CN101372472A - Method for synthesizing Zofenopril - Google Patents

Method for synthesizing Zofenopril Download PDF

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CN101372472A
CN101372472A CNA2007100452348A CN200710045234A CN101372472A CN 101372472 A CN101372472 A CN 101372472A CN A2007100452348 A CNA2007100452348 A CN A2007100452348A CN 200710045234 A CN200710045234 A CN 200710045234A CN 101372472 A CN101372472 A CN 101372472A
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reaction
zofenopril
thiophenyl
mol ratio
calcium
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马文宁
周庆武
甘益民
唐开勇
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Shanghai Haini Pharm Co Ltd Yangzijiang Pharm Group
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Shanghai Haini Pharm Co Ltd Yangzijiang Pharm Group
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Abstract

The invention provides a method for synthetizing Zofenopril Calcium salt, which takes N-acetyl-L-oxyproline as raw materials; the N-acetyl-L-oxyproline and methanol are esterified, paratoluensulfonyl chloride is sulphonated, and thiophenyl is substituted; the obtained product is hydrolyzed to be freeacid by alkali, and (cis form)-4-thiophenyl-L-proline hydrochloride is further obtained by hydrochloric acid deacetylation reaction; in addition, (S)-3-(benzoyl sulfhydryl group)-2-methylpropanoic acid reacts with thionyl chloride, and (S)-3-(benzoyl sulfhydryl group)-2-methyl propionyl chloride which then reacts with the (cis form)-4-thiophenyl-L-proline hydrochloride, so that Zofenopril freeacid is obtained; the Zofenopril freeacid is firstly made into sylvite, and then refined and purified to be calcium salt, so that the termination product is obtained. The materials of the method of the invention is easily obtained, the process route is simple, and the reaction conditions are mild; therefore, the method is easy to operate and suitable for commercial process.

Description

Method for synthesizing Zofenopril
Technical field
It is synthetic to the present invention relates to medicine, is specifically related to method for synthesizing Zofenopril.
Background technology:
Zofenopril calcium
[English name] Zofenopril calcium.
[Chinese chemical name] (4S)-1-[(2S)-3-(benzoyl sulfenyl)-2-methyl propionyl]-4-thiophenyl-L-proline(Pro) calcium
[English chemical name] (4S)-1-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L-proline calcium salt
[structural formula]
Figure A200710045234D00041
Zofenopril calcium is the first long-acting hypertensin enzymeinhibitor of the sulfydryl third generation that contains, be used for the treatment of mild to moderate essential hypertension, and be used for acute myocardial infarction and have or patient asymptomatic, that hemodynamic stability is not accepted thromboembolism treatment in 24 hours.
Synthetic method about zofenopril calcium, according to relevant bibliographical information, Zofenopril calcium has multiple synthetic route, but it synthetic all be basically by two main side chains (cis)-4-thiophenyl-proline(Pro) and (S)-3-benzoyl sulfenyl-2 Methylpropionic acid synthesizes, generally be to being connected into the zofenopril free acid with both, become sylvite then, change into calcium salt behind the purifying again.
Figure A200710045234D00042
(cis)-4-thiophenyl-proline(Pro) (S)-3-benzoyl sulfenyl-2 Methylpropionic acid
For the synthetic method of zofenopril free acid, the main difference of its difference is different and different with the preparation method of the chiral carbon of 2 (S) configurations on (S)-3-benzoyl sulfenyl-2-methylpropionyl.Thereby, mainly contain the synthetic two kinds of methods of fractionation and chirality.
Method one: (S)-3-(benzoyl sulfenyl)-2 Methylpropionic acid through oxalyl chloride handle (S)-3-(benzoyl sulfenyl)-2-methyl-prop acyl chlorides, with cis-4-(thiophenyl)-L-proline(Pro) reaction, obtain 4 (S)-1-[(2S)-3-(benzoyl sulfenyl)-2-methyl propionyl again]-4-(thiophenyl)-L-proline(Pro).
Figure A200710045234D00051
This basic skills acidylate condensation course is open in document and early stage patent already.This method is carried out next step acylation reaction again with oxalyl chloride preparation (S)-3-(benzoyl sulfenyl)-2-methyl-prop acyl chlorides, finally generates zofenopril calcium, and this method helps generating the I N-type waferN, sees CN1316992.
Method two: (±)-3-(benzoyl sulfenyl)-2 Methylpropionic acid raceme and sulfur oxychloride react (±)-3-(benzoyl sulfenyl)-2-methyl-prop acyl chlorides raceme, obtain a pair of diastereomer 4 (S)-1-[3-(benzoyl sulfenyl)-2-methyl propionyl with cis-4-(thiophenyl)-L-proline(Pro) reaction again]-4-(thiophenyl)-L-proline(Pro), the latter and dicyclohexyl amine salify, again through split 4 (S)-1-[(2S)-3-(benzoyl sulfenyl)-2-methyl propionyl]-4-(thiophenyl)-L-proline(Pro), be the zofenopril free acid, see CN1594291.
Figure A200710045234D00061
Method three: the optical purity that has split (S)-3-(benzoyl sulfenyl)-2 Methylpropionic acid and sulfur oxychloride reaction generate (S)-3-(benzoyl sulfenyl)-2-methyl-prop acyl chlorides, with cis-4-(thiophenyl)-L-proline(Pro) reaction, generate quiral products 4 (S)-1-[(2S)-3-(benzoyl sulfenyl)-2-methyl propionyl again]-4-(thiophenyl)-L-proline(Pro).See US4316906.
Figure A200710045234D00062
Report from aforesaid method three, this method is gentleer than preceding 2 kinds condition, operate more convenient, but go back defectiveness, because calcium salt is all to be difficult to dissolving at organic solvent or at inorganic solvent, therefore be difficult to make with extra care,, be necessary to make with extra care in this step of zofenopril sylvite for guaranteeing quality product.
Summary of the invention:
The technical problem to be solved in the present invention is to overcome above-mentioned weak point, the improved zofenopril calcium synthetic method of research and design.
The present invention has done following design for selecting synthetic route:
The invention provides a kind of synthetic method of Zofenopril calcium, this method is a raw material with N-acetyl-L-oxyproline, warp and methanol esterification, the tolysulfonyl chlorosulphonation, thiophenyl replaces, the product that obtains becomes free acid through basic hydrolysis again, and the reaction of hydrochloric acid deacetylation further obtains (cis)-4-thiophenyl-L-proline hydrochlorate; In addition, (S)-3-(benzoyl sulfenyl)-2 Methylpropionic acid and thionyl chloride reaction, generate (S)-3-(benzoyl sulfenyl)-2-methyl-prop acyl chlorides, again with above-mentioned (cis)-4-thiophenyl-L-proline hydrochlorate react the zofenopril free acid, XianCheng's sylvite becomes calcium salt to obtain the finished product behind the refining purifying.Concrete building-up reactions formula is as follows:
The inventive method is in raw material and the methanol esterification reaction (their mol ratio is 1:7～8) at N-acetyl-L-oxyproline, make catalyzer with tosic acid, the mol ratio of it and raw material N-acetyl-L-oxyproline be 1:5 to 1:10, temperature is a room temperature, 24～72 hours reaction times.
In the tolysulfonyl chlorosulfonation, the mol ratio of N-acetyl-L-oxyproline methyl esters and Tosyl chloride is 1:1.2～1.3, and temperature is at-10～10 ℃, 24～48 hours reaction times.Extraction solvent is a methylene dichloride.
In the thiophenyl substitution reaction, the solvent of usefulness is a sodium ethylate; The mol ratio of N-acetyl-anti--4-p-toluenesulfonyl-L-oxyproline methyl esters and thiophenol is 1:1.5～1.8, and temperature is 10～20 ℃, and in 18～24 hours reaction times, extraction solvent is a methylene dichloride.
In macromolecule alkali for hydrolysis, with the ethanolic soln (consumption mol ratio NaOH/EtOH is 1:5～6) of sodium hydroxide, 25～30 ℃ of temperature of reaction, in 18～36 hours reaction times, extraction solvent is an ether, transfers pH=1-2 with strong acid, uses re-crystallizing in ethyl acetate.
In the deacetylation reaction, mol ratio 1:3.3～4 of N-acetyl-suitable-4-thiophenyl-L-proline(Pro) and hydrochloric acid, 45～60 ℃ of temperature, 4～5 hours reaction times, stirred overnight at room temperature.The anhydrous diethyl ether washing.
In (S)-3-(benzoyl sulfenyl)-2 Methylpropionic acid and thionyl chloride reaction; generate in (S)-3-(benzoyl sulfenyl)-2-methyl-prop acyl chlorides acylation reaction; (S)-and mol ratio 1:2～3 of 3-(benzoyl sulfenyl)-2 Methylpropionic acid and acylating reagent, 60～70 ℃ of reflux temperatures.
With (cis)-4-thiophenyl-L-proline hydrochlorate react in the zofenopril free acid reaction, suitable-4-thiophenyl-L-proline hydrochlorate and (S)-3-(benzoyl sulfenyl)-2-methyl-prop acyl chlorides mol ratio is 1:1～1.2, pH=8-9, add ethyl acetate 400ml and stir 4h, transfer pH=1-2 with 6mol/L HCL.
In the zofenopril free acid becomes sylvite reaction, (4S)-1-[(2S)-3-(benzoyl sulfenyl)-2-methyl propionyl]-4-(thiophenyl)-L-proline(Pro)) with the mol ratio of potassium hydroxide be 1:1～1.1, temperature of reaction room temperature, recrystallization reagent isopropanol.
Become in the calcium salt reaction behind the refining purifying of zofenopril sylvite, (4S)-1-[(2S)-3-(benzoyl sulfenyl)-2-methyl propionyl]-mol ratio of 4-(thiophenyl)-L-proline(Pro) sylvite and Calcium dichloride dihydrate is 1:1.1～1.3, temperature of reaction is 85 ℃-90 ℃, 3～5 hours reaction times, room temperature reaction 1～2 hour, 36～48 hours time of drying.
Figure A200710045234D00081
Zofenopril calcium with the inventive method preparation has carried out structural identification, and its result is as follows:
Sample source
1, the source of highly finished product: provided by the Yangzijiang Pharmaceutical Group, Shanghai Haini Pharmaceutical Co., Ltd medicine chamber of being combined to for sample on probation, lot number is: 050301.
2, reference substance source: refining by the Yangzijiang Pharmaceutical Group, Shanghai Haini Pharmaceutical Co., Ltd medicine chamber of being combined to, lot number is 050203.
Three, the method for conclusive evidence chemical structure
3.1 high resolution mass spectrum
3.1.1 instrument model: Q-Tofmicro mass spectrograph
3.1.2 test condition: ESI Tolerance=5.0ppm DBE min=-1.5, max=50.0
3.1.3 test result: gained molecular formula C 44H 44N 2O 8S 4Ca, accurate mass several 897.1698 conforms to zofenopril calcium constituent ratio.
3.2 UV spectrum
3.2.1 instrument model: HP-8452A ultraviolet-visible pectrophotometer
3.2.2 instrumental correction: holmium glass
3.2.3 test condition:
3.2.3 test result:
Table 1, ultraviolet spectrum data tabulation
Figure A200710045234D00092
The collection of illustrative plates basically identical of sample and reference substance.
3.3 infrared spectra
3.3.1 instrument model: Nicolet FTIR-670 infrared spectrometer
3.3.2 instrumental correction: polystyrene film
3.3.3 test condition: KBr pressed disc method
3.3.4 test result:
3.3.5 resolve
A, 3058,689cm -1Hydrocarbon stretching vibration and rocking vibration for phenyl ring.
B, 2976,2933,1436,1412cm -1Stretching vibration and flexural vibration for methyl and methylene radical.
C, 1660,614,583cm -1Be carbonylic stretching vibration.
Infrared spectra has shown information such as phenyl ring, carbonyl, methyl, methylene radical.The collection of illustrative plates basically identical of sample and reference substance.
Table 2, ir data tabulation
Figure A200710045234D00101
3.4 nuclear magnetic resonance spectrum
3.4.1 instrument model: Varian INOVA-400 nuclear magnetic resonance analyser
3.4.2 test condition: solvent TFA-d 1H, 13C, DEPT, COSY, HMQC, HMBC spectrum
3.4.3 test result:
Figure A200710045234D00102
a、
Table 4, nucleus magnetic resonance 1H, COSY compose data list
Sequence number δ H(ppm) sample reference substance Proton number Multiplicity (J/Hz) COSY (position)
22 1.43 1.43 6 d 2
12 2.28 2.78 2.292.78 4 m 11
2 3.22 3.23 2 m 22
3 3.30 3.48 3.293.51 4 dd
14 3.70 4.23 3.704.24 4 dd 13
13 3.84 3.85 2 m 14
11 4.85 4.85 2 dd 12
19 7.31 7.31 2
79 7.33 7.33 4
1721 7.42 7.42 4 dd
1820 7.51 7.51 4 t
8 7.69 7.69 2 t
610 7.97 7.97 4 d
Table 5, nucleus magnetic resonance 13C, DEPT, HMBC compose data list
Sequence number δ C(ppm) sample reference substance Carbonatoms DEPT HMBC (position)
22 17.53 17.53 2 ↑
3 33.49 33.42 2 ↓
12 36.81 36.73 2 ↓
2 41.01 41.01 2 ↑
13 46.78 46.73 2 ↑
14 55.81 55.77 2 ↓
11 61.33 61.27 2 ↑
610 129.16 129.12 4 ↑
19 130.65 130.62 2 ↑
1820 130.91 130.87 4 ↑
79 131.31 131.27 4 ↑
5 133.73 133.69 2 79
1721 134.91 134.86 4 ↑
8 136.97 136.95 2 ↑
16 137.95 137.88 2 1820
15 178.88 178.77 2 11
1 179.51 179.44 2 22
4 201.14 201.15 2 3
Sample is consistent with the collection of illustrative plates of reference substance.
3.5 mass spectrum
3.5.1 instrument model: Q-Tof micro mass spectrograph
3.5.2 test condition: ESI source
3.5.3 test result:
This compound molecule formula C 44H 44CaN 2O 8S 4Molecular weight be 896, quasi-molecular ion peak m/z897[M+H] +, consistent with this compound molecular weight.The ownership of base peak: m/z 468[M-C 22H 22NO 4S 2] +Sample is consistent with the collection of illustrative plates of reference substance.
3.6 heat is analyzed
3.6.1 instrument model: P-E DSC-7 differential scanning calorimeter
3.6.2 test condition:
Figure A200710045234D00121
3.6.3 test result: (Figure 21,22)
The DSC spectrum has shown the melting curve of this compound, and the Onset value of sample is 260.92 ℃; The Onset value of reference substance is 258.07 ℃.
3.7 powder X-ray-x ray diffraction analysis x
3.7.1 instrument model: Bruker D8 Advance x-ray diffractometer
3.7.2 test condition: Target:Cu 40kv 40mA scanspeed 0.2
3.7.3 test result:
Table 6, X-diffraction data tabulation
D-value sample reference substance 2Theta sample reference substance I/I.The sample reference substance
20.21 19.89 4.36 4.43 86.3 100
18.52 18.32 4.76 4.81 51.6 72.1
4.64 4.62 19.09 19.16 74.2 64.7
4.41 4.40 20.08 20.14 100 73.2
X-ray diffraction spectra has shown the data of interplanar distance, angle and relative intensity, is the crystal type form substantially.The general data basically identical of the collection of illustrative plates of sample and reference substance.
In sum, the chemical structure of sample can be proved conclusively and be zofenopril calcium.
The inventive method has following effect: intermediate N acetyl-L-oxyproline and intermediate (S)-3-(benzoyl sulfenyl)-2 Methylpropionic acid all has commercially available product, and operational path is simple, mild condition is easy to operate, is suitable for suitability for industrialized production.
Embodiment:
Example 1 (synthesizing of N-acetyl-L-oxyproline methyl esters):
Raw material and proportioning (seeing Table 1)
Table 1
Figure A200710045234D00122
Figure A200710045234D00131
Operation:
N-acetyl-oxyproline 600g and anhydrous methanol 1000ml add in the 3000ml three-necked bottle, stir 45min and make its dissolving, add tosic acid 120g again, stirring at room 48h, and TLC (method is stated as follows) endpoint detection, the basic disappearance of raw material point is terminal point.Add solid sodium bicarbonate and transfer pH=7, filter, filtrate adds anhydrous Na 2SO 4Drying is filtered, and 50 ℃ of concentrating under reduced pressure steamings desolventize, and separates out mixing the adularescent precipitation in the oily residue adding acetone, filter, and the washing with acetone solid, filtrate concentrates, and gets faint yellow oily thing (intermediate 1) 605g, and yield is 93.2%
Synthesizing of example 2 (N-acetyl-anti--4-p-toluenesulfonyl-L-oxyproline methyl esters)
Raw material and proportioning (seeing Table 2)
Table 2
Figure A200710045234D00132
Operation:
Intermediate (1) 602g and pyridine 1200ml are placed 3000ml exsiccant three-necked bottle, stir 30min under ice bath, add Tosyl chloride 735g in batches under (0-10 ℃), stirring has solid to separate out, refrigerator is placed and is spent the night, add 600ml water and make the solid dissolving,, merge organic layer with methylene dichloride 800ml * 3 extractions, use methylene dichloride, water successively, 2mol/l HCL, saturated sodium bicarbonate, water are respectively washed twice.The organic layer dry filter, steaming desolventizes, and gets reddish-brown oily matter (intermediate 2) 928g, and yield is 84.5%.
Synthesizing of example 3 (N-acetyl-suitable-4-thiophenyl-L-proline methyl ester)
Raw material and proportioning (seeing Table 3)
Table 3
Figure A200710045234D00133
Operation:
Dehydrated alcohol 3000ml is added in the exsiccant 5000ml three-necked bottle, stir, and under the ice bath cooling, the sodium Metal 99.5 that in batches slowly adds the 103g chopping, wait to have dissolved the back and add the 450g thiophenol, stir 1h, water-bath is cooled to room temperature, disposable adding intermediate (2) 926g, stirring at normal temperature spend the night (temperature can not be too high).Remove ethanol under reduced pressure, residuum adds 1000ml water and 1000mL methylene dichloride, makes the solid dissolving, tells organic layer, and water with methylene dichloride 1000ml extraction, merges organic layer again, washes twice with water, adds anhydrous Na 2SO 4Drying is filtered, steam desolventize yellow oil intermediate (3) 627g, yield is 82.6%.
Synthesizing of example 4 (N-acetyl-suitable-4-thiophenyl-L-proline(Pro))
Raw material and proportioning (seeing Table 4)
Table 4
Figure A200710045234D00142
Operation:
1100ml ethanol and 108g sodium hydroxide are added in the 5000ml three-necked bottle, stirring and dissolving, 625g adds in the reaction flask under room temperature with intermediate (3), the adularescent solid is separated out in the reaction process, stirring is spent the night, and adds 1500mL water, with ether 2000ml extraction, water layer is transferred pH=1-2 with concentrated hydrochloric acid, suction filtration is collected the solid of separating out, washing and drying, solid re-crystallizing in ethyl acetate, get white powder intermediate (4) 476g, yield is 80.2%.
Synthesizing of example 5 (suitable-4-thiophenyl-L-proline hydrochlorate)
Raw material and proportioning (seeing Table 5)
Table 5
Operation:
470g joins in the 2000ml there-necked flask with intermediate (4), adds the HCL1000ml heated and stirred backflow 4h of 6mol/L, and room temperature slowly stirs spends the night, suction filtration is collected the solid of separating out, wash with anhydrous diethyl ether again, dry intermediate (5) 360g that gets, yield is 78.4%.
[outward appearance] white or blush solid are insoluble to ethanol
[fusing point]: 110～120 ℃
Synthesizing of example 6 ((S)-3-(benzoyl sulfenyl)-2-methyl-prop acyl chlorides)
Raw material and proportioning (seeing Table 7)
Table 7
Figure A200710045234D00151
Operation:
(S)-3-(benzoyl sulfenyl)-2 Methylpropionic acid 145g is placed 500ml exsiccant flask, add return line and hydrochloric acid absorption unit, thionyl chloride 143g is added in the bottle, stir 1h, oil bath slowly is warming up to 60 ℃-70 ℃, the about 5h of back flow reaction, unnecessary thionyl chloride (thionyl chloride can recycle) is reclaimed in distillation, get faint yellow oily thing 155g (intermediate 6), yield: 98.2%, because the acyl chlorides instability is directly used in the next step.
Example 7 ((4S)-1-[(2S)-3-(benzoyl sulfenyl)-2-methyl propionyl]-4-(thiophenyl)-L-proline(Pro)) synthetic
Raw material and proportioning (seeing Table 8)
Table 8
Figure A200710045234D00152
Operation:
160g places the 2L three-necked bottle with intermediate (5), adding distilled water 600ml stirs, regulate pH=8-9 with saturated aqueous sodium carbonate, ice bath keeps 0 ℃-10 ℃ of temperature, beginning slowly drips intermediate (6) 155g, drip saturated sodium carbonate solution simultaneously and keep reactant pH=8-9, about 1.5-2h adds.Add ethyl acetate 400ml and stir 4h, transfer pH=1-2 with 6mol/L HCL, tell ethyl acetate layer, the saturated common salt washing adds anhydrous Na 2SO 4Drying is filtered, steam desolventize light brown arborescens thing intermediate (7) 202g, yield is 75.9%.
Example 8 zofenopril sylvite ((4S)-1-[(2S)-3-(benzoyl sulfenyl)-2-methyl propionyl]-4-(thiophenyl)-L-proline(Pro) sylvite) synthetic
Raw material and proportioning (seeing Table 9)
Table 9
Figure A200710045234D00161
Operation:
In the 3000ml four-necked bottle, add dehydrated alcohol 1000ml dissolving intermediate (7) 200g, dropping is by the solution of dehydrated alcohol 320ml dissolved hydrogen potassium oxide 32.3g, stirring the adularescent solid occurs, stirring is spent the night, filter, absolute ethanol washing obtains solid, meet the requirements with isopropanol mixed solvent recrystallization two to three times to quality, water intermediate (8) the 156g yield that must decrystallize after the drying is 71.6% again.
[proterties] white solid
[fusing point] mp=201.2 ℃ of-203.7 ℃ of (documents [3]Mp=195 ℃-205 ℃)
[specific rotation] (c=1H 2O) (document [3]
Figure A200710045234D00163
)
[purity, related substance] does high pressure liquid chromatography, and total assorted calculating by area normalization method of related substance should be less than 0.5%.
Synthesizing of example 9 Zofenopril calciums
Raw material and proportioning (seeing Table 10)
Table 10
Figure A200710045234D00164
Operation:
With the dissolving crystallized calcium chloride 47g of distilled water 1800ml, solution drops in the 5000ml there-necked flask, vigorous stirring, oil bath is heated to 85 ℃-90 ℃, slowly drip the solution by distilled water 1200ml dissolved zofenopril sylvite 155g, about 3h drips, and maintenance stirs 1h, be cooled to room temperature, get white solid.Filter, distilled water wash is to there not being chlorion (Cl -), 80 ℃ of-90 ℃ of vacuum-drying 48h get white crystalline powder (product) 114g.Yield is 86.1%.
Mp=249.5 ℃-253.1 ℃ of [proterties] white crystalline powders
[proterties]
Figure A200710045234D00171
(c=1, MeOH/HCL)
(document mp=250 ℃
Figure A200710045234D00172
(C=1, MeOH/HCL) [4]
[purity, related substance] does high pressure liquid chromatography, always mixes peak area less than 1% by area normalization method main peak area greater than 99% related substance.
[structural identification] meets the basic constitutional features of this compound, proves conclusively to be zofenopril calcium
Example 10 product purification methods
According to the insoluble characteristics of Zofenopril calcium, can adopt repeatedly the method for recrystallization to improve its purity to zofenopril sylvite.
At the chiral purity problem, consider direct synthesis of chiral carbon problem in the building-up process especially.Three-step reaction has the chiral carbon transposition to replace on 4 of main rings, in the replacement process by trans change cis.For avoiding contingent incomplete SN2 to replace, avoiding high temperature (seeing 4.3.2) aspect the reaction control as far as possible.By test as can be known, improve the optical purity (seeing 4.8.2 and 4.8.3) of zofenopril potassium through isopropanol mixed solvent recrystallization method, simultaneously by optically-active spectrphotometric method for measuring specific optical rotation, chiral purity that can strict control zofenopril sylvite reaches the purpose of the chiral purity of control the finished product zofenopril calcium.This is particularly important to improving its quality product concerning the medicine zofenopril calcium that contains three chiral centres.
[refining according to] zofenopril sylvite is more stable, the isopropanol mixed solvent (10:0.5, v/v) in solubleness and temperature sensitivity especially, solubleness is bigger during high temperature, and is less during low temperature.Diastereomer, other impurity solubleness temperature influence in Virahol is little, thereby the mode by recrystallization of reaching is with the sylvite purifying.
The preparation of example 11 multiple batches of samples, the concrete data preparation of test-results is as follows, sees Table 11, table 12.
Table 11 lab scale is summary sheet as a result
Figure A200710045234D00173
Figure A200710045234D00181
Three batches of declaration sample datas of table 12 summary sheet
Figure A200710045234D00182
Figure A200710045234D00191

Claims (10)

1. the synthetic method of a Zofenopril calcium, it is characterized in that this method is a raw material with N-acetyl-L-oxyproline, warp and methanol esterification, the tolysulfonyl chlorosulphonation, thiophenyl replaces, the product that obtains becomes free acid through basic hydrolysis again, and the reaction of hydrochloric acid deacetylation further obtains (cis)-4-thiophenyl-L-proline hydrochlorate; In addition with (S)-3-(benzoyl sulfenyl)-2 Methylpropionic acid and thionyl chloride reaction, generate (S)-3-(benzoyl sulfenyl)-2-methyl-prop acyl chlorides, again with above-mentioned (cis)-4-thiophenyl-L-proline hydrochlorate react the zofenopril free acid, XianCheng's sylvite becomes calcium salt to obtain the finished product behind the refining purifying.
2. according to the synthetic method of the described a kind of Zofenopril calcium of claim 1, it is characterized in that in N-acetyl-L-oxyproline and methanol esterification reaction, their mol ratio is 1:7～8, make catalyzer with tosic acid, the mol ratio of it and raw material N-acetyl-L-oxyproline is that 1:5 is to 1:10, temperature is a room temperature, 24～72 hours reaction times.
3. according to the synthetic method of the described a kind of Zofenopril calcium of claim 1, it is characterized in that in the tolysulfonyl chlorosulfonation, the mol ratio of N-acetyl-L-oxyproline methyl esters and Tosyl chloride is 1:1.2～1.3, and temperature is at-10～10 ℃, 24～48 hours reaction times.Extraction solvent is a methylene dichloride.
4. according to the synthetic method of the described a kind of Zofenopril calcium of claim 1, it is characterized in that in the thiophenyl substitution reaction, the solvent of usefulness is a sodium ethylate; The mol ratio of N-acetyl-anti--4-p-toluenesulfonyl-L-oxyproline methyl esters and thiophenol is 1:1.5～1.8, and temperature is 10～20 ℃, and in 18～24 hours reaction times, extraction solvent is a methylene dichloride.
5. according to the synthetic method of the described a kind of Zofenopril calcium of claim 1, it is characterized in that in macromolecule alkali for hydrolysis, ethanolic soln with sodium hydroxide, consumption mol ratio NaOH/EtOH is 1:5～6,25～30 ℃ of temperature of reaction, in 18～36 hours reaction times, extraction solvent is an ether, transfer pH=1-2 with strong acid, use re-crystallizing in ethyl acetate.
6. according to the synthetic method of the described a kind of Zofenopril calcium of claim 1; it is characterized in that in the deacetylation reaction; mol ratio 1:3.3～4 of N-acetyl-suitable-4-thiophenyl-L-proline(Pro) and hydrochloric acid; 45～60 ℃ of temperature; 4～5 hours reaction times; stirred overnight at room temperature, the anhydrous diethyl ether washing.
7. according to the synthetic method of the described a kind of Zofenopril calcium of claim 1; it is characterized in that in (S)-3-(benzoyl sulfenyl)-2 Methylpropionic acid and thionyl chloride reaction; generate in (S)-3-(benzoyl sulfenyl)-2-methyl-prop acyl chlorides acylation reaction; (S)-and mol ratio 1:2～3 of 3-(benzoyl sulfenyl)-2 Methylpropionic acid and acylating reagent, 60～70 ℃ of reflux temperatures.
8. according to the synthetic method of the described a kind of Zofenopril calcium of claim 1, it is characterized in that with (cis)-4-thiophenyl-L-proline hydrochlorate react in the zofenopril free acid reaction, suitable-4-thiophenyl-L-proline hydrochlorate and (S)-3-(benzoyl sulfenyl)-2-methyl-prop acyl chlorides mol ratio is 1:1～1.2, pH=8-9, add ethyl acetate 400ml and stir 4h, transfer pH=1-2 with 6mol/L HCL.
9. according to the synthetic method of the described a kind of Zofenopril calcium of claim 1, it is characterized in that becoming in the sylvite reaction at the zofenopril free acid, (4S)-1-[(2S)-3-(benzoyl sulfenyl)-2-methyl propionyl]-4-(thiophenyl)-L-proline(Pro)) with the mol ratio of potassium hydroxide be 1:1～1.1, the temperature of reaction room temperature, recrystallization reagent isopropanol, the ratio 1:20 of Virahol and water～40.
10. according to the synthetic method of the described a kind of Zofenopril calcium of claim 1, it is characterized in that behind the refining purifying of zofenopril sylvite, becoming in the calcium salt reaction, (4S)-1-[(2S)-3-(benzoyl sulfenyl)-2-methyl propionyl]-mol ratio of 4-(thiophenyl)-L-proline(Pro) sylvite and Calcium dichloride dihydrate is 1:1.1～1.3, temperature of reaction is 85 ℃-90 ℃, 3～5 hours reaction times, room temperature reaction 1～2 hour, 36～48 hours time of drying.
CNA2007100452348A 2007-08-24 2007-08-24 Method for synthesizing Zofenopril Pending CN101372472A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013095307A1 (en) 2011-12-19 2013-06-27 Silverstone Pharma New crystal salts of zofenopril, process for obtaining them and their use in therapy
CN103936644A (en) * 2013-01-23 2014-07-23 扬子江药业集团上海海尼药业有限公司 Method for preparing zofenopril calcium
CN104844495A (en) * 2015-06-05 2015-08-19 武汉理工大学 Synthesis method of (2S,4S)-4-thiophenyl-L-proline hydrochloride
CN113403350A (en) * 2021-06-21 2021-09-17 上海克琴科技有限公司 Method for synthesizing acetylhydroxyproline catalyzed by biological enzyme

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013095307A1 (en) 2011-12-19 2013-06-27 Silverstone Pharma New crystal salts of zofenopril, process for obtaining them and their use in therapy
CN103936644A (en) * 2013-01-23 2014-07-23 扬子江药业集团上海海尼药业有限公司 Method for preparing zofenopril calcium
CN104844495A (en) * 2015-06-05 2015-08-19 武汉理工大学 Synthesis method of (2S,4S)-4-thiophenyl-L-proline hydrochloride
CN113403350A (en) * 2021-06-21 2021-09-17 上海克琴科技有限公司 Method for synthesizing acetylhydroxyproline catalyzed by biological enzyme

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