CN107056788A

CN107056788A - A kind of imidazolidinone analog derivative and its synthetic method

Info

Publication number: CN107056788A
Application number: CN201710176452.9A
Authority: CN
Inventors: 刘玉霞; 吕名秀; 杨柳; 买文鹏; 曹毅
Original assignee: Henan Institute of Engineering
Current assignee: Henan Institute of Engineering
Priority date: 2017-03-23
Filing date: 2017-03-23
Publication date: 2017-08-18

Abstract

The invention discloses a kind of imidazolidinone analog derivative and its synthetic method, the derivative it is entitled（5S）3 cyclohexyl, 2,4 dicarbapentaborane 1,3 diazabicyclo [3,3,0] octane, its synthetic method is carried out according to the following steps：First step is synthesis N tertbutyloxycarbonyl L proline, and second step is synthesis N tertbutyloxycarbonyl L prolyl dicyclohexylurea (DCU)s, and third step is synthesis（5S）3 cyclohexyl, 2,4 dicarbapentaborane 1,3 diazabicyclo [3,3,0] octane.Reactions steps of the present invention are less, yield is higher, reactions steps are more when avoiding synthesis imidazolidine ketone compounds in the past, post processing is complicated, the low defect of yield, prepare a kind of new imidazolidinone derivatives, disclosure satisfy that the demand of industrialized production imidazolidine ketone compounds.

Description

A kind of imidazolidinone analog derivative and its synthetic method

Technical field

The invention belongs to organic chemistry filed, it is related to a kind of imidazolidinone derivatives and its synthetic method.

Background technology

Natural amino acid ABUNDANT NATUREAL RESOURSES, many amino acid derivativges have good bioactivity, and this to be based on The synthesis of amino acid derivativges increasingly becomes the focus of people's research.Imidazolidinone analog derivative treatment diabetes (referring to WO2009132986A1) and in terms of hepatitis (referring to US20090099186A1) there is preferable bioactivity, can directly make Used for pharmaceutical intermediate.However, imidazolidine ketone compounds（That is imidazolidinone analog derivative）, especially some special miaows The synthesis technique of (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides derivative has the shortcomings that reactions steps are more, post processing is complicated, low yield mostly, it is difficult to directly use In industrialized production.Therefore, new imidazolidine ketone compounds are researched and developed, its synthetic method is explored, meets industrial production demand Turn into active demand.

The content of the invention

It is an object of the invention to provide a kind of new imidazolidinone analog derivative, and it is less to provide a kind of reactions steps, The higher synthetic method of yield.

To achieve the above object, the invention provides a kind of imidazolidinone analog derivative, the derivative it is entitled（5S）- 3- cyclohexyl -2,4- dicarbapentaborane -1,3- diazabicyclo [3,3,0] octane, its structural formula is：

It is above-mentioned（5S）The synthetic method of -3- cyclohexyl -2,4- dicarbapentaborane -1,3- diazabicyclos [3,3,0] octane presses following step It is rapid to carry out：

First step is added to L-PROLINE in the mixed liquor of the tert-butyl alcohol and the NaOH aqueous solution, at room temperature while stirring in batches Di-tert-butyl dicarbonate is added, after reaction terminates, through extraction, is acidified, dries, filtering removes solvent under reduced pressure, obtains N- tertiary butyloxycarbonyls Base-L-PROLINE；The molecular formula of the di-tert-butyl dicarbonate is：((CH₃)₃COCO)₂O, is abbreviated as（Boc)₂O。

Second step is that N- tertbutyloxycarbonyls-L-PROLINE is added in dichloromethane, then adds dicyclohexyl carbon Diimine, stirring reaction, filtering, are concentrated to give N- tertbutyloxycarbonyl-L- prolyl dicyclohexylurea (DCU)s at room temperature；

Third step is N- tertbutyloxycarbonyl-L- prolyl dicyclohexylurea (DCU) acetone solutions, adds concentrated hydrochloric acid, and room temperature is anti- Should, then it is neutralized to alkalescent（Alkalescent refers to pH value higher than 7 and less than or equal to 8.5 herein）, through extraction, dry, filtering subtracts Solvent is evaporated off in pressure, produces（5S）- 3- cyclohexyl -2,4- dicarbapentaborane -1,3- diazabicyclos [3,3,0] octane.

The reaction equation of above-mentioned three step reaction is：

The synthetic method route of the present invention is simple, and step only has three steps, and reaction condition is gentle, easy to operate, high income, up to 75% More than, it is adapted to industrialized production.（5S）- 3- cyclohexyl -2,4- dicarbapentaborane -1,3- diazabicyclos [3,3,0] octane is imidazoles Alkanone derivative（That is imidazolidine ketone compounds）One kind, and imidazolidine ketone compounds treatment diabetes and hepatitis etc. side Face has preferable bioactivity（Referring to WO2009132986A1 and US20090099186A1）, can be directly as in medicine Mesosome is used.

Reactions steps of the present invention are less, and yield is higher, it is to avoid reactions steps during conventional synthesis imidazolidine ketone compounds Many, post processing is complicated, the low defect of yield, prepares a kind of new imidazolidinone derivatives, disclosure satisfy that industrialized production miaow The demand of oxazolidinones.

Brief description of the drawings

Fig. 1 is（5S）The X-ray monocrystalline of -3- cyclohexyl -2,4- dicarbapentaborane -1,3- diazabicyclos [3,3,0] octane spreads out Penetrate figure.

Embodiment

With reference to Fig. 1, the invention provides a kind of imidazolidinone analog derivative, the derivative it is entitled（5S）- 3- hexamethylenes Base -2,4- dicarbapentaborane -1,3- diazabicyclo [3,3,0] octane, its structural formula is：

Its synthetic method is carried out according to the following steps：

First step is synthesis N- tertbutyloxycarbonyls-L-PROLINE, is specifically by L-PROLINE（5.75g, 50mmol）It is added to The tert-butyl alcohol（70 mL）And NaOH（3.2 g, 80 mmol）The aqueous solution（70 mL）Mixed liquor in, at room temperature while stirring in batches Add di-tert-butyl dicarbonate（12.0 g, 55 mmol）, continue to stir 12 hours, after reaction terminates, through extraction, be acidified, do Dry, filtering removes solvent under reduced pressure, obtains N- tertbutyloxycarbonyls-L-PROLINE；

Wherein, the molecular formula of di-tert-butyl dicarbonate is：((CH₃)₃COCO)₂O, is abbreviated as（Boc)₂O；Extraction is to use acetic acid second Ester extraction is excessive to remove（Boc)₂O, is then extracted with ethyl acetate after acidulation；Acidifying refers to use watery hydrochloric acid acidifying water It is about 3 mutually to make pH；The drying refers to after being extracted with ethyl acetate, and uses anhydrous sodium sulfate drying；The tertiary fourths of N- obtained by this step Oxygen carbonyl-L-PROLINE is white solid, yield 94%.Fusing point is 119.5 ~ 121.0 DEG C.

Second step be synthesis N- tertbutyloxycarbonyl-L- prolyl dicyclohexylurea (DCU)s, be specifically by N- tertbutyloxycarbonyls- L-PROLINE（2.15g, 10mol）It is added in dry dichloromethane, dicyclohexylcarbodiimide is then added while stirring （2.06 g, 10 mmol）, stirring reaction 12 hours, filtering, remove solvent concentration under reduced pressure and obtain N- tertbutyloxycarbonyls-L- at room temperature Prolyl dicyclohexylurea (DCU)；N- tertbutyloxycarbonyl-L- prolyls dicyclohexylurea (DCU) obtained by this step is colourless viscous liquid （Colorless oil）, yield is 87%.

The proton nmr spectra of N- tertbutyloxycarbonyl-L- prolyl dicyclohexylurea (DCU)s obtained by this step and carbon spectrum spectra count According to as follows：

¹H NMR (400 MHz, CDCl₃)δ:1.26~1.55 (m, 21H, -CH₂CH₂-CH₂- ,-C（CH₃）₃), 1.73~ 1.96 (m, 12H, -CH ₂ CH ₂-CH-), 3.40~3.56 (m, 3H, -NCH-), 4.17~4.42 (m,1H, -NCH-), 4.45~4.48 (m, 1H, --NCHCO-), ¹³C NMR (CDCl₃) δ: 171.7, 155.0, 154.2, 80.2, 59.1, 54.4, 50.0, 48.9, 32.7, 31.8, 31.6, 31.3, 29.1, 28.4, 28.3, 26.1, 25.9, 25.6, 25.4, 24.6. MS (ESI):m/z cacld. for C₂₃H₃₉N₃O₄ (M+Na)⁺444.3, found 444.2。

Third step is synthesis（5S）- 3- cyclohexyl -2,4- dicarbapentaborane -1,3- diazabicyclo [3,3,0] octane, specifically It is：By the N- tertbutyloxycarbonyl-L- prolyl dicyclohexylurea (DCU) acetone solutions obtained by second step, concentrated hydrochloric acid, room are added Temperature reaction 24 hours, is then neutralized to alkalescent with aqueous sodium carbonate（Alkalescent refers to pH value higher than 7 and is less than or equal to herein 8.5, preferred value is 8.0）, extracted through ethyl acetate, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, made with ethyl acetate For solvent recrystallization, produce（5S）- 3- cyclohexyl -2,4- dicarbapentaborane -1,3- diazabicyclos [3,3,0] octane.Wherein, dense salt The mass percent concentration of acid is 30%-38%, and preferred value is 35%.

（5S）The proton nmr spectra and carbon of -3- cyclohexyl -2,4- dicarbapentaborane -1,3- diazabicyclos [3,3,0] octane Modal data is as follows：

¹H NMR (400 MHz, CDCl₃)δ:1.16~2.25 (m, 14H, -CH₂CH₂-), 3.19~3.25 (m, 1H, - NCH-), 3.64~3.83 (m, 2H, -NCH₂-), 3.97~4.01 (m, 1H, -NCHCO-), ¹³C NMR (CDCl₃)δ: 174.0, 160.9, 62.8, 51.7, 45.6, 29.3, 29.1, 27.7, 26.8, 25.8, 25.0. [α]_D ²⁰：–113.0° (c 1.0, CHCl₃)。

" room temperature " in above steps, scope preferably is 25 ± 5 DEG C, and optimum value is 25 DEG C.

Above example is only used to illustrative and not limiting technical scheme, although with reference to above-described embodiment to this hair It is bright to be described in detail, it will be understood by those within the art that：Still the present invention can be modified or be waited With replacement, any modification or partial replacement without departing from the spirit and scope of the present invention, it all should cover the power in the present invention Among sharp claimed range.

Claims

1. a kind of imidazolidinone analog derivative, it is characterised in that：The derivative it is entitled（5S）The carbonyls of -3- cyclohexyl -2,4- two Base -1,3- diazabicyclo [3,3,0] octane, structural formula is：

。

2. synthesize described in claim 1（5S）- 3- cyclohexyl -2,4- dicarbapentaborane -1,3- diazabicyclos [3,3,0] octane Method, it is characterised in that carry out according to the following steps successively：

First step is synthesis N- tertbutyloxycarbonyls-L-PROLINE, is specifically that L-PROLINE is added into the tert-butyl alcohol and NaOH water In the mixed liquor of solution, di-tert-butyl dicarbonate is added portionwise while stirring at room temperature, after reaction terminates, through extraction, is acidified, does Dry, filtering removes solvent under reduced pressure, obtains N- tertbutyloxycarbonyls-L-PROLINE；

Second step is synthesis N- tertbutyloxycarbonyl-L- prolyl dicyclohexylurea (DCU)s, is specifically by N- tertbutyloxycarbonyl-L- dried meat Propylhomoserin is added in dichloromethane, then adds dicyclohexylcarbodiimide, at room temperature stirring reaction, filtering, is concentrated to give uncle N- Butoxy carbonyl-L- prolyl dicyclohexylurea (DCU)s；

Third step is synthesis（5S）- 3- cyclohexyl -2,4- dicarbapentaborane -1,3- diazabicyclo [3,3,0] octane, be specifically： N- tertbutyloxycarbonyl-L- prolyl dicyclohexylurea (DCU) acetone solutions, add concentrated hydrochloric acid, and then room temperature reaction is neutralized to weak Alkalescence, through extraction, is dried, and filtering removes solvent under reduced pressure, produced（5S）- 3- cyclohexyl -2,4- dicarbapentaborane -1,3- diazas are double Ring [3,3,0] octane.