CN105294801A - Method for synthesizing, separating and determining obeticholic acid (OCA) isomer - Google Patents
Method for synthesizing, separating and determining obeticholic acid (OCA) isomer Download PDFInfo
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Abstract
The invention relates to an obeticholic acid (OCA) isomer namely an OCA-alpha alpha beta body, a synthetic method of the OCA-alpha beta alpha body, and a method adopting the reversed phase liquid chromatography condition to separate the OCA isomer. With adoption of the technical scheme disclosed by the invention, the OCA-alpha alpha beta body and the OCA-alpha beta alpha body with the HPLC purity greater than 98% can be obtained to meet quality control of the isomer in OCA.
Description
Technical field
The present invention relates to a kind of synthesis of shellfish cholic acid (OCA) isomer difficult to understand, the separation method of shellfish cholic acid difficult to understand and isomer thereof.Relate to OCA-α α β body particularly, the synthesis of OCA-α β α body, and separation determination OCA and OCA-α α β body, the method for OCA-α β α body.
Background technology
Shellfish cholic acid (ObeticholicAcid difficult to understand, OCA), having another name called 6-ethyl goose deoxidation egg to fall apart, is a kind of newtype drug of thus being treated primary biliary sclerosis and non-alcohol fatty liver disease by the secretion of activation Buddhist nun alcohol X acceptor T suppression cell pigment 7A1 promotion cholic acid.Should pharmaceutical activity be wanted higher than ursodesoxycholic acid, side effect be low, and effectively can reduce alkaline phosphatase and serum phosphatase (alkaline phosphatase is a kind of biomarker representing hepatic diseases degree).
Shellfish cholic acid (I) difficult to understand comparatively ursodesoxycholic acid has significant clinical advantage, is in clinical investigation phase in recent years, and the medicinal application of the potential non-alcoholic fatty liver disease as a new generation is in clinical.
Document WO2013192097, US20130345188A1 report the synthetic method of shellfish cholic acid difficult to understand, and operational path is as follows:
Namely adopt compd A to be raw material, obtain compd B through the reduction of palladium carbon, then prepare OCA through tetrahydro boron sodium reduction.
According to structure, this compound contains mulitiple chiral centers, especially 6 ethyls, and the chirality of 7 hydroxyls is all introduced in building-up process.In Compound C preparation process, there is the step of configuration conversion, carry out at tetrahydro boron sodium in the process of reducing, introduce 7 chiral hydroxyl groups.Although above-mentioned reaction stereoselectivity is good, because reaction process is complicated, the factors such as configuration conversion is incomplete, cause potential shellfish cholic acid isomer difficult to understand in shellfish cholic acid difficult to understand, especially 6,7 position isomers, i.e. shellfish cholic acid α β α difficult to understand, shellfish cholic acid α α beta isomer difficult to understand.Especially in the preparation process of compd B, according to the scheme that document improves, namely adopt aqueous sodium hydroxide solution to be solvent, 100 DEG C of reactions, and carry out turning configuration, research finds, configuration conversion is incomplete, and potential introduces chiral impurity.
Document WO2013192097 reports the control limit of above-mentioned two kinds of isomer in OCA, but does not provide the synthetic method of above-mentioned isomer and the chromatography separating method with shellfish cholic acid difficult to understand.
Summary of the invention
The invention provides the preparation method of a kind of OCA isomer OCA-α β α and OCA-α α β.
The object of this invention is to provide a kind of separation determination OCA isomer method, object is to detect and is separated OCA and isomer thereof, thus is OCA quality control supplying method.
For achieving the above object, the invention provides following technical scheme:
Prepare a preparation method of OCA isomer OCA-α β α, comprise step:
1) compd A catalytic hydrogenating reduction generates compd B;
2) compd B reduces to obtain OCA – α β α;
3) OCA – α β α carries out column chromatography and obtains high-purity O CA-α β α
Described operational path is as follows:
More specifically, in step 1, described reaction carries out in a solvent, and reaction solvent is selected from methyl alcohol, ethanol, aqueous sodium hydroxide solution and composition thereof, and temperature of reaction is 25 ~ 30 DEG C, preferably 20 DEG C; The weight ratio of compd A and palladium metal is 1:0.01 ~ 0.05.
Research finds, document WO2013192097 adopts higher temperature to carry out hydrogenation, namely generates compd B, also generate Compound C in reaction process, for obtaining the compd B of higher degree, to carry out subsequent reactions, the present invention, under WO2013192097 prompting, reduces temperature of reaction, significantly can contain and turn structure process, when temperature 25 DEG C, reaction is carried out thoroughly, and can obtain the compd B of higher degree.In progressively raised temperature to 50 ~ 60 DEG C and above temperature time, the ratio of Compound C significantly increases.
According to above-mentioned experiment, reaction controlling can obtain relatively highly purified compd B at 25 DEG C, and the generation of Inhibitor C.In addition, research finds at lower temperature, and such as, when temperature of reaction is 15 DEG C, speed of response is extremely slow, and to turn structure phenomenon obvious for compd B simultaneously.
In step 2, described reduction reaction is carried out under reductive agent effect in a solvent.Reaction solvent is selected from 0.5 ~ 2% aqueous sodium hydroxide solution; Reductive agent is selected from sodium cyanoborohydride, Sodium triacetoxyborohydride, sodium borohydride, POTASSIUM BOROHYDRIDE, preferred tetrahydro boron sodium; Temperature of reaction is 30-50 DEG C, preferably 35 DEG C.The OCA-α β α purity that this step obtains, lower than 90%, needs to adopt purification step to carry out purifying further.
Document CN200680017025.6 openly adopts tetrahydro boron sodium to be reductive agent, 25% (m/v) aqueous sodium hydroxide solution is the reduction system of solvent, and prepare OCA-α β α (i.e. Compound I B in CN200680017025.6 document), document does not provide concrete operations scheme.Research shows, under literature precedents, owing to adopting high-concentration sodium hydroxide water solution system, temperature of reaction is higher, causes OCA-α β α to turn in a large number and is configured to OCA, is unfavorable for enrichment and the preparation of OCA-α β α.In the present invention, by groping different test conditionss, determining to adopt technical scheme of the present invention, the product of OCA-α β α significant enrichment can be obtained.
As can be known from the above table, along with the reduction of sodium hydroxide alkali concn, OCA-α β α purity increases, and purity is more stable in the scope of 0.5 ~ 2%.
In step 3, described column chromatography filler is selected from SP20SS, HP20SS, SP207SS, and eluent is selected from methanol/water, acetonitrile/water, acetone/water, the admixture solvents such as ethanol/water, and wherein the volume ratio of organic phase and water is 1 ~ 3:10.OCA-α β α purity after purifying can reach more than 97%, meets the quality control being used for OCA as impurity reference substance.
The present invention have selected the filler of three kinds of reverse phase filler as separation and purification OCA-α β α, and research finds, these fillers can obtain highly purified compound OCA-α β α by purifying under organic solvent/water mixture system.
| Filler | Eluent | Before crossing post | After crossing post |
| SP20SS | Methyl alcohol: water (1 ~ 3:10) | 89％ | 97.2％ |
| SP20SS | Acetone: water (1 ~ 3:10) | 89％ | 98.3％ |
| HP20SS | Methyl alcohol: water (1 ~ 3:10) | 89％ | 97.7％ |
| HP20SS | Acetone: water (1 ~ 3:10) | 89％ | 98.0％ |
| SP207SS | Methyl alcohol: water (1 ~ 3:10) | 89％ | 97.8％ |
| SP207SS | Acetone: water (1 ~ 3:10) | 89％ | 98.2％ |
Adopt purification technique scheme of the present invention, can by the purity of OCA-α β α by 90% less than being increased to more than 97%.
A preparation method of OCA isomer OCA-α α β, comprises step:
A) compd B obtains Compound C through configuration conversion;
B) Compound C reduces to obtain OCA-α α β through sodium Metal 99.5;
C) OCA-α α β carries out column chromatography and obtains OCA-α α β;
Described operational path is as follows:
More specifically, step a) in, compd B in the alkaline water aqueous solution through thermal treatment, transform obtain intermediate C, described basic solution is aqueous sodium hydroxide solution, and turning structure temperature is 75 ~ 105 DEG C, preferably 100 DEG C;
Step b) in, Compound C reduces to obtain OCA-α α β under the effect of sodium Metal 99.5, and reaction solvent is selected from 2-sec-butyl alcohol, the trimethyl carbinol, and temperature of reaction is 50 ~ 100 DEG C, preferably 75 DEG C; The mass ratio of compd B and metal Na is 1:2 ~ 5, and preferred 1:3, need add the NiCl of 2%
2catalyzed reaction.The OCA-α β α purity that this step obtains, close to 90%, needs to adopt purification step to carry out purifying further.
Document CN200680017025.6 discloses the method adopting sodium Metal 99.5 reduction to prepare isomer, namely adopts the ratio of 3:1 to 3:2 Compound C to be dissolved with the sec-butyl alcohol being dissolved with sodium Metal 99.5 and carries out being obtained by reacting object.Research shows, adopts above-mentioned reaction conditions, and sample purity is extremely low, does not reach 50%, is unfavorable for that preparing impurity reference substance uses.
Research finds, significantly strengthens the consumption of sodium Metal 99.5, and introduces the catalyst n iCl being equivalent to Compound C 2% massfraction (mass ratio of catalyzer and Compound C is 1:50)
2, OCA-α β α purity can be significantly improved.
In summary, the sodium Metal 99.5 of 3:1 equivalent is being adopted according to document, and when not adding catalytic amount NiCl2, purity only about 47%, significantly increasing sodium Metal 99.5 consumption, and when adding the NiCl2 of about 2% massfraction, OCA-α β α purity all can reach more than 80%, is conducive to follow-up separation and purification.
Step c) in, the OCA-α α β crude product of gained adopts column chromatography to carry out purifying, obtains OCA-α α β, described chromatographic column filler comprises SP20SS, HP20SS, SP207SS, eluent is selected from methanol/water, acetonitrile/water, acetone/water, the admixture solvents such as ethanol/water, the volume ratio of organic phase and water is 1 ~ 3:10, OCA-α α β purity after purifying can reach more than 98%, meets the quality control being used for OCA as impurity reference substance.
The present invention have selected the filler of three kinds of reverse phase filler as separation and purification OCA-α α β, and research finds, these fillers can obtain highly purified compound OCA-α α β by purifying under organic solvent/water mixture system.
| Filler | Eluent | Before crossing post | After crossing post |
| SP20SS | Methyl alcohol: water (1 ~ 3:10) | 86％ | 98.2％ |
| SP20SS | Acetone: water (1 ~ 3:10) | 86％ | 98.5％ |
| HP20SS | Methyl alcohol: water (1 ~ 3:10) | 86％ | 97.8％ |
| HP20SS | Acetone: water (1 ~ 3:10) | 86％ | 98.4％ |
| SP207SS | Methyl alcohol: water (1 ~ 3:10) | 86％ | 98.8％ |
| SP207SS | Acetone: water (1 ~ 3:10) | 86％ | 98.7％ |
Adopt purification technique scheme of the present invention, the purity of OCA-α β α can be increased to more than 97% by less than 90%.
In embodiment of the present invention, provide the chromatogram being separated OCA and isomer thereof, comprise and adopt high performance liquid chromatography to split, wherein chromatographic column is selected from C18 chromatographic column, filler is octadecylsilane chemically bonded silica, detector is selected from ELSD-2000 (evaporat light scattering-2000 type) detector, and moving phase is selected from acetonitrile/0.1% aqueous formic acid, methyl alcohol/0.1% aqueous formic acid; Chromatographic column temperature is 25 ~ 35 DEG C, preferably 30 DEG C, and flow rate of mobile phase is 0.5ml/min ~ 1.5ml/min, preferred 1.0ml/min, and stream of nitrogen gas is 2.0 ~ 2.5L/min, drift tube temperature 90 ~ 110 DEG C.
Below in conjunction with accompanying drawing and embodiment, the present invention is described further, it is to be appreciated that following examples are only the description of this invention, this should be interpreted as that protection scope of the present invention is only limitted to following examples.
Accompanying drawing explanation
Accompanying drawing 1: shellfish cholic acid α β α body HNMR collection of illustrative plates difficult to understand
Accompanying drawing 2: shellfish cholic acid α β α body ES-collection of illustrative plates difficult to understand
Accompanying drawing 3: shellfish cholic acid α α β body HNMR collection of illustrative plates difficult to understand
Accompanying drawing 4: shellfish cholic acid α α β body ES-collection of illustrative plates difficult to understand
Accompanying drawing 5: shellfish cholic acid (RT36.743min) difficult to understand and shellfish cholic acid α α β body (RT24.848min) difficult to understand, shellfish cholic acid α β α body (RT33.666min) HPLC color atlas difficult to understand
Accompanying drawing 6: shellfish cholic acid α β α difficult to understand, shellfish cholic acid α α β chemical structural formula difficult to understand
embodiment:
Below in conjunction with drawings and Examples, the present invention is described further, it is to be appreciated that following examples are only the description of this invention, this should be interpreted as that protection scope of the present invention is only limitted to following examples.
Embodiment 1: the preparation of intermediate B
Compound A-45 0g (mw:416.3) is dissolved in 2.5% sodium hydroxide 500mL, adds 5.0g10%Pd/C, temperature control 25 DEG C, pass into hydrogen, reaction, to completely, is reacted after terminating, filtering reacting liquid, obtain compd B after concentrated organic phase and be about 45g, gained compd B purity is 97%.
Embodiment 2: the preparation of shellfish cholic acid α β α crude product difficult to understand
Compd B 20g (mw:418.3) is dissolved in the aqueous sodium hydroxide solution of 2% of 250mL, adds tetrahydro boron sodium 12.5g, be warming up to 35 DEG C and react completely.After reaction terminates, in reaction soln, slowly drip 1M hydrochloric acid soln adjust pH about 3 ~ 4, period adds water 500ml, filters, obtains white solid 16g, HPLC purity about 89%.
Embodiment 3: the separation and purification of shellfish cholic acid α β α difficult to understand
By HP20SS400mL resin with 1L acetone soaked overnight, insert glass chromatography column, then rinse with 10L water.By 10g shellfish cholic acid difficult to understand α α β dissolving crude product in the sodium hydroxide solution of 50mL5%, gained solution is slowly flowed through chromatography column, gradient elution is carried out again with methanol/water mixed system, the ratio of methanol/water is 3:10, adopt HPLC chromatographic instrument monitoring separating effect, according to monitored results, collect the cut that target components is greater than 98%.Receive, concentrating under reduced pressure removing methyl alcohol, then separate out solid with phosphorus acid for adjusting pH to 3-5, filter, drying obtains shellfish cholic acid α α β difficult to understand, HPLC purity about 97.7%.Gained shellfish cholic acid difficult to understand α α β, through HNMR, MS confirmation, is shown in accompanying drawing 1 ~ 2.
Embodiment 4: the preparation of intermediate B
Compound A-45 0g (mw:416.3) is dissolved in methyl alcohol 500mL, adds 5.0g10%Pd/C, temperature control 25 DEG C, pass into hydrogen, reaction, to completely, is reacted after terminating, filtering reacting liquid, obtain compd B after concentrated organic phase and be about 45g, gained compd B purity is 95%.
Embodiment 5: the preparation of shellfish cholic acid α β α crude product difficult to understand
Compd B 20g (mw:418.3) is dissolved in the aqueous sodium hydroxide solution of 1% of 250mL, adds tetrahydro boron sodium 25g, be warming up to 35 DEG C and react completely.After reaction terminates, in reaction soln, slowly drip 1M hydrochloric acid soln adjust pH about 3 ~ 4, period adds water 500ml, filters, obtains white solid 17g, HPLC purity about 88%.
Embodiment 6: the separation and purification of shellfish cholic acid α β α difficult to understand
By SP207SS400mL resin with 1L acetone soaked overnight, insert glass chromatography column, then rinse with 10L water.By 10g shellfish cholic acid difficult to understand α α β dissolving crude product in the sodium hydroxide solution of 50mL5%, gained solution is slowly flowed through chromatography column, gradient elution is carried out again with acetone/water mixed system, the ratio of acetone/water is by 2:10, adopt HPLC chromatographic instrument monitoring separating effect, according to monitored results, collect the cut that target components is greater than 98%.Receive, concentrating under reduced pressure removing acetone, then separate out solid with phosphorus acid for adjusting pH to 3-5, filter, drying obtains shellfish cholic acid α β α difficult to understand, HPLC purity about 98.2%.
Embodiment 7: the preparation of intermediate C
Get compd B 20g, add 5% aqueous sodium hydroxide solution, stirring and dissolving is clarification extremely, in 100 DEG C of reflux 12h, and, be cooled to room temperature, regulate pH3-5, separate out a large amount of solid with phosphoric acid, filter, filter cake is with water washing, and drying obtains intermediate C16g.
Embodiment 8: the preparation of shellfish cholic acid α α β crude product difficult to understand
Intermediate C5g (mw:418.3), 2-butanols 250mL, catalytic amount nickelous chloride 0.1g, be heated to 75 DEG C of stirring and dissolving, add sodium Metal 99.5 12.5g after half an hour, stirring reaction is about 3h, react complete, be cooled to room temperature, by reaction solution impouring 1L water, with phosphorus acid for adjusting pH to 3.5, separatory, organic phase is evaporated to dry, and get Ao Bei cholic acid α β α crude product is about 3.5g, HPLC purity about 86%.
Embodiment 9: the preparation of shellfish cholic acid α α β crude product difficult to understand
Intermediate C5g (mw:418.3), trimethyl carbinol 250mL, catalytic amount nickelous chloride 0.1g, be heated to 75 DEG C of stirring and dissolving, add sodium Metal 99.5 12.5g after half an hour, stirring reaction is about 3h, react complete, be cooled to room temperature, by reaction solution impouring 1L water, with phosphorus acid for adjusting pH to 3.5, separatory, organic phase is evaporated to dry, and get Ao Bei cholic acid α β α crude product is about 3.5g, HPLC purity about 83%.
Embodiment 10: the separation and purification of shellfish cholic acid α α β difficult to understand
By HP20SS200mL resin with 0.5L acetone soaked overnight, insert glass chromatography column, then rinse with 5L water.By 3g shellfish cholic acid difficult to understand α β α dissolving crude product in the sodium hydroxide solution of 20mL5%, gained solution is slowly flowed through chromatography column, gradient elution is carried out again with acetone/water mixed system, the ratio of acetone/water is by 1.5:10, adopt HPLC chromatographic instrument monitoring separating effect, according to monitoring situation, collect the component that target components chromatographic purity is greater than 98%.Receive, concentrating under reduced pressure removing acetone, then separate out solid with phosphorus acid for adjusting pH to 3-5, filter, drying obtains shellfish cholic acid α β α difficult to understand, HPLC purity 98.4%, and gained shellfish cholic acid difficult to understand α β α, through HNMR, MS confirmation, is shown in accompanying drawing 3 ~ 4.
Embodiment 11: the liquid chromatography of shellfish cholic acid difficult to understand and isomer is separated
Chromatographic condition:
Moving phase: 0.1% formic acid (A): acetonitrile (B)
Chromatographic column: octadecylsilane chemically bonded silica is the chromatographic column of weighting agent
Detector: ELSD-2000
Detector parameters: gain: 1, air-flow: 2.3L/MIN, drift tube temperature: 110 DEG C
Reagent: shellfish cholic acid raw material difficult to understand, shellfish cholic acid α β α difficult to understand, shellfish cholic acid α α β difficult to understand
Solution preparation:
Precision takes shellfish cholic acid difficult to understand, shellfish cholic acid α β α difficult to understand, each 10mg of shellfish cholic acid α α β difficult to understand, is mixed with the compound sample that concentration is about 100ug/ml, as system flexibility solution.
Resolution is tested
Get system flexibility solution 10ul, sample introduction under chromatographic condition, separation detection is carried out to shellfish cholic acid difficult to understand, shellfish cholic acid α β α difficult to understand, shellfish cholic acid α α β difficult to understand, adjacent peak-to-peak resolution meets the requirements, see accompanying drawing 5, peak sequence is shellfish cholic acid α α β difficult to understand, shellfish cholic acid α β α difficult to understand, shellfish cholic acid difficult to understand.
Claims (9)
1. a preparation method of following formula: compound OCA--α β α,
Comprise step:
1) compd A catalytic hydrogenating reduction generates compd B
2) compd B reduction reaction obtains OCA-α β α;
3) OCA-α β α adopts column chromatography to carry out purifying and obtains high-purity O CA-α β α
Operational path is as follows:
2. the method for claim 1, wherein step 1) in, reaction solvent is selected from methyl alcohol, ethanol, aqueous sodium hydroxide solution and composition thereof; Temperature of reaction is 25 ~ 30 DEG C; The weight ratio of compd A and catalyst metal palladium is 1:(0.01 ~ 0.05).
3. the method for claim 1, wherein in step 2, reductive agent is selected from sodium cyanoborohydride, Sodium triacetoxyborohydride, sodium borohydride, POTASSIUM BOROHYDRIDE; Reaction solvent is selected from 0.5 ~ 2% aqueous sodium hydroxide solution; Temperature of reaction is 30 DEG C ~ 50 DEG C.
4. method described in claim 1, wherein in step 3, the chromatographic column filler of column chromatography is selected from SP20SS, HP20SS, SP207SS, eluent is selected from methanol/water, acetonitrile/water, acetone/water, the admixture solvents such as ethanol/water, the volume of organic solvent and water is (1 ~ 3): 10.
5. the preparation method of a following formula: compound OCA-α α β:
Comprise step:
A) compd B obtains Compound C through configuration conversion;
B) Compound C is through sodium Metal 99.5 reduction OCA-α α β;
C) OCA-α α β carries out column chromatography and obtains high-purity O CA-α α β;
Operational path is as follows:
6. method as claimed in claim 5, wherein step a) in, compd B carries out configuration conversion in the alkaline water aqueous solution, and basic solution is aqueous sodium hydroxide solution, and turning structure temperature is 75 ~ 105 DEG C.
7. method, wherein step b as claimed in claim 5) in, reaction solvent is selected from 2-butanols, the trimethyl carbinol; Temperature of reaction is 50 ~ 100 DEG C; The mass ratio of compd B and metal Na is 1:2 ~ 5; Catalyzer is NiCl
2, catalyst n iCl
2be 1:50 with the mass ratio of Compound C.
8. method according to claim 6, wherein step c) in, OCA-α α β crude product adopts column chromatography to carry out purifying, and described chromatographic column filler comprises SP20SS, HP20SS, SP207SS, eluent is selected from methanol/water, acetonitrile/water, acetone/water, the admixture solvents such as ethanol/water, the volume ratio of organic solvent and water is (1 ~ 3): 10.
9. an efficient liquid-phase chromatography method of separation detection OCA and OCA-α β α body, OCA-α α β, its separation condition is:
Chromatographic column: C18 chromatographic column:
Filler: octadecylsilane chemically bonded silica:
Detector: ELSD-2000 (light scattering detector)
Moving phase: mobile phase A: 0.1% aqueous formic acid; Mobile phase B: acetonitrile or methyl alcohol;
Chromatographic column temperature: 20 ~ 35 DEG C, preferably 30 DEG C
Flow rate of mobile phase: 0.5 ~ 1ml/min, preferred 1.0ml/min
Stream of nitrogen gas: 2.0 ~ 2.5L/min
Drift tube temperature: 90 ~ 110 DEG C
Gradient:
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