CN110330522A - A kind of preparation method of paricalcitol isomer impurities PY5 - Google Patents
A kind of preparation method of paricalcitol isomer impurities PY5 Download PDFInfo
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- CN110330522A CN110330522A CN201910686100.7A CN201910686100A CN110330522A CN 110330522 A CN110330522 A CN 110330522A CN 201910686100 A CN201910686100 A CN 201910686100A CN 110330522 A CN110330522 A CN 110330522A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
- C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/12—Organo silicon halides
- C07F7/121—Preparation or treatment not provided for in C07F7/14, C07F7/16 or C07F7/20
- C07F7/127—Preparation or treatment not provided for in C07F7/14, C07F7/16 or C07F7/20 by reactions not affecting the linkages to the silicon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses the preparation methods of paricalcitol isomer impurities PY5 a kind of.With (1R; 3aR; 7aR) -1- ((2R; 5R; E) -5; 6- dimethyl-g -3- alkene -2- base) -7a- methyl octahydro -4H- indoles -4- ketone be starting material, through isomerization, docking, deprotection, recrystallization and etc. obtain high-purity paricalcitol isomer impurities PY5, belong to chemistry and field of biological pharmacy.The impurity can be used as the analysis of paricalcitol finished product detection to the accurate positionin of impurity and qualitative, be conducive to reinforce the control to the impurity, and then improve the quality of paricalcitol finished product and preparation.
Description
Technical field
The invention belongs to chemistry and field of biological pharmacy, and in particular to a kind of system of paricalcitol isomer impurities PY5
Preparation Method.
Background technique
Paricalcitol (Paricalcitol) is the selectivity of Abbott company exploitation, third generation vitamin D receptor
Activator can selectively activate vitamin D receptor (VDR) and selectively as a kind of activated vitamin D therapeutic agent
Raise the calcium sensitivity receptor (CaSR) in thyroid gland, can more preferable, more efficient inhibition uremic patient PHT synthesis and point
It secretes.For preventing and treating the medicine of III, IV phase chronic kidney disease (CKD) patient secondary hyperparathyroidism (SHPT)
Object.Its structural formula is shown in formula I:
Paricalcitol property is unstable, sensitive to light and heat, and containing multiple chiral centers, and synthetic route is longer,
It is inevasible in synthesis process to be easy to produce some isomer impurities and other related substances, it is difficult to isolate and purify, thus close
At the more difficult assurance of condition, synthesis technology threshold is high, difficulty is big.Simultaneously as the content pole of paricalcitol in the formulation
It is low, belong to low-dose drugs, the physicochemical property of main ingredient itself is again extremely unstable.Therefore the quality control to bulk pharmaceutical chemicals and formulation products
Higher requirements are also raised for system.
Wherein, the isomer impurities PY5 of paricalcitol is C-14 epimers of finished product paricalcitol, knot
Structure formula as shown in 1 compound of following formula,
Through retrieving, there has been no the document reports synthesized about the impurity, therefore it is miscellaneous to provide a kind of paricalcitol isomers
The preparation method of matter PY5, the preparation for paricalcitol impurity reference substance have important practical significance.
Summary of the invention
The purpose of the present invention is to overcome the shortcomings of the existing technology, provides a kind of paricalcitol isomer impurities PY5, i.e.,
(1R, 3R) -5- (2- ((1R, 3aR, 7aR, E) -1- ((2R, 5S, E) -6- hydroxyl -5,6- dimethyl-g -3- alkene -2- base) -7a-
Methyl octahydro -4H- indoles -4- methylene) ethylidene) hexamethylene -1,3- glycol synthetic method, the synthetic method have synthesis
The advantages that route is short, easy to operate, prepares jointly in conjunction with chemical reaction and microbial reaction, high income, purity is up to 99%.
To achieve the goals above, the present invention is achieved by the following technical solutions.
The present invention provides a kind of paricalcitol isomer impurities PY5, i.e. (1R, 3R) -5- (2- ((1R, 3aR, 7aR, E) -
1- ((2R, 5S, E) -6- hydroxyl -5,6- dimethyl-g -3- alkene -2- base) -7a- methyl octahydro -4H- indoles -4- methylene) Asia second
Base) hexamethylene -1,3- glycol, structural formula is as shown in 1 compound:
Preferably, efficient liquid phase purity is more than or equal to 97.5%, is more preferably more than or equal to 98%；
The present invention also provides the purposes of the impurity, specifically utilize above-mentioned impurity PY5 for the related of paricalcitol
Substance reference substance, or for the impurity identification of paricalcitol, in the control of the quality of paricalcitol bulk pharmaceutical chemicals and preparation
Purposes.
The present invention also provides a kind of method for preparing above-mentioned paricalcitol isomer impurities PY5 impurity, including it is following
Step:
Step 1: isomerization reaction mixes compound 2 with methanol, addition sodium methoxide, after stirring and dissolving, 20~30
DEG C reaction, the reaction time is 16~17h, and temperature control reacts to complete；Reaction is finished, and water is added into reaction solution and is extracted with ethyl acetate
It takes, organic phase washing, saturated common salt washing, column purification obtains yellow oil, i.e. compound 3；
Step 2: compound 4 and anhydrous tetrahydro furan, cooling -60~-70 is added in docking reaction in the reaction system
DEG C, two (trimethyl silicon substrate) Sodamides are added dropwise, finish, keep reaction 1h, chemical combination is added dropwise between -60~-70 DEG C in control temperature
The anhydrous tetrahydrofuran solution of object 3 drips 0~5 DEG C of Bi Shengwen and reacts, end of reaction, adds water in system, and extracted with ethyl acetate
It takes, organic phase washing, saturated common salt washing, column purification obtains yellow solid, i.e. compound 5；
Step 3: compound 5 and tetrabutyl ammonium fluoride solution are added in reaction flask, are warming up to 50 DEG C by deprotection
Reaction, 0.5h fully reacting are concentrated to dryness, and column purification obtains white solid, i.e. 1 crude product of compound；
Step 4: recrystallizing and refining crude product 1 and acetone is added in reaction flask, temperature rising reflux to dissolved clarification is down to naturally
Room temperature crystallization filters, is dried under reduced pressure to obtain white solid, the i.e. highly finished product of compound 1.
Further, compound 2 is using commercially available chemicals i.e. paricalcitol B ring, with hydroxyl protection base reagent uncle
Butyldimethylchlorosilane reaction gained, wherein the structural formula of the paricalcitol B ring is as follows, No. CAS is 95716-
68-0,
Further, compound 2 the preparation method is as follows: paricalcitol B ring and imidazoles are dissolved in methylene chloride,
- 10 to 5 DEG C are cooled to hereinafter, being slowly added to tert-butyl chloro-silicane, reaction terminates, and filters, filtrate is after routine
Reason, through column chromatographic purifying to get compound 2.
What the present invention obtained beneficial has the technical effect that
1, condition of the present invention is easily-controllable, and route is simple, and raw material is easy to get, and manufacturing cost is low；
2, paricalcitol isomer impurities PY5 prepared by the present invention can be used as reference substance up to 98% or more purity
It uses, to be promoted in the analysis of paricalcitol finished product detection to the accurate positionin of impurity PY5 and qualitative, is conducive to reinforce to this
The control of impurity, and then the quality of the raising and product to the quality standard of paricalcitol bulk pharmaceutical chemicals and its preparation is controlled and is provided
Beneficial reference is also offered reference for similar compound synthesis；
3, grope by technique, it has been found that 2 compound of formula extends the reaction time under the action of sodium methoxide, can be by formula
The chiral hydrogen of 2 compounds is gradually converted to S by R, until conversion is completely, finally by column purification, the available purity that meets is wanted
The formula 3 asked puts into subsequent reactions.Also, this reaction just occurs when existing only in using 2 compound of formula as intermediate, other structures
Reaction not can be carried out, may be related with the influence of enol form interconversion for the carbonyl for facing position, to subsequent further research.
Detailed description of the invention
Fig. 1 is the nuclear magnetic spectrogram of the compounds of this invention 3.
Fig. 2 is the nuclear magnetic spectrogram of the compounds of this invention 1.
Fig. 3 is the mass spectrogram of the compounds of this invention 1.
Specific embodiment
With reference to the accompanying drawing and with specific embodiment, the present invention is furture elucidated.It should be understood that these embodiments are only used for
It is bright the present invention rather than limit the scope of the invention, after the present invention has been read, those skilled in the art are to of the invention
The modification of various equivalent forms falls within the application range as defined in the appended claims.
The raw material compound 2 that the present invention uses i.e. (1R, 3aR, 7aR) -1- ((2R, 5R, E) -5,6- dimethyl-g -3- alkene -
2- yl) -7a- methyl octahydro -4H- indoles -4- ketone is commercial chemicals, alias is paricalcitol B ring, and No. CAS is
95716-68-0, other source chemicals are commercially available.
Present invention paricalcitol isomer impurities PY5 to be prepared, structural formula is as shown in 1 compound:
Synthetic route is as follows:
Be starting material with compound 2, by isomerization reaction, docking reaction, deprotection, recrystallization purifying preparation and
?.Wherein, starting material compound 2 the preparation method is as follows: paricalcitol B ring and imidazoles are dissolved in methylene chloride, drop
To -10 to 5 DEG C hereinafter, being slowly added to tert-butyl chloro-silicane, reaction terminates temperature, filters, and filtrate passes through conventional post-processing,
Through column chromatographic purifying to get compound 2.This step is conventional hydroxyl protection reaction, can be made by usual manner, herein no longer
It repeats.
The preparation of 1 formula of embodiment, 3 compound
Compound 2 about 5g and methanol 160mL are added in reaction flask, sodium methoxide 2g is added portionwise, 20~30 DEG C of holding anti-
16~17h is answered, water 400mL is added into system, and is extracted with ethyl acetate twice for end of reaction, and each 400mL is associated with
Machine phase is washed with water 200mL, saturated salt solution 200mL, is concentrated to dryness, 100-200 mesh silica gel column purification, n-hexane: ethyl acetate
=40:1 affords the about 3.78g of compound 3.ESI-MS (m/z): 429.75 [M+Na]+
The preparation of 3 formula of embodiment, 5 compound
Under argon gas protection, compound 4, the i.e. [2- [(bis- [tertiary butyl dimethyl Sis of 3R, 5R-3,5- are added in reaction flask
Base] cyclohexene] ethyl] diphenyl phosphorus oxygen 6.5g and anhydrous tetrahydro furan 400mlL, -60~-70 DEG C are cooled under stirring, temperature control
Two (trimethyl silicon substrate) Sodamide 7mL are added dropwise, drips and finishes holding reaction 1h, the anhydrous tetrahydro furan 50mL of the about 4g of compound 3 is added dropwise
Solution.Drop finishes, 0~5 DEG C of reaction, end of reaction, adds water 500mL in system, is extracted with ethyl acetate 800mL, merge organic phase,
Water 400mL is washed, and saturated salt solution 400mL is washed, and is concentrated to dryness, 100-200 mesh silica gel column purification, n-hexane: ethyl acetate=50:
1 affords the about 2.3g of compound 5.
The preparation of 4 formula of embodiment, 1 crude compound
By the about 2.3g of compound 5, adds in the tetrabutyl ammonium fluoride tetrahydrofuran solution 100mL of 1mol/L, be warming up to 50
DEG C reaction, 0.5h fully reacting is concentrated to dryness, and 100-200 mesh silica gel column purification, methylene chloride: methanol=50:1 is afforded
Compound 6 about 1.3g, ESI-MS (m/z): 439.64 [M+Na]+。
The preparation of 5 formula of embodiment, 1 compound highly finished product
The about 148mg of crude product 1 and acetone 45mL is added in reaction flask, reflux is warming up to, filters out insoluble matter, be down to room naturally
Warm crystallization filters, is dried under reduced pressure to obtain the about 32mg of compound 1, yield: 51.6%.
ESI-MS (m/z): 439.32 [M+Na]+；Such as Fig. 3；
1H NMR(500MHz,CD3OD): δ 6.2228-6.2006 (d, J=11.2Hz, 1H, H-6)；δ5.8917-5.8694
(s, J=11.2Hz, 1H, H-7)；δ 5.3772-5.2566 (m, 2H, H-22, H-23)；δ 4.0489-3.9649 (m, 2H, H-1,
H-3)；δ 2.7904-2.7524 (m, 1H, 9a-H)；δ 2.6411-2.6152 (m, 1H, 4a-H)；δ 2.46721-2.4452 (m,
1H, 4a-H)；δ 2.1571-2.0325 (m, 2H)；δ 2.0121-1.9651 (m, 4H)；δ 1.7370-1.2120 (m, 11H)；δ
1.1377 (s, 3H, H-26)；δ 1.1005 (m, 3H, H-27)；δ 1.0452-1.0319 (d, 3H, J=6.6Hz, H-21)；δ
(1.0033-0.9895 s, 3H, J=8.9Hz, H-28)；δ 0.5862 (s, 3H, H-18), such as Fig. 2.
Parsing: nuclear magnetic resonance spectroscopy shares 15 groups of peaks and (removes solvent C D3OD and H2The peak O), from low field to high field sequence, it compares
Example is respectively as follows: 1:1:2:2:1:1:1:2:4:11:3:3:3:3:3, corresponding 41 hydrogen, and 3 active hydrogens do not go out signal peak, therefore total
Totally 44 hydrogen, with paricalcitol isomer impurities PY5 molecular formula C27H44O3It is consistent.
Embodiment 6
Using paricalcitol isomer impurities PY5 as impurity reference substance, check related in paricalcitol bulk pharmaceutical chemicals
Substance, specifically includes the following steps:
1. following chromatographic run is suitable for assay of the paricalcitol in relation to substance.
2. chromatographic condition
Chromatographic column: being filler (4.6mm × 100mm, 2.7 μm) with octadecylsilane chemically bonded silica；
Column temperature: 30 DEG C；
Mobile phase: it with acetonitrile-water (50:950) for mobile phase A, with acetonitrile-methanol (750:250) for Mobile phase B, carries out
Linear gradient elution；Runing time: 40min；
Flow velocity: 0.9ml/min；
Detection wavelength: UV252nm；
Sampling volume: 25 μ l；
Diluent: ethyl alcohol: water (50:50).
3. test solution
Paricalcitol isomer impurities PY5 about 10mg is taken, it is accurately weighed, it sets in 10ml measuring bottle, adds diluent dissolution simultaneously
It is diluted to scale, shakes up to obtain the final product.
4. the related substance reference substance solution of paricalcitol
The related substance reference substance about 10mg of paricalcitol is taken, it is accurately weighed, it sets in 50ml measuring bottle, simultaneously with diluent dissolution
It is diluted to scale, is shaken up, precision measures above-mentioned solution 1ml, sets in 100ml measuring bottle, is diluted to scale with diluent, shakes up, i.e.,
, as the related substance reference substance solution of paricalcitol.
5. operation
The related substance reference substance solution of above-mentioned diluent, paricalcitol, test solution injection liquid chromatograph are taken, and
Record chromatogram.According to the related substance peak peak area of paricalcitol in each chromatogram, it is calculated in finished product with external standard method
Content.
Disclosed above is only presently preferred embodiments of the present invention, cannot limit the right model of the present invention with this certainly
It encloses, therefore, according to equivalent variations made by claims of the present invention, still falls within the range that the present invention is covered.
Claims (3)
1. a kind of preparation method of paricalcitol isomer impurities PY5, which comprises the following steps:
Step 1: isomerization reaction mixes compound 2 with methanol, addition sodium methoxide, and after stirring and dissolving, 20 ~ 30 DEG C anti-
It answers, the reaction time is 16 ~ 17h, and temperature control is reacted to complete；Reaction is finished, and water is added into reaction solution and is extracted with ethyl acetate, has
Machine Xiang Shuixi, saturated common salt washing, column purification obtain yellow oil, i.e. compound 3；
Step 2: docking reaction is added compound 4 and anhydrous tetrahydro furan, cools down -60 ~ -70 DEG C, is added dropwise that is, in reaction system
Two (trimethyl silicon substrate) Sodamides, finish, and keep reaction 1h, and the anhydrous of compound 3 is added dropwise in control temperature between -60 ~ -70 DEG C
Tetrahydrofuran solution drips 0 ~ 5 DEG C of Bi Shengwen and reacts, end of reaction, adds water in system, and be extracted with ethyl acetate, organic phase water
It washes, saturated common salt washing, column purification obtains yellow solid, i.e. compound 5；
Step 3: compound 5 and tetrabutyl ammonium fluoride solution are added in reaction flask, are warming up to 50 DEG C by deprotection reaction
Reaction, 0.5h fully reacting are concentrated to dryness, and column purification obtains white solid to get 1 crude product of compound；
Step 4: recrystallizing and refining compound 1 and acetone is added in reaction flask, temperature rising reflux to dissolved clarification is down to room naturally
Warm crystallization filters, is dried under reduced pressure to obtain white solid, the i.e. highly finished product of compound 1.
2. preparation method according to claim 1, which is characterized in that compound 2 is vertical using commercially available chemicals i.e. pa
Ostelin B ring reacts gained with hydroxyl protection base reagent tert-butyl chloro-silicane, wherein the paricalcitol B ring
Structural formula is as follows, and No. CAS is 95716-68-0,
。
3. preparation method according to claim 2, which is characterized in that compound 2 ossify the preparation method is as follows: pa is stood
Alcohol B ring and imidazoles are dissolved in methylene chloride, are cooled to -10 to 5 DEG C hereinafter, be slowly added to tert-butyl chloro-silicane, are reacted
Terminate, filter, filtrate is by conventional post-processing, through column chromatographic purifying to get compound 2.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111499553A (en) * | 2020-05-25 | 2020-08-07 | 朗天药业(湖北)有限公司 | Preparation method of paricalcitol and injection thereof |
| CN114315535A (en) * | 2021-12-30 | 2022-04-12 | 正大制药（青岛）有限公司 | Preparation method of eldecalcitol isomer impurity |
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| CN114315535A (en) * | 2021-12-30 | 2022-04-12 | 正大制药（青岛）有限公司 | Preparation method of eldecalcitol isomer impurity |
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