CN100451010C - Method for synthesizing (R)-3-amido tetrahydrofuran - Google Patents

Abstract

The present invention relates to a synthetic method of (R)-3-amido tetrahydrofuran, which provides a synthetic method of (R)-3-amido tetrahydrofuran prepared from (S)-3-hydroxytetrahydrofuran, which has low production cost and is capable of avoiding environmental pollution and hidden danger. The synthetic method comprises the steps that sulfonic ester 3 is prepared from (S)-3-hydroxytetrahydrofuran 2 by reaction with sulfuryl chloride under the existence of 4-dimethylaminopyridine and organic alkali triethylamine; (R)-3-azidotetrahydrofuran 4 is prepared from the sulfonic ester 3 by reaction with sodium azide; the (R)-3-amido tetrahydrofuran 1 is prepared from the (R)-3-azidotetrahydrofuran 4 by Raney nickel catalytic hydrogenation. The (R)-3-amido tetrahydrofuran is prepared from the (S)-3-hydroxytetrahydrofuran by a novel synthetic method in order to avoid the use of expensive reagents of palladium-carbon, etc. Because the use of methyl iodide is avoided, the synthetic method avoids the environmental pollution and the hidden danger, reduces the production cost, has the advantages of simple synthetic route, easy acquirement of raw materials and low price and is suitable for industrial production.

Description

A kind of method of synthetic (R)-3-amido tetrahydrofuran

Technical field

The present invention relates to a kind of is raw material with (S)-3-hydroxyl tetrahydrofuran, the method for synthetic (R)-3-amido tetrahydrofuran.

Background technology

(R)-and 3-amido tetrahydrofuran 1 is a kind of important intermediate, is the crucial synthetic intermediate of synthetic antiarrhythmics Tecadenoson, the structural formula of this compound is as follows.

(R)-3-amido tetrahydrofuran 1

The method of the synthetic 3-amido tetrahydrofuran of having reported mainly contains following two kinds:

(1) reaction of 3-tetrahydrofuran (THF) carboxylic acid and diphenylphosphine acylazide (DPPA) obtains isocyanic ester; isocyanic ester generates N-carbobenzoxy-(Cbz)-3-amido tetrahydrofuran with the benzylalcohol reaction again; obtain 3-amido tetrahydrofuran (Patent US 5789416) in go down carbobenzoxy-(Cbz) protection of palladium carbon catalysis hydrogenation, synthetic route is as follows:

(2) 4-methylthio group 2-triphenyl amino-1-butanols and iodomethane reaction generate the iodate sulfonium compound, the cyclization under sodium hydride or potassium tert.-butoxide catalysis of iodate sulfonium compound generates N-trityl-3-amido tetrahydrofuran, this compound and tosic acid reaction obtain the tosilate (J.Chem.Soc. of 3-amido tetrahydrofuran, Chem.Commun.1987,6:474-475), synthetic route is as follows:

Although the synthetic route of method 1 is easily, but main limitation is price costliness such as raw material and more used reagent such as palladium-carbon in the synthetic route, productive rate is also lower, obtain owing to product must separate through rapid column chromatography simultaneously, so be not suitable for suitability for industrialized production.The synthetic route of method 2 is also shorter, and productive rate is very high.The main limitation of this route is that raw material is not easy to obtain, and the more important thing is in the process of synthetic iodate sulfonium compound to use methyl iodide.Methyl iodide toxicity is big, and environmental pollution is also very big, and costs an arm and a leg, and still in use all exists inconvenience in production.

Summary of the invention

The object of the present invention is to provide a kind of is raw material with (S)-3-hydroxyl tetrahydrofuran, the low and method that can exempt synthetic (R)-3-amido tetrahydrofuran of environmental pollution and potential safety hazard of its production cost.

Synthetic route of the present invention is as follows:

Concrete steps of the present invention are:

1) (S)-3-hydroxyl tetrahydrofuran 2 (1 mole) in the presence of 4-dimethylaminopyridine (0.25～0.5 mole) and organic bases triethylamine (1.2～1.5 moles), generate sulphonate 3 with SULPHURYL CHLORIDE (1.2～1.5 moles) reaction.Temperature of reaction is 50～80 ℃, 6～8 hours reaction times.SULPHURYL CHLORIDE refers to Tosyl chloride, parachloroben-zenesulfonyl chloride, benzene sulfonyl chloride or methylsulfonyl chloride.Reaction solvent is a halohydrocarbon, and halohydrocarbon refers to methylene dichloride, trichloromethane or 1,2-ethylene dichloride.Its mol ratio is: (S)-the 3-hydroxyl tetrahydrofuran: triethylamine: SULPHURYL CHLORIDE: 4-dimethylaminopyridine=1: (1.2～1.5): (1.2～1.5): (0.25～0.5).

2) sulphonate 3 (1 mole) generates (R)-3-azido-tetrahydrofuran (THF) 4 with sodium azide (2 moles) reaction.Reaction solvent is N, dinethylformamide.Temperature of reaction is 75～85 ℃, 8～10 hours reaction times.The mol ratio of sulphonate and sodium azide is 1: 2.

3) (R)-3-azido-tetrahydrofuran (THF) 4 generates (R)-3-amido tetrahydrofuran 1 through Raney Ni (Raney-Ni) catalytic hydrogenation.Solvent is a lower alcohol, said lower alcohol nail alcohol, ethanol.The hydrogenation temperature is 25～30 ℃, 1 hour reaction times.Catalyst consumption is every mole of 3-azido-tetrahydrofuran (THF) 100g Raney Ni.

The characteristics of synthetic route of the present invention are with a kind of new synthetic method preparation (R)-3-amido tetrahydrofuran.With (S)-3-hydroxyl tetrahydrofuran is raw material, avoids using expensive reagent such as palladium-carbon, because avoid using methyl iodide, has exempted environmental pollution and potential safety hazard, has reduced production cost simultaneously.Its synthetic line is simple, and used raw material is easy to get, and is cheap, is suitable for suitability for industrialized production.

Embodiment

The present invention is further illustrated below by embodiment.

Embodiment 1:

Step 1. preparation (S)-3-tetrahydrofuran (THF) p-toluenesulfonic esters

(S)-and the 3-hydroxyl tetrahydrofuran (3g, 34mmol), Tosyl chloride (9.74g, 51mmol), triethylamine (7ml, 51mmol), (2.12g 17mmol) adds the 50ml methylene dichloride to DMAP successively, stir, 60～70 ℃ were reacted 6～8 hours, and TLC detects raw material and disappears stopped reaction.Add the 150ml ethyl acetate, use the dilute hydrochloric acid of 100ml1N successively, 100ml water, the water washing of 100ml saturated common salt.Behind the concentrating under reduced pressure, add 50ml water and 1g sodium hydroxide, stirring is spent the night.With ethyl acetate extraction 3 times, each 30ml merges organic phase, anhydrous magnesium sulfate drying.Concentrating under reduced pressure obtains the white solid 7.26g of (S)-3-tetrahydrofuran (THF) p-toluenesulfonic esters, productive rate 88%.

${\left[\mathrm{\α}\right]}_D^{20}=+54.01(c=1,\mathrm{MeOH})$

¹H-NMR(DMSO)：δ7.80(d，J＝7.9Hz，，2H，Ar-H)，7.36(d，J＝8Hz，2H，Ar-H)，5.11(m，1H，H-3)，4.12(dd，J＝12.1，8.3Hz，1H，H-2)，3.89(dd，J＝11.7，8.3Hz，1H，H-2’)，3.79(m，2H，H-5)，2.5(s，3H，CH ₃)，2.08(m，2H，H-4)

Step 2. preparation (R)-3-amido tetrahydrofuran

Method 1:(S)-and 3-tetrahydrofuran (THF) p-toluenesulfonic esters (2.42g, 10mmol), sodium azide (1.3g, 20mmol) add 10mlN, dinethylformamide is warming up to 80 ℃, in 75～85 ℃ of insulation reaction 8～10 hours, TLC detected no raw material point, stopped reaction.Be cooled under the room temperature, add 10ml methyl alcohol, the 1g Raney Ni, 25～30 ℃ were stirred 1 hour.Filter, use the 5ml methanol wash.Concentrating under reduced pressure adds 5ml methyl alcohol in the brown residue of gained.Filter solid 1ml methanol wash.Concentrating under reduced pressure, residue are dissolved in 20ml water, use activated carbon decolorizing.Concentrating under reduced pressure is with obtaining yellow solid 0.76g behind methanol/ethyl acetate=1.7ml/9ml recrystallization, productive rate 87.4%.

MS(ESI)：88.2(M+H ⁺，100)

¹H-NMR(CD ₃OD)：δ4.10(dd，J＝15.3，7.8Hz，1H，H-2)，3.85(dd，J＝14.8，7.8Hz，1H，H-2’)，3.78(m，2H，H-5)，2.98(m，1H，H-3)，2.0(m，2H，H-4)

Extracting yellow solid 0.1g is dissolved in 10ml water, adds 0.218g one hydration tosic acid, stirs 1 hour, and concentrating under reduced pressure obtains the yellow solid 0.3g of (R)-3-amido tetrahydrofuran, productive rate 100% after the drying.

${\left[\mathrm{\α}\right]}_D^{20}=+5.08(c=3,\mathrm{MeOH}).$ m.p.＝138～139℃。

Method 2:(S)-and 3-tetrahydrofuran (THF) p-toluenesulfonic esters (2.42g, 10mmol), sodium azide (1.3g, 20mmol) add 10ml N, dinethylformamide is warming up to 80 ℃, in 75～85 ℃ of insulation reaction 8～10 hours, TLC detected no raw material point, stopped reaction.Be cooled under the room temperature, add 10ml methyl alcohol, the 1g Raney Ni, 25～30 ℃ were stirred 1 hour.Filter, use the 5ml washing with alcohol.Concentrating under reduced pressure adds 5ml ethanol in the brown residue of gained.Filter solid 1ml washing with alcohol.Concentrating under reduced pressure, residue are dissolved in 20ml water, use activated carbon decolorizing.Concentrating under reduced pressure is with obtaining yellow solid 0.74g behind methanol/ethyl acetate=1.7ml/9ml recrystallization, productive rate 85.2%.

Embodiment 2:

Step 1. preparation (S)-3-tetrahydrofuran (THF) methanesulfonates

(S)-and the 3-hydroxyl tetrahydrofuran (3g, 34mmol), methylsulfonyl chloride (5.84g, 51mmol), triethylamine (7ml, 50mmol), (2g 16mmol) adds the 50ml methylene dichloride to DMAP successively, stir, 50～60 ℃ were reacted 6～8 hours, and TLC detects no raw material point, stopped reaction.Add the 150ml ethyl acetate, use the dilute hydrochloric acid of 100ml1N successively, 100ml water, the water washing of 100ml saturated common salt.Behind the concentrating under reduced pressure, add 50ml water and 1g sodium hydroxide, stirring is spent the night.Inferior with ethyl acetate 3 extractions, each 30ml merges organic phase, anhydrous magnesium sulfate drying.Concentrating under reduced pressure obtains light yellow liquid 4.93g, productive rate 87.1%.

Step 2. preparation (R)-3-amido tetrahydrofuran is with embodiment 1.

Embodiment 3:

Step 1. preparation (S)-3-tetrahydrofuran (THF) benzene sulfonate

(S)-and the 3-hydroxyl tetrahydrofuran (3g, 34mmol), benzene sulfonyl chloride (9g, 51mmol), triethylamine (7ml, 50mmol), (2g 16mmol) adds the 50ml trichloromethane to DMAP successively, stirs, 60～70 ℃ of reactions, 6～8 hours, TLC detected no raw material point, stopped reaction.Add the 150ml ethyl acetate, use the dilute hydrochloric acid of 100ml1N successively, 100ml water, the water washing of 100ml saturated common salt.Behind the concentrating under reduced pressure, add 50ml water and 1g sodium hydroxide, stirring is spent the night.With ethyl acetate extraction 3 times, each 30ml merges organic phase, anhydrous magnesium sulfate drying.Concentrating under reduced pressure obtains white solid 6.71g, productive rate 86.3%.

Step 2. preparation (R)-3-amido tetrahydrofuran is with embodiment 1.

Embodiment 4:

Step 1. preparation (S)-3-tetrahydrofuran (THF) closilate

(S)-and the 3-hydroxyl tetrahydrofuran (3g, 34mmol), parachloroben-zenesulfonyl chloride (8.67g, 51mmol), triethylamine (5.7ml, 40.8mmol), DMAP (1.06g, 8.5mmol) add 50ml1 successively, the 2-ethylene dichloride stirs, and 70～80 ℃ were reacted 6～8 hours, TLC detects no raw material point, stopped reaction.Add the 150ml ethyl acetate, use the dilute hydrochloric acid of 100ml1N successively, 100ml water, the water washing of 100ml saturated common salt.Behind the concentrating under reduced pressure, add 50ml water and 1g sodium hydroxide, stirring is spent the night.With ethyl acetate extraction 3 times, each 30ml merges organic phase, anhydrous magnesium sulfate drying.Concentrating under reduced pressure obtains white solid 7.33g, productive rate 81.9%.

Step 2. preparation (R)-3-amido tetrahydrofuran embodiment 1.

Claims (3)

1. the method for synthetic (R) 3-amido tetrahydrofuran is characterized in that the steps include:

1) (S)-3-hydroxyl tetrahydrofuran 2 is in the presence of 4-dimethylaminopyridine and organic bases triethylamine, generate sulphonate 3 with the SULPHURYL CHLORIDE reaction, its mol ratio is: (S)-the 3-hydroxyl tetrahydrofuran: triethylamine: SULPHURYL CHLORIDE: 4-dimethylaminopyridine=1: 1.2～1.5: 1.2～1.5: 0.25～0.5, reaction solvent is a halohydrocarbon, temperature of reaction is 50～80 ℃, 6～8 hours reaction times;

2) sulphonate 3 generates (R)-3-azido-tetrahydrofuran (THF) 4 with the sodium azide reaction, and the mol ratio of sulphonate and sodium azide is 1: 2, and reaction solvent is N, dinethylformamide, and temperature of reaction is 75～85 ℃, 8～10 hours reaction times;

3) (R)-3-azido-tetrahydrofuran (THF) 4 generates (R)-3-amido tetrahydrofuran 1 through the Raney Ni catalytic hydrogenation, catalyst consumption is every mole of 3-azido-tetrahydrofuran (THF) 100g Raney Ni, solvent is methyl alcohol or ethanol, and the hydrogenation temperature is 25～30 ℃, 1 hour reaction times.

2. the method for a kind of synthetic (R)-3-amido tetrahydrofuran as claimed in claim 1 is characterized in that said SULPHURYL CHLORIDE refers to Tosyl chloride, parachloroben-zenesulfonyl chloride, benzene sulfonyl chloride or methylsulfonyl chloride.

3. the method for a kind of synthetic (R)-3-amido tetrahydrofuran as claimed in claim 1 is characterized in that said halohydrocarbon refers to methylene dichloride, trichloromethane or 1,2-ethylene dichloride.