(19) TZZ¥Z__T (11) EP 3 015 456 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 153(4) EPC (43) Date of publication: (51) Int Cl.: 04.05.2016 Bulletin 2016/18 C07D 207/22 (2006.01) C07D 207/46 (2006.01) C07D 207/16 (2006.01) (21) Application number: 14816731.5 (86) International application number: (22) Date of filing: 23.06.2014 PCT/CN2014/080520 (87) International publication number: WO 2014/206257 (31.12.2014 Gazette 2014/53) (84) Designated Contracting States: • LI, Yuanqiang AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Taizhou GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Zhejiang 318000 (CN) PL PT RO RS SE SI SK SM TR • CHE, Daqing Designated Extension States: Taizhou BA ME Zhejiang 318000 (CN) • QIAN, Lingfeng (30) Priority: 26.06.2013 CN 201310261857 Taizhou 19.11.2013 CN 201310580894 Zhejiang 318000 (CN) 10.06.2014 CN 201410255311 • ZHU, Guoliang Taizhou (71) Applicant: Zhejiang Jiuzhou Pharmaceutical Co., Zhejiang318000 (CN) Ltd. • YE, Wenfa Jiaojiang District Taizhou Taizhou City Zhejiang 318000 (CN) Zhejiang 318000 (CN) (74) Representative: Pharma Concepts GmbH (72) Inventors: Unterer Rheinweg 50 • ZHANG, Bin 4057 Basel (CH) Taizhou Zhejiang 318000 (CN) (54) PREPARATION METHOD FOR PYRROLIDINE-2-CARBOXYLIC ACID DERIVATIVES (57) The present invention relates to the field of med- ical synthesis, in particular to a preparation method for pyrrolidine-2-carboxylic acid derivatives. The present in- vention adopts the following technical solution: providing a compound having a structure of formula (E), wherein R is R1 or R2, R1 is C1-C6 an alkyl, benzyl, p-methoxy- benzyl, or p-nitrobenzyl group, and R2 is hydrogen; R3 is a protecting group of the carboxyl group; and P1 is a protecting group on nitrogen. EP 3 015 456 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 015 456 A1 Description [0001] This application claims the priority of China Patent Application No. 201310261857.4, 201310580894.1 and 201410255311.2 filed with the Patent Office of China on June 26, 2013, November 19, 2013 and June 10, 2014 suc- 5 cessively titled "Preparation method for pyrrolidine-2-carboxylic acid derivatives", the contents of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION 10 [0002] The present invention relates to the field of medical synthesis, in particular to a preparation method for pyrrolidine- 2-carboxylic acid derivatives. BACKGROUND OF THE INVENTION 15 [0003] The following compound Z is the most common intermediate used in the field of medical synthesis, 20 25 Wherein Y is a hydrogen atom or C1∼C6 alkyl. M is a hydrogen atom or a protecting group on nitrogen. X is a hydrogen atom or a protecting group of carboxyl. 30 [0004] Currently, there are a limited number of routes for preparing the above-mentioned compound, in which the yields are mostly low and the starting material is difficult to be produced. [0005] When Y is a hydrogen atom, M is t-butyloxycarboryl (Boc), and X is methyl, compound Z has the following structure of formula Z-1, 35 40 45 [0006] The PCT patent application No. WO2009118759 disclosed a method for preparing compound Z-1, which can be summarized as follows: 50 55 [0007] Wherein 9-BBN is abbreviation for 9-Borabicyclo[3.3.1]nonane, the yield is 46% in the first step, and it’s 56% in the second step. 2 EP 3 015 456 A1 [0008] When Y is a hydrogen atom, M is t-butyloxycarbonyl (Boc), and X is tert-butyl, the said compound is represented by the following formula: 5 10 [0009] The same route for preparing the above-mentioned compound was disclosed in both Bioorganic & Medicinal Chemistry Letters,21,(12),3771-3773,2011 and PCT patent application No. WO2004039367, which can be summarized 15 as follows: 20 25 [0010] The yield is 41% in Bioorganic & Medicinal Chemistry Letters, 21, (12), 3771-3773, 2011, and 27% in WO2004039367. [0011] When Y is methyl, M is t-butyloxycarbonyl and X is methyl, the said compound can be represented by formula Z-3. When Y is methyl, M is t-butyloxycarbonyl (Boc) and X is a hydrogen atom, the compound has the structure of 30 formula Z-4: 35 40 [0012] PCT patent application with publication No. WO 2012068234 disclosed the following method for preparing the two aforesaid compounds on page 876. 45 50 55 3 EP 3 015 456 A1 [0013] The above-mentioned methods are difficult to realize commercial production due to the use of high toxicity chemical such as 9-BBN, borane and sodium cyanide etc., and difficult operation processes. Therefore, it is necessary to provide novel methods to prepare the compound of formula Z. 5 SUMMARY OF THE INVENTION [0014] The present invention adopts the following technical solution: providing a compound having a structure of formula E, 10 15 20 wherein the position marked with * represents a chiral center, specifically, the configuration of carbon marked with * maybe R, or maybe S, or even may be the mixture of R and S. [0015] Preferably, the compound E has the following configuration, 25 30 R is R1 or R2, R1 is C1∼C6 alkyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, R2 is a hydrogen atom; 35 R3 is a protecting group for carboxyl; P1 is a protecting group of nitrogen. [0016] Specifically, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-amyl or n-hexyl; R3 is n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-amyl, n-hexyl, benzyl, triphenylmethyl, p-methoxybenzyl or p- 40 nitrobenzyl. P1 is acetyl, trifluoroacetyl, allyloxycarbonyl, t-butyloxycarbonyl(Boc), trimethylsilyl (TMS), tert-butyldimethylsilyl (TB- DMS), benzoyl, triphenylmethyl, p-methoxybenzyl, benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl (Moz), p- nitrobenzyl, m-nitrobenzyl, p-chlorobenzyl, m-chlorobenzyl, p-bromobenzyl, m-bromobenzyl or benzyl. [0017] Preferably, R 1 is C 1∼C6 alkyl; R 3 is tert-butyl, benzyl, p-methoxybenzyl or p-nitrobenzyl; P 1 is t-butyloxycarbonyl, 45 p-methoxybenzyl or carboxybenzyl. [0018] More preferably, R1 is methyl; R3 is tert-butyl or benzyl; P1 is t-butyloxycarbonyl. Preferably, the compound E can be described by the compound of formula e1 when R is R 1: 50 55 4 EP 3 015 456 A1 wherein R1, R3 and P1 are as defined above. [0019] The compound of formula e1 is obtained from the compound of formula g and formic mixed anhydride or alkyl formate by cyclization reaction. 5 10 wherein R3, R1 and P1 are as defined above. [0020] The cyclization reaction was performed in the presence of strong base which has the ability to remove a-H. [0021] Further, the reaction yield can be improved by adding an acid. 15 [0022] The formic mixed anhydride can be selected from formic anhydride, acetic formic anhydride, formic pivalic anhydride and formic benzoic anhydride. [0023] The alkyl formate can be selected from methyl formate, ethyl formate, propyl formate and isopropyl formate. [0024] The strong base may be selected from lithium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, sodium hydride, sodium alcoholate and potassium alcoholate. The preferable sodium alcoholate may be selected from 20 sodium methoxide, sodium ethoxide and sodium isopropylate; the preferable potassium alcoholate may be potassium methoxide, potassium ethoxide, potassium isopropoxide. [0025] The acid may be trifluoroacetic acid or acetic acid. [0026] The compound g was obtained by reacting the compound of formula h with (R3CO)2 or R3X in the presence of base, 25 30 wherein R1, R3 and P1 is as defined above, X is a halogen atom, preferably Br or Cl. [0027] The said base may be 4-(dimethylamino)pyridine (DMAP), triethylamine, pyridine, tetramethyl guanidine, 1,8- 35 diazabicyclo[5.4.0]undec-7-ene (DBU), sodium carbonate, potassium carbonate or lithium carbonate. [0028] The preferred solvent employed may include R 3OH, DMF, THF or acetonitrile. [0029] The compound E can be represented by formula e1 when R is R1, 40 45 wherein R1, R3 and P1 is as defined above. 50 [0030] The compound E is represented by formula e2 when R is R 2 (a hydrogen atom). 55 5 EP 3 015 456 A1 5 10 [0031] In this case, the said compound of formula e1 is hydrolyzed to generate the compound of formula e2. The preferred reaction reagent for the hydrolysis may be alkali base, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and so on. [0032] In another aspect, the compound of formula E is subjected to catalytic hydrogenation to obtain the compound 15 of formula D, 20 25 wherein R5 is a hydrogen atom or C1∼C6 alkyl, the specific example is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. 30 R6 is a hydrogen atom, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl. P2 is a hydrogen atom, acetyl, trifluoroacetyl, allyloxycarbonyl, t-butyloxycarbonyl (Boc), trimethylsilyl (TMS), tert- butyldimethylsilyl (TBDMS) or benzoyl. [0033] The catalyst for catalytic hydrogenation may be selected from palladium on carbon, platinum oxide, RaneyNi 35 as well as chiral catalyst. [0034] The said chiral catalyst maybe the compound represented by formula M1 or formula M2 40 45 wherein DTB is 50 55 6 EP 3 015 456 A1 X is C1~C4 alkyl. [0035] Furthermore, the compound of formula D is reduced to the compound of formula c1. 5 10 wherein R6 and P2 are as defined above. [0036] The reducing agent employed in the process above may be tributyltin hydride, triphenyltin hydride, triethyl 15 silicane, trichlorosilane, sodium borohydride, sodium trimethoxyborohydride, lithium tri-sec-butylhydridoborate, potas- sium Tri-Sec-Butylborohydride, lithium triethylborohydride, diisobutyl aluminium hydride (DIBAH) or sodium bis(2-meth- oxyethoxy)aluminiumhydride; preferably, when R 5 of compound D is a hydrogen atom, the carboxyl group can be reduced to the hydroxy group under mild reaction condition with the decrease of the formation of impurities by the activation with the addition of alkyl chloroformate such as ClCOOEt, ClCOOMe and so on to generate a mixed acid anhydride first.