CN102464692A

CN102464692A - Preparation method of ursodesoxycholic acid

Info

Publication number: CN102464692A
Application number: CN2010105450586A
Authority: CN
Inventors: 曹俊山; 郝秀利; 王淑华
Original assignee: SHANDONG AOCTER CHEMICAL CO Ltd
Current assignee: SHANDONG AOCTER CHEMICAL CO Ltd
Priority date: 2010-11-16
Filing date: 2010-11-16
Publication date: 2012-05-23

Abstract

The invention discloses a preparation method of ursodesoxycholic acid. In a technical process, with chenodeoxycholic acid (1) as a raw material, corresponding equipment is adopted, auxiliary materials are added according to matched varieties and doses, and a specific oxidant, catalyst and purifying agent undergo chemical reactions through process flows, such as an oxidation process (A), a hydrogenation process (B) and a purification process (C) under a certain temperature environment conditions. In the oxidation process (A), a pyridinium chlorochromate oxidant (3) and a solvent I (2) are added for undergoing an oxidation reaction, so that an intermediate (4) is generated; in the hydrogenation process (B), a sodium borohydride or potassium borohydride catalyst (6) and a solvent II (5) are added for undergoing a hydrogenation reaction, so that a crude ursodesoxycholic acid (9) product is obtained; and in the purification process (C), a chloroform purifying agent (11) and a solvent III (10) are added, so that the ursodesoxycholic acid (12) as a finished product is obtained. The preparation method has the advantages of reasonable process route, mild and safe chemical reaction, easy control over operating conditions, high yield and progresses on the aspects of research and production of artificial synthesis of ursodesoxycholic acid (12).

Description

A kind of preparation method of ursodesoxycholic acid

Technical field

The present invention relates to the rare Chinese medicine bear gall, relate in particular to the artificial synthesis of bear gall.

Background technology

Bear gall is traditional simply rare medicinal herbs; Ursodesoxycholic acid as bear gall contained mainly contain effective constituent; Have effects such as extremely strong promotion fat and lipid acid hydrolysis; Be mainly used in various liver and gall diseases of treatment and digestive tract diseases clinically,, good curative effect arranged all like intrahepatic cholestasis of pregnancy, gallbladder cystic fibrosis hepatopathy, alcoholic liver disease, fatty liver, gallbladdergallstonecholetithiasis, viral hepatitis etc.New research shows that ursodesoxycholic acid not only is used to treat primary biliary cirrhosis, primary sclerosing cholangitis, chronic active hepatitis etc. and has good curative effect, and can be used for treating the rejection after chronic hepatitis and the liver transplantation.Past is from bear gall, to extract bile, processes ursodesoxycholic acid, and the bear that lives receives the Animal Protection Law protection, and the bear gall source is restricted, and course of processing step is many simultaneously, the cycle is long, row yielding is low, can't satisfy medical requirement.Thereby the research of carrying out the synthetic ursodesoxycholic acid is significant.

At present, the production technique of ursodesoxycholic acid has following several routes both at home and abroad:

(1) with the Iocholic acid be raw material, yield is 38%.

(2) with the Hyodeoxycholic Acid be raw material, yield is 15%.

(3) non-cholic acid class steroidal is a raw material, and Pd/C is a catalyzer, but because expensive raw materials still is in the laboratory study stage.

Summary of the invention

The object of the invention just provides a kind of artificial synthesis of ursodesoxycholic acid, simplifies process step, guarantees operational safety, improves chemical combination quality and product yield, meets the need of market better.

Task of the present invention is to accomplish like this: studying a kind of preparation method of ursodesoxycholic acid, is raw material with the Chenodiol, in technological process, adopts reaction kettle, whizzer, strainer, Vacuumdrier; Kind, dosage by proportioning add solvent and auxiliary material, under certain temperature environment condition, adopt specific oxygenant, catalyzer and purifying agent; Carry out synthetic through oxidizing process, hydrogenation technique, purifying process, in the oxidizing process process, add PCC salt oxidizing agent and solvent I; Carry out oxidizing reaction, generate midbody, in the hydrogenation technique process; Under the gas shield of nitrogen, add Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer and solvent II, input hydrogen exchange nitrogen carries out hydrogenation reaction; Obtain the ursodeoxycholic acid crude, in the purifying process process, add chloroform purifying agent and solvent II I; Through combination reaction, process the ursodesoxycholic acid finished product.

The inventor is through discovering; Through adopting pyridinium chloro-chromate as oxygenant; Adopt Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN as catalyzer, and adopt chloroform as purifying agent, can be so that adopt the ursodesoxycholic acid of method preparation of the present invention to have high yield and purity; This is to adopt the reagent of other types to be difficult to realize, accomplishes the present invention thus.

Wherein the oxidizing process process is: earlier Chenodiol is dissolved with solvent I fully, put into stills for air blowing, add the PCC salt oxidizing agent again; In temperature of reaction, fully reacted 6～7 hours, concentrating under reduced pressure reclaims solvent I; After in slurry tank, injecting the pure water that is equivalent to 10 times of solvent I amounts, the concentrated material in the stills for air blowing is added in the slurry tank sedimentation 6～8 hours; In strainer, filter; Concentrate material and be washed till neutrality, put into Vacuumdrier after filter is done and dry, obtain particulate state or the pulverous midbody of moisture≤1wt% with pure water.Chenodiol: PCC salt oxidizing agent: the proportioning molar ratio of solvent I is 1: 1: 20～30, and temperature of reaction is 20～30 ℃.The hydrogenation technique process is: earlier Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer being joined concentration is to carry out activation in 20～25% the buck, dissolves midbody with solvent II by proportioning, adds successively in the hydrogenation still, and temperature rising reflux was lowered the temperature after 1.5 hours; After feeding the nitrogen replacement air, add Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer again, stop nitrogen then, nitrogen in the logical hydrogen exchange still; Close emptying, carry out hydrogenation reaction, reaction is put into slurry tank with hydrogenation material after accomplishing, and washes with solvent II; Washing lotion is put into slurry tank, precipitates after 6 hours, filters supernatant via strainer, squeezes into concentration kettle; Use the material in the solvent II washing-settling tank again, Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer are emitted reuse, and material is emitted through vacuum distilling in the concentration kettle, and solvent II reclaims; Liquid material is put back to concentration kettle again and is carried out crystallization, is that 20% salt sour water adds in the aqueous solution in the concentration kettle with concentration, transfers pH value to 2～3, crystallization 6 hours; Xln was put into freezing pond 8～10 hours, put into the strainer suction filtration again, be washed till neutrality with pure water; Get solid crystal, get in the Vacuumdrier again and dry, get the ursodeoxycholic acid crude of moisture≤1wt%.Midbody: Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer: the proportioning molar ratio of solvent II is 1: 1: 15～25, and the intensification temperature is 70～80 ℃, and cooling back temperature is 40 ℃, and freezing pond temperature is 0～5 ℃.The purifying process process is: elder generation is dissolved in the ursodeoxycholic acid crude fully among the solvent II I and adds in the purification kettle, adds the chloroform purifying agent again and mixes, under temperature of reaction; Kept 2～3 hours, and placed and put into strainer after 6～8 hours, the mother liquor recovery set that filters out is used; Xln with solvent II I wash the wet article of ursodesoxycholic acid, be that 5% salt sour water adds in the purification kettle with concentration, put into the ursodesoxycholic acid article that wet again; The back insulation 1.5 hours that heats up, is left standstill and was occurred crystallization in 2～3 hours to normal temperature with circulating water cooling; Put into the strainer suction filtration, mother liquor is waited until and is applied mechanically, and solid materials is washed till neutral filter with pure water and does; Put into Vacuumdrier and dry, process the ursodesoxycholic acid finished product of moisture≤1wt%.The ursodeoxycholic acid crude: the proportioning molar ratio of chloroform purifying agent: solvent II I is 1: 1: 8～12, and temperature of reaction is 20～30 ℃.Solvent I selects acetic acid for use, and solvent II is selected Virahol for use, and solvent II I selects DMF for use.Because not needing specially carboxyl to be carried out the esterification protection, the present invention can not produce qualified finished product, the two step chemical reaction step of having omitted esterification, having taken off ester, and operational path is short.Simultaneously, the solvent in the mother liquor can reuse, and has reduced production cost.

According to above-mentioned process method, the present invention has simplified process step, and operational path is reasonable; The gentle safety of combination reaction, operational condition is easy to control, good product quality; Yield, purity height can provide market required ursodesoxycholic acid, have reached predetermined purpose preferably.

Description of drawings

Fig. 1 is a manufacture craft schema of the present invention;

Fig. 2 is oxidizing process of the present invention (A) process synoptic diagram;

Fig. 3 is hydrogenation technique of the present invention (B) process synoptic diagram;

Fig. 4 is purifying process of the present invention (C) process synoptic diagram.

Among the figure, A-oxidizing process, B-hydrogenation technique, C-purifying process, Y-stills for air blowing, J-slurry tank, L-strainer, G-Vacuumdrier, w-reservoir, Q-hydrogenation still, N-concentration kettle, the freezing pond of K-, F-purification kettle;

The 1-Chenodiol, 2-solvent I, 3-PCC salt oxidizing agent, 4-midbody, 5-solvent II, 6-Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer; 7-nitrogen, 8-hydrogen, 9-ursodeoxycholic acid crude, 10-solvent II I, 11-chloroform purifying agent, 12-ursodesoxycholic acid finished product; The 13-pure water, 14-concentrates material, 15-filtrating, 16-buck, 17-hydrogenation material, 18-liquid material; 19-salt sour water, 20-xln, 21-solid crystal, the 22-ursodesoxycholic acid article that wet, 23-mother liquor, 24-solid materials.

Embodiment

Be described further below in conjunction with the accompanying drawing specific embodiments of the invention.

The PCC salt oxidizing agent is available from chemical industry ltd of Shandong HTC, and technical indicator is following: CAS:26299-14-9; Content >=98%; Orange/red powder or solid; Fusing point 195.0-202.0 ℃.

Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer are available from Anhui gold chemical industry difficult to understand ltd.Peng Qinghuana technical indicator: white crystalline powder; Content >=98%; CAS:16940-66-2.POTASSIUM BOROHYDRIDE 97MIN technical indicator: content >=97%; CAS:13762-51-1.

The chloroform purifying agent is available from Nanning Jin Feng chemical industry Ltd.

Consult Fig. 1, the preparation technology of ursodesoxycholic acid comprises: oxidizing process A, hydrogenation technique B, purifying process C.In oxidizing process A process, add Chenodiol 1, solvent I 2, PCC salt oxidizing agent 3; Separate out solvent I2 through reaction, form midbody 4. and get into hydrogenation technique B process, solvent II 5 and midbody 4 are mixed; And with Peng Qinghuana or 6 addings of POTASSIUM BOROHYDRIDE 97MIN catalyzer; In this technological process, need add nitrogen 7 and carry out gas shield, add hydrogen 8 then and displace nitrogen 7, combination reaction generates ursodeoxycholic acid crude 9.Carry out purifying process C process then, after with solvent II I 10 ursodeoxycholic acid crude 9 being dissolved fully, add chloroform purifying agent 11 again,, generate ursodesoxycholic acid finished product 12 through combination reaction.The particular content of each technological process detail respectively as after.

Consult Fig. 2, oxidizing process A process is that Chenodiol 1 is made main raw material, and the acetic acid that adds 20～30 times is made solvent I 2; Dissolve fully and put into stills for air blowing Y, add the PCC salt oxidizing agent 3 with Chenodiol 1 equivalent again, temperature is controlled between 20～30 ℃; Fully reaction is 6～7 hours, and concentrating under reduced pressure reclaims acetic acid (solvent I 2); In slurry tank J, inject 10 times of pure water 13, the more concentrated material 14 in the stills for air blowing Y is put into slurry tank J, sedimentation 6～8 hours to acetic acid (solvent I2) amount; Put into strainer L after mixing and filter, filtrating 15 gets into reservoir w and recycles, and the material in the strainer L is washed till neutral filter with pure water 13 and does; Put into Vacuumdrier G again and dry, obtain the dry product of midbody 4.

Consult Fig. 3, hydrogenation technique B process is that to prepare concentration earlier be 20～25% buck 16, and Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer 6 are added in the bucks 16, chooses Virahol and makes solvent II 5, midbody 4 dissolvings, adds successively among the hydrogenation still Q.Be warming up to 75～78 ℃, refluxing is cooled to 40 ℃ again after 1.5 hours, feed nitrogen 7 displaced air after, add with Virahol (solvent II 5) dissolved Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer 67 half hours of the interior nitrogen of logical hydrogen 8 displacement stills.Close emptying after qualified, carry out hydrogenation reaction.Reaction is put into slurry tank J with the hydrogenation material 17 in the hydrogenation still Q after accomplishing, and rinses well with Virahol (solvent II 5), with the material deposition of emitting hydrogenation still Q about 6 hours; After strainer L filters, squeeze into concentration kettle N, Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer 6 are emitted recovery to supernatant; Material reclaims Virahol (solvent II 5) 40 ℃ of temperature distillations in the concentration kettle N, and liquid material 18 is emitted metering, in concentration kettle N, injects the pure water 13 of 10 times of amounts that are equivalent to liquid material 18 then; With mixing in the water among the liquid material of the emitting 18 adding concentration kettle N; Add concentration again and be 20% salt sour water 19, between adjustment pH value to 2～3, crystallization is about 6 hours; Xln 20 is put into 0～5 ℃ freezing pond K, placed 8～10 hours.Then cold xln 20 solution are put into strainer L suction filtration, be washed till neutrality, the solid crystal in the strainer L 21 is put among the Vacuumdrier G dries again, obtain the ursodeoxycholic acid crude 9 of moisture≤1wt% with pure water 13.

Consult Fig. 4, purifying process C process is earlier ursodeoxycholic acid crude 9 to be dissolved among the DMF as solvent II I 10 fully, puts into purification kettle F; Add chloroform purifying agent 11 again, logical recirculated water remains on temperature between 20～30 ℃, reacts 2.5 hours; White crystals becomes paste by rare retrogradation, places after 6～8 hours, is released to strainer L; Filtrated stock 23 recovery set usefulness, xln get the wet article 22 of ursodesoxycholic acid with DMF (solvent II I 10) washing.With concentration is that 5% salt sour water 19 is put into purification kettle F, with wet article 22 addings of ursodesoxycholic acid, is warming up to 40～50 ℃ again; Be incubated and be cooled to normal temperature after 1.5 hours, left standstill 2～3 hours, put into strainer L suction filtration again; With pure water 13 24 washings of the solid materials among the strainer L to neutral filter is done; Leach mother liquor 23 and wait until and apply mechanically, solid materials 24 is put into Vacuumdrier G dry, promptly process the ursodesoxycholic acid finished product 12 of moisture≤1wt%.

Through detecting, the yield of ursodesoxycholic acid finished product of the present invention is more than 70%, and being far longer than with Iocholic acid (yield 38%) or Hyodeoxycholic Acid (yield 15%) is the yield of the finished product of feedstock production.The purity of ursodesoxycholic acid finished product of the present invention is 99.5%, meets the requirement of Chinese Pharmacopoeia.

Claims

1. the preparation method of a ursodesoxycholic acid is characterized in that being is raw material with Chenodiol (1), adopts reaction kettle, whizzer, strainer (L), Vacuumdrier (G) in technological process; Kind, dosage by proportioning add solvent and auxiliary material, under certain temperature environment condition, carry out synthetic through oxidizing process (A), hydrogenation technique (B), purifying process (C); In oxidizing process (A) process, add PCC salt oxidizing agent (3) and solvent I (2), carry out oxidizing reaction; Generate midbody (4), in hydrogenation technique (B) process, under the gas shield of nitrogen (7), add Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer (6) and solvent II (5); Input hydrogen (8) displacement nitrogen (7) carries out hydrogenation reaction, obtains ursodeoxycholic acid crude (9); In purifying process (C) process; Add chloroform purifying agent (11) and solvent II I (10),, process ursodesoxycholic acid finished product (12) through combination reaction.

2. according to the described ursodesoxycholic acid preparation method of claim 1, it is characterized in that said oxidizing process (A) process is: earlier Chenodiol (1) is dissolved with solvent I (2) fully, put into stills for air blowing (Y); Add PCC salt oxidizing agent (3) again, in temperature of reaction, fully reacted 6～7 hours concentrating under reduced pressure; Reclaim solvent I (2); After in slurry tank (J), injecting the pure water (13) that is equivalent to 10 times of solvent I (2) amounts, the concentrated material (14) in the stills for air blowing (Y) is added in the slurry tank (J) sedimentation 6～8 hours; In strainer (L), filter; Concentrate material (14) and be washed till neutrality, put into Vacuumdrier (G) oven dry after filter is done, obtain particulate state or the pulverous midbody (4) of moisture≤1wt% with pure water (13).

3. according to the described ursodesoxycholic acid preparation method of claim 2, it is characterized in that said Chenodiol (1): PCC salt oxidizing agent (3): the proportioning molar ratio of solvent I (2) is 1: 1: 20～30, and temperature of reaction is 20～30 ℃.

4. according to the described ursodesoxycholic acid preparation method of claim 1, it is characterized in that said hydrogenation technique (B) process is: earlier Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer (6) being joined concentration is to carry out activation in 20～25% the buck (16), dissolves midbody (4) with solvent II (5) by proportioning, adds successively in the hydrogenation still (Q); Temperature rising reflux was lowered the temperature after 1.5 hours, after feeding nitrogen (7) displaced air, added Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer (6) again; Stop nitrogen (7) then, nitrogen (7) in logical hydrogen (8) the displacement still is closed emptying; Carry out hydrogenation reaction, reaction is put into slurry tank (J) with hydrogenation material (17) after accomplishing, and washes with solvent II (5); Washing lotion is put into slurry tank (J), precipitates after 6 hours, filters supernatant via strainer (L); Squeeze into concentration kettle (N), use the material in solvent II (5) washing-settling tank (J) again, Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer (6) are emitted reuse; The interior material of concentration kettle (N) is emitted through vacuum distilling, and solvent II (5) reclaims, and liquid material (18) is put back to concentration kettle (N) again and carried out crystallization; With concentration is that 20% salt sour water (19) adds in the aqueous solution in the concentration kettle (N), transfers pH value to 2～3, crystallization 6 hours; Xln (20) was put into freezing pond (K) 8～10 hours, put into strainer (L) suction filtration again, be washed till neutrality with pure water (13); Get solid crystal (21), get into oven dry in the Vacuumdrier (G) again, get the ursodeoxycholic acid crude (9) of moisture≤1wt%.

5. according to the described ursodesoxycholic acid preparation method of claim 4; It is characterized in that said midbody (4): Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN catalyzer (6): the proportioning molar ratio of solvent II (5) is 1: 1: 15～25; The intensification temperature is 70～80 ℃; Cooling back temperature is 40 ℃, and freezing pond (K) temperature is 0～5 ℃.

6. according to the described ursodesoxycholic acid preparation method of claim 1, it is characterized in that said purifying process (C) process is: earlier ursodeoxycholic acid crude (9) is dissolved in solvent II I (10) the middle adding purification kettle (F) fully, adds chloroform purifying agent (11) again and mix; Under temperature of reaction, kept 2～3 hours, place and put into strainer (L) after 6～8 hours; The mother liquor that filters out (23) recovery set usefulness, xln with solvent II I (10) wash the wet article (22) of ursodesoxycholic acid, be in 5% salt sour water (19) the adding purification kettle (F) with concentration; Put into the wet article (22) of ursodesoxycholic acid again, the back of heating up is incubated 1.5 hours, with circulating water cooling to normal temperature; Leave standstill and occurred crystallization in 2～3 hours; Put into strainer (L) suction filtration, mother liquor (23) is waited until and is applied mechanically, and solid materials (24) is washed till neutral filter with pure water (13) and does; Put into Vacuumdrier (G) oven dry, process the ursodesoxycholic acid finished product (12) of moisture≤1wt%.

7. according to the described ursodesoxycholic acid preparation method of claim 6, it is characterized in that said ursodeoxycholic acid crude (9): the proportioning molar ratio of chloroform purifying agent (11): solvent II I (10) is 1: 1: 8～12, and temperature of reaction is 20～30 ℃.

8. according to the described ursodesoxycholic acid preparation method of claim 1, it is characterized in that said solvent I (2) selects acetic acid for use, solvent II (5) is selected Virahol for use, and solvent II I (10) selects DMF for use.