CN115160380B - 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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- CN115160380B CN115160380B CN202210987192.4A CN202210987192A CN115160380B CN 115160380 B CN115160380 B CN 115160380B CN 202210987192 A CN202210987192 A CN 202210987192A CN 115160380 B CN115160380 B CN 115160380B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- -1 Boc-amino Chemical group 0.000 claims abstract description 66
- 239000003446 ligand Substances 0.000 claims abstract description 33
- 229940024606 amino acid Drugs 0.000 claims abstract description 24
- 229910052751 metal Inorganic materials 0.000 claims abstract description 19
- 239000002184 metal Substances 0.000 claims abstract description 19
- QVHJQCGUWFKTSE-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)C(C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-UHFFFAOYSA-N 0.000 claims abstract description 15
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 claims abstract description 14
- SZXBQTSZISFIAO-ZETCQYMHSA-N (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 claims abstract description 13
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 210000004513 dentition Anatomy 0.000 claims abstract description 7
- 230000036346 tooth eruption Effects 0.000 claims abstract description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 239000004471 Glycine Substances 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 239000011261 inert gas Substances 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 229920000642 polymer Polymers 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 11
- 229910052723 transition metal Inorganic materials 0.000 abstract description 6
- 238000012986 modification Methods 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 3
- KSCBXCJUNGTAGU-UHFFFAOYSA-N C(=O)=[Pb] Chemical group C(=O)=[Pb] KSCBXCJUNGTAGU-UHFFFAOYSA-N 0.000 abstract description 2
- 230000006698 induction Effects 0.000 abstract description 2
- 230000020477 pH reduction Effects 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 150000003624 transition metals Chemical group 0.000 abstract description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 78
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 68
- 229910052799 carbon Inorganic materials 0.000 description 55
- 150000001721 carbon Chemical group 0.000 description 41
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 24
- 150000003304 ruthenium compounds Chemical class 0.000 description 21
- 230000001276 controlling effect Effects 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 229910052707 ruthenium Inorganic materials 0.000 description 6
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 5
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- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 5
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 5
- 235000004279 alanine Nutrition 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229960003136 leucine Drugs 0.000 description 5
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 5
- 229960004295 valine Drugs 0.000 description 5
- 239000004474 valine Substances 0.000 description 5
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000002211 ultraviolet spectrum Methods 0.000 description 3
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
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- 239000002243 precursor Substances 0.000 description 2
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- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 102000036675 Myoglobin Human genes 0.000 description 1
- 108010062374 Myoglobin Proteins 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
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- 230000002424 anti-apoptotic effect Effects 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 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
- NQZFAUXPNWSLBI-UHFFFAOYSA-N carbon monoxide;ruthenium Chemical group [Ru].[Ru].[Ru].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] NQZFAUXPNWSLBI-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
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- Heart & Thoracic Surgery (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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; Indicating ligand dentition degree or atom number of the ligand directly connected with metal; r is a Boc-amino acid, which is Boc-glycine, boc-alanine, boc-L-valine, boc-L-leucine or Boc-phenylalanine; compared with the prior art, the method increases the stability of the metal carbonyl lead skeleton in a bridging mode by carrying out amino acidification modification on the bridging position and the axial position of the transition metal Ru carbonyl CORMs lead structure; the compound of the invention can controllably release CO under the induction of ultraviolet irradiation and does not release 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). These endogenous CO are an important class of biological messenger molecules with a variety of therapeutic functions, such as inhibition of ischemia reperfusion injury, anti-inflammatory, anti-apoptotic and organ protection. However, free CO molecules have strong binding force with hemoglobin, are difficult to enrich in focal areas, and at the same time, high concentration of CO also prevents normal transmission of oxygen in the human body. Therefore, how to realize the targeted quantitative CO transmission is one of the key technical problems for realizing the therapeutic function in clinical application.
Under simulated physiological environment, carbon monoxide releasing compounds (CO Releasing Molecules, CORM) represented by transition metal carbonyls can degrade in situ to produce CO molecules by hydrolysis, photolysis and the like. Over ten years, a large number of transition metal carbonyl compound CORM are beginning to be applied to CO biomedical research, so that quantitative transmission of CO is basically realized, and research on the physiological treatment efficacy of CO is promoted. However, the CO release rate of most transition metal carbonyl precursor structures is difficult to control and difficult to meet the requirements of CORM drug applications in the medical field. In the prior art, cold light source irradiates CORM-1 (Mn 2(CO)10) to release CO, but the cold light source is limited by a simple coordination structure of the CORM-1, mn-CO breakage is uncontrollable, and the manganese metal has strong toxicity and cannot be applied to clinical medical treatment. CORM-2 ([ Ru (CO) 3Cl2]2) widely used at present can spontaneously release CO under the promotion of DSMO dissolution, but the CO release rate cannot be regulated and controlled, so that the bioavailability of CO is greatly reduced.
Disclosure of Invention
The invention aims to provide a compound capable of controlling CO release rate and a preparation method thereof, so as to solve the problem that the CO release rate of the traditional transition metal carbonyl compound CORMs is uncontrollable.
The invention adopts the following technical scheme: a compound with a controlled CO release rate having the formula:
wherein μ represents the number of bridging groups; /(I) Indicating ligand dentition degree or atom number of the ligand directly connected with metal;
the structural formula is as follows:
Wherein R is Boc-amino acid, and Boc-amino acid is Boc-glycine, boc-alanine, boc-L-valine, boc-L-leucine or Boc-phenylalanine.
A method for preparing a compound with controllable CO release rate, which comprises the following steps:
step S1: dissolving glycine ethylene glycol monomethyl ether ester hydrochloride and triethylamine in a mixed solvent of CH 2Cl2:CH3 OH=1:1 to obtain glycine ethylene glycol monomethyl ether ester,
Step S2: ru 3(CO)12 and Boc-amino acid are reacted in a reaction solvent to obtain a first reaction solution containing a polymer intermediate,
Step S3: adding glycine ethylene glycol monomethyl ether ester into the first reaction liquid to obtain a compound with controllable CO release rate;
the molecular formula of the compound with controllable CO release rate is as follows:
wherein μ represents the number of bridging groups; /(I) Indicating ligand dentition degree or atom number of the ligand directly connected with 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.
Further, the synthetic method route of the compound capable of controlling the CO release rate is as follows:
Further, ru 3(CO)12 in step S2: glycine ethylene glycol monomethyl ether ester: boc-amino acid=1:2:3.
Further, the reaction condition of the step S1 is that the reaction system with the temperature of 40-60 ℃ is added after filtration and stirred for 2 hours.
Further, the preparation method of glycine ethylene glycol monomethyl ether ester hydrochloride in the step S1 comprises the following steps:
Slowly dropwise adding thionyl chloride into ethylene glycol monomethyl ether cooled by ice bath at 0 ℃, reacting for 1 hour at 0 ℃, adding glycine under cooling condition, heating to 65 ℃ for reacting for two hours to obtain glycine ethylene glycol monomethyl ether ester hydrochloride,
Wherein, ethylene glycol monomethyl ether: thionyl chloride: the molar ratio of glycine is 1:1:1.2.
Further, the method comprises the steps of,
Step S2: the reaction solvent is dry toluene;
Step S2: the reaction condition is that the reaction is carried out for 7-9 hours at 110-130 ℃ under the protection of anhydrous and anaerobic atmosphere and inert gas, the temperature is reduced to 40-60 ℃, and the inert gas is N 2, he or Ar.
Further, in the step S3, the reaction time between the glycine glycol monomethyl ether ester and the first reaction solution is 2h.
The beneficial effects of the invention are as follows: compared with the prior art, the method selects Boc-amino acid with high bioavailability as a speed control bridging ligand, and water-soluble glycine ethylene glycol monomethyl ether ester as an axial ligand, so that the utilization rate of carbon monoxide in a physiological environment can be obviously improved; the compound provided by the invention has the physiological treatment effect of CO, obvious drug-like property and clinical treatment application potential; according to the invention, the bridge span position and the axial position of the transition metal Ru carbonyl CORMs lead structure are subjected to amino acidification modification, so that the stability of the metal carbonyl lead skeleton is improved in a bridging manner; the compound can controllably and slowly release CO under the induction of ultraviolet light irradiation, does not release under the condition of no irradiation, and is a key of quick control; the ultraviolet irradiation half-life of the compound prepared by the invention is more than 764 s; the amino acid ligand regulates the carbon monoxide release rate of the ruthenium carbonyl precursor structure, and the glycol ester ligand can fully ensure the water solubility and biocompatibility.
Drawings
FIG. 1 is a graph (60 μm) showing the variation of the CO slow-release ultraviolet spectrum of example 1 of the present invention;
FIG. 2 is a graph (40 μm) showing the variation of the CO slow-release ultraviolet spectrum of example 1 of the present invention;
FIG. 3 is a graph (20 μm) showing the variation of the CO slow-release ultraviolet spectrum of example 1 of the present invention;
FIG. 4 is a graph showing the kinetics of CO release by photoinduction of example 1 at various concentrations according to the present invention.
Detailed Description
The invention will be described in detail below with reference to the drawings and the detailed description.
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; /(I) Indicating ligand dentition degree or atom number of the ligand directly connected with metal;
The structural formula of the compound capable of controlling the CO release rate is as follows:
wherein R is Boc-amino acid, and the Boc-amino acid 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 ester hydrochloride and triethylamine in a mixed solvent of CH 2Cl2:CH3 OH=1:1 to obtain glycine ethylene glycol monomethyl ether ester,
Step S2: ru 3(CO)12 and Boc-amino acid are reacted in a reaction solvent to obtain a first reaction solution containing a polymer intermediate,
Step S3: adding glycine ethylene glycol monomethyl ether ester into the first reaction liquid 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:
wherein μ represents the number of bridging groups; /(I) Indicating ligand dentition degree or atom number of the ligand directly connected with 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.
The synthetic method route of the compound capable of controlling the CO release rate comprises the following steps:
The synthetic route of glycine ethylene glycol monomethyl ether ester hydrochloride in the step S1 is as follows:
the preparation method of the glycine ethylene glycol monomethyl ether ester hydrochloride in the step S1 comprises the following steps:
Slowly dropwise adding thionyl chloride into ethylene glycol monomethyl ether cooled by ice bath at 0 ℃, reacting for 1 hour at 0 ℃, adding glycine under cooling condition, heating to 65 ℃ and reacting for two hours to obtain glycine ethylene glycol monomethyl ether ester hydrochloride, wherein the ethylene glycol monomethyl ether is prepared by the following steps: thionyl chloride: the molar ratio of glycine is 1:1:1.2, and the reaction condition of the step S1 is that the glycine is filtered and then added into a reaction system at 40-60 ℃ to be stirred for 2 hours.
Ru 3(CO)12 in step S2: glycine ethylene glycol monomethyl ether ester: boc-amino acid=1:2:3; the reaction solvent is dry toluene; the reaction condition is that the reaction is carried out for 7 to 9 hours at the temperature of 110 to 130 ℃ under the protection of anhydrous and anaerobic atmosphere and inert gas, and the temperature is reduced to 40 to 60 ℃, wherein the inert gas is N 2, he or Ar; and in the step S3, the reaction time between the glycine glycol monomethyl ether ester and the first reaction solution is 2h.
Example 1
The sources of reagents used in this example are set forth in the following table:
preparing a compound with controllable CO release rate having the formula:
step S1: glycine ethylene glycol monomethyl ether ester hydrochloride (2 mmol) and triethylamine (2 mmol) are dissolved in a mixed solvent of CH 2Cl2:CH3 OH=1:1, and after filtration, the mixture is added and stirred for 2 hours, and then the mixture is filtered to obtain glycine ethylene glycol monomethyl ether ester.
Step S2: ru 3(CO)12 (1 mmol) and Boc-glycine (3 mmol) were added to a Schlenk tube, 10mL of dry toluene was added as solvent under N 2, and the temperature was set to 120℃for a reflux reaction for 8h. At this stage, the solution gradually turned to reddish-colored and CO and H 2 were evolved, and the reaction solution was cooled to 50 ℃ to obtain a first reaction solution containing the polymer intermediate.
Step S3: adding glycine ethylene glycol monomethyl ether ester into a first reaction liquid, reacting for 2 hours at 50 ℃ to finish the reaction, obtaining a compound with controllable CO release rate, filtering after the reaction is finished to obtain a yellow solution, and vacuum drying and purifying to obtain 292mg of yellow needle-like crystals, namely the glycine bridged tetracarbonyl ruthenium compound, wherein the yield is 68%.
The structural characterization data of the glycine bridged tetracarbonyl ruthenium compound of the obtained product are as follows:
The skeletal structure of the product was tested by dissolving a Boc-glycine bridged tetracarbonyl ruthenium compound in CH 2Cl2 using a model EQUINX Fourier transform infrared spectrometer (unit: wavenumber cm -1) from Bruker, germany, wherein 2028, 1975 and 1943cm -1 are metal carbonyl absorption peaks, 1743 and 1709cm -1 are C=O bond vibration absorption peaks in axial glycine ethylene glycol monomethyl ether ester, and 1598 and 1506cm -1 are Boc-glycine carboxyl C=O bond vibration absorption peaks.
Glycine bridged ruthenium tetracarbonyl compound was dissolved in CDCl 3, and the hydrogen atom and the carbon atom in the molecule were confirmed by using a 400MHz nuclear magnetic resonance spectrometer from Bruker, germany, the single peak at δ1.43 in the hydrogen spectrum was 6-CH 3 and two-NH-hydrogen atoms in Bco-amino acid, the single peak at δ2.94 was four hydrogen atoms of two-NH 2, the single peak at δ3.39 was six hydrogen atoms of both ends-OCH 3, and the triple peak at δ 4.35,3.74,3.63 was hydrogen atoms of-CH 2 in glycine ethylene glycol monomethyl ether ester and Boc-amino acid, respectively.
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, delta 155.82 is an axial ligand carbonyl alpha-CH 2 carbon atom, delta 79.47, 70.13, 64.49, 58.96 are glycine ethylene glycol monomethyl ether ester and a carbon atom of-CH 2 in Boc-amino acid, delta 46.17 is a methoxy-OCH 3 carbon atom, delta 44.45 is a carbon atom in tert-butyl- (C (CH 3)3), delta 28.39 is a carbon atom of-CH 3 in tert-butyl- (C (CH 3)3), and the accuracy of a molecular structure is proved.
The glycine bridged ruthenium tetracarbonyl compound was dissolved in methanol, and the molecular weight in the molecule was determined by using a MALDITOF mass spectrometer from Bruker, germany, and the mass-to-charge ratio was found to be m/z 928.09, thus proving that the glycine bridged ruthenium tetracarbonyl compound was correct in molecular structure.
Example 2
The procedure of this example was the same as in example 1, except that: preparing a compound with a molecular formula of controllable CO release rate as follows: The Boc-amino acid used in the step S2 was Boc-phenylalanine, 98%, and Aca Ding Shiji (Shanghai Co., ltd.) to finally obtain 325mg of bright yellow needle-like crystals, namely, phenylalanine-bridged tetracarbonyl ruthenium compound, with a yield of 63%.
The structural characterization data of the phenylalanine bridged tetracarbonyl ruthenium compound is as follows:
Phenylalanine bridged tetracarbonyl ruthenium compounds were dissolved in CH 2Cl2, and the backbone structure of the product was tested using a Bruker company EQUINX model 55 Fourier transform infrared spectrometer (unit: wavenumber cm -1), germany, wherein 2028, 1975 and 1943cm -1 are metal carbonyl absorption peaks, 1743 and 1708cm -1 are C=O bond vibration absorption peaks in axial glycine ethylene glycol monomethyl ether ester, 1595 and 1495cm -1 are Boc-phenylalanine carboxyl C=O bond vibration absorption peaks.
Phenylalanine bridged tetracarbonyl ruthenium compound was dissolved in CDCl 3, and the hydrogen atom and the carbon atom in the molecule were confirmed by using a 400MHz nuclear magnetic resonance spectrometer from Bruker, germany, wherein the single peak at delta 1.42 in the hydrogen spectrum is 6-CH 3 hydrogen atoms in Boc-phenylalanine, the dd peak at delta 4.44 is two hydrogen atoms of a-CH-group of Boc-phenylalanine molecule, the peaks at delta 4.34,3.52 and 4.30 are-CH 2 -hydrogen atoms in Boc-phenylalanine and glycine ethylene glycol monomethyl ether ester, the single peak at delta 3.39 is six hydrogen atoms of two-terminal-OCH 3, the d peaks at delta 7.28 and 7.16 are hydrogen atoms on a benzene ring, and delta 3.07 and 2.95 are-NH-and-NH 2 hydrogen atoms, respectively.
Delta 183.71 is a metal carbonyl CO carbon atom, delta 183.71 is an axial ligand CO carbon atom (COOCH 2), delta 171.56 is a Boc-phenylalanine-COO carbon atom (Boc-Phe-COO), delta 154.96 is an axial ligand carbonyl alpha-CH 2 carbon atom, delta 137.21, 129.50, 128.38 and 126.58 are benzene ring carbon atoms, delta 79.49 is a Boc-phenylalanine carboxyl alpha-CH carbon atom, delta 70.14, 64.48, 58.97 and 46.29 glycine ethylene glycol monomethyl ether ester and a-CH 2 carbon atom in Boc-phenylalanine, delta 56.59 is a methoxy-OCH 3 carbon atom, delta 39.02 is a tertiary butyl- (C (CH 3)3) carbon atom, delta 28.40 is a tertiary butyl- (C (CH 3)3) carbon atom, and the accuracy of a molecular structure is proved.
The molecular weight of the phenylalanine bridged tetracarbonyl ruthenium compound in the molecule is determined by using a MALDITOF mass spectrometer of Bruker company, germany, and the mass-to-charge ratio is measured to be m/z:1109.07, so that the molecular structure of the glycine bridged tetracarbonyl ruthenium compound is proved to be correct.
Example 3
The procedure of this example was the same as in example 1, except that: preparing a compound with a molecular formula of controllable CO release rate as follows: The Boc-amino acid used in step S2 was Boc-alanine, 99%, ara Ding Shiji (Shanghai Co., ltd.) to finally obtain 289mg of bright yellow needle-like crystals, i.e., an alanine bridged tetracarbonyl ruthenium compound, in 67% yield.
The structural characterization data of the obtained product alanine bridged tetracarbonyl ruthenium compound are as follows:
Alanine bridged ruthenium tetracarbonyl compounds were dissolved in CH 2Cl2 and the backbone structure of the product was tested using a model EQUINX fourier-variant infrared spectrometer (unit: wavenumber cm -1) from Bruker, germany, where 2028, 1975 and 1943cm -1 are metal carbonyl absorbance peaks, 1743 and 1708cm -1 are c=o bond absorbance peaks and 1592 and 1498cm -1 are Boc-alanine carboxyc=o bond absorbance peaks in axial glycine ethylene glycol monomethyl ether ester.
Alanine bridged tetracarbonyl ruthenium compound was dissolved in CDCl 3, and the molecular hydrogen atom and carbon atom were confirmed by 400MHz nmr spectrometer from Bruker, germany, where the double peak at δ1.25 in the hydrogen spectrum was-CH 3 hydrogen atom at the carboxyl β position in Boc-alanine, the single peak at δ1.43 was 6-CH 3 and two-NH-hydrogen atoms in Boc-alanine, the single peak at δ2.93 was four hydrogen atoms of two-NH 2, the single peak at δ3.39 was six hydrogen atoms of two-OCH 3, and the peaks at δ 4.36,4.12,3.74 and 3.63 were glycine ethylene glycol monomethyl ether ester and-CH 2 hydrogen atoms in Boc-alanine, respectively.
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, delta 155.11 is an axial ligand carbonyl alpha-CH 2 carbon atom, delta 79.39, 64.53, 58.96 are glycine ethylene glycol monomethyl ether ester and a carbon atom of-CH 2 in Boc-alanine, delta 70.12 is a carbon atom of Boc-alanine carboxyl alpha, delta 51.09 is a methoxy-OCH 3 carbon atom, delta 46.21 is a carbon atom of tertiary butyl- (C (CH 3)3), delta 28.40 is a carbon atom of-CH 3 in tertiary butyl- (C (CH 3)3), and delta 19.41 is a carbon atom of-CH 3 in a bridging ligand, so that the accuracy of a molecular structure is proved.
The alanine bridged tetracarbonyl ruthenium compound was dissolved in methanol, and the molecular weight in the molecule was determined by using MALDITOF mass spectrometer from Bruker, germany, and the mass-to-charge ratio was found to be m/z 956.13, thus proving that the glycine bridged tetracarbonyl ruthenium compound was correct in molecular structure.
Example 4
The procedure of this example was the same as in example 1, except that: preparing a compound with a controllable CO release rate of the formula: The Boc-amino acid used in the step S2 was Boc-L-leucine, 99%, ara Ding Shiji (Shanghai Co., ltd.) to finally obtain 288mg of orange needle-like crystals, namely, leucine bridged tetracarbonyl ruthenium compound, with a yield of 60%.
The structural characterization data of the obtained leucine bridged tetracarbonyl ruthenium compound are as follows:
Leucine bridged tetracarbonyl ruthenium compounds were dissolved in CH 2Cl2 and the backbone structure of the product was tested using a Bruker company EQUINX model Fourier transform infrared spectrometer (unit: wavenumber cm -1) of Germany, wherein 2028, 1974 and 1942cm -1 are metal carbonyl absorbance peaks, 1743 and 1710cm -1 are C=O bond absorbance peaks in axial glycine ethylene glycol monomethyl ether ester, 1591 and 1500cm -1 are Boc-L-leucine carboxyC=O bond absorbance peaks.
The leucine bridged tetracarbonyl ruthenium compound is dissolved in CDCl 3, and a 400MHz nuclear magnetic resonance spectrometer of Bruker company in Germany is adopted for confirming hydrogen atoms and carbon atoms in molecules, wherein the peak at delta 0.91 in the hydrogen spectrum is isopropyl-CH 3 hydrogen atoms in Boc-L-leucine, the single peak at delta 1.42 is 6-CH 3 and two-NH-hydrogen atoms in Boc-L-leucine, the peak at delta 1.62 is isopropyl alpha-CH 2 -hydrogen atoms, the single peak at delta 2.91 is four hydrogen atoms of two-NH 2, the single peak at delta 3.39 is six hydrogen atoms of two-OCH 3 at two ends, and the peaks at delta 4.36,4.11,3.74 and 3.63 are hydrogen atoms of glycine ethylene glycol monomethyl ether ester and Boc-L-leucine-CH 2 respectively.
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, delta 155.26 is an axial ligand carbonyl alpha-CH 2 carbon atom, delta 79.30, 64.52, 58.96 is a glycine ethylene glycol monomethyl ether ester and a carbon atom of-CH 2 in Boc-L-leucine, delta 70.13 is a carbon atom of Boc-L-leucine carboxyl alpha-position, delta 54.03 is a methoxy-OCH 3 carbon atom, delta 42.46 is a carbon atom of tert-butyl- (C (CH 3)3), delta 28.40 is a carbon atom of-CH 3 in tert-butyl- (C (CH 3)3), delta 24.93 is a carbon atom of CH-, and delta 22.84 is a carbon atom of-CH 3 in a bridging ligand, thereby proving the accuracy of a molecular structure.
The molecular weight of the leucine bridged tetracarbonyl ruthenium compound in the molecule is determined by using a MALDITOF mass spectrometer of Bruker, germany, and the mass-to-charge ratio is measured to be m/z:1041.22, so that the glycine bridged tetracarbonyl ruthenium compound is proved to have the correct molecular structure.
Example 5
The procedure of this example was the same as in example 1, except that: preparing a compound with a controllable CO release rate of the formula: The Boc-amino acid used in the step S2 is Boc-L-valine, 99%, ara Ding Shiji (Shanghai) limited company), and 333mg of orange needle-like crystals are finally obtained, namely valine bridging speed control carbon monoxide release molecules, and the yield is 73%.
The structural characterization data of the valine bridged tetracarbonyl ruthenium compound is as follows:
Valine bridged ruthenium tetracarbonyl compound was dissolved in CH 2Cl2 and the skeletal structure of the product was tested using a Bruker company EQUINX model Fourier transform infrared spectrometer (unit: wavenumber cm -1) of Germany, wherein 2028, 1974 and 1942cm -1 are metal carbonyl absorption peaks, 1743 and 1709cm -1 are C=O bond vibration absorption peaks in axial glycine ethylene glycol monomethyl ether ester, 1591 and 1499cm -1 are Boc-L-valine carboxyl C=O bond vibration absorption peaks.
Valine bridged ruthenium tetracarbonyl compound was dissolved in CDCl 3, and the hydrogen atom and the carbon atom in the molecule were confirmed by using a 400MHz nuclear magnetic resonance spectrometer from Bruker, germany, wherein the dd peak at δ0.86 in the hydrogen spectrum was isopropyl-CH 3 hydrogen atom in Boc-L-valine, the single peak at δ1.44 was 6-CH 3 and two-NH-hydrogen atoms in Boc-L-valine, the single peak at δ2.95 was four hydrogen atoms of two-NH 2, the single peak at δ3.41 was six hydrogen atoms of both ends-OCH 3, and the peaks at δ 4.39,4.08,3.76 and 3.66 were hydrogen atoms of-CH 2 in glycine ethylene glycol monomethyl ether ester and Boc-L-valine, respectively.
In the 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 axial ligand imino alpha-COO carbon atom, delta 79.29, 64.56, 58.95 is a carbon atom of-CH 2 in glycine ethylene glycol monomethyl ether ester and Boc-L-valine, delta 70.11 is a carbon atom of alpha position of Boc-L-valine ester group, delta 46.14 is a methoxy-OCH 3 carbon atom, delta 32.00 is a carbon atom of tert-butyl- (C (CH 3)3), delta 28.37 is a carbon atom of-CH 3 in tert-butyl- (C (CH 3)3), delta 28.37 is an isopropyl-CH-carbon atom, and delta 18.82 and 17.76 are carbon atoms of-CH 3 in isopropyl, so that the accuracy of a molecular structure is proved.
The molecular weight of the valine bridged tetraruthenium carbonyl compound is determined by a MALDITOF mass spectrometer of Bruker, germany, and the mass-to-charge ratio is measured to be m/z:1013.12, so that the glycine bridged tetraruthenium carbonyl compound has the correct molecular structure.
Sustained release performance test
The molecular formula of the compound with controllable CO release rate prepared in examples 1-5 was tested for CO release performance, and the specific cases are as follows:
1. CO slow release rate test
The CO release properties (half-life t 1/2) of the molecular formula of the compounds with controlled CO release rates at different concentrations were determined by myoglobin method, excited by 365nm uv spot light source, and the results are shown in figures 1-4 and table 2.
TABLE 2 CO sustained Release test results
As can be seen from fig. 1-3 and table 2, the compounds with controllable CO release rates prepared by the present invention all show good CO release performance, and the bridging Boc-amino acid ligand is key to regulating CO release rate. Example 3 with Boc-alanine as ligand showed the fastest CO release rate in response to 365nm point light source irradiation, with shorter half-lives corresponding to 60. Mu.M, 40. Mu.M and 20. Mu.M of 207s,764s and 835s, respectively. Example 2, in which Boc-phenylalanine was the ligand, had the slowest CO release rates, and the longer half-lives of 60. Mu.M, 40. Mu.M and 20. Mu.M were 1541s,1594s and 1619s, respectively.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (6)
1. A compound having a controlled rate of CO release, characterized by the formula:
[Ru2(CO)4(µ2-ŋ2-OOC-R)2(ŋ1-NH2CH2 C(=O)OCH2CH2OCH3)2], Wherein [ mu ] represents the number of bridging groups; ŋ represents ligand dentition degree or atom number of ligand directly connected with metal;
the structural formula is as follows:
，
wherein R is Boc-amino acid, and the Boc-amino acid is Boc-glycine, boc-alanine, boc-L-valine, boc-L-leucine or Boc-phenylalanine.
2. A method for preparing a compound with controllable CO release rate, which is characterized by comprising the following steps:
Step S1: dissolving glycine glycol monomethyl ether ester hydrochloride and triethylamine in a mixed solvent of CH 2Cl2 : CH3 OH=1:1 to obtain glycine glycol monomethyl ether ester,
Step S2: ru 3(CO)12 and amino acid are reacted in a reaction solvent to obtain a first reaction solution containing a polymer intermediate,
Step S3: adding glycine ethylene glycol monomethyl ether ester into the first reaction liquid to obtain a compound with controllable CO release rate;
Wherein the amino acid in the step S2 is Boc-glycine, boc-alanine, boc-L-valine, boc-L-leucine or Boc-phenylalanine;
The molecular formula of the compound capable of controlling the CO release rate is as follows:
[Ru2(CO)4(µ2-ŋ2-OOC-R)2(ŋ1-NH2CH2 C(=O)OCH2CH2OCH3)2], Wherein [ mu ] represents the number of bridging groups; ŋ represents ligand dentition degree or atom number of ligand directly connected with 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 capable of controlling a CO release rate according to claim 2, wherein Ru 3(CO)12 in step S2: glycine ethylene glycol monomethyl ether ester: boc-amino acid=1:2:3.
4. The method for preparing a compound with controllable CO release rate according to claim 2, wherein the preparation method of glycine ethylene glycol monomethyl ether ester hydrochloride in step S1 is as follows:
Slowly dropwise adding thionyl chloride into ethylene glycol monomethyl ether cooled by ice bath at 0 ℃, reacting for 1 hour at 0 ℃, adding glycine under cooling condition, heating to 65 ℃ for reacting for two hours to obtain glycine ethylene glycol monomethyl ether ester hydrochloride,
Wherein, the ethylene glycol monomethyl ether: thionyl chloride: the molar ratio of glycine is 1:1:1.2.
5. A method for preparing a compound having a controllable CO release rate according to claim 2,
Step S2: the reaction solvent is dry toluene;
Step S2: the reaction condition is that the reaction is carried out for 7-9 hours at 110-130 ℃ under the protection of anhydrous and anaerobic atmosphere and inert gas, and the temperature is reduced to 40-60 ℃, wherein the inert gas is N 2, he or Ar.
6. The method for preparing a compound with controllable CO release rate according to claim 2, wherein the reaction time between glycine ethylene glycol monomethyl ether ester and the first reaction solution in the step S3 is 2 h.
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