CN104059106B - Preparation method of sugar alcohol phosphate thiazolidine-4-carboxy compound - Google Patents
Preparation method of sugar alcohol phosphate thiazolidine-4-carboxy compound Download PDFInfo
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- CN104059106B CN104059106B CN201410302678.5A CN201410302678A CN104059106B CN 104059106 B CN104059106 B CN 104059106B CN 201410302678 A CN201410302678 A CN 201410302678A CN 104059106 B CN104059106 B CN 104059106B
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- Prior art keywords
- cysteine
- phosphoric acid
- compound
- thiazoles
- tetrahydro
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- -1 sugar alcohol phosphate Chemical class 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 11
- 239000010452 phosphate Substances 0.000 title claims abstract description 11
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims abstract description 76
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims abstract description 33
- 235000018417 cysteine Nutrition 0.000 claims abstract description 33
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 78
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 66
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 54
- 238000003756 stirring Methods 0.000 claims description 37
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- XUJNEKJLAYXESH-UWTATZPHSA-N D-Cysteine Chemical compound SC[C@@H](N)C(O)=O XUJNEKJLAYXESH-UWTATZPHSA-N 0.000 claims description 26
- 230000001476 alcoholic effect Effects 0.000 claims description 25
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- 150000002484 inorganic compounds Chemical class 0.000 claims description 9
- 229910010272 inorganic material Inorganic materials 0.000 claims description 9
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 8
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
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- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims description 4
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- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
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- PPQRONHOSHZGFQ-LMVFSUKVSA-N aldehydo-D-ribose 5-phosphate Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PPQRONHOSHZGFQ-LMVFSUKVSA-N 0.000 abstract description 12
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- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
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Abstract
The invention relates to a preparation method of a sugar alcohol phosphate thiazolidine-4-carboxy compound with the structural formula as the specification. The compound is formed by integrating three groups and can release cysteine and ribose phosphate after being absorbed in vivo. Cysteine can be used for increasing the concentration of glutathione (GSH) in cells, improving the oxidation resistance of the cells and improving the inflammation diminishing and detoxifying capabilities of a human body from inside to outside. Ribose phosphate can be used for replenishing the energy loss caused by wounds or strenuous exercise while rapidly and effectively improving the ATP (Adenosine Triphosphate) level in tissues. Bodybuilding and brain-strengthening effects can be synchronously realized through the combination of carboxylate and phosphate groups and different trace elements.
Description
Technical field
The invention belongs to phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound field, specifically refer to a kind of phosphoric acid sugar alcohols
The preparation method of tetrahydro-thiazoles-4-carboxylic acid's compound.
Background technology
Glutathione (GSH) is present in each cell of almost body.It can help body to keep normal siberian crabapple
The function of system, and there is antioxidation and integrate Detoxication, the sulfydryl on cysteine is its active group, easy and some
Medicine (as acetaminophen), toxin (such as free radical, iodoacetic acid, mustard gas, the heavy metal such as lead, hydrargyrum, arsenic) etc. combine, thus machine
The poisonous substance being harmful in vivo is converted into harmless material, excretes external, and has Detoxication.Another main life of Glutathione
Reason functions as a kind of important antioxidant in vivo, and it can dispose the free radical in human body, cleaning and purification human body
Environment pollution, thus enhance the physical and mental health of people.
The biosynthesiss first step of Glutathione (GSH) is under gamma glutamyl cysteine synthetase catalysis, in paddy ammonia
The γ of acid-form peptide bond between carboxyl and the amino of cysteine, second step is under glutathione synthetase catalysis, by ATP
The carboxyl of activation cysteine, makes it the amino condensation with glycine.But because cysteine has neurotoxicity in itself,
IC is very low, lead to intracellular L-Cysteine availability be Glutathione (GSH) biosynthetic crucial because
Element.
Previous research is it has been shown that by carrying out modifying the poison that can reduce cysteine to the amino of cysteine or sulfydryl
Property, and the prodrug as cysteine, discharge cysteine through hydrolysis or open loop, to improve in cell semicystinol concentration from
And reach the purpose of supplementary Glutathione.This kind of prodrug includes N-acetyl-L-cysteine, L-2- oxothiazolidin -4- carboxylation
Thing and 2 (R, S)-n-pro-pyl-Thiazolidine -4R- carboxylate etc..
In the energy expenditure of organism, adenosine triphosphate (ATP) is the direct sources of vital movement energy, it a large amount of
Chemical energy is stored in energy-rich phosphate bond.In the vital movement of cell, ATP away from an energy-rich phosphate bond easy fracture,
Discharge a phosphoric acid and energy.But content is not high in vivo for ATP itself, particularly under body anoxia and ischemic state,
Body ATP can significantly decline, and impact body movement function simultaneously causes biological organs to damage, it usually needs the time of several days could
Recover normal.
The synthesis of ATP mainly includes de novo synthesis and through nucleotide remedial procedures, and during this two, ribose phosphate is all
Key point, during de novo synthesis, ribose phosphate is phosphorylated to ribose 5-phosphate -1- pyrophosphoric acid (PRPP), and and adenine
Condensation forms intermediate adenosine monophosphate (AMP) and further phosphorylation forms ATP.In nucleotide remedial procedures, it is present in
Nucleotide precursor in tissue is converted into AMP, and forms ATP further.And ribose phosphate be nucleotide basic framework former
Material.Ribose phosphate plays a crucial role in the regeneration and recovery of ATP as can be seen here, but by glucose through pentose phosphate approach
Obtain ribose phosphate to be limited by glucose-6-phosphate dehydrogenase (G6PD) (G-6-PD).Supplement D ribose or ribose phosphate can make machine
Body quickly recovers ATP level, effectively improves the motor capacity of human body, to resisting fatigue, alleviates muscular soreness.In human body experience
When anoxia, ischemia or high-intensity exercise, effectively accelerate myocardial cell and Skeletal Muscle Cell ATP supplements speed, promote ischemia
Tissue, the recovery of ischaemia tissue.In normal diet, D ribose and ribose phosphate content are extremely low.
Anoxia, ischemic conditions may alternatively appear in surgical procedures, blood loss damage, cardiovascular disease, cardiomyopathy, blood class
Disease, respiratory system disease, chronic disease and high intensity physical work or high-intensity exercise.
US4719201 has been disclosed the heart that perfusion in ribose intravenous administration gives recovery from ischemia, can improve
ATP level.US6218366 discloses can increase the tolerance to anoxia by giving ribose.CN101060840A discloses logical
Cross and give ribose-cysteine treatment anoxia, ATP level in recovery organization.Ribose described in above-mentioned patent need to be through being converted into core
Sugar -5- phosphoric acid, and further phosphoric acid turns to PRPP, promotes from the beginning approach and salvage pathway, and ultimately forms ATP.
By monosaccharide, the existing multiple document reports of cysteine synthesis sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound, this
Type compound can be used for improving the level of the transmission of glutathion inside cell and ATP to treat ischemia or hypoxic conditions.
Content of the invention
It is an object of the invention to provide a kind of preparation of novel phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound of synthesis
Method, has new phosphate group.
A kind of preparation method of phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound, comprises the following steps：
1) choosing one of cysteine or phosphoric acid alcoholic compounds is raw material, by above-claimed cpd apparatus polarized
Solvent dissolves；
2) choose and there is R2The phosphoric acid alcoholic compounds solution of functional group or there is R1The cysteine solution of functional group,
12-24 hour is stirred at room temperature；
3) filter after adding ethanol, obtain with R after washing2Or R1The intermediate product of functional group；
4) nitrogen protection reactor in, by step 3) intermediate product apparatus polarized solvent dissolving after, add
There is the inorganic compound of respective element, stirring under room temperature is more than 24 hours；
5) add ethanol and lower the temperature, filter after stirring 1-3 hour, and with after washing with alcohol, obtaining phosphoric acid sugar alcohols tetrahydrochysene
Thiazole -4-carboxylic acid's compound；
Wherein, R1For H, Li, Na, K, Ca, Zn, Fe, OMe, OEt, OPr, OBu, OAc, OPh, NH4 +, HN (Me)3 +, HN
(Et)3 +, HN (Pr)3 +, HN (Bu)3 +, N (Me)4 +, N (Et)4 +, N (Pr)4 +, N (Bu)4 +Any one in functional group；
R2For H, Li, Na, K, Ca, Zn, Fe, Me, Et, Pr, Bu, Ac, Ph, NH4 +, HN (Me)3 +, HN (Et)3 +, HN
(Pr)3 +, HN (Bu)3 +, N (Me)4 +, N (Et)4 +, N (Pr)4 +, N (Bu)4 +, In functional group
Any one.
A kind of preparation method of phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound, comprises the following steps：
1) in the reactor of nitrogen protection, the one kind choosing phosphoric acid alcoholic compounds is raw material, and above-claimed cpd is used
There is the solvent dissolving of polarity；
2) add and there is the inorganic compound of respective element and lower the temperature, filter after stirring 1-3 hour, and washed with coordinative solvent
After washing, obtain phosphate alcoholic compounds；
3) in the reactor of nitrogen protection, by the solvent dissolving of above-mentioned phosphate alcoholic compounds apparatus polarized；
4) add cysteine solution, 12-24 hour is stirred at room temperature；
5) add ethanol and lower the temperature, filter after stirring 1-3 hour, and with after washing with alcohol, obtaining phosphoric acid sugar alcohols tetrahydrochysene
Thiazole -4-carboxylic acid's compound.
The structural formula of described phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound is：
Wherein, R1For H, Li, Na, K, Ca, Zn, Fe, OMe, OEt, OPr, OBu, OAc, OPh, NH4 +, HN (Me)3 +, HN
(Et)3 +, HN (Pr)3 +, HN (Bu)3 +, N (Me)4 +, N (Et)4 +, N (Pr)4 +, N (Bu)4 +Any one in functional group；
L is to include CH2,In
Any one functional group compound, all of n >=1 in this；
R2For H, Li, Na, K, Ca, Zn, Fe, Me, Et, Pr, Bu, Ac, Ph, NH4 +, HN (Me)3 +, HN (Et)3 +, HN
(Pr)3 +, HN (Bu)3 +, N (Me)4 +, N (Et)4 +, N (Pr)4 +, N (Bu)4 +, In functional group
Any one.
The structural formula of described intermediate product is：Or
Wherein, R1For H, Li, Na, K, Ca, Zn, Fe, OMe, OEt, OPr, OBu, OAc, OPh, NH4 +, HN (Me)3 +, HN
(Et)3 +, HN (Pr)3 +, HN (Bu)3 +, N (Me)4 +, N (Et)4 +, N (Pr)4 +, N (Bu)4 +Any one in functional group；
L is to include CH2,In
Any one functional group compound, all of n >=1 in this；
R2For H, Li, Na, K, Ca, Zn, Fe, Me, Et, Pr, Bu, Ac, Ph, NH4 +, HN (Me)3 +, HN (Et)3 +, HN
(Pr)3 +, HN (Bu)3 +, N (Me)4 +, N (Et)4 +, N (Pr)4 +, N (Bu)4 +, In functional group
Any one.
The described solvent with polarity is deionized water.
Described cooling refers to be cooled to less than 5 DEG C.
Described cysteine, its structural formula hasStructure is to be added in the form of acid salt.
Described cysteine, its structural formula hasStructure, from L-Cysteine, D-Cys, or
Person is the mixture of L-Cysteine and D-Cys.
In the mixture of described L-Cysteine and D-Cys, the weight ratio of L-Cysteine and D-Cys is
100：0-0：In the range of 100；It is preferably 30：70-70：30；More preferably 50：50.
The compound that described structural formula has L group is in alcohols, phenols, polyol or the polyphenolic substance of more than two carbon
At least one.
Alcohols more than described two carbon, phenols, polyol or polyphenolic substance are preferably monosaccharide and disaccharide, polysaccharide, or protect
At least one in shield, the monosaccharide and disaccharide replacing or polysaccharide.
Described monosaccharide be glyceraldehyde, ribose, deoxyribose, Fructose, glucose, glucosamine, N-acetyl-glucosamine and
Its isomer, in xylose, arabinose, mannose, rhamnose, lyxose, galactosamine or N-acetylgalactosamine
At least one.
Described phosphoric acid alcoholic compounds, its structural formula hasThe phosphoric acid of the phosphoric acid alcoholic compounds of structure
Group is at least one in monophosphate group, bis phosphoric acid group or triphosphoric acid group and its esters.
The invention has the beneficial effects as follows：
Such compound is the compound integrating three class groups, can as cysteine and phosphoribosyl prodrug,
Discharge cysteine and ribose phosphate through hydrolysis or open loop, semicystinol concentration reaches supplementary Glutathione in improving cell
Purpose and while fast and effectively improve ATP level in tissue, supplements the metal ion leading to because of wound or strenuous exercise
Run off.
Specific embodiment
To describe technical scheme by the following examples in detail, below example is only exemplary, only
Can be used for explaining and illustrate technical scheme, and be not to be construed as the restriction to technical solution of the present invention.
A kind of phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound, its structural formula is as follows：
Wherein, R1For H, Li, Na, K, Ca, Zn, Fe, OMe, OEt, OPr, OBu, OAc, OPh, NH4 +, HN (Me)3 +, HN
(Et)3 +, HN (Pr)3 +, HN (Bu)3 +, N (Me)4 +, N (Et)4 +, N (Pr)4 +, N (Bu)4 +Any one in functional group；
L is to include CH2,In
Any one functional group compound, all of n >=1 in this；
R2For H, Li, Na, K, Ca, Zn, Fe, Me, Et, Pr, Bu, Ac, Ph, NH4 +, HN (Me)3 +, HN (Et)3 +, HN
(Pr)3 +, HN (Bu)3 +, N (Me)4 +, N (Et)4 +, N (Pr)4 +, N (Bu)4 +, In functional group
Any one.
The preparation method of the first phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound, comprises the following steps：
A kind of preparation method of phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound, comprises the following steps：
1) choosing one of cysteine or phosphoric acid alcoholic compounds is raw material, by above-claimed cpd apparatus polarized
Solvent dissolves；
2) choose and there is R2The phosphoric acid alcoholic compounds solution of functional group or there is R1The cysteine solution of functional group,
12-24 hour is stirred at room temperature；R herein2The phosphoric acid alcoholic compounds solution of functional group or there is R1The cysteine of functional group is molten
The selection of liquid is basis：When step 1) in from cysteine be raw material when, step 2) in choose be with R2Functional group
Phosphoric acid alcoholic compounds solution；When step 1) in from phosphoric acid alcoholic compounds be raw material when, step 2) in choose be to have
R1The cysteine solution of functional group；
3) filter after adding ethanol, obtain with R after washing2Or R1The intermediate product of functional group；Described intermediate product
Structural formula is：Or
4) nitrogen protection reactor in, by step 3) intermediate product apparatus polarized solvent dissolving after, add
There is the inorganic compound of respective element, stirring under room temperature is more than 24 hours；In this application, related to addition has accordingly
The inorganic compound of element each means that addition has R1Or R2The inorganic salts compound of functional group.
5) add ethanol and lower the temperature, filter after stirring 1-3 hour, and with after washing with alcohol, obtaining phosphoric acid sugar alcohols tetrahydrochysene
Thiazole -4-carboxylic acid's compound；
Wherein, R1For H, Li, Na, K, Ca, Zn, Fe, OMe, OEt, OPr, OBu, OAc, OPh, NH4 +, HN (Me)3 +, HN
(Et)3 +, HN (Pr)3 +, HN (Bu)3 +, N (Me)4 +, N (Et)4 +, N (Pr)4 +, N (Bu)4 +Any one in functional group；
R2For H, Li, Na, K, Ca, Zn, Fe, Me, Et, Pr, Bu, Ac, Ph, NH4 +, HN (Me)3 +, HN (Et)3 +, HN
(Pr)3 +, HN (Bu)3 +, N (Me)4 +, N (Et)4 +, N (Pr)4 +, N (Bu)4 +, In functional group
Any one.
In all of embodiment of the application, R1And R2Included functional group all with reference to above-mentioned scope, following just not
Carry out repeat specification again.
The synthetic route of the first preparation method
Embodiment 1
Weigh 27.4 kilograms of D-ribose -5- disodic alkaliines, 50 kilograms of deionized waters stir to being completely dissolved, 12.2 kilograms
Calcium chloride solid adds after being dissolved in 18 kg of water, is stirred at room temperature more than 12 hours.Add 150 kilograms of ethanol, mistake after stirring 2 hours
Filter, collects solid, washing with alcohol, and obtaining 25.5 kilograms of white solid product is D-ribose -5- synthos.In nitrogen protection
In reaction vessel, weigh 25.5 kilograms of D-ribose -5- synthos, add double centner deionized water to stir to being completely dissolved, then
Add 15 kilograms of L-cysteine hydrochloride, stir to being completely dissolved, add 7.52 kilograms of pyridines, be stirred at room temperature little more than 24
When.Add 300 kilograms of ethanol, be cooled to less than 5 degrees Celsius, stirring was filtered after 2 hours, with cold washing with alcohol, obtain 30.36
Kilogram white solid product.Yield is 86%, and through nuclear-magnetism, infrared spectrum, mass spectrum confirms product.
Embodiment 2
Weigh 27.4 kilograms of D-ribose -5- disodic alkaliines, 50 kilograms of deionized waters stir to being completely dissolved, 13.94 thousand
Gram ferrous chloride adds after being dissolved in 25 kilograms of water, is stirred at room temperature more than 12 hours.Add 150 kilograms of ethanol, mistake after stirring 2 hours
Filter, collects solid, washing with alcohol, and obtaining 26.9 kilograms of white solid product is D-ribose -5- ferrous phosphate salt.In nitrogen protection
Reaction vessel in, weigh 26.9 kilograms of D-ribose -5- ferrous phosphate salt, add double centner deionized water to stir to completely molten
Solution, adds 15 kilograms of D-Cys hydrochlorates, stirs to being completely dissolved, adds 7.52 kilograms of pyridines, be stirred at room temperature and be more than
24 hours.Add 300 kilograms of ethanol, be cooled to less than 5 degrees Celsius, stirring was filtered after 2 hours, with cold washing with alcohol, obtain
29.78 kilogram white solid product.Yield is 81%, and through nuclear-magnetism, infrared spectrum, mass spectrum confirms product.
Embodiment 3
Weigh 27.4 kilograms of D-ribose -5- disodic alkaliines, add 50 kilograms of deionized waters to stir to after be completely dissolved, plus
Enter 16 liters of saturation calcium chloride solutions, be stirred at room temperature more than 12 hours.Add 150 kilograms of ethanol, stirring is filtered after 2 hours, collected
Solid, washing with alcohol, obtaining 25.5 kilograms of white solid product is D-ribose -5- synthos.Hold in the reaction of nitrogen protection
In device, weigh 25.5 kilograms of D-ribose -5- synthos, add double centner deionized water to stir to being completely dissolved, add 15
Kilogram L-cysteine hydrochloride and D-Cys hydrochlorate are by weight for 50：50 mixture, stirs to being completely dissolved,
Add 7.52 kilograms of pyridines, be stirred at room temperature more than 24 hours.Add 300 kilograms of ethanol, be cooled to less than 5 degrees Celsius, stirring 2 is little
When after filter, with cold washing with alcohol, obtain 30 kilograms of white solid product.Yield is 85%, and product is through nuclear-magnetism, infrared light
Spectrum, mass spectrum confirms.
In the other embodiments of this synthetic route, D-ribose -5- disodic alkaliine can be changed as needed；Oxygen
Change calcium to be replaced with other compositions, such as iron chloride, potassium chloride etc., here cannot be carried out illustrating one by one.
The preparation method of second phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound, comprises the following steps：
1) in the reactor of nitrogen protection, the one kind choosing phosphoric acid alcoholic compounds is raw material, and above-claimed cpd is used
There is the solvent dissolving of polarity；
2) add and there is the inorganic compound of respective element and lower the temperature, filter after stirring 1-3 hour, and washed with coordinative solvent
After washing, obtain phosphate alcoholic compounds；
3) in the reactor of nitrogen protection, by the solvent dissolving of above-mentioned phosphate alcoholic compounds apparatus polarized；
4) add cysteine solution, 12-24 hour is stirred at room temperature；
5) add ethanol and lower the temperature, filter after stirring 1-3 hour, and with after washing with alcohol, obtaining phosphoric acid sugar alcohols tetrahydrochysene
Thiazole -4-carboxylic acid's compound.
The synthetic route of second preparation method
Embodiment 4
In the reaction vessel of nitrogen protection, weigh 27.4 kilograms of D-ribose -5- disodic alkaliines, add 50 kilograms go from
Sub- water stirs to being completely dissolved, and adds 15.77 kilograms of L-cysteine hydrochloride, stirs to being completely dissolved, adds 7.91 thousand
Gram pyridine, was stirred at room temperature more than 24 hours.12.2 kilograms of calcium chloride solids add after being dissolved in 18 kg of water, are stirred at room temperature more than 12
Hour.150 kilograms of ethanol add, and cooling is less than 5 degrees Celsius, and stirring was filtered after 2 hours, with cold washing with alcohol, obtain 33.4
Kilogram white solid product.Yield 90%, through nuclear-magnetism, infrared spectrum, mass spectrum confirms product.
Embodiment 5
In the reaction vessel of nitrogen protection, weigh 27.4 kilograms of D-ribose -5- disodic alkaliines, add 50 kilograms go from
Sub- water stirs to being completely dissolved, and adds 15.77 kilograms of D-Cys hydrochlorates, stirs to being completely dissolved, adds 7.91 thousand
Gram pyridine, was stirred at room temperature more than 24 hours.13.94 kilograms of ferrous chloride solids add after being dissolved in 18 kg of water, are stirred at room temperature big
In 12 hours.150 kilograms of ethanol add, and cooling is less than 5 degrees Celsius, and stirring was filtered after 2 hours, with cold washing with alcohol, obtain
32.12 kilogram white solid product.Yield 83%, through nuclear-magnetism, infrared spectrum, mass spectrum confirms product.
Embodiment 6
In the reaction vessel of nitrogen protection, weigh 27.4 kilograms of D-ribose -5- disodic alkaliines, add 50 kilograms go from
Sub- water stirs to being completely dissolved, and adds 15.77 kilograms of L-cysteine hydrochloride and D-Cys hydrochlorate by weight
For 60：40 mixture, stirs to being completely dissolved, adds 7.91 kilograms of pyridines, be stirred at room temperature more than 24 hours.16 liters of saturation chlorine
Change calcium solution to add, be stirred at room temperature more than 12 hours.150 kilograms of ethanol add, and cooling is less than 5 degrees Celsius, mistake after stirring 2 hours
Filter, with cold washing with alcohol, obtains 32.65 kilograms of white solid product.Yield 88%, product is through nuclear-magnetism, infrared spectrum, mass spectrum
Confirm.
In the other embodiments of this synthetic route, D-ribose -5- disodic alkaliine can be changed as needed；Oxygen
Change calcium to be replaced with other compositions, such as iron chloride, potassium chloride etc., here cannot be carried out illustrating one by one.
In the above-mentioned preparation method of the application, the solvent with polarity is deionized water.
In the above-mentioned preparation method of the application, cooling refers to be cooled to less than 5 DEG C.
Described cysteine, its structural formula hasStructure is to be added in the form of acid salt.
In all preparation methoies of the application, its structural formula hasThe compound of group, from L- half Guang ammonia
Acid, D-Cys, or the mixture of L-Cysteine and D-Cys.
In the mixture of described L-Cysteine and D-Cys, the weight ratio of L-Cysteine and D-Cys is
100：0-0：In the range of 100；It is preferably 30：70-70：30；More preferably 50：50.
When the weight of L-Cysteine and D-Cys is than for 100：When 0, represent tetrahydro-thiazoles-4-carboxylic acid's compound bone
Frame is derived only from L-Cysteine；When the weight of L-Cysteine and D-Cys is than for 0：When 100, expression tetrahydro-thiazoles-
4- carboxylic acid compound skeleton is derived only from D-Cys.
The weight ratio preferably 30 of L-Cysteine and D-Cys：70-70：30, represent in tetrahydro-thiazoles-4-carboxylic acid
The source of compound scaffold forms, wherein, L-Cysteine and D-Cys by L-Cysteine and D-Cys mixing
Weight than by 30：70、35：65、40：60、45：55、50：50、55：45、60：40、65：35 or 70：The weight such as 30 compare group
Become, herein, enumerating of counterweight amount ratio is not to say that tetrahydro-thiazoles-4-carboxylic acid's compound scaffold derives from L-Cysteine and D-
The determination weight ratio of cysteine mixing composition, also includes the weight ratio do not enumerated, and such as 31：69 etc..But at this
In application, the weight of most preferred L-Cysteine and D-Cys is than for 50：50.
The compound that described structural formula has L group is in alcohols, phenols, polyol or the polyphenolic substance of more than two carbon
At least one.At least one in preferably monosaccharide and disaccharide, polysaccharide, or protection, the monosaccharide and disaccharide replacing or polysaccharide.Single
Sugar is glyceraldehyde, ribose, deoxyribose, Fructose, glucose, glucosamine, N-acetyl-glucosamine and its isomer, such as wood
At least one in sugar, arabinose, mannose, rhamnose, lyxose, galactosamine or N-acetylgalactosamine.
Phosphoric acid alcoholic compounds, its structural formula hasThe phosphate group of the phosphoric acid alcoholic compounds of structure is
At least one in monophosphate group, bis phosphoric acid group or triphosphoric acid group and its esters.Can in the phosphate group of the application
Think the salts such as alkali metal or transition metal.
Appointed according to three group formula structures included by monomer by phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound monomer
A kind of what form can aggregate into dimer or polymer, the polymerization of phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound
The structural formula of thing is：
Wherein, n >=2；
It is below the structural formula of two examples of dimer of phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound,
Above-mentioned dimer structure formula is intended merely to the polymerization shape of phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound is described
Formula, is not for this compound only above two structural formula is described.
Phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound and officinal salt, can use as medicine, described medicine energy
Enough discharge cysteine and ribose phosphate, semicystinol concentration reaches supplementary Glutathione purpose and fast in improving cell
While speed effectively improves ATP level in tissue, supplement and run off because of the metal ion that wound or strenuous exercise lead to.
Described medicine also includes pharmaceutical acceptable carrier, and this carrier can be solid, semi-solid or liquid diluent.
The above is only the preferred embodiment of the present invention it is noted that ordinary skill people for the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (9)
1. a kind of preparation method of phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound it is characterised in that：Comprise the following steps：
1) choosing one of cysteine or phosphoric acid alcoholic compounds is raw material, by the solvent of above-claimed cpd apparatus polarized
Dissolving；
2) when step 1) in from cysteine be raw material when, choose phosphoric acid alcoholic compounds solution room temperature stir 12-24 hour；
When step 1) in from phosphoric acid alcoholic compounds be raw material when, choose cysteine solution 12-24 hour is stirred at room temperature；
3) filter after adding ethanol, after washing, obtain intermediate product；
4) nitrogen protection reactor in, by step 3) intermediate product apparatus polarized solvent dissolving after, addition has
The inorganic compound of respective element, stirring under room temperature is more than 24 hours；
5) add ethanol lowering the temperature, filter after stirring 1-3 hour, and with after washing with alcohol, obtain phosphoric acid sugar alcohols tetrahydro-thiazoles-
4- carboxylic acid compound；
Described phosphoric acid alcoholic compounds are D-ribose -5- disodic alkaliine；The described inorganic compound with respective element is chlorine
Change calcium, ferrous chloride, iron chloride or potassium chloride.
2. a kind of preparation method of phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound it is characterised in that：Comprise the following steps：
1) in the reactor of nitrogen protection, selection phosphoric acid alcoholic compounds are raw material, by above-claimed cpd apparatus polarized
Solvent dissolves；
2) add and there is the inorganic compound of respective element and lower the temperature, filter after stirring 1-3 hour, and washed with coordinative solvent
Afterwards, phosphate alcoholic compounds are obtained；
3) in the reactor of nitrogen protection, by the solvent dissolving of above-mentioned phosphate alcoholic compounds apparatus polarized；
4) add cysteine solution, 12-24 hour is stirred at room temperature；
5) add ethanol lowering the temperature, filter after stirring 1-3 hour, and with after washing with alcohol, obtain phosphoric acid sugar alcohols tetrahydro-thiazoles-
4- carboxylic acid compound；
Described phosphoric acid alcoholic compounds are D-ribose -5- disodic alkaliine；The described inorganic compound with respective element is chlorine
Change calcium, ferrous chloride, iron chloride or potassium chloride.
3. the preparation method according to claim 1 or phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound described in 2 any one, its
It is characterised by：The described solvent with polarity is deionized water.
4. the preparation method according to claim 1 or phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound described in 2 any one, its
It is characterised by：Described cooling refers to be cooled to less than 5 DEG C.
5. the preparation method according to claim 1 or phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound described in 2 any one, its
It is characterised by：Described cysteine is to be added in the form of acid salt.
6. the preparation method according to claim 1 or phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid's compound described in 2 any one, its
It is characterised by：Described cysteine derives from L-Cysteine, D-Cys, or L-Cysteine and D- half Guang ammonia
The mixture of acid.
7. according to claim 6 phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid compound preparation method it is characterised in that：
In the mixture of described L-Cysteine and D-Cys, the weight of L-Cysteine and D-Cys is than for 100：0-0：
In the range of 100.
8. according to claim 7 phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid compound preparation method it is characterised in that：
In the mixture of described L-Cysteine and D-Cys, the weight of L-Cysteine and D-Cys is than for 30：70-
70：30.
9. according to claim 8 phosphoric acid sugar alcohols tetrahydro-thiazoles-4-carboxylic acid compound preparation method it is characterised in that：
In the mixture of described L-Cysteine and D-Cys, the weight of L-Cysteine and D-Cys is than for 50：50.
Priority Applications (1)
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