CN115160380A - Compound capable of controlling CO release rate and preparation method thereof - Google Patents
Compound capable of controlling CO release rate and preparation method thereof Download PDFInfo
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- CN115160380A CN115160380A CN202210987192.4A CN202210987192A CN115160380A CN 115160380 A CN115160380 A CN 115160380A CN 202210987192 A CN202210987192 A CN 202210987192A CN 115160380 A CN115160380 A CN 115160380A
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 10
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- 210000004513 dentition Anatomy 0.000 abstract description 5
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- 230000006907 apoptotic process Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- JYHHJVKGDCZCCL-UHFFFAOYSA-J carbon monoxide;dichlororuthenium Chemical compound [O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].Cl[Ru]Cl.Cl[Ru]Cl JYHHJVKGDCZCCL-UHFFFAOYSA-J 0.000 description 1
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- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
The invention discloses a compound capable of controlling CO release rate and a preparation method thereof, wherein the molecular formula of the compound is as follows:
wherein μ represents the number of bridging groups;
representing the degree of ligand dentition or the number of atoms of the ligand directly connected with the metal; r is Boc-amino acid which is Boc-glycine, boc-alanine, boc-L-valine, boc-L-leucine or Boc-phenylalanine; synthesis of Compounds of the inventionCompared with the prior art, the invention has the advantages that the raw materials are easy to obtain, the reaction yield is high, and the separation method is simple, and the stability of the metal carbonyl lead framework is increased in a bridging form by performing amino acid modification on the bridge span position and the axial position of the transition metal Ru carbonyl CORMs lead structure; the compound can controllably and slowly release CO under the induction of ultraviolet irradiation, and does not release CO under the condition of no irradiation.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a compound capable of controlling CO release rate and a preparation method thereof.
Background
Biomedical research has shown that hemoglobin degradation in humans continues to produce trace amounts of carbon monoxide (CO). The endogenous CO is an important biological messenger molecule and has multiple treatment functions of inhibiting ischemia-reperfusion injury, resisting inflammation, resisting apoptosis, protecting organs and the like. However, free CO molecules have strong binding force with hemoglobin, and are difficult to be enriched in a focus area, and meanwhile, the normal transmission of oxygen in a human body is hindered by high concentration of CO. Therefore, how to realize targeted quantitative delivery of CO is one of the key technical problems in clinical application for realizing the therapeutic function of CO.
Under simulated physiological environment, carbon monoxide Releasing Compounds (CORM) represented by transition metal carbonyls can be degraded in situ by hydrolysis, photolysis and the like to generate CO Molecules. In more than ten years, a large amount of transition metal carbonyl compounds CORM are applied to CO biomedical research, the quantitative transmission of CO is basically realized, and the research on the physiological treatment efficacy of CO is promoted. However, the CO release rate of most transition metal carbonyl lead structures is difficult to control, and the requirements of CORM medicine application in the medical field are difficult to meet. Prior art Cold light Source irradiation CORM-1 (Mn) 2 (CO) 10 ) Can release CO, but is limited by the simple coordination structure of CORM-1, the Mn-CO breakage is uncontrollable, and the manganese metal has strong toxicity, so that the manganese metal cannot be applied to clinical medical treatment. CORM-2 ([ Ru (CO)) is widely used at present 3 Cl 2 ] 2 ) Can spontaneously and slowly release CO under the promotion of DSMO (dimethyl-styrene-dimethyl-ammonium) cosolvent, but the CO release rate cannot be regulated and controlled, so that the bioavailability of the CO is greatly reduced.
Disclosure of Invention
The invention aims to provide a compound with a controllable CO release rate and a preparation method thereof, and aims to solve the problem that the CO release rate of the existing transition metal carbonyl compounds CORMs is uncontrollable.
The invention adopts the following technical scheme: a compound for controlling the rate of CO release having the formula:
the structural formula is as follows:
wherein, R is Boc-amino acid which is Boc-glycine, boc-alanine, boc-L-valine, boc-L-leucine or Boc-phenylalanine.
A method for preparing a compound with a controllable CO release rate, comprising the steps of:
step S1: dissolving glycine glycol monomethyl ether hydrochloride and triethylamine in CH 2 Cl 2 :CH 3 The mixed solvent of OH =1,
step S2: ru is mixed 3 (CO) 12 Reacting with Boc-amino acid in a reaction solvent to obtain a first reaction solution containing a polymer intermediate,
and step S3: adding glycine ethylene glycol monomethyl ether ester into the first reaction solution to obtain a compound with a controllable CO release rate;
the molecular formula of the compound capable of controlling the CO release rate is as follows:
the structural formula of the compound capable of controlling the CO release rate is as follows:
wherein, R is Boc-glycine, boc-alanine, boc-L-valine, boc-L-leucine or Boc-phenylalanine.
Further, the route of the synthetic method of the compound capable of controlling the CO release rate is as follows:
further, ru in step S2 3 (CO) 12 : glycine ethylene glycol monomethyl ether ester: boc-amino acid = 1.
Further, the reaction condition of the step S1 is that the reaction system at 40-60 ℃ is added after filtration and stirred for 2 hours.
Further, the preparation method of the glycine ethylene glycol monomethyl ether hydrochloride in the step S1 comprises the following steps:
slowly dripping thionyl chloride into ethylene glycol monomethyl ether cooled at 0 ℃ in an ice bath, reacting for 1 hour at 0 ℃, adding glycine under the cooling condition, heating to 65 ℃ and reacting for two hours to obtain glycine ethylene glycol monomethyl ether hydrochloride,
wherein, the ratio of ethylene glycol monomethyl ether: thionyl chloride: the molar ratio of glycine is 1.
Further, the air conditioner is provided with a fan,
step S2: the reaction solvent is dry toluene;
step S2: the reaction conditions are that the reaction is carried out for 7 to 9 hours at the temperature of between 110 and 130 ℃ in an anhydrous and oxygen-free atmosphere under the protection of inert gas, the temperature is reduced to between 40 and 60 ℃, and the inert gas is N 2 He or Ar.
Further, the reaction time of the glycine ethylene glycol monomethyl ether ester and the first reaction solution in the step S3 is 2 hours.
The invention has the beneficial effects that: compared with the prior art, the invention selects Boc-amino acid with high bioavailability as a speed-control bridging ligand and water-soluble glycine ethylene glycol monomethyl ether as an axial ligand, thus obviously improving the utilization efficiency of carbon monoxide in physiological environment; the compound of the invention has the physiological treatment efficacy of CO, obvious drug-like properties and clinical treatment application potential; according to the invention, the stability of the metal carbonyl lead framework is increased in a bridging manner by performing amino acid modification on the cross position and the axial position of the transition metal Ru carbonyl CORMs lead structure bridge; the compound can controllably and slowly release CO under the induction of ultraviolet light irradiation, and does not release CO under the condition of no light irradiation, and the ultraviolet light is the key of speed control; the half-life period of ultraviolet illumination of the compound prepared by the invention is more than 764 s; the carbon monoxide release rate of the ruthenium carbonyl lead structure is regulated by the amino acid ligand, and the water solubility and the biocompatibility of the ethylene glycol ester ligand can be fully ensured.
Drawings
FIG. 1 is a diagram showing the variation of the UV spectrum of the CO slow release in example 1 of the present invention (60 μm);
FIG. 2 is a diagram showing the variation of the UV spectrum of CO sustained release in example 1 of the present invention (40 μm);
FIG. 3 is a diagram showing the variation of UV spectrum of CO sustained release in example 1 of the present invention (20 μm);
FIG. 4 is a graph showing the kinetics of CO release of example 1 at various concentrations induced by light according to the present invention.
Detailed Description
The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.
The invention discloses a compound capable of controlling CO release rate, which has the molecular formula as follows:
wherein μ represents the number of bridging groups;
representing the degree of ligand dentition or the number of atoms of the ligand directly connected with the metal;
the compound with controllable CO release rate has the structural formula:
wherein R is Boc-amino acid which is Boc-glycine, boc-alanine, boc-L-valine, boc-L-leucine or Boc-phenylalanine.
The invention also discloses a preparation method of the compound with controllable CO release rate, which comprises the following steps:
step S1: dissolving glycine ethylene glycol monomethyl ether hydrochloride and triethylamine in CH 2 Cl 2 :CH 3 OH =1 to obtain the glycine ethylene glycol monomethyl ether ester,
step S2: ru is mixed 3 (CO) 12 Reacting with Boc-amino acid in a reaction solvent to obtain a first reaction solution containing polymer intermediate,
and step S3: adding glycine ethylene glycol monomethyl ether ester into the first reaction solution to obtain a compound with controllable CO release rate;
the molecular formula of the compound capable of controlling the CO release rate is as follows:
the compound with controllable CO release rate has the structural formula:
wherein, R is Boc-glycine, boc-alanine, boc-L-valine, boc-L-leucine or Boc-phenylalanine.
The route of the synthetic method of the compound with the controllable CO release rate is as follows:
the synthetic route of the glycine ethylene glycol monomethyl ether hydrochloride in the step S1 is as follows:
the preparation method of the glycine ethylene glycol monomethyl ether hydrochloride in the step S1 comprises the following steps:
slowly dripping thionyl chloride into ethylene glycol monomethyl ether cooled in an ice bath at 0 ℃, reacting for 1 hour at 0 ℃, adding glycine under the cooling condition, heating to 65 ℃ and reacting for two hours to obtain glycine ethylene glycol monomethyl ether hydrochloride, wherein the ethylene glycol monomethyl ether: thionyl chloride: the molar ratio of glycine is 1.
Ru in step S2 3 (CO) 12 : glycine ethylene glycol monomethyl ether ester: boc-amino acid = 1; the reaction solvent is dry toluene; the reaction conditions are that the reaction is carried out for 7 to 9 hours at the temperature of between 110 and 130 ℃ in an anhydrous and oxygen-free atmosphere under the protection of inert gas, the temperature is reduced to between 40 and 60 ℃, and the inert gas is N 2 He or Ar; and in the step S3, the reaction time from the glycine ethylene glycol monomethyl ether ester to the first reaction liquid is 2 hours.
Example 1
The sources of reagents used in this example are set forth in the following table:
preparing a compound having a controlled rate of CO release of the formula:
step S1: dissolving glycine ethylene glycol monomethyl ether hydrochloride (2 mmol) and triethylamine (2 mmol) in CH 2 Cl 2 :CH 3 And (2) adding the mixed solvent of OH = 1.
Step S2: ru addition to Schlenk tubes 3 (CO) 12 (1 mmol) and Boc-glycine (3 mmol) in N 2 10mL of dry toluene was added as a solvent under the protection of (1), and the reaction was heated under reflux at 120 ℃ for 8 hours. At this stage, the solution gradually turned a reddish blood color with CO and H 2 Discharging, and cooling the reaction liquid to 50 ℃ to obtain a first reaction liquid containing the polymer intermediate.
And step S3: and (2) adding the glycine ethylene glycol monomethyl ether ester into the first reaction solution, reacting at 50 ℃ for 2 hours to finish the reaction to obtain a compound with controllable CO release rate, filtering after the reaction is finished to obtain a yellow solution, and performing vacuum drying and purification to obtain 292mg of yellow needle crystals, namely the glycine bridged tetracarbonyl ruthenium compound, wherein the yield of the compound is 68%.
The structural characterization data of the obtained product glycine-bridged tetracarbonyldiruthenium compound is as follows:
dissolving Boc-glycine bridged tetracarbonylbis ruthenium compound in CH 2 Cl 2 In the method, a Fourier transform infrared spectrum (unit: wave number cm) of type EQUINX55 of Bruker company of Germany is adopted -1 ) The skeletal structure of the product was determined, with 2028, 1975 and 1943cm -1 Absorption peaks for metal carbonyl, 1743 and 1709cm -1 Vibration absorption peaks for C = O bond in axial glycine ethylene glycol monomethyl ether ester, 1598 and 1506cm -1 And a Boc-glycine carboxyl C = O bond shock absorption peak.
Dissolving glycine-bridged tetracarbonyl ruthenium compound in CDCl 3 In the method, a 400MHz nuclear magnetic resonance spectrometer of Bruker company of Germany is adopted to confirm hydrogen atoms and carbon atoms in molecules, and a single peak at delta 1.43 in a hydrogen spectrum is 6-CH in Bco-amino acid 3 And two-NH-hydrogen atoms, the single peak at Δ 2.94 beingtwo-NH 2 Has a single peak at delta 3.39 of four hydrogen atoms at both ends-OCH 3 The six hydrogen atoms of (1), the triplets at delta 4.35,3.74 and 3.63 are-CH in glycine ethylene glycol monomethyl ether ester and Boc-amino acid respectively 2 Hydrogen atom of (2).
In the carbon spectrum, delta 203.37 is a metal carbonyl CO carbon atom, delta 182.38 is an axial ligand CO carbon atom, delta 171.74 is a Boc-glycine-COO carbon atom, and delta 155.82 is an axial ligand carbonyl alpha-CH 2 Carbon atom, delta 79.47, 70.13, 64.49, 58.96 is glycine ethylene glycol monomethyl ether ester and Boc-amino acid middle-CH 2 Delta 46.17 is methoxy-OCH 3 Carbon atom,. Delta.44.45, is tert-butyl- (C (CH) 3 ) 3 ) Middle carbon atom, delta 28.39 is tert-butyl- (C (CH) 3 ) 3 ) middle-CH 3 Carbon atoms, which proves the accuracy of the molecular structure.
The glycine-bridged tetracarbonyldiruthenium compound is dissolved in methanol, and the molecular weight in the molecule is determined by a MALDITOF type mass spectrometer of Bruker company, germany, and the mass-to-charge ratio is measured to be m/z:928.09, so that the molecular structure of the glycine-bridged tetracarbonyldiruthenium compound is proved to be correct.
Example 2
The operation steps of this example are the same as those of example 1, except that: preparing a compound having a controllable CO release rate of the formula:
the Boc-amino acid used in the step S2 is Boc-phenylalanine, 98%, and Aladdin reagent (Shanghai) Co., ltd.), and 325mg of bright yellow needle crystal is finally obtained, namely the phenylalanine bridged tetracarbonyl ruthenium compound, and the yield is 63%.
The structural characterization data of the obtained product phenylalanine-bridged tetracarbonyldiruthenium compound are as follows:
dissolving phenylalanine bridged tetracarbonyl ruthenium compound in CH 2 Cl 2 In this case, bruker company, germany is usedEQUINX55 type Fourier transform infrared spectrum (unit: wave number cm) -1 ) The skeletal structure of the product was determined by an instrument, in which 2028, 1975 and 1943cm were -1 Absorption peaks for metal carbonyl, 1743 and 1708cm -1 Vibration absorption peaks of C = O bond in axial glycine ethylene glycol monomethyl ether ester, 1595 cm and 1495cm -1 And a Boc-phenylalanine carboxyl C = O bond shock absorption peak.
Dissolving phenylalanine bridged tetracarbonyl ruthenium compound in CDCl 3 In the method, a 400MHz nuclear magnetic resonance spectrometer of Bruker company of Germany is adopted to confirm hydrogen atoms and carbon atoms in molecules, and a single peak at delta 1.42 in a hydrogen spectrum is 6-CH in Boc-phenylalanine 3 Hydrogen atom, dd peaks at δ 4.44 for two hydrogen atoms of-CH-group of Boc-phenylalanine molecule, and peaks at δ 4.34,3.52 and 4.30 for-CH in Boc-phenylalanine and glycine ethylene glycol monomethyl ether ester 2 Hydrogen atom of (A), the single peak at delta 3.39 being terminal-OCH 3 D peaks at delta 7.28 and 7.16 are hydrogen atoms on the benzene ring, delta 3.07 and 2.95 are-NH-and-NH-respectively 2 Hydrogen atom of (2).
In the carbon spectrum, delta 203.24 is a metal carbonyl CO carbon atom, and delta 183.71 is an axial ligand CO carbon atom (COOCH) 2 ) δ 171.56 is Boc-phenylalanine-COO carbon atom (Boc-Phe-COO), δ 154.96 is the-CH in the alpha position of carbonyl of axial ligand 2 Carbon atoms, delta 137.21, 129.50, 128.38 and 126.58 are benzene ring carbon atoms, delta 79.49 is a CH carbon atom at alpha position of Boc-phenylalanine carboxyl, delta 70.14, 64.48, 58.97 and 46.29 are glycine ethylene glycol monomethyl ether ester and Boc-phenylalanine medium-CH 2 Carbon atom, delta 56.59 being methoxy-OCH 3 Carbon atom,. Delta.39.02, is tert-butyl- (C (CH) 3 ) 3 ) Middle carbon atom, delta 28.40 is tert-butyl- (C (CH) 3 ) 3 ) middle-CH 3 Carbon atoms, proving the accuracy of the molecular structure.
The phenylalanine-bridged tetracarbonyldiruthenium compound is dissolved in methanol, a MALDITOF type mass spectrometer of Bruker company of Germany is adopted to determine the molecular weight in molecules, and the mass-to-charge ratio is measured to be m/z:1109.07, so that the molecular structure of the glycine-bridged tetracarbonyldiruthenium compound is proved to be correct.
Example 3
The operation steps of this example are the same as those of example 1, except that: preparing a compound having a controlled CO release rate of the formula:
the Boc-amino acid used in the step S2 is Boc-alanine, 99%, allantin reagent (Shanghai) Co., ltd.), and bright yellow needle crystal 289mg, which is alanine bridged tetracarbonylruthenium tetracarbonyl compound, is finally obtained, and the yield is 67%.
The structural characterization data of the obtained product alanine-bridged tetracarbonyldiruthenium compound are as follows:
dissolving alanine-bridged tetracarbonyldiruthenium compound in CH 2 Cl 2 In the method, a Fourier transform infrared spectrum (unit: wave number cm) of type EQUINX55 of Bruker company of Germany is adopted -1 ) The skeletal structure of the product was determined by an instrument, in which 2028, 1975 and 1943cm were -1 Absorption peaks for metal carbonyl, 1743 and 1708cm -1 Vibration absorption peaks of C = O bond in axial glycine ethylene glycol monomethyl ether ester, 1592 cm and 1498cm -1 The peak was the Boc-alanine carboxyl C = O bond shock absorption.
Dissolving alanine-bridged tetracarbonyldiruthenium compound in CDCl 3 In the method, a 400MHz nuclear magnetic resonance spectrometer of Bruker company in Germany is adopted to confirm hydrogen atoms and carbon atoms in molecules, and a doublet at delta 1.25 in a hydrogen spectrum is-CH at a carboxyl beta position in Boc-alanine 3 Hydrogen atom, unimodal at delta 1.43 is 6-CH in Boc-alanine 3 And two-NH-hydrogen atoms, the singlet at δ 2.93 being two-NH atoms 2 Has a single peak at delta 3.39 of four hydrogen atoms at both ends-OCH 3 The peaks at delta 4.36,4.12,3.74 and 3.63 are-CH in glycine ethylene glycol monomethyl ether ester and Boc-alanine, respectively 2 Hydrogen atom of (2).
In the carbon spectrum, delta 203.37 is a metal carbonyl CO carbon atom, delta 185.61 is an axial ligand CO carbon atom, delta 171.72 is a Boc-alanine-COO carbon atom, and delta 155.11 is an axial ligand carbonylalpha-CH of the radical 2 Carbon atom, delta 79.39, 64.53, 58.96 is glycine ethylene glycol monomethyl ether ester and Boc-alanine medium-CH 2 Delta 70.12 is the carbon atom alpha to the Boc-alanine carboxyl group, delta 51.09 is methoxy-OCH 3 Carbon atom, delta 46.21 being tert-butyl- (C (CH) 3 ) 3 ) A middle carbon atom, delta 28.40 being tert-butyl- (C (CH) 3 ) 3 ) middle-CH 3 Carbon atom, delta 19.41 being-CH in bridging ligand 3 Carbon atoms, proving the accuracy of the molecular structure.
The alanine-bridged tetracarbonyldiruthenium compound is dissolved in methanol, and the molecular weight in the molecule is determined by a MALDITOF type mass spectrometer of Bruker company, germany, and the mass-to-charge ratio is measured to be m/z:956.13, thereby proving that the molecular structure of the glycine-bridged tetracarbonyldiruthenium compound is correct.
Example 4
The operation procedure of this example is the same as that of example 1, except that: preparation of a compound of formula with a controlled CO release rate:
the Boc-amino acid used in step S2 was Boc-L-leucine (99%), and Allantin reagent (Shanghai) Co., ltd.), and 288mg of orange needle-like crystals were finally obtained, which were leucine-bridged tetracarbonyldiruthenium compounds, with a yield of 60%.
The structural characterization data of the obtained product leucine-bridged tetracarbonyl ruthenium compound are as follows:
dissolving leucine bridged tetracarbonyl ruthenium compound in CH 2 Cl 2 In the method, a Fourier transform infrared spectrum (unit: wave number cm) of type EQUINX55 of Bruker company of Germany is adopted -1 ) The skeletal structure of the product was determined by an instrument, in which 2028, 1974 and 1942cm were -1 1743 and 1710cm for the absorption peaks of the metal carbonyl -1 The vibration absorption peaks of C = O bond in axial glycine ethylene glycol monomethyl ether ester are 1591 and 1500cm -1 And Boc-L-leucine carboxyl C = O bond vibration absorption peak.
Dissolving leucine-bridged tetracarbonyldiruthenium compound in CDCl 3 In the method, a 400MHz nuclear magnetic resonance spectrometer of Bruker company in Germany is adopted to confirm hydrogen atoms and carbon atoms in molecules, and a peak at delta 0.91 in a hydrogen spectrum is isopropyl-CH in Boc-L-leucine 3 Hydrogen atom, unimodal at delta 1.42 is Boc-L-leucine 6-CH 3 And two-NH-hydrogen atoms, the peak at δ 1.62 being the isopropyl α -CH 2 Hydrogen atom, single peak at δ 2.91 being two-NH 2 Has four hydrogen atoms, the single peak at delta 3.39 being two terminal-OCH 3 The peaks at delta 4.36,4.11,3.74 and 3.63 are-CH in glycine ethylene glycol monomethyl ether ester and Boc-L-leucine, respectively 2 Hydrogen atom of (2).
In the carbon spectrum, delta 203.36 is a metal carbonyl CO carbon atom, delta 185.61 is an axial ligand CO carbon atom, delta 171.73 is a Boc-L-leucine-COO carbon atom, and delta 155.26 is an alpha-CH position of a carbonyl group of the axial ligand 2 Carbon atom, delta 79.30, 64.52, 58.96 is glycine ethylene glycol monomethyl ether ester and Boc-L-leucine medium-CH 2 Delta 70.13 is the carbon atom alpha to the carboxyl group of Boc-L-leucine, delta 54.03 is methoxy-OCH 3 Carbon atom,. Delta.42.46, is tert-butyl- (C (CH) 3 ) 3 ) A middle carbon atom, delta 28.40 being tert-butyl- (C (CH) 3 ) 3 ) middle-CH 3 Carbon atom, delta 24.93 is a CH-carbon atom, delta 22.84 is-CH in a bridging ligand 3 Carbon atoms, proving the accuracy of the molecular structure.
The leucine-bridged tetracarbonyldiruthenium compound is dissolved in methanol, and the molecular weight in the molecule is determined by a MALDITOF type mass spectrometer of Bruker company in Germany, and the mass-to-charge ratio is measured to be m/z:1041.22, thereby proving that the molecular structure of the glycine-bridged tetracarbonyldiruthenium compound is correct.
Example 5
The operation steps of this example are the same as those of example 1, except that: preparation of a compound of formula with a controlled CO release rate:
the Boc-amino acid used in step S2 was Boc-L-valine of 99%, aladdin reagent (Shanghai) Co., ltd.) to finally obtain 333mg of orange needle-like crystals, i.e., valine-bridged rapid-control carbon monoxide-releasing molecules with a yield of 73%.
The structural characterization data of the obtained product valine-bridged tetracarbonyldiruthenium compound are as follows:
dissolving valine-bridged tetracarbonyl ruthenium compound in CH 2 Cl 2 In the above, a Fourier transform infrared spectrum (unit: wavenumber cm) of type EQUINX55 from Bruker, germany was used -1 ) The skeletal structure of the product was determined by an instrument, in which 2028, 1974 and 1942cm were -1 Absorption peaks for metal carbonyl, 1743 and 1709cm -1 Vibration absorption peaks of C = O bond in axial glycine ethylene glycol monomethyl ether ester, 1591 and 1499cm -1 The Boc-L-valine carboxyl C = O bond vibration absorption peak.
Dissolving valine-bridged tetracarbonyldiruthenium compound in CDCl 3 In the method, a 400MHz nuclear magnetic resonance spectrometer of Bruker company in Germany is adopted to confirm hydrogen atoms and carbon atoms in molecules, and a dd peak at delta 0.86 in a hydrogen spectrum is isopropyl-CH in Boc-L-valine 3 Hydrogen atom, unimodal at delta 1.44 is Boc-L-valine 6-CH 3 And two-NH-hydrogen atoms, the singlet at δ 2.95 being two-NH atoms 2 Has a single peak at delta 3.41 of four hydrogen atoms at both ends-OCH 3 The peaks at delta 4.39,4.08,3.76 and 3.66 are-CH in glycine ethylene glycol monomethyl ether ester and Boc-L-valine, respectively 2 Hydrogen atom of (2).
In a carbon spectrum, delta 203.37 is a metal carbonyl CO carbon atom, delta 184.34 is an axial ligand CO carbon atom, delta 171.71 is a Boc-L-valine-COO carbon atom, delta 155.35 is an alpha-COO carbon atom of an imino group of an axial ligand, delta 79.29, 64.56 and 58.95 are glycine ethylene glycol monomethyl ether ester and-CH in Boc-L-valine 2 Delta 70.11 is a carbon atom at the alpha position of Boc-L-valine ester group, delta 46.14 is methoxy-OCH 3 Carbon atom,. Delta.32.00, being tert-butyl- (C (CH) 3 ) 3 ) Middle carbon atom, delta 28.37 is tert-butyl- (C (CH) 3 ) 3 ) middle-CH 3 Carbon atom, delta 28.37 is an isopropyl-CH-carbon atom, delta 18.82 and 17.76 are isopropyl-middle-CH 3 Carbon atoms, which proves the accuracy of the molecular structure.
The valine-bridged tetracarbonyldiruthenium compound is dissolved in methanol, and the molecular weight in the molecule is determined by a MALDITOF type mass spectrometer of Bruker company in Germany, and the mass-to-charge ratio is measured to be m/z:1013.12, so that the molecular structure of the glycine-bridged tetracarbonyldiruthenium compound is proved to be correct.
Test for Slow Release Property
The molecular formulas of the compounds with controllable CO release rates prepared in examples 1-5 were tested for CO release performance, as follows:
1. CO Slow Release Rate test
The CO release performance (half-life period t) of the molecular formula of the compound with different concentrations and controllable CO release rate is measured by adopting a myoglobin method and 365nm ultraviolet point light source excitation 1/2 ) The results are shown in FIGS. 1-4 and Table 2.
Table 2 results of the CO slow release test
As can be seen from FIGS. 1-3 and Table 2, the compounds with controllable CO release rate prepared by the invention all show good CO slow release performance, and the bridged Boc-amino acid ligand is the key for regulating the CO release rate. Example 3, in which Boc-alanine was the ligand, showed the fastest CO release rate in response to 365nm spot light irradiation, corresponding to 60. Mu.M, 40. Mu.M and 20. Mu.M half-lives of 207s,764s and 835s, respectively. Example 2, in which Boc-phenylalanine was the ligand, showed the slowest CO release rate, corresponding to 60. Mu.M, 40. Mu.M and 20. Mu.M half-life times of 1541s,1594s and 1619s, respectively.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents, improvements, etc. within the spirit and scope of the present invention.
Claims (8)
1. A compound capable of controlling the rate of release of CO, having the formula:
[Ru 2 (CO) 4 (μ 2 -η 2 -OOC-R) 2 (η 1 -NH 2 CH 2 C(＝O)OCH 2 CH 2 OCH 3 ) 2 ]wherein μ represents the number of bridging groups; eta represents the degree of ligand dentification or the number of atoms of the ligand in direct connection with the metal;
the structural formula is as follows:
wherein R is Boc-amino acid which is Boc-glycine, boc-alanine, boc-L-valine, boc-L-leucine or Boc-phenylalanine.
2. A method for preparing a compound with a controllable CO release rate, comprising the steps of:
step S1: dissolving glycine ethylene glycol monomethyl ether hydrochloride and triethylamine in CH 2 Cl 2 :CH 3 OH =1 to obtain the glycine ethylene glycol monomethyl ether ester,
step S2: ru is mixed 3 (CO) 12 Reacting with Boc-amino acid in a reaction solvent to obtain a first reaction solution containing polymer intermediate,
and step S3: adding glycine ethylene glycol monomethyl ether ester into the first reaction solution to obtain a compound with controllable CO release rate;
the molecular formula of the compound capable of controlling the CO release rate is as follows:
[Ru 2 (CO) 4 (μ 2 -η 2 -OOC-R) 2 (η 1 -NH 2 CH 2 C(＝O)OCH 2 CH 2 OCH 3 ) 2 ]wherein μ represents the number of bridging groups; eta represents the degree of ligand dentification or the number of atoms of the ligand directly connected with the metal;
the structural formula of the compound capable of controlling the CO release rate is as follows:
wherein, R is Boc-glycine, boc-alanine, boc-L-valine, boc-L-leucine or Boc-phenylalanine.
3. The method for preparing a compound with controllable CO release rate according to claim 2, wherein the route of the method for synthesizing the compound with controllable CO release rate is as follows:
4. the method of claim 3, wherein the step S2 comprises Ru 3 (CO) 12 : glycine ethylene glycol monomethyl ether ester: boc-amino acid = 1.
5. The method for preparing a compound with a controlled CO release rate according to claim 3, wherein the reaction condition of step S1 is that after filtration, the reaction system is added at 40-60 ℃ and stirred for 2h.
6. The method for preparing a compound with a controllable CO release rate according to claim 2, wherein the method for preparing glycine ethylene glycol monomethyl ether hydrochloride in the step S1 comprises the following steps:
slowly dripping thionyl chloride into ethylene glycol monomethyl ether cooled at 0 ℃ in an ice bath, reacting for 1 hour at 0 ℃, adding glycine under the cooling condition, heating to 65 ℃ and reacting for two hours to obtain glycine ethylene glycol monomethyl ether hydrochloride,
wherein the ethylene glycol monomethyl ether: thionyl chloride: the molar ratio of glycine is 1.
7. The method for preparing a compound with a controlled CO release rate according to claim 2,
step S2: the reaction solvent is dry toluene;
step S2: the reaction conditions are that the reaction is carried out for 7 to 9 hours at the temperature of between 110 and 130 ℃ in an anhydrous and oxygen-free atmosphere under the protection of inert gas, the temperature is reduced to between 40 and 60 ℃, and the inert gas is N 2 He or Ar.
8. The method for preparing a compound with a controllable CO release rate according to claim 2, wherein the reaction time of the glycine ethylene glycol monomethyl ether ester and the first reaction solution in the step S3 is 2h.
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| CN107033191A (en) * | 2017-06-20 | 2017-08-11 | 陕西师范大学 | Ruthenium carbon monoxide-releasing molecules CORM 2 safe synthetic method |
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| CN107033191A (en) * | 2017-06-20 | 2017-08-11 | 陕西师范大学 | Ruthenium carbon monoxide-releasing molecules CORM 2 safe synthetic method |
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| MARZENA FANDZLOCH ET AL.,: "Sawhorse-type ruthenium complexes with triazolopyrimidine ligands-what do they represent in terms of cytotoxic and CORM compounds?", DALTON TRANSACTIONS, vol. 51, 8 May 2022 (2022-05-08), pages 8804 - 8820 * |
| SHUHONG YANG ET AL.,: "Photo-activated CO-releasing molecules (PhotoCORMs) of robust sawhorse scaffolds [µ2-OOCR 1 , η1-NH2CHR 2 (Cv O] OCH3, Ru(I) 2CO 4]", DALTON TRANSACTIONS, vol. 45, 14 January 2016 (2016-01-14), pages 3727 - 3733 * |
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