CN101798332A - Cholic acid coupling compound, preparation method and application thereof - Google Patents
Cholic acid coupling compound, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a coupling compound (I) of a cholic acid compound and cystamine, a preparation method of the compound and application thereof in preparing therapeutic drugs of taurine and cholic acid coupling compounds. In the formula of the coupling compound, R1, R2 and R3 represent H, alpha-OH, beta-OH and =O; and the R1, the R2 and the R3 can be same or different.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to the conjugates (I) of cholic acid compounds and cystamine, its preparation method and the application in preparation taurine cholic acid class conjugate class medicine.
R in the formula
1, R
2, R
3Expression H, α-OH, β-OH ,=O; R
1, R
2And R
3Can be identical, also can be different.
Background technology
The cholic acid compounds extensively is present in people and the mammiferous bile, can promote the absorption of fat and liposoluble vitamin by its enterohepatic circulation.In the human liver, the cholic acid compounds is synthetic by cholesterol, be subjected to the interference of some diseases when the human body enterohepatic circulation, when making the metabolism of cholic acid compounds be subjected to hindering, can cause multiple hepatobiliary system disease, as: cholestasis, fatty liver, cholesterol type calculus, bile reflux gastritis, courage source property pancreatitis, hyperlipidaemia, and various hepatitis etc.At present, be mostly to give ectogenic cholic acid compounds or its amino acid conjugates for the treatment of this class hepatobiliary system disease clinically.
In natural bile, the cholic acid compounds is many to be combined with taurine, forms ox sulphur bile acide; because this class conjugated bile acids content in animal bile is less, it originates limited in a large number, and ox sulphur bile acide compounds wetting ability is strong; the extraction separation difficulty, cost is higher.Therefore, the existing cholic acid conjugate class medicine major part of using clinically is to obtain by chemical synthesis, existing document: J Lipid Research 1973,14,367; J LipidResearch 1977,18,404; J Lipid Research 1989,30,771; Acta Chem Scand 1963,17,173; Bioorganic ﹠amp; Medicinal Chemistry 1996,4 (6), and 885; Synlett 1995,861; Lipids1997,32 (7), 775; J Am Chem Soc 1937,59,2532; US 5362891; US 5508453; US 5565587; Chinese Journal of Pharmaceuticals 2003,34 (12), 594; Chinese Pharmaceutical Journal 1997,32 (4), 236; CN 1896091; CN 101307088; CN 101503454 grades have been described the preparation method of this class cholic acid conjugate class medicine, and these methods can be divided into following several according to the Different Strategies of cholic acid compounds and taurine formation amido linkage:
Method one:
Carboxyl in cholic acid compounds molecule chloro-formic ester, N-ethoxycarbonyl-2-oxyethyl group-1; 2-dihydroquinoline (EEDQ), carbodiimide (DCC, EDCI), diethyl phosphorocyanidate (DEPC), 2-chloro-4; 6-dimethoxy-1; 3; 5-triazine (CDMT), chlorination 4-(4; 6-dimethoxy-1; 3; 5-triazine-2-yl)-activation of condensing agents such as 4-methylmorpholine salt (DMTMM), sulfhydryl compound; form mixed acid anhydride or active ester; and then with taurine compound reaction, get taurine cholic acid conjugate class medicine through aftertreatment.
Method two:
The cholic acid compounds becomes ester with alcohol under sulphuric acid catalysis, with hydrazine hydrate react corresponding hydrazides, after diazotization generates acyl azide again with the reaction of taurine compounds, through conventional aftertreatment, taurine cholic acid conjugate class medicine.
Method three:
The female ring of cholic acid compounds is gone up hydroxyl protect with process for hydroformylation, generate corresponding acyl chlorides with the sulfur oxychloride effect then, with the reaction of taurine compounds, conventional aftertreatment gets taurine cholic acid conjugate class medicine again.
Method four:
Cholic acid compounds and chloro-formic ester effect; after forming mixed acid anhydride; react with phenolic compound (as: p-NP, ethyl-para-hydroxyphenyl ketone etc.); form the active phenolic ester of corresponding cholic acid compounds; react with the taurine compounds again; through aftertreatment, get taurine cholic acid conjugate class medicine.
Above-mentioned synthetic method exists uses cost of material higher and be not easy to obtain (as: EEDQ, DEPC, ethyl-para-hydroxyphenyl ketone etc.); Severe reaction conditions (needing absolute anhydrous solvent); Reactions steps is many, total recovery is on the low side; " three wastes " discharging is serious in the preparation process; Deficiencies such as operation and last handling process are loaded down with trivial details; Make the preparation cost of cholic acid conjugate class medicine higher, the technical scale preparation is restricted.Therefore, this area need develop still that raw material is cheap and easy to get, reaction conditions is gentle, easy and simple to handle, yield is high, the cholic acid conjugate class medicine synthetic method of " environmental protection ".
Summary of the invention
The objective of the invention is to disclose the key intermediate that a kind of novel being used to prepares taurine cholic acid class conjugate---the conjugates (I) of cholic acid compounds and cystamine;
Another object of the present invention is to disclose the preparation method of such novel cpd;
The 3rd purpose of the present invention is to disclose the application of such key intermediate in preparation taurine cholic acid class conjugate medicine.
The chemical structural formula of the conjugates (I) of cholic acid compounds proposed by the invention and cystamine is:
R in the formula
1, R
2, R
3Expression H, α-OH, β-OH ,=O; R
1, R
2And R
3Can be identical, also can be different.
The conjugates (I) of cholic acid compounds proposed by the invention and cystamine can utilize cholic acid compounds and corresponding cystamine compounds to prepare under the condensing agent existence condition; the conjugates of gained cholic acid compounds and cystamine (I) can be used for preparing taurine cholic acid class conjugate class medicine, and its synthetic route is as follows:
R in the formula
1, R
2, R
3Expression H, α-OH, β-OH ,=O; R
1, R
2And R
3Can be identical, also can be different.
The conjugates (I) of cholic acid compounds that above-mentioned chemical equation provides and cystamine and be used to prepare the synthetic method of taurine cholic acid class conjugate class medicine, its concrete steps are:
A) be starting raw material with the cholic acid compounds, with the cystamine compounds through condensation reaction, make the conjugates (I) of cholic acid compounds and cystamine;
B) by steps A) the cholic acid compounds that obtains and the conjugates (I) of cystamine, get taurine cholic acid class conjugate (II) through oxidizing reaction.
Each step of this synthetic method specifically describes as follows:
Steps A): cholic acid compounds and cystamine compounds through condensing agent effect generation condensation reaction, get the conjugates (I) of cholic acid compounds and cystamine under alkalescence and appropriate solvent condition.
Wherein the cholic acid compounds comprises: cholic acid (R
1=H, R
2=α-OH, R
3=α-OH), Deoxycholic Acid (R
1=H, R
2=H, R
3=α-OH), lithocholic acid (R
1=H, R
2=H, R
3=H), 7-ketone group lithocholic acid (R
1=H, R
2=C=O, R
3=H), Iocholic acid (R
1=α-OH, R
2=H, R
3=α-OH), Hyodeoxycholic Acid (R
1=α-OH, R
2=H, R
3=H), Chenodiol (R
1=H, R
2=α-OH, R
3=H), ursodesoxycholic acid (R
1=H, R
2=β-OH, R
3=H);
The cystamine compounds comprises: cystamine free alkali, cystamine inorganic acid salt (as: hydrochloride, Hydrogen bromide, vitriol, nitrate, phosphoric acid salt etc.), cystamine organic acid salt (as: formic acid, acetate, propionic acid, phenylformic acid, toxilic acid, fumaric acid, succsinic acid, tartrate, citric acid etc.; Alkylsulphonic acid is as methylsulphonic acid, ethylsulfonic acid, camphorsulfonic acid etc.; Aryl sulfonic acid is as Phenylsulfonic acid, tosic acid etc.);
The condensation reaction solvent for use is: water, C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
3-8Aliphatic ketone, C
5-10Fat alkane (as: normal hexane, normal heptane etc.), N, dinethylformamide, ethers (as: ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether etc.), C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene etc.), aromatic hydrocarbon or substituted aroma hydrocarbon, acetonitrile, reaction can be carried out in single solvent, also can in mixed solvent, carry out, the mixed solvent volume ratio is 1: 0.1～10, preferred solvent is tetrahydrofuran (THF), N, dinethylformamide, water, methylene dichloride, Virahol, acetone, ethyl acetate, toluene, tetrahydrofuran (THF)/water (1: 0.1～2.0);
The used alkali of condensation reaction is basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, trimethylamine class or quaternary ammonium bases (as: triethylamine, Tributylamine, trioctylamine, pyridine, N, N-dimethyl-α-Ben Yian, 4-methylmorpholine, TBAH), preferred bases is: sodium bicarbonate, salt of wormwood, triethylamine, N-methylmorpholine, pyridine; The molar feed ratio of alkali consumption and cystamine compounds is 0～8.0: 1.0, and preferred molar feed ratio is 0～4.5: 1.0;
The molar feed ratio of cholic acid compounds and cystamine compounds is 1.9～4.0: 1.0, and preferred molar feed ratio is 2.0～2.5: 1.0;
The used condensing agent of condensation reaction is: chloroformic acid C
1-8Aliphatic alcohol ester compounds (as: Vinyl chloroformate, the chloroformic acid tert-butyl ester, chloroformic acid benzyl ester etc.), N-ethoxycarbonyl-2-oxyethyl group-1,2-dihydroquinoline (EEDQ), carbodiimide compound (as: DCC, EDCI), diethyl phosphorocyanidate (DEPC), 2-chloro-4,6-dimethoxy-1,3,5-triazine (abbreviating CDMT as), chlorination 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-and 4-methylmorpholine salt (abbreviating DMTMM as), preferred condensing agent is: Vinyl chloroformate, dicyclohexylcarbodiimide (DCC), DMTMM;
The molar feed ratio of used condensing agent and cholic acid compounds is 1.0～4.5: 1.0, and preferred molar feed ratio is 1.0～2.5: 1.0;
Setting-up point is 0～130 ℃, and preferable reaction temperature is 0～50 ℃; Condensation reaction time is 30 minutes～48 hours, and the preferred reaction time is 1～20 hour.
Step B): the conjugates of cholic acid compounds and cystamine (I) through oxidizing reaction, gets taurine cholic acid class conjugate (II) under appropriate solvent and oxygenant existence condition.Wherein, the oxidizing reaction solvent for use is: water, C
1-6Lipid acid, C
1-6Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, tetrahydrofuran (THF), N, dinethylformamide, C
3-8Aliphatic ketone, preferred solvent are water, formic acid, acetate, methyl alcohol, tetrahydrofuran (THF); Used oxygenant is: aqueous hydrogen peroxide solution (H
2O
2Content is 5%～90%), C
1-6The superoxide of lipid acid (as: peroxyformic acid, Peracetic Acid etc.), benzoyl hydroperoxide compounds (as: metachloroperbenzoic acid, benzoyl hydroperoxide etc.), urea-hydrogen peroxide mixture, peroxyboric acid, C
3-8Aliphatic ketone or C
3-8The superoxide of alicyclic ketone (as: acetone peroxide, cyclohexanone peroxide), preferred oxidant is: aqueous hydrogen peroxide solution (H
2O
2Content is 20%～70%), urea-hydrogen peroxide mixture, peroxyformic acid, Peracetic Acid, metachloroperbenzoic acid; The molar feed ratio of oxygenant and cholic acid cystamine class conjugates (I) is 5.0～20.0: 1.0, and preferred molar feed ratio is 8.0～13.0: 1.0; Oxidizing reaction temperature is-50～50 ℃, and preferable reaction temperature is-15～30 ℃; Oxidation time is 20 minutes～48 hours, and the preferred reaction time is 1～12 hour.
The invention has the advantages that: compared with prior art; this method raw materials used cheap and easy to get, reaction conditions is gentle, the reaction required solvent need not have water treatment; easy and simple to handle, cost is low, yield is high, " three wastes " pollute fewly, is fit to a large amount of preparation taurine cholic acid class conjugate medicines.
Embodiment
Can further describe the present invention by the following examples, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.
One. the preparation of the conjugates of cholic acid compounds and cystamine (I)
The preparation of embodiment 1 ursodesoxycholic acid cystamine conjugates
In reaction flask, add ursodesoxycholic acid 20.0 gram (50.95mmol), 100 milliliters of tetrahydrofuran (THF)s and 8.16 milliliters of triethylamines (58.5mmol), be cooled to 0-5 ℃, drip 5.6 milliliters of Vinyl chloroformates (58.5mmol), 5～10 ℃ of insulated and stirred were reacted 30 minutes then, add 2-aminoethyl disulfide dihydrochloride 5.7 grams (25.0mmol) and triethylamine 8.16 milliliters (58.5mmol) and be dissolved in the solution of 100 ml deionized water, 0～5 ℃ of insulated and stirred reaction is after 1 hour, again in stirring at room reaction 10 hours.After reaction finishes, remove tetrahydrofuran (THF) under reduced pressure, filter the white solid of separating out, the gained filter cake is with methanol (1: 1) mixed solvent recrystallization, white crystalline powder solid 20.74 grams of ursodesoxycholic acid cystamine conjugates, mp150～152 ℃,
Yield 92.0%;
1HNMR (400MHz, DMSO-d
6) δ: δ: 8.01 (t, J=5.6Hz, 2H, 2 * NH), 4.47 (brs, 2H, 2 * 7 β-OH), 3.88 (brs, 2H, 2 * 3 α-OH), 3.42～3.36 (m, 4H, 2 * C
7-H, 2 * C
3-H), 3.30 (t, J=7.2Hz, 4H, 2 * HNCH
2), 2.75 (t, J=7.2Hz, 4H, 2 * SCH
2), 0.88 (d, J=8.4Hz, 6H, 2 * 21-CH
3), 0.87 (s, 6H, 2 * 19-CH
3), 0.61 (s, 6H, 2 * 18-CH
3);
13C-NMR (100MHz, DMSO-d
6) δ: 173.29,70.19,69.92,60.21,56.36,55.19,43.55,43.46,42.65,39.23,38.35,38.18,37.85,37.72,35.44,35.30,34.21,32.86,32.06,30.69,28.68,27.17,23.79,21.34,18.92,12.50.
The preparation of embodiment 2 ursodesoxycholic acid cystamine conjugates
In reaction flask, add ursodesoxycholic acid 2.0 grams (5.1mmol), 15 milliliters of tetrahydrofuran (THF)s and cystamine 0.39 gram (2.55mmol), after stirring at room is even, put and be cooled to 0-5 ℃ in the ice bath, add DCC 1.16 grams (5.6mmol), 0-5 ℃ of insulated and stirred reaction is after 1 hour, being warming up to room temperature reacted 15 hours again, after reaction finishes, the white solid that filtration is separated out, filtrate decompression is steamed and is desolventized, and resistates restrains with methanol (1: 1) mixed solvent recrystallization, the white crystalline powder solid 2.16 that gets ursodesoxycholic acid cystamine conjugates, mp150～152 ℃
Yield 95.8%;
1The HNMR data and
13C-NMR data and embodiment 1 basically identical.
The preparation of embodiment 3 ursodesoxycholic acid cystamine conjugates
With 2-aminoethyl disulfide dihydrochloride 0.57 gram (2.5mmol), anhydrous K
2CO
30.7 gram (5.0mmol) and 30 milliliters of mixing of Virahol, stirring at room reaction 30 minutes adds ursodesoxycholic acid 2.0 gram (5.1mmol) and chlorination 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine salt 1.84 grams (6.63mmol), stirring at room reaction 6 hours.After reaction finishes, filter, filtrate decompression is steamed and is desolventized, and resistates is with methanol (1: 1) mixed solvent recrystallization, white crystalline powder solid 2.23 grams of ursodesoxycholic acid cystamine conjugates, mp150～152 ℃,
Yield 99.0%;
1The HNMR data and
13C-NMR data and embodiment 1 basically identical.
The preparation of embodiment 4 Chenodiol cystamine conjugates
Operating process just substitutes ursodesoxycholic acid anhydrous K with embodiment 3 with Chenodiol
2CO
3Substitute with the 4-methylmorpholine, the white crystalline powder solid of Chenodiol cystamine conjugates, mp143～145 ℃,
Yield 98.0%;
1HNMR (400MHz, DMSO-d
6) δ: 8.00 (t, J=5.6Hz, 2H, 2 * NH), 3.84～3.81 (m, 2H, 2 * C
7-H), 3.33～3.28 (m, 6H, 2 * C
3-H, 2 * HNCH
2), 2.75 (t, J=7.2Hz, 4H, 2 * SCH
2), 0.88 (d, J=8.4Hz, 6H, 2 * 21-CH
3), 0.84 (s, 6H, 2 * 19-CH
3), 0.60 (s, 6H, 2 * 18-CH
3);
13C-NMR (100MHz, DMSO-d
6) δ: 173.32,70.48,66.37,60.20,56.36,55.99,48.69,42.81,40.53,38.34,37.82,35.99,35.84,35.35,35.30,34.80,32.76,31.96,30.77,29.65,28.18,24.35,24.01,20.88,18.73,12.32.
The preparation of embodiment 5 Hyodeoxycholic Acid cystamine conjugates
Operating process just substitutes ursodesoxycholic acid anhydrous K with embodiment 3 with Hyodeoxycholic Acid
2CO
3Substitute with triethylamine, Virahol substitutes with deionized water, the white crystalline powder solid of Hyodeoxycholic Acid cystamine conjugates, mp150～152 ℃,
Yield 97.2%;
1HNMR (400MHz, DMSO-d
6) δ: 8.02 (t, J=5.6Hz, 2H, 2 * NH), 4.45 (d, J=4.0Hz, 2H, 2 * 6 α-OH), 4.26 (d, J=4.0Hz, 2H, 2 * 3 α-OH), 3.84～3.81 (m, 2H, 2 * C
6-H), 3.30～3.28 (m, 6H, 2 * C
3-H, 2 * HNCH
2), 2.75 (t, J=7.2Hz, 4H, SCH
2), 0.88 (d, J=6.0Hz, 6H, 2 * 21-CH
3), 0.84 (s, 6H, 2 * 19-CH
3), 0.60 (s, 6H, 2 * 18-CH
3);
13C-NMR (100MHz, DMSO-d
6) δ: 173.23,70.47,66.35,60.22,56.37,55.99,48.71,42.81,40.07,38.33,37.82,36.00,35.85,35.35,34.80,32.75,31.96,31.15,30.79,29.69,28.18,24.36,24.03,20.88,18.74,12.33.
The preparation of embodiment 6 cholic acid cystamine conjugates
Operating process just substitutes ursodesoxycholic acid anhydrous K with embodiment 3 with cholic acid
2CO
3Substitute with the 4-methylmorpholine, the white crystalline powder solid of cholic acid cystamine conjugates, mp148～150 ℃,
Yield 99.0%;
1HNMR (400MHz, DMSO-d
6) δ: 7.99 (t, J=5.6Hz, 2H, 2 * NH), 3.78 (m, 2H, 2 * C
12-H), 3.61 (m, 2H, 2 * C
7-H), 3.45 (brs, 6H, 2 * 12 α-OH, 2 * 7 α-OH, 2 * 3 α-OH), 3.33～3.28 (m, 4H, 2 * HNCH
2), 3.19～3.17 (m, 2H, 2 * C
3-H), 2.75 (t, J=6.8Hz, 4H, 2 * SCH
2), 0.91 (d, J=8.4Hz, 6H, 2 * 21-CH
3), 0.81 (s, 6H, 2 * 19-CH
3), 0.58 (s, 6H, 2 * 18-CH
3);
13C-NMR (100MHz, DMSO-d
6) δ: 173.36,71.48,70.90,66.71,60.23,46.61,46.19,41.98,41.81,38.35,37.80,35.77,35.59,35.34,34.84,32.95,32.13,30.84,29.00,27.77,26.66,23.27,23.07,21.22,17.55,12.80.
The preparation of embodiment 77-ketone group lithocholic acid cystamine conjugates
Operating process just substitutes anhydrous K with ursodesoxycholic acid with 7-ketone group lithocholic acid with embodiment 3
2CO
3Substitute with the 4-methylmorpholine, the white crystalline powder solid of 7-ketone group lithocholic acid cystamine conjugates, mp146～148 ℃,
Yield 98.0%;
1HNMR (400MHz, DMSO-d
6) δ: 8.00 (t, J=5.6Hz, 2H, 2 * NH), 3.33～3.28 (m, 6H, 2 * C
3-H, 2 * HNCH
2), 2.90 (dd, 2H, J
1=6.0Hz, J
2=12.0Hz, C
6 β-H), 2.75 (t, J=6.8Hz, 4H, 2 * SCH
2), 2.44 (t, 2H, J=12.0Hz, C
6 α-H), 1.17 (s, 6H, 2 * 19-CH
3), 0.88 (d, J=8.4Hz, 6H, 2 * 21-CH
3), 0.61 (s, 6H, 2 * 18-CH
3);
13C-NMR (100MHz, DMSO-d
6) δ: 211.83,173.21,69.55,54.83,49.28,49.04,45.85,45.53,42.65,42.63,39.76,39.08,38.34,37.83,35.24,35.22,34.33,32.77,32.02,30.27,28.33,24.86,23.25,21.69,18.85,12.36.
The preparation of embodiment 8 lithocholic acid cystamine conjugates
Operating process just substitutes ursodesoxycholic acid anhydrous K with embodiment 3 with lithocholic acid
2CO
3Substitute with the 4-methylmorpholine, get the white crystalline powder solid of lithocholic acid cystamine conjugates, yield 96.6%.
The preparation of embodiment 9 Deoxycholic Acid cystamine conjugates
Operating process just substitutes ursodesoxycholic acid anhydrous K with embodiment 3 with Deoxycholic Acid
2CO
3Substitute with the 4-methylmorpholine, get the white crystalline powder solid of Deoxycholic Acid cystamine conjugates, yield 98.0%.
The preparation of embodiment 10 Iocholic acid cystamine conjugates
Operating process just substitutes ursodesoxycholic acid anhydrous K with embodiment 3 with Iocholic acid
2CO
3Substitute with the 4-methylmorpholine, get the white crystalline powder solid of Iocholic acid cystamine conjugates, yield 95.9%.
Two. the preparation of taurine cholic acid class conjugate (II)
The preparation of embodiment 11 ursodeoxycholic acids
With 30%H
2O
2The aqueous solution 13.2 milliliters of (130mmol), 100 milliliters of mixing of anhydrous formic acid, stirring at room reaction 2 hours, put in the cryosel bath and be cooled to-5～0 ℃, add ursodesoxycholic acid cystamine conjugates 9.01 grams (10.0mmol) in batches, continue insulated and stirred reaction 5 hours, reaction adds saturated NaHSO after finishing
3The aqueous solution destroys excessive superoxide; remove by filter a small amount of insolubles, the gained filtrate decompression is steamed and is desolventized, and transfers pH to 1～2 with 10% aqueous hydrochloric acid; add small amount of seeds; in-5～0 ℃ of stirring 12 hours, suction filtration, filter cake washs with small amount of acetone; use acetone-water (12: 1) recrystallization again; ursodeoxycholic acid white powder solid 7.59 gram, mp143～145 ℃
Yield 75.9%.
1HNMR(400MHz，D
2O)δ：3.64～3.61(m，2H，C
7-H，C
3-H)，3.61(t，J＝7.2Hz，2H，CH
2NH)，3.12(t，J＝7.2Hz，2H，C
H 2SO
3H)，2.38～2.32(m，1H，C
23-H)，2.24～2.22(m，1H，C
23-H)，2.07～2.05(m，1H，C
12-H
β)，1.99～1.74(m，5H，C
16-H
α，C
15-H
α，C
6-H
β，C
1-H
a，C
22-H
β)，1.67～1.59(m，5H，C
2-H
β，C
4-H
α，C
6-H
α，C
4-H
B，C
5-H
β)，1.55～1.43(m，5H，C
8-H
β，C
9-H
α，C
11-H
α，C
15-H
β，C
20-H)，1.43～1.22(m，6H，C
22-H
α，C
16-H
β，C
11-H
β，C
14-H
α，C
2-H
α，C
12-H
α)，1.16～1.08(m，2H，C
17-H
α，C
1-H
β)，1.01(d，J＝4.2Hz，3H，CH
3-21)，0.98(s，3H，CH
3-19)，0.74(s，3H，CH
3-18)；
13CNMR(100MHz，D
2O)δ：179.2，73.5，73.4，58.2，57.3，52.5，46.1，45.7，44.9，42.8，41.9，39.4，38.8，37.9，37.8，37.6，36.4，35.4，34.4，32.3，31.0，29.2，26.0，24.0，21.1，14.7；ESI-MS(m/z，-Q)：498.4(M-H)
-。
The preparation of embodiment 12 ursodeoxycholic acids
Ursodesoxycholic acid cystamine conjugates 4.51 gram (5.0mmol) is dissolved in 50 milliliters of the methyl alcohol; put in the cryosel bath and be cooled to-5～0 ℃; add urea-hydrogen peroxide mixture 5.65 grams (60.0mmol) in batches; continue insulated and stirred reaction 8 hours; after reaction finishes, add a small amount of dimethyl sulphide and destroy excessive superoxide, remove by filter a small amount of insolubles; the gained filtrate decompression is steamed and is desolventized; transfer pH to 1～2 with aqueous hydrochloric acid, add small amount of seeds, stirred 12 hours in-5～0 ℃; suction filtration; filter cake washs with small amount of acetone, uses acetone-water (12: 1) recrystallization again, gets ursodeoxycholic acid white powder solid 4.15 grams; mp143～145 ℃
Yield 83.0%.
1The HNMR data,
13C-NMR and ESI-MS data and embodiment 11 basically identicals.
The preparation of embodiment 13 ursodeoxycholic acids
Operating process is with embodiment 12, just urea-hydrogen peroxide mixture is substituted with metachloroperbenzoic acid, ursodeoxycholic acid white powder solid, mp142～145 ℃,
Yield 65.0%.
1The HNMR data,
13C-NMR and ESI-MS data and embodiment 11 basically identicals.
The preparation of embodiment 14 Taurochenodeoxycholic Acids
Operating process is with embodiment 12, just ursodesoxycholic acid cystamine conjugates is substituted with Chenodiol cystamine conjugates, Taurochenodeoxycholic Acid white powder solid, mp133～135 ℃,
Yield 85.1%.
1HNMR(400MHz，D
2O)δ：3.87(m，1H，C
7-H)，3.57(t，J＝7.2Hz，2H，CH
2NH)，3.48(m，1H，C
3-H)，3.07(t，J＝7.2Hz，2H，C
H 2SO
3H)，2.34～2.29(m，1H，C
23-H)，2.19～2.16(m，1H，C
23-H)，2.14～2.07(m，1H，C
4-H
α)，1.96～1.94(m，3H，C
16-H
α，C
12-H
β，C
6-H
β)，1.86～1.82(m，2H，C
1-H
α，C
9-H
α)，1.72～1.62(m，4H，C
15-H
α，C
22-H
β，C
4-H
β，C
2-H
β)，1.59～1.51(m，2H，C
6-H
α，C
11-H
α)，1.49～1.32(m，6H，C
8-H
β，C
20-H，C
22-H
α，C
14-H
α，C
5-H
β，C
2-H
α)，1.30～1.21(m，4H，C
12-H
α，C
16-H
β，C
11-H
β，C
17-H
α)，1.12～0.98(m，2H，C
15-H
β，C
1-H
β)，0.97(d，J＝4.2Hz，3H，CH
3-21)，0.92(s，3H，CH
3-19)，0.67(s，3H，CH
3-18)；
13CNMR(100MHz，D
2O)δ：179.5，74.7，71.2，58.0，53.1，52.9，45.3，44.5，42.5，42.4，41.6，38.5，38.3，38.0，37.7，37.4，35.7，35.5，34.7，32.9，30.1，26.6，26.0，23.8，21.3，14.8；ESI-MS(m/z，-Q)：498.1(M-H)
-。
The preparation of 15 Ns of sulphur Hyodeoxycholic Acids of embodiment
Operating process is with embodiment 12, just ursodesoxycholic acid cystamine conjugates is substituted with Hyodeoxycholic Acid cystamine conjugates, ox sulphur Hyodeoxycholic Acid white powder solid, mp198～200 ℃,
Yield 78.5%.
1HNMR(400MHz，D
2O)δ：4.12(m，1H，C
6-H)，3.69(m，1H，C
3-H)，3.60(t，J＝7.2Hz，2H，CH
2NH)，3.11(t，J＝7.2Hz，2H，C
H 2SO
3H)，2.39～2.31(m，1H，C
23-H)，2.25～2.16(m，1H，C
23-H)，2.07～1.91(m，2H，C
4-H
α，C
16-H
α，)，1.83～1.76(m，3H)，1.75～1.66(m，4H)，1.53～1.32(m，7H)，1.31～1.17(m，8H)，1.02(d，J＝4.8Hz，3H，CH
3-21)，0.99(s，3H，CH
3-19)，0.73(s，3H，CH
3-18)；
13CNMR(100MHz，D
2O)δ：179.4，74.0，70.8，58.7，52.8，50.7，45.7，43.0，42.7，38.7，38.5，38.3，38.2，37.8，36.8，35.9，34.7，33.2，32.6，31.1，30.7，27.1，26.5，23.9，21.4，15.1；ESI-MS(m/z，-Q)：498.3(M-H)
-。
The preparation of embodiment 16 taurocholates
Operating process is with embodiment 12, just ursodesoxycholic acid cystamine conjugates is substituted with cholic acid cystamine conjugates, taurocholate white powder solid, mp126～128 ℃,
Yield 79.4%.
1HNMR(400MHz，D
2O)δ：3.96(m，1H，C
12-H)，3.80(m，1H，C
7-H)，3.47(t，J＝7.2Hz，2H，CH
2NH)，3.41～3.37(m，1H，C
3-H)，2.98(t，J＝7.2Hz，2H，C
H 2SO
3H)，2.25～2.19(m，1H，C
23-H)，2.13～2.07(m，1H，C
23-H)，2.03～1.97(m，2H，C
9-H
α，C
4-H
α)，1.96～0.91(m，20H)，0.88(d，J＝4.0Hz，3H，CH
3-21)，0.82(s，3H，CH
3-19)，0.62(s，3H，CH
3-18)；
13CNMR(100MHz，D
2O)δ：177.0，72.80，71.47，67.99，49.81，46.17，46.00，41.43，41.32，39.58，38.38，35.37，35.18，35.12，34.50，34.10，32.35，31.54，29.29，27.97，27.36，26.37，23.12，22.41，16.79，12.32；ESI-MS(m/z，-Q)：514.0(M-H)
-。
The preparation of 17 Ns of sulphurs of embodiment-7-ketone group lithocholic acid
Operating process just substitutes ursodesoxycholic acid cystamine conjugates with embodiment 12 with 7-ketone group lithocholic acid cystamine conjugates, get ox sulphur 7-ketone group lithocholic acid white powder solid, and mp224～226 ℃ (dec),
Yield 73.7%;
1HNMR (400MHz, D
2O) δ: 3.75～3.65 (m, 1H, C
3-H), 3.62 (t, 2H, J=7.6Hz, 2 * HNCH
2), 3.16 (dd, 1H, J
1=6.8Hz, J
2=10.8Hz, C
6 β-H), 3.15 (t, J=7.6Hz, 2H, SCH
2), 2.79 (t, 1H, J=10.8Hz, C
6 α-H), 1.31 (s, 3H, 19-CH
3), 1.02 (d, J=6.4Hz, 3H, 21-CH
3), 0.76 (s, 3H, 18-CH
3);
13C-NMR (100MHz, D
2O) δ: 211.94,172.94,69.54,54.80,51.00,49.25,49.05,45.84,45.51,42.65,42.62,39.05,37.80,35.75,35.25,35.19,34.30,32.90,31.93,30.21,28.28,24.84,23.22,21.67,18.81,12.33; ESI-MS (m/z ,-Q): 496.1 (M-H)
-
The preparation of embodiment 18 taurolithocholic acids
Operating process is with embodiment 12, just ursodesoxycholic acid cystamine conjugates is substituted with lithocholic acid cystamine conjugates, taurolithocholic acid white powder solid, mp210～212 ℃,
Yield 84.5%; ESI-MS (m/z ,-Q): 482.2 (M-H)
-
The preparation of embodiment 19 taurodeoxycholic acids
Operating process is with embodiment 12, just ursodesoxycholic acid cystamine conjugates is substituted with Deoxycholic Acid cystamine conjugates, taurodeoxycholic acid white powder solid, mp184～186 ℃,
Yield 77.6%.
1HNMR(400MHz，D
2O)δ：4.05(m，1H，C
12-H)，3.60(m，1H，C
3-H)，3.58(t，J＝7.2Hz，2H，CH
2NH)，3.09(t，J＝7.2Hz，2H，C
H 2SO
3H)，2.40～2.31(m，1H，C
23-H)，2.27～2.16(m，1H，C
23-H)，1.00(d，J＝4.8Hz，3H，CH
3-21)，0.90(s，3H，CH
3-19)，0.69(s，3H，CH
3-18)；
13CNMR(100MHz，D
2O)δ：179.6，75.7，74.2，52.8，50.7，49.1，49.0，45.1，38.7，38.4，38.3，38.2，38.1，36.8，36.2，35.0，34.4，32.3，30.9，30.3，30.2，29.0，26.7，26.0，19.5，15.4；ESI-MS(m/z，-Q)：498.0(M-H)
-。
The preparation of 20 Ns of sulphur Iocholic acids of embodiment
Operating process just substitutes ursodesoxycholic acid cystamine conjugates with embodiment 12 with Iocholic acid cystamine conjugates, get ox sulphur Iocholic acid white powder solid; ESI-MS (m/z ,-Q): 514.2 (M-H)
-
The invention is not restricted to the foregoing description.
Claims (10)
1. a class has the cholic acid compounds of following general formula and the conjugates (I) of cystamine:
It is characterized in that R
1, R
2, R
3Expression H, α-OH, β-OH ,=O; R
1, R
2And R
3Can be identical, also can be different.
2. the preparation method of the conjugates (I) of cholic acid compounds as claimed in claim 1 and cystamine, it is characterized in that with cholic acid compounds and cystamine compounds be starting raw material, under alkalescence and appropriate solvent condition, through condensing agent effect generation condensation reaction, get the conjugates (I) of cholic acid compounds and cystamine.
3. preparation method as claimed in claim 2 is characterized in that the cholic acid compounds is: cholic acid, Deoxycholic Acid, lithocholic acid, 7-ketone group lithocholic acid, Iocholic acid, Hyodeoxycholic Acid, Chenodiol, ursodesoxycholic acid; The cystamine compounds is: cystamine free alkali, cystamine inorganic acid salt, cystamine organic acid salt.
4. preparation method as claimed in claim 2 is characterized in that the condensation reaction solvent for use is: water, C
1-6Fatty Alcohol(C12-C14 and C12-C18), C
3-8Aliphatic ketone, C
5-10Fat alkane, N, dinethylformamide, ethers, C
1-6Lipid acid and C
1-6Ester that Fatty Alcohol(C12-C14 and C12-C18) forms, halohydrocarbon, aromatic hydrocarbon or substituted aroma hydrocarbon, acetonitrile, reaction can be carried out in single solvent, also can carry out in mixed solvent, and the mixed solvent volume ratio is 1: 0.1～10; The used alkali of condensation reaction is: basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, trimethylamine class or quaternary ammonium bases; The molar feed ratio of alkali consumption and cystamine compounds is 0～8.0: 1.0; The used condensing agent of condensation reaction is: chloroformic acid C
1-8Aliphatic alcohol ester compounds, N-ethoxycarbonyl-2-oxyethyl group-1,2-dihydroquinoline, carbodiimide compound, diethyl phosphorocyanidate, 2-chloro-4,6-dimethoxy-1,3, and 5-triazine, chlorination 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine salt.
5. preparation method as claimed in claim 2, the molar feed ratio that it is characterized in that cholic acid compounds and cystamine compounds is 1.9～4.0: 1.0; The molar feed ratio of condensing agent and cholic acid compounds is 1.0～4.5: 1.0.
6. preparation method as claimed in claim 2 is characterized in that setting-up point is 0～130 ℃; Condensation reaction time is 30 minutes～48 hours.
7. a method for preparing taurine cholic acid class conjugate class medicine is characterized in that, the conjugates of cholic acid compounds and cystamine (I) through oxidizing reaction, gets taurine cholic acid class conjugate under appropriate solvent and oxygenant existence condition.
8. the preparation method of taurine cholic acid class conjugate class medicine as claimed in claim 7 is characterized in that the oxidizing reaction solvent for use is: water, C
1-6Lipid acid, C
1-6Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, tetrahydrofuran (THF), N, dinethylformamide, C
3-8Aliphatic ketone; Used oxygenant is: aqueous hydrogen peroxide solution (H
2O
2Content is 5%～90%), C
1-6The superoxide of lipid acid, benzoyl hydroperoxide compounds, urea-hydrogen peroxide mixture, peroxyboric acid, C
3-8Aliphatic ketone or C
3-8The superoxide of alicyclic ketone.
9. the preparation method of taurine cholic acid class conjugate class medicine as claimed in claim 7 is characterized in that the molar feed ratio of oxygenant and cholic acid cystamine class conjugates (I) is 5.0～20.0: 1.0; Oxidizing reaction temperature is-50～50 ℃; Oxidation time is 20 minutes～48 hours.
10. the purposes of the conjugates (I) of cholic acid compounds as claimed in claim 1 and cystamine is characterized in that being used to prepare taurine cholic acid class conjugate class medicine.
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|---|---|---|---|---|
| CN104844677A (en) * | 2015-04-16 | 2015-08-19 | 广州市盈宇医药科技有限公司 | tauroursodeoxycholic acid synthesis method |
| WO2023217237A1 (en) * | 2022-05-13 | 2023-11-16 | 苏州慧疗生物医药科技有限公司 | Lipid compound, and composition, preparation and use thereof |
-
2010
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Non-Patent Citations (1)
| Title |
|---|
| 《Bollettino Chimico Farmaceutico》 19651231 G B Crippa et al Nuovi Radioprotettori Particolari Derivati Amidici Dell'Acido Colico 479-484 1 第104卷, 2 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104844677A (en) * | 2015-04-16 | 2015-08-19 | 广州市盈宇医药科技有限公司 | tauroursodeoxycholic acid synthesis method |
| WO2023217237A1 (en) * | 2022-05-13 | 2023-11-16 | 苏州慧疗生物医药科技有限公司 | Lipid compound, and composition, preparation and use thereof |
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