CN102030734A - Method for synthesizing chiral pharmaceutical intermediate 3-amino tetrahydropyrane and salt thereof - Google Patents
Method for synthesizing chiral pharmaceutical intermediate 3-amino tetrahydropyrane and salt thereof Download PDFInfo
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Abstract
The invention relates to a new method for synthesizing chiral pharmaceutical intermediate 3-amino tetrahydropyrane and salt thereof, in particular to a method for synthesizing racemic pharmaceutical intermediate 3-amino tetrahydropyrane and salt thereof. The method is characterized by comprising a step C of: cooling glycol 3 and triphenyl phosphorus to the temperature of below 0 DEG C in an ice bath under the protection of nitrogen; slowly dropwise adding diisopropyl azodicarboxylate or diethyl azodicarboxylate into a mixture of the glycol 3 and the triphenyl phosphorus; reacting at the temperature of between 10 and 30 DEG C after dripping until the reaction is performed completely; and concentrating and drying to obtain a white solid 4 rough product, wherein the molar ratio of the glycol to the triphenyl phosphorus to the diisopropyl azodicarboxylate or the diethyl azodicarboxylate is 1:(1-3):(1-3); the used raw materials are cheap and readily available; a synthesis route is short; all reaction intermediates and a final product are not required to be subjected to column chromatographic purification; and a large amount of R or S-type 3-amino tetrahydropyrane with high optical activity and racemate thereof can be conveniently prepared from natural L or D-type glutamic acid or racemate thereof serving as a raw material. The method has the advantages of low cost and higher efficiency; and an obtained product has high chemical purity and optical purity.
Description
Technical field
The present invention relates to the 3-amino tetrahydro pyran, particularly a kind of chiral medicinal intermediate 3-amino tetrahydro pyran (and new synthetic method of salt.
Background technology
The 3-amino tetrahydro pyran is a colourless oil liquid, and molecular formula is C
5H
11NO, molecular weight are 101.15.Its hydrochloride is the crystallinity white powder, and molecular formula is C
5H
12ClNO, molecular weight are 137.61.Generally it being prepared into hydrochloride and using, is a kind of important medicine intermediate, is mainly used in the synthetic of newtype drug ampa receptor toughener.Such medicine (U.S. Pat 20100120764) is mainly used in the treatment Parkinson's disease, schizophrenia, sleep shock, nervous system disorderss such as emotionally disturbed and amnesia.
A large amount of experiments experiment data find that chiral separation becomes chipal compounds, and a lot of specific character are arranged, as to split a kind of chiral structure in back be main active substance, and another chiral structure reason of side effect exactly; Therefore world wide is expressed keen interest to chipal compounds, the new drug official written reply separately with the compound after the chiral separation as a kind new medicine.But the problem that often exists in actual synthetic is that what usually to synthesize is raceme, but not the single chiral structure is big as raceme being split the difficulty difficulty, the cost height.
Bibliographical information is not seen in the development of chirality (racemize) 3-amino tetrahydro pyran and hydrochloride thereof, production at present.The contriver finds a kind of low cost through a large amount of experiments, and is efficient, the method for the synthesis of chiral of high yield (racemize) 3-amino tetrahydro pyran (hydrochloride).
Summary of the invention
The objective of the invention is (disclosing) provides a kind of low cost, efficient, the synthetic hand-type racemize 3-amino tetrahydro pyran of high yield and the synthetic method of salt thereof.
The present invention with: step C is under the nitrogen protection, in organic solvent, add glycol 3 and triphenyl phosphorus, be cooled to below 10 ℃ in ice bath, slowly drip diisopropyl azodiformate or diethyl azodiformate to it, drip and finish the 10-30 ℃ of reaction in back to complete, concentrate drying obtains white solid 4 crude products; Wherein said glycol: triphenyl phosphorus: the mol ratio of diisopropyl azodiformate or diethyl azodiformate is 1: 1-3: 1-3; Described organic solvent is chloroform, methylene dichloride or tetrahydrofuran (THF).
Concrete grammar is as follows
A, be raw material with L-L-glutamic acid or D-L-glutamic acid, adopt ordinary method by the carboxyl esterification to L-glutamic acid, the back obtains the diester 2 of amido protecting to the protection of amino,
B, with going back original reagent ester reduction is obtained glycol 3 then;
Under C, the nitrogen protection, in organic solvent, add glycol 3 and triphenyl phosphorus, be cooled to below 10 ℃, slowly drip diisopropyl azodiformate or diethyl azodiformate to it in ice bath, drip and finish the 10-30 ℃ of reaction in back to complete, concentrate drying obtains white solid 4 crude products; Wherein said glycol: triphenyl phosphorus: the mol ratio of diisopropyl azodiformate or diethyl azodiformate is 1: 1-3: 1-3; Obtain the pyran derivate 4 of 3-amido protecting;
The pyran derivate 4 deprotection bases of D, 3-amido protecting generate 3-amino tetrahydro pyran and salt thereof.
In the carboxyl esterification reaction as L-glutamic acid in a kind of optimal way steps A, adopt C1-C8 halogenated alkyl thing (or C1-C8 alkyl alcohol) esterification with it.
As the described halogenated alkyl thing of further optimal way be the Bian bromine or or methyl iodide, C1-C8 halogenated alkyl things such as monobromethane.
As the described alkyl alcohol of further optimal way is methyl alcohol, C1-C8 alkyl alcohols such as ethanol.
As adopting tert-Butyl dicarbonate, Bian bromine, triphenylmethyl chloride, chloroformic acid benzyl ester in the amido protecting reaction in a kind of optimal way steps A.
As reductive agent described in a kind of optimal way step B is NaBH
4, LiBH
4Or LiAlH
4
Pass through HCl, CF as the deprotection base described in a kind of optimal way step D
3(HCl, CF under COOH or the acidic conditions
3COOH, CH3COOH or HCOOH) the shortening realization.
Synthetic route is as follows:
The present invention at first adopts the carboxyl esterification of ordinary method with L-L-glutamic acid or D-L-glutamic acid, after with amido protection in the L-glutamic acid, described ordinary method can for
1) glutamic acid diester 2 of amido protecting is synthetic
Method A: in having the three-necked bottle of agitator, add entry (8-24 times of envelope-bulk to weight ratio), sodium hydroxide (2-6mol), salt of wormwood (5-15mol) and L-L-glutamic acid (or D-L-glutamic acid 1mol), be heated to backflow, slowly splash into benzyl bromine (4-12mol), be added dropwise to complete the afterreaction mixture and reflux again and stir certain hour (0.5-16h).Be cooled to 10-30 ℃, add ethyl acetate extraction, organic phase salt water washing, anhydrous sodium sulfate drying obtains crude product 2 after treatment, is directly used in next step reaction.
Method B: in having the three-necked bottle of agitator, add alcohol (methyl alcohol, ethanol, propyl alcohol etc., 5-15 times of envelope-bulk to weight ratio [5-15 times of volume of solvent restrains L-glutamic acid as the 5-15 milliliter to 1 to 1 times of weight L-glutamic acid], down together), be cooled to 0 ℃, slowly splash into trimethylchlorosilane 4-16mol, after stirring for some time, add 1mol L-L-glutamic acid (or D-L-glutamic acid) solid, finish the back and be stirred to for 10-30 ℃ and react completely.The ice bath cooling splashes into triethylamine (5-20mol) and tert-Butyl dicarbonate (Boc to reaction solution successively
2O) 1-2mol, a complete back is stirred to for 10-30 ℃ and reacts completely.Concentrate, residue is poured in the water, uses ethyl acetate extraction.Merge organic phase, after the salt water washing, anhydrous sodium sulfate drying, the elimination siccative, filtrate concentrating obtains compound 2, is directly used in next step reaction.
2) glycol 3 of amido protecting is synthetic
Reductive agent (the NaBH that in the three-necked bottle that has agitator, adds under the nitrogen protection
4, LiBH
4Or LiAlH
4) 2-8mol, ice bath cooling adds 5-30 times of envelope-bulk to weight ratio of exsiccant tetrahydrofuran (THF) to it down, and the tetrahydrofuran solution of 1mol raw material 2 slowly is added drop-wise in the reaction flask, drips slowly to rise to 10-30 ℃ to reacting completely after finishing.Reaction system is cooled to 0 ℃, and ethyl acetate extraction is used in cancellation reaction (slowly dripping frozen water does not produce to there being bubble).Merge organic phase, add anhydrous sodium sulfate drying, the elimination siccative concentrates, and drying obtains light yellow oil and is crude product glycol 3, is directly used in next step reaction.
3) the amino pyran derivate 4 of 3-is synthetic
In having the three-necked bottle of agitator, add glycol 1mol under the nitrogen protection; 5-40 times of envelope-bulk to weight ratio of methylene dichloride (or chloroform) and triphenyl phosphorus 1-3mol; ice bath is cooled to 0 ℃; to its slow diisopropyl azodiformate (DIAD) or diethyl azodiformate (DEAD) that drips 1-3mol, drip and finish the 10-30 ℃ of reaction in back extremely fully.Concentrate drying obtains white solid 4 crude products, is directly used in next step reaction.
4) 3-amino tetrahydro pyran hydrochloride is synthetic
Method A: the amino pyran derivate 4 of the 3-of the benzyl protection of 1mol is dissolved in contains HCl[or formic acid; acetate etc.] (5%-15%) alcohol of weight ratio (methyl alcohol or ethanol) [or toluene; 1; the 4-dioxane] (3-20 times of envelope-bulk to weight ratio; 3-20 times of volume of solvent is to the amino pyran derivate 4 of 1 times of weight 3-) in; add 5%-20%[with respect to the amino pyran derivate 4 of 3-; the Pd/C that adds the weight percent of 5%-20%; as adding 5-20 gram Pd/C in 100 grams 4] Pd/C; under the 5-40 kilogram pressure, 20-80 ℃ is stirred to and reacts completely.Be cooled to 10-30 ℃, filtrate concentrates.Obtain white solid and be product.Total recovery is 30.8% (in L-glutamic acid).Product purity＞98%, ee＞99%.
Method B: the amino pyran derivate 4 of 3-that the carbonic acid tert-butyl ester (Boc) of a certain amount of 1mol is protected is dissolved in the alcohol (methyl alcohol or ethanol, 5-30 times of envelope-bulk to weight ratio), feeds hydrogen chloride gas to reacting completely.Concentrate, obtain white solid and be product.Total recovery is 37.4% (in L-glutamic acid).Product purity＞98%, ee＞99%.1H?NMR(400MHz，DMSO)：δ8.37(s，3H)，3.80(dd，J＝11.4，3.0Hz，1H)，3.68-3.57(m，1H)，3.56-3.38(m，2H)，3.12(d，J＝2.7Hz，1H)，2.08-1.87(m，1H)，1.83-1.59(m，2H)，1.57-1.39(m，1H)。
5) the 3-amino tetrahydro pyran is synthetic
3-amino tetrahydro pyran hydrochloride 1mol is dissolved in the methylene dichloride (5-30 times of envelope-bulk to weight ratio), slowly splashes into excessive alkali (triethylamine, diisopropylethylamine, Anhydrous potassium carbonate or anhydrous sodium carbonate) 2-5mol under 10-30 ℃, stir half an hour, concentrate.Residue filters with 10-30 times of envelope-bulk to weight ratio extraction of methyl tertiary butyl ether, and filtrate concentrating promptly gets product.
1H?NMR(400MHz，DMSO)δ6.16(s，2H)，3.77-3.59(m，2H)，3.39-3.19(m，1H)，3.08(t，J＝9.6Hz，1H)，2.79(dd，J＝8.3，4.3Hz，1H)，1.96-1.84(m，1H)，1.72-1.56(m，1H)，1.56-1.39(m，1H)，1.33(td，J＝12.9，3.8Hz，1H)。
Beneficial effect
1, the raw material of above-mentioned preparation method's use cheaply is easy to get, and synthetic route is short, and all reaction intermediates and final product do not need the column chromatography purifying.Utilizing present method, is R or the amino pyrans of S type 3-or its racemoid that raw material can prepare high optical activity easily in a large number with natural L or D type L-glutamic acid or its racemoid.Compare with traditional chemistry fractionation or asymmetric method synthesis of optically active material, present method is with low cost, and is more efficient, product chemical purity that obtains and optical purity height.These advantages have greatly reduced production cost, can be used for suitability for industrialized production, for market provides high purity, and the product of high optical activity, thus obtain high economic benefit.
2, innovative point is to adopt to exist at diisopropyl azodiformate (DIAD) or diethyl azodiformate (DEAD) and triphenyl phosphorus and issues living intramolecularly Mitsunobu and react among the present invention, with described glycol cyclization, form the target compound skeleton cleverly.
3, the present invention not only can use the reaction of chirality L-glutamic acid, be that the mixture of D-L-glutamic acid and L-L-glutamic acid reacts to raceme L-glutamic acid simultaneously, product forms the 3-amino tetrahydro pyran and the salt of raceme, for related compound provides enlightenment, and the range of application of expansion.
Description of drawings
Fig. 1 is the chirality high performance liquid phase collection of illustrative plates of 3-phenyl-N-(3-THP trtrahydropyranyl) acrylamide (R)/(S) mixture
Fig. 2 is the chirality high performance liquid phase collection of illustrative plates of (S)-3-phenyl-N-(3-THP trtrahydropyranyl) acrylamide
Fig. 3 is the chirality high performance liquid phase collection of illustrative plates of (R)-3-phenyl-N-(3-THP trtrahydropyranyl) acrylamide
Fig. 4 is the nucleus magnetic hydrogen spectrum of the amino pyranium salt hydrochlorate of 3-
Embodiment
1, synthetic (the method A) of the two benzyl esters (2a) of 5-(2-dibenzyl amino) pentanedioic acid
In having the three-necked bottle of agitator, add 1200 ml waters, 1.6mol sodium hydroxide (65 gram), 2.2mol salt of wormwood (306 gram), 1.2mol L-glutamic acid (180 gram), 4.8mol benzyl bromine (2457 gram), drip finish after, reflux and stirred 30 minutes, be cooled to 10-30 ℃, add 1200 milliliters of extractions of ethyl acetate, organic phase is washed with 600 mL of saline, anhydrous sodium sulfate drying, the elimination siccative concentrates, obtain 300 gram crude products, be directly used in next step reaction.
1H?NMR(400MHz，CDCl3)δ7.55-7.21(m，20H)，5.30(d，J＝12.2Hz，1H)，5.25-5.13(m，1H)，5.07-4.96(m，2H)，3.92(d，J＝13.7Hz，2H)，3.54(d，J＝13.7Hz，2H)，3.44(q，J＝7.3Hz，1H)，2.54(dt，J＝16.6，7.1Hz，1H)，2.44-2.32(m，1H)，2.18-2.05(m，2H).MS(ESI)M/Z508[M+H]
+
1,5-(2-dibenzyl amino) pentanediol (3) synthetic
In having the three-necked bottle of agitator, add 300 milliliters of tetrahydrofuran (THF)s, the ice bath cooling adds 0.1mol Lithium Aluminium Hydride (3.8 gram) down in batches, 1, the tetrahydrofuran solution of the two benzyl esters of 5-(2-dibenzyl amino) pentanedioic acid (27.6mmol ester (14 gram), 100 milliliters of THF), slowly rise to 10-30 ℃ to reacting completely.Slowly splash into the sodium hydroxide solution of 17 ml waters and 17 milliliter 15%, filter.Filtrate is used 200 milliliters of extractions of ethyl acetate, the organic phase anhydrous sodium sulfate drying, and the elimination siccative concentrates, and drying obtains 7.2 gram products.
1H?NMR(400MHz，CDCl
3)δ7.39-7.16(m，10H)，3.92-3.75(m，2H)，3.63(t，J＝6.3Hz，2H)，3.58-3.40(m，4H)，3.12(s，1H)，2.92-2.64(m，1H)，1.95-1.73(m，1H)，1.59-1.42(m，3H)，1.36-1.17(m，1H).MS(ESI)M/Z?300[M+H]
+
Synthesizing of 3-dibenzyl amino tetrahydropyrans (4)
N
2Protection down; in having the three-necked bottle of agitator, add 2.38mol 1; 5-(2-dibenzyl amido) pentanediol (780 gram); 5 liters of methylene dichloride and 3.33mol triphenyl phosphorus (873 gram); in reaction mixture, add 3.33mol diisopropyl azodiformate (DIAD then; 673 grams), be stirred to and react completely.Concentrate, obtain white crude product 706 grams, promptly obtain 3-dibenzyl amino tetrahydropyrans.MS(ESI)M/Z?282[M+H]
+
Synthetic (the method A) of 3-amino tetrahydro pyran hydrochloride
0.36mol 3-dibenzyl amino tetrahydropyrans crude product (100 gram) is dissolved in the methanol solution (HCl content 5%) of 500 milliliters of hydrogenchloride, adding 10 grams 10% palladium carbon, 20 kilograms of pressure, 60 ℃ are reacted down to complete.Be cooled to 10-30 ℃, filter, concentrate, in residue, add 200 milliliters of methyl tertiary butyl ethers, be stirred to a large amount of solids and separated out.Filter, obtain 21.2 gram white solids after the drying and be pure product.
Synthesizing of 3-amino tetrahydro pyran
0.073mol 3-amino tetrahydro pyran hydrochloride (10 gram) is dissolved in 100 milliliters of methylene dichloride, slowly splashes into 0.21mol triethylamine (21 gram) under 10-30 ℃, stir half an hour, concentrate.Residue stirs half an hour with 150 milliliters of methyl tertiary butyl ethers, filters, and filtrate concentrating promptly gets product 7.4 grams.
1H?NMR(400MHz，DMSO)δ6.16(s，2H)，3.77-3.59(m，2H)，3.39-3.19(m，1H)，3.08(t，J＝9.6Hz，1H)，2.79(dd，J＝8.3，4.3Hz，1H)，1.96-1.84(m，1H)，1.72-1.56(m，1H)，1.56-1.39(m，1H)，1.33(td，J＝12.9，3.8Hz，1H).
1, synthetic (the method B) of 5-(2-t-butoxycarbonyl amino) valeric acid dimethyl ester (2b)
Add 7 liters of methyl alcohol in having the three-necked bottle of agitator, be cooled to 0 ℃, slowly splash into 12.1mol trimethylchlorosilane (1320 gram), stir after 30 minutes, add 4.8mol L-glutamic acid (700 gram), room temperature reaction is to reacting completely.Be cooled to 0 ℃, slowly splash into 25.6mol triethylamine (2600 gram) and 5.76mol tert-Butyl dicarbonate (1257 gram) successively, a complete back is stirred to for 10-30 ℃ and reacts completely.Concentrate, residue is poured in 5 premium on currency, with 9 liters of ethyl acetate extractions 2 times, merges organic phase, after 4 liters of salt water washings, and anhydrous sodium sulfate drying, the elimination siccative, filtrate concentrating obtains light yellow oil 1300 and restrains and be product.
1H?NMR(400MHz，CDCl
3)δ5.09(s，1H)，4.33(s，1H)，3.75(s，3H)，3.68(s，3H)，2.52-2.31(m，2H)，2.19(td，J＝13.5，7.4Hz，1H)，1.95(td，J＝14.6，8.1Hz，1H)，1.44(s，9H).MS(ESI)M/Z?276[M+H]
+
1,5-(2-dibenzyl amino) pentanediol (3) synthetic
In having the three-necked bottle of agitator, add 300 milliliters of tetrahydrofuran (THF)s, the ice bath cooling adds 0.1mol Lithium Aluminium Hydride (3.8 gram) down in batches, 1, the tetrahydrofuran solution of the two benzyl esters of 5-(2-dibenzyl amino) pentanedioic acid (27.6mmol ester (14 gram), 100 milliliters of THF), slowly rise to 10-30 ℃ to reacting completely.Slowly splash into the sodium hydroxide solution of 17 ml waters and 17 milliliter 15%, filter.Filtrate is used 200 milliliters of extractions of ethyl acetate, the organic phase anhydrous sodium sulfate drying, and the elimination siccative concentrates, and drying obtains 7.2 gram products.
1H?NMR(400MHz，CDCl
3)δ7.39-7.16(m，10H)，3.92-3.75(m，2H)，3.63(t，J＝6.3Hz，2H)，3.58-3.40(m，4H)，3.12(s，1H)，2.92-2.64(m，1H)，1.95-1.73(m，1H)，1.59-1.42(m，3H)，1.36-1.17(m，1H).MS(ESI)M/Z?300[M+H]
+
Synthesizing of 3 dibenzyl amino tetrahydropyranss (4)
N
2Protection down; in having the three-necked bottle of agitator, add 2.38mol 1; 5-(2-dibenzyl amido) pentanediol (780 gram); 5 liters of methylene dichloride and 6.66mol triphenyl phosphorus (873 gram); in reaction mixture, add 6.66mol diisopropyl azodiformate (DIAD then; 673 grams), be stirred to and react completely.Concentrate, obtain white crude product 720 grams, promptly obtain 3-dibenzyl amino tetrahydropyrans.MS(ESI)M/Z?282[M+H]
+。
Synthetic (the method B) of 3-amino tetrahydro pyran hydrochloride
4.2mol 3-t-butoxycarbonyl amino tetrahydropyrans (4b) crude product (850 gram) is dissolved in 2.5 liters of methyl alcohol, feeds hydrogen chloride gas under the ice bath, 10-30 ℃ is reacted down to complete.Spin off solvent, in residue, add 1000 milliliters of methyl tertiary butyl ethers, be stirred to a large amount of solids and separated out.Filter, obtain the pure product of white solid 276 grams after the drying.
1H?NMR(400MHz，DMSO)δ8.37(s，3H)，3.80(dd，J＝11.4，3.0Hz，1H)，3.68-3.57(m，1H)，3.56-3.38(m，2H)，3.12(d，J＝2.7Hz，1H)，2.08-1.87(m，1H)，1.83-1.59(m，2H)，1.57-1.39(m，1H).
Synthesizing of 3-amino tetrahydro pyran
0.073mol 3-amino tetrahydro pyran hydrochloride (10 gram) is dissolved in 100 milliliters of methylene dichloride, slowly splashes into 0.21mol triethylamine (21 gram) under 10-30 ℃, stir half an hour, concentrate.Residue stirs half an hour with 150 milliliters of methyl tertiary butyl ethers, filters, and filtrate concentrating promptly gets product 7.4 grams.
1H?NMR(400MHz，DMSO)δ6.16(s，2H)，3.77-3.59(m，2H)，3.39-3.19(m，1H)，3.08(t，J＝9.6Hz，1H)，2.79(dd，J＝8.3，4.3Hz，1H)，1.96-1.84(m，1H)，1.72-1.56(m，1H)，1.56-1.39(m，1H)，1.33(td，J＝12.9，3.8Hz，1H).
Synthesizing of 3-dibenzyl amino tetrahydropyrans (4)
N
2Protection down; in having the three-necked bottle of agitator, add 2.38mol 1; 5-(2-dibenzyl amido) pentanediol (780 gram); 5 liters of methylene dichloride and 9.99mol triphenyl phosphorus (873 gram); in reaction mixture, add 9.99mol diisopropyl azodiformate (DIAD then; 673 grams), be stirred to and react completely.Concentrate, obtain white crude product 720 grams, promptly obtain 3-dibenzyl amino tetrahydropyrans.MS(ESI)M/Z?282[M+H]
+。
All the other steps are identical with embodiment 1.
Embodiment 4
Detect: 3-amino tetrahydro pyran molecule itself does not have uv-absorbing, can not directly detect its ee value with liquid phase process.We derive itself and cinnamyl chloride reaction for having the cinnamide of uv-absorbing, with chirality HPLC it have been done the ee. pH-value determination pH.The results are shown in accompanying drawing 1-3:
Column： CHlRALPAK?IA?0.46cm×25cm，5μm
Mobile?Phase：n-heptane/EtOH＝80/20(v/v％)
Detector： UV?214nm
Flow?Rate： 0.7mL/min
Column?Temp.：ambient?temp.
Claims (8)
1. the synthetic method of chiral medicinal intermediate 3-amino tetrahydro pyran and salt thereof, it is characterized in that: step C is under the nitrogen protection, in organic solvent, add glycol 3 and triphenyl phosphorus, be cooled to below 0 ℃ in ice bath, slowly drip diisopropyl azodiformate or diethyl azodiformate to it, drip and finish the 10-30 ℃ of reaction in back to complete, concentrate drying obtains white solid 4 crude products; Wherein said glycol: triphenyl phosphorus: the mol ratio of diisopropyl azodiformate or diethyl azodiformate is 1: 1-3: 1-3;
Concrete grammar is as follows
A, be raw material with L-L-glutamic acid or D-L-glutamic acid, adopt ordinary method by the carboxyl esterification to L-glutamic acid, the back obtains the diester 2 of amido protecting to the protection of amino,
With going back original reagent the ester reduction is obtained glycol 3 then;
Under nitrogen protection, in organic solvent, add glycol 3 and triphenyl phosphorus, be cooled to below 0 ℃, slowly drip diisopropyl azodiformate or diethyl azodiformate to it in ice bath, drip and finish the 10-30 ℃ of reaction in back to complete, concentrate drying obtains white solid 4 crude products; Wherein said glycol: triphenyl phosphorus: the mol ratio of diisopropyl azodiformate or diethyl azodiformate is 1: 1-3: 1-3; Obtain the pyran derivate 4 of 3-amido protecting;
The pyran derivate 4 deprotection bases of D, 3-amido protecting generate 3-amino tetrahydro pyran and salt thereof.
2. the synthetic method of a kind of chiral medicinal intermediate 3-amino tetrahydro pyran according to claim 1 and salt thereof is characterized in that adopting C1-C8 halogenated alkyl thing or the esterification with it of C1-C8 alkyl alcohol in the carboxyl esterification reaction of L-glutamic acid in the steps A.
3. the synthetic method of a kind of chiral medicinal intermediate 3-amino tetrahydro pyran according to claim 2 and salt thereof is characterized in that described halogenated alkyl thing is Bian bromine, methyl iodide or monobromethane.
4. the synthetic method of a kind of chiral medicinal intermediate 3-amino tetrahydro pyran according to claim 2 and salt thereof is characterized in that described alkyl alcohol is methyl alcohol, ethanol, propyl alcohol or butanols.
5. the synthetic method of a kind of chiral medicinal intermediate 3-amino tetrahydro pyran according to claim 1 and salt thereof is characterized in that adopting tert-Butyl dicarbonate, Bian bromine, triphenylmethyl chloride or chloroformic acid benzyl ester in the amido protecting reaction in the steps A.
6. the synthetic method of a kind of chiral medicinal intermediate 3-amino tetrahydro pyran according to claim 1 and salt thereof is characterized in that reductive agent described in the step B is NaBH4, LiBH4 or LiAlH4.
7. according to the synthetic method of a kind of chiral medicinal intermediate 3-amino tetrahydro pyran according to claim 1 and salt thereof, it is characterized in that described organic solvent is chloroform, methylene dichloride or tetrahydrofuran (THF).
8. the synthetic method of a kind of chiral medicinal intermediate 3-amino tetrahydro pyran according to claim 1 and salt thereof; it is characterized in that the deprotection base described in the step D is by HCl under HCl or CF3COOH or the acidic conditions; there are shortening realization down in CF3COOH, CH3COOH or HCOOH.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850395A (en) * | 2012-10-11 | 2013-01-02 | 常州储能材料与器件研究院 | Method for synthesizing glyphosate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1823051A (en) * | 2003-07-14 | 2006-08-23 | 宇部兴产株式会社 | Process for production of 4-aminotetrahydropyrans and salts thereof with acids, intermediates for the process, and process for production thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1823051A (en) * | 2003-07-14 | 2006-08-23 | 宇部兴产株式会社 | Process for production of 4-aminotetrahydropyrans and salts thereof with acids, intermediates for the process, and process for production thereof |
Non-Patent Citations (2)
| Title |
|---|
| 《J. Med. Chem.》 20021127 Stephen Hanessian, et al. The Power of Visual Imagery in Drug Design. Isopavines as a New Class of Morphinomimetics and Their Human Opioid Receptor Binding Activity 34-48 1-8 第46卷, 第1期 2 * |
| 《Tetrahedron Letters》 19981231 Martin Oestreich, et al. (-)-Sparteine-Mediated Stereoselective Intramolecular Carbolithiation of Alkynes 1745-1748 1-8 第39卷, 2 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850395A (en) * | 2012-10-11 | 2013-01-02 | 常州储能材料与器件研究院 | Method for synthesizing glyphosate |
| CN102850395B (en) * | 2012-10-11 | 2015-08-05 | 常州储能材料与器件研究院 | A kind of method of synthesizing glyphosate |
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