CN109970648A - Amidine and the like is catalyzed the list guard method of diaza cycloaliphatic ring tertbutyloxycarbonyl - Google Patents

Amidine and the like is catalyzed the list guard method of diaza cycloaliphatic ring tertbutyloxycarbonyl Download PDF

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CN109970648A
CN109970648A CN201910225812.9A CN201910225812A CN109970648A CN 109970648 A CN109970648 A CN 109970648A CN 201910225812 A CN201910225812 A CN 201910225812A CN 109970648 A CN109970648 A CN 109970648A
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acid
boc
diaza
amidine
reaction
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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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D229/00—Heterocyclic compounds containing rings of less than five members having two nitrogen atoms as the only ring hetero atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • 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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    • C07—ORGANIC CHEMISTRY
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/04—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine 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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    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/02—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 2
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    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
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    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
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Abstract

The present invention is a kind of under the catalysis of amidine and the like, carries out single boc-protected green synthesis method to diaza cycloaliphatic ring.It is characterized in that all kinds of diaza fat cycle compounds make solvent with water and alcohol; in the presence of a certain amount of acid; amidine and the like catalyst is added; di-tert-butyl dicarbonate (Boc acid anhydrides) is used to protect reagent as Boc; it is reacted in certain temperature, is separated finally by vacuum distillation and obtain target product list N-Boc- diaza fat cycle compound.The present invention has innovatively used amidine and the like as list Boc guard catalyst, and more traditional synthetic method is more environmentally protective, safety, save the cost.

Description

Amidine and the like is catalyzed the list guard method of diaza cycloaliphatic ring tertbutyloxycarbonyl
Technical field
The invention belongs to medicine intermediate synthesis technology fields, and in particular in the presence of a kind of amidine and the like catalyst Diaza cycloaliphatic ring prepares the green synthesis method of corresponding list Boc diaza fat cycle compound.
Background technique
1-Boc-1,3- diazetidine (formula 1), 1-Boc-1,2- diazetidine (formula 2), 1-Boc-1,2- miaow Oxazolidine, 1-Boc-1,3- imidazolidine, 1-Boc piperazine, 1-Boc pyridazine, 1-Boc pyrimidine, 1-Boc-1,2- Diazesuberane, 1- The structures such as Boc-1,3- Diazesuberane and 1-Boc-1,4- Diazesuberane are drug common elements structure as follows (formula 1).
According to the literature:
The synthetic method of 1-Boc-1,3- imidazolidine:
Article " the Preparation of diamines by that Neil J. Ashweek, Iain Coldham etc. is delivered for 2003 It is write under nitrogen protection in lithiation-substitution of imidazolidines and pyrimidines ", With N- benzyl ethylenediamine, formaldehyde is raw material, with CHCl3For solvent, 18h is stirred at room temperature, adds di-tert-butyl dicarbonate reaction 18h.3- benzyl -1- tertbutyloxycarbonyl imidazoles can be obtained.ARNOLD, Lee Daniel etc. the 2016 patent WO delivered It is reported in 2016/168619 Al: under protection of argon gas, using DCM as solvent, starting N-benzyl imidazoles, two carbon being added at 0 DEG C Sour di tert butyl carbonate, triethylamine make base reagent, react at room temperature 6h, 3- benzyl -1- tertbutyloxycarbonyl imidazoles can be obtained；Again with methanol Make solvent, 10%Pd/C is catalyst, sloughs benzyl by catalytic hydrogenation, obtains 1- tertbutyloxycarbonyl imidazoles 87%.Reaction Equation (formula 2) is as follows.
The synthetic method of 1-Boc-1,2- imidazolidine:
Rosa E. Melendez and William D. Lubell 2003 on " JACS " and Wei-Jun Zhang, Article " the Impact of Azaproline on Amide Cis-Trans that Anders Berglund etc. is delivered for 2002 Isomerism:Conformational Analyses and NMR Studies of Model Peptides Including TRH Analogues " reports 1-Boc-1, the synthetic method of 2- imidazolidine: using DMF as solvent at 0 DEG C, N- benzyloxy is added Carbonyl-N- tertbutyloxycarbonyl hydrazine and NaH, are stirred at room temperature 30min, add 1,3- dibromopropane, are stirred overnight, and obtain the tertiary fourth of 1- Oxygen carbonyl -2- benzyloxycarbonyl group imidazoles；Using 10%Pd/C as catalyst, methanol is solvent, and room temperature catalytic hydrogenation is de- at 1atm H2 Benzyloxycarbonyl group is removed, 1- tertbutyloxycarbonyl imidazoles 95% is obtained.Reaction equation is following (formula 3).
。
The synthetic method of 1-Boc- piperazine mainly has two classes, the first kind: not using di-tert-butyl dicarbonate as raw material；Second class: with Di-tert-butyl dicarbonate is raw material.
Article " the Polystyrene-Based Deblocking- that Louis A. Carpino etc. is delivered in nineteen eighty-three Scavening Agents for the 9-Fluorenylmethyloxycarbonyl Amino-Protecting Group” Middle report is raw material with the piperazine of one times of equivalent nitrine t-butyl formate and one times of equivalent, and CH2Cl2 makees solvent, is reacted at room temperature, place Reason obtains 80% 1-Boc- piperazine.In 2017, special CN106810467A was also reported with nitrine t-butyl formate Wang Guichun Isopropyl ethereal solution is raw material, with ethyl alcohol and water as solvent (ethyl alcohol: water 2:1), reacts 4h under the conditions of 15 DEG C of temperature, processing obtains 66.9% 1-Boc- piperazine.Reaction equation is following (formula 4).
Article " Phenyl esters, the preferred reagents for that Kyrie Pappas etc. was delivered in 2009 Mono-acylation of polyamines in the presence of water " report with one times of equivalent PhOBoc and One times of equivalent piperazine is raw material, water as solvent, is reacted for 24 hours under nitrogen protection.The 1-Boc- piperazine 68% that room temperature reaction obtains, 55 DEG C reaction obtains product 87%, and heating reflux reaction obtains product 71%.Reaction equation is following (formula 5).
Article " the Selective Deprotection of that Hiroyuki Naito etc. was delivered in 2010 In Methanesulfonamides to Amines " report aoxidized by deprotonation and 02 so that Methanesulfomide deprotection at For its parent amine.Reaction equation is following (formula 6).
There are many reaction condition and catalyst systems again using di-tert-butyl dicarbonate as raw material for second class, mainly have
1) soda acid is not added in reaction
Article " Design, Synthesis, the and Structure- that Iman A. Moussa etc. is delivered for 2010 on JMC Affinity Relationships of Regioisomeric N-Benzyl Alkyl EtherPiperazine Two carbonic acid of the piperazine of twice equivalent of report and one times of equivalent in Derivatives as σ -1 Receptor Ligands " Di tert butyl carbonate, CH2Cl2Make solvent, react 22h at room temperature, obtains 1-Boc- piperazine (81%).Andreas Faust etc. 2008 In article " Synthesis and Evaluation of a Novel Fluorescent Photoprobe for 1-Boc- piperazine (68%) is obtained with identical reaction condition in ImagingMatrix Metalloproteinases ".Reaction side Formula is following (formula 7).
It is published within Hailin Zheng etc. 2005 in the article of " Bioorganic & Medicinal Chemistry " With di-tert-butyl dicarbonate (12.77mmol), piperazine (23.22mmol), methanol as solvent is added dropwise under ice bath, reacts at room temperature Two days, obtain 1-Boc- piperazine yield (71%).Article " the Micelles for that Yun Suk Jo etc. is delivered for 2009 Delivery of Nitric Oxide " is reported equally using methanol as solvent, and it is as follows to obtain yield (66%) reaction equation (formula 8).
Tan Jun, Cui Xiaoyuan, Liu Zhende wait 2017 in article " the green industrialized preparation of N- tert-butoxycarbonyl-piperazine " It reports and uses material ratio (Boc Suan Gan ︰ piperazine)=1 ︰ 3, Jia Chun ︰ water (1 ︰ 5) is added dropwise as reaction dissolvent, ice bath, room temperature 14h is reacted, processing obtains product (85.8%).Reaction equation is following (formula 9).
2) reaction plus alkali
It reports in the article delivered on " J. Med. Chem. " with the tert-butyl alcohol and water within Laura C. Meurer etc. 1992 Make solvent, NaOH makees acid binding agent, and di-tert-butyl dicarbonate is added dropwise at 5 DEG C, and room temperature reaction overnight, obtains 1-Boc- piperazine (78.8%).Reaction equation is following (formula 10).
It seals in the quiet article " synthesis of antidepressant medicine vilazodone intermediate " delivered in 2011 to report and be made with methanol Solvent, triethylamine make acid binding agent, and overnight, processing obtains product (80%) for room temperature reaction.Reaction equation is following (formula 11).
3) acid adding is reacted:
Jin Delong, Zhang Xuemei, Liu Huan are waited and are reported in " new technique for synthesizing of N- tert-butoxycarbonyl-piperazine " article with anhydrous Piperazine and di-tert-butyl dicarbonate are its molar ratio (1:1.0) of raw material, and using glacial acetic acid as medium, reaction temperature is 0 ~ 5 DEG C , reaction time 8h, reaction yield 64.71%.Reaction equation is following (formula 12).
It is reported in the patent " CN108003062A " that Wang Yuqin, Zhan Yujin etc. were delivered in 2017 with water as solvent, is used One times of equivalent piperazine and one times of equivalent di-tert-butyl dicarbonate are raw material, are first added 20% to piperazine aqueous solution at-5-0 DEG C Sulfuric acid solution stirs 0.5h, adds 0-5 DEG C of reaction 1h of di-tert-butyl dicarbonate, and processing obtains yield 90%.Reaction equation (formula 13) as follows.
4) reaction plus catalyst
Ravi Varala, Sreelatha Nuvula etc. 2006 in article " Molecular Iodine-Catalyzed Report utilizes molecule I in Facile Procedure for N-Boc Protection of Amines "2Catalytic action, 30min is reacted at room temperature with methanol as solvent using the di-tert-butyl dicarbonate and piperazine of same equivalent, processing obtains yield (80%).Reaction equation is following (formula 14).
Sadula Sunitha, Sanjit Kanjilal etc. is delivered for 2008 on " Tetrahedron Letters " Article in write and use a kind of ionic liquid methyl imidazolium tetrafluoroborate [(HMIm) BF4] as catalyst, the two of equivalent Dimethyl dicarbonate butyl ester and piperazine react at room temperature, obtain 1-Boc- piperazine (98%).Reaction equation is following (formula 15).
It is reported in the article delivered on " Tetrahedron Letters " within Biswanath Das etc. 2006 and uses sulphur Acid functionalization silica (Cat.) is used as catalyst, CH2Cl2Make solvent to protect single N-Boc of piperazine, obtains product 94%. Reaction equation is following (formula 16).
The synthetic method of 1-Boc pyridazine:
In the patent EP1762568A1 that KANAYA, Naoaki, Daiichi Pharma. Co., Ltd. etc. were delivered in 2007 It reports with methanol as solvent, using two tertiary two carbonic esters of fourth and hexahydro-pyridazine as raw material, reacts at room temperature 15h, processing obtains uncle 1- Butoxy carbonyl pyridazine 43%.Reaction equation is following (formula 17).
Tetsuya Toya, Kentaro Yamaguchi, Yasuyuki Endo etc. 2002 in Bioorganic & The article delivered on Medicinal Chemistry reports: using DMF as solvent at 0 DEG C, N- benzyloxycarbonyl group-N- uncle is added Butoxy carbonyl hydrazine and NaH, are stirred at room temperature 30min, add Isosorbide-5-Nitrae-dibromobutane, are stirred overnight, and obtain 1- tertbutyloxycarbonyl -2- Benzyloxycarbonyl group pyridazine 91%；Using 10%Pd/C as catalyst, methanol is solvent, and room temperature catalytic hydrogenation sloughs benzyloxy at 1atm H2 Carbonyl obtains 1- tertiary butyloxycarbonyl radical pyridazine 98%.Stephen P.East,Andrew Ayscough, Ian Toogood- Johnson waits the article delivered on Bioorganic & Medicinal Chemistry Letters in 2011 to use together The method of sample obtains 1- tertbutyloxycarbonyl -2- benzyloxycarbonyl group pyridazine 94%；1- tertiary butyloxycarbonyl radical pyridazine 78-100%.Alangudi The patent US 2003O2251O2A1 that Sankaranarayanan, Ahmedabad (IN) were delivered in 2003 is molten with acetonitrile Carbonic acid ammonia is added in agent, and Isosorbide-5-Nitrae-dibromobutane and N- benzyloxycarbonyl group-N- tertbutyloxycarbonyl hydrazine are heated to reflux 15h, obtain the tertiary fourth oxygen of 1- Carbonyl -2- benzyloxycarbonyl group pyridazine 83%；5%Pd/C is catalyst, methanol and water as solvent, the catalytic hydrogenation 6h at 3.4 atm H2 Obtain 1- tertiary butyloxycarbonyl radical pyridazine 82%.Reaction equation is following (formula 18).
The synthetic method of 1-Boc tetrahydropyrimidine:
Petar O. Nikiforov, Sachin Surade waits the text delivered on " Org. Biomol. Chem. " in 2016 Chapter is reported with Isosorbide-5-Nitrae, and 5,6- tetrahydropyridines and di-tert-butyl dicarbonate are raw material, and triethylamine makees alkali, using tetrahydrofuran as molten Agent, 0-20 DEG C of reaction overnight obtain 1-Boc-4,5,6- tri- pyridinium hydroxides (66%), and again with methanol makees solvent, and NaBH is added4At 0 DEG C 2h is reacted, 1-Boc tetrahydropyrimidine (64%) can be obtained.Reaction equation is following (formula 19).
The synthetic method of 1-Boc-1,2- Diazesuberane:
With Tetsuya Toya, Kentaro Yamaguchi, Yasuyuki Endo's synthetic method etc. 2002 exists The article report synthesis 1- tertiary butyloxycarbonyl radical pyridazine method delivered on Bioorganic Medicinal Chemistry is similar, Using pentamethylene bromide and N- benzyloxycarbonyl group-N- tertbutyloxycarbonyl hydrazine as Material synthesis 1- benzyloxycarbonyl group -1,2- diaza cycloheptyl Alkane -1- carboxylic acid tert-butyl ester, then catalytic hydrogenation slough benzyloxycarbonyl group, obtain 1,2- Diazesuberane -1- carboxylic acid tert-butyl ester 98%. Reaction equation is following (formula 20).
The synthetic method of 1-Boc-1,4- Diazesuberane:
Grazia Sellitto, Aurora Faruolo etc. 2010 in " Bioorganic & Medicinal The article delivered on Chemistry " reports the solution of methylene chloride (45mL) and homopiperazine (1.84g, 18mmol) at 0 DEG C Middle dropwise addition di-tert-butyl dicarbonate solution (2g, 9mmol, in 18mL methylene chloride)), it stirs 1 hour, target can be obtained Compound 1-Boc-1,4- Diazesuberane (88%).Reaction equation is following (formula 21).
Nitrine t-butyl formate and high piperazine are applied in the Chinese patent " CN106810467A " delivered for Wang Guichun, Liu Min 2017 Piperazine reacts at 0-30 DEG C in organic solvent, and single boc-protected homopiperazine can be obtained.Reaction equation is following (formula 22).
Summary of the invention
It is substrate that the present invention, which selects diaza fat cyclics, with methanol, ethyl alcohol or isopropanol and isometric water As solvent, acid is used as medium, and amidine and the like is used as catalyst, carries out list Boc protection reaction with di-tert-butyl dicarbonate, Its synthetic route (boc2) is following (formula 23- formula 27):
The present invention relates to the green syts that a kind of amidine and the like is catalyzed the single boc-protected diaza fat cycle compound of preparation Method, this method comprises the following steps: first diaza fat cycle compound is dissolved in the mixed liquor of alcohol and water, then plus to its Middle addition suitable acid continuously adds amidine of catalytic amount and the like catalyst and a certain amount of two after low temperature stirs 30 minutes Dimethyl dicarbonate butyl ester, the reaction was continued 2 hours or so after adding, and is finished with GC detection reaction, after reaction solution concentration and recovery solvent, It is evaporated under reduced pressure to target list againN- Boc diaza fat cycle compound.
Specific method:
Illustrate specific process step of the invention by the following examples, but is not limited by the example.
Its step are as follows (formula 28) for the synthesis of 1. 1-Boc- piperazine of embodiment:
The preparation of 1-Boc- piperazine: 10.3g(0.12mol is added in 500mL there-necked flask) piperazine, be added 150mL methanol and 150mL water, stirring are completely dissolved to piperazine, add 11.0g(0.21mol) formic acid stirring 0.5h, continuously add 0.11g (0.0012mol) B amidine hydrochloric acid salt catalyst and 8.73g(0.04mol) di-tert-butyl dicarbonate, stirs 2h at room temperature, uses gas Phase chromatography (GC retention time: starting piperazine 4.3min；Target product 1-Boc- piperazine: 11.6min；Impure by-products 1,4- Double Boc- piperazines: 17.4min) detection reaction, by reaction solution concentration and recovery solvent after fully reacting, then be evaporated under reduced pressure collection 165 ~ 175oThe fraction of C/5mmHg obtains target product 22.0g, reaction yield 98.6%.
Its step are as follows (formula 29) for the synthesis of 2. 1-Boc- piperazine of embodiment:
The preparation of 1-Boc- piperazine: 10.3g(0.12mol is added in 500mL there-necked flask) piperazine, be added 150mL methanol and 150mL water, stirring are completely dissolved to piperazine, add 14.4g(0.24mol) acetic acid stirring 0.5h, continuously add 0.11g (0.0012mol) B amidine hydrochloric acid salt catalyst and 8.73g(0.04mol) di-tert-butyl dicarbonate, stirs 2h at room temperature, uses gas Phase chromatography (GC retention time: starting piperazine 4.3min；Target product 1-Boc- piperazine: 11.6min；Impure by-products 1,4- Double Boc- piperazines: 17.4min) detection reaction, by reaction solution concentration and recovery solvent after fully reacting, then be evaporated under reduced pressure collection 165 ~ 175oThe fraction of C/5mmHg obtains target product 21.9g, reaction yield 98.0%.
Its step are as follows (formula 30) for the synthesis of 3. 1-Boc- piperazine of embodiment:
The preparation of 1-Boc- piperazine: 10.3g(0.12mol is added in 500mL there-necked flask) piperazine, be added 150mL methanol and 150mL water, stirring are completely dissolved to piperazine, add 16.5g(0.36mol) formic acid stirring 0.5h, continuously add 0.072g (0.0012mol) urea seeding agent and 8.73g(0.04mol) di-tert-butyl dicarbonate, stirs 2h at room temperature, uses gas-chromatography (GC retention time: starting piperazine 4.3min；Target product 1-Boc- piperazine: 11.6min；The bis- Boc- of impure by-products 1,4- Piperazine: 17.4min) detection reaction, by reaction solution concentration and recovery solvent after fully reacting, then it is evaporated under reduced pressure collection 165 ~ 175oC/ The fraction of 5mmHg obtains target product 22.1g, reaction yield 98.9%.
Its step are as follows (formula 31) for the synthesis of 4. 1-Boc- piperazine of embodiment:
The preparation of 1-Boc- piperazine: 10.3g(0.12mol is added in 500mL there-necked flask) piperazine, be added 150mL ethyl alcohol and 150mL water, stirring are completely dissolved to piperazine, add 17.5mL(0.21mol) concentrated hydrochloric acid stirring 0.5h, continuously add 0.11g (0.0012mol) B amidine hydrochloric acid salt catalyst and 8.73g(0.04mol) di-tert-butyl dicarbonate, stirs 2h at room temperature, uses gas Phase chromatography (GC retention time: starting piperazine 4.3min；Target product 1-Boc- piperazine: 11.6min；Impure by-products 1,4- Double Boc- piperazines: 17.4min) detection reaction, by reaction solution concentration and recovery solvent after fully reacting, then be evaporated under reduced pressure collection 165 ~ 175oThe fraction of C/5mmHg obtains target product 21.1g, reaction yield 94.4%.
Embodiment 5.1-Boc- tetrahydro-pyrazole, its step are as follows (formula 32):
The preparation of 1-Boc- tetrahydro-pyrazole: 10g(0.14mol is added in 500mL there-necked flask) pyrazoles pyridine, 150mL methanol is added With the mixed liquor of 150mL water, stirring is completely dissolved to pyrazoles pyridine, is added 0.42mol acid stirring 0.5h, is continuously added 0.072g (0.0012mol) urea seeding agent and 8.73g(0.04mol) di-tert-butyl dicarbonate, stirs 2h at room temperature, uses gas-chromatography (GC retention time: starting piperazine 3.8min；Target product 1-Boc- piperazine: 10.3min；The bis- Boc- of impure by-products 1,4- Piperazine: 15.9min) detection reaction, by reaction solution concentration and recovery solvent after fully reacting, then be evaporated under reduced pressure collection 104~ 114oThe fraction of C/5mmHg obtains target product 23.0g, reaction yield 95.6%.
Embodiment 6.1-Boc pyrimidine, its step are as follows (formula 33):
The preparation of 1-Boc tetrahydropyrimidine: 10g(0.12mol is added in 500mL there-necked flask) tetrahydropyrimidine, 150mL ethyl alcohol is added With 150mL water, stirring is completely dissolved to piperazine, adds 17.5mL(0.21mol) concentrated hydrochloric acid stirring 0.5h, it continuously adds 0.11g(0.0012mol) B amidine hydrochloric acid salt catalyst and 8.73g(0.04mol) di-tert-butyl dicarbonate, 2h is stirred at room temperature, Use gas-chromatography (GC retention time: starting piperazine 4.6min；Target product 1-Boc- piperazine: 11.9min；Impure by-products The bis- Boc- piperazines of Isosorbide-5-Nitrae-: 17.8min) detection reaction, by reaction solution concentration and recovery solvent after fully reacting, then it is evaporated under reduced pressure receipts Collection 165 ~ 175oThe fraction of C/5mmHg obtains target product 21.7g, reaction yield 97.2%.
7. list Boc of embodiment protects diaza fat cycle compound GC analysis method:
Using Shimadzu GC-2014C type gas chromatograph, gas chromatographic column: Wondacap5 capillary chromatographic column (column length: 30m, it is interior Diameter: 0.25 mm, film thickness: 0.25um, maximum operation (service) temperature: 325 oC) 50-220 DEG C of column temperature program heating, 10oC/min, sample introduction Device temperature 220oC, detector temperature 220oC, H21.5MPa is pressed before pressure 0.1MPa, 0.16 MPa of air, column.
Invention advantage:
Method provided by the invention has mainly used amidine and the like to protect as single Boc of diaza fat cycle compound Catalyst, advantage mainly have at following 4 points:
(1) it is protected for the first time using the highly selective list Boc of the cheap catalyst system catalysis diaza cycloaliphatic ring such as amidine or urea.
(2) catalyst, which is added, makes single boc-protected diaza fat cycle compound yield higher, greatly reduced double The generation of Boc diaza fat cycle compound, improves the selectivity of reaction, reduces the step of target product isolates and purifies, Save the cost.
(2) operation step is simple, and raw material is easy to get, and reaction carries out at normal temperature, can greatly save the energy, reduces Production cost.
(3) progress that amidine and the like catalyst accelerates reaction is added, greatly reduces the reaction time, so that the production cycle It shortens dramatically.
(4) amidine and the like catalyst usage amount is low, does not influence separation and purification of products and purity, environmentally friendly.

Claims (9)

1. a kind of use diaza fat cycle compound for starting material, with amidine and the like for catalyst preparation list N-Boc The synthetic method of diaza fat cycle compound, synthesis step are as follows:
The diaza fat cycle compound of 3mol is added in 1000mL reaction flask, is dissolved with the mixed liquor of alcohol and water, then plus to The acid that 9mol is wherein added continuously adds two carbonic acid of amidine of catalytic amount and the like He 1mol after low temperature stirs 30 minutes Di tert butyl carbonate (abbreviation Boc acid anhydrides), the reaction was continued 2 hours or so after adding, and is finished with GC detection reaction, reaction solution is concentrated back After receiving solvent, then it is evaporated under reduced pressure to target listN- Boc diaza fat cycle compound.
2. synthetic method according to claim 1, it is characterized in that using amidine and the like catalyst, highly selective generation Single N-Boc diaza fat cycle compound, product selectivity is high, and by-product is doubleN- Boc diaza fat cycle compound is few, target Produce rate is higher, more succinct efficient compared with conventional method.
3. synthesis step according to claim 1, it is characterized in that list Boc protection raw material substrate diaza aliphatic ring structure formula is such as Shown in lower:
。
4. synthesis step according to claim 1, it is characterized in that list Boc protection diaza cycloaliphatic ring target product structural formula is such as Shown in lower:
。
5. synthetic method according to claim 1, it is characterized in that the amidine and the like of catalyst has: ethanamidine and its hydrochloric acid Salt, carbonamidine and its hydrochloride, benzamidine and its hydrochloride, urea, thiocarbamide, guanidine and its hydrochloride, trifluoroacetamidine and its hydrochloride, amidine Base thiocarbamide, 2- methoxvacetamidine and its hydrochloride, general structure are as follows:
R1: for alkane, benzyl, trifluoromethyl, aromatic radical or containing hetero atom (hetero atoms such as oxygen, sulphur, nitrogen) substituted aromatic base；R2: for Nitrogen or oxygen.
6. synthetic method according to claim 1, it is characterized in that the use of the type of acid includes inorganic acid: phosphoric acid, sulfuric acid, salt Acid, nitric acid, boric acid, hydrobromic acid etc.；Organic acid: sulfamic acid, hydroxyacetic acid, citric acid, acetic acid, formic acid, propionic acid, ethanedioic acid, Ethylenediamine tetra-acetic acid, benzoic acid, succinic acid, p-methyl benzenesulfonic acid etc..
7. synthetic method according to claim 1, it is characterized in that the mixed solution of alcohol and water is made in solvent, the kind of used alcohol Class includes methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, tert-butyl alcohol etc..
8. synthetic method according to claim 1, it is characterized in that catalyst amidine and the like dosage is substrate phenodiazine heterolipid The 0.01% ~ 20% of fat cycle compound mole.
9. synthetic method according to claim 1, it is characterized in that di-tert-butyl dicarbonate (abbreviation Boc2) can be used for by other The acid anhydrides of amido protecting is replaced.
CN201910225812.9A 2019-03-25 2019-03-25 Method for catalyzing single protection of diaza aliphatic ring tert-butyloxycarbonyl by amidine and analogue thereof Expired - Fee Related CN109970648B (en)

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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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