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Methods for Preparing Bile Acids

a bile acid and bile acid technology, applied in the field of steroid synthesis, can solve the problems of prion contamination of such sources, and achieve the effect of high purity in the composition of cholic acid

Pending Publication Date: 2022-01-13
MEDY TOX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The method yields high-purity cholic acid, deoxycholic acid, and chenodeoxycholic acid compositions that are free from animal-derived impurities, suitable for pharmaceutical and cosmetic applications, particularly effective for non-surgical fat removal with high efficacy and safety.

Problems solved by technology

Pathogens such as prions can contaminate such sources.

Method used

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  • Methods for Preparing Bile Acids
  • Methods for Preparing Bile Acids
  • Methods for Preparing Bile Acids

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Cholic Acid from DHEA: Route 1

[0189]

[0190]Step 1

[0191]To a flask was added DHEA (50.00 g, 173.36 mmol, 1.00 eq) and DCM (1.00 L) at 15° C. Then, it was cooled to 0° C., TEMPO (2.73 g, 17.34 mmol, 0.10 eq) was added, and DDQ (86.58 g, 381.39 mmol, and 2.20 eq) was added in portions at 0° C. The reaction mixture was warmed to 25° C. and stirred at 25° C. for 48 hrs, TLC showed one new main spot was formed. The reaction was filtered, and the filtrate was washed with saturated Na2SO3 (100 mL*2) and brine (200 mL*2). The combined organic phase was dried with anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (PE / EA=50 / 1 to 10 / 1) to afford Compound 1 (39.0 g, 135.35 mmol, 78.08% yield) as white solid. 1H NMR, (400 MHz, CDCl3); δ=6.21 (s, 2H), 5.78-5.71 (m, 1H), 2.66-2.55 (m, 1H), 2.53-2.46 (m, 1H), 2.46-2.35 (m, 2H), 2.22-2.13 (m, 2H), 2.08-2.01 (m, 1H), 1.92 (td, J=3.1, 13.0 Hz, 1H), 1.80-1.69 (m, 3H), 1.56-1.50 (m, 1H), 1.48-1.42 ...

example 2

Synthesis of Cholic Acid from DHEA: Route 2

[0218]

[0219]Step 1

[0220]To a mixture of DHEA (20.00 g, 69.34 mmol, 1.00 eq) and 2-pyridylmethanamine (37.49 g, 346.70 mmol, 35.37 mL, 5.00 eq) in toluene(250.00 mL) was added PTSA (358.23 mg, 2.08 mmol, 0.03 eq) at 25° C., the mixture was stirred at 120° C. for 2 hrs with Dean-Stark apparatus. Then the reaction mixture was diluted with EA (400 ml), washed with saturated NaHCO3 (100 ml*2) and water (100 ml*2). The organic layer was concentrated. The residue was triturated by EA (30 ml) at 25° C. to afford Compound 13 (23.40 g, 57.80 mmol, 83.36% yield, 93.5% purity) as white solid. 1H NMR, (400 MHz, CDCl3): δ=8.54 (d, J=4.1 Hz, 1H), 7.67 (dt, J=1.7, 7.7 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.19-7.11 (m, 1H), 5.40 (br d, J=4.9 Hz, 1H), 4.70-4.53 (m, 2H), 3.63-3.48 (m, 1H), 2.54-2.43 (m, 1H), 2.38-2.25 (m, 3H), 2.15-2.03 (m, 2H), 1.96-1.85 (m, 3H), 1.75-1.70 (m, 1H), 1.64-1.36 (m, 6H), 1.26-1.10 (m, 2H), 1.07 (s, 3H), 1.03 (br d, J=4.5 Hz, 1H), 0....

example 3

Synthesis of Cholic Acid from Ac-DHEA

[0250]

[0251]Step 1

[0252]To a flask was added Ac-DHEA (50 g, 151.30 mmol, 1.0 eq) and toluene (1 L), 2-pyridylmethanamine (37.49 g, 346.72 mmol, 35.37 ml, 5.0 eq) was added to the reaction at 15° C., followed by adding PTSA (781.64 mg, 4.54 mmol, 0.03 eq) at 15° C. The reaction was heated to 110° C. with Dean-Stark apparatus for 2 hours. The reaction was cooled to 15° C., EA (1 L) was added to the reaction. The resulting mixture was washed with saturated NaHCO3 (2*100 ml) and water (2*100 ml). The organic layer was concentrated in vacuo. The residue was re-crystallized by EA (65 ml) to give compound 25 (54.0 g, 84.86% yield) as light yellow solid.

[0253]Step 2

[0254]To a 100 ml flask was added compound 25 (10 g, 23.78 mmol, 1.00 eq) sodium ascorbate (9.42 g, 47.55 mmol, 2.00 eq) and Cu(OTf)2 (19.78 g, 54.69 mmol, 2.30 eq) at 25° C. Acetone (90 mL) and MeOH (90 mL) was added to the flask to prepare a solution. After stirred at 25° C. for 5 mins, O2 (...

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Abstract

The present disclosure provides methods of preparing cholic acid, deoxycholic acid, or chenodeoxycholic acid, an ester thereof, or a pharmaceutically or cosmetically acceptable salt thereof, and novel and useful synthetic intermediates, for example, as described for methods 1, 1A, 1B, 2, 3, 3A, and 4. The method can start with a plant derived steroid as a starting material, such as dehydroepiandrosterone (DHEA) or Acetyl-dehydroepiandrosterone (Ac-DHEA). Also provided are pharmaceutical or cosmetic compositions and uses thereof, which comprise one or more of cholic acid, deoxycholic acid, or chenodeoxycholic acid, an ester thereof, or a pharmaceutically or cosmetically acceptable salt thereof, which is of high purity, for example, free of animal derived impurities.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a continuation of U.S. application Ser. No. 16 / 636,260, which is a 35 U.S.C. § 371 national phase of PCT / CN2018 / 098535, having an international filing date of Aug. 3, 2018, which claims priority to PCT / CN2017 / 095784, filed on Aug. 3, 2017, the contents of which are herein incorporated by reference in their entirety.BACKGROUND OF THE INVENTIONField of the Invention[0002]The present disclosure is generally related to the field of steroid synthesis, e.g., methods of preparing a bile acid (e.g., cholic acid, deoxycholic acid, or chenodeoxycholic acid) from a plant derived steroid, and novel synthetic intermediates. The present disclosure is also related to pharmaceutical or cosmetic compositions comprising a bile acid (e.g., cholic acid, deoxycholic acid, or chenodeoxycholic acid) or its ester(s) or salt(s), and pharmaceutical or cosmetic uses thereof.Background Art[0003]Bile acids such as deoxycholic acid, cholic acid and ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07J9/00C07J5/00C07J1/00
CPCC07J9/005C07J5/0015C07J1/0011C07J1/0018C07J1/0003A61P31/04C07J13/005C07J13/007C07J43/003C07J71/001Y02P20/55A61K31/575A61K8/63
Inventor LIU, DEJUNQIAN, YINGZHELEE, JUNHOSONG, YOONSEOK
Owner MEDY TOX INC
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