CN1955176A - Optical separation method substituting oxyphosphonate acetate - Google Patents
Optical separation method substituting oxyphosphonate acetate Download PDFInfo
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- CN1955176A CN1955176A CN 200510030873 CN200510030873A CN1955176A CN 1955176 A CN1955176 A CN 1955176A CN 200510030873 CN200510030873 CN 200510030873 CN 200510030873 A CN200510030873 A CN 200510030873A CN 1955176 A CN1955176 A CN 1955176A
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- acetate
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- phosphinyl
- oxopropoxy
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Abstract
This invention provides a optical resolution preparation that substitutes oxygen phosphino-acetic acid, concretely relating to optical resolution preparation of 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. The preparation of this invention uses 10,11-di-H Cinchonidine shown in following formula(1) as resolution agent, compared with present resolution preparation, the yield and optical purity of resolution is obviously raised, it need 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 split the method that replacement phosphinyl acetate obtains its single enantiomer.More specifically, the present invention relates to the method for optical resolution of 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.
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 following defective in actual applications in this method: the 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.
The object of the present invention is to provide a kind of replacement phosphinyl acetate of resolution of racemic to obtain the method for its single enantiomer, utilize above-mentioned [(R)-[(1S)-2-methyl isophthalic acid-(1-oxopropoxy) propoxy-] (4-benzene butyl) phosphinyl] acetate and 10, the racemoid that the salt optical resolution that 11-dihydro cinchovatin generates 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 splits efficient and is higher than existing method for splitting, and the resolving agent consumption that is used to split is few, is fit to suitability for industrialized production.
The method according to this invention, adopt 10 shown in the following formula (1), 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 as the formula (4), have very high optical purity, it can be without refining, free resultant formula (2) compound of direct acidifying; Perhaps, also can be with formula (4) compound through behind 1 recrystallization, the free higher formula of purity (2) compound that obtains of acidifying.
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, their structural formula is as shown in the formula shown in (4) and the formula (5).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 that 11-dihydro cinchovatin generates, promptly the solubleness of formula (4) compound 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 shown in the formula (5) that 11-dihydro cinchovatin generates is bigger, stays in the solution.Collection separate out by formula (2) compound and 10, salt shown in the formula (4) 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 (1); 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, and 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 (4) that 11-dihydro cinchovatin generates, may be mixed with by formula (3) compound and 10, salt or other impurity shown in the formula (5) 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 shown in the formula (4) 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, salt joins in the aqueous solution of mineral acid (example hydrochloric acid, sulfuric acid, phosphoric acid etc.) shown in the formula (4) that 11-dihydro cinchovatin generates, and 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(pH2.0)=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 (4) 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 (1) (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 (4) that 11-dihydro cinchovatin (1) 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 (1) 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 (4) that 11-dihydro cinchovatin (1) generates recrystallization 1 time in ethyl acetate, obtain purifying by (2) and 10, the salt (4) of 11-dihydro cinchovatin (1) generation is white solid: fusing point 125.5-126.5 ℃, [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 (4) that 11-dihydro cinchovatin (1) 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 (1) (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 (4) that 11-dihydro cinchovatin (1) generates is white solid (5.88g): fusing point 122.1-125.4 ℃.
Get above-mentioned by (2) and 10, the salt (4) that 11-dihydro cinchovatin (1) generates, recrystallization is 1 time in ethyl acetate, obtain purifying by (2) and 10, the salt (4) of 11-dihydro cinchovatin (1) generation is white solid: fusing point 123.4-126.5 ℃.
Embodiment 3:
With 10,11-dihydro cinchovatin (1) (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 (4) that 11-dihydro cinchovatin (1) generates is white solid (3.13g): fusing point 124.9-126 ℃, [α]
20 D-29.6 ° (c=1, MeOH).
Embodiment 4:
With 10,11-dihydro cinchovatin (1) (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 (4) that 11-dihydro cinchovatin (1) generates is white solid (0.49g): fusing point 125-126.4 ℃, [α]
20 D-32 ° (c=1, MeOH).
Embodiment 5:
With 10,11-dihydro cinchovatin (1) (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 (4) that 11-dihydro cinchovatin (1) generates is white solid (8.63g): fusing point 125-126 ℃.
Get above-mentioned by (2) and 10, the salt (4) that 11-dihydro cinchovatin (1) 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 (1) (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 (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 (8)
1. 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 an optical resolution, it is characterized in that adopting 10 shown in the following formula (1), 11-dihydro cinchovatin is as resolving agent.
2. method according to claim 1, it comprises 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 1 and 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 1 and 2, solvent for use comprises 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 1 and 2, wherein the fractured operation temperature range by 0 ℃ to the boiling point of employing solvent.
7. method according to claim 1 and 2, in the split process step 1) prepared 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 chemical structure is as shown in the formula shown in (4):
8. 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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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100308738A CN100497335C (en) | 2005-10-27 | 2005-10-27 | Optical resolution method substituting oxyphosphonate acetate |
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|---|---|---|---|
| CNB2005100308738A CN100497335C (en) | 2005-10-27 | 2005-10-27 | Optical resolution method substituting oxyphosphonate acetate |
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| Publication Number | Publication Date |
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| CN1955176A true CN1955176A (en) | 2007-05-02 |
| CN100497335C CN100497335C (en) | 2009-06-10 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100488969C (en) * | 2005-10-27 | 2009-05-20 | 上海医药工业研究院 | Optically active substituted oxyphosphonate salt acetate and its use |
| US20100297711A1 (en) * | 2009-05-25 | 2010-11-25 | Dipharma Francis S.R.L. | Process for the synthesis of fosinopril and intermediates thereof |
Family Cites Families (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 |
| CN100488969C (en) * | 2005-10-27 | 2009-05-20 | 上海医药工业研究院 | Optically active substituted oxyphosphonate salt acetate and its use |
-
2005
- 2005-10-27 CN CNB2005100308738A patent/CN100497335C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100488969C (en) * | 2005-10-27 | 2009-05-20 | 上海医药工业研究院 | Optically active substituted oxyphosphonate salt acetate and its use |
| US20100297711A1 (en) * | 2009-05-25 | 2010-11-25 | Dipharma Francis S.R.L. | Process for the synthesis of fosinopril and intermediates thereof |
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| Publication number | Publication date |
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| CN100497335C (en) | 2009-06-10 |
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