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Chenodeoxycholic acid, ケノデオキシコール酸

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Skeletal formula of chenodeoxycholic acid

ChemSpider 2D Image | chenodeoxycholic acid | C24H40O4Chenodeoxycholic acid.png

Chenodeoxycholic acid

Chenodiol

  • Molecular FormulaC24H40O4
  • Average mass392.572
UNII-0GEI24LG0J
ケノデオキシコール酸
474-25-9 [RN]
chenodeoxycholic acid [JP15] [Wiki]
(+)-chenodeoxycholic acid
(3a,5b,7a)-3,7-dihydroxy-cholan-24-oic acid
(3α,5β,7α,8ξ,20R)-3,7-Dihydroxycholan-24-säure[German] [ACD/IUPAC Name]
(4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-Dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
0GEI24LG0J
17b-(1-Methyl-3-carboxypropyl)etiocholane-3a,7a-diol
207-481-8[EINECS]
3a,7a-dihydroxy-5b-cholan-24-oic acid
3a,7a-dihydroxy-5b-cholanic acid; anthropodesoxycholic acid; gallodesoxycholic acid; 17b-(1-methyl-3-carboxypropyl)etiocholane-3a,7a-diol; chenic acid; chenodeoxycholic acid; CDC
Chenodeoxycholate;
Chenodeoxycholic acid;
3alpha,7alpha-Dihydroxy-5beta-cholanic acid;
Chenodiol

Synthesis ReferenceHenry Francis Frost, Fritz Fabian, Christopher James Sharpe, William Arthur Jones, “Process for preparing chenodeoxycholic acid.” U.S. Patent US4022806, issued October, 1974. US4022806

First ref 

  • By Windaus, A.; Bohne, A.; Schwarzkopf, E.
  • From Z. physiol. Chem. (1924), 140, 177-85
  • By Wieland, Heinrich; Reverey, Gustav
  • From Z. physiol. Chem. (1924), 140, 186-202.  

Title: Chenodiol
CAS Registry Number: 474-25-9
CAS Name: (3a,5b,7a)-3,7-Dihydroxycholan-24-oic acid
Additional Names: 3a,7a-dihydroxy-5b-cholanic acid; anthropodesoxycholic acid; gallodesoxycholic acid; 17b-(1-methyl-3-carboxypropyl)etiocholane-3a,7a-diol; chenic acid; chenodeoxycholic acid; CDC
Trademarks: Chendol (CP Pharm.); Chenocol (Astellas); Chenofalk (Falk); Chenossil (Sanofi-Aventis); Cholanorm (Grñenthal); Fluibil (Zambon)
Molecular Formula: C24H40O4
Molecular Weight: 392.57
Percent Composition: C 73.43%, H 10.27%, O 16.30%
Literature References: A major bile acid in many vertebrates, occurring as the N-glycine and/or N-taurine conjugate. With other bile acids, forms mixed micelles with lecithin in bile which solubilize cholesterol and thus facilitates its excretion. Facilitates fat absorption in the small intestine by micellar solubilization of fatty acids and monoglycerides. Has cathartic properties since it induces fluid secretion from large intestine. Main constituent of the bile of hens, geese and other fowl; occurs in appreciable amounts in the bile of hamster, hog, guinea pig, bear and man. Epimeric with ursodiol, q.v. Isoln: Windhaus et al.,Z. Physiol. Chem.140, 177 (1924); Wieland, Reveney, ibid. 186. Configuration: Lettré, Ber.68, 766 (1935). Prepn from cholic acid: Fieser, Rajagopalan, J. Am. Chem. Soc.72, 5530 (1950); Hauser et al.,Helv. Chim. Acta43, 1595 (1960); Hofmann, Acta Chem. Scand.17, 173 (1963). Alternate prepns: Sato, Ikekawa, J. Org. Chem.24, 1367 (1959); T. Iida, F. C. Chang, ibid.46, 2786 (1981). Stereoselective total synthesis: T. Kametani et al.,J. Am. Chem. Soc.103, 2890 (1981). Asymmetric total synthesis of (+)-form:eidem,J. Org. Chem.47, 2331 (1982). Dissolution of cholesterol gallstones: Danzinger et al.,N. Engl. J. Med.286, 1 (1972); Bell et al.,LancetII, 1213 (1972). Use in long-term treatment of cerebrotendinous xanthomatosis: V. M. Berginer et al.,N. Engl. J. Med.311, 1649 (1984). Monograph on bile acids: The Bile Acids, 2 vols., P. P. Nair, D. Kritchevsky, Eds. (Plenum Press, New York, 1971, 1973). Review of pharmacology and therapeutic use of chenodeoxycholic acid: J. H. Iser, A. Sali, Drugs21, 90-119 (1981). Effect on cholesterol and bile acid metabolism: G. S. Tint et al.,Gastroenterology91, 1007 (1986).
Properties: Needles from ethyl acetate + heptane, mp 119°. [a]D20 +11.5° (dioxane). Freely sol in methanol, alc, acetone, acetic acid; more sol in ether and ethyl acetate than deoxycholic acid. Practically insol in water, petr ether, benzene. High solvent power for alkali soaps, but does not form “choleic” acid addition compds as does deoxycholic acid. Forms beautiful cryst salts of Na, K and Ba. While the acid is tasteless, the Na salt tastes slightly sweet at first, then bitter.
Melting point: mp 119°
Optical Rotation: [a]D20 +11.5° (dioxane)
Derivative Type: Diformate
Molecular Formula: C25H40O6
Molecular Weight: 436.58
Percent Composition: C 68.78%, H 9.23%, O 21.99%
Properties: Clusters of needles from alc; mp with slight effervescence at 137°, upon further heating solidifies again, and finally melts around 172°.
Melting point: mp with slight effervescence at 137°
Derivative Type: Methyl ester
Molecular Formula: C25H42O4
Molecular Weight: 406.60
Percent Composition: C 73.85%, H 10.41%, O 15.74%
Properties: Fine needles from benzene + heptane, mp 90-91°. [a]D25 +20°.
Melting point: mp 90-91°
Optical Rotation: [a]D25 +20°
Therap-Cat: Anticholelithogenic.
Keywords: Cholelitholytic Agent.
SPECIFIC ROTATION
+13.23 °   ethanol ,  589.3 nm;  21 °C, Yonemura, Sadatomo; Journal of Biochemistry 1926, Vol6, Pg287-96
+12.5 °  chloroform, 589.3 nm; 17 °C  Plattner, Pl. A.; Helvetica Chimica Acta 1944, Vol27, Pg748-57
MP
Chenodeoxycholic acid (or Chenodiol) is an epimer of ursodeoxycholic acid (DB01586). Chenodeoxycholic acid is a bile acid naturally found in the body. It works by dissolving the cholesterol that makes gallstones and inhibiting production of cholesterol in the liver and absorption in the intestines, which helps to decrease the formation of gallstones. It can also reduce the amount of other bile acids that can be harmful to liver cells when levels are elevated.

Chenodeoxycholic acid (also known as chenodesoxycholic acidchenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. It occurs as a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165–167 °C. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the main bile acids produced by the liver.[1]

It was first isolated from the bile of the domestic goose, which gives it the “cheno” portion of its name (Greek: χήν = goose).[2]

Chenodeoxycholic acid and cholic acid are the two primary bile acids in humans. Some other mammals have muricholic acid or deoxycholic acid rather than chenodeoxycholic acid.[1]

Chenodeoxycholic acid is synthesized in the liver from cholesterol by a process which involves several enzymatic steps.[1] Like other bile acids, it can be conjugated in the liver with taurine or glycine, forming taurochenodeoxycholate or glycochenodeoxycholate. Conjugation results in a lower pKa. This means the conjugated bile acids are ionized at the usual pH in the intestine and will stay in the gastrointestinal tract until reaching the ileum where most will be reabsorbed. Bile acids form micelles which facilitate lipid digestion. After absorption, they are taken up by the liver and resecreted, so undergoing an enterohepatic circulation. Unabsorbed chenodeoxycholic acid can be metabolised by bacteria in the colon to form the secondary bile acid known as lithocholic acid.

Chenodeoxycholic acid is the most potent natural bile acid at stimulating the nuclear bile acid receptor, farnesoid X receptor (FXR).[3]The transcription of many genes is activated by FXR.

Indication

Chenodiol is indicated for patients with radiolucent stones in well-opacifying gallbladders, in whom selective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age. Chenodiol will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.

Associated Conditions

Pharmacodynamics

It acts by reducing levels of cholesterol in the bile, helping gallstones that are made predominantly of cholesterol to dissolve. Chenodeoxycholic acid is ineffective with stones of a high calcium or bile acid content.

Mechanism of action

Chenodiol suppresses hepatic synthesis of both cholesterol and cholic acid, gradually replacing the latter and its metabolite, deoxycholic acid in an expanded bile acid pool. These actions contribute to biliary cholesterol desaturation and gradual dissolution of radiolucent cholesterol gallstones in the presence of a gall-bladder visualized by oral cholecystography. Bile acids may also bind the the bile acid receptor (FXR) which regulates the synthesis and transport of bile acids.

EMA

On 16 December 2014, orphan designation (EU/3/14/1406) was granted by the European Commission to Sigma-Tau Pharma Ltd, United Kingdom, for chenodeoxycholic acid for the treatment of inborn errors in primary bile acid synthesis.

The sponsorship was transferred to sigma-tau Arzneimittel GmbH, Germany, in May 2015.

Chenodeoxycholic acid has been authorised in the EU as Chenodeoxycholic acid sigma-tau since 10 April 2017.

The name of the product changed to Chenodeoxycholic acid Leadiant in May 2017.

The sponsorship was transferred to Leadiant GmbH, Germany, in June 2017.

On 16 February 2017, the Committee for Orphan Medicinal Products (COMP) concluded its review of the designation EU/3/14/1406 for Chenodeoxycholic acid sigma-tau (chenodeoxycholic acid) as an orphan medicinal product for the treatment of inborn errors in primary bile acid synthesis. The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the condition, and the existence of other methods of treatment. As other methods of treatment are authorised in the European Union (EU), the COMP also considered whether the medicine is of significant benefit to patients with inborn errors in primary bile acid synthesis. The COMP recommended that the orphan designation of the medicine be maintained1.


1 The maintenance of the orphan designation at time of marketing authorisation would, except in specific situations, give an orphan medicinal product 10 years of market exclusivity in the EU. This means that in the 10 years after its authorisation similar products with the same therapeutic indication cannot be placed on the market.

http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2015/02/WC500183233.pdf

Therapeutic applications

Chenodeoxycholic acid has been used as medical therapy to dissolve gallstones.[4]

Chenodeoxycholic acid can be used in the treatment of cerebrotendineous xanthomatosis.[5]

The Australian biotechnology company Giaconda has tested a treatment for Hepatitis C infection that combines chenodeoxycholic acid with bezafibrate.[6]

As diarrhea is a complication of chenodeoxycholic acid therapy, it has also been used to treat constipation.[7][8]

In supramolecular chemistrymolecular tweezers based on a chenodeoxycholic acid scaffold is a urea receptor that can contain anionsin its binding pocket in order of affinity: H2PO4 (dihydrogen phosphate) > Cl > Br > I reflecting their basicities (tetrabutylammonium counter ion).[9]

Molecular tweezer based on chenodeoxycholic acid
PAPER
1H and 13C NMR characterization and stereochemical assignments of bile acids in aqueous media
Lipids (2005), 40, (10), 1031-1041.
https://onlinelibrary.wiley.com/doi/abs/10.1007/s11745-005-1466-1

PAPER

Improved Chemical Synthesis, X-Ray Crystallographic Analysis, and NMR Characterization of (22R)-/(22S)-Hydroxy Epimers of Bile Acids
Lipids (2014), 49, (11), 1169-1180.

Improved Chemical Synthesis, X‐Ray Crystallographic Analysis, and NMR Characterization of (22R)‐/(22S)‐Hydroxy Epimers of Bile Acids

PAPER

A Practical and Eco-friendly Synthesis of Oxo-bile Acids

By Han, Young Taek and Yun, HwayoungFrom Organic Preparations and Procedures International, 48(1), 55-61; 2016

DOI:10.1080/00304948.2016.1127101

General Procedure

An aqueous solution of 0.2 M NaBrO3 (1.5 equiv. per hydroxy group) was added dropwise to a slurry of bile acid (1 equiv.) and ceric ammonium nitrate (0.05 equiv.) in 20% aqueous acetonitrile (0.2 M) at 80°C over 20 min. The bile acid slowly dissolved in a few minutes, and then the color of the reaction mixture changed to orange. The reaction mixture was stirred at the same temperature and the progress of the reaction was monitored by TLC on silica gel (1:20 MeOH-CH2Cl2) until disappearance of the starting material and partially oxidized intermediates. It was then cooled in an ice bath and quenched with aqueous Na2S2O3 solution. Water was added slowly to the resulting white suspension until no more oxo-bile acid precipitated. The white solid was collected, washed with water until the filtrate was colorless, and then dried in vacuo at 50°C. Methyl 3,7α-Diacetoxy-12-oxo-5β-cholanoate(3),21 was obtained in 92% yield (275 mg) as a white solid from 300 mg (0.590 mmol) of 2 via the general procedure. mp. 176-178°C, lit.22 mp. 178-179°C, IR (thin film, neat): 2947 (m), 2873 (s), 1736 (w), 1706 (w), 1436 (s), 1365 (m) cm-1; 1H-NMR (400 MHz, CDCl3): δ 4.96 (m, 1H, 7-CH), 4.55 (m, 1H, 3-CH), 3.64 (s, 3H), 2.49 (t, 1H, J = 12.6 Hz), 2.41-0.80 (m, 23H), 2.01 (s, 3H), 2.00 (s, 3H), 1.01 (s, 3H, 18-CH3), 1.00 (s, 3H, 19-CH3), 0.83 (d, 3H, J = 6.6 Hz, 21-CH3); 13C-NMR (CDCl3, 100 MHz): δ 214.0 (12-C), 174.6 (24-C), 170.7 (C = O), 170.2 (C = O), 73.5 (3-C), 70.5 (7-C), 57.1 (13-C), 53.1 (14-C), 51.5 (CH3O), 46.3 (17-C), 40.5 (5-C), 37.9 (11-C), 37.8 (4-C), 37.6 (8-C), 35.54 (9-C), 35.52 (20-C), 34.9 (1-C), 34.5 (10-C), 31.3 (6-C), 31.2 (22-C), 30.4 (23-C), 27.4 (16-C), 26.5 (2-C), 23.8 (15-C), 22.1 (19-C), 21.51 (CH3CO2), 21.46 (CH3CO2), 18.6 (21-C), 11.5 (18-C); LR-MS (FABC) m/z 505 (M+H +). HR-MS (FABC): Calcd for C29H45O7 (M+H +): 505.3165. Found 505.3161.

next step

R:KOH, R:N2H4

NOTE STARTING  IS BILE ACID AS BELOW

Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

  • 5β-Cholan-24-oic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (8CI)
  • 5β-Cholanic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (6CI,7CI)
  • 3α,7α-Diacetoxy-12-oxo-5β-cholan-24-oic acid methyl ester
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholanate
CAS 28535-81-1
C29 H44 O7  504.66
Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

PAPER

https://pubs.acs.org/doi/pdf/10.1021/jo01091a623

Journal of Organic Chemistry
Volume24
Pages1367-8
Journal
1959

DOI:10.1021/jo01091a623

Chenodeoxycholic acid (V). Five hundred mg. of the above ester IV was hydrolyzed with 80 ml. of ethanolic 5% potassium hydroxide for 4 hr. After partial concentration of the volume and addition of water, the reaction product was acidified with hydrochloric acid. The resulting precipitate was collected, dried, and crystallized from ethyl acetate. A quantitative crop (400 mg.) of prisms melting at 143- 145° were obtained. Recrystallization from the same solvent yielded a product of m.p. 145-146°, [ ]2 +10.7° (dioxane). Anal. Caled, for C24H40O4: C, 73.43; H, 10.27. Found: C, 73.49; H, 10.31.

NOTE I IS BILE ACID

Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

  • 5β-Cholan-24-oic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (8CI)
  • 5β-Cholanic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (6CI,7CI)
  • 3α,7α-Diacetoxy-12-oxo-5β-cholan-24-oic acid methyl ester
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholanate
CAS 28535-81-1
C29 H44 O7  504.66
Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

PATENT

https://patents.google.com/patent/CN102060902A/en

chenodeoxycholic acid (3 α, 7 α – dihydroxy _5 β – cholestane-24-oic acid) Chenodeoxycholic Ac id (referred to as CDCA), clinically used to correct dissolving cholesterol calculi and bile saturation drugs, the main function is to reduce the cholesterol in the bile saturation, large doses can inhibit the synthesis of cholesterol CDCA and increasing bile gallstone patients cholesterol level in a non-saturated, thereby preventing the formation of cholesterol gallstones of cholesterol and promote stone dissolve and fall off. It also has significant anti-asthmatic, anti-inflammatory, antitussive and expectorant effects.

[0003] Synthesis of chenodeoxycholic acid or ursodeoxycholic acid (3 α, 7β_ -5β_ dihydroxy-cholestane-24-oic acid, ursodeoxycholic Acid, referred UDCA), a key intermediate. Ursodeoxycholic acid is the main active ingredient of precious Chinese medicine bear bile, used in a variety of clinical hepatobiliary disease and dyspepsia. Currently we bear bile resources are scarce, mainly used synthetic chemical ursodeoxycholic acid as a clinical treatment. Therefore, the preparation of chenodeoxycholic acid is also important for the preparation of ursodeoxycholic acid.

[0004] CDCA mainly come from poultry or livestock bile extraction. Traditional extraction process complicated operation, low yield, (pharmaceutical industry, 1987,18 (9), 416; Chinese Journal of Biochemical Pharmaceutics, 1996,17 (1), 17; Applied Technology, 1998, (4), 9; CN1850846A ) can not meet the needs of modern industry. Chemical synthesis of chenodeoxycholic acid have also been reported (Japanese Journal of Chemistry 1955,76 (3), 297 -J Org Chem 1982,47 (2): 2331; Journal of Biochemical Pharmaceutics 1987,1,6 -, Tap Chi Duoc ^ oc2004 , 44 (1), 11; CN1869043A), but lower yield widespread pollution major problem, especially in the oxidation reaction is often used to expensive, and polluting agents.Therefore, to reduce pollution, reduce environmental hazards, streamline operations, improve yield, reduce costs, important for the synthesis of chenodeoxycholic acid.

 Figure CN102060902AD00041

n particular by the following steps:

(1) Preparation of cholate: bile acid in alcohol, concentrated hydrochloric acid as catalyst, at reflux, cooling and crystallization, filtration, and washed with methanol.

[0008] (2) Preparation of 3α, 7α- diacetyl hydroxy -12α- cholate: bile acid ester was dissolved in dichloromethane and triethylamine was added with stirring acetic anhydride and the catalyst N, N- dimethyl pyridine, methylene chloride was distilled off, poured into water, filtered to give 3α, 7α- diacetyl -12 α – hydroxy cholate.

[0009] (3) 3α, 7α- diacetyl -12– Preparation oxo chenodeoxycholic acid ester: Take 3 α, 7 α – diacetyl -12 α – hydroxy cholate dissolved in ethyl acetate and methanol, bromide and tetrabutylammonium bromide as catalyst, and acetic acid was added dropwise under stirring hypochlorite, the organic solvent was distilled off and filtered, to give 12-oxo-3,7-diacetyl Chenodeoxy cholate.

[0010] (4) i2 – Preparation oxo chenodeoxycholic acid: 3,7-diacetyl-12-oxo-chenodeoxycholic acid ester added ethanol – sodium hydroxide solution, at reflux.PH adjusted with hydrochloric acid value of the reaction system acidic, ethanol was distilled off, and filtered to give 12- oxo crude chenodeoxycholic acid, fine recrystallization.

[0011] Preparation of chenodeoxycholic acid (5): 12- oxo take chenodeoxycholic acid, ethylene glycol and solid sodium hydroxide, hydrated corpus, refluxed for 2 hours, gradually warming evaporated partially hydrated corpus, continue to heat up to 150 ° C, continued to reflux, cooled to room temperature, poured into water, adjusting the PH with hydrochloric acid, the white precipitate was filtered, washed with water to give crude chenodeoxycholic acid, recrystallization

Azusa mouth

M ο not mesh

[0012] Step (1): cholic acid to alcohol weight to volume ratio of 1: 2 ~ 5, the volume ratio of concentrated hydrochloric acid to alcohol is 10 wide: 100, 5-5 hours reflux time was 0.5.

[0013] Step (2): cholate: acetic anhydride molar ratio = 1: 2 ~ 5, the reaction temperature, time; Tl2O hours; cholate was added per mole of N, N- dimethylpyridine wide 5g.

[0014] Step (; 3): The hypochlorite is sodium hypochlorite or calcium hypochlorite; bromide is sodium bromide, potassium bromide and the like.

[0015] Step (4): recrystallization from a solvent with an alcohol such: as methanol or ethanol.

[0016] Step (5): recrystallization solvent is a water-miscible organic solvents, such as: methanol, ethanol, acetonitrile, acetone and the like.

[0017] Step (cholate was used ¾ of methyl cholate, ethyl cholate, cholic acid or cholic acid propyl ester; Step (3) used as 3 [alpha], 7 α – diacetyl -12 α – hydroxy cholate as 3 α, 7 α – diacetyl -12 α – hydroxy methyl cholate, 3 α, 7α- diacetyl -12 α – hydroxy bile acid ethyl ester, 3 α, 7α- diacetyl yl -12 α – hydroxy acid or ester 3α, 7α- diacetyl -12 α – hydroxy acid ester.

[0018] The invention has the advantages: in cholic acid as raw materials, and the choice of bromide tetrabutylammonium bromide as catalyst, in a non-polluting oxidizing agent is hypochlorite, Intermediate 3 α, 7 α – Diacetyl _12_ oxo chenodeoxycholic acid ester yield of 90% or more, thereby improving the yield of the final product of chenodeoxycholic acid, 99% yield, low cost and no pollution, very convenient for industrial production. detailed description

[0019] The present invention will be better described, for example is as follows:

(1) Preparation of methyl cholate: bile acid 5. lg, 15ml of anhydrous methanol, heating the whole solution. Refluxed for 3 hours, was added 0. 4ml concentrated hydrochloric acid, the reaction was stopped after 30min, after slow cooling, and filtered to give methyl cholate 5. 05g, 95% yield. 1HNMR (CDCl3):. Δ 0. 70 (s, 3H, 18- CH3), 0.90 (s, 3H, 19- CH3), 0.98 (d, 3H, 21-CH3), 3 50 (m, 1H, 3 β -H), 3. 67 (s, 3H, OCH3), 3. 87 (s, 1H, 7 β -H), 3. 99 (s, 1H, 12 β -H).

[0020] (2) Preparation of 3α, 7α- methyl cholate diacetyl-hydroxy -12α-: bile acid methyl ester 4. 71g (Ilmmol) IOOml was placed in a flask, was added methylene chloride 30ml, triethylamine 3 . Chiu 1, stirred at room temperature, was added dropwise acetic anhydride 2. 7ml (28. 6mmo 1), followed by addition of 20mg N, N- dimethylpyridine catalyst, the reaction time of 7 hours, methylene chloride was distilled off, into the water, filtered to give a white solid. The crude product was recrystallized from methanol to give white crystals 4. 05g, yield 67.2%. 1H NMR (CDCl3) δ: 4.90 (m, 1H, 7 β -H), 4. 59 (s, 1H, 3 β -H), 4 01 (s, 1H, 12 β -H), 3 67.. (s, 3Η, OCH3), 2. 08 (s, 3Η, CH3CO), 2. 02 (s, 3Η, CH3CO), 0. 98 (s, 3Η, 21-CH3), 0. 93 (s, 3Η , 19-CH3), 0.69 (s, 3Η, 18_CH3).

[0021] (3) 3α, 7α – 12-oxo-diacetyl chenodeoxycholic acid methyl ester prepared: Take 3 α, 7 α – diacetyl -12 α- hydroxy methyl cholate 1.917 g ( 3. 79mmol) was placed in a 50ml round bottom flask, 12ml of ethyl acetate was added, 5ml methanol, stirring at room temperature, was added 0. 25g 0. Ig of potassium bromide and tetrabutylammonium bromide. Was added dropwise a solution of acetic acid and 6g of sodium hypochlorite (7%) (5.62mmol), for 10 hours. Methanol was distilled off under reduced pressure and ethyl acetate, filtered, washed with water, and dried to give crude 1.915g, 1.75g as a white solid after recrystallization from methanol, yield 91.2%. 1H bandit R (CDCl3) δ:.. 4. 99 (d, 1H, 7 β-H), 4 60 (m, 1H, 3 β-H), 3 67 (s, 3H, OCH3), 2. 07 (s, 6H, CH3CO), 1. 03 (s, 6H, I8-CH3 and 19-CH3), 0. 82 (d, 3H, 21-CH3) ο

[0022] (4) 12- oxo chenodeoxycholic acid Preparation: Take 3 α, 7 α – diacetyl _12_ oxo chenodeoxycholic acid methyl ester 1. 56g, was dissolved in 30ml 95% ethanol was added 3. 2g of sodium hydroxide, heated at reflux for 5 hours. PH adjusted with hydrochloric acid value of the reaction system, most of the ethanol was distilled off, filtered, washed with water, and dried to give a white solid 12- oxo-1 crude chenodeoxycholic acid, recrystallized from methanol ^ g 1. 25g, yield rate of 96%. Tun bandit R (CDCl3) δ:. 3.96 (d, 1H, 7 β-H), 3 47 (m, 1H, 3 β-H), 1.03 (s, 3H, 19_CH3), 0.89 (s, 3H, 18_CH3 ), 0 · 70 (d, 3 H, 21_CH3).

[0023] Preparation of chenodeoxycholic acid (5): 12- oxo take chenodeoxycholic acid 0. 9g, 15ml ethylene glycol was added solid sodium hydroxide and 1. 5g, 15ml hydrated corpus (80%) , 120 ° C reflux for 2 hours, change return device is a distillation apparatus, was gradually warmed evaporated amount hydrated corpus, continue to heat up to 150 ° C, continuing reflux for 4h, cooled to room temperature, poured into water, adjusted with HCl of PH3, white precipitated, was filtered cake was washed with water, and dried to give crude chenodeoxycholic acid 0. 92g, recrystallized from methanol to give 0. 86g, 99 (s, 1H, C00H).

Paper

https://pubs.acs.org/doi/abs/10.1021/ja01168a045

Reactions of 2-Arylcyclohexanones. IV. Michael Addition of Malonic Ester to 2-Phenyl-Δ2-cyclohexenone

J. Am. Chem. Soc.195072 (12), pp 5529–5530
DOI: 10.1021/ja01168a045
Publication Date: December 1950
PAPER
Hauser et al., Helv. Chim. Acta 43, 1595 (1960);
Paper

The Preparation of Chenodeoxycholic Acid and Its Glycine and Taurine Conjugates.Hofmann, Alan F.

Pages: 173-186.
DOI number: 10.3891/acta.chem.scand.17-0173
Download as: PDF DjVu
PAPER
Sato, Ikekawa, J. Org. Chem. 24, 1367 (1959)

Preparation of Chenodeoxycholic Acid

J. Org. Chem.195924 (9), pp 1367–1368
DOI: 10.1021/jo01091a623
Publication Date: September 1959
PAPER
J. Org. Chem. 47, 2331 (1982)

Further studies on the synthesis of thienamycin: a facile and stereoselective synthesis of a bicyclic .beta.-keto ester by 1,3-dipolar cycloaddition

J. Org. Chem.198247 (12), pp 2328–2331
DOI: 10.1021/jo00133a019
PAPER
PATENT

Chenodeoxycholic acid (3α, 7α- -5β- dihydroxy-cholestane acid) Chenodeoxycholic Acid (referred to as CDCA), a medicine for treating gallstones. 1848 first discovered in goose bile, 1924, known as the CDCA. By reducing cholesterol absorption, synthesis, the bile cholesterol decreased, thereby suppressing cholesterol gallstone formation and promote dissolution, and can reduce cholesterol saturation.

Chenodeoxycholic acid addition pharmaceutically itself, but also as the preparation of ursodeoxycholic acid (3α, 7β- -5β- dihydroxy bile acid, abbreviated UDCA) starting material. Ursodeoxycholic acid is the main active ingredient contained bile valuable medicine, in clinical treatment of various gastrointestinal diseases and bladder diseases. But the limited sources of bear bile medicine, and contrary to the principles of animal protection. So, dwindling source of natural bear bile, can not meet the medical requirements. Therefore, the preparation of chenodeoxycholic acid is also of great significance for further preparation of ursodeoxycholic acid.

CDCA bile extracted mainly from poultry or animal bile extraction methods in the past as it involves toxic chemicals (animal biological pharmacy, 1981, People’s Medical Publishing House, P259; pharmaceutical industry, 1987,18 (2): 75-76; ) or unsafe to use a large amount of organic solvent (Chinese Journal of biochemical Pharmaceutics, 1996,17 (1): 17; application technology, 1998,4: 9-10; US Patent, 3,965,131; US Patent, 4,331,607; USPatent, 4,163,017), can not be meet the requirements of modern industry, CDCA and low purity prepared costly.

PATENT

https://patents.google.com/patent/WO2007069814A1/en

Chenodeoxycholic acid is generally contained in bile of cow, swine, bear, or poultry such as chicken or goose, as well as in bile of human. Chenodeoxycholic acid is used as starting material for the preparation of ursodeoxycholic acid which is effective to alleviate biliary system diseases, hyperlipidemia, cholelithiasis, and chronic liver diseases, and a typical process for preparing ursodeoxycholic acid known in the art is as follows.

A typical process for preparing chenodeoxycholic acid comprises the steps of: esterifying cholic acid (3α,7α,12θ!-trihydroxy cholic acid) with methyl; protecting the hydroxyl group of 3α and Ia position by acetylating them with anhydrous acetic acid; oxidizing the hydroxyl group of 12α position to carbonyl group by using chromic acid, and then removing the carbonyl group by Wolff-kichner reduction reaction; hydrolyzing and deprotecting the obtained product to yield chenodeoxycholic acid. The above process requires the reaction to be maintained at a high temperature of more than 200 °C , and the supply of raw material may be interrupted by bovine spongiform encephalopathy, etc. Bile ,of poultry contains chenodeoxycholic acid, lithocholic acid, and a small amount of cholic acid. Thus, the process for separating chenodeoxycholic acid from poultry is well known in the art, but is not economically reasonable due to the supply decrease of raw material and low yield [see, Windhaus et al, I Physiol. Chem., 140, 177-185 (1924)].

US Patent No. 4,186,143 disclosed a process for purely separating and purifying chenodeoxycholic acid from chenodeoxycholic acid mixture derived from natural swine bile. This process comprises the major steps of: pre-treatment to remove 3ohydroxy-6- oxo-5/3-cholic acid by saponification of bile; esterification of bile acid; acetylation of bile acid ester; removal of intermediate product by using non-polar organic solvent; crystallization of acetylated ester of formula I; deprotection; and production of the compound of formula I by using crystallization in organic solvent. However, this patent does not describe HPLC content for acetylated ester of formula I, and the purity of the final product is very low since the specific rotatory power is [ofo25 +13.8° (c=l, CHCl3), and the melting point is 119-121 °C [STD: [α]D 25 +15.2°(c=l, CHCl3), melting point 127- 129 “C]. Also, the crystallization for purifying the final product requires a very long time (i.e., 16-48 hours), and the entire process is complex as eight (8) steps. Thus, when purifying the compound of formula I by using the above process, the yield of the final product becomes low, and the reaction time is as long as 12 days. Therefore, the process is not economically reasonable.

Step 6: Deprotection and crystallization of chenodeoxycholic acid

To 220ml of water were added 24.5g of chenodeoxycholic acid-diacetate-ester and 29.5g of sodium hydroxide, and then the solution was stirred with reflux for 4 hours. To the solution was added 370ml of water. The solution’s pH is adjusted to 2.0-3.0 by using 59ml of hydrochloric acid. Then, the solution was stirred at 35-45 °C for 1 hour, and then filtered. The filtered material was washed with 24.5ml of water and dried in vacuum at 70 °C to obtain 19.5g of pure chenodeoxycholic acid, m.p.: 160-161 °C, [α]o25 +13.0°(c=l, CHCl3).

Step 8: Production of the compound of formula I

The reaction solution was extracted by using ethyl acetate, and aqueous layer was discarded therefrom. Ethyl acetate layer in the solution was washed with 6% saline, and the solution was distilled to about 90ml. This solution was cooled, kept cool for one day after adding 90ml of hexane, and filtered. Thus filtered material was washed with 20ml of hexane, and dried in vacuum at 60 °C to produce 12.7g of chenodeoxycholic acid. m.p. 142-1450C; [α]D 25 +13.0°(c=l, CHCl3). INDUSTRIAL APPLICABILITY The present invention can purify chenodeoxycholic acid of formula I from swine bile solid in high yield and purity. Also, the present invention is suitable for industrial purification by reducing the purification time.

PATENT

https://patents.google.com/patent/CN102060902A/en

chenodeoxycholic acid (3 α, 7 α – dihydroxy _5 β – cholestane-24-oic acid) Chenodeoxycholic Ac id (referred to as CDCA), clinically used to correct dissolving cholesterol calculi and bile saturation drugs, the main function is to reduce the cholesterol in the bile saturation, large doses can inhibit the synthesis of cholesterol CDCA and increasing bile gallstone patients cholesterol level in a non-saturated, thereby preventing the formation of cholesterol gallstones of cholesterol and promote stone dissolve and fall off. It also has significant anti-asthmatic, anti-inflammatory, antitussive and expectorant effects.

[0003] Synthesis of chenodeoxycholic acid or ursodeoxycholic acid (3 α, 7β_ -5β_ dihydroxy-cholestane-24-oic acid, ursodeoxycholic Acid, referred UDCA), a key intermediate. Ursodeoxycholic acid is the main active ingredient of precious Chinese medicine bear bile, used in a variety of clinical hepatobiliary disease and dyspepsia. Currently we bear bile resources are scarce, mainly used synthetic chemical ursodeoxycholic acid as a clinical treatment. Therefore, the preparation of chenodeoxycholic acid is also important for the preparation of ursodeoxycholic acid.

[0004] CDCA mainly come from poultry or livestock bile extraction. Traditional extraction process complicated operation, low yield, (pharmaceutical industry, 1987,18 (9), 416; Chinese Journal of Biochemical Pharmaceutics, 1996,17 (1), 17; Applied Technology, 1998, (4), 9; CN1850846A ) can not meet the needs of modern industry. Chemical synthesis of chenodeoxycholic acid have also been reported (Japanese Journal of Chemistry 1955,76 (3), 297 -J Org Chem 1982,47 (2): 2331; Journal of Biochemical Pharmaceutics 1987,1,6 -, Tap Chi Duoc ^ oc2004 , 44 (1), 11; CN1869043A), but lower yield widespread pollution major problem, especially in the oxidation reaction is often used to expensive, and polluting agents.Therefore, to reduce pollution, reduce environmental hazards, streamline operations, improve yield, reduce costs, important for the synthesis of chenodeoxycholic acid.

 Preparation of chenodeoxycholic acid.

[0007]

Figure CN102060902AD00041
Preparation of chenodeoxycholic acid (5): 12- oxo take chenodeoxycholic acid 0. 9g, 15ml ethylene glycol was added solid sodium hydroxide and 1. 5g, 15ml hydrated corpus (80%) , 120 ° C reflux for 2 hours, change return device is a distillation apparatus, was gradually warmed evaporated amount hydrated corpus, continue to heat up to 150 ° C, continuing reflux for 4h, cooled to room temperature, poured into water, adjusted with HCl of PH3, white precipitated, was filtered cake was washed with water, and dried to give crude chenodeoxycholic acid 0. 92g, recrystallized from methanol to give 0. 86g, 99% yield. .. 1HnMR (CD3SOCD3) S: 0.60 (s, 3H, 18- CH3), 0 90 (s, 3H, 19_CH3), 0.95 (d, 3H, 21-CH3), 3 47 (s, IH, 3 β – H), 3. 96 (s, 1H, 7 β -H), 11. 94 (s, 1H, C00H).
PATENT

Cholic acid esters prepared by (1) Weigh 50 g of cholic acid, dissolved in 150 ml of anhydrous methanol was added 5 ml of concentrated hydrochloric acid was refluxed for 30 minutes, cooled slowly into the freezer, the available capacity methyl cholate It was 95%.

(2) hydroxy -12α- diacetyl – Preparation of methyl cholate methyl cholate weighed 50 g, was dissolved in 100 ml of pyridine was purified, dissolved completely, 100 ml of acetic anhydride was stirred at room temperature for 3 to 4 hours, poured into 500 ml of water, a white precipitate in the refrigerator, filtered the next day, diacetyl -12α- available hydroxy – methyl cholate, yield 40%.

(3) 3α, 7α–diacetoxy-12-oxo – Preparation of methyl cholanic acid prepared above was weighed 25 g of crude product, dissolved in 250 ml of acetone, filtered to remove insolubles, the stirring conditions , the Jones reagent was slowly added, at room temperature for 30 minutes, filtered, water was added to the filtrate precipitated white precipitate was filtered available 3α, 7α–diacetoxy-12-oxo – methyl-cholanic acid. The yield was 100%.

(4) 12- oxo – Preparation of chenodeoxycholic acid in ethanol 10% – sodium hydroxide solution and saponified for 1 hour at room temperature, the solution was acidified, poured into water to give 12- oxo – chenodeoxycholic acid , 100% yield.Recrystallized in absolute ethanol.

Preparation of chenodeoxycholic acid (5) was weighed 12- oxo – chenodeoxycholic acid, 20 grams, was added 300 ml of ethylene glycol and 30 g of solid sodium hydroxide and 300 ml of hydrazine hydrate (85%), 100 ℃ refluxed for 2 hours, warming gradually raised to 130. ℃, generated by hydrazine hydrate was distilled off, continue to heat up to 185 ~ 190 ℃, continued reflux for 4 hours, cooled to a lower temperature, poured into water and heat, PH adjusted with hydrochloric acid (20%) 3, a white precipitate was filtered cake was washed with water to give chenodeoxycholic acid.

(6) Purification of chenodeoxycholic acid obtained weighed amount of chenodeoxycholic acid, dissolved with a small amount of ethanol, was impregnated on a silica gel column petroleum ether, liquid flow linear velocity by column chromatography 1 ~ 5cm / control points, with petroleum ether: acetone = 2, begins to elute, detected by TLC chromatography therebetween, Junichi appearance of spots to be chenodeoxycholic acid appears to start collecting the eluate until no Chenodeoxy acid spots, distillation under reduced pressure and dried to give pure higher chenodeoxycholic acid.

PATENTS

Publication numberPriority datePublication dateAssigneeTitle
WO2007069814A1 *2005-12-122007-06-21Daewoong Pharmaceutical Co., Ltd.Purification process for chenodeoxycholic acid
WO2007078039A1 *2005-12-302007-07-12Daewoong Pharmaceutical Co., Ltd.Purification process for chenodeoxycholic acid
CN100484952C2005-12-132009-05-06山东博尔德生物科技有限公司Method for producing high-purity chenodeoxy cholic acid from poultry and livestock bile
CN102060902A *2011-01-212011-05-18郑州大学Chenodeoxycholic acid synthesis method
CN102286051A *2011-08-152011-12-21上海华震科技有限公司A method for separating chenodeoxycholic acid and ursodeoxycholic acid
CN102690856A *2012-05-302012-09-26绵阳劲柏生物科技有限责任公司Process using microbial solution to prepare free bile acid
CN102703556A *2012-05-302012-10-03绵阳劲柏生物科技有限责任公司Method for separating chenodeoxycholic acid from duck bile by using macroporous resin
CN101830956B2008-11-192012-11-21毕小升Preparation method for separating and purifying chenodeoxycholic acid in porcine bile paste or leftovers
CN102827234A *2012-08-302012-12-19苏州天绿生物制药有限公司Method for separating and purifying chenodeoxycholic acid from duck gall
CN103360454A *2013-05-062013-10-23广西大学Method for separating and purifying chenodeoxycholic acid from goose bile
US3919266A1972-09-211975-11-11Intellectual Property Dev CorpProduction of bile acids
FR2429224A1 *1978-06-191980-01-18Canada Packers LtdChenodeoxycholic acid recovery from porcine bile – useful for dissolving gall stones in vivo
JPS60181096A *1984-02-281985-09-14Tokyo Tanabe Co LtdPurification of bile acid
EP0386538A21989-03-061990-09-12ERREGIERRE INDUSTRIA CHIMICA SpaProcess for preparing high purity 3-alpha-7-beta-dihydroxycholanic acid
JPH03227998A *1990-02-021991-10-08Showa Denko KkMethod for purifying chenodeoxycholic acid
CN1528779A *2003-09-292004-09-15华东理工大学Method for preparing cheodexycholic acid
Family To Family Citations
GB1450939A *1973-12-191976-09-29Intellectual Property
US4186143A *1977-06-201980-01-29Canada Packers LimitedChenodeoxycholic acid recovery process
KR100658512B1 *2005-12-302006-12-11주식회사 대웅제약Purification process for chenodeoxycholic acid

References

  1. Jump up to:a b c Russell DW (2003). “The enzymes, regulation, and genetics of bile acid synthesis”Annu. Rev. Biochem72: 137–74. doi:10.1146/annurev.biochem.72.121801.161712PMID 12543708.
  2. Jump up^ Carey MC (December 1975). “Editorial: Cheno and urso: what the goose and the bear have in common”. N. Engl. J. Med293 (24): 1255–7. doi:10.1056/NEJM197512112932412PMID 1186807.
  3. Jump up^ Parks DJ, Blanchard SG, Bledsoe RK, et al. (May 1999). “Bile acids: natural ligands for an orphan nuclear receptor”Science284 (5418): 1365–8. doi:10.1126/science.284.5418.1365PMID 10334993.
  4. Jump up^ Thistle JL, Hofmann AF (September 1973). “Efficacy and specificity of chenodeoxycholic acid therapy for dissolving gallstones”N. Engl. J. Med289 (13): 655–9. doi:10.1056/NEJM197309272891303PMID 4580472.
  5. Jump up^ Berginer VM, Salen G, Shefer S (December 1984). “Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid”N. Engl. J. Med311 (26): 1649–52. doi:10.1056/NEJM198412273112601PMID 6504105.
  6. Jump up^ Giaconda. “Press release”. Retrieved 5 April 2014.
  7. Jump up^ Bazzoli F, Malavolti M, Petronelli A, Barbara L, Roda E (1983). “Treatment of constipation with chenodeoxycholic acid”. J. Int. Med. Res11 (2): 120–3. PMID 6852359.
  8. Jump up^ Rao AS, Wong BS, Camilleri M, et al. (November 2010). “Chenodeoxycholate in females with irritable bowel syndrome-constipation: a pharmacodynamic and pharmacogenetic analysis”Gastroenterology139 (5): 1549–58, 1558.e1. doi:10.1053/j.gastro.2010.07.052PMC 3189402Freely accessiblePMID 20691689.
  9. Jump up^ Ki Soo Kim, Hong-Seok Kim Molecular Tweezer Based on Chenodeoxycholic Acid:Synthesis, Anion Binding Properties. Bulletin of the Korean Society 1411-1413 2004 Article ArchivedSeptember 27, 2007, at the Wayback Machine.
Chenodeoxycholic acid
Skeletal formula of chenodeoxycholic acid
Ball-and-stick model of the chenodeoxycholic acid molecule
Names
IUPAC names

chenodiol
OR
3α,7α-dihydroxy-5β-cholanic acid
OR
5β-cholanic acid-3α,7α-diol
OR
(R)-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.006.803
EC Number 207-481-8
KEGG
PubChem CID
UNII
Properties
C24H40O4
Molar mass 392.57 g/mol
Melting point 165 to 167 °C (329 to 333 °F; 438 to 440 K)
Pharmacology
A05AA01 (WHO)
License data
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
No verify (what is YesNo ?)
Infobox references

////////////////////Chenodeoxycholic acid,  ケノデオキシコール酸 , orphan designation

[H][C@@]1(CC[C@@]2([H])[C@]3([H])[C@H](O)C[C@]4([H])C[C@H](O)CC[C@]4(C)[C@@]3([H])CC[C@]12C)[C@H](C)CCC(O)=O

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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