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.