CN100488969C - Optically active substituted oxyphosphonate salt acetate and its use - Google Patents
Optically active substituted oxyphosphonate salt acetate and its use Download PDFInfo
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- CN100488969C CN100488969C CNB2005100308723A CN200510030872A CN100488969C CN 100488969 C CN100488969 C CN 100488969C CN B2005100308723 A CNB2005100308723 A CN B2005100308723A CN 200510030872 A CN200510030872 A CN 200510030872A CN 100488969 C CN100488969 C CN 100488969C
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- propoxy
- acetate
- phosphinyl
- oxopropoxy
- methyl isophthalic
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- -1 oxyphosphonate salt acetate Chemical class 0.000 title abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 58
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- 230000003287 optical effect Effects 0.000 claims abstract description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 50
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 claims description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 238000001640 fractional crystallisation Methods 0.000 claims description 2
- 239000011260 aqueous acid Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract 9
- 229910052760 oxygen Inorganic materials 0.000 abstract 3
- 239000001301 oxygen Substances 0.000 abstract 3
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 abstract 3
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 abstract 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 238000001953 recrystallisation Methods 0.000 description 11
- 238000000967 suction filtration Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 229960001880 fosinopril sodium Drugs 0.000 description 6
- TVTJZMHAIQQZTL-WATAJHSMSA-M sodium;(2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylate Chemical compound [Na+].C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C([O-])=O)CCCC1=CC=CC=C1 TVTJZMHAIQQZTL-WATAJHSMSA-M 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 230000005526 G1 to G0 transition Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229960002429 proline Drugs 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XRZWVSXEDRYQGC-ZJUUUORDSA-N (2s,4s)-4-cyclohexylpyrrolidin-1-ium-2-carboxylate Chemical compound C1N[C@H](C(=O)O)C[C@H]1C1CCCCC1 XRZWVSXEDRYQGC-ZJUUUORDSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- LKHYFCSSVZVVNF-UHFFFAOYSA-N ethyl hexanoate;sodium Chemical compound [Na].CCCCCC(=O)OCC LKHYFCSSVZVVNF-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 238000000711 polarimetry Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
This invention provides a salt that is produced by [(R)-[(1S)-2-methyl-1- (1-keto-propoxy)propoxy](4-benzene butyl) oxygen phosphino]acetic acid and 10,11-di-H Cinchonidine, its structure is shown by formula(1). This invention also provides preparation of using this salt to optically split racemoid which consists of [(R)-[(1S)-2-methyl-1-(1-keto-propoxy)propoxy](4-benzene butyl) oxygen phosphino] acetic acid and [(S)-[(1R)-2-methyl-1-(1-keto-propoxy) propoxy](4- benzene butyl) oxygen phosphino] acetic acid. Compared with present resolution preparation, the yield and optical purity of resolution is obviously raised, it needs not recryst many times to depurate, and dosis of resolution agent is reduced.
Description
Technical field
The present invention relates to split in the chemical field method of enantiomeric mixture, be specifically related to by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and 10, the salt that 11-dihydro cinchovatin generates, and the method for carrying out the high-level efficiency optical resolution by the described replacement phosphinyl of this salt pair acetate.
Background technology
The structural formula of [(R)-[(1S)-2-methyl isophthalic acid-(1 oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate is respectively as shown in the formula shown in (2) and (3), their polarimetry nature is opposite, constitutes racemic modification under the equivalent condition together.Wherein [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate is the important intermediate of preparation angiotensin-converting enzyme (ACE) inhibitor fosinopril sodium (fosinopril sodium).
Annotate: alphabetical S in the chemical structural formula and R are used to indicate the configuration of chiral centre.
The racemoid of being made up of [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate of the present invention can be according to U.S. Pat 4873356 or the described step preparation of US5008399.
Fosinopril sodium, chemistry (4S)-4-cyclohexyl by name-1-[[(R)-[(1S)-and 2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphono] acetyl]-the L-Sodium proline, can be used for treating hypertension and heart failure.The chemical structural formula of fosinopril sodium is as the formula (9):
Annotate: alphabetical S in the chemical structural formula and R are used to indicate the configuration of chiral centre.
U.S. Pat 4,873,356 and US5,008,399 to have disclosed with the cinchovatin shown in the chemical formula (6) be resolving agent, the method for the racemoid that optical resolution is made up of [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate.
This method can make formula (2) compound and cinchovatin generate as shown in the formula the salt shown in (7) and separate out from split mother liquor, carries out purifying by recrystallization then.
But there is deficiency in actual applications in this method, salt shown in the formula (7) that resulting formula (2) compound and cinchovatin generate need just can obtain pure product through recrystallization repeatedly, for example, successively with re-crystallizing in ethyl acetate 1 time, with acetonitrile recrystallization 2 times with re-crystallizing in ethyl acetate 3 times.Certainly will reduce resolution yield like this, increase solvent consumption, time consumption and energy consumption.
Summary of the invention
For the method for optical resolution yield that overcomes the existing racemoid of forming by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate not high, and defectives such as solvent consumption is many propose the present invention.
It is a kind of by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and 10, the salt that 11-dihydro cinchovatin generates that one object of the present invention is to provide.Can carry out high efficiency optical resolution to described replacement phosphinyl acetate by this salt, the resolving agent consumption that is used to split is few, is fit to suitability for industrialized production.
A further object of the invention be to provide utilize that above-mentioned [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and 10,11-dihydro cinchovatin generates the method for the racemoid formed by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate of salt optical resolution.
Provided by the invention by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and 10, the salt that 11-dihydro cinchovatin generates, its structure is as shown in the formula shown in (1):
Method of the present invention, adopt 10 shown in the following formula (4), 11-dihydro cinchovatin is as resolving agent, the racemoid that optical resolution is made up of [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (the 4-benzene butyl) phosphinyl] acetate shown in [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate shown in the formula (2) and the formula (3).
[(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and 10, the salt that 11-dihydro cinchovatin generates has very high optical purity, it can be without refining, directly acidifying free resultant [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate; Perhaps, also can be with it through behind 1 recrystallization, acidifying is free to obtain higher [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (the 4-benzene butyl) phosphinyl] acetate of purity.
Particularly, method provided by the invention comprises racemoid and the resolving agent of forming by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate 10,11-dihydro cinchovatin mixes in appropriate solvent, form a pair of diastereomeric salt, promptly by formula (2) compound, formula (3) compound is respectively with 10, the salt that 11-dihydro cinchovatin generates, according to the difference of their solubleness, can separate by the method for fractional crystallization.
By formula (2) compound [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and 10, the salt solubility that 11-dihydro cinchovatin generates is less, separates out from solution; By formula (3) compound [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and 10, the salt solubility that 11-dihydro cinchovatin generates is bigger, stays in the solution.Collection separate out by formula (2) compound and 10, the salt that 11-dihydro cinchovatin generates is through acidifying is free can obtain [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate.
The optical activity resolving agent 10 that is adopted among the present invention, 11-dihydro cinchovatin are known compound [Helv.Chim.Acta., 1932,15:557 as the formula (4); J.Am.Chem.Soc., 2000,122 (51): 12675], have another name called: 10, the 11-dihydro-(8 α, 9R)-cinchonane-9-alcohol.
10,11-dihydro cinchovatin can prepare by the cinchovatin shown in the optionally partial reduction formula (6).Reaction formula is as follows:
When splitting, resolving agent 10,11-dihydro cinchovatin is 2:1 to 0.2:1 with the mol ratio of the racemoid of being made up of formula (2) and formula (3) compound that is split, more preferably 1:1 to 0.5:1 is preferably 0.5:1 to 0.8:1.Solvent for use during fractionation can be ester class (as ethyl acetate, butylacetate etc.), ketone (as acetone, methyl ethyl ketone etc.), ethers (as tetrahydrofuran (THF)), have the alcohols (as methyl alcohol, ethanol, Virahol, propyl carbinol etc.) of 1 to 4 carbon atom) or the mixture of above-mentioned solvent.Preferred solvent is an ethyl acetate.The fractured operation temperature range by 0 ℃ to the boiling point of employing solvent.
From split mother liquor, separate out by formula (2) compound and 10, salt shown in the formula (1) that 11-dihydro cinchovatin generates, may be mixed with by formula (3) compound and 10, salt or other impurity that 11-dihydro cinchovatin generates can be pulled an oar by recrystallization or solvent and be improved optical purity and chemical purity.Can be by usual method by formula (2) compound and 10, dissociate in the salt that 11-dihydro cinchovatin generates [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate.For example, will be by formula (2) compound and 10, the salt that 11-dihydro cinchovatin generates joins in the aqueous solution of mineral acid (example hydrochloric acid, sulfuric acid, phosphoric acid etc.), makes formula (2) compound free.Formula (2) compound that dissociates can be used organic solvent (as ethyl acetate, methylene dichloride, toluene etc.) extraction separation.Resolving agent 10,11-dihydro cinchovatin then generates water miscible salt with acid and stays in the acid liquid, can dissociate 10 by the alkalization acid liquid, and 11-dihydro cinchovatin is separated out it and is reclaimed from water, and the rate of recovery can reach 98%.
The optical purity of [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate that fractionation obtains can be checked by chiral stationary phase HPLC.Chromatographic condition is chiral stationary phase: Daicel Chiralpak AD-RH post (150*4.6mm, 5 μ m), moving phase: ethanol/50mmol/L H
3PO
4-KH
2PO
4(pH 2.0)=70/30 (v/v), flow velocity: 0.3mL/min detects wavelength: 254nm, column temperature: room temperature.
[(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate that fractionation obtains, can be according to U.S. Pat 5,008,399 or EP442,378 disclosed method and the trans-4-cyclohexyl shown in the formula (8)-L-proline(Pro) condensation prepared fosinopril sodium.Chemical equation is as follows:
The invention has the advantages that: adopt above-mentioned method for splitting, compound and 10 shown in the formula that obtains (2), salt has very high optical purity shown in the formula (1) that 11-dihydro cinchovatin generates: it is without refining, and directly the ee value of free gained formula (2) compound of acidifying is 97.3%; Perhaps, through behind 1 recrystallization, the ee value of free gained formula (2) compound of acidifying can reach 99.8%.Adopt this method, can obviously improve resolution yield, and reduce solvent consumption.
The present invention be advantageous in that: resolving agent 10,11-dihydro cinchovatin consumption is less, and can reclaim on simple and effective ground, helps reducing cost, and reduces environmental pollution.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.Among each embodiment, symbols such as (1), (2) are represented above represented compounds such as chemical formula (1), (2) separately.
The fusing point instrument: YRT-3 drug melting point instrument, polarimeter: Perkin Elmer Polarimeter 341, the HPLC instrument is made up of assemblies such as Waters 510 pumps, 484 UV-detector.
Embodiment 1:
With 10,11-dihydro cinchovatin (4) (3.56g, 12mmol) and ethyl acetate (30ml) be mixed into suspension liquid, add the racemoid (7.68g that is formed by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (2) and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (3) then, 20mmol), under agitation reflux to solid all dissolves, while hot suction filtration.In filtrate, add crystal seed, cooling crystallization.Suction filtration, vacuum-drying obtains by (2) and 10, and the salt (1) that 11-dihydro cinchovatin (4) generates is white solid (4.3g): fusing point 125-126 ℃, [α]
20 D-31.7 ° (c=1, MeOH).It is free to get the acidifying of wherein a part of usefulness dilute hydrochloric acid, gets oily matter (2) with dichloromethane extraction then: [α]
20 D+ 45.2 ° (c=1, EtOAc), it is 97.3% that chiral stationary phase HPLC measures the ee value.
Get above-mentioned by (2) and 10, the salt (1) that 11-dihydro cinchovatin (4) generates recrystallization 1 time in ethyl acetate, obtain purifying by (2) and 10, the salt (1) of 11-dihydro cinchovatin (4) generation is white solid: 125.5-126.5 ℃ of fusing points, [α]
20 D-31.8 ° (c=1, MeOH).
Ultimate analysis: C
19H
29O
6PC
19H
24N
2O
| ％ | C | H | N |
| Calculated value | 67.04 | 7.85 | 4.12 |
| Measured value | 67.08 | 7.73 | 4.14 |
Get above-mentioned purifying by (2) and 10, the salt (1) that 11-dihydro cinchovatin (4) generates, free with the dilute hydrochloric acid acidifying, use dichloromethane extraction then, obtain oily matter (2): [α]
20 D+ 45.1 ° (c=1, EtOAc), it is 99.8% that chiral stationary phase HPLC measures the ee value.
Embodiment 2:
With 10,11-dihydro cinchovatin (4) (7.11g, 24mmol) and ethyl acetate (68ml) be mixed into suspension liquid, add the racemoid (11.53g that is formed by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (2) and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (3) then, 30mmol), being heated with stirring to solid all dissolves.Cooling crystallization.Suction filtration, vacuum-drying obtains by (2) and 10, and the salt (1) that 11-dihydro cinchovatin (4) generates is white solid (5.88g): 122.1-125.4 ℃ of fusing points.
Get above-mentioned by (2) and 10, the salt (1) that 11-dihydro cinchovatin (4) generates, recrystallization is 1 time in ethyl acetate, obtain purifying by (2) and 10, the salt (1) of 11-dihydro cinchovatin (4) generation is white solid: 123.4-126.5 ℃ of fusing points.
Embodiment 3:
With 10,11-dihydro cinchovatin (4) (2.96g, 10mmol) and ethyl acetate (60ml) be mixed into suspension liquid, add the racemoid (7.68g that is formed by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (2) and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (3) then, 20mmol), being heated with stirring to solid all dissolves.Cooling crystallization.Suction filtration, vacuum-drying obtains by (2) and 10, and the salt (1) that 11-dihydro cinchovatin (4) generates is white solid (3.13g): 124.9-126 ℃ of fusing points, [α]
20 D-29.6 ° (c=1, MeOH).
Embodiment 4:
With 10,11-dihydro cinchovatin (4) (0.45g, 1.5mmol) and acetone (5ml) be mixed into suspension liquid, add the racemoid (0.96g that is formed by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (2) and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (3) then, 2.5mmol), be heated with stirring to solid and all dissolve.Cooling crystallization.Suction filtration, vacuum-drying obtains by (2) and 10, and the salt (1) that 11-dihydro cinchovatin (4) generates is white solid (0.49g): 125-126.4 ℃ of fusing points, [α]
20 D-32 ° (c=1, MeOH).
Embodiment 5:
With 10,11-dihydro cinchovatin (4) (7.1g, 24mmol) and ethyl acetate (60ml) be mixed into suspension liquid, add the racemoid (15.4g that is formed by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (2) and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (3) then, 40mmol), under agitation reflux to solid all dissolves.In gained solution, add crystal seed, cooling crystallization.Suction filtration, vacuum-drying obtains by (2) and 10, and the salt (1) that 11-dihydro cinchovatin (4) generates is white solid (8.63g): fusing point 125-126 ℃.
Get above-mentioned by (2) and 10, the salt that 11-dihydro cinchovatin (4) generates (5.43g, 8mmol) free with the dilute hydrochloric acid acidifying, get oily matter (2) with dichloromethane extraction then.Merge the sour water layer, add ammoniacal liquor (25%) and regulate pH to 9.8, separate out white solid.Suction filtration, vacuum-drying is reclaimed and is obtained 10,11-dihydro cinchovatin (4) (6.96g, the rate of recovery 98%): fusing point 235-236 ℃.
Above-mentioned oily matter (2) is dissolved in anhydrous methylene chloride (60ml), and (0.81g 8mmol), is chilled to-10 ℃ then, and (0.96g 8mmol), stirred 1 hour to add pivalyl chloride to add pyridine (3) and triethylamine.(1.87g 8mmol), rises to 25 ℃ and stirred 2 hours to add trans-4-cyclohexyl-L-proline hydrochlorate again.After reaction solution usefulness dilute hydrochloric acid (3*60ml) washing, concentrating under reduced pressure gets oily matter.
Above-mentioned oily matter is dissolved in acetone (60ml), adds the solution (8ml) of 1mol/L Sodium Ethylhexanoate in the acetone of moisture 13.56% (v/v) again.Stirring and crystallizing 2 hours.Suction filtration, with acetone (17ml) washing, vacuum-drying gets fosinopril sodium (9) (3.7g): fusing point 193-194 ℃, [α]
20 D-5.1 ° (c=2, MeOH).
Comparative example:
With cinchovatin (6) (10g, 34mmol) and ethyl acetate (60ml) be mixed into suspension liquid, add the racemoid (13g that is formed by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (2) and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate (3) then, 34mmol), under agitation reflux to solid all dissolves, while hot suction filtration.In filtrate, add crystal seed, cooling crystallization.Suction filtration obtains the salt (7) by (2) and cinchovatin (6) generation, is near-white solid (weight in wet base 12g).With the above-mentioned salt (7) that generates by (2) and cinchovatin (6) with ethyl acetate and each recrystallization of acetonitrile 1 time, obtain purifying by the salt (7) of (2) and cinchovatin (6) generation (7g).
Get the salt (7) by (2) and cinchovatin (6) generation of above-mentioned purifying, free with the dilute hydrochloric acid acidifying, use dichloromethane extraction then, get oily matter (2): it is 95.4% that chiral stationary phase HPLC measures the ee value.
Relatively
| The mol ratio of resolving agent and the racemoid of forming by (2) and (3) | The recrystallization number of times | (2) and the yield (%) of the salt that generates of resolving agent | Ee value (%) | |
| Embodiment 1 | 0.6：1 | 0 | 63 | 97.3 |
| Comparative example | 1：1 | 2 | 61 | 95.4 |
The method of conclusion: embodiment 1 is compared with the method for comparative example, has the following advantages: the resolving agent consumption is few, need not recrystallization, and yield and optical purity are all higher.
Claims (7)
1. structural formula is as shown in the formula (1)
Shown by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and 10, the salt that 11-dihydro cinchovatin generates.
2. utilize to generate the method for the racemoid that the described salt optical resolution of claim 1 is made up of [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate, it is characterized in that comprising the following steps:
1) racemoid that will form by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate, with 10,11-dihydro cinchovatin generates diastereomeric salt in solvent;
2) isolate by [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and 10, the salt that 11-dihydro cinchovatin generates by fractional crystallization;
3) the free step 2 of the acidifying) salt that is generated, obtain [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate.
3. method according to claim 2, wherein resolving agent 10, and 11-dihydro cinchovatin is 0.8: 1 to 0.5: 1 with the mol ratio of the racemoid of being made up of [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and [(S)-[(1R)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate.
4. method according to claim 2, solvent for use is the mixture of ethyl acetate, acetone or above-mentioned solvent when wherein splitting.
5, method according to claim 4, solvent for use is an ethyl acetate when wherein splitting.
6. method according to claim 2, wherein the fractured operation temperature range by 0 ℃ to the boiling point of employing solvent.
7. method according to claim 2 is at completing steps 3) afterwards, comprise also by what alkalization was generated and contain resolving agent 10 that the aqueous acid of 11-dihydro cinchovatin comes free and reclaims 10, the step of 11-dihydro cinchovatin.
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| IT1394407B1 (en) * | 2009-05-25 | 2012-06-15 | Dipharma Francis Srl | PROCEDURE FOR THE PREPARATION OF FOSINOPRIL AND ITS INTERMEDIATES |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4873356A (en) * | 1987-09-30 | 1989-10-10 | E. R. Squibb & Sons, Inc. | Method for preparing phosphinic acids used in preparing ace inhibitors and intermediates produced thereby |
| US5008399A (en) * | 1990-01-19 | 1991-04-16 | E. R. Squibb & Sons, Inc. | Diastereoselective preparation of phosphinate esters |
| CN1955176A (en) * | 2005-10-27 | 2007-05-02 | 上海医药工业研究院 | Optical Resolution Method of Substituted Phosphinylacetic Acids |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4873356A (en) * | 1987-09-30 | 1989-10-10 | E. R. Squibb & Sons, Inc. | Method for preparing phosphinic acids used in preparing ace inhibitors and intermediates produced thereby |
| US5008399A (en) * | 1990-01-19 | 1991-04-16 | E. R. Squibb & Sons, Inc. | Diastereoselective preparation of phosphinate esters |
| CN1955176A (en) * | 2005-10-27 | 2007-05-02 | 上海医药工业研究院 | Optical Resolution Method of Substituted Phosphinylacetic Acids |
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