycarbonylmethylenetriphenylphosphine (2.12g, 6.08mmol) and THF (15mL) were placed in a 100mL single-neck flask in this order and reacted for 4h under reflux. After completion of TLC reaction, the reaction was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA 3/1, v/v) to obtain compound 3(1.10g, white solid, molar yield 94%).
(2-4) in a 250mL single-neck flask, sodium hydride (913mg,22.83mmol) and 50mL of toluene were sequentially added, and after stirring for 15min, triethyl phosphonoacetate (4.5mL,22.83mmol), compound 2(5.00g,15.22mmol) and reacted at 0 ℃ for 4 h. TLC detection of the starting material reaction was completed, and then concentrated under reduced pressure and slurried with methanol to obtain Compound 3 (white solid, 5.64g, molar yield 93%). mp 160-162 ℃.1H NMR(400MHz,CDCl3)6.81(dd,J=15.3,9.0Hz,1H),5.71(d,J=13.4Hz,2H),4.24-4.09(m,2H),2.45-2.21(m,5H),2.00(d,J=12.6Hz,2H),1.80(m,1H),1.76-1.33(m,7H),1.26(m,6H),1.17(s,3H),1.08(d,J=6.2Hz,3H),1.05-0.86(m,3H),0.73(s,3H).13C NMR(100MHz,CDCl3)199.70,171.51,167.16,154.56,123.94,119.21,60.27,55.78,54.98,53.84,42.82,39.80,39.54,38.69,35.80,35.70,34.08,32.98,32.06,28.19,24.28,21.10,19.31,17.49,14.40,12.32.HRMS(ESI):calcd forC26H38NaO3[M+Na]+,421.2713,found421.2708.
EXAMPLE III preparation of Compound of formula (4)
(3-1) Compound 3(1.0g,2.51mmol), 20mL of isopropanol, 1.0g of Raney Ni, H were added in this order to an autoclave2(4.0MPa), sodium t-butoxide (482mg,5.02mmol), reaction was carried out at 90 ℃ for 48 hours. After completion of TLC detection, acetic acid was added to adjust pH to 5, and the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and dissolved in ethyl acetate (30mL), washed with water and saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (PE: EA: 2:1) to give lithocholic acid (841mg, white solid, molar yield 89%).
(3-2) to the autoclave were added compound 3(1.0g,2.51mmol), 20mL of isopropyl alcohol, sodium tert-butoxide (482mg,5.02mmol) and 1.0g of Raney Ni, H in this order2After replacement, the pressure is increased to 4.0MPa, and the reaction is carried out for 24h at 90 ℃. After TLC detection of the completion of the reaction of the starting materials, acetic acid was added to adjust the pH to 5, followed by suction filtration with celite, and the filtrate was concentrated under reduced pressure and then dissolved in ethyl acetate (30mL), washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (PE: EA: 2:1) to give lithocholic acid (white solid, 860mg, 91% yield). mp is 185-186.5 ℃.1H NMR(500MHz,DMSO-d6)11.93(s,1H),4.42(d,J=3.6Hz,1H),3.41-3.33(m,1H),2.27-2.18(m,1H),2.14-2.05(m,1H),1.92(d,J=10.8Hz,1H),1.83-1.74(m,2H),1.71-1.64(m,2H),1.62-1.57(m,1H),1.56-1.46(m,2H),1.39-1.29(m,7H),1.25-1.12(m,6H),1.11-1.00(m,4H),0.94-0.88(m,1H),0.87(t,J=3.1Hz,6H),0.61(s,3H).13C NMR(125MHz,DMSO-d6)175.28,70.32,56.51,56.01,42.73,42.01,40.44,40.15,36.74,35.85,35.62,35.30,34.66,31.18,31.14,30.83,28.18,27.37,26.63,24.31,23.73,20.89,18.58,12.32.HRMS(ESI):calcd for C24H40NaO4[M+Na]+,399.2870,found399.2885.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
Claims (10)
1. A method for synthesizing lithocholic acid, comprising the steps of:
step (a): in a first solvent, using BA shown in a formula (1) as a raw material to carry out oxidation reaction to obtain a compound shown in a formula (2);
step (b): in a second solvent, carrying out a Wittig reaction on the compound shown in the formula (2) to obtain a compound shown in the formula (3);
step (c): in a third solvent, carrying out reduction reaction on the compound of the formula (3) to obtain lithocholic acid of the compound of the formula (4);
the reaction process is shown as a reaction formula (i):
2. the method according to claim 1, wherein in step (a), the oxidation reaction is specifically: in the first solvent, BA shown in a formula (1), TEMPO, sodium bicarbonate, tetrabutylammonium bromide and an oxidizing agent are subjected to oxidation reaction to obtain a compound shown in a formula (2).
3. The method according to claim 2, wherein the molar ratio of BA, TEMPO, sodium bicarbonate, tetrabutylammonium bromide and the oxidizing agent represented by formula (1) is 1: (0-1): (0-20): (0-1): (1-5); and/or the oxidant is selected from one or more of N-chlorosuccinimide NCS, N-bromosuccinimide NBS and 2-iodosylbenzoic acid IBX; and/or, the first solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide and water; and/or the temperature of the oxidation reaction is 0-30 ℃; and/or the time of the oxidation reaction is 2-8 h.
4. The method as claimed in claim 1, wherein in step (b), the Wittig reaction is specifically: in the second solvent, the compound of the formula (2) and carbethoxy methylene triphenylphosphine are subjected to a Wittig reaction to obtain a compound of the formula (3).
5. The process according to claim 4, wherein the compound of formula (2) is present in a molar ratio of 1: (1-5); and/or the second solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran and hexane; and/or the temperature of the Wittig reaction is 80-130 ℃; and/or the Wittig reaction time is 2-8 h.
6. The method as claimed in claim 1, wherein in step (b), the Wittig reaction is specifically: in the second solvent, carrying out Wittig reaction on the compound shown in the formula (2), sodium hydride and triethyl phosphonoacetate to obtain the compound shown in the formula (3).
7. The method of claim 6, wherein the second solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, hexane; and/or the molar ratio of the compound of formula (2), sodium hydride and triethyl phosphonoacetate is 1: (1-5): (1-5); and/or the temperature of the Wittig reaction is 0-30 ℃; and/or the Wittig reaction time is 2-8 h.
8. The method according to claim 1, wherein in step (c), the reduction reaction is specifically: the compound of formula (3), sodium tert-butoxide, Raney's nickel are dissolved in the third solvent, H2Pressurizing after replacement, and carrying out reduction reaction to obtain lithocholic acid.
9. The process of claim 8, wherein the compound of formula (3) is present in a molar ratio of sodium tert-butoxide to 1: (1-5); and/or the mass ratio of the compound of the formula (3) to the Raney nickel is 1: (0.1-5).
10. The method of claim 8, wherein the third solvent is selected from one or more of isopropanol, n-butanol, ethanol, methanol, t-butanol; and/or the pressure intensity of the reduction reaction is 1-10 MPa; and/or the temperature of the reduction reaction is 40-120 ℃; and/or the time of the reduction reaction is 5-48 h.
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CN111560045A (en) * | 2020-06-23 | 2020-08-21 | 江苏佳尔科药业集团股份有限公司 | Method for synthesizing lithocholic acid by taking BA as raw material |
CN112375117A (en) * | 2020-11-14 | 2021-02-19 | 湖南科瑞生物制药股份有限公司 | Preparation method of lithocholic acid and intermediate thereof |
-
2020
- 2020-06-23 CN CN202010578080.4A patent/CN111560045A/en not_active Withdrawn
- 2020-12-07 CN CN202011415144.5A patent/CN112625079A/en active Pending
-
2021
- 2021-01-11 WO PCT/CN2021/071035 patent/WO2021258723A1/en active Application Filing
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2021258723A1 (en) * | 2020-06-23 | 2021-12-30 | 江苏佳尔科药业集团股份有限公司 | Method for synthesizing lithocholic acid with ba as raw material |
CN112375117A (en) * | 2020-11-14 | 2021-02-19 | 湖南科瑞生物制药股份有限公司 | Preparation method of lithocholic acid and intermediate thereof |
CN113943336A (en) * | 2021-04-09 | 2022-01-18 | 华东师范大学 | Method for synthesizing cholesterol by taking BA as raw material |
CN114524856A (en) * | 2022-01-27 | 2022-05-24 | 华东师范大学 | Synthetic method of high-purity plant source cholesterol |
CN114524856B (en) * | 2022-01-27 | 2024-03-15 | 华东师范大学 | Synthesis method of high-purity plant-derived cholesterol |
WO2023179721A1 (en) * | 2022-03-25 | 2023-09-28 | 苏州恩泰新材料科技有限公司 | 7-ketolithocholic acid intermediate, synthesis method therefor, and application thereof |
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WO2021258723A1 (en) | 2021-12-30 |
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