CN105294478B - A kind of diastereoisomer of aliskiren, Preparation Method And The Use - Google Patents
A kind of diastereoisomer of aliskiren, Preparation Method And The Use Download PDFInfo
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Abstract
The present invention relates to the diastereoisomer of (2S, 4R, 5R, 7S) configuration of aliskiren, its molecular structure such as formula 4R, shown in 5R 1.The invention further relates to (the 2S of the aliskiren, 4R, 5R, 7S) the preparation method of the diastereoisomer of configuration, and its for the purposes of quality control in the production or preparation of the content and aliskiren and its salt of optical isomer in the purity, detection aliskiren and its salt that detect aliskiren and its salt.
Description
Technical field
The present invention relates to a kind of diastereoisomer, in particular it relates to a kind of aliskiren (2S, 4R, 5R,
7S) the diastereoisomer of configuration.The invention further relates to the diastereo-isomerism of (2S, 4R, 5R, 7S) configuration of the aliskiren
The preparation method and its usage of body.
Background technology
Aliskiren (1) is a kind of new direct renin inhibitor of non-peptides, relevant 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, be characterized in, by dose-dependently reducing RA, RAS being 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 WO02/02508 employs following conjunction
Into route：
Patent WO2007/045420 then employs another synthetic route：
Key point in the synthesis of aliskiren is that four chiralitys in molecule are built using the method for asymmetric syntheses
Center, so as to obtain 4 hydroxyls for S configurations, 5 bit aminos are that S configurations, 2 and 7 isopropyls are the single optics pair of S configurations
Reflect body.Wherein, for 4 hydroxyls and the building process of 5 bit amino chiral centres, solved in above-mentioned known synthetic method
Certainly.In the synthetic method as shown in above-mentioned patent WO02/02508, the double bond of compound 7 and hypobromous acid are carried out into stereoselectivity
Addition reaction, obtain the compound 4 of (3S, 5R, 1 ' S, 3 ' S) configuration, and further hindrance obtains A Liji
Logical sequence；In the synthetic method as shown in above-mentioned patent WO2007/045420, then the double bond of compound 16 and hypobromous acid are carried out into solid
The addition reaction of selectivity, and further hindrance obtains aliskiren.
It is well known that no matter which kind of chemical reaction to carry out 4 hydroxyls and 5 bit amino chiral centres using in synthetic method
Build, its stereoselectivity is unlikely to be 100%, more or less there may be 4 R and 5 isomers of R configurations, from
And (2S, 4R, 5R, 7S) configuration is more or less mixed into when the aliskiren for obtaining (2S, 4S, 5S, 7S) configuration is ultimately generated
Isomers, i.e. compound 4R, 5R-1.The configuration of 2,7, the isomers is consistent with target molecule aliskiren, only 4,5
Configuration is inconsistent.
Additionally, 4 hydroxyls and 5 bit aminos have relatively active chemical reaction property, its S configuration is anti-in subsequent chemistry
Should, long term storage, be processed into pharmaceutical preparation during, how to keep 4 hydroxyls and 5 bit amino configurations constant, be also prepare
Aliskiren process needs the key factor for considering.
As other chemical synthetic drugs, the purity of pharmaceutically active substance (API) is that aliskiren commercialization is utilized
A key index.Initiation material, reaction intermediate and accessory substance, degraded may be introduced in the production process of API to produce
Thing etc. is referred to as the impurity about 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 that API must have enough purity, and the content of its impurity need to control to specify in medicine quality standard
Limit within.Single optical antipode medicine this kind of for aliskiren, with 4 chiral centres, in theory with 15
Individual optical isomer, the chemical molecular formula of these isomers is identical with aliskiren, and every physicochemical property is also same or similar, but
They there may be relatively big difference into the drug effect after human body and the toxicity to human body with aliskiren.ICH requirements can by these
The optical isomer of energy carries out limit research as impurity, to ensure the drug effect and toxicity of medicine.Such as in the ICHQ7A of API productions
In guideline, the requirement of standardization is proposed to supplementary material and working condition, needed in certain moment of production API
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, be typically with external standard method, or the correction up factor Self-control method, its precondition is to obtain
The reference substance of tested impurity.
In sum, minimum to ensure the drug effect uniformity and toxicity of aliskiren marketed products, optimal method is to adopt
Controlled such as 4R with high performance liquid chromatography, the content of 5R-1 impurity, using existing high performance liquid chromatography such as external standard method or plus
The Self-control method of correction factor, is required to 4R, and 5R-1 compounds are used as reference substance.However, up to the present, it has not been found that
There is the report of related compounds 4R, 5R-1.It is therefore desirable to develop the preparation method of compound 4R, 5R-1 to obtain reference substance, with
And a kind of content of isomer analysis method, for the optical purity inspection of aliskiren or its salt, and then for A Liji
The quality control of logical sequence or its salt.
The content of the invention
First aspect present invention is related to a kind of diastereoisomer of (2S, 4R, 5R, 7S) configuration of aliskiren, its point
Minor structure such as formula 4R, shown in 5R-1, chemical name is：(2S, 4R, 5R, 7S) -5- amino-N- (2- amine formyl -2- methyl-props
Base) -4- hydroxyl -2- isopropyls -7- (4- methoxyl groups -3- (3- methoxy propoxies) benzyl) -8- methyl pelargonamides.
Second aspect present invention is related to the diastereomeric of (2S, 4R, 5R, 7S) configuration of the aliskiren of first aspect present invention
The preparation method of isomers, it is comprised the following steps：
A) it is the initiation material of synthesis with compound (3S, 5R, 1 ' S, 3 ' S) -4 as follows, its chemical name is：
(3S, 5R) -5- [the bromo- 3- of (1S, 3S) -1- [[4- methoxyl groups -3- (3- methoxy propoxies) phenyl] methyl] -4- methyl amyls]
(the 3H)-furanone of dihydro -3- isopropyls -2；
B) compound (3S, 5R, 1 ' S, 3 ' S) -4 and reaction of sodium azide are obtained into compound (3S, 5R, 1 ' as follows
R, 3 ' S) -5；
C) by compound (3S, 5R, 1 ' R, 3 ' S) -5 and 3- amino -2, the change that 2-- dimethyl propylamines react as follows
Compound 4R, 5R-2；
D) by compound 4R, 5R-2 obtains the compound of formula 4R, 5R-1 by catalytic hydrogenation, wherein, it is preferred to use palladium carbon is urged
The method for changing hydrogenation；
The preparation method of any one according to a second aspect of the present invention, it is characterised in that in the item of (1)~(12) below
Or it is multinomial：
(1) in step b), the solvent of compound (3S, 5R, 1 ' S, 3 ' S) -4 solution is selected from DMF, three
Propane diols, pyridine, 1-METHYLPYRROLIDONE etc., preferably tripropylene glycol；
(2) in step b), compound (3S, 5R, 1 ' S, 3 ' S) -4 is 1: 3~1: 10 with the mol ratio of sodium azide, preferably
1∶5；
(3) in step b), reaction temperature is 60~100 DEG C, preferably 80~90 DEG C；
(4) in step b), reaction adds a kind of organic amine, such as diethylin -1- propylamine after terminating, and adds water and one
Plant solvent to be extracted, wherein described solvent is selected from methyl tertiary butyl ether(MTBE), dichloromethane, ethyl acetate etc.；Organic layer is with dilute
Hydrochloric acid, saturated sodium bicarbonate wash with salt water washing, and with after anhydrous sodium sulfate drying concentrate, residue by silicagel column chromatographic purifying
Obtain compound (3S, 5R, 1 ' R, 3 ' S) -5；
(5) in step c), reaction dissolvent is selected from methyl tertiary butyl ether(MTBE), tetrahydrofuran, 1-METHYLPYRROLIDONE, chloroform etc.,
It is preferred that methyl tertiary butyl ether(MTBE)；
(6) in step c), organic base is added in the reactive mixture, wherein, described organic base is selected from pyridine, 2- hydroxyls
Pyridine, triethylamine, amantadine etc., preferably 2 hydroxy pyrimidine；
(7) in step c), reaction temperature is 40~110 DEG C, more preferably preferably 60~100 DEG C, 70~90 DEG C；
(8) in step c), water and a kind of solvent is added to carry out extracting operation after completion of the reaction, wherein described solvent is selected from
Methyl tertiary butyl ether(MTBE), dichloromethane, ethyl acetate etc.；Organic layer is concentrated after drying, and residue by silicagel column chromatographic purifying is obtained
Compound 4R, 5R-2；
(9) in step d), described palladium carbon is the palladium carbon containing palladium 5% to 10%；
(10) in step d), the solvent of compound 4R, 5R-2 is selected from methyl tertiary butyl ether(MTBE), ethanol, methyl alcohol, tetrahydrochysene furan
Mutter, ethyl acetate, ethyl ester isopropyl ester, dichloromethane, preferably methyl alcohol, tetrahydrofuran；
(11) in step d), wherein the pressure of catalytic hydrogenation is 1~10bar, preferably 1~3bar；
(12) in step d), catalytic hydrogenation is filtered after finishing, and filtrate sequentially adds saturated sodium bicarbonate solution and salt
Water carries out extracting operation, and organic layer is concentrated after drying, and residue purifies to obtain compound 4R, 5R-1 through column chromatography.
In embodiments of the invention, as compound (3S, 5R, 1 ' S, 3 ' S) -4 of initiation material according to patent
Method in WO02/02508 described in embodiment C1 is prepared.
In embodiments of the invention, it is 1: 3 that mol ratio is added in the solution of compound (3S, 5R, 1 ' S, 3 ' S) -4
~1: 10 sodium azide, preferred ratio is 1: 5, wherein described solvent can be selected from DMF, 3 third
Glycol, pyridine, 1-METHYLPYRROLIDONE etc., preferably tripropylene glycol, reaction temperature are 60~100 DEG C, preferably 80~90 DEG C, reaction
48~72 hours, water and a kind of solvent is added to carry out extracting operation, wherein described solvent is selected from methyl tertiary butyl ether(MTBE), dichloromethane
Alkane, ethyl acetate etc., organic layer is concentrated after drying, and residue by silicagel column chromatographic purifying obtains compound (3S, 5R, 1 ' R, 3 '
S)-5。
In embodiments of the invention, add in the reaction system of compound (3S, 5R, 1 ' R, 3 ' S) -5 and compound 6
Enter organic base, wherein described organic base is selected from pyridine, 2 hydroxy pyrimidine, triethylamine, amantadine etc., preferably 2- hydroxyls pyrrole
Pyridine, wherein reaction dissolvent are selected from methyl tertiary butyl ether(MTBE), tetrahydrofuran, 1-METHYLPYRROLIDONE, chloroform etc., preferably methyl tertbutyl
Ether, reaction temperature is positively retained at 40~110 DEG C, and preferably 60~100 DEG C, within the scope of more preferably 70~90 DEG C, reaction is finished
Adding water and a kind of solvent afterwards carries out extracting operation, wherein described solvent is selected from methyl tertiary butyl ether(MTBE), dichloromethane, acetic acid second
Ester etc.；Organic layer is concentrated after drying, and residue by silicagel column chromatographic purifying obtains compound 4R, 5R-2.
In embodiments of the invention, palladium carbon is added in compound 4R, the solution of 5R-2, is passed through pressurized with hydrogen hydrogen
Change, wherein described palladium carbon is the palladium carbon containing palladium 5% to 10%；Wherein described solvent is selected from methyl tertiary butyl ether(MTBE), ethanol, first
Alcohol, tetrahydrofuran, ethyl acetate, ethyl ester isopropyl ester, dichloromethane etc., preferably methyl alcohol, tetrahydrofuran；The wherein pressure of hydrogenation reaction
Power is 1~10bar, preferably 1~3bar.Sequentially adding saturated sodium bicarbonate solution and salt solution after completion of the reaction carries out extraction behaviour
Make, organic layer is concentrated after drying, and residue by silicagel column chromatographic purifying obtains compound 4R, 5R-1.
Third aspect present invention further relates to a kind of method for detecting optical isomer content in aliskiren or its salt, the party
Method using the external standard method in high performance liquid chromatography (HPLC), with the aliskiren of any one of first aspect present invention (2S,
4R, 5R, 7S) diastereoisomer of configuration is reference substance, calculates the non-of (2S, 4R, 5R, 7S) configuration in aliskiren or its salt
The content of enantiomter.
The method of any one according to a third aspect of the present invention, wherein the high performance liquid chromatography is characterised by following
(1)~(5) one or more in item：
(1) chromatographic column is chiral column, preferably AD-H types, IC posts or OJ-3R posts, more preferably CHIRALPAK AD-H types hand
Property post (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, preferably n-hexane-absolute ethyl alcohol (containing 0.2% diethylamine) (90: 10)；
(3) Detection wavelength is 200~300nm, preferably 280nm；
(4) flow velocity is 0.5~1.5ml/min, preferably 1.0ml/min；
(5) column temperature is 25~35 DEG C, 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) determined with HPLC methods and contain a certain amount of compound 4R, the peak area of the reference substance solution of 5R-1；
2) peak area of the compound 4R, 5R-1 that contain in the sample that aliskiren or its salt are determined 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, 5R-1.
In embodiments of the invention, the computational methods of compound 4R, 5R-1 content are：Aliskiren hemifumarate
Middle compound
In formula, ASampleIt is compound 4R in need testing solution, the peak area of 5R-1；
WIt is rightIt is compound 4R, the sample weighting amount (mg) of 5R-1；
VSampleIt is the constant volume (ml) of need testing solution；
AIt is rightIt is compound 4R, the peak area of 5R-1；
VIt is rightIt is compound 4R, the constant volume (ml) of 5R-1；
WSampleIt is the sample weighting amount (mg) of need testing solution.
Fourth aspect present invention is related to a kind of method for detecting optical isomer content in aliskiren or its salt, the method
Using the Self-control method of the correction up factor in high performance liquid chromatography, with the aliskiren of any one of first aspect present invention
(2S, 4R, 5R, 7S) configuration diastereoisomer relative to aliskiren or its salt slope of standard curve ratio for correction
The factor, calculates the content of the diastereoisomer of (2S, 4R, 5R, 7S) configuration in aliskiren or its salt.
The method of any one according to a fourth aspect of the present invention, wherein the high performance liquid chromatography is characterised by following
(1)~(5) one or more in item：
(1) chromatographic column is chiral column, preferably AD-H types, IC posts or OJ-3R posts, more preferably CHIRALPAK AD-H types hand
Property post (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
It is n-hexane-absolute ethyl alcohol (containing 0.2% diethylamine) (90: 10)；
(3) Detection wavelength is 200~300nm, preferably 280nm；
(4) flow velocity is 0.5~1.5ml/min, preferably 1.0ml/min；
(5) column temperature is 25~35 DEG C, 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 reality of the invention
Apply in scheme, the Self-control method of the correction up factor refers to：
1) solution of serial various concentrations is prepared as sample with aliskiren or its salt and compound 4R, 5R-1, is drawn
Standard curve tries to achieve slope, and the correction factor of compound 4R, 5R-1 is calculated by slope；
2) peak area and compound 4R of the aliskiren contained in the sample that aliskiren or its salt are determined with HPLC methods,
The peak area of 5R-1；
3) content of compound 4R, 5R-1 in aliskiren or its salt is calculated by correction factor.
In embodiments of the invention, the computing formula of compound 4R, 5R-1 content is：
Compound in aliskiren or its salt
In formula, A4R5R-1It is compound 4R in need testing solution, the peak area of 5R-1；
f4R5R-1It is compound 4R, 5R-1 is relative to aliskiren or the correction factor of its salt；
AIt is rightIt is the peak area of aliskiren or its salt in contrast solution.
Wherein f4R5R-1=KAliskiren/K4R, 5R-1,
The computational methods of wherein K values are：As abscissa, peak area is that ordinate draws mark to concentration with array of linear solution
Directrix curve, obtains compound 4R, 5R-1 and aliskiren and its corresponding slope value K of salt.
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, 5R-1 is prepared, high performance liquid chromatography, the color of use is carried out
Spectral condition is：Chromatographic column is chiral column, preferably AD-H types, IC posts or OJ-3R posts, and more preferably CHIRALPAK AD-H types are chiral
Post (4.6mm × 250mm, 5 μm)；Mobile phase is n-hexane-absolute ethyl alcohol (containing 0.2%~0.5% diethylamine) (90~10 to 10
~90), preferably n-hexane-absolute ethyl alcohol (contain 0.2% diethylamine) (90: 10)；Detection wavelength is 200~300nm, preferably
280nm；Flow velocity is 0.5~1.5ml/min, preferably 1.0ml/min；Column temperature is 25~35 DEG C, preferably 30 DEG C；
Individually sample introduction and mixing sample introduction, then respectively obtain retention time, the guarantor of compound 4R, 5R-1 of aliskiren
Stay time and both separation degrees of data.
In specific embodiments of the present invention, the retention time of wherein aliskiren is about 21.1min, compound 4R,
The retention time of 5R-1 is about 25.1min, and both chromatographic peaks can reach preferably separation, its separating degree under the liquid-phase condition
It is 2.7.
The invention further relates to the diastereoisomer of (2S, 4R, 5R, 7S) configuration of the aliskiren of first aspect present invention
The purposes of optical isomer content in for detecting aliskiren or its salt.
The invention further relates to the diastereoisomer of (2S, 4R, 5R, 7S) configuration of the aliskiren of first aspect present invention
The purposes of quality control in production or preparation for aliskiren or its salt.
The invention further relates to the diastereoisomer of (2S, 4R, 5R, 7S) configuration of the aliskiren of first aspect present invention
Purposes for detecting the purity of aliskiren or its salt.
Brief description of the drawings
Fig. 1：The ESI-MS collection of illustrative plates of compound 4R, 5R-1
Fig. 2：Compound 4R, 5R-1's1H-NMR collection of illustrative plates
Fig. 3：Compound 4R, 5R-1's13C-NMR collection of illustrative plates
Fig. 4：Compound 4R, 5R-1's1H-1HCOSY collection of illustrative plates
Fig. 5：The HSQC collection of illustrative plates of compound 4R, 5R-1
Fig. 6：The HPLC collection of illustrative plates of aliskiren hemifumarate
Fig. 7：The HPLC collection of illustrative plates of compound 4R, 5R-1
Fig. 8：The HPLC collection of illustrative plates that compound 4R, 5R-1 mix with aliskiren hemifumarate
Specific 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 unreceipted specific in embodiment
Condition person, the condition advised according to normal condition or manufacturer is carried out.Agents useful for same or the unreceipted production firm person of instrument, are
Can by city available from conventional products.
In the examples below, described concentration, beCarried out on R-200 type Rotary Evaporators；Described
HPLC chromatogram, is to be determined on Shimadzu LC-10ATvp high performance liquid chromatographs, wherein using the hand of CHIRALPAK AD-H types
Property chromatographic column；Mass spectrum is determined on JEOL AccuTOF CS (JMS T100CS) type mass spectrograph；Nuclear magnetic resonance1H compose and13C spectrums exist
Determined on Bruker AVANCEIII400 type NMRs；Described optical activity, is surveyed on WZZ-2S type automatic polarimeters
It is fixed, wherein, the computing formula of the specific rotation of sample is：
D is the D lines of sodium spectrum in formula, and to determine length of tube (dm), α is the optical activity for measuring to l.
Embodiment 1(3S, 5R) -5- [(1R, 3S) -1- azidos -3- [[4- methoxyl groups -3- (3- methoxy propoxies) benzene
Base] methyl] -4- methyl amyls] and (the 3H)-furanone of dihydro -3- isopropyls -2 (3S, 5R, 1 ' R, 3 ' S-5) preparation
It is the initiation material of synthesis with compound (3S, 5R, 1 ' S, 3 ' S) -4 as follows, its chemical name is：(3S,
5R) -5- [the bromo- 3- of (1S, 3S) -1- [[4- methoxyl groups -3- (3- methoxy propoxies) phenyl] methyl] -4- methyl amyls] two
(the 3H)-furanone of hydrogen -3- isopropyls -2.Compound (3S, 5R, 1 ' S, 3 ' S) -4 is by embodiment C1 in patent WO02/02508
It is prepared by described method.
By compound (3S, 5R, 1 ' S, 3 ' S) -4 (10.0g, 20mmol), sodium azide (6.5g, 100mmol) and 3 third
In 80 DEG C of stirring reactions 48 hours, reactant mixture was cooled to room temperature to the mixture of glycol (80ml) and water (53ml), adds two
Ethylamino- -1- propylamine (8ml), reacts 3 hours then at being stirred at room temperature.Reactant mixture is poured into water (200ml), methyl- tert is used
Butyl ether (3 × 200ml) is extracted, and organic phase is successively with hydrochloric acid (200ml), 5% sodium acid carbonate (200ml), the water (3 of 0.5N
× 200ml), salt solution (200ml) washes.After organic phase is dried with anhydrous sodium sulfate (200g), filter and be concentrated under reduced pressure, column chromatography is pure
Change (column chromatography silica gel, mobile phase：Ethyl acetate/n-hexane=1: 5), obtains compound (3S, 5R, 1 ' R, 3 ' S- as follows
5) (6.9g, yield 75.0%) is pale yellow oil.1H-NMR (400MHz, CDCl3, ppm-1)δ：0.82-0.98 (m,
12H), 1.44-1.50 (m, 2H), 1.68-1.83 (m, 3H), 1.96-2.22 (m, 5H), 2.47-2.53 (m, 1H), 2.67-
2.71 (dd, 1H), 3.11-3.16 (m, 1H), 3.30 (s, 3H), 3.52 (t, 2H), 3.78 (s, 3H), 4.05 (t, 2H), 4.16-
4.21 (m, 1H), 6.59-6.92 (m, 3H) .ESI-MS (m/z)：484.3(MNa+).
Embodiment 2(2S, 4R, 5R, 7S)-N- (3- amino -2,2- dimethyl -3- oxygen propyl group) -5- azido -4- hydroxyls -
The preparation of 2- isopropyls -7- (4- methoxyl groups -3- (3- methoxy propoxies) benzyl) -8- methyl pelargonamide (4R, 5R-2)
By (3S, 5R, 1 ' R, 3 ' S-5) (2.0g, 4.3mmol), 3- amino -2,2- dimethylpropionamides (2.5g,
22mmol), after 2 hydroxy pyrimidine (0.5g, 5.2mmol), triethylamine (0.3g) and methyl tertiary butyl ether(MTBE) (25ml) mixing, stirring
Backflow dissolving.80-90 DEG C of bath temperature, stirring reaction 20 hours, evaporated under reduced pressure solvent adds dichloromethane (30ml) and water (25ml)
Stirring and dissolving, water is mutually extracted twice with dichloromethane (15ml), merges organic phase, and after washing 3 times with water (15ml), with nothing
Aqueous sodium persulfate is evaporated after drying, and obtains grease, and grease silica gel column chromatography purified into (mobile phase：Ethyl acetate/petroleum ether
=compound 4R, 5R-2 (1.9g, 78.3% yield) as follows 1/1) is obtained for colorless oil.1H-NMR (400MHz,
CDCl3, ppm-1)δ：0.88-0.98 (m, 12H), 1.20 (s, 6H), 1.44-1.63 (m, 3H), 1.69-1.93 (m, 5H),
2.05-2.31 (m, 4H), 2.65-2.70 (dd, 1H), 3.02-3.05 (m, 1H), 3.34-3.46 (m, 6H), 3.56 (t, 2H),
3.82 (s, 3H), 4.09 (t, 2H), 5.62 (brs, 1H), 6.05 (brs, 1H), 6.49 (brs, 1H), 6.70-6.79 (m, 3H)
.ESI-MS(m/z)：578.3(MH+).
Embodiment 3(2S, 4R, 5R, 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, 5R-1)
The compound (1.4g, 2.4mmol) of the 4R that will be obtained in embodiment 2,5R-2 is dissolved in methyl alcohol (50ml), and to this
Palladium carbon (10%, 0.3g) is added in solution.Hydrogen is passed through to this reaction solution, Hydrogen Vapor Pressure is kept for 2.0bar is stirred overnight.Will
Reactant mixture is filtered, and saturated sodium bicarbonate solution and salt solution are sequentially added in filtrate carries out extracting operation, and organic layer is through drying
After concentrate, the residue for obtaining carries out silica gel column chromatography purifying (mobile phase：Ethanol/ethyl acetate=1/1), evaporated under reduced pressure solvent
4R is obtained, 5R-1 (0.9g, 69.0% yield), is white solid.
Compound 4R, 5R-1 to gained carry out angle-of-rotation measuring：This product about 0.2g is taken, it is accurately weighed, put 25ml measuring bottles
In, plus ethanol makes to dissolve and be diluted to scale, shakes up to obtain test liquid.Take test liquid and optical activity is determined on automatic polarimeter, weight
Re-reading number 3 times, takes arithmetic mean of instantaneous value.The compound 4R, 5R-1 and aliskiren of measure are (by the China Resources Double-Crane Pharmaceutical Co., Ltd limited public affairs of share
Department prepares and provides according to the method described in the embodiment G1 in patent US7,009,078) optical activity result such as table 1
It is shown.
Table 1
Computing formula according to specific rotation is calculated, and the specific rotation of compound 4R, 5R-1 is [α]D 20=+22.9 ° of (ethanol, C
=8.33mg/ml)；Used as reference, the specific rotation of aliskiren is [α]D 20=-11.4 ° (ethanol, C=8.21g/m1).
To compound 4R, the 5R-1 of gained, carry out mass spectrum (Fig. 1), proton nmr spectra (Fig. 2), carbon spectrum (Fig. 3),1H-1HCOSY spectrums (Fig. 4), the measure of hsqc spectrum (Fig. 5), as a result find：
1H-NMR (400MHz, CDCl3, ppm-1) δ：0.86-0.99 (m, 12H), 1.04-1.07 (m, 1H), 1.20 (s,
6H), 1.47-1.48 (m, 1H), 1.58-1.88 (m, 5H), 2.00-2.23 (m, 4H), 2.48-2.50 (m, 1H), 2.64-2.69
(dd, 1H), 3.10-3.15 (m, 1H), 3.33-3.40 (m, 5H), 3.57 (t, 2H), 3.83 (s, 3H), 4.09 (t, 2H), 5.75
(brs, 1H), 6.45 (brs, 1H), 6.55 (brs, 1H), 6.67-6.80 (m, 3H)
13C-NMR (400MHz, CDCl3, ppm-1) δ：17.8,19.7,20.1,20.2,24.0,24.2,29.1,29.6,
30.7,34.2,35.2,36.6,42.8,43.1,47.1,51.7,54.1,56.0,58.6,66.1,69.3,73.8,111.8,
114.5,121.3,134.2,147.6,148.2,176.4,179.7.
ESI-MS(m/z)：552.4(MH+), 574.4 (MNa+)。
1H-1The result of HCOSY tests is shown in Fig. 4, and the result of HSQC tests is shown in Fig. 5.Result above with target compound
Chemical constitution is consistent.
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：Example 3 gained compound 4R, appropriate 5R-1, accurately weighed, addition n-hexane：
Absolute ethyl alcohol (1: 1) dissolves and is settled to scale, obtains every ml 4R containing compound, the solution of 5R-10.5mg.
The preparation of need testing 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 is prepared and provided) it is appropriate, it is accurately weighed, add n-hexane：
Absolute ethyl alcohol (1: 1) dissolves and is settled to scale, obtains solution of every ml containing aliskiren hemifumarate 0.2mg.
Plus the preparation of the mixed solution of compound 4R, 5R-1：Precision weighs aliskiren hemifumarate and chemical combination respectively
Thing 4R, appropriate 5R-1, add n-hexane：Absolute ethyl alcohol (1: 1) dissolves and is settled to scale.
Operation：It is accurate respectively to draw 10 μ l reference substance solutions, need testing solution and add the mixed solution of compound 4R, 5R-1
Injection liquid chromatograph, record chromatogram (Fig. 6, Fig. 7, Fig. 8).Compound 4R, 5R-1, aliskiren are in above-mentioned chromatogram
Retention time respectively may be about 25.1min, 21.1min, and both separating degrees are about 2.7.
External standard method calculates the content of compound 4R, 5R-1 in need testing solution：If need testing solution is in compound 4R, 5R-1
Position there is corresponding chromatographic peak, according to the corresponding peak area of reference substance solution, in calculating need testing solution using external standard method
The content of compound 4R, 5R-1.
Computing formula：
Compound in aliskiren hemifumarate
In formula, ASampleIt is compound 4R in need testing solution, the peak area of 5R-1；
WIt is rightIt is compound 4R, the sample weighting amount (mg) of 5R-1；
VSampleIt is the constant volume (ml) of need testing solution；
AIt is rightIt is compound 4R, the peak area of 5R-1；
VIt is rightIt is compound 4R, the constant volume (ml) of 5R-1；
WSampleIt is the sample weighting amount (mg) of need testing solution.
Specific data are as follows：
| Project | Numerical value |
| 5.39mg | |
| 10.73mg | |
| 282825 | |
| 31641 | |
| 10ml | |
| 50ml |
| Compound 4R in need testing solution, 5R-1 content % | Do not detect |
| Compound 4R in mixed solution, 5R-1 content % | 28.1% |
Embodiment 5Light in the Self-control method method detection aliskiren and its salt of the correction up factor in high performance liquid chromatography
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, 5R-1 array of linear solution：Example 3 gained compound 4R, appropriate 5R-1, precision claim
It is fixed, add n-hexane：Absolute ethyl alcohol (1: 1) dissolves and is settled to scale, obtains every ml 4R containing compound, the line of 5R-10.5mg
Property stock solution.Stepwise dilution obtain concentration be 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
Medicine company limited company prepares and provides according to patent US7, the method described in embodiment G1 in 009,078) it is appropriate,
It is accurately weighed, add n-hexane：Absolute ethyl alcohol (1: 1) dissolves and is settled to scale, obtains every ml fumaric acid containing aliskiren half
The linear stock solution of salt 0.5mg.Stepwise dilution obtain concentration be 0.1,0.2,0.3,0.4, the array of linear solution of 0.5mg/ml.
The preparation of need testing solution：Take aliskiren hemifumarate appropriate, it is accurately weighed, add n-hexane：Anhydrous second
Alcohol (1: 1) dissolves and is settled to scale, obtains solution of every ml containing aliskiren hemifumarate 0.2mg.
The preparation of contrast solution：Precision measures need testing solution 5ml, is placed in 10ml measuring bottles, adds n-hexane：Anhydrous second
Alcohol (1: 1) dissolves and is settled to scale.
Plus the mixed solution of compound 4R, 5R-1：Precision weighs aliskiren hemifumarate and compound 4R respectively,
Appropriate 5R-1, adds n-hexane：Absolute ethyl alcohol (1: 1) dissolves and is settled to scale.
Chromatographic run：Precision draws each μ l of linear solvent 10 injections liquid chromatograph, records chromatogram.It is molten with array of linear
The concentration of liquid is abscissa, and peak area is that ordinate draws standard curve, obtains compound 4R, 5R-1 and aliskiren and its salt
Corresponding slope value K.
The correction factor of compound 4R, 5R-1 relative to aliskiren hemifumarate
F=KAliskiren/K4R, 5R-1
It is 1.0055 that compound 4R, 5R-1 are calculated relative to the correction factor f values of aliskiren and its salt.
It is accurate respectively to draw need testing solution and the μ l of contrast solution 10 injection liquid chromatographs, record chromatogram.If right
There is chromatographic peak in compound 4R, the 5R-1 positions answered, then its content is：
Compound in aliskiren hemifumarate
In formula, A4R5R-1It is compound 4R in need testing solution, the peak area of 5R-1；
f4R5R-1It is compound 4R, correction factors (1.0055) of the 5R-1 relative to aliskiren hemifumarate；
AIt is rightIt is the peak area of aliskiren hemifumarate in contrast solution.
Specific data are as follows：
| Project | Numerical value |
| 31641 | |
| 56695 | |
| Compound 4R in need testing solution, 5R-1 content % | Do not detect |
| Compound 4R, 5R-1 content % | 28.0% |
Although specific embodiment of the 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 guarantor of the invention
Within the scope of shield.Four corner of the invention is given by appended claims and its any equivalent.
Claims (9)
1. the preparation method of the diastereoisomer of (2S, 4R, 5R, 7S) configuration of aliskiren, it is comprised the following steps：
A) it is the initiation material of synthesis with compound (3S, 5R, 1 ' S, 3 ' S) -4 as follows, its chemical name is：(3S,
5R) -5- [(1 ' S, 3 ' S) bromo- 3- of -1- [[4- methoxyl groups -3- (3- methoxy propoxies) phenyl] methyl] -4- methyl amyls] two
(the 3H)-furanone of hydrogen -3- isopropyls -2；
B) compound (3S, 5R, 1 ' S, 3 ' S) -4 and reaction of sodium azide are obtained into compound as follows (3S, 5R, 1 ' R, 3 '
S)-5；Specifically reaction condition is：Compound (3S, 5R, 1 ' S, 3 ' S) -4 10.0g, sodium azide 6.5g and tripropylene glycol 80ml
And the mixture of water 53ml, in 80 DEG C of stirring reactions 48 hours, reactant mixture is cooled to room temperature, adds diethylin -1- propylamine
8ml, reacts 3 hours then at being stirred at room temperature；Reactant mixture is poured into water 200ml, is extracted with 3 × 200ml of methyl tertiary butyl ether(MTBE)
Take, organic phase is washed with the hydrochloric acid 200ml of 0.5N, 5% sodium acid carbonate 200ml, 3 × 200ml of water, salt solution 200ml successively, organic
After mutually being dried with anhydrous sodium sulfate 200g, filter and be concentrated under reduced pressure, silica gel column chromatography purifying, wherein mobile phase be ethyl acetate/
N-hexane=1:5, obtain 6.9g pale yellow oils, yield 75.0%；
C) compound that compound (3S, 5R, 1 ' R, 3 ' S) -5 and 3- amino -2,2- dimethyl propylamines are reacted as follows
4R,5R-2；
D) by compound 4R, 5R-2 obtains compound 4R, 5R-1 by catalytic hydrogenation；
Wherein, the molecular structure such as formula 4R of the diastereoisomer of (2S, 4R, 5R, 7S) configuration of aliskiren, shown in 5R-1,
Chemical name is：(2S, 4R, 5R, 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,
2. the preparation method of claim 1, by compound 4R in step d), method preparedization that 5R-2 passes through palladium carbon catalytic hydrogenation
Compound 4R, 5R-1.
3. the preparation method of claim 1 or 2, it is characterised in that one or more in the item of (1)~(8) below：
(1) in step c), reaction dissolvent is selected from methyl tertiary butyl ether(MTBE), tetrahydrofuran, 1-METHYLPYRROLIDONE and chloroform；
(2) in step c), organic base is added in the reactive mixture, wherein, described organic base is selected from pyridine, 2- hydroxyl pyrroles
Pyridine, triethylamine and amantadine；
(3) in step c), reaction temperature is 40~110 DEG C；
(4) in step c), water and a kind of solvent is added to carry out extracting operation after completion of the reaction, wherein described solvent is selected from methyl
Tertbutyl ether, dichloromethane and ethyl acetate；Organic layer is concentrated after drying, and residue by silicagel column chromatographic purifying obtains compound
4R,5R-2；
(5) in step d), described palladium carbon is containing 5% to 10% palladium carbon；
(6) in step d), the solvent of compound 4R, 5R-2 is selected from methyl tertiary butyl ether(MTBE), ethanol, methyl alcohol, tetrahydrofuran, acetic acid second
Ester, ethyl ester isopropyl ester and dichloromethane；
(7) in step d), wherein the pressure of catalytic hydrogenation is 1~10bar；
(8) in step d), catalytic hydrogenation sequentially adds saturated sodium bicarbonate solution and salt solution and carries out extracting operation after finishing,
Organic layer is concentrated after drying, and residue by silicagel column chromatographic purifying obtains compound 4R, 5R-1.
4. the preparation method of claim 3, reaction dissolvent is methyl tertiary butyl ether(MTBE) in wherein step c).
5. the preparation method of claim 3, the organic base added in reactant mixture in wherein step c) is 2 hydroxy pyrimidine.
6. the preparation method of claim 3, reaction temperature is 60~100 DEG C in wherein step c).
7. the preparation method of claim 3, reaction temperature is 70~90 DEG C in wherein step c).
8. the preparation method of claim 3, the solvent of compound 4R, 5R-2 is methyl alcohol or tetrahydrofuran in wherein step d).
9. the preparation method of claim 3, the pressure of catalytic hydrogenation is 1~3bar in wherein step d).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002008172A1 (en) * | 2000-07-25 | 2002-01-31 | Speedel Pharma Ag | Process for the preparation of substituted octanoyl amides |
| US7009078B1 (en) * | 1999-07-29 | 2006-03-07 | Speedel Pharma Ag | Production of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-arly-octanoylamides |
| CN102164903A (en) * | 2008-07-23 | 2011-08-24 | 帝斯曼知识产权资产管理有限公司 | Synthesis routes to 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides |
| CN104058990A (en) * | 2013-03-21 | 2014-09-24 | 博瑞生物医药技术(苏州)有限公司 | Separation analysis method of aliskiren and salts thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7009078B1 (en) * | 1999-07-29 | 2006-03-07 | Speedel Pharma Ag | Production of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-arly-octanoylamides |
| WO2002008172A1 (en) * | 2000-07-25 | 2002-01-31 | Speedel Pharma Ag | Process for the preparation of substituted octanoyl amides |
| CN102164903A (en) * | 2008-07-23 | 2011-08-24 | 帝斯曼知识产权资产管理有限公司 | Synthesis routes to 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides |
| CN104058990A (en) * | 2013-03-21 | 2014-09-24 | 博瑞生物医药技术(苏州)有限公司 | Separation analysis method of aliskiren and salts thereof |
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