CN101591402A - 6-deoxy-sulfones cyclodextrin derivatives and preparation method thereof - Google Patents
6-deoxy-sulfones cyclodextrin derivatives and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
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- A—HUMAN NECESSITIES
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
Abstract
The invention provides the 6-deoxy-sulfones cyclodextrin derivatives, structure with general formula (I), be to be raw material with 6-deoxy thioether amino acid cyclodextrin derivative or 6-deoxy thioether cyclodextrin derivative, by oxidizing reaction 1, obtain 6-deoxidation sulfoxide group cyclodextrin derivative, further oxidation obtains 6-deoxidation sulfuryl cyclodextrin derivative.Wherein the 6-deoxy thioether amino acid cyclodextrin derivative is to adopt to contain R
3Substituent acetate obtains two halogenide through halogenating reaction, obtains acid amides with amino acid condensation again, adds sulphur reagent and obtains sulfocompound, obtains sulfhydryl compound through removing protecting group, obtains with the condensation of halo cyclodextrin again.Compound provided by the invention can be used for reversing patient or animal muscle relaxant inductive neuromuscular relaxation phenomenon, and muscle relaxant inductive flaccidity is had reverse, antagonistic action, can use in the medicine of preparation flesh pine antagonistic action.
Description
Technical field
The invention belongs to the chemical pharmaceutical field, relate to 6-deoxy-sulfones cyclodextrin derivatives and preparation method thereof, relate generally to 6-deoxidation sulfoxide group cyclodextrin derivative and 6-deoxidation sulfuryl cyclodextrin derivative and preparation method thereof, and the purposes in preparation flesh pine antagonistic action medicine.
Technical background
Fujita.K. had synthesized mono-substituted 2-hydroxyethyl sulfo-cyclodextrin in the Tetr.Lett. reported first in 1980, and Ling.C. in 1993 and Darry.R. report have synthesized the 2-hydroxyethyl sulfo-cyclodextrin of full replacement, and its structural formula is:
Tubashi in 1986, I. report on J.A.C.S. and have synthesized adjacent carboxyl phenyl sulfo-cyclodextrin; Nineteen ninety-five Guillo, the F. report has synthesized carboxyl methyl sulfo-cyclodextrin; Baer in 1996, H.H. and Santoyo-Gonzalez, F. has prepared 2, and 3-dihydroxyl rosickyite is for cyclodextrin.Its structural formula is:
B＝HOOCCH
2；PhCOOH；HOCH
2(HO)CHCH
2；
Patent CN1402737 has reported the preparation of similar compounds, and its chemical structure is formula (IV):
Wherein m is 0 to 7, n is 1 to 8 and m+n=7 or 8;
R is (C
1-C
6) alkylidene group, optional by 1 to 3 OH group or (CH
2) the r-phenylene-(CH2)
t-replace;
R and t are 0 to 4 independently of one another;
X
1Be COOH, CONHR
6, NHCOR
7, SO
2OH, PO (OH)
2, O (CH
2-CH
2-O) u-H, OH or tetrazolium-5-base;
R
6Be hydrogen, (C
1-3) alkyl;
R
7It is carboxyl phenyl;
U is in 1 to 3.
Sugammadex is the 6-mercapto-cyclodextrin derivative among a kind of CN1402737, in July, 2007, the sugammadex (Bridion) of Schering Plough company went on the market, be used to reverse conventional neuromuscular blocking drug Zemuron or the vecuronium bromide effect of using, can reverse the used Zemuron effect of adult, the conventional children of reverse and the used Zemuron effect of teenager (2～17 years old) immediately.
The muscle relaxant skeletal muscle that relaxes also claims muscle relaxant, is adjuvant drug important in the general anesthesia, in order to be convenient to do endotracheal intubation and to keep good flesh pine in art when the general anesthesia induction.Use muscle relaxant can avoid the detrimentally affect of dark general anesthesia to human body.Muscle relaxant is applicable to that also the urgent patient eliminates the antagonism between patient's autonomous respiration and the mechanical ventilation when mechanical ventilation, and in order to treat spastic disease etc.
Use muscle relaxant to must be noted that airway management, make assisted respiartion or control breathing, guarantee the effective and enough per minute air flows of patient according to flesh pine degree.
The narcology specialty is the excessive risk specialty of generally acknowledging.According to The World Health Organization's statistical information, anaesthetize related mortality in recent years developed country's average out to 1: 100000～1: 300000, developing country be 1: 5000～: 10000, some backward countries even higher.Investigating (including 198103 example anesthesia cases in) by the French Ministry of Health great complication of whole nation anesthesia for one finds, postoperative respiration inhibition (account for death 61%) is an anesthesia associated death most important reason in this investigation, and is not the difficult intubation that everybody guesses.This shows that postoperative neuromuscular blockade effect residual is the Hazard Factor that attract great attention.
Judge that whether neuromuscular function returns to normally is very difficult after using muscle relaxant clinically.Remaining muscle relaxant can suppress the reaction of respiratory centre to the anoxic ventilation; Infringement FI flow velocity causes that the upper respiratory tract blocks and dysphagia; Prolong the hospital stays, increase post-operative complication incidence and mortality ratio; Cause throat's muscle dysfunction, mistake is inhaled incidence to be increased.Therefore safely, effectively, the remaining muscle relaxant effect of antagonism is very important to clinical anesthesia.
Existing flesh pine antagonism anticholinesterase can temporarily suppress to decompose the acetylcholinesterase of vagusstoff, is increased in neuromuscular junction portion vagusstoff concentration, impels excited transmission of neuromuscular to recover normal.Anticholinesterase drug has prostigmin(e), edrophonium chloride and Pyridostigmine, and it reaches the peak effect time and is respectively 7～11min, 1～2min and 15～20min.The onset of Pyridostigmine is the slowest, does not therefore conform to clinical requirement.The complication of anticholinesterase drug or untoward reaction simultaneously is also relatively more serious.
Before the potassium channel blocade acts on neuromuscular junction, blocked potassium ion and flowed out, prolonged neural unpolarizing and increased time and the burst size that discharges vagusstoff by nerve ending.But this class medicine does not have specificity, can act on all nerve ending, therefore can cause multiple serious adverse effects, and this has limited it in clinical use.
Sugammadex can chelating steroid class muscle relaxant and make it break away from acetylcholine receptor, reverse neuromuscular block effect rapidly, has the not available characteristic of other muscle relaxant antagonists: promptly muscle relaxant rapid performance antagonistic action in the short period of time can given, the minor operation that the time that also is applicable to is short, more can be used as the rescue medication of " not only can't intubate but also can't ventilate " case.Because its effect does not relate to the muscarinic acceptor, does not therefore need to share with anticholinergic drug.Can also the antagonism degree of depth flesh pine effect, shorten muscular tension time of recovery, and do not have heavily curarization behind the antagonism and take place.Sugammadex has significant advantage than existing flesh pine antagonist.
Summary of the invention
The purpose of this invention is to provide the 6-deoxy-sulfones cyclodextrin derivatives, have the structure of general formula (I):
Formula (I)
Wherein m is 0,1, in 2,3,4,5,6,7,8 one;
N is 1,1, in 2,3,4,5,6,7,8,9 one;
M+n is 6,7, in 8 or 9 one;
Q is in 1 or 2;
R is (C
1-C
6) alkylidene group, optional by 1 to 3 OH group or (CH
2) the r-phenylene-(CH2)
t-replace, wherein r is in 0,1,2,3 or 4 one, t is in 0,1,2,3 or 4;
X is COOH, CONHR
1, NHCOR
2, SO
2OH, PO (OH)
2, O (CH
2-CH
2-O) in u-H, OH or the tetrazolium-5-base, wherein R
1Be hydrogen, (C
1-3) alkyl the or contain (C of COOH
1-3) in the alkyl one, R
2Be carboxyl phenyl, u is in 1,2 or 3.
Described 6-deoxy-sulfones cyclodextrin derivatives (I) is 6-deoxidation sulfoxide group cyclodextrin derivative when q is 1, have the structure of general formula (II):
Formula (II)
Described 6-deoxy-sulfones cyclodextrin derivatives (I) is 6-deoxidation sulfuryl cyclodextrin derivative when q is 2, have the structure of general formula (III):
Formula (III)
Another object of the present invention provides the preparation method of 6-deoxy-sulfones cyclodextrin derivatives (I): with 6-deoxy thioether amino acid cyclodextrin derivative (V) or with the disclosed 6-mercapto-cyclodextrin of CN1402737 derivative (IV) is raw material, by oxidizing reaction 1, obtain 6-deoxidation sulfoxide group cyclodextrin derivative (II), compound (II) further obtains 6-deoxidation sulfuryl cyclodextrin derivative (III) by oxidizing reaction 2.
Reaction formula:
Wherein m, n, m+n, R, X, X
1As described in compound (I),
R
3Be H, CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, (CH
2)
3CH
3, C (CH
3)
3Or C
6H
5In one;
R
4Be H, CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH
2CH
3(CH
3) CH, CH
2CH (CH
3)
2, CH
2C
6H
5, CH
3SCH
2CH
2Or H
2NC (O) CH
2In one.
The used oxygenant of above-mentioned oxidizing reaction 1 and oxidizing reaction 2 steps is peracid salt and organo-peroxide, as peroxidation sulfuric acid, H
2O
2, KClO
4, H
2SO
4, KMnO
4, Na
2O
2Or K
2O
2In a kind of.
It is as follows that another object of the present invention provides structure of 6-deoxy thioether amino acid cyclodextrin derivative (V) and preparation method thereof:
Wherein: M, n, m+n are as described in the compound (I);
R
3, R
4As compound (II) with (III);
R
5Be phenyl or pyridyl;
A is among OH, Cl or the Br.
The preparation method of 6-deoxy thioether amino acid cyclodextrin derivative (V) is to adopt to contain R
3Substituent acetate (a) is that starting raw material and halide reagent obtain two halogenide (b) through halogenating reaction; obtain corresponding amide (c) with amino acid condensation; add sulphur reagent thiylation group then and obtain corresponding sulfocompound (d); obtain sulfhydryl compound (e) through removing protecting group, in the presence of alkali, obtain a series of 6-deoxy thioether amino acid cyclodextrin derivatives (V) and salt thereof with the condensation of halo cyclodextrin.
The related R that contains
3Substituting group is the alkane or the aromatic hydrocarbons of hydrogen and short carbon chain, as methyl, ethyl, and propyl group, sec.-propyl, butyl, a kind of in the tertiary butyl or the phenyl; Related halide reagent is chlorine element, bromine, sulfur oxychloride, phosphorus tribromide or phosphorus trichloride; The amino acid that is adopted be natural amino acid as: sweet, the third, a word used in person's names, bright, different bright, l-asparagine, phenylpropyl alcohol or methionine(Met) etc.; The sulphur reagent of related displacement thiylation group is: sulfo-nicotinic acid, sodium disulfide, thioacetic acid, Sulfothiorine or thiobenzoic acid, preferred sulfo-nicotinic acid; Related protecting group removes and is meant basic hydrolysis, and used alkali is mineral alkali such as ammoniacal liquor, sodium hydroxide or potassium, or the aqueous solution of yellow soda ash or potassium etc.; Related in the presence of alkali with the condensation reaction of halo cyclodextrin in, alkali is meant sodium hydride or potassium, sodium amide or potassium, sodium alkoxide or potassium; The halo cyclodextrin is meant: the cyclodextrin of 6,7,8 or 9 yuan of rings that chlorine, bromine, iodine replace; The 6-deoxy thioether amino acid cyclodextrin derivative and the salt thereof of related acquisition are meant sylvite, sodium salt or lithium salts, particular certain cancers.
A further object of the present invention provides Compound I I, III, the application of V in preparation flesh pine antagonistic action medicine.Confirm that through pharmacological evaluation Compound I I provided by the invention, III, V can be used for reversing patient or animal muscle relaxant inductive neuromuscular relaxation phenomenon, and muscle relaxant inductive flaccidity is had reverse, antagonistic action.
Among Compound I I provided by the invention, III, the V any mixes with pharmaceutical excipient and obtains medicinal compositions, can prepare formulation and can be tablet, capsule or injection.
6-deoxidation sulfoxide group cyclodextrin derivative provided by the invention (II), 6-deoxidation sulfuryl cyclodextrin derivative (III) and 6-deoxy thioether amino acid cyclodextrin derivative (V) can be fast, safety, antagonism steroid class non-depolarizing muscular relaxant effectively, can with the neuromuscular blocking drug combination, stop it to play a role in neuromuscular junction place, thereby reverse the effect of flesh pine, no obvious adverse reaction may greatly be taken on a new look the present situation of clinical anesthesia.Neuromuscular blockade was complete when the anesthesia doctor increased muscle relaxant dosage or skin suture when surgical operation closes to an end, do not have very big misgivings again yet, as long as art finishes the medicine that gives compound of the present invention, patient's neuromuscular conduction function just can be recovered rapidly; For some burns, hyperpotassemia or the unusual patient of blood plasma pseudocholinesterase, in the time of can't using sux-cert, the medicine of Zemuron and compound of the present invention becomes first-selection; In addition, if find that after anesthesia induction or emergency treatment intubate give non-depolarizing muscular relaxant patient belongs to difficult intubation, the situation that " can't intubate; can't ventilate " occur, can use compound of the present invention and stop the effect of flesh pine rapidly, recover normal expiratory positive airway pressure rapidly, guarantee patient's life security.
6-deoxy thioether amino acid cyclodextrin derivative of the present invention (V) is significantly different with the 6-mercapto-cyclodextrin derivative (IV) among the CN1402737.X in the compound (IV) is CONHR
1The time, R
1Be hydrogen, (C
1-3) alkyl; And X is CONHR in the 6-deoxy thioether amino acid cyclodextrin derivative of the present invention (V)
1The time, R
1Be CHR
4COOH.Another characteristics of 6-deoxy thioether amino acid cyclodextrin derivative of the present invention (V) be 6 of cyclodextrin to go up what replace be amino acid, and what replace on the cyclodextrin in the compound (IV) is non-amino acid.Compound 6-deoxy-sulfones sulfone cyclodextrin derivative of the present invention (I) and 6-deoxy thioether amino acid cyclodextrin derivative (V) have stable good aqueous solubility, the drug candidate of the neuromuscular anesthesia that can be used for reversing drug-induced.The amino acid aboundresources is safe simultaneously, helps improving drug safety.
Embodiment
The present invention is further elaborated by following examples, but is not to limit the invention by any way with it.
Synthesizing of embodiment 1 alpha-chloro acetyl-glycine
Add glycine 90g (1.2mol) in the 2000mL four-hole reaction flask, add the about 400mL stirring and dissolving of water, add the anhydrous sodium carbonate 64g (0.6mol) of porphyrize gradually.After adding and dissolving, bathe cooling with cryosel, vigorous stirring limit, limit drips the about 135.5g of alpha-chloro Acetyl Chloride 98Min. (1.2mol), drips sodium carbonate solution, makes reaction solution keep weakly alkaline, adds the back and continues stirring 4h, and hcl acidifying is to pH=1.With ethyl acetate extraction 2 times, combining extraction liquid adds an amount of anhydrous sodium sulfate drying and spends the night, and filters, and filtrate decompression has been distilled to crystallization and has separated out, and placement is spent the night, and filters, dry colourless needle crystal 123.6g, yield about 68%.
Synthesizing of embodiment 2 alpha-chloro phenylacetyl glycine
Add glycine 90g (1.2mol) in the 2000mL four-hole reaction flask, add the about 400mL stirring and dissolving of water, add the anhydrous sodium carbonate 64g (0.6mol) of porphyrize gradually.After adding and dissolving, bathe cooling with cryosel, vigorous stirring limit, limit drips the about 226.85g of alpha-chloro phenyllacetyl chloride (1.2mol), drips sodium carbonate solution, makes reaction solution keep weakly alkaline, adds the back and continues stirring 4h, and hcl acidifying is to pH=1.With ethyl acetate extraction 2 times, combining extraction liquid adds an amount of anhydrous sodium sulfate drying and spends the night, and filters, and filtrate decompression has been distilled to crystallization and has separated out, and placement is spent the night, and filters, dry colourless needle crystal 180.3, yield about 66%.
The preparation of the sylvite aqueous solution of embodiment 3 sulfo-nicotinic acid
(42g, 0.75mol) Sodium sulfhydrate, 150ml water, stirring and dissolving.(49.54g, 0.35mol) nicotinoyl chlorine, controlled temperature are no more than 15 ℃ in dropping under the ice bath cooling.After dripping, continue stirring 1 hour, be cooled to 0 ℃ then, add the hydrochloric acid neutralization, filter, get solid sulfur, slowly add the potash water dissolving again, filter, get the yellow aqueous solution 60.6g of sulfo-nicotinic acid sylvite, yield 97.7% for nicotinic acid.
Synthesizing of embodiment 4 α-nicotinoyl mercapto acetyl glycine
7.5g (0.1mol) glycine is dissolved in the 60ml diluted sodium hydroxide solution, cryosel is cooled to below 0 ℃, drip 11.3g (0.1mol) alpha-chloro Acetyl Chloride 98Min. and 50ml diluted sodium hydroxide solution under the vigorous stirring simultaneously, keep reaction solution to be alkalescence, add the back and continue to stir 1 hour.The sylvite aqueous solution that adds 17.73g (0.1mol) sulfo-nicotinic acid then, room temperature are placed and are spent the night.Hcl acidifying is separated out solid to PH3, filter, washing, dry, white solid 20.3g, yield 80%.
Synthesizing of embodiment 5 α-nicotinoyl mercaptopropionylglycine
7.5g (0.1mol) glycine is dissolved in the 60ml diluted sodium hydroxide solution, cryosel is cooled to below 0 ℃, drip 12.7g (0.1mol) alpha-chloro propionyl chloride and 50ml diluted sodium hydroxide solution under the vigorous stirring simultaneously, keep reaction solution to be alkalescence, add the back and continue to stir 1 hour.The sylvite aqueous solution that adds 17.73g (0.1mol) sulfo-nicotinic acid then, room temperature are placed and are spent the night.Hcl acidifying is separated out solid to PH3, filter, washing, dry, white solid 22.3g, yield 83.5%.
Synthesizing of embodiment 6 α-nicotinoyl mercapto phenylacetylglycine
7.5g (0.1mol) glycine is dissolved in the 60ml diluted sodium hydroxide solution, cryosel is cooled to below 0 ℃, drip 22.76g (0.1mol) alpha-chloro phenyllacetyl chloride and 50ml diluted sodium hydroxide solution under the vigorous stirring simultaneously, keep reaction solution to be alkalescence, add the back and continue to stir 1 hour.The sylvite aqueous solution that adds 17.73g (0.1mol) sulfo-nicotinic acid then, room temperature are placed and are spent the night.Hcl acidifying is separated out solid to PH3, filter, washing, dry, white solid 27g, yield 81.8%.
Synthesizing of embodiment 7 α-benzoyl mercapto acetyl glycine
7.5g (0.1mol) glycine is dissolved in the 60ml diluted sodium hydroxide solution, cryosel is cooled to below 0 ℃, drip 11.3g (0.1mol) alpha-chloro Acetyl Chloride 98Min. and 50ml diluted sodium hydroxide solution under the vigorous stirring simultaneously, keep reaction solution to be alkalescence, add the back and continue to stir 1 hour.The sylvite aqueous solution that adds 17.63g (0.1mol) thiobenzoic acid then, room temperature are placed and are spent the night.Hcl acidifying is separated out solid to PH3, filter, washing, dry, white solid 21.38g, yield 84.4%.
Synthesizing of embodiment 8 α-benzoyl mercapto phenylacetylglycine
7.5g (0.1mol) glycine is dissolved in the 60ml diluted sodium hydroxide solution, cryosel is cooled to below 0 ℃, drip 18.9g (0.1mol) alpha-chloro phenyllacetyl chloride and 50ml diluted sodium hydroxide solution under the vigorous stirring simultaneously, keep reaction solution to be alkalescence, add the back and continue to stir 1 hour.The sylvite aqueous solution that adds 17.63g (0.1mol) thiobenzoic acid then, room temperature are placed and are spent the night.Hcl acidifying is separated out solid to PH3, filter, washing, dry, white solid 27.67g, yield 84%.
Synthesizing of embodiment 9 2-sulfydryl ethanoyl-glycine
Add sodium sulphite (NaS9H2O) 132g (0.55mol) in the 500mL beaker, add the about 150mL stirring and dissolving of water, continue to add sublimed sulphur 17.6g (0.55mol), heated and stirred makes dissolving, and reaction makes red-brown sodium disulfide solution, and is standby.Add alpha-chloro acetyl-glycine 83.35g (0.55mol) in the 2000mL four-hole bottle, add water 500mL, stir the anhydrous sodium carbonate 28.5g (0.27mol) that adds porphyrize down gradually, stirring and dissolving.Drip the sodium disulfide solution that makes then, control reaction temperature is no more than 35 ℃ simultaneously, and stirring reaction 10h generates α-dithio diacetyl group glycine.Under the ice-water bath cooling, add sulfuric acid acidation to pH=1, excessive sulfide is decomposed.Solution after reaction finished filters; filtrate places the 2000mL four-hole bottle in addition, and gradation adds zinc powder 82g (1.25mol) under ice-water bath cooling and stirring, continues at after adding under the room temperature and reacts 2～3h; placement spend the night (storage vessel be full of as far as possible or with nitrogen protection to improve yield, down with).Filter, filtrate is with ethyl acetate extraction 3～4 times, and anhydrous sodium sulfate drying spends the night.Filter, filtrate has been concentrated into micro-crystallization and has separated out, and low temperature is placed, and filters, and vacuum-drying gets 2-sulfydryl ethanoyl-glycine crude product.
Synthesizing of embodiment 10 2-sulfydryl benzoyl-glycine
Add sodium sulphite (NaS9H2O) 132g (0.55mol) in the 500mL beaker, add the about 150mL stirring and dissolving of water, continue to add sublimed sulphur 17.6g (0.55mol), heated and stirred makes dissolving, and reaction makes red-brown sodium disulfide solution, and is standby.Add alpha-chloro benzoylglycine 125.2g (0.55mol) in the 2000mL four-hole bottle, add water 500mL, stir the anhydrous sodium carbonate 28.5g (0.27mol) that adds porphyrize down gradually, stirring and dissolving.Drip the sodium disulfide solution that makes then, control reaction temperature is no more than 35 ℃ simultaneously, and stirring reaction 10h generates the two benzoylglycines of α-dithio.Under the ice-water bath cooling, add sulfuric acid acidation to pH=1, excessive sulfide is decomposed.Solution after reaction finished filters; filtrate places the 2000mL four-hole bottle in addition, and gradation adds zinc powder 82g (1.25mol) under ice-water bath cooling and stirring, continues at after adding under the room temperature and reacts 2～3h; placement spend the night (storage vessel be full of as far as possible or with nitrogen protection to improve yield, down with).Filter, filtrate is with ethyl acetate extraction 3～4 times, and anhydrous sodium sulfate drying spends the night.Filter, filtrate has been concentrated into micro-crystallization and has separated out, and low temperature is placed, and filters, and vacuum-drying gets 2-sulfydryl benzoyl-glycine crude product.
Synthesizing of embodiment 11 2-sulfydryl ethanoyl-glycine
30g (0.12mol) α-nicotinoyl mercapto acetyl glycine is suspended in the 100ml water, adds strong aqua 30ml with in the sodium bicarbonate and back, and room temperature is placed and spent the night, and filters then, removes the benzamide of separating out, and the filtrate decompression ammonia excretion adds hcl acidifying.Aqueous solution ethyl acetate extraction concentrates, and separates out solid, filters, and drying gets white crystals 14.6g, yield 83%.
Synthesizing of embodiment 12 2-sulfydryl benzoyl-glycine
30g (0.11mol) α-nicotinoyl mercapto benzoyl-glycine is suspended in the 100ml water, adds strong aqua 30ml with in the sodium bicarbonate and back, and room temperature is placed and spent the night, and filters then, removes the benzamide of separating out, and the filtrate decompression ammonia excretion adds hcl acidifying.Aqueous solution ethyl acetate extraction concentrates, and separates out solid, filters, and drying gets white crystals 16.88g, yield 82.5%.
Synthesizing of embodiment 13 2-sulfydryl ethanoyl-glycine
30g (0.11mol) 2-sulfydryl benzoyl-glycine is suspended in the 100ml water, adds strong aqua 30ml with in the sodium bicarbonate and back, and room temperature is placed and spent the night, and filters then, removes the benzamide of separating out, and the filtrate decompression ammonia excretion adds hcl acidifying.Aqueous solution ethyl acetate extraction concentrates, and separates out solid, filters, and drying gets white crystals 14.3g, yield 81%.
Synthesizing of embodiment 14 2-sulfydryl benzoyl-glycine
30g (0.11mol) α-benzoyl mercapto benzoyl-glycine is suspended in the 100ml water, adds strong aqua 30ml with in the sodium bicarbonate and back, and room temperature is placed and spent the night, and filters then, removes the benzamide of separating out, and the filtrate decompression ammonia excretion adds hcl acidifying.Aqueous solution ethyl acetate extraction concentrates, and separates out solid, filters, and drying gets white crystals 16.76g, yield 81.7%.
Embodiment 15
Making with extra care of N-(2-sulfydryl ethanoyl)-glycine: in 50 ℃ of following tepors dissolvings, can add 0.01% activated carbon decolorizing with 5～6 times of ethyl acetate, placement is spent the night, filtration under diminished pressure, and vacuum-drying gets highly finished product.Measure fusing point, recrystallization is 1～2 time in case of necessity, the about 60g of finished product, yield is about 65%, m.p.96～98 ℃ (document yield 29%, m.p.96～97.5 ℃).
With triphenylphosphine (30.1 grams, 15 equivalents) stirring and dissolving is in the dry dimethyl formamide (160 milliliters). in 10 minutes, add iodine (30.5 grams, 15.6 equivalent) and have heat release. add exsiccant Y cyclodextrin (10 grams then, 7.7 mmole), 70 ℃ of mixture heating up also kept 24 hours. cooling mixture, in mixture, add sodium methylate (3.1 gram sodium are in 50 ml methanol), 300 milliliters of impouring methyl alcohol, be evaporated to dried, add 500 milliliters of entry in the residue, pass through solid collected by filtration; Filtrate decompression concentrates, and adds ethanol and separates out precipitation, obtains the full deoxidation of yellow solid 6--6-periodo-γ-Huan Hujing (16.2 gram) in 70 ℃ of following dryings of vacuum, and it is not further purified and continues to use.
With (1.22 milliliters of N-(2-sulfydryl ethanoyl)-glycine; 14.0 mmole) at room temperature be dissolved in the exsiccant dimethyl formamide (45 milliliters). add sodium hydride (1 in three batches to this solution; 23 grams; 30.8 mmole; 60%). continued to stir the mixture 30 minutes. dropwise be added in the 45 milliliters of full deoxidation of the 6-in the exsiccant dimethyl formamide-6-periodo-γ-Huan Hujings (3.12 grams to this mixture; 1.40 solution mmole). after the adding, reaction mixture is heated to 70 ℃ and kept 12 hours.After the cooling, add entry (10 milliliters) and concentrate volume to 40 milliliter in a vacuum, add ethanol (150 milliliters) to this and cause precipitation to this mixture.By solid collected by filtration precipitation and dialysis 36 hours. concentrate volume to 20 milliliter in a vacuum, add ethanol, obtain white solid by overanxious collecting precipitation and drying, yield 47% to this.
Embodiment 16
Making with extra care of N-(2-mercapto radical propionyl group)-glycine: in 50 ℃ of following tepors dissolvings, can add 0.01% activated carbon decolorizing with 5～6 times of ethyl acetate, placement is spent the night, filtration under diminished pressure, and vacuum-drying gets highly finished product.Measure fusing point, recrystallization is 1～2 time in case of necessity, gets the about 60g of finished product, and yield is about 65%, m.p.96～98.
With triphenylphosphine (30.1 grams, 15 equivalents) stirring and dissolving is in the dry dimethyl formamide (160 milliliters). in 10 minutes, add iodine (30.5 grams, 15.6 equivalent) and have heat release. add exsiccant Y cyclodextrin (10 grams then, 7.7 mmole), 70 ℃ of mixture heating up also kept 24 hours. cooling mixture, in mixture, add sodium methylate (3.1 gram sodium are in 50 ml methanol), 800 milliliters of impouring methyl alcohol, be evaporated to dried, add 500 milliliters of entry in residue, by solid collected by filtration, filtrate decompression concentrates, add ethanol and separate out precipitation, obtain the full deoxidation of yellow solid 6--6-periodo-γ-Huan Hujing (16.2 gram) in 70 ℃ of following dryings of vacuum.
With (1.22 milliliters of N-(2-mercapto radical propionyl group)-glycine; 14.0 mmole) at room temperature be dissolved in the exsiccant dimethyl formamide (45 milliliters); add sodium hydride (1 in three batches to this solution; 23 grams; 30.8 mmole; 60%); continued to stir the mixture 30 minutes; dropwise be added in the 45 milliliters of full deoxidation of the 6-in the exsiccant dimethyl formamide-6-periodo-γ-Huan Hujings (3.12 grams to this mixture; 1.40 solution mmole); after the adding, reaction mixture is heated to 70 ℃ and kept 12 hours.After the cooling, add entry (10 milliliters) and concentrate volume to 40 milliliter in a vacuum, add ethanol (150 milliliters) to this and cause precipitation to this mixture.By solid collected by filtration precipitation and dialysis 36 hours. concentrate volume to 20 milliliter in a vacuum, add ethanol, obtain white solid CD-13, weigh 1.3 grams, yield 43% by overanxious collecting precipitation and drying to this.CD-13 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.46 (CH
3, d, 3H), 2.55 (CH
2, m, 2H), 3.02 (CH, m, H), 3.65 (CH, m, H), 3.72 (2CH, s, 2H), 4.12 (CH
2, s, 2H), 4.16 (CH, m, H), 5.01 (CH, s, H) ppm.
Embodiment 17
Making with extra care of N-(2-sulfydryl benzoyl)-glycine: in 50 ℃ of following tepors dissolvings, can add 0.01% activated carbon decolorizing with 5～6 times of ethyl acetate, placement is spent the night, filtration under diminished pressure, and vacuum-drying gets highly finished product.Measure fusing point, recrystallization is 1～2 time in case of necessity, the about 60g of finished product, yield is about 65%, m.p.96～98 ℃ (document yield 29%, m.p.96～9715 ℃).
With triphenylphosphine (30.1 grams, 15 equivalents) stirring and dissolving is in the dry dimethyl formamide (160 milliliters). in 10 minutes, add iodine (30.5 grams, 15.6 equivalent) and have heat release. add exsiccant Y cyclodextrin (10 grams then, 7.7 mmole), 70 ℃ of mixture heating up also kept 24 hours. cooling mixture, in mixture, add sodium methylate (3.1 gram sodium are in 50 ml methanol), 800 milliliters of impouring methyl alcohol, be evaporated to dried, in residue, add 500 milliliters of entry, pass through solid collected by filtration, filtrate decompression concentrates, add ethanol and separate out precipitation, obtain the full deoxidation of yellow solid 6--6-periodo-γ-Huan Hujing (16.2 gram) in 70 ℃ of following dryings of vacuum, it is not further purified and continues to use.
With (1.22 milliliters of N-(2-sulfydryl benzoyl)-glycine; 14.0 mmole) at room temperature be dissolved in the exsiccant dimethyl formamide (45 milliliters). add sodium hydride (1 in three batches to this solution; 23 grams; 30.8 mmole; 60%). continued to stir the mixture 30 minutes. dropwise be added in the 45 milliliters of full deoxidation of the 6-in the exsiccant dimethyl formamide-6-periodo-γ-Huan Hujings (3.12 grams to this mixture; 1.40 solution mmole). after the adding, reaction mixture is heated to 70 ℃ and kept 12 hours.After the cooling, add entry (10 milliliters) and concentrate volume to 40 milliliter in a vacuum, add ethanol (150 milliliters) to this and cause precipitation to this mixture.By solid collected by filtration precipitation and dialysis 36 hours. concentrate volume to 20 milliliter in a vacuum, add ethanol, obtain white solid by overanxious collecting precipitation and drying, yield 50% to this.This compound (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 2.69,2.44 (CH
2, m, 2H), 3.02 (CH, m, H), 3.73 (2CH, s, 2H), 4.14 (CH
2, s, 2H), 4.76 (CH, d, H), 5.03 (CH, s, H), 7.06 (CH, d, H), 7.25 (CH, m, H), 7.34 (CH, t, H) ppm.
Embodiment 18
Complete (2-carboxy ethyl) sulfoxide-γ-Huan Hujing of the full deoxidation-6-of 6-, complete (2-carboxy ethyl) sulfone of the full deoxidation-6-of 6--γ-Huan Hujing preparation
Complete (2-carboxy ethyl) thioether of the full deoxidation-6-of 6--γ-Huan Hujing 108.9g (50mmol) is suspended in the 100ml acetate, stirs to drip 8.5g (75mmol) 30%H down
2O
2The aqueous solution, room temperature reaction 6 hours adds alcohol and separates out solid in reaction solution, and recrystallizing methanol obtains complete (2-carboxy ethyl) sulfoxide-γ-Huan Hujing (CD-2) of the full deoxidation-6-of 6-.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-2 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 2.57 (CH
2, t, 2H), 2.73 (CH
2, q, 2H), 2.81 (CH
2, t, 2H), 3.02 (CH, m, H), 3.71 (2CH, s, 2H), 3.90 (CH, m, H), 5.02 (CH, m, H) ppm.
Complete (2-carboxy ethyl) thioether of the full deoxidation-6-of 6--γ-Huan Hujing 108.9g (50mmol) is suspended in the 100ml acetate, stirs to drip 28.3g (250mmol) 30%H down
2O
2The aqueous solution keeps 40-60 ℃ of reaction 5 hours, adds alcohol and separate out solid in reaction solution, and recrystallizing methanol obtains complete (2-carboxy ethyl) sulfone-γ-Huan Hujing (CD-3) of the full deoxidation-6-of 6-.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-3 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 2.73 (CH
2, t, 2H), 3.01 (CH, m, H), 3.53 (CH
2, q, 2H), 3.66 (CH
2, d, 2H), 3.76 (2CH, d, 2H), 3.92 (CH, m, H), 5.0 (CH, m, H) ppm.
Embodiment 19
Complete (2-carboxy ethyl) sulfoxide-alpha-cylodextrin of the full deoxidation-6-of 6-, complete (2-carboxy ethyl) sulfone of the full deoxidation-6-of 6--alpha-cylodextrin preparation
(81.7g 50mmol) is suspended in the 100ml acetate complete (2-carboxy ethyl) thioether-alpha-cylodextrin of the full deoxidation-6-of 6-, stirs to drip 8.5g (75mmol) 30%H down
2O
2The aqueous solution, room temperature reaction 6 hours adds alcohol and separates out solid in reaction solution, and recrystallizing methanol obtains complete (2-carboxy ethyl) sulfoxide-alpha-cylodextrin (CD-5) of the full deoxidation-6-of 6-.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-5 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 2.54 (CH
2, t, 2H), 2.71 (CH
2, q, 2H), 2.84 (CH
2, t, 2H), 3.05 (CH, m, H), 3.77 (2CH, s, 2H), 3.95 (CH, m, H), 5.08 (CH, m, H) ppm.
(81.7g 50mmol) is suspended in the 100ml acetate complete (2-carboxy ethyl) thioether-alpha-cylodextrin of the full deoxidation-6-of 6-, stirs to drip 28.3g (250mmol) 30%H down
2O
2The aqueous solution keeps 40-60 ℃ of reaction 5 hours, adds alcohol and separate out solid in reaction solution, and recrystallizing methanol obtains complete (2-carboxy ethyl) sulfone-alpha-cylodextrin (CD-6) of the full deoxidation-6-of 6-.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-6 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 2.79 (CH
2, t, 2H), 3.00 (CH, m, H), 3.52 (CH
2, q, 2H), 3.69 (CH
2, d, 2H), 3.75 (2CH, d, 2H), 3.92 (CH, m, H), 5.06 (CH, m, H) ppm.
Embodiment 20
Complete (2-carboxy ethyl) sulfoxide-beta-cyclodextrin of the full deoxidation-6-of 6-, complete (2-carboxy ethyl) sulfone of the full deoxidation-6-of 6--beta-cyclodextrin preparation
(95.3g 50mmol) is suspended in the 100ml acetate complete (2-carboxy ethyl) thioether-beta-cyclodextrin of the full deoxidation-6-of 6-, stirs to drip 8.5g (75mmol) 30%H down
2O
2The aqueous solution, room temperature reaction 6 hours adds alcohol and separates out solid in reaction solution, and recrystallizing methanol obtains complete (2-carboxy ethyl) sulfoxide of the full deoxidation-6-of 6--beta-cyclodextrin CD-8.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-8 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 2.59 (CH
2, t, 2H), 2.71 (CH
2, q, 2H), 2.83 (CH
2, t, 2H), 3.08 (CH, m, H), 3.75 (2CH, s, 2H), 3.94 (CH, m, H), 5.04 (CH, m, H) ppm.
(95.3g 50mmol) is suspended in the 100ml acetate complete (2-carboxy ethyl) thioether-beta-cyclodextrin of the full deoxidation-6-of 6-, stirs to drip 28.3g (250mmol) 30%H down
2O
2The aqueous solution keeps 40-60 ℃ of reaction 5 hours, adds alcohol and separate out solid in reaction solution, and recrystallizing methanol obtains complete (2-carboxy ethyl) sulfone of the full deoxidation-6-of 6--beta-cyclodextrin CD-9.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-9 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 2.81 (CH
2, t, 2H), 3.07 (CH, m, H), 3.51 (CH
2, q, 2H), 3.69 (CH
2, d, 2H), 3.79 (2CH, d, 2H), 3.93 (CH, m, H), 5.05 (CH, m, H) ppm.
Embodiment 21
Complete (2-carboxy ethyl) sulfone-δ of the complete full deoxidation-6-of (2-carboxy ethyl) sulfoxide-δ-cyclodextrin, 6-of the full deoxidation-6-of 6--cyclodextrin preparation
(122.5g 50mmol) is suspended in the 100ml acetate complete (2-carboxy ethyl) thioether-δ of the full deoxidation-6-of 6--cyclodextrin CD-10, stirs to drip 8.5g (75mmol) 30%H down
2O
2The aqueous solution, room temperature reaction 6 hours adds alcohol and separates out solid in reaction solution, and recrystallizing methanol obtains complete (2-carboxy ethyl) sulfoxide-δ of the full deoxidation-6-of 6--cyclodextrin CD-11.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-11 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 2.59 (CH
2, t, 2H), 2.77 (CH
2, q, 2H), 2.86 (CH
2, t, 2H), 3.03 (CH, m, H), 3.76 (2CH, s, 2H), 3.92 (CH, m, H), 5.06 (CH, m, H) ppm.
(122.5g 50mmol) is suspended in the 100ml acetate complete (2-carboxy ethyl) thioether-δ of the full deoxidation-6-of 6--cyclodextrin CD-10, stirs to drip 28.3g (250mmol) 30%H down
2O
2The aqueous solution keeps 40-60 ℃ of reaction 5 hours, adds alcohol and separate out solid in reaction solution, and recrystallizing methanol obtains complete (2-carboxy ethyl) sulfoxide-δ of the full deoxidation-6-of product 6--cyclodextrin CD-12.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-12 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 2.80 (CH
2, t, 2H), 3.08 (CH, m, H), 3.54 (CH
2, q, 2H), 3.70 (CH
2, d, 2H), 3.73 (2CH, d, 2H), 3.9 (CH, m, H), 5.01 (CH, m, H) ppm.
Embodiment 22
Complete (the 2-propionyl glycine) sulfoxide-γ-Huan Hujing of the full deoxidation-6-of 6-, complete (2-propionyl glycine) sulfone of the full deoxidation-6-of 6--γ-Huan Hujing preparation
(122.9g 50mmol) is suspended in the 100ml acetate complete (the 2-propionyl glycine) thioether-γ-Huan Hujing CD-13 of the full deoxidation-6-of 6-, stirs to drip 8.5g (75mmol) 30%H down
2O
2The aqueous solution, room temperature reaction 6 hours adds alcohol and separates out solid in reaction solution, and recrystallizing methanol obtains complete (the 2-propionyl glycine) sulfoxide-γ-Huan Hujing CD-14 of the full deoxidation-6-of 6-.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-14 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.56 (CH
3, d, 3H), 2.75 (CH
2, m, 2H), 3.01 (CH, m, H), 3.69 (CH, m, H), 3.76 (2CH, s, 2H), 3.92 (CH, m, H), 4.18 (CH
2, s, 2H), 5.07 (CH, s, H) ppm.
(122.9g 50mmol) is suspended in the 100ml acetate complete (the 2-propionyl glycine) thioether-γ-Huan Hujing CD-13 of the full deoxidation-6-of 6-, stirs to drip 28.3g (250mmol) 30%H down
2O
2The aqueous solution keeps 40-60 ℃ of reaction 5 hours, adds alcohol and separate out solid in reaction solution, and recrystallizing methanol obtains complete (the 2-propionyl glycine) sulfone-γ-Huan Hujing CD-15 of the full deoxidation-6-of 6-.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-15 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.59 (CH
3, d, 3H), 3.02 (CH, m, H), 3.53 (CH
2, m, 2H), 3.78 (2CH, s, 2H), 3.93 (CH, m, H), 4.13 (CH, s, H), 4.19 (CH
2, t, 2H), 5.05 (CH, s, H) ppm.
Embodiment 23
Complete (2-propionyl glycine) thioether of the full deoxidation-6-of 6--alpha-cylodextrin preparation
With (1.22 milliliters of 3-thiohydracrylic acids, 14.0 mmole) at room temperature be dissolved in the exsiccant dimethyl formamide (45 milliliters). add sodium hydride (1 in three batches to this solution, 23 grams, 30.8 mmole, 60%). continued to stir the mixture 30 minutes. dropwise be added in the full deoxidation of the 6--6-periodo-alpha-cylodextrin solution that contains 2.7 grams in 45 milliliters of exsiccant dimethyl formamides to this mixture. after the adding, reaction mixture is heated to 70, and " C also kept 12 hours.After the cooling, add entry (10 milliliters) and concentrate volume to 40 milliliter in a vacuum, add ethanol (150 milliliters) to this and cause precipitation to this mixture.By solid collected by filtration precipitation and dialysis 36 hours. concentrate volume to 20 milliliter in a vacuum, add ethanol, obtain white solid title compound (CD-16), weigh 1.1 grams by overanxious collecting precipitation and drying to this.CD-16 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.55 (CH
3, d, 3H), 2.59 (CH
2, m, 2H), 3.01 (CH, m, H), 3.68 (CH, m, H), 3.71 (2CH, s, 2H), 4.11 (CH
2, s, 2H), 4.20 (CH, m, H), 5.05 (CH, s, H) ppm.
Embodiment 24
Complete (the 2-propionyl glycine) sulfoxide-alpha-cylodextrin of the full deoxidation-6-of 6-, complete (2-propionyl glycine) sulfone of the full deoxidation-6-of 6--alpha-cylodextrin preparation
(92.2g 50mmol) is suspended in the 100ml acetate complete (the 2-propionyl glycine) thioether-alpha-cylodextrin CD-16 of the full deoxidation-6-of 6-, stirs to drip 8.5g (75mmol) 30%H down
2O
2The aqueous solution, room temperature reaction 6 hours adds alcohol and separates out solid in reaction solution, and recrystallizing methanol obtains products C D-17.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-17 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.57 (CH
3, d, 3H), 2.65 (CH
2, m, 2H), 3.02 (CH, m, H), 3.69 (CH, m, H), 3.77 (2CH, s, 2H), 3.93 (CH, m, H), 4.14 (CH
2, s, 2H), 5.01 (CH, s, H) ppm.
(92.2g 50mmol) is suspended in the 100ml acetate complete (the 2-propionyl glycine) thioether-alpha-cylodextrin CD-16 of the full deoxidation-6-of 6-, stirs to drip 28.3g (250mmol) 30%H down
2O
2The aqueous solution keeps 40-60 ℃ of reaction 5 hours, adds alcohol and separate out solid in reaction solution, and recrystallizing methanol obtains products C D-18.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-18 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.58 (CH
3, d, 3H), 3.04 (CH, m, H), 3.57 (CH
2, m, 2H), 3.73 (2CH, s, 2H), 3.94 (CH, m, H), 4.11 (CH, s, H), 4.16 (CH
2, t, 2H), 5.07 (CH, s, H) ppm.
Embodiment 25
Complete (2-propionyl glycine) thioether of the full deoxidation-6-of 6--beta-cyclodextrin preparation
With tiopronin (0.42g, 2.6mmol) be dissolved among the dry DMF of 2ml, after the dissolving, in this liquid, add NaH (0.11g under the ice bath fully in batches, 2.75mmol, 60%), adds and continue to stir the mixture 30 minutes, dropwise add the full deoxidation of 6--6-periodo-beta-cyclodextrin solution of the 0.7g (0.37mmol) of the dry DMF of 1.3ml to this mixture, finish, reaction solution is heated to 20 ℃ of reactions 12 hours, and the some plate is followed the tracks of and reacted completely, and adds less water, transfer PH to approximate 6, add small amount of ethanol, a large amount of ether, the adularescent precipitation is separated out, ethyl acetate is washed, centrifugal, vacuum-drying gets CD-19 pulverulent solids 0.8g.CD-19 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.51 (CH
3, d, 3H), 2.57 (CH
2, m, 2H), 3.00 (CH, m, H), 3.61 (CH, m, H), 3.75 (2CH, s, 2H), 4.16 (CH
2, s, 2H), 4.21 (CH, m, H), 5.08 (CH, s, H) ppm.
Embodiment 26
Complete (the 2-propionyl glycine) sulfoxide-beta-cyclodextrin of the full deoxidation-6-of 6-, complete (2-propionyl glycine) sulfone of the full deoxidation-6-of 6--beta-cyclodextrin preparation
Complete (the 2-propionyl glycine) thioether-beta-cyclodextrin (107.57g of the full deoxidation-6-of 6-; 50mmol) be suspended in the 100ml acetate; stir and drip 8.5g (75mmol) the 30%H2O2 aqueous solution down; room temperature reaction 6 hours; in reaction solution, add alcohol and separate out solid; recrystallizing methanol obtains complete (the 2-propionyl glycine) sulfoxide-beta-cyclodextrin CD-20 of the full deoxidation-6-of 6-.H2O2 excessive in the filtrate removes by adding Sulfothiorine.CD-20 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.54 (CH
3, d, 3H), 2.73 (CH
2, m, 2H), 3.01 (CH, m, H), 3.63 (CH, m, H), 3.73 (2CH, s, 2H), 3.95 (CH, m, H), 4.14 (CH
2, s, 2H), 5.07 (CH, s, H) ppm.
(107.57g 50mmol) is suspended in the 100ml acetate complete (the 2-propionyl glycine) thioether-beta-cyclodextrin of the full deoxidation-6-of 6-, stirs to drip 28.3g (250mmol) 30%H down
2O
2The aqueous solution keeps 40-60 ℃ of reaction 5 hours, adds alcohol and separate out solid in reaction solution, and recrystallizing methanol obtains complete (the 2-propionyl glycine) sulfoxide-beta-cyclodextrin CD-21 of the full deoxidation-6-of 6-.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-21 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.59 (CH
3, d, 3H), 3.07 (CH, m, H), 3.52 (CH
2, m, 2H), 3.76 (2CH, s, 2H), 3.91 (CH, m, H), 4.11 (CH, s, H), 4.14 (CH
2, t, 2H), 5.00 (CH, s, H) ppm.
Embodiment 27
Complete (2-propionyl glycine) thioether-δ of the full deoxidation-6-of 6--cyclodextrin preparation
With tiopronin (0.42g, 2.6mmol) be dissolved among the dry DMF of 2ml, after the dissolving, in this liquid, add NaH (0.11g under the ice bath fully in batches, 2.75mmol, 60%), adds and continue to stir the mixture 30 minutes, dropwise add the full deoxidation of 6--6-periodo-δ-cyclodextrin soln of the 1g (0.4mmol) of the dry DMF of 1.3ml to this mixture, finish, reaction solution is heated to 20 ℃ of reactions 12 hours, and the some plate is followed the tracks of and reacted completely, and adds less water, transfer PH to approximate 6, add small amount of ethanol, a large amount of ether, the adularescent precipitation is separated out, ethyl acetate is washed, centrifugal, vacuum-drying gets CD-22 pulverulent solids 0.9g.CD-22 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.52 (CH
3, d, 3H), 2.53 (CH
2, m, 2H), 3.03 (CH, m, H), 3.69 (CH, m, H), 3.78 (2CH, s, 2H), 4.14 (CH
2, s, 2H), 4.23 (CH, m, H), 5.09 (CH, s, H) ppm.
Embodiment 28
Complete (2-propionyl glycine) sulfoxide-δ-cyclodextrin, δ of the full deoxidation-6-of 6--complete (the 2-propionyl glycine) sulfone of full deoxidation-6--beta-cyclodextrin preparation
(138.3g 50mmol) is suspended in the 100ml acetate complete (the 2-propionyl glycine) thioether-δ-cyclodextrin of the full deoxidation-6-of 6-, stirs to drip 8.5g (75mmol) 30%H down
2O
2The aqueous solution, room temperature reaction 6 hours adds alcohol and separates out solid in reaction solution, and recrystallizing methanol obtains complete (the 2-propionyl glycine) sulfoxide-δ-cyclodextrin (CD-23) of the full deoxidation-6-of 6-.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-23 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.58 (CH
3, d, 3H), 2.70 (CH
2, m, 2H), 3.02 (CH, m, H), 3.69 (CH, m, H), 3.71 (2CH, s, 2H), 3.94 (CH, m, H), 4.14 (CH
2, s, 2H), 5.09 (CH, s, H) ppm.
(138.3g 50mmol) is suspended in the 100ml acetate complete (the 2-propionyl glycine) thioether-δ-cyclodextrin of the full deoxidation-6-of 6-, stirs to drip 28.3g (250mmol) 30%H down
2O
2The aqueous solution keeps 40-60 ℃ of reaction 5 hours, adds alcohol and separate out solid in reaction solution, and recrystallizing methanol obtains δ-complete (2-propionyl glycine) sulfone-beta-cyclodextrin (CD-24) of full deoxidation-6-.Excessive H in the filtrate
2O
2Remove by adding Sulfothiorine.CD-24 is (D in heavy water
2O) ' H nuclear magnetic resonance spectrum: δ 1.51 (CH
3, d, 3H), 3.03 (CH, m, H), 3.55 (CH
2, m, 2H), 3.79 (2CH, s, 2H), 3.93 (CH, m, H), 4.11 (CH, s, H), 4.14 (CH
2, t, 2H), 5.06 (CH, s, H) ppm.
Embodiment 29
The healthy adult rabbit, the auricular vein injection gives Zemuron 100ug/kg, and 3ml/kg notes observing, and when ears were sagging, recording medicine amount and flesh unclamped time beginning.Behind the flesh pine, auricular vein is injected CD-2, CD-3, CD-8, CD-9, CD-13, CD-14, CD-15, the CD-19 to CD-24 of 3mg/kg fast, and administration in 10 seconds finishes.The record rabbit ear is holded up the time.The results are shown in Table 1:
Table 1
Action recovered normal when sequence number compound coding Zemuron antagonist ears were holded up
Time between dosage (μ g) dosage (mg)
1 physiological saline 300 63 minutes and 40 seconds 4 minutes 52 seconds
2 CD-2 300 61 minutes and 15 seconds 1 minute 24 seconds
3 CD-3 300 60 minutes and 54 seconds 1 minute 12 seconds
4 CD-8 300 60 minutes and 30 seconds 0 minute 45 seconds
5 CD-9 300 60 minutes and 37 seconds 0 minute 56 seconds
6 CD-13 300 60 minutes and 15 seconds 0 minute 16 seconds
7 CD-14 300 60 minutes and 16 seconds 0 minute 16 seconds
8 CD-15 300 60 minutes and 15 seconds 0 minute 17 seconds
9 CD-19 300 60 minutes and 12 seconds 0 minute 12 seconds
10 CD-20 300 60 minutes and 13 seconds 0 minute 14 seconds
11 CD-21 300 60 minutes and 12 seconds 0 minute 12 seconds
12 CD-22 300 60 minutes and 35 seconds 0 minute 37 seconds
13 CD-23 300 60 minutes and 40 seconds 0 minute 44 seconds
14 CD-24 300 60 minutes and 36 seconds 0 minute 37 seconds
Embodiment 30
The freeze-dried preparation technology of 6-deoxy thioether amino acid cyclodextrin derivative (V) medicinal compositions, realized by following steps:
(1) get the amino acid cyclodextrin derivative highly finished product under the aseptic condition, place container, the water for injection that adds 30-70 times of weight makes its dissolving, adds medicinal basic and regulates pH value to 6-8;
(2) add pharmaceutical excipient, carry out the autoclave sterilization sterilization by the requirement of injection, adopt filtering with microporous membrane, filtrate is carried out packing by every 0.4-0.8ml, adopt quick freezing, per minute reduces 10-15 ℃, cools to-30 to-50 ℃ until solution, keeps 2-3 hour, heat to-20 to-35 ℃ again, carry out sublimation drying, goods are taken out, sealing and promptly obtaining proterties is colourless loose shape block.
The described medicinal basic of step 1 is yellow soda ash, sodium bicarbonate or salt of wormwood etc.
Claims (7)
1. 6-deoxy-sulfones cyclodextrin derivatives, it is characterized in that the having general formula structure of (I):
Wherein m is 0,1, in 2,3,4,5,6,7 or 8 one;
N is 1,1, in 2,3,4,5,6,7,8 or 9 one;
M+n is 6,7, in 8 or 9 one;
Q is in 1 or 2;
R is C
1-C
6Alkylidene group, optional by 1 to 3 OH group or (CH
2) the r-phenylene-(CH2)
t-replace, wherein r is in 0,1,2,3 or 4 one, t is in 0,1,2,3 or 4;
X is COOH, CONHR
1, NHCOR
2, SO
2OH, PO (OH)
2, O (CH
2-CH
2-O) in u-H, OH or the tetrazolium-5-base, wherein R
1Be hydrogen, (C
1-3) alkyl the or contain (C of COOH
1-3) in the alkyl one, R
2Be carboxyl phenyl, u is in 1,2 or 3.
2. a kind of 6-deoxy-sulfones cyclodextrin derivatives according to claim 1 is characterized in that: described 6-deoxy-sulfones cyclodextrin derivatives (I) is 6-deoxidation sulfoxide group dextrin derivative when q is 1, have the structure of formula (II):
Described 6-deoxy-sulfones cyclodextrin derivatives (I) is 6-deoxidation sulfuryl dextrin derivative when q is 2, have the structure of formula (III):
3. the preparation method of a kind of 6-deoxy-sulfones cyclodextrin derivatives according to claim 1 and 2, it is characterized in that realizing with following steps: with 6-deoxy thioether amino acid cyclodextrin derivative (V) or with 6-deoxy thioether cyclodextrin derivative (IV) is raw material, by oxidizing reaction 1, obtain 6-deoxidation sulfoxide group cyclodextrin derivative (II), compound (II) obtains 6-deoxidation sulfuryl cyclodextrin derivative (III) by oxidizing reaction 2
Reaction formula:
Wherein m, n, m+n, R, X, X
1According to claim 1,
R
3Be H, CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, (CH
2)
3CH
3, C (CH
3)
3Or C
6H
5In one;
R
4Be H, CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH
2CH
3(CH
3) CH, CH
2CH (CH
3)
2, CH
2C
6H
5, CH
3SCH
2CH
2Or H
2NC (O) CH
2In one;
Described oxidizing reaction 1 and oxidizing reaction 2 used oxygenants are peracid salt or organo-peroxide, select peroxidation sulfuric acid, H for use
2O
2, KClO
4, H
2SO
4, KMnO
4, Na
2O
2Or K
2O
2In a kind of.
4. preparation method according to claim 3 is characterized in that: described 6-deoxy thioether amino acid cyclodextrin derivative (V) prepares by following steps: with containing R
3Substituent acetate (a) is that starting raw material and halide reagent obtain two halogenide (b) through halogenating reaction; obtain acid amides (c) with amino acid condensation; add sulphur reagent then and obtain sulfocompound (d); obtain sulfhydryl compound (e) through removing protecting group; in the presence of alkali, obtain 6-deoxy thioether amino acid cyclodextrin derivative (V) or its salt with the condensation of halo cyclodextrin
Reaction formula:
Wherein: M, n, m+n according to claim 1,
R
3, R
4As described in claim 3,
R
5Be phenyl or pyridyl;
A is among OH, Cl or the Br.
The described R that contains
3Substituent acetate (a) is the alkane or the aromatic hydrocarbons of hydrogen and short carbon chain, selects a kind of in methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl or the phenyl for use; Described halide reagent is a kind of in chlorine, bromine, sulfur oxychloride, phosphorus tribromide or the phosphorus trichloride; Used amino acid is natural amino acid; Described sulphur reagent is selected a kind of in sulfo-nicotinic acid, sodium disulfide, thioacetic acid, Sulfothiorine or the thiobenzoic acid for use; Described protecting group removes and is meant basic hydrolysis, and used alkali is mineral alkali, sodium hydroxide or potassium, the aqueous solution of yellow soda ash or potassium; Alkali in described and the condensation reaction of halo cyclodextrin is to select sodium hydride or potassium for use, sodium amide or potassium, sodium alkoxide or potassium; Used halo cyclodextrin is selected the cyclodextrin of 6,7,8 or 9 yuan of rings of chlorine, bromine or iodine replacement for use; The amino acid cyclodextrin derivative of described acquisition and salt thereof are meant sylvite, sodium salt or lithium salts.
5. preparation method according to claim 4 is characterized in that: natural amino acid select for use sweet, third, a kind of in a word used in person's names, bright, different bright, l-asparagine, phenylpropyl alcohol or the methionine(Met).
6. the application of a kind of 6-deoxy-sulfones cyclodextrin derivatives according to claim 1 and 2 in preparation flesh pine antagonistic action medicine.
7. preparation method according to claim 4 is characterized in that: the application of described compound V in preparation flesh pine antagonistic action medicine.
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| CN2009100981834A CN101591402B (en) | 2009-05-05 | 2009-05-05 | 6-deoxy-sulfones cyclodextrin derivatives and preparation method thereof |
| PCT/CN2010/072334 WO2010127600A1 (en) | 2009-05-05 | 2010-04-29 | 6-deoxidized sulfone cyclodextrin derivatives and preparation method thereof |
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| JP2000344803A (en) * | 1999-06-04 | 2000-12-12 | Nippon Shokuhin Kako Co Ltd | Preparation of cyclodextrin derivative |
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| CN1211024C (en) * | 2003-03-13 | 2005-07-20 | 吉林大学 | Use of cyclodextrin derivs. in beverage |
| US20050153932A1 (en) * | 2003-10-08 | 2005-07-14 | Sprengers Erik D. | Controlled muscle relaxation |
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| CN101591402B (en) * | 2009-05-05 | 2011-11-30 | 杭州奥默医药技术有限公司 | 6-deoxy-sulfones cyclodextrin derivatives and preparation method thereof |
-
2009
- 2009-05-05 CN CN2009100981834A patent/CN101591402B/en active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| CN101591402B (en) | 2011-11-30 |
| WO2010127600A1 (en) | 2010-11-11 |
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