CN110511152B - Preparation method of voglibose impurity I hydrochloride - Google Patents
Preparation method of voglibose impurity I hydrochloride Download PDFInfo
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- CN110511152B CN110511152B CN201910880204.1A CN201910880204A CN110511152B CN 110511152 B CN110511152 B CN 110511152B CN 201910880204 A CN201910880204 A CN 201910880204A CN 110511152 B CN110511152 B CN 110511152B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- 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 provides a preparation method of voglibose impurity I hydrochloride, which comprises the following steps: performing epoxide amination on (S) - (ethylene oxide methyl) tert-butyl carbamate and tetrabenzylvaliolamine to obtain a compound shown in a formula III; carrying out benzyl protection on hydroxyl of the compound in the formula III to obtain a compound in a formula IV; deprotecting the amino protecting group of the compound of formula IV to obtain a compound of formula V; the compound of the formula V and (2R,2S,4S,5S) -5-hydroxy-2, 3, 4-tri (benzyloxy) -5- [ (benzyloxy) methyl ] -cyclohexanone undergo a condensation reduction reaction to obtain the compound of the formula VI. The preparation method of the impurity I hydrochloride of the voglibose, provided by the invention, has a simple process flow, fills the gap in the existing technology for preparing the impurity I of the voglibose, can be used for qualitative and quantitative researches on the impurity in the production of the voglibose, and can improve the quality standard of the voglibose, thereby improving the medication safety of the voglibose.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of voglibose impurity I hydrochloride.
Background
Voglibose, chemical name (+) -1L- [1 (hydroxy), 2,4,5/3] -5- [ 2-hydroxy-1- (hydroxymethyl) ethyl ] amino-1- (hydroxymethyl) -1,2,3, 4-cyclohexanetetraol, CAS:83480-29-9, has a chemical structure shown in formula:
voglibose was first developed by Takeda, japan, first in 1994 under the trade name "Basen", in korea in 1998, and in china in 1999, and is used for the treatment of postprandial blood glucose elevation in diabetes. Voglibose entered the catalog of national basic medical insurance, industry and commerce insurance and fertility insurance drugs in 2009. At present, voglibose is widely used for preventing and treating type I and type II diabetes and combined medicines. Voglibose has no stimulation to insulin secretion compared with sulfonylureas, has the effect of moderating but not inhibiting the digestion and absorption of saccharides compared with biguanides, and has less dosage and less side effects such as abdominal distension compared with acarbose.
The quality standards for voglibose are documented in the japanese pharmacopoeia JP17 and the korean pharmacopoeia 10 th edition, and currently the chinese pharmacopoeia is discussed. Structures that may contain impurities are not specified in the japanese pharmacopoeia JP17 and the korean pharmacopoeia 10 th edition, but there are three impurities that specify retention times of about 1.7, 2.0 and 2.3 relative to voglibose. The structures of voglibose, which may contain three impurities, are clearly indicated in japanese IF documents of voglibose and the first public edition of the "chinese pharmacopoeia" 2020. The structural formula is as follows:
the three impurities are subjected to system applicability experiments and impurity control in a mixed contrast mode, the impurity I and the impurity II are isomers, and at present, no report about preparation of the impurity I exists. The impurity I of the voglibose is an impurity concerned in a voglibose quality standard, and has great significance for the research of substances related to the voglibose, so that the method for preparing the impurity I of the voglibose is significant.
Disclosure of Invention
The invention aims to disclose a preparation method of voglibose impurity I hydrochloride, which has simple process flow and fills the blank of the prior art for preparing the voglibose impurity I, and the prepared voglibose impurity I hydrochloride can be used for qualitative and quantitative research on impurities in the production of voglibose, can improve the quality standard of the voglibose, and thus improves the medication safety of the voglibose.
In order to achieve the aim, the invention provides a preparation method of voglibose impurity I hydrochloride, which comprises the following steps:
the method comprises the following steps: performing epoxide amination on (S) - (ethylene oxide methyl) tert-butyl carbamate and tetrabenzylvaliolamine to obtain a compound shown in a formula III;
step two: carrying out benzyl protection on hydroxyl of the compound in the formula III to obtain a compound in a formula IV;
step three: deprotecting the amino protecting group of the compound of formula IV to obtain a compound of formula V;
step four: carrying out condensation reduction reaction on the compound shown in the formula V and (2R,2S,4S,5S) -5-hydroxy-2, 3, 4-tri (benzyloxy) -5- [ (benzyloxy) methyl ] -cyclohexanone to obtain a compound shown in a formula VI;
step five: deprotection of a hydroxyl protecting group of the compound shown in the formula VI and salification are carried out to obtain high-purity voglibose impurity I hydrochloride; the overall reaction flow is:
in some embodiments, in step two, the hydroxy group of the compound of formula iii is benzyl protected under basic conditions to provide the compound of formula iv.
In some embodiments, in step two, the base used is potassium hydroxide or sodium hydroxide.
In some embodiments, in step two, the hydroxy protecting reagent used is benzyl chloride or benzyl bromide.
In some embodiments, in step three, the amino protecting group of the compound of formula iv is deprotected under the action of an acid to provide the compound of formula v.
In some embodiments, in step three, the acid used is trifluoroacetic acid or hydrochloric acid.
In some embodiments, in step four, the reducing agent used is sodium cyanoborohydride.
In some embodiments, in step five, the hydroxyl protecting group of the compound of formula vi is deprotected by catalytic hydrogenation to form a salt, resulting in high purity voglibose impurity I hydrochloride.
In some embodiments, in step five, the catalyst used is palladium on carbon.
In some embodiments, in step five, the salt former reagent is hydrogen chloride gas.
Compared with the prior art, the invention has the beneficial effects that: the preparation method of the impurity I hydrochloride of the voglibose, provided by the invention, has a simple process flow, fills the gap in the existing technology for preparing the impurity I of the voglibose, can be used for qualitative and quantitative researches on the impurity in the production of the voglibose, and can improve the quality standard of the voglibose, thereby improving the medication safety of the voglibose.
Drawings
FIG. 1 is a mass spectrum of voglibose impurity I hydrochloride;
FIG. 2 is a mass spectrum of voglibose impurity I hydrochloride;
FIG. 3 is a nuclear magnetic diagram (1H spectrum) of Voglibose impurity I hydrochloride.
Detailed Description
The present invention is described in detail with reference to the embodiments shown in the drawings, but it should be understood that these embodiments are not intended to limit the present invention, and those skilled in the art should understand that functional, methodological, or structural equivalents or substitutions made by these embodiments are within the scope of the present invention.
The invention discloses a preparation method of voglibose impurity I hydrochloride, which comprises the following steps:
the method specifically comprises the following steps:
the method comprises the following steps: performing epoxide amination on the (S) - (oxiranylmethyl) carbamic acid tert-butyl ester and tetrabenzylvaliolamine to obtain a compound shown in a formula III, namely tert-butyl ((2S) -3-hydroxy-2- (((2S, 3R, 4S,5S) -2,3, 4-tris (benzyloxy) -5- ((benzyloxy) methyl) -5-hydroxycyclohexyl) amino) propyl) carbamic acid tert-butyl ester;
the specific method comprises the following steps:
5.53g of tetrabenzylvaliolamine (2.77 g of tert-butyl (S) - (oxiranylmethyl) carbamate and 140ml of methanol are added into a reaction bottle, the mixture is heated and refluxed for 18 hours, the mixture is concentrated in vacuum to be dry, the residue is dissolved in toluene, the mixture is washed with water, dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue is purified by a silica gel column to obtain 5.3g of oily matter, namely the compound shown in the formula III, wherein the molar yield is 73%.
Step two: benzyl protection of the hydroxy group of the compound of formula III gives the compound of formula IV, i.e. tert-butyl ((2S) -3-benzyloxy-2- (((2S, 3R, 4S,5S) -2,3, 4-tris (benzyloxy) -5- ((benzyloxy) methyl) -5-hydroxycyclohexyl) amino) propyl) carbamate;
in the second step, the hydroxyl of the compound in the formula III is subjected to benzyl protection under an alkaline condition to obtain a compound in the formula IV, the used alkali is potassium hydroxide or sodium hydroxide, and the used hydroxyl protecting reagent is benzyl chloride or benzyl bromide;
the specific method comprises the following steps:
adding 7.27g of the compound shown in the formula III, 1.4g of benzyl chloride, 0.1g of potassium iodide, 0.5g of sodium hydroxide and 100ml of acetonitrile into a reaction bottle, heating to reflux, filtering after the reaction is finished, washing a filter cake by using the acetonitrile, concentrating the filtrate to be dry, and purifying by using a silica gel column to obtain 5.39g of oily matter, namely the compound shown in the formula IV, wherein the molar yield is 66%.
Step three: deprotecting the amino protecting group of the compound of formula iv to obtain a compound of formula v, i.e., (1S, 2S, 3R, 4S) -5- (((S) -1-amino-3- (benzyloxy) propan-2-yl) amino) -2,3, 4-tris (benzyloxy) -1- ((benzyloxy) methyl) cyclohexanol;
in the third step, the amino protecting group of the compound shown in the formula IV is deprotected under the action of acid to obtain a compound shown in the formula V, and the acid is trifluoroacetic acid or hydrochloric acid;
the specific method comprises the following steps:
adding 8.17g of the compound shown in the formula IV and THF into a reaction bottle, stirring to dissolve the compound, dropwise adding 9ml of 4% hydrochloric acid until the reaction is completed, concentrating the solution in vacuum to remove the THF, adding dichloromethane, washing the solution with saturated sodium bicarbonate, washing the solution with water for 3 times, drying the filtrate with anhydrous sodium sulfate, and concentrating the dried filtrate under reduced pressure to obtain 5.88g of a solid, namely the compound shown in the formula V, wherein the molar yield is 87%.
Step four: carrying out condensation reduction reaction on the compound shown in the formula V and (2R,2S,4S,5S) -5-hydroxy-2, 3, 4-tri (benzyloxy) -5- [ (benzyloxy) methyl ] -cyclohexanone to obtain a compound shown in a formula VI; in the fourth step, the reducing agent is sodium cyanoborohydride;
the specific method comprises the following steps:
7.17g of the compound of the formula V, (2R,2S,4S,5S) -5-hydroxy-2, 3, 4-tris (benzyloxy) -5- [ (benzyloxy) methyl ] -cyclohexanone and 70ml of methanol are added to the reaction flask, stirred at room temperature for 1h and cooled to 0 ℃. 0.88g of sodium cyanoborohydride was added, and after completion of the reaction, methanol was removed by vacuum concentration. DCM and 2mol/L hydrochloric acid are added into the residue, and the pH is adjusted to 5-6. Separating liquid and keeping water phase. The pH was adjusted to about 8 with sodium hydroxide. The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. Pulping with petroleum ether and crystallizing to obtain 7.01g of solid, namely the compound shown in the formula VI, with the molar yield of 55%.
Step five: deprotection and salt formation of the hydroxyl protecting group of the compound shown in the formula VI are carried out to obtain high-purity voglibose impurity I hydrochloride, namely (1S,1 'S, 2S, 2' S,3R,3 'R, 4S, 4' S,5S,5 'S) -5, 5' - ((R) -3-hydroxypropyl-1, 2-diyl) bis (azenediyl) bis ((hydroxymethyl) cyclohexyl-1, 2,3, 4-tetraol) hydrochloride;
in the fifth step, the hydroxyl protecting group of the compound shown in the formula VI is subjected to catalytic hydrogenation deprotection to form a salt, and high-purity voglibose impurity I hydrochloride is obtained; the catalyst is palladium carbon, and the salifying agent is hydrogen chloride gas.
The specific method comprises the following steps:
adding 12.5g of a compound VI, THF, 130ml of methanol and 12.5g of palladium carbon into a reaction bottle, carrying out hydrogenation reduction at room temperature under 4 pressures, continuing stirring for 1h after no hydrogen is absorbed, filtering, washing a filter cake with methanol, carrying out vacuum concentration on a filtrate, removing trace water with absolute ethyl alcohol, dissolving with ethyl acetate, and introducing hydrogen chloride gas to obtain 4.38g of white solid of voglibose impurity I hydrochloride, wherein the molar yield is 85%.
[M-2HCl+H]+＝443.27；[M-2HCl+Cl]+＝477.26；1HNMR(D2O,400MHz)＝3.9164～3.9581(dd，1H)；＝3.2656～3.3323(t，1H)；＝3.4129～3.927(bs，16H)。
The hydrochloride of voglibose impurity II can be prepared in the above manner by replacing tert-butyl (S) - (oxiranylmethyl) carbamate with tert-butyl (R) - (oxiranylmethyl) carbamate.
Performing mass spectrum detection on the prepared voglibose impurity I hydrochloride, wherein the detection result is shown in a figure 1 and a figure 2; nuclear magnetic resonance spectrum detection is carried out on the prepared voglibose impurity I hydrochloride, and the detection result is shown in figure 3.
Performing mass spectrum detection on the prepared voglibose impurity I hydrochloride, wherein the detection result is shown in a figure 1 and a figure 2; nuclear magnetic resonance spectrum detection is carried out on the prepared voglibose impurity I hydrochloride, and the detection result is shown in figure 3.
Molecular ion peaks according to FIG. 1 ([ M-2HCl + H)]+)443.27 and the molecular ion peaks of FIG. 2 ([ M-2HCl + Cl)]+)477.26 it can be seen that the detected molecular ion peak corresponds to the molecular weight of voglibose impurity I hydrochloride (514.77).
The graph analysis is carried out on the graph shown in the figure 3, wherein the total number of 25 hydrogen atoms (3.9164-3.9581, dd, 1H; (3.2656-3.3323, 1H; (3.4129-3.9277, bs, 16H); (15 active hydrogens) (11 alcoholic hydroxyl hydrogens, 2 amino hydrogens and 2 hydrogens in hydrochloric acid) are shared by the impurity I hydrochloride of the voglibose, and the graph analysis result and the molecular formula (C) of the impurity I hydrochloride of the voglibose are shared by the graph analysis result17H36Cl2N2O11) The results are consistent.
The above-listed detailed description is only a specific description of a possible embodiment of the present invention, and they are not intended to limit the scope of the present invention, and equivalent embodiments or modifications made without departing from the technical spirit of the present invention should be included in the scope of the present invention.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (10)
1. The preparation method of voglibose impurity I hydrochloride is characterized by comprising the following steps:
the method comprises the following steps: performing epoxide amination on (S) - (ethylene oxide methyl) tert-butyl carbamate and tetrabenzylvaliolamine to obtain a compound shown in a formula III;
step two: carrying out benzyl protection on hydroxyl of the compound in the formula III to obtain a compound in a formula IV;
step three: deprotecting the amino protecting group of the compound of formula IV to obtain a compound of formula V;
step four: carrying out condensation reduction reaction on the compound shown in the formula V and (2R,2S,4S,5S) -5-hydroxy-2, 3, 4-tri (benzyloxy) -5- [ (benzyloxy) methyl ] -cyclohexanone to obtain a compound shown in a formula VI;
step five: deprotection of a hydroxyl protecting group of the compound shown in the formula VI and salification are carried out to obtain voglibose impurity I hydrochloride; the overall reaction flow is:
2. the preparation method of voglibose impurity I hydrochloride according to claim 1, wherein in step two, the hydroxyl group of the compound of formula III is benzyl-protected under basic conditions to obtain the compound of formula IV.
3. The method for preparing voglibose impurity I hydrochloride according to claim 2, wherein the base used in step two is potassium hydroxide or sodium hydroxide.
4. The method for preparing voglibose impurity I hydrochloride according to claim 2, wherein in step two, the hydroxyl protecting reagent used is benzyl chloride or benzyl bromide.
5. The preparation method of voglibose impurity I hydrochloride according to claim 1, characterized in that in step three, the amino protecting group of the compound of formula IV is deprotected under the action of an acid to obtain the compound of formula V.
6. The method for preparing voglibose impurity I hydrochloride according to claim 5, wherein in step three, the acid used is trifluoroacetic acid or hydrochloric acid.
7. The method for preparing voglibose impurity I hydrochloride according to claim 1, wherein in step four, the reducing agent used is sodium cyanoborohydride.
8. The preparation method of voglibose impurity I hydrochloride according to claim 1, characterized in that, in step five, the hydroxyl protecting group of the compound of formula VI is subjected to catalytic hydrogenation deprotection to form a salt, so as to obtain voglibose impurity I hydrochloride.
9. The method for preparing voglibose impurity I hydrochloride according to claim 8, wherein in step five, the catalyst used is palladium on carbon.
10. The method for preparing voglibose impurity I hydrochloride according to claim 8, wherein in step five, the salifying agent is hydrogen chloride gas.
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| JP2020155508A JP6852215B2 (en) | 2019-09-18 | 2020-09-16 | Voglibose Impurity I Hydrochloride Preparation Method |
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| EP0056194B1 (en) * | 1981-01-05 | 1984-09-12 | Takeda Chemical Industries, Ltd. | N-substituted pseudo-aminosugars, their production and use |
| WO1999050217A1 (en) * | 1998-03-31 | 1999-10-07 | Bayer Aktiengesellschaft | Valiolone, a method of preparing it, and its use to prepare acarbose and voglibose |
| AU2002344083A1 (en) * | 2002-03-27 | 2003-10-08 | Sawai Pharmaceutical Co., Ltd. | Process for preparation of voglibose |
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| CN103588650A (en) * | 2012-08-15 | 2014-02-19 | 中国医药集团总公司四川抗菌素工业研究所 | High-purity voglibose and preparation method thereof |
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