CN1039230C - Synthesis of water-soluble bis-organo-substituted germanium compounds - Google Patents
Synthesis of water-soluble bis-organo-substituted germanium compounds Download PDFInfo
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- CN1039230C CN1039230C CN95100844A CN95100844A CN1039230C CN 1039230 C CN1039230 C CN 1039230C CN 95100844 A CN95100844 A CN 95100844A CN 95100844 A CN95100844 A CN 95100844A CN 1039230 C CN1039230 C CN 1039230C
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- CN
- China
- Prior art keywords
- water
- solid
- germanium
- organic
- sesquioxide
- Prior art date
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- Expired - Fee Related
Links
- 150000002291 germanium compounds Chemical class 0.000 title claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title claims description 4
- 238000003786 synthesis reaction Methods 0.000 title claims description 4
- 229940093626 germanium sesquioxide Drugs 0.000 claims abstract description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006722 reduction reaction Methods 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000010189 synthetic method Methods 0.000 claims abstract description 3
- 239000007787 solid Substances 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 7
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- XEABSBMNTNXEJM-UHFFFAOYSA-N propagermanium Chemical compound OC(=O)CC[Ge](=O)O[Ge](=O)CCC(O)=O XEABSBMNTNXEJM-UHFFFAOYSA-N 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- -1 germanium series compound Chemical class 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 238000007670 refining Methods 0.000 claims description 3
- VPMMMQIATACXDN-UHFFFAOYSA-N 1-carboxypropan-2-ylgermanium Chemical compound CC([Ge])CC(O)=O VPMMMQIATACXDN-UHFFFAOYSA-N 0.000 claims description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 230000002045 lasting effect Effects 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 238000011084 recovery Methods 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 238000007259 addition reaction Methods 0.000 abstract description 2
- 239000002955 immunomodulating agent Substances 0.000 abstract description 2
- 229940121354 immunomodulator Drugs 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 150000002290 germanium Chemical class 0.000 abstract 1
- 229910052732 germanium Inorganic materials 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 235000015110 jellies Nutrition 0.000 description 3
- 239000008274 jelly Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 1
- 235000011511 Diospyros Nutrition 0.000 description 1
- 244000236655 Diospyros kaki Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NNOAUHIBBXZFRF-UHFFFAOYSA-N O(O)O.[Ge] Chemical compound O(O)O.[Ge] NNOAUHIBBXZFRF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229910000078 germane Inorganic materials 0.000 description 1
- SFRGJTLLCUCVMH-UHFFFAOYSA-N germanium;propanoic acid Chemical compound [Ge].CCC(O)=O SFRGJTLLCUCVMH-UHFFFAOYSA-N 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention belongs to a synthetic method of water-soluble double-organic substituted germanium compound. The invention selects organic germanium sesquioxide as a starting material, and prepares a water-soluble compound of bi-organic substituted germanium through reduction and addition reaction in concentrated hydrochloric acid. The compound has high water solubility and good thermal stability, and the structural property of the compound is unchanged after the compound is placed in the air for a long time. The compounds are expected to be applied as anticancer agents or immunomodulators.
Description
The invention belongs to the synthetic method of water-soluble two organic replacement germanium compounds.
1985, people such as the rich and autumn leaves light hero of Japan's scholar persimmon basic annals disclose a kind of " organic germanium compounds II replaces the simple zone of trichlorine germanium propionic acid and ester and selects the germane base to be combined to method " the 272nd page of SYNTHESIS (synthesize) magazine, and this method is employing HGeCl
3In hydrochloric acid soln, carry out addition reaction with vinylformic acid or other unsaturated carboxylic acid.Reaction product is carried out hydrolysis reaction and is obtained carboxyethyl germanium sesquioxide or derivative behind recrystallizing and refining.
This compounds has function anticancer and that regulate immunity of organism, and wherein Ge-132 has carried out I phase and the clinical anticancer test of II phase, but this compounds is water-soluble good inadequately under physiological condition, and Ge-132 solubleness in 25 ℃ of water only is 1.09g/100ml water.
The present invention seeks to utilize organic germanium compounds to have to improve immunological competence, various biological effect such as antitumor, and have extremely low characteristics of toxicity, selecting organic germanium sesquioxide for use is starting raw material, through reaction process such as reduction, addition in concentrated hydrochloric acid solution, synthetic water-soluble pair of organic germanium compounds of a class.
It is the synthetic organic germanium series compound with following array structure of starting raw material that the present invention selects organic germanium sesquioxide for use:
R wherein
1, R
2, R
3, R
4Be H ,-CH
3Group, synthesis step is as follows:
1) in concentrated hydrochloric acid solution, with Zn powder or NaH
2PO
2H
2O or H
3PO
2Solution is made reductive agent, the reduction organic germanium sesquioxide comprises Ge-132, carboxylic sec.-propyl germanium sesquioxide, the Alpha-Methyl carboxyethyl germanium sesquioxide, reduction reaction temperature is a reflux temperature, the mol ratio of reductive agent and organic germanium sesquioxide is 1～6,0.5～6 hour recovery time, gets settled solution after the reduction;
2) with settled solution under reflux temperature and lasting stirring condition, dropwise addition of acrylic acid or Ba Dousuan, with the amount ratio that is reduced sesquioxide be 1～4 (mol ratio), after dropwising, continued the stirring heating back flow reaction 2-20 hour, reacted solution is separated out crystalline solid or colloidal solid through placing, and collects solid;
3) solid is water-soluble, filter, collect filtrate, evaporation is separated out crystalline solid or colloidal solid after making filtrate concentrating, cooling;
4) with solid recrystallizing and refining in organic solvents such as water or acetone, acetonitrile, obtaining product yield is 20-70%.
The two organic replacement germanium compounds of synthetic of the present invention have very high water-soluble, and dissolve in organic solvents such as acetone, acetonitrile methanol, ethanol, dimethyl sulfoxide (DMSO), dimethyl formamide.And have thermostability preferably, do not decompose only dehydration being arranged below 300 ℃, place in that air is medium-term and long-term, structure, character do not change, with in the alkali and after, the sodium of generation, potassium, ammonium salt etc. are also soluble in water.
The above-mentioned pair of organic germanium compounds and salt thereof have kept the bio-active group of bata-carboxyethyl germanium sesquioxide, are hopeful to be applied as carcinostatic agent and immunomodulator etc.
Embodiment provided by the invention is as follows: embodiment 1: synthetic pair-propyloic germanium oxyhydroxide.
0.04molNaH
2PO
4H
2The O heating is dissolved in 3mlH
2O adds the 16ml concentrated hydrochloric acid, removes by filter NaCl, collects filtrate, places flask.
In flask, add 0.01molGe-132, stirring heating back flow reaction 3 hours.
In flask, add 0.02mol vinylformic acid, continued the stirring heating back flow reaction 15 hours, be chilled to room temperature, place, separate out white crystalline solid, it is soluble in water to collect solid, filters, and collects filtrate, filtrate warm evaporating into closely in beaker done, and crystalline solid is separated out in cooling, collects solid.
Solid is recrystallization in water or acetone or acetonitrile, yield 65%, and product is analyzed.
C
6H
12GeO
62H
2The O results of elemental analyses is as follows:
C：24.88％(24.95％)，H：5.16％(5.58％)，Ge：25.07％(25.15％)
In the bracket is theoretical value.
Mass spectrometry results MS-FAB has M+H
+Peak: 255
NMR analytical results (D
2O, DSS are standard):
δ=1.66 (4H, triplet), δ=2.73 (4H, triplet)
IR, hot analytical results are slightly.
Embodiment 2:
Synthetic pair-carboxylic sec.-propyl germanium oxyhydroxide
Experimental technique and condition are with embodiment 1, and difference is to replace Ge-132 and replace vinylformic acid with Ba Dousuan with carboxylic sec.-propyl germanium sesquioxide,
During the product recrystallization, separate out jelly earlier.Through placing, jelly changes crystal into.
The product analysis result is as follows:
C
8H
16GeO
6?C：33.84％(34.21％)，H：5.07％(5.70％)，Ge：25.63％(25.87％)
In the bracket is theoretical value.
Mass spectrometry results MS-FAB has M+H
+Peak: 283
All the other analytical resultss slightly.
Embodiment 3:
Synthetic propyloic, carboxylic sec.-propyl germanium oxyhydroxide.
Experimental technique and process are with embodiment 1, after difference is reduction reaction; Gradation adds the Ba Dousuan solid but not vinylformic acid, during the product recrystallization, gets jelly.The dry solid product that gets.
Claims (1)
1. the synthetic method of water-soluble two organic replacement germanium compounds, it is characterized in that selecting for use organic germanium sesquioxide is the synthetic organic germanium series compound with following array structure of starting raw material:
R wherein
1, R
2, R
3, R
4Be H ,-CH
3Group, synthesis step is as follows:
1) in concentrated hydrochloric acid solution, with Zn powder or NaH
2PO
2H
2O or H
3PO
2Solution is made reductive agent, the reduction organic germanium sesquioxide comprises Ge-132, carboxylic sec.-propyl germanium sesquioxide, the Alpha-Methyl carboxyethyl germanium sesquioxide, reduction reaction temperature is a reflux temperature, the mol ratio of reductive agent and organic germanium sesquioxide is 1～6, recovery time 0.5-6 hour, gets settled solution after the reduction;
2) with settled solution under reflux temperature and lasting stirring condition, dropwise addition of acrylic acid, α-Jia Jibingxisuan or Ba Dousuan, carboxylic acid is 1～4 (mol ratio) with the amount ratio that is reduced sesquioxide, after dropwising, continued the stirring heating back flow reaction about 2～20 hours, reacted solution is separated out crystalline solid or colloidal solid through placing, and collects solid;
3) solid is water-soluble, filter, collect filtrate, evaporation is separated out crystalline solid or colloidal solid after making filtrate concentrating, cooling;
4) with solid recrystallizing and refining in water or acetone, acetonitrile organic solvent, obtaining product yield is 20-70%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95100844A CN1039230C (en) | 1995-03-20 | 1995-03-20 | Synthesis of water-soluble bis-organo-substituted germanium compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95100844A CN1039230C (en) | 1995-03-20 | 1995-03-20 | Synthesis of water-soluble bis-organo-substituted germanium compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1133845A CN1133845A (en) | 1996-10-23 |
| CN1039230C true CN1039230C (en) | 1998-07-22 |
Family
ID=5073640
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95100844A Expired - Fee Related CN1039230C (en) | 1995-03-20 | 1995-03-20 | Synthesis of water-soluble bis-organo-substituted germanium compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1039230C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100386334C (en) * | 2004-10-26 | 2008-05-07 | 中国科学院长春应用化学研究所 | Organic germanium-base quinolinate compound and its synthesis method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1076198A (en) * | 1992-12-28 | 1993-09-15 | 方景昌 | Compound of organo-germanium salts |
| CN1093710A (en) * | 1993-04-15 | 1994-10-19 | 贵州大学 | Theapolyhenol germanium and preparation method thereof |
-
1995
- 1995-03-20 CN CN95100844A patent/CN1039230C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1076198A (en) * | 1992-12-28 | 1993-09-15 | 方景昌 | Compound of organo-germanium salts |
| CN1093710A (en) * | 1993-04-15 | 1994-10-19 | 贵州大学 | Theapolyhenol germanium and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《SYNTHSIS》1985.1.1 柿丰纪博，秋叶光雄"有机锗化合物" * |
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| Publication number | Publication date |
|---|---|
| CN1133845A (en) | 1996-10-23 |
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