- Preparation method of antihypertensive medicine key intermediate of trans-4-cyclohexyl-L-proline
-
The invention discloses a preparation method of trans-4-cyclohexyl-L-proline. The method comprises the following steps of (1) under the effect of an acid-binding agent, 4S-hydroxy-N-Boc-L-proline ester 6 and sulfonyl chloride are subjected to condensation to generate sulphonate 5, wherein R is C1-4 alkyl; (2) under the effects of a copper catalyst, lithium salt and organic alkali, the sulphonate 5and cyclohexylmagnesium bromide take nucleophilic substitution to generate a compound 4; (3) the compound 4 is hydrolyzed by lithium hydroxide to obtain (4S)-N-Boc-4-cyclohexyl-L-proline (a compound3); (4) the compound 3 is subjected to Boc removal under the condition of hydrochloric acid or trifluoroacetic acid/methylene dichloride; a target product 2 is prepared. The preparation method has thebeneficial effects that the target product structure and chirality are introduced through sulphonate and Grignard reagent nucleophilic substitution; the defects of the existing noble metal reductionmethod are overcome; the operation of the method is simple; the conditions are mild; the yield is good; the chemical purity and the optical purity are very high; the preparation method is suitable forindustrial production.
- -
-
-
- Preparation methods of antihypertensive Fosinopril sodium and key intermediate thereof
-
The invention relates to preparation methods of an antihypertensive Fosinopril sodium and a key intermediate thereof trans-4-phenyl-L-proline suitable for industrial production. Synthesis of the key intermediate trans-4-phenyl-L-proline has high chiral selectivity, and the method is simple and easy to operate.
- -
-
-
- A practical synthesis of optically active δ-nitro-α-ketoesters and 4-cyclohexyl-proline catalyzed by chiral squamides
-
Inexpensive and readily available squamides derived from 9-amino-9-deoxyepiquinine or 9-amino-9-deoxyepiquinidine were found to be superior catalysts for the asymmetric conjugate additions of t-butyl nitroacetate to β,γ-unsaturated-α-ketoesters. After the subsequent decarboxylation with silica gel, a variety of δ-nitro-α-ketoesters were obtained in good yields and with excellent enantioselectivities. The products were further transformed into ethyl 4-aryl-prolinate via a cascade nitro reduction and amination. A new synthesis of (2S,4S)-4-cyclohexyl-proline was also developed. A practical synthesis of optically active δ-nitro-α-ketoesters and 4-aryl-proline derivatives is described.
- Liu, Ri-Long,Yan, Yun-Yun,Zhang, Ting,Zhang, Xue-Jing,Yan, Ming
-
p. 1416 - 1422
(2015/12/09)
-
- A convenient method for synthesis of trans-4-cyclohexyl-L-proline
-
A convenient method for the synthesis of the fosinopril precursor, trans-4-cyclohexyl-L-proline 1, has been developed. A highly stereoselective alkylation of N-benzyl-pyroglutamic acid 2 with 3-bromocyclohexene at -10°C and subsequent hydrogenolysis affor
- Chen, Xiao,Du, Da-Ming,Hua, Wen-Ting
-
-
- Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines
-
Analogues of captopril, enalaprilat, and the phosphinic acid [[hydroxy(4-phenylbutyl)phosphinyl]acetyl)-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
- Krapcho,Turk,Cushman,Powell,DeForrest,Spitzmiller,Karanewsky,Duggan,Rovnvak,Schwartz,Natarajan,Godfrey,Ryono,Neubeck,Atwa,Petrillo Jr.
-
p. 1148 - 1160
(2007/10/02)
-
- Process and intermediates for preparing trans-4-substituted-s-prolines
-
4-Substituted proline derivatives having the formula STR1 can be prepared by reacting the compound having the formula STR2 with a compound having the formula STR3 to obtain a compound having the formula STR4 (a novel intermediate), alkylating that compoun
- -
-
-
- Conversion of L-Pyroglutamic Acid to 4-Alkyl-Substituted L-Prolines. The Synthesis of trans-4-Cyclohexyl-L-proline
-
(S)-5-(Hydroxymethyl)-2-pyrrolidinone (3), prepared from L-pyroglutamic acid, was condensed with benzaldehyde to obtain the O,N-acetal 4 in excellent yield.Alkylation of 4 with 3-bromocyclohexene followed by reduction gave trans-4-cyclohexyl-L-prolinol (7) in good chemical yield with excellent stereoselectivity.Sequential N-protection, oxidation of the alcohol to the acid, and N-deprotection furnished trans-4-cyclohexyl-L-proline (1) in excellent yield and quality.Compound 1 serves as an intermediate for the preparation of ACE inhibitors including Fosenopril.
- Thottathil, John K.,Moniot, Jerome L.,Mueller, Richard H.,Wong, Michael K. Y.,Kissick, Thomas P.
-
p. 3140 - 3143
(2007/10/02)
-