CN101863817A - Preparation method of (2S, 4R)-4-aminopyrroline-1,2-dicarboxylic acid-1-tertiary butyl ester-2-methyl ester hydrochloride - Google Patents
Preparation method of (2S, 4R)-4-aminopyrroline-1,2-dicarboxylic acid-1-tertiary butyl ester-2-methyl ester hydrochloride Download PDFInfo
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Abstract
The invention relates to a preparation method of a compound, in particular to a preparation method of (2S, 4R)-4-aminopyrroline-1,2-dicarboxylic acid-1-tertiary butyl ester-2-methyl ester hydrochloride. The method comprises the following steps of: synthesizing (2S, 4R)-4-hydroxylpyrroline-2-carboxylic acid methyl ester hydrochloride; (2) synthesizing (2S, 4R)-4-mesyloxy-1,2-pyrroline dicarboxylic acid-1-tertiary butyl ester-2-methyl ester; (3) synthesizing (2S, 4R)-4-mesyloxy-1,2-pyrroline dicarboxylic acid-1-tertiary butyl ester-2-methyl ester; (4) synthesizing (2S, 4R)-4-benzoyloxy-1,2-pyrroline dicarboxylic acid-1-tertiary butyl ester-2-methyl ester; (5) synthesizing (2S, 4R)-4-hydroxyl-1,2-pyrroline dicarboxylic acid-1-tertiary butyl ester-2-methyl ester; (6) synthesizing (2S, 4R)-4-mesyloxy-1,2-pyrroline dicarboxylic acid-1-tertiary butyl ester-2-methyl ester; (7) synthesizing (2S, 4R)-4-triazo-1,2-pyrroline dicarboxylic acid-1-tertiary butyl ester-2-methyl ester; (8) synthesizing (2S, 4R)-4-amino-1,2-pyrroline dicarboxylic acid-1-tertiary butyl ester-2-methyl ester; and (9) synthesizing the final product.
Description
Technical field
The present invention relates to the synthetic method of organic compound.
Background technology
The finished product that the present invention need make analyze theoretically can set out by oxyproline synthetic, but owing to relate to the upset of chiral centre, therefore need to use the D-oxyproline, consider huge price variance between D-oxyproline and the L-oxyproline, adopt the D-oxyproline as raw material, productive rate and purity are not desirable especially, the more important thing is that production cost is too high, influences its application.
Summary of the invention
The objective of the invention is to overcome above-mentioned not enough problem, provide a kind of (2S, 4R)-4-amino pyrroline-1, the synthetic method of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride, technology is reasonable, makes reaction system purity ideal, the productive rate height is suitable for industrialization.
The technical scheme that the present invention is adopted for achieving the above object is: (2S, 4R)-4-amino pyrroline-1, the method for making of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride, concrete synthetic route is as follows:
The first step is synthesized (2S, 4R)-4-hydroxyl pyrroline-2-carboxylate methyl ester hydrochloride (2): in the organic solvent cold soln of L-oxyproline, slowly add thionyl chloride, the mol ratio of raw material L-oxyproline and thionyl chloride is 1: 1.0-2.0, add the back and rose to stirring at room naturally 1 hour, refluxed 4 hours, underpressure distillation is removed organic solvent and is obtained intermediate product No. 2 again;
Synthetic (2S of second step, 4R)-4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (3): No. 2 intermediate products are dissolved in the halogenated alkane, keep temperature to be no more than 10 degree, add triethylamine and Boc acid anhydrides, at room temperature continue reaction 5 hours again, reaction mixture is used 5% dilute hydrochloric acid, water, saturated sodium bicarbonate solution and saturated common salt water washing successively, the siccative drying, underpressure distillation removes and desolvates, residuum is also freezing with the normal hexane washing, and underpressure distillation is removed normal hexane and obtained intermediate product No. 3;
Synthetic (2S of the 3rd step, 4R)-and 4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (4): No. 3 intermediate products are dissolved in the halogenated alkane, keep temperature to be no more than 5 degree, add triethylamine and methylsulfonyl chloride, under uniform temp, continue reaction 3 hours again.Reaction mixture is used 5% dilute hydrochloric acid, water, saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous magnesium sulfate drying, and underpressure distillation removes and desolvates, and residuum obtains intermediate product No. 4 with normal hexane vibration and freezing and crystallizing;
The 4th step (2S, 4R)-4-benzoyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (5): the dimethyl sulphoxide solution of No. 4 intermediate products and Sodium Benzoate is heated to 90 ℃ stirs and be cooled to room temperature in 7 hours then, reaction mixture adds the ethyl acetate dilution, water and saturated common salt water washing successively, organic phase siccative drying, distillation are removed to desolvate and are obtained oily matter, slowly add normal hexane and the crystallization of vibrating obtains intermediate product No. 5;
Synthetic (2S of the 5th step, 4S)-4-hydroxyl-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (6): at the alcoholic solution of No. 5 intermediate products, the middle salt of wormwood that adds, at room temperature stirred 1 hour, and regulated the pH value to neutral with concentrated hydrochloric acid, distillation for removing methanol, add the ethyl acetate dilution, wash with water; Organic phase saturated common salt water washing, water is saturated with sodium-chlor, chloroform extraction, and use the saturated common salt water washing, and the organic phase of merging siccative drying, underpressure distillation removes to desolvate and obtains oily matter, and the normal hexane crystallization obtains intermediate product No. 6;
Synthetic (2S of the 6th step, 4S)-and 4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (7): No. 6 intermediate products are dissolved in the halogenated alkane, keep temperature to be no more than 5 degree, add triethylamine and methylsulfonyl chloride, under uniform temp, continue reaction 1 hour again.Reaction mixture is used 5% dilute hydrochloric acid, water, saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous magnesium sulfate drying, and freezing and crystallizing obtains intermediate product No. 7 except that desolvating also in underpressure distillation;
Synthetic (2S of the 7th step, 4R)-4-azido--1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (8): No. 7 intermediate products are dissolved in dimethyl sulfoxide (DMSO), add sodiumazide, oil bath keeps stirring reaction under 70-120 ℃ of condition of temperature, disappear until raw material, be cooled to room temperature, add the ethyl acetate dilution, water and saturated common salt water washing, the siccative drying, underpressure distillation removes and desolvates; Residuum adds entry, ethyl acetate extraction, and water washing, the siccative drying, steaming removes ethyl acetate and obtains intermediate product No. 8;
Synthetic (2S of the 8th step, 4R)-4-amino-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (9): with the alcoholic solution of No. 8 intermediate products, under 15-30 ℃, a 3-5 normal atmosphere, it is catalyst hydrogenation 6-12 hour with 10% palladium carbon, filter, remove catalyzer, get colourless transparent solution, steaming desolventizes residuum and gets intermediate product No. 9;
Synthetic (2S of the 9th step, 4R)-4-amino-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride (10): No. 9 intermediate products are dissolved in 230 milliliters of solvents, under the ice bath agitation condition, slowly add hydrogenchloride-methanol solution of 5%, regulate pH to 4-5, continue to stir 20-40min, controlled temperature is in the time of 28～35 ℃, and steaming desolventizes, topple over after residuum washs with ether and remove ether, add ethyl acetate again and separate out white solid finished product 10.
The described second step material molar ratio is No. 2 intermediate products: triethylamine: Boc acid anhydrides=1: 1.9-2.4: 1.1-1.4.
Described the 3rd step material molar ratio is No. 3 intermediate products: triethylamine: methylsulfonyl chloride=1: 1.10-1.15: 1.0-1.5.
Described the 4th step material molar ratio is No. 4 intermediate products: phenylformic acid steel=1: 2; Reaction times 6-7 hour, the control product did not lump when aftertreatment was separated out.
Described the 5th step material molar ratio is No. 5 intermediate products: salt of wormwood=1: 1; Reaction times 0.5-3 hour, 1 hour preferred reaction time; At first reaction solution is transferred to neutrality by alkalescence during aftertreatment, steam methyl alcohol then, add ethyl acetate again and water extracts.
Described the 6th step material molar ratio is No. 6 intermediate products: triethylamine: methylsulfonyl chloride=1: 1.1-1.5: 1.2-1.5; 1 hour reaction times.
Described halogenated alkane adopts methylene dichloride, chloroform or ethylene dichloride.
Siccative adopts anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous or anhydrous sodium sulphate etc. in described each step.
Described the 3rd step, the 6th step adopt ice-water bath cooling conservation degree to be no more than 5 degree.
Alcoholic solution in described the 5th step, the 8th step adopts methyl alcohol, ethanol or aqueous isopropanol.
Solvent in described the 9th step adopts methyl alcohol, ethanol or ethyl acetate solution.
Starting raw material of the present invention is selected the L-oxyproline, and reaction scheme reasonable in design, L-oxyproline carry out twice chirality upset after esterification and Boc-protection, finally synthetic target product.Though the synthesis step of this route is longer, each the step reaction that relates to is fairly simple, and major part is common reaction, and involved reagent is also most of cheap and easy to get, and product yield and purity are more satisfactory, therefore are applicable to suitability for industrialized production.
Analyze with regard to each step reaction below: the first step synthetic (2S, 4R)-4-hydroxyl pyrroline-2-carboxylate methyl ester hydrochloride (2).Second step was the Boc protective reaction of raw material classics with the first step product; will slowly add when adding Boc, the too fast intensification of adding is too fast, and difficult control of temperature is in 10 degree; react No. 3 intermediate products after acid, water, alkali, salt water washing, removing desolvates obtains the oily product.Can remove at last handling process although it is generally acknowledged the Boc acid anhydrides, in fact still have a large amount of Boc acid anhydrides in the product, cause product purity not high (0038-05).Further experiment shows, repeatedly uses the normal hexane washing can improve the purity of product, but can reduce productive rate, after normal hexane washing 3 times, can obtain 95% purity and 80% yield.
No. 3 intermediate products that the 3rd step made with second step are raw material, react with raw material triethylamine and methylsulfonyl chloride rational proportion, the purity of methylsulfonyl chloride and consumption, methylsulfonyl chloride can cause reaction not exclusively very little, the too many impure yield that all can influence these step No. 4 intermediate products of product that reaches, in addition in the last handling process during with the normal hexane washing impurity-removing solid separate out fully more, yield is high more.
The 4th step was a raw material with the 3rd No. 4 intermediate products making of step, though the reaction times of bibliographical information is reaction overnight, and processing condition design of the present invention, just complete substantially after being reflected at 6 hours, thoroughly reaction in 7 hours; The operation of aftertreatment is extremely important, wants edged vibration in limit when adding normal hexane, had better not allow the product of separating out form piece, otherwise can make not thorough that product washes, and normal hexane can not add too fast, and the quantity not sufficient that adds can cause solid product can not separate out fully.
No. 5 intermediate products that the 5th step made with four-step reaction are raw material, and with the salt of wormwood rational proportion, strict controlling reaction time 1-3 hour, the reaction times, long meeting caused the racemization of hydrolysate, and the reaction times is preferably 1 hour.The aftertreatment of reaction also is very crucial, and the way in former steps is that reaction mixture is directly diluted with ethyl acetate, uses water stratification, but because methyl alcohol is the water-soluble ethyl acetate that also is dissolved in, make relatively difficulty of score layer, often can not layering, perhaps need a large amount of ethyl acetate and water.Dilute with ethyl acetate if use instead earlier methyl alcohol to be steamed again, the method that adds water stratification, this method is very effective when handling small amount of sample, but when handling a large amount of methyl alcohol, because distillation is carried out under reaction conditions, along with the prolongation of distillation time, be equivalent to the reaction times also prolonging, finally caused the racemization product yield of product extremely low; Therefore post-treating method of the present invention at first transfers to neutrality with reaction solution by alkalescence, steams methyl alcohol then, adds ethyl acetate again and water extracts.So neither need a large amount of water and ethyl acetate, also can not cause the racemization of product, the purity of product also is improved, and brings up to more than 98% from about 90%.
The 6th step employing the 5th step No. 6 intermediate products of synthetic and raw material triethylamine, methylsulfonyl chloride rational proportion, during 1 hour reaction times, raw material transforms substantially, and major part is a target product, and along with the prolongation of time, side reaction increases gradually, and target product content descends rapidly.
The 7th step adopted No. 7 intermediate products of the 6th step synthetic to react, and this step reaction itself is simpler, but need use the reagent sodiumazide in reaction, and it is careful to need in operating process, does not make sodiumazide and acid or metallic contact, with blast protection!
The 8th step adopted No. 8 intermediate products of the 7th step synthetic to carry out catalytic hydrogenation reaction, and the hydrogenation in this step carries out in autoclave, under the condition of 0.4Mpa and room temperature, reaction can be carried out very smoothly, raw material transforms fully, the recycling of palladium catalyst carbon, and the rate of recovery is 100%.
The 9th step was adopted the synthetic finished product of No. 9 intermediate products of the 8th step synthetic, because contain the Boc group in the product structure, this group is under acidic conditions, when being 60 ℃, temperature stirs thoroughly hydrolysis in 1 hour, therefore the system potential of hydrogen is controlled in the time of need be to salify, and the present invention is set at the pH4-5 of 0-20 degree and reaction solution with salt-forming condition, steams when desolventizing in aftertreatment, controlled temperature is no more than 35 ℃, prevents this group hydrolysis and yield is reduced; Be insoluble to ether behind the product salify, available ether is removed impurity, and then separates out the solid finished product with ethyl acetate.
Embodiment
Below in conjunction with specific embodiment the present invention is described in further detail, but the present invention is not limited to specific embodiment.
Embodiment 1
(2S, 4R)-4-amino pyrroline-1, the synthetic method of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride:
The first step synthetic (2S, 4R)-4-hydroxyl pyrroline-2-carboxylate methyl ester hydrochloride (2): in anhydrous methanol (40 milliliters) cold soln of L-oxyproline (7.0 grams, 0.054 mole), slowly drip thionyl chloride (7.3 grams, 0.058 mole).Add the back and rose to stirring at room naturally 1 hour, refluxed 4 hours again, underpressure distillation removes to desolvate and obtains intermediate product No. 2; Product: white solid, 10.3 grams, productive rate 99%.
Synthetic (2S of second step, 4R)-4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (3): with No. 2 intermediate product (30.0 grams, 0.17 mole) be dissolved in the methylene dichloride (360 milliliters), the ice-water bath cooling adds triethylamine (64.0 milliliters, 0.46 mole) and Boc acid anhydrides (53.1 grams, 0.23 mole), at room temperature continue reaction 5 hours again.Reaction mixture is used 5% dilute hydrochloric acid (500 milliliters), water (500 milliliters), saturated sodium bicarbonate solution (100 milliliters) and saturated aqueous common salt (100 milliliters) washing, anhydrous magnesium sulfate drying successively.Underpressure distillation removes and desolvates, and residuum washs three times with normal hexane (150 milliliters) and be freezing, and underpressure distillation is removed normal hexane and obtained intermediate product No. 3; Product: viscous liquid, 27.0 grams, purity 95%, yield 80%.
Synthetic (2S of the 3rd step, 4R)-4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (4): with No. 3 intermediate product (21.4 grams, 0.096 mole) be dissolved in the methylene dichloride (220 milliliters), ice-water bath is cooled to below 5 degree, adds triethylamine (10.2 grams, 0.102 mole) and methylsulfonyl chloride (12.9 grams, 0.113 mole), under uniform temp, continue reaction 3 hours again.Reaction mixture is used 5% dilute hydrochloric acid (200 milliliters), water (200 milliliters), saturated sodium bicarbonate solution (200 milliliters) and saturated aqueous common salt (200 milliliters) washing, anhydrous magnesium sulfate drying successively.Underpressure distillation removes and desolvates, and residuum obtains intermediate product No. 4 with normal hexane (60ml) vibration and freezing and crystallizing; Product: white solid, 24.6 grams, purity 92%, yield 87.9%.
The 4th step (2S, 4R)-4-benzoyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (5): with No. 4 intermediate product (5.7 grams, 0.017 mole) and the dimethyl sulphoxide solution (57 milliliters) of Sodium Benzoate (5.1 gram, 0.035 mole) be heated to 90 ℃ of stirrings and be cooled to room temperature in 7 hours then.Reaction mixture dilutes with ethyl acetate (110 milliliters), water (170 milliliters) and saturated aqueous common salt (110 milliliters) washing.Organic phase anhydrous magnesium sulfate drying, distillation remove to desolvate and obtain oily matter.Slowly add the normal hexane (20 milliliters) and the crystallization of vibrating and obtain intermediate product No. 5; Product: white solid weighs 4.7 grams, purity 94%, yield 76%.
Synthetic (2S of the 5th step, 4S)-4-hydroxyl-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (6): at No. 5 intermediate product (4.0 grams, 0.011 add salt of wormwood (1.6 grams, 0.011 mole) in methyl alcohol (60 milliliters) solution mole), at room temperature stirred 1 hour, regulate the pH value to neutral with concentrated hydrochloric acid, distillation for removing methanol adds ethyl acetate (13 milliliters) dilution, water (70 milliliters) washing; Organic phase uses sodium-chlor saturated with saturated aqueous common salt (70 milliliters) washing, water, and chloroform (100 milliliters) extracts, and washs with saturated aqueous common salt (100 milliliters).The organic phase anhydrous magnesium sulfate drying that merges, underpressure distillation remove to desolvate and obtain oily matter.The normal hexane crystallization obtains intermediate product No. 6; Product: white solid weighs 24.6 grams, yield 77.6%, purity 98%.
Synthetic (2S of the 6th step, 4S)-4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (7): with No. 6 intermediate product (24.6 grams, 0.10 mole) be dissolved in the methylene dichloride (550 milliliters), ice-water bath is cooled to below 5 degree, adds triethylamine (16.2 grams, 0.16 mole) and methylsulfonyl chloride (14.9 grams, 0.13 mole), under uniform temp, continue reaction 1 hour again.Reaction mixture is used 5% dilute hydrochloric acid (500 milliliters), water (500 milliliters), saturated sodium bicarbonate solution (500 milliliters) and saturated aqueous common salt (500 milliliters) washing successively, anhydrous magnesium sulfate drying, freezing and crystallizing obtains intermediate product No. 7 except that desolvating also in underpressure distillation, product: white solid, 44.8 gram, purity 88%, yield 95.1%.
The 7th step synthetic (2S, 4R)-4-azido--1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (8): with No. 7 intermediate products (12.5 grams, 0.039 mole) be dissolved in dimethyl sulfoxide (DMSO) (170ml), add sodiumazide (5.1 grams, 0.078 mole), oil bath, stirring reaction 6h under 90 ℃ of conditions, cooling, with ethyl acetate (250 milliliters) dilution, water (250 milliliters) and saturated aqueous common salt (250 milliliters) washing, anhydrous magnesium sulfate drying, underpressure distillation removes and desolvates; Residuum adds entry (25 milliliters), ethyl acetate (30 milliliters) extraction, water (25 milliliters * 3) washing.Anhydrous magnesium sulfate drying, steaming removes ethyl acetate and obtains intermediate product No. 8; Product: light brown mucus weighs 27.45 grams, purity 91%, yield 97.6%.
Synthetic (2S of the 8th step, 4R)-4-amino-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (9):, under 25 ℃, 4 normal atmosphere, be catalyst hydrogenation 6 hours with 10% palladium carbon (4.2 gram) with the methanol solution (210 milliliters) of No. 8 intermediate products (27.4 grams, 0.1 mole).Filter, remove catalyzer, get colourless transparent solution, steaming desolventizes residuum and gets intermediate product No. 9; Product: light brown mucus weighs 23.0 grams, purity 91%, yield 92.9%.
Synthetic (2S of the 9th step, 4R)-4-amino-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride (10): with No. 9 intermediate product (23.0 grams, 0.014 mole) be dissolved in 230 milliliters of absolute methanol solutions, under the ice bath agitation condition, hydrogenchloride-methanol solution of Dropwise 5 %, regulate pH to 4, continue to stir 30min, controlled temperature is in the time of 28～35 ℃, steaming desolventizes, and topples over after residuum washs with ether (150 milliliters) and removes ether, adds ethyl acetate (100 milliliters) again and separates out white solid 10.Product: white solid weighs 18.9 grams, purity 98.5%, yield 71.6%.
Embodiment 2,3,4
According to embodiment 1 described processing step synthetic (2S, 4R)-4-amino pyrroline-1, the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride, raw material and processing condition that each step is adopted are as follows:
The first step synthetic (2S, 4R)-4-hydroxyl pyrroline-2-carboxylate methyl ester hydrochloride (2) is identical with embodiment 1;
Second step synthetic (2S, 4R)-4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (No. 3 intermediate products)
Annotate: wherein proportioning raw materials is meant intermediate product No. 2: triethylamine: the BOC acid anhydrides; Reaction times is 4 hours.
The 3rd step synthetic (2S, 4R)-4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (4)
Annotate: wherein proportioning raw materials is No. 3 intermediate products: triethylamine: methylsulfonyl chloride, the reaction times is 4 hours, temperature 0-5 ℃.
The 4th step synthetic (2S, 4R)-4-benzoyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (5):
Annotate: proportioning raw materials is No. 4 intermediate products: Sodium Benzoate; Want limit edged vibration when aftertreatment adds normal hexane, do not allow the product of separating out form piece, add to solid product and separate out fully.
The 5th step synthetic (2S, 4S)-4-hydroxyl-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (6):
Annotate: proportioning raw materials is intermediate product No. 5: salt of wormwood, temperature of reaction is room temperature.Aftertreatment steams methyl alcohol with in the reaction solution and back earlier, carries out aftertreatment then.
The 6th step synthetic (2S, 4S)-4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (7),
Annotate: proportioning raw materials is No. 6 intermediate products: triethylamine: methylsulfonyl chloride; In 1 hour reaction times.
Synthetic (2S of the 7th step, 4R)-4-azido--1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (8): identical with embodiment 1, CPW8269-0060-11A, the gas phase analysis result, raw material reaction is complete, and near the principal product peak of CPW8269-0060-11A gas-matter analytical results retention time 15.4 is target product---No. 8 intermediate products.
Synthetic (2S of the 8th step, 4R)-4-amino-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (9): identical with embodiment 1, in autoclave, carry out, under the condition of 0.4Mpa and room temperature, reaction can be carried out very smoothly, and raw material transforms fully, palladium catalyst carbon reclaims, and the rate of recovery is 100%.
Synthetic (2S of the 9th step, 4R)-4-amino-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride (10): identical with embodiment 1, because contain the Boc group in the product structure, this group is under acidic conditions, when being 60 ℃, temperature stirs thoroughly hydrolysis in 1 hour, the system potential of hydrogen is controlled during therefore to salify, and salt-forming condition is set at pH 〉=4 of low temperature and reaction solution, when the aftertreatment steaming desolventizes, controlled temperature is no more than 35 ℃, prevents this group hydrolysis and yield is reduced.Be insoluble to ether behind this step product salify, available ether is removed impurity, and then separates out the product solid with ethyl acetate, the purity of product＞98%.
The above; only be the preferable embodiment of the present invention; but protection scope of the present invention is not limited thereto; anyly be familiar with those skilled in the art in the technical scope that the present invention discloses; be equal to replacement or change according to technical scheme of the present invention and inventive concept thereof, all should be encompassed within protection scope of the present invention.
Claims (10)
1. (2S, 4R)-4-amino pyrroline-1, the method for making of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride is characterized in that: concrete synthetic route is as follows:
The first step is synthesized (2S, 4R)-4-hydroxyl pyrroline-2-carboxylate methyl ester hydrochloride (2): in the organic solvent cold soln of L-oxyproline, slowly add thionyl chloride, the mol ratio of raw material L-oxyproline and thionyl chloride is 1: 1.0-2.0, add the back and rose to stirring at room naturally 1 hour, refluxed 4 hours, underpressure distillation is removed organic solvent and is obtained intermediate product No. 2 again;
Synthetic (2S of second step, 4R)-4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (3): No. 2 intermediate products are dissolved in the halogenated alkane, keep temperature to be no more than 10 degree, add triethylamine and Boc acid anhydrides, at room temperature continue reaction 5 hours again, reaction mixture is used 5% dilute hydrochloric acid, water, saturated sodium bicarbonate solution and saturated common salt water washing successively, the siccative drying, underpressure distillation removes and desolvates, residuum is also freezing with the normal hexane washing, and underpressure distillation is removed normal hexane and obtained intermediate product No. 3;
Synthetic (2S of the 3rd step, 4R)-and 4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (4): No. 3 intermediate products are dissolved in the halogenated alkane, keep temperature to be no more than 5 degree, add triethylamine and methylsulfonyl chloride, under uniform temp, continue reaction 3 hours again.Reaction mixture is used 5% dilute hydrochloric acid, water, saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous magnesium sulfate drying, and underpressure distillation removes and desolvates, and residuum obtains intermediate product No. 4 with normal hexane vibration and freezing and crystallizing;
The 4th step (2S, 4R)-4-benzoyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (5): the dimethyl sulphoxide solution of No. 4 intermediate products and Sodium Benzoate is heated to 90 ℃ stirs and be cooled to room temperature in 7 hours then, reaction mixture adds the ethyl acetate dilution, water and saturated common salt water washing successively, organic phase siccative drying, distillation are removed to desolvate and are obtained oily matter, slowly add normal hexane and the crystallization of vibrating obtains intermediate product No. 5;
Synthetic (2S of the 5th step, 4S)-4-hydroxyl-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (6): at the alcoholic solution of No. 5 intermediate products, the middle salt of wormwood that adds, at room temperature stirred 1 hour, and regulated the pH value to neutral with concentrated hydrochloric acid, distillation for removing methanol, add the ethyl acetate dilution, wash with water; Organic phase saturated common salt water washing, water is saturated with sodium-chlor, chloroform extraction, and use the saturated common salt water washing, and the organic phase of merging siccative drying, underpressure distillation removes to desolvate and obtains oily matter, and the normal hexane crystallization obtains intermediate product No. 6;
Synthetic (2S of the 6th step, 4S)-and 4-mesyloxy-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (7): No. 6 intermediate products are dissolved in the halogenated alkane, keep temperature to be no more than 5 degree, add triethylamine and methylsulfonyl chloride, under uniform temp, continue reaction 1 hour again.Reaction mixture is used 5% dilute hydrochloric acid, water, saturated sodium bicarbonate solution and saturated common salt water washing successively, anhydrous magnesium sulfate drying, and freezing and crystallizing obtains intermediate product No. 7 except that desolvating also in underpressure distillation;
Synthetic (2S of the 7th step, 4R)-4-azido--1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (8): No. 7 intermediate products are dissolved in dimethyl sulfoxide (DMSO), add sodiumazide, oil bath keeps stirring reaction under 70-120 ℃ of condition of temperature, disappear until raw material, be cooled to room temperature, add the ethyl acetate dilution, water and saturated common salt water washing, the siccative drying, underpressure distillation removes and desolvates; Residuum adds entry, ethyl acetate extraction, and water washing, the siccative drying, steaming removes ethyl acetate and obtains intermediate product No. 8;
Synthetic (2S of the 8th step, 4R)-4-amino-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl esters (9): with the alcoholic solution of No. 8 intermediate products, under 15-30 ℃, a 3-5 normal atmosphere, it is catalyst hydrogenation 6-12 hour with 10% palladium carbon, filter, remove catalyzer, get colourless transparent solution, steaming desolventizes residuum and gets intermediate product No. 9;
Synthetic (2S of the 9th step, 4R)-4-amino-1, the 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride (10): No. 9 intermediate products are dissolved in 230 milliliters of solvents, under the ice bath agitation condition, slowly add hydrogenchloride-methanol solution of 5%, regulate pH to 4-5, continue to stir 20-40min, controlled temperature is in the time of 28～35 ℃, and steaming desolventizes, topple over after residuum washs with ether and remove ether, add ethyl acetate again and separate out white solid finished product 10.
2. (2S according to claim 1,4R)-4-amino pyrroline-1, the method for making of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride is characterized in that: the second step material molar ratio is No. 2 intermediate products: triethylamine: Boc acid anhydrides=1: 1.9-2.4: 1.1-1.4.
3. (2S according to claim 1,4R)-4-amino pyrroline-1, the method for making of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride is characterized in that: the 3rd step material molar ratio is No. 3 intermediate products: triethylamine: methylsulfonyl chloride=1: 1.10-1.15: 1.0-1.5.
4. according to claim 1 (2S, 4R)-4-amino pyrroline-1, the method for making of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride is characterized in that: the 4th step material molar ratio is No. 4 intermediate products: phenylformic acid steel=1: 2; Reaction times 6-7 hour, the control product did not lump when aftertreatment was separated out.
5. according to claim 1 (2S, 4R)-4-amino pyrroline-1, the method for making of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride is characterized in that: the 5th step material molar ratio is No. 5 intermediate products: salt of wormwood=1: 1; Reaction times 0.5-3 hour, 1 hour preferred reaction time; At first reaction solution is transferred to neutrality by alkalescence during aftertreatment, steam methyl alcohol then, add ethyl acetate again and water extracts.
6. (2S according to claim 1,4R)-4-amino pyrroline-1, the method for making of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride is characterized in that: the 6th step material molar ratio is No. 6 intermediate products: triethylamine: methylsulfonyl chloride=1: 1.1-1.5: 1.2-1.5; 1 hour reaction times.
According to claim 1-6 arbitrary described (2S, 4R)-4-amino pyrroline-1, the method for making of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride is characterized in that: halogenated alkane adopts methylene dichloride, chloroform or ethylene dichloride; Siccative adopts anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous or anhydrous sodium sulphate etc.
8. arbitrary described (2S, 4R)-4-amino pyrroline-1, the method for making of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride is characterized in that: the 3rd step, the 6th step adopt ice-water bath cooling conservation degree to be no more than 5 degree according to claim 1-6.
9. arbitrary described (2S, 4R)-4-amino pyrroline-1, the method for making of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride is characterized in that: the alcoholic solution in the 5th step, the 8th step adopts methyl alcohol, ethanol or aqueous isopropanol according to claim 1-6.
10. arbitrary described (2S, 4R)-4-amino pyrroline-1, the method for making of the 2-dicarboxylic acid-1-tert-butyl ester-2-methyl ester hydrochloride is characterized in that: the solvent in the 9th step adopts methyl alcohol, ethanol or ethyl acetate solution according to claim 1-6.
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| CN114605310A (en) * | 2022-04-09 | 2022-06-10 | 都创(上海)医药科技股份有限公司 | Synthesis method of aza five-membered ring and three-membered ring carboxylate derivative and salt thereof |
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| WO2001026644A2 (en) * | 1999-10-14 | 2001-04-19 | Curis, Inc. | Mediators of hedgehog signaling pathways, compositions and uses related thereto |
| US20080188545A1 (en) * | 2006-12-21 | 2008-08-07 | Alimardanov Asaf R | Synthesis of pyrrolidine compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001026644A2 (en) * | 1999-10-14 | 2001-04-19 | Curis, Inc. | Mediators of hedgehog signaling pathways, compositions and uses related thereto |
| US20080188545A1 (en) * | 2006-12-21 | 2008-08-07 | Alimardanov Asaf R | Synthesis of pyrrolidine compounds |
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| 《Bioorganic & Medicinal Chemistry》 20021231 Hiroshi Marusawa et al. Synthesis and Biological Activity of 1-Phenylsulfonyl-4-Phenylsulfonylaminopyrrolidine Derivatives as Thromboxane A2 Receptor Antagonists 第1401页图2，第1405页左栏第3段-1406页左栏第2段 1-10 第10卷, 2 * |
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| CN114605310A (en) * | 2022-04-09 | 2022-06-10 | 都创(上海)医药科技股份有限公司 | Synthesis method of aza five-membered ring and three-membered ring carboxylate derivative and salt thereof |
| CN114605310B (en) * | 2022-04-09 | 2024-05-07 | 都创(上海)医药科技股份有限公司 | Synthesis method of aza five-membered ring and three-membered ring carboxylic ester derivative and salt thereof |
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