CN109970648B - Method for catalyzing single protection of diaza aliphatic ring tert-butyloxycarbonyl by amidine and analogue thereof - Google Patents

Method for catalyzing single protection of diaza aliphatic ring tert-butyloxycarbonyl by amidine and analogue thereof Download PDF

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CN109970648B
CN109970648B CN201910225812.9A CN201910225812A CN109970648B CN 109970648 B CN109970648 B CN 109970648B CN 201910225812 A CN201910225812 A CN 201910225812A CN 109970648 B CN109970648 B CN 109970648B
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马梦林
程泓睿
杨露
曹永静
詹庆明
马梦森
杨维清
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Xihua University
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    • C07D231/04—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
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Abstract

The invention relates to a green synthesis method for single Boc protection of a diaza-aliphatic ring under the catalysis of amidine and analogues thereof. It is characterized by that various diaza-aliphatic cyclic compounds use water and alcohol as solvent, in the presence of a certain quantity of acid, amidine and its analogue catalyst are added, di-tert-butyl dicarbonate (Boc anhydride) is used as Boc protecting reagent, and reacted at a certain temp., and finally the target product mono-N-Boc-diaza-aliphatic cyclic compound is obtained by reduced pressure distillation separation. The invention innovatively uses amidine and analogues thereof as the single Boc protection catalyst, and is more environment-friendly, safer and cost-saving compared with the traditional synthetic method.

Description

Method for catalyzing single protection of diaza aliphatic ring tert-butyloxycarbonyl by amidine and analogue thereof
Technical Field
The invention belongs to the field of a medical intermediate synthesis process, and particularly relates to a green synthesis method for preparing a corresponding single Boc diaza-alicyclic compound through a diaza-alicyclic ring in the presence of an amidine and analogue catalyst thereof.
Background
The structures of 1-Boc-1, 3-diazetidine (formula 1), 1-Boc-1, 2-diazetidine (formula 2), 1-Boc-1, 2-imidazolidine, 1-Boc-1, 3-imidazolidine, 1-Boc piperazine, 1-Boc pyridazine, 1-Boc pyrimidine, 1-Boc-1, 2-diazepane, 1-Boc-1, 3-diazepane, and 1-Boc-1, 4-diazepane are shown below as common unit structures of drugs (formula 1).
Figure 830181DEST_PATH_IMAGE001
According to the literature reports:
the synthesis method of 1-Boc-1, 3-imidazolidine comprises the following steps:
the "Preparation of diamines by dissociation-catalysis of imidazole and pyrimidines" published in 2003 by Neil J. Ashweek, Iain Colldmam et al, writes to N-benzylethylenediamine, formaldehyde as raw material and CHCl as pesticides under nitrogen protection3The mixture is taken as a solvent and stirred for 18 hours at room temperature, and then di-tert-butyl dicarbonate is added for reaction for 18 hours. Thus obtaining the 3-benzyl-1-tert-butyloxycarbonylimidazole. ARNOLD, Lee Daniel et Al 2016, reported in WO 2016/168619 Al: under the protection of argon, DCM is used as a solvent, raw materials of N-benzyl imidazole, di-tert-butyl dicarbonate and triethylamine are added at 0 ℃ to serve as an alkali reagent, and the mixture reacts for 6 hours at room temperature to obtain 3-benzyl-1-tert-butoxycarbonylimidazole; then methanol is used as a solvent, 10 percent Pd/C is used as a catalyst, and benzyl is removed through catalytic hydrogenation reaction to obtain the 1-tert-butyloxycarbonylimidazole 87 percent. The reaction equation (formula 2) is as follows.
Figure 731010DEST_PATH_IMAGE002
The synthesis method of the 1-Boc-1, 2-imidazolidine comprises the following steps:
the synthesis of 1-Boc-1, 2-imidazolidine was reported by "JACS" in Rosa E, Melendez and William D, Lubell 2003 and by "Impact of Azaproline on Amide Cis-Trans isometrism: structural analytes and NMR students of Model Peptides Including TRH analytes" in Wei-Jun Zhang, Anders Berglund et al 2002: adding N-benzyloxycarbonyl-N-tert-butoxycarbonylhydrazine and NaH at 0 ℃ by taking DMF as a solvent, stirring at room temperature for 30min, adding 1, 3-dibromopropane, and stirring overnight to obtain 1-tert-butoxycarbonyl-2-benzyloxycarbonyl imidazole; using 10% Pd/C as catalyst and methanol as solvent, catalyzing and hydrogenating at room temperature under 1atm H2 to remove carbobenzoxy to obtain 1-tert-butyloxycarbonylimidazole 95%. The reaction equation is as follows (formula 3).
Figure 182851DEST_PATH_IMAGE003
。
The synthesis method of 1-Boc-piperazine mainly comprises two types, namely a first type: di-tert-butyl dicarbonate is not used as a raw material; the second type: di-tert-butyl dicarbonate is used as a raw material.
Louis A. Carpino et al reported in "Polystyrene-Based Deblocking-screening Agents" published in 1983 for the 9-fluorinated methyl vinyl Amino-Protecting Group "that one equivalent of t-butyl azidoformate and one equivalent of piperazine were used as starting materials, and CH2Cl2 was used as a solvent, and the reaction was carried out at room temperature to obtain 80% 1-Boc-piperazine. CN106810467A of Wangchun, 2017, also reported that a solution of t-butyl azidoformate in isopropyl ether was used as a raw material, and the raw material was reacted at 15 ℃ for 4 hours with ethanol and water as solvents (ethanol: water 2: 1) to obtain 66.9% 1-Boc-piperazine. The reaction equation is as follows (formula 4).
Figure 765011DEST_PATH_IMAGE004
Kyree Pappas et al, 2009, "Phenyl esters, preferred reagents for mono-acylation of polyamines in the presence of water" reported a reaction of one equivalent of PhOBoc and one equivalent of piperazine as starting materials in water as a solvent under nitrogen for 24 h. 68% of 1-Boc-piperazine obtained by room temperature reaction, 87% of product obtained by 55 ℃ reaction, and 71% of product obtained by heating reflux reaction. The reaction equation is as follows (formula 5).
Figure 517066DEST_PATH_IMAGE005
Hiroyuki Naito et al, in the 2010 article "Selective protection of Methanesulfonamides to Amines" reported Deprotection of methanesulfonamide to its parent amine by deprotonation and 02 oxidation. The reaction equation is as follows (equation 6).
Figure 930075DEST_PATH_IMAGE006
The second kind uses di-tert-butyl dicarbonate as raw material and has several reaction conditions and catalyst systems, mainly including
1) The reaction does not add acid or alkali
An article published by Iman A, Moussa et al in JMC in 2010 "Design, Synthesis, and Structure-Affinity Relationships of registration N-Benzyl Alkyl ether piperazine Derivatives as. sigma. -1 Receptor Ligands" reported two equivalents of piperazine and one equivalent of di-tert-butyl dicarbonate, CH2Cl2As a solvent, reaction was carried out at room temperature for 22h to obtain 1-Boc-piperazine (81%). Andrea Faust et al 2008 in the article "Synthesis and Evaluation of a Novel Fluorescent Photoprobe for ImagingMatrix Metalloteinases" used the same reaction conditions to obtain 1-Boc-piperazine (68%). The reaction equation is as follows (equation 7).
Figure 180796DEST_PATH_IMAGE007
Hailin Zheng et al 2005 published in Bioorganic & Medicinal Chemistry using di-tert-butyl dicarbonate (12.77 mmol), piperazine (23.22 mmol), methanol as a solvent, added dropwise in an ice bath and reacted at room temperature for two days to give 1-Boc-piperazine in 71% yield. The yield (66%) was also reported by using methanol as a solvent in the article "Micelles for Delivery of Nitric Oxide" published in 2009 by Yun Suk Jo et al, equation (equation 8) below.
Figure 973172DEST_PATH_IMAGE008
Tanjun, catalytic source, Liu Zhede and the like in 2017 in the article 'green industrial preparation of N-tert-butyloxycarbonylpiperazine' report that the product (85.8%) is obtained by using a material ratio (Boc anhydride: piperazine) = 1: 3 and methanol: water (1: 5) as a reaction solvent, dropwise adding in an ice bath, and reacting at room temperature for 14 h. The reaction equation is as follows (formula 9).
Figure 314154DEST_PATH_IMAGE009
2) Alkali is added in the reaction
Laura C. Meurer et al, 1992, in J. Med. chem. published by the name of "J. Med. chem. reported that tert-butanol and water were used as solvents, NaOH was used as an acid-binding agent, di-tert-butyl dicarbonate was added dropwise at 5 ℃ and reacted overnight at room temperature to give 1-Boc-piperazine (78.8%). The reaction equation is as follows (equation 10).
Figure 291206DEST_PATH_IMAGE010
In the article published in 2011, "synthesis of intermediate of antidepressant drug vilazodone", methanol is used as solvent, triethylamine is used as acid-binding agent, and the reaction is carried out overnight at room temperature, thus obtaining the product (80%). The reaction equation is as follows (equation 11).
Figure 983219DEST_PATH_IMAGE011
3) Adding acid in the reaction:
jindelong, Zhang Xuemei, Liuhuan, and the like report that the molar ratio (1: 1.0) of anhydrous piperazine and di-tert-butyl dicarbonate is used as raw materials, glacial acetic acid is used as a medium, the reaction temperature is 0-5 ℃, the reaction time is 8 hours, and the reaction yield is 64.71 in a new synthesis process of N-tert-butyloxycarbonylpiperazine. The reaction equation is as follows (equation 12).
Figure 910111DEST_PATH_IMAGE012
In patent "CN 108003062A" published in 2017 by royal yuqin, jensenjin et al, water was used as solvent, one equivalent of piperazine and one equivalent of di-tert-butyl dicarbonate were used as raw materials, a 20% sulfuric acid solution was added to a piperazine aqueous solution at-5-0 ℃, stirred for 0.5h, and then di-tert-butyl dicarbonate was added for reaction at 0-5 ℃ for 1h, and the yield was 90% after treatment. The reaction equation is as follows (formula 13).
Figure 105600DEST_PATH_IMAGE013
4) Reaction with catalyst
The use of molecule I was reported by Ravi Varala, Sreelatha Nuvula et al 2006 in the article "Molecular Iodine-Catalyzed face Procedure for N-Boc Protection of Amines2The reaction was carried out at room temperature for 30min using equivalent amounts of di-tert-butyl dicarbonate and piperazine and methanol as a solvent to obtain a yield (80%). The reaction equation is as follows (equation 14).
Figure 987975DEST_PATH_IMAGE014
An ionic liquid methylimidazolium tetrafluoroborate [ (HMIm) BF4] as a catalyst was written by Sadila Sunitha, Sanjit Kanjilal et al, 2008 on Tetrahedron Letters, and an equivalent amount of di-tert-butyl dicarbonate was reacted with piperazine at room temperature to give 1-Boc-piperazine (98%). The reaction equation is as follows (equation 15).
Figure 167283DEST_PATH_IMAGE015
Biswanath Das et al, 2006, published in "Tetrahedron Letters" reported the use of sulfonic acid functionalized silica (Cat.) as a catalyst, CH2Cl2The single N-Boc protection of piperazine was performed as solvent to obtain 94% product. The reaction equation is as follows (equation 16).
Figure 832620DEST_PATH_IMAGE016
The synthesis method of 1-Boc pyridazine comprises the following steps:
KaNAYA, Naoaki, Daiichi Pharma. Co., Ltd. et al, patent EP1762568A1 issued in 2007 reported that 1-t-butoxycarbonylpyridazine 43% was obtained by reacting di-t-butyldicarbonate and hexahydropyridazine as raw materials at room temperature for 15 hours using methanol as a solvent. The reaction equation is as follows (equation 17).
Figure 679353DEST_PATH_IMAGE017
An article published in Bioorganic & Medicinal Chemistry by Tetsuya Toya, Kentaro Yamaguchi, Yasuyuki Endo et al 2002 reports that N-benzyloxycarbonyl-N-t-butoxycarbonylhydrazine and NaH were added at 0 ℃ in DMF as a solvent, stirred at room temperature for 30min, added with 1, 4-dibromobutane, and stirred overnight to give 91% of 1-t-butoxycarbonyl-2-benzyloxycarbonyl pyridazine; catalytic hydrogenation is carried out at room temperature under 1atm of H2 by taking 10% Pd/C as catalyst and methanol as solvent to remove carbobenzoxy, thus obtaining 98% of 1-tert-butoxycarbonylpyridazine. East, Andrew Ayscough, Ian touch-Johnson, et al, 2011 Bioorganic & Medicinal Chemistry Letters published in the same manner to obtain 94% 1-tert-butoxycarbonyl-2-benzyloxycarbonyl pyridazine; 78-100% of 1-tert-butyloxycarbonylpyridazine. Alanggudi Sankaranarayana, Ahmedabad (IN) patent US 2003O2251O2A1 published in 2003 was heated to reflux for 15h with ammonia carbonate, 1, 4-dibromobutane and N-benzyloxycarbonyl-N-t-butoxycarbonylhydrazine to give 83% 1-t-butoxycarbonyl-2-benzyloxycarbonylpyridazine; 5% Pd/C as a catalyst, methanol and water as a solvent, and carrying out catalytic hydrogenation under 3.4 atm of H2 for 6H to obtain 82% of 1-tert-butoxycarbonylpyridazine. The reaction equation is as follows (equation 18).
Figure 201470DEST_PATH_IMAGE018
The synthesis method of 1-Boc tetrahydropyrimidine comprises the following steps:
a report on the use of 1,4,5, 6-tetrahydropyridine and di-tert-butyl dicarbonate as starting materials and triethylamine as a base was published by Petar O. Nikiforov, Sachin Surde, et al, 2016, at org. Biomol. chemTetrahydrofuran as solvent and through overnight reaction at 0-20 deg.c to obtain 1-Boc-4,5, 6-trihydropyridine (66%), methanol as solvent and NaBH4Reacting at 0 ℃ for 2h to obtain 1-Boc tetrahydropyrimidine (64%). The reaction equation is as follows (equation 19).
Figure 868075DEST_PATH_IMAGE019
The synthesis method of 1-Boc-1, 2-diazepane comprises the following steps:
the synthesis method is similar to the 1-tert-butoxycarbonylpyridazine synthesis method reported in Tetsuya Toya, Kentaro Yamaguchi, Yasuyuki Endo et al 2002 by Bioorganic & Medicinal Chemistry, 1, 5-dibromopentane and N-benzyloxycarbonyl-N-tert-butoxycarbonylhydrazine are used as raw materials to synthesize 1-benzyloxycarbonyl-1, 2-diazacycloheptane-1-carboxylic acid tert-butyl ester, and the benzyloxycarbonyl is removed by catalytic hydrogenation to obtain 98% of 1, 2-diazacycloheptane-1-carboxylic acid tert-butyl ester. The reaction equation is as follows (equation 20).
Figure 130910DEST_PATH_IMAGE020
The synthesis method of 1-Boc-1, 4-diazepane comprises the following steps:
a publication in "Bioorganic & Medicinal Chemistry" by Grazia Sellitto, Aurora Faruolo et al 2010 reports that a solution of di-tert-butyl dicarbonate (2 g, 9mmol in 18mL of methylene chloride) was added dropwise to a solution of 0 deg.C methylene chloride (45 mL) and homopiperazine (1.84 g, 18 mmol) and stirred for 1 hour to give the desired compound 1-Boc-1, 4-diazepane (88%). The reaction equation is as follows (equation 21).
Figure 894467DEST_PATH_IMAGE021
In Wangcuchun, Chinese patent CN106810467A published in 2017 by willow-sensitive is applied tert-butyl azidoformate and homopiperazine to react in an organic solvent at 0-30 ℃, and then the homopiperazine protected by single Boc can be obtained. The reaction equation is as follows (equation 22).
Figure 603797DEST_PATH_IMAGE022
Disclosure of Invention
The invention selects diaza-aliphatic ring compound as substrate, methanol, ethanol or isopropanol and water with the same volume as solvent, acid as medium, amidine and analogues thereof as catalyst, and di-tert-butyl dicarbonate is used for single Boc protection reaction, and the synthetic route (Boc 2) is as follows (formula 23-formula 27):
Figure 6965DEST_PATH_IMAGE023
Figure 827154DEST_PATH_IMAGE024
Figure 569851DEST_PATH_IMAGE025
Figure 715661DEST_PATH_IMAGE026
Figure 340546DEST_PATH_IMAGE027
the invention relates to a green synthesis method for preparing a single Boc protected diazacyclo compound by amidine and analogues thereof, which comprises the following steps: dissolving a diaza-aliphatic cyclic compound in a mixed solution of alcohol and water, adding a proper amount of acid, stirring at low temperature for 30 minutes, continuing to add a catalytic amount of amidine and analogue catalyst and a certain amount of di-tert-butyl dicarbonate, continuing to react for about 2 hours after the addition is finished, detecting by GC, and adding a catalyst, a catalyst and a catalyst into the mixture, wherein the catalyst is a mixture of water, alcohol and waterConcentrating the reaction solution to recover the solvent, and then distilling under reduced pressure to obtain the target sheetN-Boc diazacyclo compound.
The specific method comprises the following steps:
the following examples illustrate specific process steps of the present invention, but are not intended to limit the invention.
Example 1.1 Synthesis of Boc-piperazine the procedure was as follows (formula 28):
Figure 26743DEST_PATH_IMAGE028
preparation of 1-Boc-piperazine: adding 10.3g (0.12 mol) of piperazine into a 500mL three-necked bottle, adding 150mL of methanol and 150mL of water, stirring until the piperazine is completely dissolved, adding 11.0g (0.21 mol) of formic acid, stirring for 0.5h, continuously adding 0.11g (0.0012 mol) of acetamidine hydrochloride catalyst and 8.73g (0.04 mol) of di-tert-butyl dicarbonate, stirring for 2h at room temperature, detecting and reacting by using a gas chromatography (GC retention time: 4.3min for raw material piperazine; 11.6min for target product 1-Boc-piperazine; 17.4min for impurity byproduct 1, 4-di-Boc-piperazine), concentrating and recovering solvent from the reaction solution after the reaction is completed, and then carrying out reduced pressure distillation and collecting 165-175oC/5mmHg fraction, 22.0g of the objective product was obtained, reaction yield 98.6%.
Example 2.1 Synthesis of Boc-piperazine the procedure was as follows (formula 29):
Figure 436995DEST_PATH_IMAGE029
preparation of 1-Boc-piperazine: adding 10.3g (0.12 mol) of piperazine into a 500mL three-necked flask, adding 150mL of methanol and 150mL of water, stirring until the piperazine is completely dissolved, adding 14.4g (0.24 mol) of acetic acid, stirring for 0.5h, adding 0.11g (0.0012 mol) of acetamidine hydrochloride catalyst and 8.73g (0.04 mol) of di-tert-butyl dicarbonate, stirring for 2h at room temperature, detecting the reaction by using gas chromatography (GC retention time: 4.3min for raw material piperazine; 11.6min for target product 1-Boc-piperazine; 17.4min for impurity byproduct 1, 4-di-Boc-piperazine), concentrating and recovering the reaction solution after the reaction is completelyThe solvent is distilled and collected under reduced pressure for 165-175oC/5mmHg fraction, 21.9g of the objective product was obtained, the reaction yield was 98.0%.
Example 3.1 Synthesis of Boc-piperazine the procedure was as follows (formula 30):
Figure 740325DEST_PATH_IMAGE030
preparation of 1-Boc-piperazine: adding 10.3g (0.12 mol) of piperazine into a 500mL three-necked bottle, adding 150mL of methanol and 150mL of water, stirring until the piperazine is completely dissolved, adding 16.5g (0.36 mol) of formic acid, stirring for 0.5h, continuously adding 0.072g (0.0012 mol) of urea catalyst and 8.73g (0.04 mol) of di-tert-butyl dicarbonate, stirring for 2h at room temperature, detecting and reacting by using gas chromatography (GC retention time: 4.3min for raw material piperazine; 11.6min for target product 1-Boc-piperazine; 17.4min for impurity byproduct 1, 4-di-Boc-piperazine), concentrating and recovering solvent after the reaction is complete, and then carrying out reduced pressure distillation and collecting 165-175oC/5mmHg fraction, 22.1g of the objective product was obtained, and the reaction yield was 98.9%.
Example 4.1 Synthesis of Boc-piperazine the procedure was as follows (formula 31):
Figure 868818DEST_PATH_IMAGE031
preparation of 1-Boc-piperazine: adding 10.3g (0.12 mol) of piperazine into a 500mL three-necked bottle, adding 150mL of ethanol and 150mL of water, stirring until the piperazine is completely dissolved, adding 17.5mL (0.21 mol) of concentrated hydrochloric acid, stirring for 0.5h, continuously adding 0.11g (0.0012 mol) of acetamidine hydrochloride catalyst and 8.73g (0.04 mol) of di-tert-butyl dicarbonate, stirring for 2h at room temperature, detecting and reacting by using a gas chromatography (GC retention time: 4.3min for raw material piperazine; 11.6min for target product 1-Boc-piperazine; 17.4min for impurity byproduct 1, 4-di-Boc-piperazine), concentrating and recovering solvent from reaction liquid after reaction is completed, and then carrying out reduced pressure distillation and collecting 165-175oC/5mmHg fraction, 21.1g of the objective product was obtained, the reaction yield was 94.4%.
Example 5.1-Boc-tetrahydropyrazole, the procedure is as follows (formula 32):
Figure 483339DEST_PATH_IMAGE032
preparation of 1-Boc-tetrahydropyrazole: adding 10g (0.14 mol) of pyridine into a 500mL three-necked bottle, adding a mixed solution of 150mL of methanol and 150mL of water, stirring until the pyridine is completely dissolved, adding 0.42mol of acid, stirring for 0.5h, continuously adding 0.072g (0.0012 mol) of urea catalyst and 8.73g (0.04 mol) of di-tert-butyl dicarbonate, stirring for 2h at room temperature, detecting the reaction by using gas chromatography (GC retention time: 3.8min for raw material piperazine; 10.3min for target product 1-Boc-piperazine; 15.9min for impurity byproduct 1, 4-di-Boc-piperazine), concentrating the reaction solution after the reaction is complete, recovering the solvent, and carrying out reduced pressure distillation and collection for 104-114 minoThe C/5mmHg fraction gave 23.0g of the desired product, in a reaction yield of 95.6%.
Example 6.1-Boc pyrimidine, procedure was as follows (formula 33):
Figure 482519DEST_PATH_IMAGE033
preparation of 1-Boc tetrahydropyrimidine: adding 10g (0.12 mol) of tetrahydropyrimidine into a 500mL three-necked bottle, adding 150mL of ethanol and 150mL of water, stirring until piperazine is completely dissolved, adding 17.5mL (0.21 mol) of concentrated hydrochloric acid, stirring for 0.5h, continuously adding 0.11g (0.0012 mol) of acetamidine hydrochloride catalyst and 8.73g (0.04 mol) of di-tert-butyl dicarbonate, stirring for 2h at room temperature, detecting the reaction by using gas chromatography (GC retention time: 4.6min for raw material piperazine; 11.9min for target product 1-Boc-piperazine; 17.8min for impurity byproduct 1, 4-di-Boc-piperazine), concentrating the reaction solution after the reaction is completed, recovering the solvent, and carrying out reduced pressure distillation to collect 165-175oC/5mmHg fraction, 21.7g of the objective product was obtained, and the reaction yield was 97.2%.
Example 7 single Boc protection diazacyclo compound GC analysis method:
adopting an Shimadzu GC-2014C type gas chromatograph, and adopting a gas chromatographic column:wondacap5 capillary chromatography column (column length: 30m, inner diameter: 0.25 mm, film thickness: 0.25um, maximum use temperature: 325 oC) Column temperature programmed heating of 50-220 deg.C, 10 deg.CoC/min, injector temperature 220oC, detector temperature 220oC，H2The pressure intensity is 0.1MPa, the air pressure is 0.16 MPa, and the front column pressure is 1.5 MPa.
The invention has the advantages that:
the method provided by the invention mainly uses amidine and analogues thereof as a single Boc protection catalyst of the diazacyclo compound, and has the following advantages:
(1) the single Boc protection of the diaza-aliphatic ring is catalyzed by cheap catalyst systems such as amidine or urea for the first time.
(2) The catalyst is added, so that the yield of the single Boc protected diaza-aliphatic cyclic compound is higher, the generation of the double Boc diaza-aliphatic cyclic compound is greatly reduced, the reaction selectivity is improved, the steps of separating and purifying a target product are reduced, and the cost is saved.
(2) The reaction operation steps are simple, the raw materials are easy to obtain, the reaction is carried out at normal temperature, the energy can be greatly saved, and the production cost is reduced.
(3) The amidine and the similar catalyst are added to accelerate the reaction, so that the reaction time is greatly reduced, and the production period is greatly shortened.
(4) The amidine and the like catalyst have low usage amount, do not influence the separation and purification and purity of the product, and are environment-friendly.

Claims (6)

1. A synthetic method for preparing a single N-Boc diazacyclo compound by using a diazacyclo compound as a starting material and acetamidine hydrochloride or urea as a catalyst comprises the following synthetic steps:
adding 3mol of diaza-aliphatic cyclic compound into a 1000mL reaction bottle, dissolving the diaza-aliphatic cyclic compound by using a mixed solution of alcohol and water, adding 9mol of acid into the reaction bottle, stirring the mixture at a low temperature for 30 minutes, continuously adding catalytic amount of acetamidine hydrochloride or urea and 1mol of di-tert-butyl dicarbonate, continuously reacting the mixture for about 2 hours after the addition is finished, detecting the reaction by using GC, and reacting the mixtureConcentrating the reaction solution, recovering solvent, and distilling under reduced pressure to obtain target sheetN-Boc diazacyclo compound.
2. The synthetic method according to claim 1, wherein the single N-Boc protected starting substrate diazahydroaliphatic ring has the following structural formula:
Figure 616935DEST_PATH_IMAGE001
。
3. the method of claim 1, wherein the target product is a mono-N-Boc protected diazahiphatic ring having the formula:
Figure 927831DEST_PATH_IMAGE002
。
4. the method according to claim 1, wherein the acid used is selected from the group consisting of inorganic acids: phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid, boric acid, hydrobromic acid; organic acid: sulfamic acid, glycolic acid, citric acid, acetic acid, formic acid, propionic acid, oxalic acid, ethylenediamine tetraacetic acid, benzoic acid, succinic acid and p-toluenesulfonic acid.
5. The method according to claim 1, wherein a mixed solution of an alcohol and water is used as the solvent, and the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol and t-butanol.
6. The method as claimed in claim 1, wherein the amount of the acetamidine hydrochloride or urea used as the catalyst is 0.01-20% of the molar amount of the diaza-alicyclic compound as the substrate.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1980912A (en) * 2004-07-01 2007-06-13 第一制药株式会社 Pyrazole derivatives
CN102167700A (en) * 2010-02-25 2011-08-31 上海药明康德新药开发有限公司 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and preparation method thereof
CN108003062A (en) * 2017-12-25 2018-05-08 常州吉恩药业有限公司 A kind of synthetic method of list BOC protections bisamination compound

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1980912A (en) * 2004-07-01 2007-06-13 第一制药株式会社 Pyrazole derivatives
CN102167700A (en) * 2010-02-25 2011-08-31 上海药明康德新药开发有限公司 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and preparation method thereof
CN108003062A (en) * 2017-12-25 2018-05-08 常州吉恩药业有限公司 A kind of synthetic method of list BOC protections bisamination compound

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