CN103232368B - A kind of synthetic method of (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate - Google Patents
A kind of synthetic method of (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate Download PDFInfo
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Abstract
The invention provides the synthetic method of one (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, belong to technical field of medicine synthesis.It solve the synthetic method product yield synthesizing (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate in prior art low, need column chromatography for separation, be not suitable for the problem of large-scale industrial production.This synthesis step comprises: 1) hydroxyl oxygen on equal amido phenenyl alcohol is changed into aldehyde radical and obtain p-nitrophenyl acetaldehyde; 2) (R)-2-amino-1-phenylethyl alcohol reduction amination is obtained (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol; 3) with (Boc)
2o replaces amino the final product on (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol.Synthetic method of the present invention becomes to produce cost low, and the finished product yield is high, is applicable to large-scale industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of pharmaceutical intermediate, particularly relate to the synthetic method of one (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, belong to technical field of medicine synthesis.
Background technology
Through data presentation, at present by the large contingent of overactive bladder puzzlement, as just about there are 3,300 ten thousand people in the U.S..Use Mirabegron that detrusor smooth muscle can be made to relax and become lax in the storage of filling of bladder-urination cycle, thus promote to increase bladder capacity, therefore Mirabegron is used to treat the overactive bladder mixing urge incontinence, urgent urination, frequency symptoms.In addition, along with the raising of people's social and economic activities, diabetes become the endocrine metabolism disease of a kind of common puzzlement people gradually.Find the more general antidiabetic oral medicine of amide derivatives and insulin preparation after deliberation, there is the effect better promoting insulin secretion and the effect strengthening insulin receptivity, thus more effectively can control blood sugar.
And (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, be the synthesis important intermediate of Mirabegron and the important intermediate of synthesizing amide derivative, its chemical structural formula is:
About the document of synthesis (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate has Chinese patent application file (publication number: CN1218045A) in prior art, it relates to the synthetic method that one prepares (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, and this synthetic route is:
There is following problem in this synthetic method:
1), employ poisonous S-Styrene oxide 98min. reagent in this synthetic method, this reagent has restraining effect to nervus centralis, and have stimulation and sensitization to skin, positive findings appears in multiple mutagenicity test, unfavorable to operator.
2), employ expensive S-Styrene oxide 98min. reagent in this synthetic method, and need column chromatography for separation after completion of the reaction, cause production cost high.
3), after completion of the reaction reaction solution just need can obtain sterling through twice column chromatography for separation, post-processing step is loaded down with trivial details and can produce a large amount of three wastes, and product yield is low, is only 22%.
Summary of the invention
The object of the invention is to for exist in prior art deficiency, provide a kind of yield high, cost is low, the method for synthesis (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate that environmental pollution is little.
Above-mentioned purpose of the present invention can be realized by following technical proposal: a kind of synthetic method of (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, and this synthetic method comprises the following steps:
S1, oxidizing reaction: with p-nitrophenyl ethanol for raw material, make itself and oxygenant carry out oxidizing reaction in a solvent, makes the hydroxyl on described p-nitrophenyl ethanol be oxidized to aldehyde radical, obtain p-nitrophenyl acetaldehyde.
S2, reduction amination: above-mentioned obtained p-nitrophenyl acetaldehyde is carried out reductive amination process with (R)-2-amino-1-phenylethyl alcohol under the effect of reductive agent, obtain (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol after the amino on (R)-2-amino-1-phenylethyl alcohol and the aldehyde radical dehydrating condensation on p-nitrophenyl acetaldehyde are reduced.
S3, substitution reaction: by above-mentioned obtained (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol and (Boc)
2o reacts, and makes amino quilt (Boc) on (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol
2o replaces, and obtains final product (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.
In the synthetic method of above-mentioned (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate; described step S1 specifically comprises the steps: under the protection of nitrogen; p-nitrophenyl ethanol and oxygenant are added forming reactions liquid in solvent; by reaction solution return stirring to reacting completely; reaction solution after reacting completely is down to room temperature; suction filtration obtains filter cake and filtrate, washing leaching cake, and merging, concentrated filtrate obtain p-nitrophenyl acetaldehyde.
As preferably, oxygenant described in step S1 is adjacent iodoxybenzoic acid, potassium permanganate, Manganse Dioxide, Dai Si-Martin's oxygenant, 2, one or more in 2,6,6-tetramethyl piperidine oxide compound, pyridinium chloro-chromate, clorox, oxygen, nitric acid, aluminium sesquioxide.The mol ratio of described oxygenant and p-nitrophenyl ethanol is (2 ~ 4): 1.
Further preferably, the oxygenant described in step S1 is adjacent iodoxybenzoic acid.Adjacent iodoxybenzoic acid is compared with other oxygenants, and react comparatively rapid in the present reaction, aftertreatment is simpler, makes that this reactor product yield is high and side reaction is few, is almost quantitative reaction, and usage quantity is low thus reduce production cost.
As preferably, the solvent described in step S1 be in ethyl acetate, Isosorbide-5-Nitrae-dioxane, trichloromethane, 1,2-ethylene dichloride, acetone, benzene, acetonitrile, tetrahydrofuran (THF), toluene one or more.
Further preferably, the solvent described in step S1 is ethyl acetate, 1,2-ethylene dichloride.Ethyl acetate and 1,2-ethylene dichloride and other solvent phase ratios, have the reaction times in the present reaction fast, yield is high, and impurities left is few, the simple and low cost and other advantages of aftertreatment.
In the synthetic method of above-mentioned (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate; described step S2 specifically comprises the steps: under the protection of nitrogen; the solvent being dissolved with p-nitrophenyl acetaldehyde obtained in step S1 is added drop-wise to forming reactions liquid in (R)-2-amino-1-phenylethyl alcohol; under stirring, reductive agent is joined in reaction solution, be stirred to and react completely.Saturated aqueous ammonium chloride is added drop-wise in the reaction solution reacted completely and carries out cancellation reaction, then wash with water, separate organic phase.Obtaining crude product by dry for organic phase, concentrated, crude product recrystallization obtains (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol.
Wherein substance reaction large for expression activitiy can fall by cancellation reaction, prevents side reaction.
As preferably, the solvent described in step S2 is one or more in methylene dichloride, tetrahydrofuran (THF), ethanol, ethylene dichloride, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, normal heptane, formic acid, toluene, acetonitrile, acetic acid, hexanaphthene, water.
Further preferably, the solvent described in step S2 is methylene dichloride, tetrahydrofuran (THF).Methylene dichloride and tetrahydrofuran (THF), relative to other solvents, have cost low, and aftertreatment is simple in the present reaction, and product loss is little, yield advantages of higher.
As preferably, the reductive agent described in step S2 is one or more in sodium borohydride, metallic nickel, hydrogen, titanium tetrachloride, Lithium Aluminium Hydride, sodium cyanoborohydride, sodium triacetoxy borohydride, borine, tetra isopropyl titanium.
Further preferably, the reductive agent described in step S2 is sodium borohydride.Sodium borohydride is applied very extensive in the industrial production, and cheap and easy to get, its activity is moderate, and aftertreatment is in the reaction simple, can improve the yield of product.
As preferably, the reductive agent described in step S2 is (1 ~ 3) with the mol ratio of (R)-2-amino-1-phenylethyl alcohol: 1.
In the synthetic method of above-mentioned (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, described step S3 specifically comprises the steps: (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol obtained in step S2 to be dissolved in solvent, stirs lower to (Boc)
2o is added drop-wise in solvent, reaction solution is risen to room temperature, be stirred to and react completely, the reaction solution reacted completely directly is concentrated to obtain crude product, and crude product recrystallization obtains final product (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.
As preferably, solvent described in step S3 is tetrahydrofuran (THF), 1, one or more in 4-dioxane, methyl alcohol, the trimethyl carbinol, acetone, ethanol, n-propyl alcohol, Virahol, DMF, acetonitrile, 1,2-glycol dimethyl ether, normal hexane, methylene dichloride, water.
Further preferably, the solvent described in step S3 is tetrahydrofuran (THF), methyl alcohol.Tetrahydrofuran (THF) and methyl alcohol boiling point low, aftertreatment is in the reaction simple, can improve product yield.
As preferably, (Boc) described in step S3
2o with the mol ratio of (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol is: (1 ~ 3): 1.
The chemical equation of synthetic method of the present invention is as follows:
In sum, the present invention has the following advantages:
1, the crude product in synthetic method of the present invention does not need purifying just reducible amination, and reagent used and solvent are regular industrial specification, and be applicable to industrialized production, environmental pollution is little, and processing safety is high.
2, in synthetic method of the present invention with adjacent iodoxybenzoic acid for oxygenant, oxidation products directly and next step raw material reduction amination, the raw material used and reagent cheap and easy to get, cost is low.
3, adopt synthetic method post-reaction treatment of the present invention simple, yield is high, purity Gao Keda more than 99%, good product quality, and recrystallization sterling.
Accompanying drawing explanation
Fig. 1 is the liquid chromatogram of (R)-4-nitrophenethyl-(2-hydroxyl-2-the styroyl)-t-butyl carbamate adopting synthetic method of the present invention to prepare.
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of (R)-4-nitrophenethyl-(2-hydroxyl-2-the styroyl)-t-butyl carbamate adopting synthetic method of the present invention to prepare.
Embodiment
Be below specific embodiments of the invention and by reference to the accompanying drawings, technical scheme of the present invention is further described, but the present invention be not limited to these embodiments.
Embodiment 1
Under the protection of nitrogen, 1.67g p-nitrophenyl ethanol and the adjacent iodoxybenzoic acid of 7g are dissolved in forming reactions liquid in 50mL ethyl acetate, successively by little for reaction solution return stirring 1 complete up to TLC detection reaction.The reaction solution reacted completely is down to room temperature, and suction filtration obtains filtrate and filter cake.Filter cake 20mL ethyl acetate washes twice to obtain p-nitrophenyl acetaldehyde, filtrate merges, concentrated after apply mechanically.
When 0 DEG C, under the protection of nitrogen, by 1.37g(R)-2-amino-1-phenylethyl alcohol adds in 100mL there-necked flask, then the 50mL methylene dichloride being dissolved with described p-nitrophenyl acetaldehyde crude product is added drop-wise to forming reactions liquid in there-necked flask.Under the protection of nitrogen, continue stirring 1 hour, while stirring 0.76g sodium borohydride is added in reaction solution.Reaction solution stirs 3 little complete up to TLC detection reaction under the condition of 0 DEG C.In the reaction solution of complete reaction, drip 10mL saturated aqueous ammonium chloride carry out cancellation reaction, then add the water washing twice of 40mL respectively, separate organic phase.Organic phase is used 5g anhydrous sodium sulfate drying, concentrate to obtain crude product.Crude product obtains 2.5g (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol by normal heptane and re-crystallizing in ethyl acetate again.
When 0 DEG C, (the R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol described in 2.5g is dissolved in the tetrahydrofuran (THF) of 50mL, by 2.86g(Boc under stirring)
2o is added drop-wise to forming reactions liquid in tetrahydrofuran (THF), reaction solution is risen to stirring at room temperature to reacting completely, and the reaction solution reacted completely directly is concentrated to obtain crude product.Crude product normal heptane and re-crystallizing in ethyl acetate obtain 3.0g (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.Purity is 99.85%, and chiral purity is 99.0%, and yield is 89.3%.
Embodiment 2
Under the protection of nitrogen, 3.34g p-nitrophenyl ethanol and 10.1g potassium permanganate are dissolved in 100mL1 successively, forming reactions liquid in 4-dioxane, by little for reaction solution return stirring 3 complete up to TLC detection reaction.The reaction solution reacted completely is down to room temperature, and suction filtration obtains filtrate and filter cake.Filter cake 40mL1,4-dioxane washes twice to obtain p-nitrophenyl acetaldehyde, filtrate merges, concentrated after apply mechanically.
When 0 DEG C, under the protection of nitrogen, by 2.7g(R)-2-amino-1-phenylethyl alcohol adds in 250mL there-necked flask, then the 100mL tetrahydrofuran (THF) being dissolved with described p-nitrophenyl acetaldehyde crude product is added drop-wise to forming reactions liquid in there-necked flask.Under the protection of nitrogen, continue stirring 2 hours, while stirring 2.3g metallic nickel is added in reaction solution.Reaction solution stirs 3 little complete up to TLC detection reaction under the condition of 0 DEG C.In the reaction solution of complete reaction, drip 20mL saturated aqueous ammonium chloride carry out cancellation reaction, then add the water washing twice of 80mL respectively, separate organic phase.Organic phase is used 10g anhydrous sodium sulfate drying, concentrate to obtain crude product.Crude product obtains 4.98g (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol by normal heptane and re-crystallizing in ethyl acetate again.
When 0 DEG C, (the R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol described in 4.98g is dissolved in the methyl alcohol of 100mL, by 5.48g(Boc under stirring)
2o is added drop-wise to forming reactions liquid in methyl alcohol, reaction solution is risen to stirring at room temperature to reacting completely, and the reaction solution reacted completely directly is concentrated to obtain crude product.Crude product normal heptane and re-crystallizing in ethyl acetate obtain 5.8g (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.Purity is 98.92%, and chiral purity is 99.60%, two step total recoverys is 74.32%.
Embodiment 3
Under the protection of nitrogen, 2.5g p-nitrophenyl ethanol and 3.1g Manganse Dioxide are dissolved in 80mL1 successively, forming reactions liquid in 2 ethylene dichloride, by little for reaction solution return stirring 2 complete up to TLC detection reaction.The reaction solution reacted completely is down to room temperature, and suction filtration obtains filtrate and filter cake.Filter cake 30mL1,2 ethylene dichloride wash twice to obtain p-nitrophenyl acetaldehyde, filtrate merges, concentrated after apply mechanically.
When 0 DEG C, under the protection of nitrogen, by 2.05g(R)-2-amino-1-phenylethyl alcohol adds in 250mL there-necked flask, then the 80mL tetrahydrofuran (THF) being dissolved with described p-nitrophenyl acetaldehyde crude product is added drop-wise to forming reactions liquid in there-necked flask.Under the protection of nitrogen, continue stirring 2 hours, while stirring 1.03g sodium borohydride is added in reaction solution.Reaction solution stirs 3 little complete up to TLC detection reaction under the condition of 0 DEG C.In the reaction solution of complete reaction, drip 15mL saturated aqueous ammonium chloride carry out cancellation reaction, then add the water washing twice of 60mL respectively, separate organic phase.Organic phase is used 7g anhydrous sodium sulfate drying, concentrate to obtain crude product.Crude product obtains 3.7g (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol by normal heptane and re-crystallizing in ethyl acetate again.
When 0 DEG C, (the R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol described in 3.7g is dissolved in the methylene dichloride of 80mL, by 4.16g(Boc under stirring)
2o is added drop-wise to forming reactions liquid in methylene dichloride, reaction solution is risen to stirring at room temperature to reacting completely, and the reaction solution reacted completely directly is concentrated to obtain crude product.Crude product normal heptane and re-crystallizing in ethyl acetate obtain 4.48g (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.Purity is 99.06%, and chiral purity is 99.95%, and yield is 76.8%.
Extract (R)-4-nitrophenethyl-(2-hydroxyl-2-the styroyl)-t-butyl carbamate sample adopting synthetic method of the present invention to prepare immediately to be detected by liquid chromatography.
Testing conditions: instrument: Agilent 1100 high performance liquid chromatograph;
Chromatographic column: Luna C18,4.6mm × 250mm, 5 μm;
Column temperature: 25 DEG C;
Flow velocity: 1.0mL/min;
Determined wavelength: 210nm;
Sampling volume: 5ul;
Moving phase: acetonitrile: 0.1% phosphate aqueous solution=60:40 (v/v);
Working time: 25min.
After detecting, as shown in Figure 1, analytical results is as shown in table 1 for the liquid chromatogram of sample.
Table 1: (the R)-4-nitrophenethyl adopting synthetic method of the present invention to obtain-(2-hydroxyl-2-styroyl)-t-butyl carbamate sample chromatogram analytical results
As can be seen from Fig. 1 and table 1: (the R)-4-nitrophenethyl adopting synthetic method of the present invention to prepare-(2-hydroxyl-2-styroyl)-t-butyl carbamate purity is higher, reaches 99.85%.
(R)-4-nitrophenethyl-(2-hydroxyl-2-the styroyl)-t-butyl carbamate sample adopting synthetic method of the present invention to prepare is carried out hydrogen nuclear magnetic resonance spectrum analysis, the results are shown in accompanying drawing 2.
Specific embodiment described herein is only to the explanation for example of the present invention's spirit.Those skilled in the art can make various amendment or supplement or adopt similar mode to substitute to described specific embodiment, but can't depart from spirit of the present invention or surmount the scope that appended claims defines.
Although made a detailed description the present invention and quoted some specific embodiments as proof, to those skilled in the art, only otherwise it is obvious for leaving that the spirit and scope of the present invention can make various changes or revise.
Claims (5)
1. the synthetic method of (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, it is characterized in that, this synthetic method comprises the following steps:
S1, oxidizing reaction: under the protection of nitrogen, p-nitrophenyl ethanol and oxygenant are added forming reactions liquid in solvent, by reaction solution return stirring to reacting completely, reaction solution after reacting completely is down to room temperature, suction filtration obtains filter cake and filtrate, washing leaching cake, merging, concentrated filtrate obtain p-nitrophenyl acetaldehyde;
S2, reduction amination: above-mentioned obtained p-nitrophenyl acetaldehyde is carried out reductive amination process with (R)-2-amino-1-phenylethyl alcohol under the effect of reductive agent, obtain (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol after the amino on (R)-2-amino-1-phenylethyl alcohol and the aldehyde radical dehydrating condensation on p-nitrophenyl acetaldehyde are reduced;
S3, substitution reaction: by above-mentioned obtained (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol and (Boc)
2o reacts, and makes amino quilt (Boc) on (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol
2o replaces, and obtains final product (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate, described (Boc)
2o with the mol ratio of (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol is: 1 ~ 3:1;
Wherein, the oxygenant described in step S1 is adjacent iodoxybenzoic acid, and described solvent is ethyl acetate, and the mol ratio of described oxygenant and p-nitrophenyl ethanol is (2-4): 1, and described solvent is ethyl acetate; Step S2 specifically comprises the steps: under the protection of nitrogen; the solvent being dissolved with p-nitrophenyl acetaldehyde obtained in step S1 is added drop-wise to forming reactions liquid in (R)-2-amino-1-phenylethyl alcohol; under stirring, reductive agent is joined in reaction solution; be stirred to and react completely; saturated aqueous ammonium chloride is added drop-wise in the reaction solution reacted completely and carries out cancellation reaction; wash with water again; separate organic phase; obtaining crude product by dry for organic phase, concentrated, crude product recrystallization obtains (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol.
2. the synthetic method of (R)-4-nitrophenethyl according to claim 1-(2-hydroxyl-2-styroyl)-t-butyl carbamate, it is characterized in that, solvent described in step S2 is one or more in methylene dichloride, tetrahydrofuran (THF), ethanol, ethylene dichloride, methyl alcohol, Virahol, Isosorbide-5-Nitrae-dioxane, normal heptane, formic acid, toluene, acetonitrile, acetic acid, hexanaphthene, water.
3. the synthetic method of (R)-4-nitrophenethyl according to claim 1-(2-hydroxyl-2-styroyl)-t-butyl carbamate, it is characterized in that, reductive agent described in step S2 is one or more in sodium borohydride, metallic nickel, hydrogen, titanium tetrachloride, Lithium Aluminium Hydride, sodium cyanoborohydride, sodium triacetoxy borohydride, borine, tetra isopropyl titanium, and described reductive agent is 1 ~ 3:1 with the mol ratio of (R)-2-amino-1-phenylethyl alcohol.
4. the synthetic method of (R)-4-nitrophenethyl according to claim 1-(2-hydroxyl-2-styroyl)-t-butyl carbamate, it is characterized in that, described step S3 specifically comprises the steps: (R)-2-p-nitrophenyl ethylamino--1-phenylethyl alcohol obtained in step S2 to be dissolved in solvent, stirs lower to (Boc)
2o is added drop-wise in solvent, reaction solution is risen to room temperature, be stirred to and react completely, the reaction solution reacted completely directly is concentrated to obtain crude product, and crude product recrystallization obtains final product (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate.
5. the synthetic method of (the R)-4-nitrophenethyl according to claim 1 or 4-(2-hydroxyl-2-styroyl)-t-butyl carbamate, it is characterized in that, solvent described in step S3 is tetrahydrofuran (THF), 1,4-dioxane, methyl alcohol, the trimethyl carbinol, acetone, ethanol, n-propyl alcohol, Virahol, N, one or more in dinethylformamide, acetonitrile, 1,2-glycol dimethyl ether, normal hexane, methylene dichloride, water.
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