CN106220528B - 4- positions epimer, the preparation method and the usage of aliskiren - Google Patents
4- positions epimer, the preparation method and the usage of aliskiren Download PDFInfo
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- CN106220528B CN106220528B CN201610578429.8A CN201610578429A CN106220528B CN 106220528 B CN106220528 B CN 106220528B CN 201610578429 A CN201610578429 A CN 201610578429A CN 106220528 B CN106220528 B CN 106220528B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/20—Preparation of optical isomers by separation of optical isomers
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Abstract
The present invention relates to 4 epimers of aliskiren, its molecular structure is as shown in formula 4R 1.The invention further relates to the preparation method of 4 epimers of the aliskiren, and its in purity, detection aliskiren and its salt for detecting aliskiren and its salt in the content of optical isomer and the production or preparation of aliskiren and its salt quality control purposes.
Description
The application is entitled " 4- positions epimer, the preparation method and the usage of aliskiren ", the applying date
For on 2 28th, 2014, the divisional application of the application of Application No. 201410070646.7.
Technical field
The present invention relates to a kind of epimer, in particular it relates to a kind of 4- positions epimerism of aliskiren
Body.The invention further relates to the preparation method and its usage of the 4- positions epimer of the aliskiren.
Background technology
Aliskiren (1) is a kind of new direct renin inhibitor of non-peptides, related pharmacodynamics, pharmacokinetics and
Clinical study results have in detail in the periodicals such as Drugs of the Future, Vol.26, No12, pp1139-1143 (2001)
Statement, its main feature is that by dose-dependently reducing renin activity, renin-angiotensin system is reduced from source
(RAS) chief active peptide --- the generation of Angiotensin II, effectively reduces the blood pressure level of Mild or moderate hypertension patient.
Aliskiren is listed in the U.S. first in the form of its fumarate in March, 2007, trade name TEKTURNATM, through clinic
Research confirms there is good antihypertensive effect, it has also become few side effects, the antihypertensive new drug of brand-new type of drug safety.
Existing patent document US5,559,111, EP0678503, WO02/02508, WO2007/045420, WO2011/
019789 and US7,009,078 etc. reports the synthetic method of aliskiren, for example, patent US7,009,078 employ it is following
Synthetic route：
Patent WO2007/045420 then employs another synthetic route：
Key point in the synthesis of aliskiren is in four chiralitys in using the method for asymmetric syntheses structure molecule
Center, thus obtain 4 hydroxyls be S configurations, 5 bit aminos be S configurations, 2 and single optics pair that 7 isopropyls are S configurations
Reflect body.Wherein, for the building process of 4 hydroxyl chiral centres, it is resolved in above-mentioned known synthetic method.It is such as above-mentioned special
Sharp US7, shown in 009,078 in synthetic method, the addition that the double bond of compound 7 is carried out to stereoselectivity with hypobromous acid is anti-
Should, the compound 4 of (3S, 5S, 1'R, 3'S) configuration is obtained, and further hindrance obtains aliskiren；It is such as above-mentioned
Shown in patent WO2007/045420 in synthetic method, then the double bond of compound 16 and hypobromous acid are subjected to stereoselectivity
Addition reaction, and further hindrance obtains aliskiren.
It is well known which kind of chemical reaction no matter to carry out the structure of 4 hydroxyl chiral centres in synthetic method using, it is vertical
Body is selectively unlikely to be 100%, more or less there may be the isomers of 4 R configurations, so as to ultimately generate to obtain
The isomers of (2S, 4R, 5S, 7S) configuration, i.e. compound are more or less mixed into during the aliskiren of (2S, 4S, 5S, 7S) configuration
4R-1.The isomers 2, the configuration of 5,7 are consistent with target molecule aliskiren, the inconsistent isomers of only 4 configurations, change
It is known as " epimer " on.
In addition, 4 hydroxyls have relatively active chemical reaction property, its S configuration is in subsequent chemical reaction, long-term storage
During depositing, being processed into pharmaceutical preparation, how to keep 4 hydroxyl configurations constant, and prepare aliskiren process to need to examine
The key factor considered.
As other chemical synthetic drugs, the purity of pharmaceutically active substance (API) is that aliskiren commercialization utilizes
A key index.Starting material, reaction intermediate and accessory substance, degraded production may be introduced in the production process of API
Thing etc. is known as the impurity in relation to material, and some of which impurity is probably harmful to patient, for drug safety, international man's medicine note
Volume coordinates committee's meeting (ICH) and requires API to have enough purity, and the content of its impurity need to be controlled to be provided in medicine quality standard
Limit within.For this kind of single optical antipode medicine of aliskiren, there are 4 chiral centres, in theory with 15
A optical isomer, the chemical molecular formula of these isomers is identical with aliskiren, and every physicochemical property is also same or similar, but
They enter the drug effect after human body and there may be relatively big difference with aliskiren to the toxicity of human body.ICH requirements can by these
The optical isomer of energy carries out limit research as impurity, to ensure the drug effect of medicine and toxicity.Such as in the ICHQ7A of API productions
In guideline, the requirement of standardization is proposed to supplementary material and working condition, is needed in some moment of production API in
Impurity in mesosome or finished product is tested, especially using high performance liquid chromatography (HPLC) method.Using HPLC method sample surveys
In certain impurity content, typically using external standard method, or the Self-control method of the correction up factor, its precondition be obtain
The reference substance of tested impurity.
In conclusion to ensure that the drug effect uniformity of aliskiren marketed products and toxicity are minimum, optimal method is to adopt
The content such as 4R-1 impurity is controlled with high performance liquid chromatography, using the either correction up of existing high performance liquid chromatography such as external standard method
The Self-control method of the factor, is required to 4R-1 compounds as reference substance.However, up to the present, it has not been found that relatedization
The report of compound 4R-1.It is therefore desirable to develop the preparation method of compound 4R-1 to obtain reference substance, and a kind of isomery
Body content analysis method, for the optical purity inspection of aliskiren or its salt, and then for the matter of aliskiren or its salt
Amount control.
The content of the invention
First aspect present invention is related to a kind of 4- positions epimer of aliskiren, its molecular structure such as formula 4R-1 institutes
Show, chemical name is：(2S, 4R, 5S, 7S) -5- amino-N- (2- amine formyl -2- methyl-propyls) -4- hydroxyl -2- isopropyls -
7- (4- methoxyl groups -3- (3- methoxy propoxies) benzyl) -8- methyl pelargonamides, or its pharmaceutically acceptable salt.
Second aspect of the present invention is related to the preparation method of the 4- positions epimer of the aliskiren of first aspect present invention,
It comprises the following steps：
A) starting material with compound 2 as follows for synthesis, its chemical name are：
(2S, 4S, 5S, 7S) -5- azidos-N- (2- amine formyl -2- methyl-propyls) -4- hydroxyl -2- isopropyls -7-
(4- methoxyl groups -3- (3- methoxy propoxies) benzyl) -8- methyl pelargonamides；
B) compound 2 and a kind of oxidant reaction are obtained into compound 3 as follows, wherein, the oxidant is selected from
Chromium trioxide-pyridine complex compound, manganese dioxide, three n-butoxy aluminium and Dai Si-Martin cross iodine alkane, and preferably Dai Si-Martin crosses iodine
Alkane；
C) compound 3 and metallic boron hydrides are reacted to obtain compound 2 as follows and the racemization of compound 4R-2
Body mixture, wherein, the boron hydride is selected from potassium borohydride, sodium borohydride, lithium borohydride；
D) the step c) racemic mixtures obtained are obtained into compound 1 and compound as follows by catalytic hydrogenation
The racemic mixture of 4R-1, wherein, it is preferred to use the method for palladium carbon catalytic hydrogenation；
E) racemic mixture separation in step d) is prepared to the 4- positions of the aliskiren of first aspect present invention
Epimer.
The preparation method of any one according to a second aspect of the present invention, it is characterised in that one in the item of following (1)~(11)
It is or multinomial：
(1) in step b), the solvent of 2 solution of compound is selected from chloroform, dichloromethane；
(2) in step b), reaction temperature is -30~10 DEG C, preferably -20~0 DEG C；
(3) in step b), add saturated sodium bicarbonate after oxidation reaction and hypo solution carries out extraction behaviour
Make, organic layer concentrates after drying, and residue purifies to obtain compound 3 through column chromatography；
(4) in step c), the solvent of 3 solution of compound is selected from methanol, ethanol, tetrahydrofuran；
(5) in step c), reaction temperature is -10~60 DEG C, preferably 0~50 DEG C；
(6) ammonium chloride solution is added in step c), after reduction reaction and dichloromethane carries out extracting operation, organic layer
Concentrate after drying, residue through column chromatography (such as silica gel column chromatography) purify compound 2 and compound 4R-2 raceme
Mixture；
(7) in step d), the palladium carbon is the palladium carbon containing palladium 5%~10%；
(8) in step d), the solvent of the racemic mixture of dissolved compound 2 and compound 4R-2 is selected from methyl tertbutyl
Ether, ethanol, methanol, tetrahydrofuran, ethyl acetate, ethyl ester isopropyl ester, dichloromethane, preferably methanol, tetrahydrofuran；
(9) in step d), wherein the pressure of catalytic hydrogenation is 1~10bar, preferably 1~3bar；
(10) in step d), saturated sodium bicarbonate solution is sequentially added after catalytic hydrogenation and brine is extracted
Operation, organic layer concentrates after drying, residue through column chromatography purify the raceme of compound 1 and compound 4R-1 mixes
Thing；
(11) in step e), the separation method is the racemic mixture for obtaining step d) in preparative liquid chromatograph
On carry out separation and be prepared into compound 4R-1, wherein use Chiralpak IA or similar models prepares column as chromatographic column, with
N-hexane and ethanol (containing 0.2% diethylamine) are mobile phase, and wherein n-hexane and ethanol volume ratio are 80:20~60:40, preferably
70:30。
In embodiments of the invention, the compound 2 as starting material refers to patent US7, the side in 009,078
Method prepares.Specifically preparation method is：By (3S, 5S) -5- [(1S, 3S) -1- azidos -3- [[4- methoxyl group -3- (3-
Methoxy propoxy) phenyl] methyl] -4- methyl amyls] dihydro -3- isopropyls -2 (3H)-furanone (5) and about 5 molar equivalents
3- amino -2,2- dimethylpropionamides (6), the 2 hydroxy pyrimidine of about 1 molar equivalent, the triethylamine of catalytic amount and a kind of solvent
After mixing, dissolving is stirred at reflux.Wherein, the solvent be selected from methyl tertiary butyl ether(MTBE), tetrahydrofuran, 1-methyl-2-pyrrolidinone,
Toluene etc.；Reaction temperature is positively retained at 40~120 DEG C, preferably 80~110 DEG C, within the scope of more preferably 90~100 DEG C.Reaction
After add water and a kind of solvent and carry out extracting operation, wherein the solvent is selected from methyl tertiary butyl ether(MTBE), dichloromethane, second
Acetoacetic ester etc.；Organic layer concentrates after drying, and residue purifies to obtain compound 2 through column chromatography.
In embodiments of the invention, a kind of oxidant stirring reaction is added in the solution of compound 2, wherein described
The solvent of 2 solution of compound be selected from chloroform, dichloromethane etc., wherein the oxidant is selected from chromium trioxide-pyridine complexing
Thing, manganese dioxide, three n-butoxy aluminium, Dai Si-Martin cross iodine alkane etc., and it is oxidant that preferably Dai Si-Martin, which crosses iodine alkane, reaction temperature
Spend for -30~10 DEG C, preferably -20~0 DEG C, add saturated sodium bicarbonate after completion of the reaction and hypo solution is extracted
Operation, organic layer concentrate after drying, and residue purifies to obtain compound 3 through column chromatography.
In embodiments of the invention, a kind of reducing agent stirring reaction is added in the solution of compound 3, wherein described
Reducing agent be selected from metallic boron hydrides, such as potassium borohydride, sodium borohydride, lithium borohydride etc.；The wherein described compound 3 is molten
The solvent of liquid is selected from methanol, ethanol, tetrahydrofuran etc.；Reaction temperature is -10~60 DEG C, preferably 0~50 DEG C.After completion of the reaction plus
Enter ammonium chloride solution and dichloromethane carries out extracting operation, organic layer concentrates after drying, and residue is purified through column chromatography to be changed
The racemic mixture of compound 2 and compound 4R-2.
In embodiments of the invention, in the solution of above-claimed cpd 2 and the racemic mixture of compound 4R-2
Palladium carbon is added, pressurized with hydrogen hydrogenation is passed through, wherein the palladium carbon is the palladium carbon containing palladium 5%~10%；The wherein described racemization
The solvent of body mixture solution is selected from methyl tertiary butyl ether(MTBE), ethanol, methanol, tetrahydrofuran, ethyl acetate, ethyl ester isopropyl ester, two
Chloromethanes etc., preferably methanol, tetrahydrofuran；Wherein the pressure of hydrogenation reaction is 1~10bar, preferably 1~3bar.Reaction finishes
After sequentially add saturated sodium bicarbonate solution and brine and carry out extracting operation, organic layer concentrates after drying, and residue is through column layer
Analysis purify compound 1 and compound 4R-1 racemic mixture；
In embodiments of the invention, by the racemic mixture of above-claimed cpd 1 and compound 4R-1 in preparation solution
Separation is carried out on chromatography and is prepared into compound 4R-1, wherein using Chiralpak IA or preparing column similar to model as color
Column is composed, with n-hexane:Ethanol (0.2% diethylamine) is mobile phase, and wherein n-hexane and ethanol volume ratio are 80:20~60:40,
It is preferred that 70:30.
Third aspect present invention further relates to a kind of method for detecting optical isomer content in aliskiren and its salt, the party
Method uses the external standard method in high performance liquid chromatography (HPLC), with the 4- positions epimerism of the aliskiren of first aspect present invention
Body is reference substance, calculates the content of 4 epimers in aliskiren and its salt.
The method of any one according to a third aspect of the present invention, wherein the high performance liquid chromatography is characterized in that following
(1)~(5) it is one or more in item：
(1) chromatographic column is chiral column, preferably AD-H types, IC columns or OJ-3R columns, more preferably CHIRALPAK AD-H type hands
Property column (4.6mm × 250mm, 5 μm)；
(2) mobile phase is that n-hexane-absolute ethyl alcohol (containing 0.2%~0.5% diethylamine) (90~10 to 10~90) is stream
Dynamic phase, is preferably n-hexane-absolute ethyl alcohol (containing 0.2% diethylamine) (90:10)；
(3) Detection wavelength is 200~300nm, is preferably 280nm；
(4) flow velocity is 0.5~1.5ml/min, is preferably 1.0ml/min；
(5) column temperature is 25~35 DEG C, is preferably 30 DEG C.
In the present invention, the external standard method is method well known in the art.In embodiments of the invention, the external standard
Method refers to：
1) with the peak area of reference substance solution of the HPLC methods measure containing a certain amount of compound 4R-1；
2) peak area of the compound 4R-1 contained in the sample of aliskiren or its salt is measured with HPLC methods；
3) it is worth to the compound contained in the sample of aliskiren or its salt by calculating the ratio of peak area 1) and 2)
The content of 4R-1.
In specific embodiments of the present invention, the calculation formula of the optical isomer 4R-1 contents is：
In formula, ASampleFor the peak area of compound 4R-1 in test solution；
WIt is rightFor the sample weighting amount (mg) of compound 4R-1；
VSampleFor the constant volume (ml) of test solution；
AIt is rightFor the peak area of compound 4R-1；
VIt is rightFor the constant volume (ml) of compound 4R-1；
WSampleFor the sample weighting amount (mg) of test solution.
Fourth aspect present invention is related to a kind of method for detecting optical isomer content in aliskiren and its salt, this method
Using the Self-control method of the correction up factor in high performance liquid chromatography, with the correction of the 4- positions epimer of aliskiren
The factor, calculates the content of 4 epimers in aliskiren and its salt.
The method of any one according to a fourth aspect of the present invention, wherein the high performance liquid chromatography is characterized in that following
(1)~(5) it is one or more in item：
(1) chromatographic column is chiral column, preferably AD-H types, IC columns or OJ-3R columns, more preferably CHIRALPAK AD-H type hands
Property column (4.6mm × 250mm, 5 μm)；
(2) mobile phase is n-hexane-absolute ethyl alcohol (containing 0.2%~0.5% diethylamine) (90~10 to 10~90), preferably
For n-hexane-absolute ethyl alcohol (containing 0.2% diethylamine) (90:10)；
(3) Detection wavelength is 200~300nm, is preferably 280nm；
(4) flow velocity is 0.5~1.5ml/min, is preferably 1.0ml/min；
(5) column temperature is 25~35 DEG C, is preferably 30 DEG C.
In the present invention, the Self-control method of the correction up factor is method well known in the art.In the reality of the present invention
Apply in scheme, the Self-control method of the correction up factor refers to：
1) using aliskiren and compound 4R-1 as sample, the solution of serial various concentrations is prepared, draws standard curve
Slope is tried to achieve, the correction factor of compound 4R-1 is calculated by slope；
2) peak area and compound 4R- of the aliskiren contained in the sample of aliskiren or its salt are measured with HPLC methods
1 peak area；
3) contents of the compound 4R-1 in aliskiren is calculated by correction factor.
In specific embodiments of the present invention, the calculation formula of the optical isomer 4R-1 contents is：
In formula, A4R-1For the peak area of compound 4R-1 in test solution；
f4R-1Correction factor for compound 4R-1 relative to aliskiren hemifumarate；
AIt is rightFor the peak area of aliskiren in contrast solution.
Wherein, compound 4R-1 relative to aliskiren hemifumarate correction factor f=KAliskiren/K4R-1,
Wherein K is the slope value of standard curve.
In the present invention, the method that the high performance liquid chromatography is known in the art.In embodiments of the invention,
The specific method of the high performance liquid chromatography is：
The solution of certain density aliskiren and compound 4R-1 are prepared, carries out high performance liquid chromatography, the chromatography of use
Condition is：Chromatographic column is chiral column, preferably AD-H types, IC columns or OJ-3R columns, more preferably CHIRALPAK AD-H type chiral columns
(4.6mm×250mm,5μm)；Mobile phase for n-hexane-absolute ethyl alcohol (containing 0.2%~0.5% diethylamine) (90~10 to 10~
90), it is preferably n-hexane-absolute ethyl alcohol (containing 0.2% diethylamine) (90:10)；Detection wavelength is 200~300nm, is preferably
280nm；Flow velocity is 0.5~1.5ml/min, is preferably 1.0ml/min；Column temperature is 25~35 DEG C, is preferably 30 DEG C；
Individually sample introduction and mixing sample introduction, then respectively obtain the reservation of the retention time, compound 4R-1 of aliskiren
Time and both separation degrees of data.
In specific embodiments of the present invention, the retention time of wherein aliskiren is about 21.2min, compound 4R-1
Retention time be about 23.7min, both chromatographic peak can reach preferable separation under the liquid-phase condition, its separating degree is
1.7。
4- positions epimer the invention further relates to the aliskiren of first aspect present invention is used to detect aliskiren
And its in salt optical isomer content purposes.
The invention further relates to first aspect present invention aliskiren 4- positions epimer be used for aliskiren and its
The purposes of quality control in the production or preparation of salt.
4- positions epimer the invention further relates to the aliskiren of first aspect present invention is used to detect aliskiren
And its purposes of the purity of salt.
Brief description of the drawings
Fig. 1：The ESI-MS collection of illustrative plates of compound 4R-1
Fig. 2：Compound 4R-1's1H-NMR collection of illustrative plates
Fig. 3：Compound 4R-1's13C-NMR collection of illustrative plates
Fig. 4：Compound 4R-1's1H-1HCOSY collection of illustrative plates
Fig. 5：The HSQC collection of illustrative plates of compound 4R-1
Fig. 6：The HPLC collection of illustrative plates of aliskiren hemifumarate
Fig. 7：The HPLC collection of illustrative plates of compound 4R-1
Fig. 8：The HPLC collection of illustrative plates that compound 4R-1 is mixed with aliskiren hemifumarate
Embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is not specified in embodiment specific
Condition person, the condition suggested according to normal condition or manufacturer carry out.Reagents or instruments used without specified manufacturer, is
Can be with conventional products that are commercially available.
In the examples below, prepared by the separation, is carried out on Shimadzul C20A type preparative liquid chromatographs, its
It is middle to use Chiralpak IA or prepare column similar to model as chromatographic column；The concentration, beR-200 types revolve
Turn to carry out on evaporimeter；The HPLC chromatogram, is measured on Shimadzu LC-10ATvp high performance liquid chromatographs；Mass spectrum exists
Measured on JEOL AccuTOF CS (JMS T100CS) type mass spectrograph；Nuclear magnetic resonance1H compose and13C is composed in Bruker
Measured in AVANCEIII400 type Nuclear Magnetic Resonance；The optical activity, is measured on WZZ-2S type automatic polarimeters, its
In, the calculation formula of the specific rotation of sample is：
D is the D lines of sodium spectrum in formula, and l is measure length of tube (dm), and α is the optical activity measured.
Embodiment 1(2S, 5S, 7S) -5- azidos-N- (2- amine formyl -2- methyl-propyls) -2- isopropyls -7- (4- first
Epoxide -3- (3- methoxy propoxies) benzyl) -8- methyl -4- oxygen pelargonamides (3) preparation
Starting material with compound 2 as follows for synthesis, its chemical name are：
(2S, 4S, 5S, 7S) -5- azidos-N- (2- amine formyl -2- methyl-propyls) -4- hydroxyl -2- isopropyls -7-
(4- methoxyl groups -3- (3- methoxy propoxies) benzyl) -8- methyl pelargonamides.Compound 2 passes through in patent US7,009,078
It is prepared by the method described in embodiment F1.
Dai Si-Martin is added into dichloromethane (100ml) solution of compound 2 (4.0g, 6.9mmol) and crosses iodine alkane
(2.9g, 6.9mmol), when addition, maintain the temperature at -20 DEG C.Finish, be to slowly warm up to 0 DEG C and reaction solution is stirred 3 at 0 DEG C
Hour.Saturated sodium bicarbonate and sodium thiosulfate solution (each 20ml) are separately added into reaction solution, question response liquid becomes clarification
Backward reaction solution in add dichloromethane (50ml), separate organic phase after stirring, and extracted again with dichloromethane (50ml)
Water mutually twice, merges all organic phases, and is evaporated after organic phase is dried with anhydrous sodium sulfate, and residue is through silica gel column chromatography
Purifying, obtains the crude product (4.4g, 100% yield) of compound 3 as follows, is yellow oil.ESI-MS(m/z):
576.0(MH+)。
Embodiment 2(2S, 5S, 7S) -5- azido -4- hydroxy-ns-(2- amine formyl -2- methyl-propyls) -2- isopropyls -
The preparation of 7- (4- methoxyl groups -3- (3- methoxy propoxies) benzyl) -8- methyl pelargonamide (mixture of 2 and 4R-2)
The crude product of the intermediate 3 (4.4g, 6.9mmol) obtained in embodiment 1 is dissolved in methanol (50ml), and is heated to
50 DEG C, sodium borohydride (0.52g, 13.8mmol) is added portionwise into solution.Finish, reaction solution continues stirring 30 minutes at 50 DEG C
Afterwards, it is cooled to room temperature.Saturated aqueous ammonium chloride (20ml) is added into reaction solution, isolates organic phase after stirring, then with two
Chloromethanes (50ml) aqueous phase extracted is twice.Merge all organic phases, be evaporated after being dried with anhydrous sodium sulfate, obtain residue, will
Residue purifies (mobile phase with silica gel column chromatography：Ethyl acetate/petroleum ether=1/1) obtain the mixed of 2 and 4R-2 as follows
Compound (3.0g, 75% yield), is colorless oil.ESI-MS(m/z):578.1(MH+)。
Embodiment 3(2S, 4R, 5S, 7S) -5- amino-N- (2- amine formyl -2- methyl-propyls) -4- hydroxyl -2- isopropyls
The preparation of base -7- (4- methoxyl groups -3- (3- methoxy propoxies) benzyl) -8- methyl pelargonamide (4R-1)
The mixture (3.0g, 5.2mmol) of obtained in embodiment 22 and 4R-2 is dissolved in methanol (50ml), and to this
Palladium carbon (containing palladium 10%, 0.5g) is added in solution.Hydrogen is passed through to this reaction solution, keeps Hydrogen Vapor Pressure stirred for 2.0bar
Night.Reaction mixture is filtered, filtrate solvent evaporated, obtained residue carries out separation preparation on preparative liquid chromatograph,
Wherein use Chiralpak IA's to prepare column as chromatographic column, with n-hexane:Ethanol (containing 0.2% diethylamine)=70:30 be stream
Dynamic phase, evaporated under reduced pressure solvent obtains 4R-1 (0.8g, 35% yield), is white solid.
Angle-of-rotation measuring is carried out to the compound 4R-1 of gained：This product about 0.2g is taken, it is accurately weighed, put in 25ml measuring bottles,
Add ethanol to make dissolving and be diluted to scale, shake up to obtain test liquid.Take test liquid to measure optical activity on automatic polarimeter, repeat to read
Number 3 times, takes arithmetic mean of instantaneous value.The results are shown in Table 1 for measure.
Table 1
Calculated according to the calculation formula of specific rotation, the specific rotation of compound 4R-1 is [α]D 20=0 ° of (ethanol, C=
8.05mg/ml)；As reference, the specific rotation of aliskiren is [α]D 20=-11.4 ° (ethanol, C=8.21g/ml).
To the compound 4R-1 of gained, carry out mass spectrum (Fig. 1), nuclear magnetic resonance spectroscopy (Fig. 2), carbon spectrum (Fig. 3),1H-1HCOSY
(Fig. 4), the measure of hsqc spectrum (Fig. 5) are composed, it turns out that：
1H-NMR(400MHz,CDCl3,ppm-1)δ:0.80-0.92(m,12H),1.16-1.30(m,8H),1.41-1.44
(m,1H),1.61-1.88(m,5H),2.06-2.12(m,2H),2.38-2.52(m,3H),2.68-2.70(m,1H),3.28-
3.47(m,6H),3.57(t,2H),3.83(s,3H),4.09(t,2H),5.85-6.00(bs,1H),6.35-6.49(br,
2H),6.68-6.79(m,3H).
13C-NMR(400MHz,CDCl3,ppm-1)δ:17.9,19.4,20.0,20.3,23.9,24.0,29.2,29.5,
31.0 32.5,37.3,42.5,43.0,47.2,51.9,53.3,56.0,58.6,66.1,69.3,74.2,111.7,114.5,
121,.2,134.2,147.6.,148.2,176.4,179.8.
ESI-MS(m/z):552.4(MH+)。
1H-1HCOSY tests the result is shown in Fig. 4, HSQC tests the result is shown in Fig. 5.
Result above is consistent with the chemical constitution of target compound.
Embodiment 4Optical isomer content in external standard method detection aliskiren and its salt in high performance liquid chromatography
Liquid chromatograph model：Shimadzu LC-10ATvp
Chromatographic column type：CHIRALPAK AD-H types chiral column (4.6mm × 250mm, 5 μm)；
Mobile phase：N-hexane-absolute ethyl alcohol (containing 0.2% diethylamine) (90:10)；
Detection wavelength：280nm；
Flow velocity：1.0ml/min；
Column temperature：30℃；
Sample size：10μl
Diluent：N-hexane：Absolute ethyl alcohol (1:1)
The preparation of reference substance solution：3 gained compound 4R-1 of Example is appropriate, accurately weighed, adds n-hexane：It is anhydrous
Ethanol (1:1) dissolve and be settled to scale, obtain the solution of every ml 4R-1 containing compound 0.1mg.
The preparation of test solution：Aliskiren hemifumarate is taken (by China Resources Double-Crane Pharmaceutical Co., Ltd.'s foundation
Patent US7, the method described in embodiment G1 in 009,078 are prepared and provide) in right amount, it is accurately weighed, add n-hexane：
Absolute ethyl alcohol (1:1) dissolve and be settled to scale, obtain the solution of every ml 0.2mg containing aliskiren hemifumarate.
Add the preparation of the mixed solution of compound 4R-1：Precision weighs aliskiren hemifumarate and compound respectively
Appropriate 4R-1, according to 1:1 equal proportion mixing, adds n-hexane：Absolute ethyl alcohol (1:1) dissolve and be settled to scale.
Operation：It is accurate respectively to draw 10 μ l reference substance solutions, test solution and the mixed solution note for adding compound 4R-1
Enter liquid chromatograph, record chromatogram (Fig. 6, Fig. 7, Fig. 8).The reservation of compound 4R-1, aliskiren in above-mentioned chromatogram
Time respectively may be about 21.2min, 23.7min, both separating degrees are about 1.7.
External standard method calculates the content of compound 4R-1 in test solution：If test solution is in the position of compound 4R-1
There is corresponding chromatographic peak, according to the corresponding peak area of reference substance solution, compound in test solution is calculated using external standard method
The content of 4R-1.
Calculation formula：
In formula, ASampleFor the peak area of compound 4R-1 in test solution；
WIt is rightFor the sample weighting amount (mg) of compound 4R-1；
VSampleFor the constant volume (ml) of test solution；
AIt is rightFor the peak area of compound 4R-1；
VIt is rightFor the constant volume (ml) of compound 4R-1；
WSampleFor the sample weighting amount (mg) of test solution.
Specific data are as shown in table 2.
Table 2
| Project | Numerical value |
| WIt is right | 10.36mg |
| WSample | 10.24mg |
| AIt is right | 107689 |
| ASample | 116203 |
| VIt is right | 100ml |
| VSample | 50ml |
| Compound 4R-1 contents % in test solution | Do not detect |
| Compound 4R-1 contents % in mixed solution | 54.6% |
Light in the Self-control method method detection aliskiren and its salt of the correction up factor in 5 high performance liquid chromatography of embodiment
Learn content of isomer
Liquid chromatograph model：Shimadzu LC-10ATvp
Chromatographic column type：CHIRALPAK AD-H types chiral column (4.6mm × 250mm, 5 μm)；
Mobile phase：N-hexane-absolute ethyl alcohol (containing 0.2% diethylamine) (90:10)；
Detection wavelength：280nm；
Flow velocity：1.0ml/min；
Column temperature：30℃；
Sample size：10μl
Diluent：N-hexane：Absolute ethyl alcohol (1:1)
The preparation of compound 4R-1 array of linear solution：Take compound 4R-1 appropriate, it is accurately weighed, add n-hexane：Nothing
Water-ethanol (1:1) dissolve and be settled to scale, obtain the linear stock solution of every ml 4R-1 containing compound 0.5mg.Dilute step by step
To concentration for 0.1,0.2,0.3,0.4, the array of linear solution of 0.5mg/ml.
The preparation of aliskiren hemifumarate array of linear solution：Aliskiren hemifumarate is taken (by the double cranes in China Resources
According to patent US7, the method described in embodiment G1 in 009,078 is prepared and provides for medicine company limited company) in right amount,
It is accurately weighed, add n-hexane：Absolute ethyl alcohol (1:1) dissolve and be settled to scale, obtain every ml and contain aliskiren and its salt
The linear stock solution of 0.5mg.Step by step dilution obtain concentration for 0.1,0.2,0.3,0.4, the array of linear solution of 0.5mg/ml.
The preparation of test solution：Take aliskiren hemifumarate appropriate, it is accurately weighed, add n-hexane：Anhydrous second
Alcohol (1:1) dissolve and be settled to scale, obtain the solution of every ml 0.2mg containing aliskiren.
The preparation of contrast solution：Precision measures test solution 5ml, is placed in 10ml measuring bottles, adds n-hexane：Anhydrous second
Alcohol (1:1) dissolve and be settled to scale.
Add the mixed solution of compound 4R-1：Precision weighs aliskiren hemifumarate respectively and compound 4R-1 is fitted
Amount, according to 1:1 equal proportion mixing, adds n-hexane：Absolute ethyl alcohol (1:1) dissolve and be settled to scale.
Chromatographic run：Precision draws each 10 μ l of linear solvent injections liquid chromatograph, records chromatogram.It is molten with array of linear
The concentration of liquid is abscissa, and peak area draws standard curve for ordinate, obtains compound 4R-1 and aliskiren and its salt pair
The slope value K answered.
Compound 4R-1 relative to aliskiren hemifumarate correction factor
F=KAliskiren/K4R-1
It is 0.9974 that compound 4R-1, which is calculated, relative to the correction factor f values of aliskiren and its salt.
It is accurate respectively to draw test solution and 10 μ l of contrast solution injection liquid chromatographs, record chromatogram.If right
There is chromatographic peak in the compound 4R-1 positions answered, then its content is：
In formula, A4R-1For the peak area of compound 4R-1 in test solution；
f4R-1Correction factor (0.9974) for compound 4R-1 relative to aliskiren hemifumarate；
AIt is rightFor the peak area of aliskiren in contrast solution.
Specific data are as shown in table 3.
Table 3
| Project | Numerical value |
| A4R-1 | 116203 |
| AIt is right | 106532 |
| Compound 4R-1 contents % in test solution | Do not detect |
| Compound 4R-1 contents % | 54.4% |
Although the embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to disclosed all teachings, various modifications and replacement can be carried out to those details, these change in the guarantor of the present invention
Within the scope of shield.The four corner of the present invention is provided by appended claims and its any equivalent.
Present invention additionally comprises following items：
1. a kind of 4- positions epimer of aliskiren, as shown in formula 4R-1, chemical name is its molecular structure：(2S,
4R, 5S, 7S) -5- amino-N- (2- amine formyl -2- methyl-propyls) -4- hydroxyl -2- isopropyls -7- (4- methoxyl group -3- (3-
Methoxy propoxy) benzyl) -8- methyl pelargonamides, or its pharmaceutically acceptable salt.
2. the preparation method of the 4- positions epimer of the aliskiren of project 1, it comprises the following steps：
A) starting material with compound 2 as follows for synthesis, its chemical name are：(2S, 4S, 5S, 7S) -5- is folded
Nitrogen base-N- (2- amine formyl -2- methyl-propyls) -4- hydroxyl -2- isopropyls -7- (4- methoxyl groups -3- (3- methoxy propoxies)
Benzyl) -8- methyl pelargonamides；
B) compound 2 and a kind of oxidant reaction are obtained into compound 3 as follows, wherein, the oxidant is selected from
Chromium trioxide-pyridine complex compound, manganese dioxide, three n-butoxy aluminium and Dai Si-Martin cross iodine alkane, and preferably Dai Si-Martin crosses iodine
Alkane；
C) compound 3 and metallic boron hydrides are reacted to obtain compound 2 as follows and the racemization of compound 4R-2
Body mixture, wherein, the boron hydride is selected from potassium borohydride, sodium borohydride, lithium borohydride；
D) the step c) racemic mixtures obtained are obtained into compound 1 and compound as follows by catalytic hydrogenation
The racemic mixture of 4R-1, wherein, it is preferred to use the method for palladium carbon catalytic hydrogenation；
E) racemic mixture separation in d) is prepared to the 4- positions epimerism of the aliskiren of claim 1
Body.
3. the preparation method of project 2, it is characterised in that one or more in the item of following (1)~(11)：
(1) in step b), the solvent of 2 solution of compound is selected from chloroform, dichloromethane；
(2) in step b), reaction temperature is -30~10 DEG C, preferably -20~0 DEG C；
(3) in step b), add saturated sodium bicarbonate after oxidation reaction and hypo solution carries out extraction behaviour
Make, organic layer concentrates after drying, and residue purifies to obtain compound 3 through column chromatography；
(4) in step c), the solvent of 3 solution of compound is selected from methanol, ethanol, tetrahydrofuran；
(5) in step c), reaction temperature is -10~60 DEG C, preferably 0~50 DEG C；
(6) ammonium chloride solution is added in step c), after reduction reaction and dichloromethane carries out extracting operation, organic layer
Concentrate after drying, residue through column chromatography purify compound 2 and compound 4R-2 racemic mixture；
(7) in step d), the palladium carbon is the palladium carbon containing palladium 5%~10%；
(8) in step d), the solvent of the racemic mixture of dissolved compound 2 and compound 4R-2 is selected from methyl tertbutyl
Ether, ethanol, methanol, tetrahydrofuran, ethyl acetate, ethyl ester isopropyl ester, dichloromethane, preferably methanol, tetrahydrofuran；
(9) in step d), wherein the pressure of catalytic hydrogenation is 1~10bar, preferably 1~3bar；
(10) in step d), saturated sodium bicarbonate solution is sequentially added after catalytic hydrogenation and brine is extracted
Operation, organic layer concentrates after drying, residue through column chromatography purify the raceme of compound 1 and compound 4R-1 mixes
Thing；
(11) in step e), the separation method is the racemic mixture for obtaining step d) in preparative liquid chromatograph
On carry out separation and be prepared into compound 4R-1, wherein use Chiralpak IA or similar models prepares column as chromatographic column, with
N-hexane:Ethanol (containing 0.2% diethylamine) is mobile phase, and wherein n-hexane and ethanol volume ratio are 80:20~60:40, preferably
70:30。
4. a kind of method for detecting optical isomer content in aliskiren and its salt, this method use high performance liquid chromatography
External standard method in method, using the 4- position epimers of the aliskiren of claim 1 as reference substance, calculates aliskiren and its salt
In 4 epimers content.
5. the method for project 4, wherein the high performance liquid chromatography is characterized in that one in the item of following (1)~(5)
It is or multinomial：
(1) chromatographic column is chiral column, preferably AD-H types, IC columns or OJ-3R columns, more preferably CHIRALPAK AD-H type hands
Property column (4.6mm × 250mm, 5 μm)；
(2) mobile phase is that n-hexane-absolute ethyl alcohol (containing 0.2%~0.5% diethylamine) (90~10 to 10~90) is stream
Dynamic phase, is preferably n-hexane-absolute ethyl alcohol (containing 0.2% diethylamine) (90:10)；
(3) Detection wavelength is 200~300nm, is preferably 280nm；
(4) flow velocity is 0.5~1.5ml/min, is preferably 1.0ml/min；
(5) column temperature is 25~35 DEG C, is preferably 30 DEG C.
6. a kind of method for detecting optical isomer content in aliskiren and its salt, this method use high performance liquid chromatography
The Self-control method of the correction up factor in method, with the correction factor of the 4- positions epimer of aliskiren, calculates A Liji
The content of 4 epimers in logical sequence and its salt.
7. the method for project 6, wherein the high performance liquid chromatography is characterized in that one in the item of following (1)~(5)
It is or multinomial：
(1) chromatographic column is chiral column, preferably AD-H types, IC columns or OJ-3R columns, more preferably CHIRALPAK AD-H type hands
Property column (4.6mm × 250mm, 5 μm)；
(2) mobile phase is n-hexane-absolute ethyl alcohol (0.2%~0.5% diethylamine) (90~10 to 10~90), is preferably
N-hexane-absolute ethyl alcohol (0.2% diethylamine) (90:10)；
(3) Detection wavelength is 200~300nm, is preferably 280nm；
(4) flow velocity is 0.5~1.5ml/min, is preferably 1.0ml/min；
(5) column temperature is 25~35 DEG C, is preferably 30 DEG C.
8. the 4- positions epimer of the aliskiren of project 1 contains for detecting optical isomer in aliskiren and its salt
The purposes of amount.
9. the 4- positions epimer of the aliskiren of project 1 is used for quality in the production or preparation of aliskiren and its salt
The purposes of control.
10. the 4- positions epimer of the aliskiren of project 1 is used for the purposes for detecting the purity of aliskiren and its salt.
Claims (8)
1. a kind of method for detecting optical isomer content in aliskiren and its salt, this method are used in high performance liquid chromatography
External standard method, using the 4- position epimers of aliskiren as reference substance, calculate 4 epimers in aliskiren and its salt
Content, wherein the high performance liquid chromatography is characterized in that：
(1) chromatographic column is AD-H types, IC columns or OJ-3R columns；
(2) mobile phase is n-hexane-absolute ethyl alcohol；Wherein, n-hexane:Absolute ethyl alcohol is 90:10 to 10:90, absolute ethyl alcohol contains
0.2%~0.5% diethylamine；
(3) Detection wavelength is 280nm；
(4) flow velocity is 1.0ml/min；With
(5) column temperature is 30 DEG C；
The structure of the 4- positions epimer of the aliskiren is as follows：
2. the method for claim 1 wherein chromatographic column is CHIRALPAK AD-H type chiral columns.
3. the method for claim 2, wherein, CHIRALPAK AD-H types chiral column is 4.6mm × 250mm, 5 μm.
4. the method for claim 1 wherein n-hexane:Absolute ethyl alcohol is 90:10.
5. a kind of method for detecting optical isomer content in aliskiren and its salt, this method are used in high performance liquid chromatography
The correction up factor Self-control method, with the correction factor of the 4- positions epimer of aliskiren, calculate aliskiren and
The content of 4 epimers in its salt, wherein the high performance liquid chromatography is characterized in that：
(1) chromatographic column is AD-H types, IC columns or OJ-3R columns；
(2) mobile phase is n-hexane-absolute ethyl alcohol；Wherein, n-hexane:Absolute ethyl alcohol is 90:10 to 10:90, absolute ethyl alcohol contains
0.2%~0.5% diethylamine；
(3) Detection wavelength is 280nm；
(4) flow velocity is 1.0ml/min；
(5) column temperature is 30 DEG C.
6. the method for claim 5, wherein, chromatographic column is CHIRALPAK AD-H type chiral columns.
7. the method for claim 6, wherein, CHIRALPAK AD-H types chiral column is 4.6mm × 250mm, 5 μm.
8. the method for claim 5, wherein, n-hexane:Absolute ethyl alcohol is 90:10.
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| CN103207247A (en) * | 2012-12-21 | 2013-07-17 | 北京万全德众医药生物技术有限公司 | Method of separating and determining aliskiren intermediate and optical isomers thereof by using liquid chromatography |
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