CN102344399A - Stereomers of (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid and preparation method for salt thereof - Google Patents
Stereomers of (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid and preparation method for salt thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 150000003839 salts Chemical class 0.000 title claims abstract description 23
- JHHOFXBPLJDHOR-ZJUUUORDSA-N (2s,4s)-4-phenylpyrrolidin-1-ium-2-carboxylate Chemical compound C1N[C@H](C(=O)O)C[C@H]1C1=CC=CC=C1 JHHOFXBPLJDHOR-ZJUUUORDSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 230000032050 esterification Effects 0.000 claims abstract description 14
- 238000005886 esterification reaction Methods 0.000 claims abstract description 14
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000005864 Sulphur Substances 0.000 claims abstract description 10
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 6
- 230000029936 alkylation Effects 0.000 abstract description 4
- 238000005804 alkylation reaction Methods 0.000 abstract description 4
- JHHOFXBPLJDHOR-NXEZZACHSA-N (2r,4s)-4-phenylpyrrolidine-2-carboxylic acid Chemical compound C1N[C@@H](C(=O)O)C[C@H]1C1=CC=CC=C1 JHHOFXBPLJDHOR-NXEZZACHSA-N 0.000 abstract description 3
- JHHOFXBPLJDHOR-UWVGGRQHSA-N (2s,4r)-4-phenylpyrrolidin-1-ium-2-carboxylate Chemical compound C1N[C@H](C(=O)O)C[C@@H]1C1=CC=CC=C1 JHHOFXBPLJDHOR-UWVGGRQHSA-N 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract 2
- 208000024172 Cardiovascular disease Diseases 0.000 abstract 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 abstract 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- PMMYEEVYMWASQN-IUYQGCFVSA-N trans-4-hydroxy-D-proline Chemical compound O[C@@H]1CN[C@@H](C(O)=O)C1 PMMYEEVYMWASQN-IUYQGCFVSA-N 0.000 abstract 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000005457 ice water Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- -1 methyl ester hydrochloride Chemical class 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- NJMASXVCJXPDME-UHFFFAOYSA-N 1-benzoyl-4-phenylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)C1CC(C=2C=CC=CC=2)CN1C(=O)C1=CC=CC=C1 NJMASXVCJXPDME-UHFFFAOYSA-N 0.000 description 6
- JHHOFXBPLJDHOR-UHFFFAOYSA-N 4-phenylpyrrolidin-1-ium-2-carboxylate Chemical compound C1NC(C(=O)O)CC1C1=CC=CC=C1 JHHOFXBPLJDHOR-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000010009 beating Methods 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- AGEBJYJJWHBPJT-UHFFFAOYSA-N $l^{1}-oxidanylsulfonylmethane Chemical compound CS([O])(=O)=O AGEBJYJJWHBPJT-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound 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 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 3
- LWFBRHSTNWMMGN-UHFFFAOYSA-N 4-phenylpyrrolidin-1-ium-2-carboxylic acid;chloride Chemical compound Cl.C1NC(C(=O)O)CC1C1=CC=CC=C1 LWFBRHSTNWMMGN-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229960002429 proline Drugs 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960002490 fosinopril Drugs 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- JHHOFXBPLJDHOR-VHSXEESVSA-N (2r,4r)-4-phenylpyrrolidine-2-carboxylic acid Chemical compound C1N[C@@H](C(=O)O)C[C@@H]1C1=CC=CC=C1 JHHOFXBPLJDHOR-VHSXEESVSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses isomers of (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid (D) and a preparation method for salt thereof, and particularly discloses diastereoisomers [(2R,4S)-4-phenylpyrrolidine-2-carboxylic acid (A) and (2S, 4R)-4-phenylpyrrolidine-2-carboxylic acid (B)] and an enantiomer (C) of the (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid (D) and a preparation method for the salt thereof. In the preparation method disclosed by the invention, the corresponding isomers A, B and C are obtained by taking D-hydroxyproline or L-hydroxyproline as a starting material through esterification, hydroxyl protection, sulphur esterification, Friedel-Craft alkylation, hydrolysis and deprotection reaction. The compounds are used for preparing anti-cardiovascular disease drugs and controlling the quality of the drugs.
Description
Technical field
The invention belongs to biomedicine field, be specifically related to (2S, 4S)-the 4-Phenylpyrrolidine-isomer of 2-carboxylic acid and the preparation method of salt thereof.
Background technology
Fosinopril is the plain CEI of a kind of novel hypertension, and Angiotensin II content is reduced, vasodilation, thus play hypotensive effect.The impurity D that is mentioned in the SQ-28555 USP standard has related to corresponding isomer.The direct absolute configuration preparation method of present bibliographical information related impurities; Document (J.Med.Chem.1988,31,1148-1160) reported with one of them diastereomer (2S of (2S)-4-oxo proline(Pro) preparation; 4R)-4-Phenylpyrrolidine-2-carboxylic acid (route is following); But the price of (2S)-4-oxo proline(Pro) is higher in this route, and preparation cost is high, and the product optical purity of preparation is low.
Summary of the invention
For solving the problems of the technologies described above; The invention provides a kind of new preparation route; With the relatively low D-oxyproline of cost (or L-oxyproline) be raw material synthesized respectively (2S, 4S)-the corresponding diastereomer and the enantiomer of the single configuration of 4-Phenylpyrrolidine-2-carboxylic acid.
Can conveniently prepare 4-Phenylpyrrolidine-2-carboxylic acid through this method with high optically pure absolute configuration.The present invention obtain (2S 4S)-4-Phenylpyrrolidine-2-carboxylic acid can further prepare fosinopril and isomer thereof, and can be used as the quality of its key intermediate control medicine.
(2S, 4S)-4-Phenylpyrrolidine-2-carboxylic acid isomer's method, concrete technical scheme is as with hereinafter described to the invention provides the high optical purity of a kind of preparation.
A kind of (2R; 4S)-preparation method of 4-Phenylpyrrolidine-2-carboxylic acid (A) or its salt; Comprise: with the D-oxyproline is starting raw material, through esterification, go up protection base, sulphur esterification, Fu Ke alkylation, hydrolysis, deprotection obtain (2R, 4S)-4-Phenylpyrrolidine-2-carboxylic acid; Shown in A, this isomer obtains corresponding salt after acidifying.
A kind of (2R; 4S)-preparation method of 4-Phenylpyrrolidine-2-carboxylic acid (B) or its salt; Comprise: with the L-oxyproline is starting raw material, through esterification, go up protection base, sulphur esterification, Fu Ke alkylation, hydrolysis, deprotection obtain corresponding isomer (2S, 4R)-4-Phenylpyrrolidine-2-carboxylic acid; Shown in B, this isomer obtains corresponding salt after acidifying.
A kind of (2R; 4R)-preparation method of 4-Phenylpyrrolidine-2-carboxylic acid (C) or its salt; Comprise: with the D-oxyproline is starting raw material, through esterification, go up protection base, sulphur esterification, Fu Ke alkylation, hydrolysis, deprotection obtain (2R, 4R)-4-Phenylpyrrolidine-2-carboxylic acid; Shown in C, this isomer obtains corresponding salt after acidifying.
The structural formula of the compound of mentioning among the present invention is as shown in the table:
Wherein, R
1Or R
2Be aryl or substituted aryl, preferred phenyl, the substituted phenyl of low alkyl group or the substituted phenyl of halogen atom, more preferably phenyl.
Preparing method suc as formula compound shown in the A and salt thereof of the present invention specifically may further comprise the steps:
(1) will obtain suc as formula the compound shown in 6 through over-churning suc as formula the compound shown in 5;
(2) will obtain suc as formula the compound shown in 7 suc as formula behind the protection base on the compound shown in 6;
(3) will obtain suc as formula the compound shown in 8 suc as formula the compound shown in 7 through the sulphur esterification;
(4) will obtain suc as formula the compound shown in 9 suc as formula the compound shown in 8 through the Fu Ke alkylated reaction;
(5) will obtain suc as formula the compound shown in 10 suc as formula the compound shown in 9 through hydrolysis reaction; With
(6) will and after acidifying, obtain corresponding salt suc as formula the compound deprotection shown in 10 suc as formula the compound shown in the A.
Preparing method suc as formula compound shown in the B and salt thereof of the present invention specifically may further comprise the steps:
(1) will obtain suc as formula the compound shown in 15 through over-churning suc as formula the compound shown in 14;
(2) will obtain suc as formula the compound shown in 16 suc as formula behind the protection base on the compound shown in 15;
(3) will obtain suc as formula the compound shown in 17 suc as formula the compound shown in 16 through the sulphur esterification;
(4) will obtain suc as formula the compound shown in 18 suc as formula the compound shown in 17 through the Fu Ke alkylated reaction;
(5) will obtain suc as formula the compound shown in 19 suc as formula the compound shown in 18 through hydrolysis reaction; With
(6) will and after acidifying, obtain corresponding salt suc as formula the compound deprotection shown in 19 suc as formula the compound shown in the B.
Preparing method suc as formula compound shown in the C and salt thereof of the present invention specifically may further comprise the steps:
(1) will obtain suc as formula the compound shown in 6 through over-churning suc as formula the compound shown in 5;
(2) will obtain suc as formula the compound shown in 7 suc as formula behind the protection base on the compound shown in 6;
(3) will obtain suc as formula the compound shown in 11 suc as formula the compound shown in 7 through the sulphur esterification;
(4) will obtain suc as formula the compound shown in 12 suc as formula the compound shown in 11 through the Fu Ke alkylated reaction;
(5) will obtain suc as formula the compound shown in 13 suc as formula the compound shown in 12 through hydrolysis reaction; With
(6) will and after acidifying, obtain corresponding salt suc as formula the compound deprotection shown in 13 suc as formula the compound shown in the C.
The acid of using in the above-mentioned acidifying is selected from arbitrary organic acid or mineral acid, preferred hydrochloric acid, sulfuric acid, acetate, methylsulfonic acid, phosphoric acid, Citric Acid or tartrate, more preferably hydrochloric acid or acetate.
Embodiment
The following stated is merely preferred embodiment of the present invention; Be not in order to limit essence technology contents scope of the present invention; Essence technology contents of the present invention is broadly to be defined in the claim scope of application, and if any technological entity or method that other people accomplish are defined identical with the claim scope of application; Also or a kind of change of equivalence, all will be regarded as and be covered by among this claim scope.
The preparation of embodiment 1.D-oxyproline methyl ester hydrochloride
In the 250ml there-necked flask, add anhydrous methanol 100ml, ice bath stirs 0.5h down.Acetyl Chloride 98Min. (8.67g 0.11mol) splashes in the reaction solution, under this temperature of reaction, stirs 1h, D-oxyproline hydrochloride (10g 0.06mol) adds in batches, after reaction solution slowly is heated to backflow, react about 10h.The TLC detection reaction is complete.Solvent evaporated gets the light yellow oily of 11.2g, and filter with 30ml anhydrous diethyl ether making beating 5hr the back, and vacuum-drying obtains 10.3g white solid D-oxyproline methyl ester hydrochloride, yield 95%.
The preparation of embodiment 2.1-benzoyl--D-oxyproline methyl esters
In the 250ml there-necked flask, add 60ml water and 30ml dioxane, (10.3g 0.057mol) adds D-oxyproline methyl ester hydrochloride in batches; Ice bath stirs 0.5h down, and the dropping triethylamine (12.6g, 0.125mol); Finish, slowly drip the Benzoyl chloride 99min. that dilutes with the 30ml dioxane (8.13g, 0.0578mol); Move to normal temperature after stirring 3h, and the TLC detection (DCM: MeOH=5: 1, the triketohydrindene hydrate colour developing) react completely.Solvent evaporated adds ETHYLE ACETATE 200ml and 100ml water, standing demix, and water layer is with ethyl acetate extraction (100ml * 3); The combined ethyl acetate layer, and use saturated NaHCO3 (50ml * 2) respectively, 10% Hydrocerol A (50ml * 2); Use 20g anhydrous sodium sulfate drying 5h at last, solvent evaporated gets the thick material 19.5g of off-white color, adds 30ml ETHYLE ACETATE; Making beating 5h filters, and vacuum-drying gets 11.5g white solid 1-benzoyl--D-oxyproline methyl esters.Yield 81%.
Embodiment 3.1-benzoyl--4-is trans-preparation of (methylsulfonyl oxygen)-D-proline(Pro)
Add during three mouthfuls of round bottoms of 250mL burn toluene (64ml), methanesulfonic (2.5ml, 0.038mol), add under the mechanical stirring triethylamine (5.6ml, 0.038mol); Be warming up to 55 ℃, add triphenylphosphine (10.5g, 0.04mol), 1-benzoyl--D-oxyproline methyl esters (8.0g; 0.032mol), splash under the nitrogen protection diisopropyl azodiformate (8ml, 0.04mol); Finish, be warming up to 75～85 ℃, reaction 5h.The TLC detection reaction is complete, stops heating, temperature drop to 0 in ice bath is controlled down～5 ℃; (2g sodium hydroxide is dissolved in 58mL water to the dropping sodium aqueous solution, and 1.5eq), 0～5 ℃ is stirred 5～6h; Regulate pH=6～7 (consuming concentrated hydrochloric acid 9mL) with concentrated hydrochloric acid, 0～5 ℃ is stirred 1h.Filter, reaction flask and filter cake are with frozen water (12ml * 2) washing, and filtrating is left standstill separatory; Water is regulated pH=4 (consuming concentrated hydrochloric acid 1ml) with concentrated hydrochloric acid; Add ETHYLE ACETATE (100ml * 3) extraction, the combined ethyl acetate layer adds 20g anhydrous sodium sulfate drying 6h; Filter solvent evaporated obtains off-white color solid 1-benzoyl--4-trans-(methylsulfonyl oxygen)-D-proline(Pro) 5.2g.Yield 51%.
Embodiment 4. (2R, 4S)-preparation of 1-benzoyl--4-Phenylpyrrolidine-2-carboxylic acid
Add aluminum trichloride (anhydrous) (11.4g in the 250ml single necked round bottom flask; 0.086mol), benzene (75ml), ice-water bath cooling under the nitrogen protection, 1-benzoyl--4-is trans-(methylsulfonyl oxygen)-D-proline(Pro) (7.5g; 0.024mol) add in batches; 20min consuming time finishes (6～8 ℃ of interior temperature) stirring 4～5h under the ice-water bath altogether, rises to stirring at room 12h afterwards naturally.The TLC detection reaction is complete.The ice-water bath cooling dropwise adds 3N hydrochloric acid (the 22.5ml concentrated hydrochloric acid is dissolved in 67.5ml water) down, finishes to stir 2h under the ice-water bath, filter, and with frozen water (15ml * 2) washing leaching cake.Draw dried filter cake as far as possible, obtain the 6.5g white solid (2R, 4S)-1-benzoyl--4-Phenylpyrrolidine-2-carboxylic acid.Yield 92%
Embodiment 5. (2R, 4S)-preparation of 4-Phenylpyrrolidine-2-carboxylic acid hydrochloride
In 100ml single port bottle, take by weighing (2R, 4S)-(5g, 0.0169mol), the 50ml 6N HCl good dilution is added in the reaction flask reflux 20h to 1-benzoyl--4-Phenylpyrrolidine-2-carboxylic acid.Solvent evaporated adds 50ml EA and 50ml water, and the evaporate to dryness organic layer adds 10ml acetone making beating 5h, filtration obtain white solid (2R, 4S)-4-Phenylpyrrolidine-2-carboxylic acid 2g.Yield 51%, optical purity is greater than 99%.
MS(m/z)：192(M+H
+)
1H?NMR：(400MHz，CD
3OD)，δ(ppm)7.28-7.40(m，5H)，4.58-4.62(dd，1H)，3.73-3.79(m，1H)，3.67-3.72(m，1H)，3.32-3.37(m，1H)，2.85-2.92(m，1H)，2.18-2.27(dt，1H).
13C?NMR：(100MHz，DMSO-D
6)，δ(ppm)170.22，139.41，129.16，127.80，127.69，59.36，50.72，42.93，36.30.
The preparation of embodiment 6.L-oxyproline methyl ester hydrochloride
In the 250ml there-necked flask, add anhydrous methanol 100ml, ice bath stirs 0.5h down.Acetyl Chloride 98Min. (17.3g 0.22mol) splashes in the reaction solution, under this temperature of reaction, stirs 1h, L-oxyproline hydrochloride (20g 0.12mol) adds in batches, after reaction solution slowly is heated to backflow, react about 10h.Solvent evaporated gets 22g off-white color solid, and filter with 50ml acetone making beating 5hr the back, and vacuum-drying obtains 18.9g white solid L-oxyproline methyl ester hydrochloride.
The preparation of embodiment 7.1-benzoyl--L-oxyproline methyl esters
In the 250ml there-necked flask, add 90ml water and 45ml dioxane, (10.3g 0.057mol) adds L-oxyproline methyl ester hydrochloride in batches, and ice bath stirs 0.5h down; (12.6g 0.125mol), finishes, and slowly drips the Benzoyl chloride 99min. (8.13g with the dilution of 45ml dioxane to drip triethylamine; 0.0578mol), moving to normal temperature behind the stirring 3h, TLC detects to reacting completely; Solvent evaporated adds ETHYLE ACETATE 200ml and 100ml water, standing demix; Water layer is with ethyl acetate extraction (100 * 3), the combined ethyl acetate layer, and use saturated NaHCO respectively
3(50ml * 2), 10% Hydrocerol A (50ml*2) is used 20g anhydrous sodium sulfate drying 5h at last; Solvent evaporated gets off-white color solid 19.5g, adds 30ml ETHYLE ACETATE, making beating 5h; Filter, vacuum-drying gets 13.2g white solid 1-benzoyl--L-oxyproline methyl esters.
Embodiment 8.1-benzoyl--4-is trans-preparation of (methylsulfonyl oxygen)-L-proline methyl ester
In the 250ml there-necked flask, add the 150ml anhydrous methylene chloride, (14.7g 0.1mol) adds 1-benzoyl--L-oxyproline, and cryosel is bathed to stir down and is cooled to 0 ℃; (20.2g 0.2mol), stirs 10min to add triethylamine; (22.9g 0.2mol), stirs 1h under the ice bath to drip methane sulfonyl chloride; Forward room temperature to, reaction 8h, the TLC detection reaction is complete.Add entry (75ml*3) washing, solvent evaporated, with re-crystallizing in ethyl acetate obtain white solid 1-benzoyl--4-trans-(methylsulfonyl oxygen)-L-proline methyl ester 8.6g.
Embodiment 9.1-benzoyl--4-is trans-preparation of (methylsulfonyl oxygen)-L-proline(Pro)
In the 250ml single port bottle, add 100ml toluene, add in batches 1-benzoyl--4-trans-(methylsulfonyl oxygen)-L-proline methyl ester (10g; 0.031mol), low temperature is bathed down to 0～5 ℃, and (1.86g sodium hydroxide is dissolved in 46.5ml water dropwise to add aqueous sodium hydroxide solution; 0.0465mol), 0～5 ℃ is stirred 5～6h, and TLC detects; Complete hydrolysis is regulated pH=4 with concentrated hydrochloric acid under 0～5 ℃, moves to room temperature; Add ethyl acetate extraction (100ml * 2), combined ethyl acetate, solvent evaporated obtains 8.9g off-white color solid 1-benzoyl--4-trans-(methylsulfonyl oxygen)-L-proline(Pro).
Embodiment 10. (2S, 4R)-preparation of 1-benzoyl--4-Phenylpyrrolidine-2-carboxylic acid
Add aluminum trichloride (anhydrous) (11.4g in the 250ml there-necked flask; 0.086mol), benzene (100ml); Ice-water bath cooling, 1-benzoyl--4-is trans-and (7.5g 0.024mol) adds (methylsulfonyl oxygen)-L-proline(Pro) in batches; (6～8 ℃ of interior temperature) stirs 4～5h under the ice-water bath, rises to stirring at room 12h afterwards naturally.The TLC detection reaction is complete.Ice-water bath cooling dropwise adds 3N hydrochloric acid (the 22.5ml concentrated hydrochloric acid is dissolved in 67.5ml water) down, finish and stir 2h ice-water bath under, filtration, and with frozen water (15ml * 2) washing leaching cake obtain the 5.2g white solid (2S, 4R)-1-benzoyl--4-Phenylpyrrolidine-2-carboxylic acid.
Embodiment 11. (2S, 4R)-preparation of 4-Phenylpyrrolidine-2-carboxylic acid hydrochloride
Add in the 250ml single port bottle (2S, 4R)-(5g, 0.017mol), water (50ml), concentrated hydrochloric acid (50ml), reflux state stirs 20h down to 1-benzoyl--4-Phenylpyrrolidine-2-carboxylic acid.The TLC detection reaction is complete, is evaporated to driedly, adds entry (100ml), extracts with ETHYLE ACETATE (50mL * 2); Water is evaporated to dried, adds 20ml acetone, stirs 5h, filters; Obtain the 2.8g white solid (2S, 4R)-4-Phenylpyrrolidine-2-carboxylic acid, pure greater than 99% through detection optical.
MS(m/z)：192(M+H
+)
1H?NMR：(400MHz，CD
3OD)，δ(ppm)7.28-7.40(m，5H)，4.58-4.62(dd，1H)，3.73-3.79(m，1H)，3.67-3.72(m，1H)，3.32-3.37(m，1H)，2.85-2.92(m，1H)，2.18-2.27(dt，1H).
13C?NMR：(100MHz，CD
3OD)，δ(ppm)169.59，137.70，128.64，127.36，126.85，59.57，50.91，43.32，35.91.
The preparation of embodiment 12.1-benzoyl--4-cis-(methylsulfonyl oxygen)-D-proline methyl ester
In the 250ml there-necked flask, add the 150ml anhydrous methylene chloride, (14.7g 0.1mol) adds 1-benzoyl--D-oxyproline methyl esters, and cryosel is bathed to stir down and is cooled to 0 ℃; (20.2g 0.2mol), stirs 10min to add triethylamine; (22.9g 0.2mol), stirs 1h under the ice bath to drip methane sulfonyl chloride; Forward room temperature to, reaction 8h, TLC detects.Add entry (75ml * 3) washing, solvent evaporated, column chromatography obtains white solid 1-benzoyl--4-cis-(methylsulfonyl oxygen)-D-proline methyl ester 5.2g.
The preparation of embodiment 13.1-benzoyl--4-cis-(methylsulfonyl oxygen)-D-proline(Pro)
In the 250ml single port bottle, add 100ml toluene, add 1-benzoyl--4-cis-(methylsulfonyl oxygen)-D-proline methyl ester (10g in batches; 0.031mol), low temperature is bathed down to 0～5 ℃, and (1.86g sodium hydroxide is dissolved in 46.5mL water dropwise to add aqueous sodium hydroxide solution; 0.0465mol), 0～5 ℃ is stirred 5～6h, and TLC detects complete hydrolysis; Regulate pH=4 with concentrated hydrochloric acid under 0～5 ℃, move to room temperature, add ethyl acetate extraction (100ml * 2); Combined ethyl acetate, solvent evaporated obtain 8.2g off-white color solid 1-benzoyl--4-cis-(methylsulfonyl oxygen)-D-proline(Pro).
Embodiment 14. (2R, 4R)-preparation of 1-benzoyl--4-Phenylpyrrolidine-2-carboxylic acid
Add aluminum trichloride (anhydrous) (11.4g in the 250ml there-necked flask; 0.086mol), benzene (100ml); (7.5g 0.024mol) adds in batches for ice-water bath cooling, 1-benzoyl--4-cis-(methylsulfonyl oxygen)-D-proline(Pro); (6～8 ℃ of interior temperature) stirs 4～5h under the ice-water bath, rises to stirring at room 12h afterwards naturally.The TLC detection reaction is complete.The ice-water bath cooling down; Dropwise add 3N hydrochloric acid (the 22.5ml concentrated hydrochloric acid is dissolved in 67.5ml water); Finish and stir 2h under the ice-water bath, add ethyl acetate extraction (150ml * 2), combined ethyl acetate; Evaporate to dryness ETHYLE ACETATE obtain the thick material of 5.6g (2R, 4R)-1-benzoyl--4-Phenylpyrrolidine-2-carboxylic acid.
Embodiment 15. (2R, 4R)-preparation of 4-Phenylpyrrolidine-2-carboxylic acid hydrochloride
Add in the 250ml single port bottle (2R, 4R)-(3g, 0.01mol), water (20ml), concentrated hydrochloric acid (20ml), reflux state stirs 20h down to 1-benzoyl--4-Phenylpyrrolidine-2-carboxylic acid.The TLC detection reaction is complete, is evaporated to driedly, adds entry (50ml), and with ETHYLE ACETATE (50ml * 2) extraction, water is evaporated to dried, adds 10ml acetone, stirs 5h, filters, and obtains the 1.2g white solid, and is pure greater than 99% through detection optical.
MS(m/z)：192(M+H
+)，
1H?NMR：(400MHz，CD
3OD)，δ(ppm)7.29-7.39(m，5H)，4.68-4.72(dd，1H)，3.83-3.88(dd，1H)，3.51-3.59(m，1H)，3.32-3.37(m，1H)，2.66-2.73(m，1H)，2.53-2.59(m，1H).
13C?NMR：(100MHz，CD
3OD)，δ(ppm)170.07，137.99，128.66，137.34，126.93，59.34，51.29，41.91，35.56.
Claims (9)
1. preparation method suc as formula the compound or its salt shown in the A may further comprise the steps:
(1) will obtain suc as formula the compound shown in 6 through over-churning suc as formula the compound shown in 5,
(2) will suc as formula the compound shown in 6 after the hydroxyl protecting group protection, obtain suc as formula the compound shown in 7,
(3) will obtain suc as formula the compound shown in 8 suc as formula the compound shown in 7 through the sulphur esterification,
(4) will obtain suc as formula the compound shown in 9 suc as formula the compound shown in 8 through the Fu Ke alkylated reaction,
(5) will be suc as formula the compound shown in 9 through hydrolysis reaction, obtain suc as formula the compound shown in 10 and
(6) will and after acidifying, obtain corresponding salt suc as formula the compound deprotection shown in 10 suc as formula the compound shown in the A;
R wherein
1Be aryl or substituted aryl;
Said acid is selected from mineral acid or organic acid.
2. preparation method suc as formula the compound or its salt shown in the B specifically may further comprise the steps:
(1) will obtain suc as formula the compound shown in 15 through over-churning suc as formula the compound shown in 14,
(2) will suc as formula the compound shown in 15 after the hydroxyl protecting group protection, obtain suc as formula the compound shown in 16,
(3) will obtain suc as formula the compound shown in 17 suc as formula the compound shown in 16 through the sulphur esterification,
(4) will obtain suc as formula the compound shown in 18 suc as formula the compound shown in 17 through the Fu Ke alkylated reaction,
(5) will be suc as formula the compound shown in 18 through hydrolysis reaction, obtain suc as formula the compound shown in 19 and
(6) will and after acidifying, obtain corresponding salt suc as formula the compound deprotection shown in 19 suc as formula the compound shown in the B;
R wherein
2Be aryl or substituted aryl;
Said acid is selected from mineral acid or organic acid.
3. preparation method suc as formula the compound or its salt shown in the C specifically may further comprise the steps:
(1) will obtain suc as formula the compound shown in 6 through over-churning suc as formula the compound shown in 5,
(2) will obtain suc as formula the compound shown in 7 suc as formula behind the protection base on the compound shown in 6,
(3) will obtain suc as formula the compound shown in 11 suc as formula the compound shown in 7 through the sulphur esterification,
(4) will obtain suc as formula the compound shown in 12 suc as formula the compound shown in 11 through the Fu Ke alkylated reaction,
(5) will be suc as formula the compound shown in 12 through hydrolysis reaction, obtain suc as formula the compound shown in 13 and
(6) will and after acidifying, obtain corresponding salt suc as formula the compound deprotection shown in 13 suc as formula the compound shown in the C;
R wherein
1Be aryl or substituted aryl;
Said acid is selected from mineral acid or organic acid.
4. like the described preparation method of the arbitrary claim of claim 1 to 3, it is characterized in that: wherein said acid is selected from hydrochloric acid, sulfuric acid, acetate, methylsulfonic acid, phosphoric acid, Citric Acid or tartrate.
5. preparation method as claimed in claim 4 is characterized in that described acid is hydrochloric acid or acetate.
6. like claim 1 or 3 described preparing methods, it is characterized in that described R
1Be phenyl, the substituted phenyl of low alkyl group or the substituted phenyl of halogen atom.
7. preparation method as claimed in claim 6 is characterized in that described R
1Be phenyl.
8. preparation method as claimed in claim 2 is characterized in that described R
2Be phenyl, the substituted phenyl of low alkyl group or the substituted phenyl of halogen atom.
9. preparation method as claimed in claim 8 is characterized in that described R
2Be phenyl.
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|---|---|---|---|---|
| CN107365268A (en) * | 2016-05-11 | 2017-11-21 | 常州制药厂有限公司 | A kind of preparation method of depressor fosinopril sodium and its key intermediate |
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|---|---|---|---|---|
| US4912230A (en) * | 1988-09-16 | 1990-03-27 | E. R. Squibb & Sons, Inc. | Process for stereochemically inverting a hydroxy function of an ester by a modified Mitsunobu reaction process |
| US4912231A (en) * | 1987-06-15 | 1990-03-27 | E. R. Squibb & Sons, Inc. | Process for preparing (trans)-4-phenyl-L-proline derivatives |
| CN101367839A (en) * | 2007-08-14 | 2009-02-18 | 常州华生制药有限公司 | Preparation method for fosinopril and its salt |
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2011
- 2011-08-06 CN CN2011102242533A patent/CN102344399A/en active Pending
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| US4912231A (en) * | 1987-06-15 | 1990-03-27 | E. R. Squibb & Sons, Inc. | Process for preparing (trans)-4-phenyl-L-proline derivatives |
| US4912230A (en) * | 1988-09-16 | 1990-03-27 | E. R. Squibb & Sons, Inc. | Process for stereochemically inverting a hydroxy function of an ester by a modified Mitsunobu reaction process |
| CN101367839A (en) * | 2007-08-14 | 2009-02-18 | 常州华生制药有限公司 | Preparation method for fosinopril and its salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107365268A (en) * | 2016-05-11 | 2017-11-21 | 常州制药厂有限公司 | A kind of preparation method of depressor fosinopril sodium and its key intermediate |
| CN107365268B (en) * | 2016-05-11 | 2021-02-05 | 常州制药厂有限公司 | Preparation method of antihypertensive drug fosinopril sodium and key intermediate thereof |
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